Divergence among Local Structure, Dynamics, and Nucleation Outcome in Heterogeneous Nucleation of Close-Packed Crystals.

Heterogeneous crystal nucleation is the dominant mechanism of crystallization in most systems, yet its underlying physics remains an enigma. While emergent interfacial crystalline order precedes heterogeneous nucleation, its importance in the nucleation mechanism is unclear. Here, we use path sampling simulations of two model systems to demonstrate that crystalline order in its traditional sense is not predictive of the outcome of the heterogeneous nucleation of close-packed crystals. Consequently, structure-based collective variables (CVs) that reliably describe homogeneous nucleation can be poor descriptors of heterogeneous nucleation. This divergence between structure and nucleation outcome is accompanied by an intriguing dynamical anomaly, wherein low-coordinated crystalline particles outpace their liquid-like counterparts. We use committor analysis, high-throughput screening, and machine learning to devise CV optimization strategies and present suitable structural heuristics within the metastable fluid for CV prescreening. Employing such optimized CVs is pivotal for properly characterizing the mechanism of heterogeneous nucleation in metallic and colloidal systems.

Effectiveness of Bupropion and Varenicline for Smokers With Baseline Depressive Symptoms.

INTRODUCTION: Smokers with concurrent depression are less likely to achieve abstinence, even with pharmacotherapy. The purpose of this secondary data analysis was to evaluate if the presence of any depressive symptoms at baseline alters the effectiveness of bupropion and varenicline for smoking cessation. AIMS AND METHODS: Eligible participants were enrolled via the internet and randomized 1:1 to receive a 12-week supply of either bupropion (n = 465) or varenicline (n = 499). Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-2). Follow-up surveys were conducted at weeks 4, 8, 12, 26, and 52 to assess self-reported quit. The primary outcome was 7-day point prevalence abstinence at 12 weeks follow-up (end-of-treatment). RESULTS: Participants who endorsed any depressive symptoms (PHQ-2 > 0; n = 280) were less likely to be quit at end-of-treatment compared to participants who did not endorse any symptoms (PHQ-2 = 0; n = 684) (OR = 0.56, 95% CI: 0.38 to 0.8, p = .003). Within the varenicline group, quit outcomes did not differ between those with and without depressive symptoms (21.3% vs. 26.9%, respectively). Within the bupropion group, however, those with symptoms had a significantly reduced quit rate compared to those without symptoms (7.0% vs. 17.3%, respectively). CONCLUSIONS: The presence of even one symptom of depression at the start of a quit attempt may adversely affect quit outcomes. Patients should be assessed for depressive symptoms when planning to quit smoking as it may inform the approach to treatment. However, future studies are needed to confirm these findings. IMPLICATIONS: Findings from the current study illustrate the importance of evaluating baseline sub-clinical depressive symptoms before a quit attempt using first-line pharmacotherapies. This secondary analysis of a large-scale randomized trial suggests that bupropion may be less effective for those with baseline depressive symptoms while varenicline may be equally effective for those with and without depressive symptoms.

Can nicotine replacement therapy be personalized? A statistical learning analysis.

BACKGROUND: Technology has made automated care personalization practical, but useful personalization requires information about systematic differences between individuals in the effectiveness of different interventions. Here, we used observational data to search for differences in smoking cessation treatment outcomes associated with interactions between participant characteristics and different types and doses of nicotine replacement therapy (NRT). METHODS: We analyzed 33,077 enrollments in a large primary care smoking cessation program in Ontario, Canada. We considered 10 types and combinations of NRT, as well as the provided daily dose of nicotine. We used ridge regression to fit one main effects model and one model including all possible interactions between these measures and a range of demographic and health variables. We then compared the predictive accuracy of these models in a held-out 25 % testing subset using areas under the receiver operating characteristic curve (AUROC) and the integrated discrimination improvement index (IDI). We used random forest multiple imputation to address missing data. RESULTS: The model including main effects only modestly predicted quit success at 6 months (AUROC = 0.646, 95 % CI = 0.631, 0.660). The final model with all interactions had essentially identical performance (AUROC = 0.640, 95 % CI = 0.626, 0.654; IDI = -0.0066). CONCLUSION: We found no evidence of meaningful interactions between treatment outcomes and participants' characteristics, NRT type, or NRT dose. Although data are observational, these findings suggest that the effectiveness of different types and doses of NRT do not vary substantially with participant characteristics. Personalization based on the overall likelihood of quit success, or using genetic or other biological data, remains possible.

