Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma.

Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem-like cells, a source of post-treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM-infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)-ß-mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single-cell transcriptomics demonstrated that both tumour and haematopoietic-derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co-expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti-tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways.

KvSNP: accurately predicting the effect of genetic variants in voltage-gated potassium channels.

MOTIVATION: Non-synonymous single nucleotide polymorphisms (nsSNPs) in voltage-gated potassium (Kv) channels cause diseases with potentially fatal consequences in seemingly healthy individuals. Identifying disease-causing genetic variation will aid presymptomatic diagnosis and treatment of such disorders. NsSNP-effect predictors are hypothesized to perform best when developed for specific gene families. We, thus, created KvSNP: a method that assigns a disease-causing probability to Kv-channel nsSNPs. RESULTS: KvSNP outperforms popular non gene-family-specific methods (SNPs&GO, SIFT and Polyphen) in predicting the disease potential of Kv-channel variants, according to all tested metrics (accuracy, Matthews correlation coefficient and area under receiver operator characteristic curve). Most significantly, it increases the separation of the median predicted disease probabilities between benign and disease-causing SNPs by 26% on the next-best competitor. KvSNP has ranked 172 uncharacterized Kv-channel nsSNPs by disease-causing probability. AVAILABILITY AND IMPLEMENTATION: KvSNP, a WEKA implementation is available at www.bioinformatics.leeds.ac.uk/KvDB/KvSNP.html. CONTACT: d.r.westhead@leeds.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Physician advice for smoking cessation.

BACKGROUND: Healthcare professionals frequently advise patients to improve their health by stopping smoking. Such advice may be brief, or part of more intensive interventions. OBJECTIVES: The aims of this review were to assess the effectiveness of advice from physicians in promoting smoking cessation; to compare minimal interventions by physicians with more intensive interventions; to assess the effectiveness of various aids to advice in promoting smoking cessation, and to determine the effect of anti-smoking advice on disease-specific and all-cause mortality. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register. Date of the most recent search: September 2007. SELECTION CRITERIA: Randomized trials of smoking cessation advice from a medical practitioner in which abstinence was assessed at least six months after advice was first provided. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the setting in which advice was given, type of advice given (minimal or intensive), and whether aids to advice were used, the outcome measures, method of randomization and completeness of follow up. The main outcome measure was abstinence from smoking after at least six months follow up. We also considered the effect of advice on mortality where long-term follow-up data were available. We used the most rigorous definition of abstinence in each trial, and biochemically validated rates where available. Subjects lost to follow up were counted as smokers. Effects were expressed as relative risks. Where possible, meta-analysis was performed using a Mantel-Haenszel fixed effect model. MAIN RESULTS: We identified 41 trials, conducted between 1972 and 2007, including over 31,000 smokers. In some trials, subjects were at risk of specified diseases (chest disease, diabetes, ischaemic heart disease), but most were from unselected populations. The most common setting for delivery of advice was primary care. Other settings included hospital wards and outpatient clinics, and industrial clinics. Pooled data from 17 trials of brief advice versus no advice (or usual care) detected a significant increase in the rate of quitting (relative risk (RR) 1.66, 95% confidence interval (CI) 1.42 to 1.94). Amongst 11 trials where the intervention was judged to be more intensive the estimated effect was higher (RR 1.84, 95% CI 1.60 to 2.13) but there was no statistical difference between the intensive and minimal subgroups. Direct comparison of intensive versus minimal advice showed a small advantage of intensive advice (RR 1.37, 95% CI 1.20 to 1.56). Direct comparison also suggested a small benefit of follow-up visits. Only one study determined the effect of smoking advice on mortality. This study found no statistically significant differences in death rates at 20 years follow up. AUTHORS' CONCLUSIONS: Simple advice has a small effect on cessation rates. Assuming an unassisted quit rate of 2 to 3%, a brief advice intervention can increase quitting by a further 1 to 3%. Additional components appear to have only a small effect, though there is a small additional benefit of more intensive interventions compared to very brief interventions.

Nicotine replacement therapy for smoking cessation.

