The effect of branded versus standardized e-cigarette packaging and device designs: an experimental study of youth interest in vaping products.

OBJECTIVES: Standardized ('plain') packaging is effective in reducing the appeal of cigarettes among young people. This study examined the impact of plain packaging and brand imagery on interest in trying e-cigarettes among youth. STUDY DESIGN: Experimental design. METHODS: Two online experiments were conducted in February 2020 as part of the ITC Youth Tobacco & Vaping Survey, conducted with 13,624 16- to 19-year-olds in Canada, England, and the USA. In the between-group Experiment 1, participants were randomized to view a set of 3 e-cigarette brands, in either their original external packaging ('branded' condition) or standardized olive-green packaging ('standardized' condition), and asked to select the product they would be most interested in trying. The within-group Experiment 2 examined brand imagery directly on devices, including potential differences in appeal among subgroups. Each participant viewed 4 pod-style e-cigarette devices: one 'plain' and 3 in colourful 'skins'. Logistic regression models were conducted to test the effect of condition, adjusting for demographics, smoking and vaping status. RESULTS: In Experiment 1, participants in the 'standardized' packaging condition were significantly more likely to indicate 'I have no interest in trying any of these products' (72.3%) than those in the 'branded' condition (66.9%, AOR 1.45, 95% CI 1.33-1.59). Experiment 2 results indicated differences in e-cigarette appeal by sex in the selection of male- and female-oriented designs, and by cannabis use for a Rastafarian-themed design. CONCLUSIONS: Brand imagery on e-cigarettes can target products to specific subgroups. Removal of imagery, in the form of standardized packaging, has the potential to reduce interest in trying e-cigarettes among young people.

Coaching to enhance qualified surgeons' non-technical skills: a systematic review.

INTRODUCTION: The lack of an effective continuing professional development programme for qualified surgeons, specifically one that enhances non-technical skills (NTS), is an issue receiving increased attention. Peer-based coaching, used in multiple professions, is a proposed method to deliver this. The aim of this study was to undertake a systematic review of the literature to summarize the quantity and quality of studies involving surgical coaching of NTS in qualified surgeons. METHODS: A systematic search of the literature was performed through MEDLINE, EMBASE, Cochrane Collaboration and PsychINFO. Studies were selected based on predefined inclusion and exclusion criteria. Data for the included studies was independently extracted by two reviewers and the quality of the studies evaluated using the Medical Education and Research Study Quality Instrument (MERSQI). RESULTS: Some 4319 articles were screened from which 19 met the inclusion criteria. Ten studies involved coaching of individual surgeons and nine looked at group coaching of surgeons as part of a team. Group coaching studies used non-surgeons as coaches, included objective assessment of NTS, and were of a higher quality (average MERSQI 13.58). Individual coaching studies focused on learner perception, used experienced surgeons as coaches and were of a lower quality (average MERSQI 11.58). Individual coaching did not show an objective improvement in NTS for qualified surgeons in any study. CONCLUSION: Surgical coaching of qualified surgeons' NTS in a group setting was found to be effective. Coaching of individual surgeons revealed an overall positive learner perception but did not show an objective improvement in NTS for qualified surgeons.

Factors related to adolescents' estimation of peer smoking prevalence.

Although adolescents who overestimate peer smoking prevalence are more likely to smoke, little research has focused on the factors associated with why the majority of adolescents overestimate peer smoking rate. The purpose of this study was to examine demographic, social, environmental and behavioural characteristics related to overestimation of peer smoking prevalence among secondary school students. The current study analysed data collected in two Canadian studies that used the Tobacco Module of the School Health Action, Planning and Evaluation System, a school-based questionnaire. One study surveyed 23 458 students (Grades 9-13) in 29 schools during 2001-02, and the other surveyed 25 452 students in 39 schools in 2003. Results of multiple logistic regression indicate that grade, gender, close friends' smoking, seeing smoking at school, family members' smoking, smoking in the home and smoking status have a clear association with overestimation; school smoking rate and susceptibility to smoking show a tentative relationship and warrant further study. Other factors may also be important for prevalence estimation, and further research is needed to identify these factors. Since adolescents tend to overestimate peer smoking prevalence and perceived prevalence is in turn linked to smoking behaviour, interventions should focus on creating realistic perceptions of smoking prevalence.