Video Game to Attenuate Pandemic-Related Stress From an Equity Lens: Development and Usability Study.

BACKGROUND: The emergence of the novel coronavirus (COVID-19) has introduced additional pressures on an already fragile mental health care system due to a significant rise in depression, anxiety, and stress among Canadians. Although cognitive behavioral therapy (CBT) is known to be an efficacious treatment to reduce such mental health issues, few people have access to CBT in an engaging and sustainable manner. To address this gap, a collaboration between the Centre for Addiction and Mental Health (CAMH) and the National Research Council of Canada (NRC) developed CBT-based self-led, online, clinician-tested modules in the form of a video game, named Legend of Evelys, and evaluated its usability in the attenuation of a COVID-19-related increase in stress. OBJECTIVE: We here present the conceptualization and design of new self-care modules in the form of a video game, its implementation in a technological infrastructure, and inclusivity and privacy considerations that informed the development. A usability study of the modules was performed to assess the video game's usability, user engagement, and user perceptions. METHODS: The development of the video game involved establishment of a technology infrastructure for secure implementation of the software for the modules and a clinician-led assessment of the clinical utility of these modules through two "whiteboard" sessions. The usability study was informed by a mixed methods sequential explanatory design to evaluate the intervention of the mobile app through two distinct phases: quantitative data collection using in-app analytics data and two surveys, followed by qualitative data collection by semistructured interviews. RESULTS: A total of 32 participants trialed the app for 2 weeks. They used the video game an average of six times and rated the game as "good" based on the Systems Usability Scale score. In terms of stress reduction, the study demonstrated a significant difference in the participants' Perceived Stress Scale score at baseline (mean 22.14, SD 6.187) compared with that at the 2-week follow-up (mean 18.04, SD 6.083; t27=3.628, P=.001). Qualitative interviews helped participants identify numerous functionality issues and provided specific recommendations, most of which were successfully integrated into the video game for future release. CONCLUSIONS: Through this collaboration, we have established that it is possible to incorporate CBT exercises into a video game and have these exercises adopted to address stress. While video games are a promising strategy to help people with their stress and anxiety, there is a further need to examine the real-world effectiveness of the Legend of Evelys in reducing anxiety.

Evaluating the effectiveness of bupropion and varenicline for smoking cessation using an internet-based delivery system: A pragmatic randomized controlled trial (MATCH study).

BACKGROUND: Traditional randomized controlled trials have demonstrated the efficacy of pharmacotherapy for smoking cessation. However, accessibility to treatments remains a barrier, necessitating the remote delivery of evidence-based cessation interventions. The aim of this study was to evaluate the effectiveness of an online treatment that included first-line prescription medications using a pragmatic randomized controlled trial design. METHODS: This study was a two-group, parallel block randomized, open label, controlled trial, and conducted exclusively online. Participants were randomised (1:1) to either bupropion (150 mg) or varenicline (1 mg) for twelve weeks. Medication was couriered to participants. The primary outcome was 7-day point prevalence abstinence (PPA; defined as 0 cigarette puffs in the last 7 days) at 12 weeks. Secondary outcomes were 7-day PPA at 4-, 8-, 26-, and 52-weeks follow-up. Adverse events were evaluated at each follow-up session during treatment. RESULTS: The varenicline group (n = 499) had significantly higher 7-day PPA (30.3%) compared to the bupropion group (n = 465; 19.6%) at end of treatment (OR=2.08, 95% CI: 1.49-2.90, p < 0.001). Seven-day PPA was also higher for the varenicline group at 4-weeks (OR=1.71, 95% CI: 1.23-2.40 p = 0.0001), and 8-weeks follow-up (OR=1.95, 95% CI: 1.43-2.67 p < 0.0001), but not at post-treatment follow-up. More adverse events were reported in the varenicline group, compared to bupropion. CONCLUSIONS: This internet-based pharmacotherapy intervention was a feasible and effective method of treatment delivery for smoking cessation. This method can be used to increase the accessibility and availability of cessation interventions, decreasing the burden of smoking-related diseases. TRIAL REGISTRATION: This trial was registered with clinical trials.gov under NCT02146911. Registered 26 May 2014, https://clinicaltrials.gov/ct2/show/NCT02146911.