BACKGROUND: The aim of nicotine replacement therapy (NRT) is temporarily to replace much of the nicotine from cigarettes to reduce motivation to smoke and nicotine withdrawal symptoms, thus easing the transition from cigarette smoking to complete abstinence. OBJECTIVES: The aims of this review were:To determine the effect of NRT compared to placebo in aiding smoking cessation, and to consider whether there is a difference in effect for the different forms of NRT (chewing gum, transdermal patches, nasal spray, inhalers and tablets/lozenges) in achieving abstinence from cigarettes. To determine whether the effect is influenced by the dosage, form and timing of use of NRT; the intensity of additional advice and support offered to the smoker; or the clinical setting in which the smoker is recruited and treated. To determine whether combinations of NRT are more likely to lead to successful quitting than one type alone. To determine whether NRT is more or less likely to lead to successful quitting compared to other pharmacotherapies. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register for papers with 'nicotine' or 'NRT' in the title, abstract or keywords. Date of most recent search July 2007. SELECTION CRITERIA: Randomized trials in which NRT was compared to placebo or to no treatment, or where different doses of NRT were compared. We excluded trials which did not report cessation rates, and those with follow up of less than six months. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of participants, the dose, duration and form of nicotine therapy, the outcome measures, method of randomization, and completeness of follow up. The main outcome measure was abstinence from smoking after at least six months of follow up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. We calculated the risk ratio (RR) for each study. Where appropriate, we performed meta-analysis using a Mantel-Haenszel fixed-effect model. MAIN RESULTS: We identified 132 trials; 111 with over 40,000 participants contributed to the primary comparison between any type of NRT and a placebo or non-NRT control group. The RR of abstinence for any form of NRT relative to control was 1.58 (95% confidence interval [CI]: 1.50 to 1.66). The pooled RR for each type were 1.43 (95% CI: 1.33 to 1.53, 53 trials) for nicotine gum; 1.66 (95% CI: 1.53 to 1.81, 41 trials) for nicotine patch; 1.90 (95% CI: 1.36 to 2.67, 4 trials) for nicotine inhaler; 2.00 (95% CI: 1.63 to 2.45, 6 trials) for oral tablets/lozenges; and 2.02 (95% CI: 1.49 to 3.73, 4 trials) for nicotine nasal spray. The effects were largely independent of the duration of therapy, the intensity of additional support provided or the setting in which the NRT was offered. The effect was similar in a small group of studies that aimed to assess use of NRT obtained without a prescription. In highly dependent smokers there was a significant benefit of 4 mg gum compared with 2 mg gum, but weaker evidence of a benefit from higher doses of patch. There was evidence that combining a nicotine patch with a rapid delivery form of NRT was more effective than a single type of NRT. Only one study directly compared NRT to another pharmacotherapy. In this study quit rates with nicotine patch were lower than with the antidepressant bupropion. AUTHORS' CONCLUSIONS: All of the commercially available forms of NRT (gum, transdermal patch, nasal spray, inhaler and sublingual tablets/lozenges) can help people who make a quit attempt to increase their chances of successfully stopping smoking. NRTs increase the rate of quitting by 50-70%, regardless of setting. The effectiveness of NRT appears to be largely independent of the intensity of additional support provided to the individual. Provision of more intense levels of support, although beneficial in facilitating the likelihood of quitting, is not essential to the success of NRT.

Nursing interventions for smoking cessation.

BACKGROUND: Healthcare professionals, including nurses, frequently advise patients to improve their health by stopping smoking. Such advice may be brief, or part of more intensive interventions. OBJECTIVES: To determine the effectiveness of nursing-delivered smoking cessation interventions. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group specialized register and CINAHL in July 2007. SELECTION CRITERIA: Randomized trials of smoking cessation interventions delivered by nurses or health visitors with follow up of at least six months. DATA COLLECTION AND ANALYSIS: Two authors extracted data independently. The main outcome measure was abstinence from smoking after at least six months of follow up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Where statistically and clinically appropriate, we pooled studies using a Mantel-Haenszel fixed effect model and reported the outcome as a risk ratio (RR) with 95% confidence interval (CI). MAIN RESULTS: Forty-two studies met the inclusion criteria. Thirty-one studies comparing a nursing intervention to a control or to usual care found the intervention to significantly increase the likelihood of quitting (RR 1.28, 95% CI 1.18 to 1.38). There was heterogeneity among the study results, but pooling using a random effects model did not alter the estimate of a statistically significant effect. In a subgroup analysis there was weaker evidence that lower intensity interventions were effective (RR 1.27, 95% CI 0.99 to 1.62). There was limited indirect evidence that interventions were more effective for hospital inpatients with cardiovascular disease than for inpatients with other conditions. Interventions in non-hospitalized patients also showed evidence of benefit. Nine studies comparing different nurse-delivered interventions failed to detect significant benefit from using additional components. Five studies of nurse counselling on smoking cessation during a screening health check, or as part of multifactorial secondary prevention in general practice (not included in the main meta-analysis) found nursing intervention to have less effect under these conditions. AUTHORS' CONCLUSIONS: The results indicate the potential benefits of smoking cessation advice and/or counselling given by nurses to patients, with reasonable evidence that intervention is effective. The evidence of an effect is weaker when interventions are brief and are provided by nurses whose main role is not health promotion or smoking cessation. The challenge will be to incorporate smoking behaviour monitoring and smoking cessation interventions as part of standard practice, so that all patients are given an opportunity to be asked about their tobacco use and to be given advice and/or counselling to quit along with reinforcement and follow up.