Measuring therapy adherence in Parkinson's disease: a comparison of methods.

UNLABELLED: The objective of this study was to assess different methods of measuring therapy adherence in Parkinson's disease (PD). In a single centre observational study, 112 patients with idiopathic PD were randomised to a crossover trial of active monitoring (n = 69, simple tablet count and electronic monitoring), or to no monitoring (n = 43, control group). All patients completed a self report and visual analogue scale (VAS) indicating therapy intake. In the active monitoring group, 56 (81% of cases) used > or = 80% of their medication, and 13 (19% of cases) used <80%, based on electronic monitoring. Median adherence for self report was 100% (interquartile range (IQR) 100 to 100) and for VAS was 100% (IQR 95 to 100), in both active and control groups. Patients taking > or = 80% of prescribed medication had a median total adherence of 98% (IQR 93 to 101) by electronic monitoring, which was similar to that from other METHODS: self report 100%, IQR 100 to 100; VAS 100%, IQR 95 to 100; simple tablet count 98%, IQR 89 to 100. Median total adherence in patients taking <80% of medication was significantly lower by electronic monitoring (69%, IQR 44 to 74) than by other methods: self report 100%, IQR 100 to 100; VAS 100%, IQR 95 to 100; and simple tablet count 90%, IQR 78 to 100 (all p<0.0001). Sensitivities of self report (10%), VAS (17%), and simple tablet count (50%) were all low for detecting suboptimal medicine intake. Self report, VAS, and simple tablet counts are insensitive as predictors of suboptimal medicine usage in PD. How patients take their medicines influences interpretation of the therapy response and consequent management decisions, with implications for clinical trial analysis and clinical practice.

Statin administration prior to ischaemic stroke onset and survival: exploratory evidence from matched treatment-control study.

In addition to their lipid-lowering effects, it has been speculated that statins may also have beneficial effects on cerebral circulation and brain parenchyma during ischaemic stroke and reperfusion. We hypothesized that patients who had taken statins prior to stroke onset may have a better survival rate at 1 month and during the follow-up period. We retrospectively studied consecutive ischaemic stroke patients admitted to an acute stroke unit and at least a month's follow-up. From these, we included those patients who, at admission, had reported the use of a statin prior to the stroke onset in the statin group (n = 205). Each patient in the statin group was matched with two patients who reported no statin use (n = 410). Using logistic regression and Cox proportional hazards models, we adjusted for variables that significantly differed between treatment groups or that independently predicted mortality. After adjusting for those variables, statin use was associated with reduced mortality at 1 month [odds ratio 0.24; 95% confidence interval (CI) 0.09-0.67] and during the follow-up period (hazard ratio 0.57; 95% CI 0.35-0.93). The use of statins prior to stroke onset is associated with improved stroke survival within this cohort study with matched controls.

An oral yohimbine/L-arginine combination (NMI 861) for the treatment of male erectile dysfunction: a pharmacokinetic, pharmacodynamic and interaction study with intravenous nitroglycerine in healthy male subjects.