How to quantify and avoid finite size effects in computational studies of crystal nucleation: The case of homogeneous crystal nucleation.

Finite size artifacts arise in molecular simulations of nucleation when critical nuclei are too close to their periodic images. A rigorous determination of what constitutes too close is, however, a major challenge. Recently, we devised rigorous heuristics for detecting such artifacts based on our investigation of how system size impacts the rate of heterogeneous ice nucleation [S. Hussain and A. Haji-Akbari, J. Chem. Phys. 154, 014108 (2021)]. We identified the prevalence of critical nuclei spanning across the periodic boundary, and the thermodynamic and structural properties of the liquid occupying the inter-image region as indicators of finite size artifacts. Here, we further probe the performance of such heuristics by examining the dependence of homogeneous crystal nucleation rates in the Lennard-Jones (LJ) liquid on system size. The rates depend non-monotonically on system size and vary by almost six orders of magnitude for the range of system sizes considered here. We confirm that the prevalence of spanning critical nuclei is the primary indicator of finite size artifacts and almost fully explains the observed variations in rate. Proximity, or structuring of the inter-image liquid, however, is not as strong of an indicator due to the fragmented nature of crystalline nuclei. As a result, the dependence of rate on system size is subtle for the systems with a minuscule fraction of spanning critical nuclei. These observations indicate that our heuristics are universally applicable to different modes of nucleation (homogeneous and heterogeneous) in different systems even if they might be overly stringent for homogeneous nucleation, e.g., in the LJ system.

Treatment use patterns in a large extended-treatment tobacco cessation program: predictors and cost implications.

BACKGROUND: Tobacco dependence follows a chronic and relapsing course, but most treatment programmes are short. Extended care has been shown to improve outcomes. Examining use patterns for longer term programmes can quantify resource requirements and identify opportunities for improving retention. METHODS: We analyse 38 094 primary care treatment episodes from a multisite smoking cessation programme in Ontario, Canada that provides free nicotine replacement therapy (NRT) and counselling. We calculate distributional measures of weeks of NRT used, clinical visits attended and total length of care. We then divide treatment courses into four exclusive categories and fit a multinomial logistic regression model to measure associations with participant characteristics, using multiple imputation to address missing data. RESULTS: Time in treatment (median=50 days), visits (median=3) and weeks NRT used (median=8) were well below the maximum available. Of all programme enrolments, 28.8% (95% CI=28.3% to 29.3%) were single contacts, 31.3% (30.8% to 31.8%) lasted <12 weeks, 19.2% (18.8% to 19.6%) were ≥12 weeks with an 8-week interruption and 20.7% (20.3%-21.1%) were ≥12 weeks without interruptions. Care use was most strongly associated with participant age and whether the nicotine patch was dispensed at the first visit. CONCLUSION: Treatment use results imply that the marginal costs of extending treatment programmes are relatively low. The prevalence of single contacts supports additional engagement efforts at the initial visit, while interruptions in care highlight the ability of longer term care to address relapse. Results show that use of the nicotine patch is associated with retention in care, and that improving engagement of younger patients should be a priority.