Intervenciones de enfermería para el abandono del hábito de fumar

Antecedentes: Los profesionales de la salud, incluidos los enfermeros, suelen aconsejar a las personas que mejoren su salud dejando de fumar. Dicho consejo puede ser breve o formar parte de intervenciones de mayor intensidad. Objetivos: Determinar la efectividad de las intervenciones para dejar de fumar realizadas por enfermeras en adultos. Establecer si las intervenciones para dejar de fumar realizadas por enfermeras son más efectivas que ninguna intervención; son más efectivas si la intervención es más intensiva; difieren en efectividad con el estado de salud y el entorno de los participantes; son más efectivas si incluyen seguimientos; son más efectivas si incluyen ayudas que demuestran el efecto fisiopatológico del tabaquismo. (AU)

Interventions for smokeless tobacco use cessation.

BACKGROUND: Use of smokeless tobacco (ST) can lead to nicotine addiction and long-term use can lead to health problems including periodontal disease and cancer. OBJECTIVES: To assess the effects of behavioural and pharmacologic interventions for the treatment of ST use. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, Web of Science, PsycINFO, Dissertation Abstracts Online, and Scopus. Date of last search: March, 2007. SELECTION CRITERIA: Randomized trials of behavioural or pharmacological interventions to help users of ST to quit with follow up of at least six months. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. MAIN RESULTS: Two trials of bupropion SR did not detect a benefit of treatment at six months or longer (Odds Ratio (OR) 0.86, 95% Confidence Interval (CI): 0.47 to 1.57). Four trials of nicotine patch did not detect a benefit (OR 1.16, 95% CI: 0.88 to 1.54), nor did two trials of nicotine gum (OR 0.98, 95% CI: 0.59 to 1.63). There was statistical heterogeneity among the results of 12 behavioural interventions included in the meta-analyses. Six trials showed significant benefits of intervention. In post-hoc subgroup analyses, behavioural interventions which include telephone counselling or an oral examination may increase abstinence rates more than interventions without these components. AUTHORS' CONCLUSIONS: Behavioural interventions should be used to help ST users to quit and telephone counselling or an oral examination may increase abstinence rates. Pharmacotherapies have not been shown to affect long-term abstinence.

Interventions for smoking cessation in hospitalised patients.

BACKGROUND: An admission to hospital provides an opportunity to help people stop smoking. Individuals may be more open to help at a time of perceived vulnerability, and may find it easier to quit in an environment where smoking is restricted or prohibited. Initiating smoking cessation services during hospitalisation may help more people to make and sustain a quit attempt. OBJECTIVES: To determine the effectiveness of interventions for smoking cessation that are initiated for hospitalised patients. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group register which includes papers identified from CENTRAL, MEDLINE, EMBASE and PSYCINFO in January 2007, and CINAHL in August 2006 for studies of interventions for smoking cessation in hospitalised patients, using terms including (hospital and patient*) or hospitali* or inpatient* or admission* or admitted. SELECTION CRITERIA: Randomized and quasi-randomized trials of behavioural, pharmacological or multicomponent interventions to help patients stop smoking, conducted with hospitalised patients who were current smokers or recent quitters (defined as having quit more than one month before hospital admission). The intervention had to start in the hospital but could continue after hospital discharge. We excluded studies of patients admitted for psychiatric disorders or substance abuse, studies that did not report abstinence rates and studies with follow up of less than six months. DATA COLLECTION AND ANALYSIS: Two authors extracted data independently for each paper, with disagreements resolved by consensus. MAIN RESULTS: Thirty-three trials met the inclusion criteria. Intensive counselling interventions that began during the hospital stay and continued with supportive contacts for at least one month after discharge increased smoking cessation rates after discharge (Odds Ratio (OR) 1.65, 95% confidence interval (CI) 1.44 to 1.90; 17 trials). No statistically significant benefit was found for less intensive counselling interventions. The one study that tested a single brief (<=15 minutes) in-hospital intervention did not find it to be effective (OR 1.16, 95% CI 0.80 to 1.67). Counselling of longer duration during the hospital stay was not associated with a higher quit rate (OR 1.08, 95% CI 0.89 to 1.29, eight trials). Even counselling that began in the hospital but had less than one month of supportive contact after discharge did not show significant benefit (OR 1.09, 95% CI 0.91 to 1.31, six trials). Adding nicotine replacement therapy (NRT) did not produce a statistically significant increase in cessation over what was achieved by intensive counselling alone (OR 1.47, 95% CI 0.92 to 2.35, five studies). The one study that tested the effect of adding bupropion to intensive counselling had a similar nonsignificant effect (OR 1.56, 95% CI 0.79 to 3.06). A similar pattern of results was observed in smokers admitted to hospital because of cardiovascular disease (CVD). In this subgroup, intensive intervention with follow-up support increased the odds of smoking cessation (OR 1.81, 95% CI 1.54 to 2.15, 11 trials), but less intensive interventions did not. One trial of intensive intervention including counselling and pharmacotherapy for smokers admitted with CVD assessed clinical and health care utilization endpoints, and found significant reductions in all-cause mortality and hospital readmission rates over a two-year follow-up period. AUTHORS' CONCLUSIONS: High intensity behavioural interventions that begin during a hospital stay and include at least one month of supportive contact after discharge promote smoking cessation among hospitalised patients. These interventions are effective regardless of the patient's admitting diagnosis. lnterventions of lower intensity or shorter duration have not been shown to be effective in this setting. There is insufficient direct evidence to conclude that adding NRT or bupropion to intensive counselling increases cessation rates over what is achieved by counselling alone, but the evidence of benefit for NRT has strengthened in this update and the point estimates are compatible with research in other settings showing that NRT and bupropion are effective.