AIMS: Interaction of phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction with organic nitrates could lead to severe hypotension. NMI 861 is a combination of 7.7 mg yohimbine tartrate and 6 g l-arginine glutamate. A similar oral combination, which contains the same amount of yohimbine and L-arginine, has been shown to improve erectile function in previous studies. METHODS: In two placebo-controlled, randomized, double-blind, two-way crossover design studies we aimed to assess first the pharmacokinetics and pharmacodynamics of a single oral dose of NMI 861 administered in 16 healthy male subjects, and then the pharmacodynamics of orally administered NMI 861 in combination with intravenous nitroglycerine (GTN) in 12 healthy male subjects. Systolic (SBP) and diastolic (DBP) blood pressures, pulse rate and adverse events were measured in each study. RESULTS: NMI 861 was well tolerated by all subjects with no significant adverse reactions reported. For L-arginine, mean C(max) +/- SEM (range) was 42 +/- 2.2 (28-63) microg ml(-1) and t(max) (range) was 0.88 (0.50-1.5) h. AUC and t(1/2) were not calculated for L-arginine because of the presence of endogenous concentrations and the contribution from food sources. For yohimbine, mean C(max) was 42 +/- 11 (2.8-128) ng ml(-1); t(max) was 0.57 (0.25-1.0) h; mean AUC(0,8 h) was 65 +/- 24 (5.4-332), ng ml(-1) h and t(1/2) was 1.0 +/- 0.34 (0.40-6.0) h. There was a small but significant difference in the mean change from baseline for SBP from 0 to 6 h after NMI 861 treatment compared with placebo (0.8 +/- 1.4 vs-4.1 +/- 2.1 mmHg, respectively; 95% CI 0.0, 9.8 mmHg (P = 0.047)). There was no significant difference in SBP between treatments for the studied periods 6-12 h and 12-24 h. There was no significant difference in DBP or pulse between NMI 861 and placebo treatments for the three studied time periods. In the study designed to investigate the interaction of organic nitrate with NMI 861, subjects were infused intravenously with increasing doses of GTN (15 min each dose) at 2.5, 5, 10, 20 and 40 microg min(-1) starting 40 min after a single oral dose of either NMI 861 or placebo. There was no significant difference in the hypotensive response induced by GTN between the NMI 861 and placebo treatments. The mean maximum changes from baseline during GTN infusion for subjects administered with either NMI 861 or placebo were a decrease of 16.9 +/- 3.4 vs 13.6 +/- 2.4 mmHg (mean difference between treatments -3.3 mmHg, 95% CI -12.7, 6.0 mmHg (P = 0.460)) for SBP, a decrease of 14.7 +/- 2.0 vs 14.0 +/- 2.0 mmHg for DBP (mean difference -0.7 mmHg, 95% CI -8.2, 6.8 mmHg (P = 0.835)), and an increase of 11.8 +/- 1.9 vs 14.1 +/- 2.4 beats min(-1) for pulse, respectively (mean difference -2.3 beats min(-1), 95% CI -9.3, 4.5 beats min(-1) (P = 0.464)). CONCLUSIONS: Acute oral administration of NMI 861 was found to be well tolerated and bioavailable in healthy male subjects and no significant hypotensive interaction with intravenous GTN was detected at the doses investigated.

Renal cell carcinoma may adapt to and overcome anti-angiogenic intervention with thalidomide.

OBJECTIVE: To report on the failure of thalidomide to inhibit tumour growth in an animal model of human renal cell carcinoma (RCC). MATERIALS AND METHODS: An orthotopic xenograft model of human RCC was used in which tumour cells were implanted in the left kidney of male 'severe combined immunodeficient' mice. Thalidomide was administered by intraperitoneal injection and after 34 days the mice were killed. The extent of tumour growth was compared in treated and untreated mice. Total RNA was extracted from both tumour-affected and contralateral kidneys, and analysed by reverse transcription-polymerase chain reaction for various genes implicated in angiogenesis and metastasis in RCC. RESULTS: Thalidomide failed to inhibit the growth of xenograft tumours. The expression of angiogenic genes, e.g. vascular endothelial growth factor and fibroblast growth factor type 2 (FGF-2) within normal and tumour-affected kidney tissue was not reduced by thalidomide. Intratumoral transcription of beta3-integrin, a critical component of angiogenesis, was significantly increased in response to thalidomide treatment (P < 0.01). There was also a trend to increased expression of FGF-2 and tumour necrosis factor-alpha in thalidomide-treated tumours. CONCLUSIONS: These findings suggest that RCC is capable of adapting to the inhibitory effects of thalidomide. The current uncertainty surrounding the action of thalidomide in vivo warrants caution about its use in humans. Further studies of thalidomide should be carried out in animal models, particularly to establish its safety and effectiveness as part of a combined therapeutic strategy.

Vasorelaxant properties of isolated human radial arteries: comparison with internal mammary arteries.