Role of Nanoscale Interfacial Proximity in Contact Freezing in Water.

Contact freezing is a mode of atmospheric ice nucleation in which a collision between a dry ice nucleating particle (INP) and a water droplet results in considerably faster heterogeneous nucleation. The molecular mechanism of such an enhancement is, however, still a mystery. While earlier studies had attributed it to collision-induced transient perturbations, recent experiments point to the pivotal role of nanoscale proximity of the INP and the free interface. By simulating the heterogeneous nucleation of ice within INP-supported nanofilms of two model water-like tetrahedral liquids, we demonstrate that such nanoscale proximity is sufficient for inducing rate increases commensurate with those observed in contact freezing experiments, but only if the free interface has a tendency to enhance homogeneous nucleation. Water is suspected of possessing this latter property, known as surface freezing propensity. Our findings therefore establish a connection between the surface freezing propensity and kinetic enhancement during contact nucleation. We also observe that faster nucleation proceeds through a mechanism markedly distinct from classical heterogeneous nucleation, involving the formation of hourglass-shaped crystalline nuclei that conceive at either interface and that have a lower free energy of formation due to the nanoscale proximity of the interfaces and the modulation of the free interfacial structure by the INP. In addition to providing valuable insights into the physics of contact nucleation, our findings can assist in improving the accuracy of heterogeneous nucleation rate measurements in experiments and in advancing our understanding of ice nucleation on nonuniform surfaces such as organic, polymeric, and biological materials.

How to quantify and avoid finite size effects in computational studies of crystal nucleation: The case of heterogeneous ice nucleation.

Computational studies of crystal nucleation can be impacted by finite size effects, primarily due to unphysical interactions between crystalline nuclei and their periodic images. It is, however, not always feasible to systematically investigate the sensitivity of nucleation kinetics and mechanism to system size due to large computational costs of nucleation studies. Here, we use jumpy forward flux sampling to accurately compute the rates of heterogeneous ice nucleation in the vicinity of square-shaped model structureless ice nucleating particles (INPs) of different sizes and identify three distinct regimes for the dependence of rate on the INP dimension, L. For small INPs, the rate is a strong function of L due to the artificial spanning of critical nuclei across the periodic boundary. Intermediate-sized INPs, however, give rise to the emergence of non-spanning "proximal" nuclei that are close enough to their periodic images to fully structure the intermediary liquid. While such proximity can facilitate nucleation, its effect is offset by the higher density of the intermediary liquid, leading to artificially small nucleation rates overall. The critical nuclei formed at large INPs are neither spanning nor proximal. Yet, the rate is a weak function of L, with its logarithm scaling linearly with 1/L. The key heuristic emerging from these observations is that finite size effects will be minimal if critical nuclei are neither spanning nor proximal and if the intermediary liquid has a region that is structurally indistinguishable from the supercooled liquid under the same conditions.

Seasonal Variation in Demand for Smoking Cessation Treatment and Clinical Outcomes.

INTRODUCTION: Smoking behaviour shows seasonal variation, with cigarette consumption and youth smoking onset highest in summer and smoking-related web searches and sales of nicotine replacement products highest in winter. Variation in demand for clinical care and in outcomes has not been explored. AIMS AND METHODS: We measure seasonal variation in enrolments, total clinical visits, visits per enrolment, and treatment outcome (7-day abstinence at 6-month follow-up) from 2015 to 2018 in a large (n = 85 869) clinical cohort from 454 clinics across Ontario, Canada. We model seasonality using harmonic logistic and negative binomial regression. For individual-level outcomes, we adjust for variables, selected a priori, known to be associated with treatment use or outcomes. Data are nearly complete for 3 outcomes, but 6m abstinence is missing for 45% of participants. We use multiple imputation to adjust for missing data. RESULTS: All four outcomes showed significant seasonal variation (all p <.001). Total enrolments and visits were 20%-25% higher in January-April than in June-September. Visits per enrolment varied slightly, with lowest levels from May-July. Abstinence at 6 months was lowest among individuals enrolled from February-May and highest for those enrolled from July-November, with an absolute peak-trough difference of 4.3% (95% CI = 3.2% to 5.5%). CONCLUSIONS: There is meaningful seasonal variation in demand for, and outcomes of, smoking cessation treatment. Climate and weather may be indirectly responsible. Seasonal differences underscore the general importance of contextual factors in smoking cessation, may be useful in program promotion, and may explain some variability in outcomes in evaluation and research. IMPLICATIONS: Demand for tobacco cessation treatment and clinical outcomes vary seasonally. This underscores the importance of context in substance-related problems, and implies that some variability in research and evaluation results may be due to the time of year data were collected. Promotion efforts might usefully consider seasonal effects to smooth out demand and possibly improve outcomes.