Interventions to reduce harm from continued tobacco use.

BACKGROUND: It may be reasonable to try to reduce the harm from continued smoking amongst smokers unable or unwilling to quit. Possible approaches to reduce the exposure to toxins from smoking include reducing the amount of tobacco used, and using less toxic products. The interventions evaluated in controlled trials have predominantly attempted to reduce the number of cigarettes smoked. OBJECTIVES: To assess the effect of interventions intended to reduce the harm from smoking on the following: biomarkers of damage caused by tobacco, biomarkers of tobacco exposure, number of cigarettes smoked, quitting, and long-term health status. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group Specialised Register using free text and MeSH terms for harm reduction, smoking reduction and cigarette reduction. The initial search was in March 2006, updated in March 2007. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of interventions in tobacco users to reduce amount smoked, or to reduce harm from smoking by means other than cessation. Outcomes were change in cigarette consumption, markers of cigarette exposure and any markers of damage or benefit to health, measured at least six months from the start of the intervention. DATA COLLECTION AND ANALYSIS: We pooled trials with similar interventions and outcomes using a fixed-effect model. Other studies were summarised narratively. MAIN RESULTS: The 13 included trials all evaluated interventions to help smokers cut down the amount smoked. Self-reported reduction in cigarettes per day (CPD) was validated by reduction in carbon monoxide (CO) levels. Most trials tested nicotine replacement therapy (NRT) to assist reduction. No eligible studies evaluated the use of potentially reduced-exposure products. In a pooled analysis of eight trials, NRT significantly increased the odds of reducing CPD by 50% or more for people using nicotine gum or inhaler or a choice of product compared to placebo (n=3273, odds ratio [OR] 2.02, 95% confidence interval [CI] 1.55 to 2.62). Where average changes from baseline were compared for different measures, CO and cotinine consistently showed smaller reductions than CPD. Whilst the effect for NRT was significant, small numbers of people in either treatment or control group successfully sustained a reduction of 50% or more. Use of NRT also significantly increased the odds of quitting (OR 1.90, 95% CI 1.46 to 2.47). One trial of bupropion failed to detect an effect on reduction or cessation. Four trials of different types of advice and instructions on reducing CPD did not provide clear evidence. AUTHORS' CONCLUSIONS: There is insufficient evidence about long-term benefit to give firm support the use of interventions intended to help smokers reduce but not quit tobacco use. Some people who do not wish to quit can be helped to cut down the number of cigarettes smoked and reduce their carbon monoxide levels by using nicotine gum or nicotine inhaler. Because the long-term health benefit of a reduction in smoking rate is unclear this application of NRT is more appropriately used as a precursor to quitting.

Antidepressants for smoking cessation.