Radial arteries, used in revascularisation surgery, are prone to spasm. We have examined the ability of nitrovasodilators, calcium channel blockers, and K(ATP) channel openers to cause vasodilation, and to attenuate contractions due to depolarisation and receptor activation in radial and mammary arteries used in coronary artery bypass graft surgery. Two to three millimetre rings of artery obtained from patients at surgery were studied in organ baths in vitro. Constriction to KC1 and phenylephrine was examined before and again after treatment of the rings with drug or vehicle. Calcium channel blockers were the only compounds to inhibit contractions to both KC1 and phenylephrine. Sodium nitroprusside attenuated constriction to phenylephrine but not KC1 in both vessels. K(ATP) channel openers similarly attenuated constriction to phenylephrine in radial arteries but were much less effective in mammary arteries. These studies support the continued use of calcium blockers after revascularisation with radial artery but suggest that other classes of drug may be as effective at minimising spasm due to receptor mediated constriction.

Update on rilmenidine: clinical benefits.

Rilmenidine is an imidazoline derivative that appears to lower blood pressure (BP) by an interaction with imidazoline (I1) receptors in the brainstem (and kidneys). Rilmenidine is as effective in monotherapy as all other first-line classes of drugs, including diuretics, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, and calcium antagonists. It is well tolerated and can be taken in combination for greater efficacy. Sedation and dry mouth are not prominent side effects and withdrawal hypertension is not seen when treatment is stopped abruptly. Recently, in addition to a reduction in BP, this agent has been shown to improve glucose tolerance, lipid risk factors, and insulin sensitivity. These changes would be consistent with a reduction in long-term cardiovascular risk, as would recently described actions on the heart (reducing left ventricular hypertrophy) and the kidney (reducing microalbuminuria). Although no data are yet available from prospective long-term outcome studies, rilmenidine could represent an important new development in antihypertensive therapy and the prevention of cardiovascular disease.

Antihypertensive drugs in the elderly--the evidence of benefit.

Hypertension is a major cardiovascular risk factor. The commonest mode of death in the elderly is a cardiovascular one and so the treatment of hypertension in the elderly population is an important clinical objective. The choice of which antihypertensive drug to prescribe is expanding and an evidence-based approach should be applied. In recent years more studies have been carried out into the efficacy of the various antihypertensive drugs in the elderly. This review looks at the "hard" outcome data for each major drug class and their suitability for prescribing in the elderly. The differing drug classes are divided into 3 categories based on the weight of evidence supporting them--established, emerging, and add-on therapies. Currently, and until the publication of ongoing trials into newer therapies such as ACE inhibitors and calcium-channel blockers, outcome data suggests that thiazides remain the drug of first choice except where other therapies are indicated for coexistant conditions or more than one drug is required to achieve the desired response.

Coplanar recognition by a Rebek cleft is provided by cooperative structural effects involving a combination of O-H...O, O-H...N, and C-H...O forces.

Reaction of 2,7-di-tert-butyl-9,9-dimethyl-4,5-xanthenedicarboxylic acid (1), a Rebek cleft, with 1,2-trans-bis(2-pyridyl)ethylene (2) yields a three-component organic assembly, 2(1).2 (3), of nanoscale dimensions that is held together by 10 cooperative O-H.N, O-H.O, and C-H.O hydrogen bonds. The cleft adopts a planar conformation, by forming an intramolecular O-H.O hydrogen bond, which enables the host to recognize the guest in a coplanar orientation that facilitates the cooperativity displayed by the multiple forces.

Radial artery hypertrophy occurs in coronary atherosclerosis and is independent of blood pressure.

Endothelial dysfunction, believed to underlie the structural changes of atherosclerosis, is a systemic phenomenon. Despite this, the radial artery has been considered as devoid of atherosclerosis and is commonly used as a conduit in coronary artery bypass grafting (CABG). Recently, histological study has shown intimal hyperplasia and other structural changes consistent with early atherosclerosis in the radial artery. The objective of the present study was to determine if structural changes in the radial artery could be detected in vivo in patients with coronary atherosclerosis. Using high resolution echo-tracking, measurements of radial artery internal diameter, wall thickness and wall cross-sectional area were made in 25 patients awaiting CABG and in 20 controls. Digital and brachial blood pressures were also recorded. Mean arterial pressures did not differ between the patient and control groups. All measures of wall thickness were greater in the patient than the control group. Neither current arterial pressures nor past history of hypertension correlated with wall thickness. Using a model of analysis of covariance, coronary artery disease was the best single predictor of intima-media thickness, R(2)=48%, n=44, P<0.0005. We concluded that increased radial artery wall thickness can be demonstrated in vivo in patients with coronary atherosclerosis. This is a novel observation which seems to be independent of blood pressure, and is consistent both with the hypothesis of systemic endothelial dysfunction leading to systemic structural changes and also to the recent histological evidence for atherosclerotic changes in this vessel.