Studying rare events using forward-flux sampling: Recent breakthroughs and future outlook.

Rare events are processes that occur upon the emergence of unlikely fluctuations. Unlike what their name suggests, rare events are fairly ubiquitous in nature, as the occurrence of many structural transformations in biology and material sciences is predicated upon crossing large free energy barriers. Probing the kinetics and uncovering the molecular mechanisms of possible barrier crossings in a system is critical to predicting and controlling its structural and functional properties. Due to their activated nature, however, rare events are exceptionally difficult to study using conventional experimental and computational techniques. In recent decades, a wide variety of specialized computational techniques-known as advanced sampling techniques-have been developed to systematically capture improbable fluctuations relevant to rare events. In this perspective, we focus on a technique called forward flux sampling [Allen et al., J. Chem. Phys. 124, 024102 (2006)] and overview its recent methodological variants and extensions. We also provide a detailed overview of its application to study a wide variety of rare events and map out potential avenues for further explorations.

Varenicline and Bupropion for Long-Term Smoking Cessation (the MATCH Study): Protocol for a Real-World, Pragmatic, Randomized Controlled Trial.

BACKGROUND: Varenicline and bupropion are efficacious, prescription-only pharmacotherapies for smoking cessation; however, their real-world impact is limited by prescriber knowledge, affordability, and accessibility. OBJECTIVE: The primary objective of the MATCH (Medication Aids for Tobacco Cessation Health) study was to evaluate the real-world, long-term effectiveness of mailed bupropion and varenicline in a sample of interested smokers with the utilization of Web-based recruitment and follow-up. In addition, the study aims to investigate the genotypic and phenotypic predictors of cessation. METHODS: This is a two-group, parallel block, randomized (1:1) open-label clinical trial. This study will be conducted online with the baseline enrollment through the study's website and follow-up by emails. In addition, medication prescriptions will be filled by the study contract pharmacy and couriered to participants. Individuals who smoke ≥10 cigarettes per day and intend to quit within the next 30 days will be recruited through Public Health Units and Tobacco Control Area Networks throughout Ontario by word-of-mouth and the internet. Eligible participants will receive an email with a prescription for 12-week assigned medication and a letter to take to their physician. The recruitment and randomization will continue until 500 participants per arm have received medication. All participants will receive weekly motivational emails during the treatment phase. The primary outcome measure is the smoking status after 6 months, biochemically confirmed by mailed-in salivary cotinine. Follow-ups will be conducted through emails after 4, 8, 12, 26, and 52 weeks of starting the treatment to assess the smoking prevalence and continuous smoking abstinence. In addition, mailed-in saliva samples will be used for genetic and nicotine metabolism analyses. Furthermore, personality characteristics will be assessed using the Big Five Aspect Scales. RESULTS: The project was funded in 2014 and enrollment was completed in January 2017. Data analysis is currently underway. CONCLUSIONS: To the best of our knowledge, this is the first randomized controlled trial to mass distribute prescription medications for smoking cessation. We expect this method to be logistically feasible and cost effective with quit outcomes that are comparable to published clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02146911; https://clinicaltrials.gov/ct2/show/NCT02146911 (Archived by WebCite at http://www.webcitation.org/72CZ6AvXZ). REGISTERED REPORT IDENTIFIER: RR1-10.2196/10826.