BACKGROUND: There are at least two theoretical reasons to believe antidepressants might help in smoking cessation. Nicotine withdrawal may produce depressive symptoms or precipitate a major depressive episode and antidepressants may relieve these. Nicotine may have antidepressant effects that maintain smoking, and antidepressants may substitute for this effect. Alternatively, some antidepressants may have a specific effect on neural pathways underlying nicotine addiction, (e.g. blocking nicotine receptors) independent of their antidepressant effects. OBJECTIVES: The aim of this review is to assess the effect of antidepressant medications in aiding long-term smoking cessation. The medications include bupropion; doxepin; fluoxetine; imipramine; moclobemide; nortriptyline; paroxetine; sertraline, tryptophan and venlafaxine. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register which includes trials indexed in MEDLINE, EMBASE, SciSearch and PsycINFO, and other reviews and meeting abstracts, in September 2006. SELECTION CRITERIA: We considered randomized trials comparing antidepressant medications to placebo or an alternative pharmacotherapy for smoking cessation. We also included trials comparing different doses, using pharmacotherapy to prevent relapse or re-initiate smoking cessation or to help smokers reduce cigarette consumption. We excluded trials with less than six months follow up. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of study population, the nature of the pharmacotherapy, the outcome measures, method of randomization, and completeness of follow up. The main outcome measure was abstinence from smoking after at least six months follow up in patients smoking at baseline, expressed as an odds ratio (OR). We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed-effect model. MAIN RESULTS: Seventeen new trials were identified since the last update in 2004 bringing the total number of included trials to 53. There were 40 trials of bupropion and eight trials of nortriptyline. When used as the sole pharmacotherapy, bupropion (31 trials, odds ratio [OR] 1.94, 95% confidence interval [CI] 1.72 to 2.19) and nortriptyline (four trials, OR 2.34, 95% CI 1.61 to 3.41) both doubled the odds of cessation. There is insufficient evidence that adding bupropion or nortriptyline to nicotine replacement therapy provides an additional long-term benefit. Three trials of extended therapy with bupropion to prevent relapse after initial cessation did not find evidence of a significant long-term benefit. From the available data bupropion and nortriptyline appear to be equally effective and of similar efficacy to nicotine replacement therapy. Pooling three trials comparing bupropion to varenicline showed a lower odds of quitting with bupropion (OR 0.60, 95% CI 0.46 to 0.78). There is a risk of about 1 in 1000 of seizures associated with bupropion use. Concerns that bupropion may increase suicide risk are currently unproven. Nortriptyline has the potential for serious side-effects, but none have been seen in the few small trials for smoking cessation. There were six trials of selective serotonin reuptake inhibitors; four of fluoxetine, one of sertraline and one of paroxetine. None of these detected significant long-term effects, and there was no evidence of a significant benefit when results were pooled. There was one trial of the monoamine oxidase inhibitor moclobemide, and one of the atypical antidepressant venlafaxine. Neither of these detected a significant long-term benefit. AUTHORS' CONCLUSIONS: The antidepressants bupropion and nortriptyline aid long-term smoking cessation but selective serotonin reuptake inhibitors (e.g. fluoxetine) do not. Evidence suggests that the mode of action of bupropion and nortriptyline is independent of their antidepressant effect and that they are of similar efficacy to nicotine replacement. Adverse events with both medications are rarely serious or lead to stopping medication.

Nicotine receptor partial agonists for smoking cessation.

BACKGROUND: Nicotine receptor partial agonists may help smokers to quit by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). Varenicline was developed as a nicotine receptor partial agonist from cytisine, a drug widely used in central and eastern Europe for smoking cessation. The first trial reports of varenicline were released in 2006, and further trials are underway. OBJECTIVES: The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('varenicline' or 'cytisine' or 'Tabex' or 'nicotine receptor partial agonist') and 'smoking' in the title or abstract, or as keywords. We also searched MEDLINE, EMBASE, PsycINFO and CINAHL using MeSH terms and free text, and we contacted authors of trial reports for additional information where necessary. The last search was in October 2006. SELECTION CRITERIA: We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow up. The main outcome measured was abstinence from smoking after at least six months from the beginning of treatment. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we performed meta-analysis using the Mantel-Haenszel fixed-effect model. MAIN RESULTS: We found five trials of varenicline compared with placebo for smoking cessation; three of these also included a bupropion experimental arm. We also found one relapse prevention trial, comparing varenicline with placebo. The six trials covered 4924 participants, 2451 of whom used varenicline. We identified one trial of cytisine (Tabex) for inclusion. The pooled odds ratio (OR) for continuous abstinence at 12 months for varenicline versus placebo was 3.22 (95% confidence interval [CI] 2.43 to 4.27). The pooled OR for varenicline versus bupropion was 1.66 (95% CI 1.28 to 2.16). The main adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. The two trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated and effective during long-term use. The one cytisine trial included in this review found that more participants taking cytisine stopped smoking compared with placebo at two-year follow up, with an OR of 1.77 (95% CI 1.30 to 2.40). AUTHORS' CONCLUSIONS: Varenicline increased the odds of successful long-term smoking cessation approximately threefold compared with pharmacologically unassisted quit attempts. In trials reported so far, more participants quit successfully with varenicline than with bupropion. The effectiveness of varenicline as an aid to relapse prevention has not been clearly established. The main adverse effect of varenciline is nausea, but this is mostly at mild to moderate levels and tends to reduce with habituation. There is a need for independent trials of varenicline versus placebo, to test the early findings. There is also a need for direct comparisons with nicotine replacement therapy, and for further trials with bupropion, to establish the relative efficacy of the treatments.Cytisine may also increase the chances of quitting, but the evidence at present is inconclusive.

Opioid antagonists for smoking cessation.