Rilmenidine: a clinical overview.

Rilmenidine is an antihypertensive agent with selectivity for I1 imidazoline receptors that acts both centrally by reducing sympathetic overactivity and in the kidney by inhibiting the Na+/H+ antiport. Rilmenidine provides antihypertensive efficacy comparable with that of diuretics, beta-blockers, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors. Experience from trials and clinical practice highlights rilmenidine's clinical and metabolic acceptability in hypertensive populations, including those at special risk because of old age, renal impairment, diabetes mellitus, or dyslipidemia. In the at-risk hypertensive, rilmenidine reduces left ventricular hypertrophy to a similar degree to other reference agents. New studies show a significant improvement in glucose metabolism in metabolic syndrome patients treated with rilmenidine, and a significant reduction in microalbuminuria during rilmenidine treatment of hypertensive type 2 diabetics. Thus the efficacy/tolerance ratio of rilmenidine supports its role as a first-line antihypertensive option for all groups of hypertensive patient, with specific advantages in some at-risk populations.

DNA synthesis and apoptosis in smooth muscle cells from a model of genetic hypertension.

The present study was designed to assess vascular smooth muscle cell (VSMC) proliferation and apoptosis in primary cultured VSMCs prepared from the aortic tunica media of adult (4 to 5 months old) age- and gender-matched groups of stroke-prone spontaneously hypertensive rats (SHRSP) and the normotensive reference strain, Wistar-Kyoto (WKY) rats. In the present study, VSMC proliferation was assessed with measurement of DNA synthesis in response to stimulation of G(0)/G(1) arrested VSMCs with 10% serum, whereas apoptosis was measured in response to serum deprivation. Apoptosis in aortic VSMCs was assessed in vitro with the technique of Annexin V binding in combination with propidium iodide exclusion with bivariate flow cytometric analysis. The percentage of necrotic VSMCs in the cell populations was assessed simultaneously. The light-scattering properties of the cells were assessed to provide further information on cell shrinkage and chromatin condensation. Results of the present study have shown enhanced DNA synthesis in VSMCs from SHRSP (n=10; 5.2+/-0.9 cpmx10(3)/mg protein) compared with WKY (n=12; 2.4+/-0.7 cpmx10(3) /mg protein; P<0.05, 95% CI, -5271 to -296). In addition, the results of the present study have demonstrated the role of serum in the survival of VSMCs in vitro, because SHRSP VSMCs underwent significantly more apoptosis in response to insult by serum deprivation (n=13; 10.21+/-1.8%) than WKY VSMCs (n=7; 3.44+/-1.4%; P<0.01, 95% CI, -11.5 to -2.0). Thus, it appears that both proliferation and apoptosis are enhanced in synthetic phenotype aortic medial VSMCs from the SHRSP in vitro.

Bradykinin B(2) receptor antagonism attenuates blood pressure response to acute angiotensin-converting enzyme inhibition in normal men.

The physiological effects of angiotensin-converting enzyme (ACE) inhibition may be in part mediated by bradykinin. We investigated the effect of coadministration of the specific bradykinin B(2) receptor antagonist icatibant on hemodynamic and neurohormonal responses to acute intravenous ACE inhibition in normal men on a normal sodium diet. We performed a 4-phase, double-blind, double-dummy, placebo-controlled study in 12 male volunteers. The bradykinin antagonist icatibant (10 mg IV) was coadministered over the first 15 minutes of a 2-hour infusion of the ACE inhibitor perindoprilat (1.5 mg IV). Perindoprilat inhibited ACE activity and elicited the expected changes in active renin concentration and angiotensin peptides. Over the 3 hours after the start of drug infusion, perindoprilat lowered and icatibant increased mean arterial blood pressure (each P<0.0005 versus placebo). Coadministration of icatibant attenuated the mean arterial blood pressure response to perindoprilat (P<0.0005) but had no effect on neurohormonal responses to perindoprilat. Our study indicates that the bradykinin B(2) receptor antagonist icatibant attenuates the short-term blood pressure-lowering effect of acute ACE inhibition in normal men on a normal sodium diet. Bradykinin B(2) receptor antagonism alone increases resting blood pressure. Bradykinin may be involved in the control of blood pressure in the resting state in humans.

