The majority of current smokers in the United States want to quit smoking; however, long-term abstinence rates do not improve beyond 30%, despite the availability of effective pharmaco-behavioral treatments and increased outreach of awareness programs on quitting benefits. One of the reasons is non-adherence to pharmacological treatment. Pharmacological treatments are developed to alleviate withdrawal symptoms experienced during a quit attempt. However, without continued treatment adherence, especially in the first few weeks of a quit attempt (when withdrawal symptoms fluctuate the most), the chances of relapse peak. Thus, adherence to pharmacological treatments must be improved to sustain long-term smoking abstinence. Moreover, smoking cessation is a complex and time-varying process. Therefore, the time-varying causal structure of adherence and smoking cessation must be studied carefully.The time-varying mechanisms underlying the smoking cessation process can be captured efficiently through intensive longitudinal data and quantified through appropriate methods. Mediation analysis is an efficient tool for studying such mechanisms. However, despite the time-varying nature of the data, existing approaches for assessing mediation provide overall average (in)direct effects over time and omit describing the temporal characteristic of the dynamic effect. This dissertation research aims to develop a new approach to estimating time-varying causal (in)direct effects of pharmacological treatments on daily smoking cessation outcome(s) mediated via daily treatment adherence. Additionally, it is hypothesized that adherence is influenced by daily stress events related to social contextual factors, not treatment-induced. The purpose of this research is to derive time-varying causal (in)direct effects. A local polynomial regression-based approach integrated with the mediational g-formula was proposed as a possible solution. Furthermore, since no other studies have studied time-specific mediation effects using a potential outcomes framework-based method, the performance of the proposed method was tested using two simulation studies. Finally, the optimum analytical approach (based on the findings from the simulation studies) was applied to answer the substantive research questions on smoking cessation using empirical data from a smoking cessation clinical trial. This dissertation is divided into six chapters. A brief overview of the chapters is as follows: Chapter 1 provides a comprehensive background and rationale for the methodological and substantive research that motivated this work. The chapter concludes with the three specific aims addressed in this research and a summary of the next steps. In Chapter 2, the longitudinal causal frameworks and the assumptions required to interpret the estimated time-varying (in)direct effects as causal are described in detail. These frameworks were further used in Chapters 3 and 4 for the two simulation studies that evaluated the performance of the proposed new approach. The simulation study in Chapter 3 evaluates the time-varying (in)direct effects in a longitudinal study in the absence of exposure-induced time-varying confounding of a mediator-outcome pathway. Four outcome scenarios with a binary exposure, a binary mediator, and a time-varying binary confounder of the mediator-outcome pathway were examined: 1) continuous outcome, 2) rare binary outcome, 3) common binary outcome, and 4) count outcome that is not zero-inflated. Two types of path-specific causal estimands are identifiable for these scenarios. The findings suggest good performance of the proposed analytical approach in producing accurate effect estimates (reduced bias and reasonable coverage) of these estimands for all the outcome scenarios. The simulation study in Chapter 4 evaluates the time-varying (in)direct effects in a longitudinal study in the presence of exposure-induced time-varying confounding of a mediator-outcome pathway. A zero-inflated count outcome scenario with a binary exposure, a binary mediator, and a time-varying binary confounder of the mediator-outcome pathway was examined. Four types of path-specific causal estimands are identifiable for this scenario, and the findings suggest good performance of the proposed analytical approach in producing accurate effect estimates. Chapter 5 uses the Wisconsin Smokers Health Study II data to assess the mechanisms via which pharmacological smoking cessation treatments affect the cessation-related outcome(s) in the presence of time-varying confounding that is not exposure induced. We found that individuals randomized to Nicotine Patch only group have better smoking cessation outcome(s) compared to individuals on Varenicline or combination Nicotine Replacement Therapy. This is due to better adherence among Nicotine Patch-only users. Finally, Chapter 6 presents the concluding remarks, including key findings from the three studies, limitations, and recommendations for future research. / Epidemiology