BACKGROUND: The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. Smokers report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking. OBJECTIVES: To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group specialized register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using 'Narcotic antagonists' and smoking terms in March 2006. We also contacted investigators, when possible, for information on unpublished studies. SELECTION CRITERIA: We considered randomized controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of study population, the nature of the drug therapy, the outcome measures, method of randomization, and completeness of follow up. The main outcome measure was cotinine- or carbon monoxide-verified abstinence from smoking after at least six months follow up in patients smoking at baseline. Where appropriate, we performed meta-analysis using a fixed-effect model (Mantel-Haenszel odds ratios). MAIN RESULTS: Four trials of naltrexone met inclusion criteria for meta-analyses for long-term cessation. All four trials failed to detect a significant difference in quit rates between naltrexone and placebo. In a pooled analysis there was no significant effect of naltrexone on long-term abstinence, and confidence intervals were wide (odds ratio 1.26, 95% confidence interval 0.80 to 2.01). No trials of naloxone or buprenorphine reported long-term follow up. AUTHORS' CONCLUSIONS: Based on limited data from four trials it is not possible to confirm or refute whether naltrexone helps smokers quit. The confidence intervals are compatible with both clinically significant benefit and possible negative effects of naltrexone in promoting abstinence. Data from larger trials of naltrexone are needed to settle the question of efficacy for smoking cessation.

Telephone counselling for smoking cessation.

BACKGROUND: Telephone services can provide information and support for smokers. Counselling may be provided proactively or offered reactively to callers to smoking cessation helplines. OBJECTIVES: To evaluate the effect of proactive and reactive telephone support to help smokers quit. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register for studies using free text term 'telephone*' or the keywords 'telephone counselling' or 'Hotlines' or 'Telephone' . Date of the most recent search: January 2006. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials in which proactive or reactive telephone counselling to assist smoking cessation was offered to smokers or recent quitters. DATA COLLECTION AND ANALYSIS: Trials were identified and data extracted by one person (LS) and checked by a second (TL). The main outcome measure was the odds ratio for abstinence from smoking after at least six months follow up. We selected the strictest measure of abstinence, using biochemically validated rates where available. We considered participants lost to follow-up to be continuing smokers. Where trials had more than one arm with a less intensive intervention we used only the most similar intervention without the telephone component as the control group in the primary analysis. We assessed statistical heterogeneity amongst sub groups of clinically comparable studies using the I(2) statistic. Where appropriate, we pooled studies using a fixed-effect model. A meta-regression was used to investigate the effect of differences in planned number of calls. MAIN RESULTS: Forty-eight trials met the inclusion criteria. Among smokers who contacted helplines, quit rates were higher for groups randomised to receive multiple sessions of call-back counselling (eight studies, >18,000 participants, odds ratio (OR) for long term cessation 1.41, 95% confidence interval (CI) 1.27 to 1.57). Two of these studies showed a significant benefit of more intensive compared to less intensive intervention. Telephone counselling not initiated by calls to helplines also increased quitting (29 studies, >17,000 participants, OR 1.33, 95% CI 1.21 to 1.47). A meta-regression detected a significant association between the maximum number of planned calls and the effect size. There was clearer evidence of benefit in the subgroup of trials recruiting smokers motivated to quit. Of two studies that provided access to a hotline one showed a significant benefit and one did not. Two studies comparing different counselling approaches during a single session did not detect significant differences. A further seven studies were too diverse to contribute to meta-analyses and are discussed separately. AUTHORS' CONCLUSIONS: Proactive telephone counselling helps smokers interested in quitting. There is evidence of a dose response; one or two brief calls are less likely to provide a measurable benefit. Three or more calls increases the odds of quitting compared to a minimal intervention such as providing standard self-help materials, brief advice, or compared to pharmacotherapy alone. Telephone quitlines provide an important route of access to support for smokers, and call-back counselling enhances their usefulness.

Nicobrevin for smoking cessation.

BACKGROUND: Nicobrevin is a proprietary product marketed as an aid to smoking cessation. It contains quinine, menthyl valerate, camphor and eucalyptus oil. OBJECTIVES: The objective of this review was to assess the effects of Nicobrevin on long term smoking cessation SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register. SELECTION CRITERIA: Randomized trials comparing Nicobrevin to placebo or an alternative therapeutic control, which reported smoking cessation with at least six months follow up. DATA COLLECTION AND ANALYSIS: Data were sought on the outcome, method of randomization, and completeness of follow up. MAIN RESULTS: We identified no trials meeting the full inclusion criteria including long-term follow up. AUTHORS' CONCLUSIONS: There is no evidence available from long-term trials that Nicobrevin can aid smoking cessation.

Self-help interventions for smoking cessation.