Public health impact of a novel smoking cessation outreach program in Ontario, Canada.

BACKGROUND: Provision of evidence-based smoking cessation treatment may contribute to health disparities if barriers to treatment are greater for more disadvantaged groups. We describe and evaluate the public health impact of a novel outreach program to improve access to smoking cessation treatment in Ontario, Canada. METHODS: We partnered with Public Health Units (PHUs) located across the province to deliver single-session workshops providing standardized evidence-based content and 10 weeks (2007-2008) or 5 weeks (2008-2016) of nicotine replacement therapy (NRT). Participants completed a baseline assessment and were followed up by phone or e-mail at 6 months. We used the RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance) framework to evaluate the public health impact of the program from 2007 to 2016. Given the iterative design and changes in implementation over time, data is presented annually or bi-annually. RESULTS: There were 26,122 enrollments from 2007 to 2016. Between 31 and 442 workshops were held annually. The annual reach was estimated to be 0.1-0.3% of eligible smokers in Ontario. Participants were older, smoked more heavily, had a lower household income, were more likely to be female and be diagnosed with a mood or anxiety disorder, and less likely to have a postsecondary degree compared to average Ontario smokers eligible for participation. The intervention was effective; at 6-month follow-up 22-33% of respondents reported abstinence from smoking. Adoption by PHUs was 81% by the second year of operation and remained high (72-97%) thereafter, with the exception of 2009-2010 (33-56%) when the program was temporarily unavailable to PHUs due to lack of funding. Implementation at the organizational level was not tracked; however, at the individual level, approximately half of participants used most or all of the NRT received. On average, maintenance of the program was high, with PHUs conducting workshops for 7 of the 10 years (2007-2016) and 4 of the 5 most recent years (2012-2016). CONCLUSIONS: The smoking cessation program had a high rate of adoption and maintenance, reached smokers over a large geographic area, including individuals more likely to experience disparities, and helped them make successful quit attempts. This novel model can be adopted in other jurisdictions with limited resources.

How to adapt existing evidence-based clinical practice guidelines: a case example with smoking cessation guidelines in Canada.

OBJECTIVE: To develop and encourage the adoption of clinical practice guidelines (CPGs) for smoking cessation in Canada by engaging stakeholders in the adaptation of existing high-quality CPGs using principles of the ADAPTE framework. METHODS: An independent expert body in guideline review conducted a review and identified six existing CPGs, which met a priori criteria for quality and potential applicability to the local context. Summary statements were extracted and assigned a grade of recommendation and level of evidence by a second expert panel. Regional knowledge exchange brokers recruited additional stakeholders to build a multidisciplinary network of over 800 clinicians, researchers and decision-makers from across Canada. This interprofessional network and other stakeholders were offered various opportunities to provide input on the guideline both online and in person. We actively encouraged end-user input into the development and adaptation of the guidelines to ensure applicability to various practice settings and to promote adoption. RESULTS: The final guideline contained 24 summary statements along with supporting clinical considerations, across six topic area sections. The guideline was adopted by various provincial/territorial and national government and non-governmental organisations. CONCLUSIONS: This method can be applied in other jurisdictions to adapt existing high-quality smoking cessation CPGs to the local context and to facilitate subsequent adoption by various stakeholders.

Association between adherence to free nicotine replacement therapy and successful quitting.