Coordinate regulation of yeast ribosomal protein genes is associated with targeted recruitment of Esa1 histone acetylase.

The Esa1-containing NuA4 histone acetylase complex can interact with activation domains in vitro and stimulate transcription on reconstituted chromatin templates. In yeast cells, Esa1 is targeted to a small subset of promoters in an activator-specific manner. Esa1 is specifically recruited to ribosomal protein (RP) promoters, and this recruitment appears to require binding by Rap1 or Abf1. Esa1 is important for RP transcription, and Esa1 recruitment to RP promoters correlates with coordinate regulation of RP genes in response to growth stimuli. However, following Esa1 depletion, H4 acetylation decreases dramatically at many loci, but transcription is not generally affected. Therefore, the transcription-associated targeted recruitment of Esa1 to RP promoters occurs in a background of more global nontargeted acetylation that is itself not required for transcription.

Pharmacological characterisation of endothelium-dependent relaxation in human radial artery: comparison with internal thoracic artery.

OBJECTIVE: The aim of this study was to investigate the contribution of nitric oxide/prostanoid-independent pathways to endothelium-dependent vasorelaxation in human conduit arteries. METHODS: Rings of internal thoracic artery (ITA) and radial artery (RA) taken from patients undergoing coronary artery bypass graft surgery were suspended in 10-ml organ baths and relaxation to carbachol and bradykinin studied in the presence and absence of nitric oxide synthase (NOS) inhibitors and potassium channel blockers. RESULTS: No significant relaxation to carbachol or bradykinin was observed in ITA after NOS inhibition. In contrast, in RA less than 40% attenuation of relaxation to carbachol or bradykinin was achieved with any of the NOS inhibitors. In the presence of 20 mM K+ relaxation to carbachol and bradykinin was inhibited by 28 +/- 9% and 42 +/- 9% while in the presence of L-NAME 200 microM + 20 mM K+ relaxation was inhibited by 66 +/- 6% and 70 +/- 4% respectively in this artery. Tetraethylammonium, glibenclamide, apamin and iberiotoxin had little effect on relaxation to carbachol but charybdotoxin alone and charybdotoxin plus apamin attenuated relaxation to carbachol by 23 +/- 4% and 49 +/- 9% in RA. In the presence of L-NAME 200 microM attenuation of these relaxations were increased to 60 +/- 4% and 78 +/- 4%. CONCLUSION: In ITA relaxations to carbachol and bradykinin were mediated via nitric oxide. In contrast in RA, a conduit vessel of similar diameter, both nitric oxide-dependent and independent pathways appeared to contribute to vascular relaxation. This nitric oxide-independent relaxation involved opening of Ca2+ activated potassium channel(s). The existence of alternative pathways mediating endothelium-independent relaxation could be important under pathological conditions and may contribute to the long term survival of radial artery grafts.

Mortality amongst patients of the Glasgow Blood Pressure Clinic was high in the 1970s and 80s but has fallen since, why?

Established in 1968 the Glasgow Blood Pressure Clinic has over 11,000 patients on its computer record. Up to 1980, mortality from all-causes and from cardiovascular causes was high: relative risks compared with two local control populations were greater than 2.0. Since 1980, all-cause mortality has decreased to 1.31 (859 deaths, CI 1.23-1.39). Lower mortality from cardiovascular causes, particularly coronary heart disease, contributes to the decrease. Reasons for the decrease are under investigation currently. Referral of patients with slightly lower blood pressure contributes, as may better blood pressure control with newer antihypertensive drugs. ACE inhibitors and calcium channel blockers were introduced in 1980 and during the 16-year period to 1995, all-cause mortality has decreased most in patients taking ACE inhibitor. A decrease also occurred in patients taking antihypertensive drugs other than ACE inhibitor.