BACKGROUND: Many smokers give up smoking on their own, but materials giving advice and information may help them and increase the number who quit successfully. OBJECTIVES: The aims of this review were to determine the effectiveness of different forms of self-help materials, compared with no treatment and with other minimal contact strategies; the effectiveness of adjuncts to self help, such as computer-generated feedback, telephone hotlines and pharmacotherapy; and the effectiveness of approaches tailored to the individual compared with non-tailored materials. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register using the terms 'self-help', 'manual*' or 'booklet*'. Date of the most recent search April 2005. SELECTION CRITERIA: We included randomized trials of smoking cessation with follow up of at least six months, where at least one arm tested a self-help intervention. We defined self help as structured programming for smokers trying to quit without intensive contact with a therapist. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the participants, the nature of the self-help materials, the amount of face-to-face contact given to intervention and to control conditions, outcome measures, method of randomization, and completeness of follow up. The main outcome measure was abstinence from smoking after at least six months follow up in people smoking at baseline. We used the most rigorous definition of abstinence in each trial, and biochemically validated rates when available. Where appropriate, we performed meta-analysis using a fixed-effect model. MAIN RESULTS: We identified sixty trials. Thirty-three compared self-help materials to no intervention or tested materials used in addition to advice. In 11 trials in which self help was compared to no intervention there was a pooled effect that just reached statistical significance (N = 13,733; odds ratio [OR] 1.24, 95% confidence interval [CI] 1.07 to 1.45). This analysis excluded two trials with strongly positive outcomes that introduced significant heterogeneity. Four further trials in which the control group received alternative written materials did not show evidence for an effect of the smoking self-help materials. We failed to find evidence of benefit from adding self-help materials to face-to-face advice, or to nicotine replacement therapy. There were seventeen trials using materials tailored for the characteristics of individual smokers, where meta-analysis supported a small benefit of tailored materials (N = 20,414; OR 1.42, 95% CI 1.26 to 1.61). The evidence is strongest for tailored materials compared to no intervention, but also supports tailored materials as more helpful than standard materials. Part of this effect could be due to the additional contact or assessment required to obtain individual data. A small number of other trials failed to detect benefits from using additional materials or targeted materials, or to find differences between different self-help programmes. AUTHORS' CONCLUSIONS: Standard self-help materials may increase quit rates compared to no intervention, but the effect is likely to be small. We failed to find evidence that they have an additional benefit when used alongside other interventions such as advice from a healthcare professional, or nicotine replacement therapy. There is evidence that materials that are tailored for individual smokers are effective, and are more effective than untailored materials, although the absolute size of effect is still small.

Group behaviour therapy programmes for smoking cessation.

BACKGROUND: Group therapy offers individuals the opportunity to learn behavioural techniques for smoking cessation, and to provide each other with mutual support. OBJECTIVES: We aimed to determine the effects of smoking cessation programmes delivered in a group format compared to self-help materials, or to no intervention; to compare the effectiveness of group therapy and individual counselling; and to determine the effect of adding group therapy to advice from a health professional or to nicotine replacement. We also aimed to determine whether specific components increased the effectiveness of group therapy. We aimed to determine the rate at which offers of group therapy are taken up. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group Trials Register, with additional searches of MEDLINE and PsycINFO, including the terms behavior therapy, cognitive therapy, psychotherapy or group therapy, in January 2005. SELECTION CRITERIA: We considered randomized trials that compared group therapy with self help, individual counselling, another intervention or no intervention (including usual care or a waiting list control). We also considered trials that compared more than one group programme. We included those trials with a minimum of two group meetings, and follow up of smoking status at least six months after the start of the programme. We excluded trials in which group therapy was provided to both active therapy and placebo arms of trials of pharmacotherapies, unless they had a factorial design. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the participants, the interventions provided to the groups and the controls, including programme length, intensity and main components, the outcome measures, method of randomization, and completeness of follow up. The main outcome measure was abstinence from smoking after at least six months follow up in patients smoking at baseline. We used the most rigorous definition of abstinence in each trial, and biochemically validated rates where available. Subjects lost to follow up were analyzed as continuing smokers. Where possible, we performed meta-analysis using a fixed-effects (Mantel-Haenszel) model. MAIN RESULTS: A total of 55 trials met inclusion criteria for one or more of the comparisons in the review. Sixteen studies compared a group programme with a self-help programme. There was an increase in cessation with the use of a group programme (N = 4395, odds ratio (OR) 2.04, 95% confidence interval (CI) 1.60 to 2.60). Group programmes were more effective than no intervention controls (seven trials, N = 815, OR 2.17, 95% CI 1.37 to 3.45). There was no evidence that group therapy was more effective than a similar intensity of individual counselling. There was limited evidence that the addition of group therapy to other forms of treatment, such as advice from a health professional or nicotine replacement, produced extra benefit. There was variation in the extent to which those offered group therapy accepted the treatment. There was limited evidence that programmes which included components for increasing cognitive and behavioural skills and avoiding relapse were more effective than same length or shorter programmes without these components. This analysis was sensitive to the way in which one study with multiple conditions was included. We did not find an effect of manipulating the social interactions between participants in a group programme on outcome. AUTHORS' CONCLUSIONS: Group therapy is better for helping people stop smoking than self help, and other less intensive interventions. There is not enough evidence to evaluate whether groups are more effective, or cost-effective, than intensive individual counselling. There is not enough evidence to support the use of particular psychological components in a programme beyond the support and skills training normally included.

Individual behavioural counselling for smoking cessation.