INTRODUCTION: Providing free nicotine replacement therapy (NRT) can be a cost-effective strategy for increasing quit attempts and cessation rates at a population level. However, the optimal amount of NRT to provide is unknown. Associations between duration of NRT use and abstinence may be overestimated as a result of reverse causality due to discontinuation following relapse. We examined the association between adherence to 10weeks of cost-free NRT and quit success at 6-month follow-up, after controlling for reverse causation by excluding participants who reported nonadherence due to relapse. METHODS: Individuals 18years or older who smoked at least 10 cigarettes daily and intended to quit within 30days received 10weeks of NRT at a smoking cessation workshop. There were 3922 participants who attended one of 114 workshops in 70 different localities in Ontario, Canada from 2007 to 2008. RESULTS: At end of treatment participants were asked whether they had used "all" of the NRT (20%), "most" of it (28%), "some" of it (47%), or whether they "did not use any" of it (5%). After controlling for reverse causation and adjusting for potential confounding variables, poorer quit success was reported by those who used either some (AOR=0.43, 95% CI=0.26-0.69, p=0.001) or none (AOR=0.30, 95% CI=0.09-0.95, p=0.041) of the NRT versus all 10weeks. Post-estimation contrasts revealed using some versus most of the NRT was also associated with poorer quit success (p=0.026). CONCLUSIONS: After controlling for reverse causation, adherence to 10weeks of cost-free NRT was associated with successful abstinence at six months post-treatment.

A success story: identified gaps and the way forward for low HIV prevalence in Bangladesh.

Bangladesh remains a low prevalence country for HIV infection. In this article we attempt to address the reasons for the present success in this country and the challenges lying ahead to minimise the spread of HIV in the future.

Empowering smokers with a web-assisted tobacco intervention to use prescription smoking cessation medications: a feasibility trial.

BACKGROUND: Varenicline and bupropion, efficacious smoking cessation medications, have had suboptimal impact due to barriers at the patient, practitioner and system level. This study explored the feasibility of a web-assisted tobacco intervention offering free prescription smoking cessation medication by mail if the smoker visited a physician for authorization. METHODS: Adult Ontarians, smoking at least 10 cigarettes daily, intending to quit within 30 days, with no contraindications to bupropion or varenicline were eligible. After an online assessment, eligible participants received an electronic personalized printable prescription form for a 12-week course of varenicline or bupropion to bring to a physician within 3 weeks for authorization, if appropriate. The physician's office faxed prescriptions to an online pharmacy that couriered medication to the patient following medication counselling by telephone. Weekly motivational emails were sent during treatment. Participants were asked to complete follow-up questionnaires online at 7, 11, 15 and 41 weeks after enrollment. RESULTS: In total, 1214 individuals submitted an online assessment from April to September 2010 and 73.6 % (95 % confidence interval (CI) = 71.1-76.1 %; n = 893) were eligible. At least 65.8 % (95 % CI = 62.7-68.9 %; n = 588) of eligible participants subsequently visited a physician and 58.7 % (95 % CI = 55.5-61.9 %; n = 524) received medication (50.6 % varenicline [n = 265] and 49.4 % bupropion [n = 259]). Reasons for not filling a prescription were failure to visit a physician (80.1 %; 95 % CI = 73.8-86.5 %; n = 121), physician not prescribing the medication (15.9 %; 95 % CI = 10.1-21.7 %; n = 24) or other reasons (4.0 %; 95 % CI = 0.9-7.1 %; n = 6). Follow-up response rate was 66.7 % (95 % CI = 63.7-69.8 %; n = 596). Minimal issues were encountered with printing the prescription or medication delivery. CONCLUSIONS: This study establishes the feasibility of using the Internet and free medication to enable smokers to engage physicians to treat this addiction. Implementation of this intervention can be scaled up by leveraging existing healthcare systems to treat smokers on a population level. Further evaluation in a randomized controlled trial is necessary. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01023659.

The impact of chronic bupropion on plasma cotinine and on the subjective effects of ad lib smoking: a randomized controlled trial in unmotivated smokers.