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Cigarette smoking is prevalent worldwide and has consistently been the top preventable cause of many serious diseases., which result in huge mortality, morbidity, and economic loss, in recent decades. In recent years, nicotine vaccines that can induce production of nicotine specific antibodies in human have emerged as a promising medicine to treat tobacco addiction. In the past decade, there have been numerous nicotine vaccine candidates evaluated in human clinical trials, including NicVaxNicVAX®, TA-NICTA-NIC®, Nic002NIC002®, NiccineNiccine®, and SEL-068SEL-068®. . However, traditional nicotine vaccine designs haves many disadvantages, including low immunogenicity, low specificity, difficulty in integration of molecular adjuvants, and short immune response persistence. To overcome the above limitations, in this study, various nanoparticle-based vaccine delivery systemsvaccine componentss have been developed and evaluated as potential delivery vehicles for vaccines against nicotine addiction. Firstly, a nicotine vaccine was synthesized by conjugating bovine serum albumin (BSA)-nicotine complex to the surface of nano-sized cationic liposome. Significantly higher anti-nicotine antibody titer was achieved in mice by liposome delivered nicotine vaccine compared with nicotine-BSA vaccine. Secondly, a novel nanoparticle (NP)-based delivery platform was constructed by incorporating a negatively charged nanohorn into cationic liposome to improve the stability of liposome and reduce nanoparticle flocculation. Subsequently, nicotine vaccine was constructed by conjugating nicotine-BSA complex to the surface of the nanohorn supported liposome (NsL). Marked improvement in stability in vitro and significant increase in titer of anti-nicotine antibodies were detected in nanohorn supported liposome ( NsL) delivered vaccine than liposome delivered vaccine. In addition, NsL nicotine vaccine exhibited good safety in mice after multiple injections. Thirdly, lipid- poly(lactic-co-glycolic acid) (PLGA) hybrid NPs were constructed as vaccine delivery system. due to the fact that nanohorn is not currently approved for clinical use, we substituted the nanohorn with poly(lactic-co-glycolic acid) (PLGA) nanoparticles and constructed PLGA-lipid hybrid nanoparticles. Preliminary results showed that PLGA-lipid hybrid NPs nanoparticles exhibited improved stability, better controlled release of antigens, as well as enhanced uptake by dendritic cell (DC). A lipid-PLGA hybrid NPnanoparticle was also developed that was structurally responsive to low pH challenge. The lipid shell of the hybrid nanoparticle was rapidly disintegrated under a low pH challenge, which resembles the acidic environment of endosomes in DCsdendritic cells. The hybrid NPs exhibited minimal antigen release in human serum at physiological pH, but a faster release of antigen from this NP compared to non-pH sensitive NPs was observed in DC. In the final study, hybrid NPnanoparticles with various cholesterol concentrations were constructed. Slower and more controlled release of antigens in both human serum and phosphate buffered saline were detected in nanoparticles with higher cholesterol content. However, nanoparticles containing higher cholesterol showed poorer stability due to increase fusion among NPnanoparticles. It was later found that PEGylation of NPs can effectively minimize fusion caused size increase after long term storage, leading to improved cellular uptake. The findings from this study on the nanohorn-lipids based nicotine vaccine as well as lipid-PLGA hybrid NPs may provide solid basis for future development of lipid-PLGA based nicotine vaccine. / Ph. D.

Yes / Smokers attend preferentially to cigarettes and other smoking-related cues in the environment, in what is known as an attentional bias. There is evidence that attentional bias may contribute to craving and failure to stop smoking. Attentional retraining procedures have been used in laboratory studies to train smokers to reduce attentional bias, although these procedures have not been applied in smoking cessation programmes. This trial will examine the efficacy of multiple sessions of attentional retraining on attentional bias, craving, and abstinence in smokers attempting cessation. This is a double-blind randomised controlled trial. Adult smokers attending a 7-session weekly stop smoking clinic will be randomised to either a modified visual probe task with attentional retraining or placebo training. Training will start 1 week prior to quit day and be given weekly for 5 sessions. Both groups will receive 21 mg transdermal nicotine patches for 8–12 weeks and withdrawal-orientated behavioural support for 7 sessions. Primary outcome measures are the change in attentional bias reaction time and urge to smoke on the Mood and Physical Symptoms Scale at 4 weeks post-quit. Secondary outcome measures include differences in withdrawal, time to first lapse and prolonged abstinence at 4 weeks post-quit, which will be biochemically validated at each clinic visit. Follow-up will take place at 8 weeks, 3 months and 6 months post-quit. This is the first randomised controlled trial of attentional retraining in smokers attempting cessation. This trial could provide proof of principle for a treatment aimed at a fundamental cause of addiction. / National Institute for Health Research (NIHR) Doctoral Research Fellowship (DRF) awarded to RB (DRF-2009-02-15)

published_or_final_version / Community Medicine / Master / Master of Public Health

Syfte: Att utvärdera vilken rökavvänjnings metod som är mest effektiv vid kronisk obstruktiv lungsjukdom. Det som undersöktes var de förbättringar i patientresultatet av de olika rökavvänjnings metoderna. Mål: Databassökning samt identifiering av relevant litteratur.Bedömning av kvaliteten på de inkluderade studierna ochsammanställning och sammanfattning av dokumentationen respektive resultat. Studie typer: Sammanställningar och systematiska sammanställningar. Källor: MEDLINE, CINAHL och Cochrane Bibliotek. Metoder: Litteratursökning utfördes, sammanställningarna bedömdes med AMSTAR 2 och PRISMA formulären. Informationen sammanställdes i tabell som sammanfattade resultaten. Resultat: 10 systematiska sammanställningar med medel till hög PRISMA och AMSTAR 2 poäng samlades med en variation av 370 – 13000 KOL-patienter. Dödlighet, sjuklighet och livskvalité visade positiva resultat, andel personer som slutade röka visade också signifikanta siffror.Slutsats: Det finns bevis av interventioner som har positiv effekt på KOL-patienter att sluta röka. Intensiv farmakoterapi rådgivning och motiverande samtal visade bästa resultat för en KOL-patient. / Purpose: To evaluate which smoking cessation method is most effective in chronic obstructive pulmonary disease. What was investigated were the improvements in the patient result of different smoking cessation methods. Objective: Database search and identification of relevant literature.Assessment of quality of the included studiescompilation and summary of the documentation and the result. Studies: Reviews and systematic reviews. Sources: MEDLINE, CINAHL and Cochrane Library. Methods: Literature search was performed, the reviews were assessed with AMSTAR 2 and PRISMA. The information was extracted in tables.Results: 10 systematic reviews with high PRISMA and AMSTAR 2 score were collected with a variety of 370-13000 COPD patients. Mortality, morbidity and quality of life showed positive results, the proportion of people who quit smoking also showed significant numbers. Conclusion: There is evidence of interventions that have a positive effect on COPD patients to quit smoking. Intensive pharmacotherapy counseling and motivational interviewing showed the best results for a COPD patient.

published_or_final_version / Community Medicine / Master / Master of Public Health

published_or_final_version / Community Medicine / Master / Master of Public Health