BACKGROUND: Individual counselling from a smoking cessation specialist may help smokers to make a successful attempt to stop smoking. OBJECTIVES: The objective of the review is to determine the effects of individual counselling. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group Specialized Register for studies with counsel* in any field. Date of the most recent search: December 2004. SELECTION CRITERIA: Randomized or quasi-randomized trials with at least one treatment arm consisting of face-to-face individual counselling from a healthcare worker not involved in routine clinical care. The outcome was smoking cessation at follow up at least six months after the start of counselling. DATA COLLECTION AND ANALYSIS: Both authors extracted data. The intervention and population, method of randomization and completeness of follow up were recorded. MAIN RESULTS: We identified 21 trials with over 7000 participants. Eighteen trials compared individual counselling to a minimal behavioural intervention, four compared different types or intensities of counselling. Individual counselling was more effective than control. The odds ratio for successful smoking cessation was 1.56 (95% confidence interval 1.32 to 1.84). In a subgroup of three trials where all participants received nicotine replacement therapy the point estimate of effect was smaller and did not reach significance (odds ratio 1.34, 95% confidence interval 0.98 to 1.83). We failed to detect a greater effect of intensive counselling compared to brief counselling (odds ratio 0.98, 95% confidence interval 0.61 to 1.56). AUTHORS' CONCLUSIONS: Smoking cessation counselling can assist smokers to quit.

Interventions for preventing tobacco sales to minors.

BACKGROUND: Laws restricting sales of tobacco products to minors exist in many countries, but young people may still purchase cigarettes easily. OBJECTIVES: The review assesses the effects of interventions to reduce underage access to tobacco by deterring shopkeepers from making illegal sales. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction group trials register, MEDLINE and EMBASE. Date of the most recent searches: September 2004. SELECTION CRITERIA: We included controlled trials and uncontrolled studies with pre- and post intervention assessment of interventions to change retailers' behaviour. The outcomes were changes in retailer compliance with legislation (assessed by test purchasing), changes in young people's smoking behaviour, and perceived ease of access to tobacco products. DATA COLLECTION AND ANALYSIS: One reviewer prescreened studies for relevance, and both reviewers independently assessed the studies for inclusion. One reviewer extracted data from included studies and the second checked them. Study designs and types of intervention were heterogeneous so results were synthesized narratively, with greater weight given to controlled studies. MAIN RESULTS: We identified 34 studies of which 14 had data from a control group for at least one outcome. Giving retailers information was less effective in reducing illegal sales than active enforcement or multicomponent educational strategies, or both. No strategy achieved complete, sustained compliance. In three controlled trials, there was little effect of intervention on youth perceptions of access or prevalence of smoking. AUTHORS' CONCLUSIONS: Interventions with retailers can lead to large decreases in the number of outlets selling tobacco to youths. However, few of the communities studied in this review achieved sustained levels of high compliance. This may explain why there is limited evidence for an effect of intervention on youth perception of ease of access to tobacco, and on smoking behaviour.

Relapse prevention interventions for smoking cessation.

BACKGROUND: Several treatments can help smokers make a successful quit attempt, but many initially successful quitters relapse over time. There are interventions designed to help prevent relapse. OBJECTIVES: To assess whether specific interventions for relapse prevention reduce the proportion of recent quitters who return to smoking. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction group trials register in September 2004 for studies mentioning relapse prevention or maintenance in title, abstracts or keywords. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of relapse prevention interventions with a minimum follow up of six months. We included smokers who quit on their own, or were undergoing enforced abstinence, or who were participating in treatment programmes. We included trials that compared relapse prevention interventions to a no intervention control, or that compared a cessation programme with additional relapse prevention components to a cessation programme alone. DATA COLLECTION AND ANALYSIS: Studies were screened and data extracted by one author and checked by a second. Disagreements were resolved by discussion or referral to a third author. MAIN RESULTS: Forty studies met inclusion criteria, but were heterogeneous in terms of populations and interventions. We considered studies that randomized abstainers separately from studies that randomized participants prior to their quit date. We detected no benefit of brief and 'skills-based' relapse prevention interventions for women who had quit smoking due to pregnancy, or for smokers undergoing a period of enforced abstinence. We also failed to detect significant effects in trials in other smokers who had quit on their own or with a formal programme. Amongst trials recruiting smokers and evaluating the effect of additional relapse prevention components we also found no evidence of benefit in any subgroup. We did not find that providing training in skills thought to be needed for relapse avoidance reduced relapse, but most studies did not use experimental designs best suited to the task, and had limited power to detect expected small differences between interventions. AUTHORS' CONCLUSIONS: At the moment there is insufficient evidence to support the use of any specific intervention for helping smokers who have successfully quit for a short time to avoid relapse. The verdict is strongest for interventions focusing on identifying and resolving tempting situations, as most studies were concerned with these. There is very little research available regarding other approaches. Until more evidence becomes available it may be more efficient to focus resources on supporting the initial cessation attempt rather than on additional relapse prevention efforts.