Bupropion is an efficacious non-nicotine medication for smoking cessation; however, its cessation-mediating mechanism is unclear. This randomized, placebo-controlled trial examined the effect of bupropion SR (300 mg/day for 6 weeks) on plasma cotinine and on the subjective effects of smoking in 24 current daily smokers who were not trying to quit or reduce smoking. Subjective effects of smoking, as well as cue-elicited responses were assessed at bi-weekly experimental sessions using validated scales. Several indices of cigarette consumption were measured. Plasma cotinine decreased from 280 (+/-133) microg/l at baseline to 205 (+/-108) microg/l at end of treatment in the bupropion group (p=0.036), but no significant change was found in the placebo group. Daily cigarette count and puff topography did not significantly change in either group. In contrast to placebo, bupropion increased post-smoking satiety (p=0.045). Both groups reported higher craving (p=0.025) and withdrawal (p=0.014) after exposure to smoking-related pictures, compared to neutral pictures. This biased reactivity was not significantly affected by treatment condition (p>0.1). Therefore, bupropion does not appear to impact the smokers' response to conditioned smoking-related cues but influences the unconditioned subjective effects of smoking in unmotivated smokers. This study is among the first to systematically investigate the effect of chronic bupropion administration, free from the confounding effect of the smoker's motivation to quit smoking.

Isoform-dependent feedback regulation of serine O-acetyltransferase isoenzymes involved in L-cysteine biosynthesis of Entamoeba histolytica.

Serine acetyltransferase (SAT; EC 2.3.1.30) catalyzes the CoA-dependent acetylation of the side chain hydroxyl group of l-serine to form O-acetyl serine, in the first step of the L-cysteine biosynthetic pathway. Since this pathway is selectively present in a few parasitic protists and absent in mammals, it represents a reasonable target to develop new chemotherapeutics. Entamoeba histolytica apparently possesses three SAT isotypes (EhSAT1-3) showing 48-73% mutual identity, a calculated molecular mass of 34.4-37.7 kDa, and an isoelectric point of 5.70-6.63. To better understand the role of individual SAT isotypes, we determined kinetic and inhibitory parameters of recombinant SAT isotypes. While the three SAT isotypes showed comparable Km and k(cat) for L-serine and acetyl-CoA, they showed remarkable differences in their sensitivity to inhibition by L-cysteine. The Ki values for L-cysteine varied by 100-fold (4.7-460 microM) among SAT isotypes (EhSAT1

Possible involvement of adrenomedullin in lipopolysaccharide-induced small-intestinal motility changes in conscious rats.

BACKGROUND: Adrenomedullin is a vasodilator peptide that displays a variety of effects, such as hypotension and vasodilatation. The aim of this study was to test the effect of intravenous adrenomedullin on the motility pattern of the small intestine, and the functional involvement of adrenomedullin in endotoxin-induced small-intestinal motility disturbance. METHODS: Jejunal motility was recorded in fasted conscious rats, using miniature strain-gauge force transducers sutured to the serosal surface of the small-intestinal wall. RESULTS: Intravenous administration of adrenomedullin at doses of 3, 6, and 10 microg/kg per min over 30 min disrupted phase 3 of the migrating motor complex, with the disruption lasting for 61.9 +/- 5.1, 52.2 +/- 10.6, and 74.1 +/- 25.2 min, respectively. The interval from drug administration to the onset of disruption decreased as the dose of adrenomedullin increased to 41.5 +/- 11.0, 11.6 +/- 3.4, and 0 min, respectively (P < 0.05). An increase in the motility index was also dose-dependent (P < 0.05) at these doses of adrenomedullin. Lipopolysaccharide (50 microg/kg) induced disruption of phase 3, which lasted for 138.7 +/- 5.4 min. Previous administration of the putative adrenomedullin-receptor antagonist, AM (22-52), at a 50 microg/kg dose, attenuated the disruption induced by lipopolysaccharide to 74.4 +/- 3.5 min (P < 0.01). CONCLUSIONS: Our findings (1) suggest that intravenous adrenomedullin causes small-intestinal motility disturbances, and (2) support the hypothesis that adrenomedullin overproduction plays an important role in lipopolysaccharide-induced disruption of the motility pattern in the small intestine in rats.