伐伦克林对戒除低烟量烟草的帮助随机双盲安慰剂对照研

11 December 2010 Volume 341, Issue 7785一.Research1. Stopping smokeless tobacco with varenicline: randomised double blind placebo controlled trial伐伦克林对戒除低烟量烟草的帮助：随机双盲安慰剂对照研究2. Risk of recurrence after a first seizure and implications for driving: further analysis of the Multicentre study of early Epilepsy and Single Seizures首次癫痫发作后再发风险及其对驾驶的影响：早期癫痫和单次发作的多中心研究的进一步分析3. Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study卡马西平的宫内暴露和先天畸形：系统回顾和病例对照研究4. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial在4.5-9个月时接种标准麻疹疫苗对儿童死亡率的非特异性效果：随机对照试验二. Clinical ReviewInvestigating and managing chronic scrotal pain调查和处理慢性阴囊疼痛三. Practice1. Easily Missed?: Infective endocarditis容易忽视：？感染性心内膜炎2. Lesson of the Week: Acute liver failure after administration of paracetamol at the maximum recommended daily dose in adults本周课程：成人扑热息痛每日最大推荐用量使用时的急性肝衰竭四. AnalysisHow do patients use information on health providers?病人如何利用关于健康提供者的信息What do patients want of performance information?病人想要什么样的表现信息？五. ObservationsLobby Watch: The Institute for Fiscal StudiesLobby Watch：财政研究学院六. FeatureResearch Ethics: The rules of retraction研究伦理学：撤销的法则Briefing: The Bribery Act: what it means for you主要信息：受贿艺术：对你意味着什么呢？Conflict and Rape: After war, what next?冲突和强奸：战后，接下来是什么呢？Commentary: what interventions work for victims of conflict related rape?评论：什么样的噶怒措施对冲突中的强奸受害人有用呢？七. News1. Low dose aspirin reduces risk of dying from a range of cancers小剂量阿司匹林可降低多种癌症死亡的风险2. Negotiators try to persuade Japan, Canada, and Russia to soften opposition to climate treaty谈判专家努力说服日本，加拿大和俄罗斯软化对气候变化协议的反对3. Consultants should be available to admit patients to hospital 12 hours a day顾问应该对住院病人提供每天12小时可能的服务4. Senior Tory minister is asked to scrutinise Lansley’s plans for NHS保守党资深部长要求审议国民保健服务Lansley计划5. Cuts in social care could put pressure on hospitals to care for dying patients在社会关怀的削减可能把照顾临终病人的压力转嫁给医院6. French doctors demand to know why drug stayed on the market for so long法国医生要求知道药物在市场上停留如此久的原因7. European Medicines Agency widens access to its documents欧洲药品管理局扩大获取其文件的范围8. New centre opens up clinical trials to more cancer patients新中心对更多的癌症患者开放临床试验9. Tight regulation of French drug reps mean French doctors get more balanced information than doctors in the US与法国医药代表的紧密关系意味着法国医生获得比美国医生更多的平衡信息10. Independent drug review group in Canada is squeezed out加拿大独立审查组药物小组财政紧张八. Research摘要1. Stopping smokeless tobacco with varenicline: randomised double blind placebo controlled trial伐伦克林对戒除低烟量烟草的帮助：随机双盲安慰剂对照研究Objective To assess the efficacy and safety of varenicline (a licensed cigarette smoking cessation aid) in helping users of smokeless tobacco to quit.Design Double blind, placebo controlled, parallel group, multicentre, randomised controlled trial.Setting Medical clinics (mostly primary care) in Norway and Sweden.Participants Men and women aged ≥18 who used smokeless tobacco at least eight times a day, with no abstinence period over three months within one year before screening, who wanted to quit all tobacco use. Participants were excluded if they used any other form of tobacco (except smokeless tobacco) or medication to stop smoking within three months of screening or had any pre-existing medical or psychiatric condition.Interventions Varenicline 1 mg twice daily (titrated during the first week) or placebo for 12 weeks, with 14 weeks’ follow-up after treatment.Main outcome measures The primary end point was the four week continuous abstinence rate at the end of treatment (weeks 9-12) confirmed with cotinine concentration. A secondary end point was continuous abstinence rate for weeks 9-26. Safety and tolerability were also evaluated.Results 431 participants (213 varenicline; 218 placebo) were randomised and received at least one dose of study drug. Participants’ demographics and baseline use of smokeless tobacco were similar (89% (189) and 90% (196), respectively, were men; mean age in both groups was 43.9; participants used smokeless tobacco products about 15 times a day, and about 80% first used smokeless tobacco within 30 minutes after awakening). Continuous abstinence rate at week 9-12 was higher in the varenicline group than the placebo group (59% (125) v 39% (85);relative risk 1.60, 95% confidence interval 1.32 to 1.87, P<0.001; risk difference 20%; number needed to treat 5). The advantage of varenicline over placebo persisted through 14 weeks of follow-up (continuous abstinence rate at week 9-26 was 45% (95) v 34% (73); relative risk 1.42, 1.08 to 1.79, P=0.012; risk difference 11%; number needed to treat 9). The most common adverse events in the varenicline group compared with the placebo group were nausea (35% (74) v 6% (14)), fatigue (10% (22) v 7% (15)), headache (10% (22) v 9% (20)), and sleep disorder (10% (22) v 7% (15)). Few adverse events led to discontinuation of treatment (9% (19) and 4% (9), respectively), and serious adverse events occurred in two (1%) and three (1%) participants, respectively.Conclusion Varenicline can help people to give up smokeless tobacco and has an acceptable safety profile. The response rate in the placebo group in this study was high, suggesting a population less resistant to treatment than smokers.2. Risk of recurrence after a first seizure and implications for driving: further analysis of the Multicentre study of early Epilepsy and Single Seizures首次癫痫发作后再发风险及其对驾驶的影响：早期癫痫和单次发作的多中心研究的进一步分析Objective To determine for how long after a first unprovoked seizure a driver must be seizure-free before the risk of recurrence in the next 12 months falls below 20%, enabling them to regain their driving licence.Design Randomised controlled trial: Multicentre study of early Epilepsy and Single Seizures (MESS).Setting UK hospital outpatient clinics from 1 January 1993 to 31 December 2000.Participants People entered MESS if they had had one or more unprovoked seizures and both the participant and the clinician were uncertain about the need to start antiepileptic drug treatment. The subset of people used for this analysis comprised participants aged at least 16 years with a single unprovoked seizure.Main outcome measure Risk of seizure recurrence in the 12 months after a seizure-free period of 6, 12, 18, or 24 months from the date of the first (index) seizure. Regression modelling was used to investigate how antiepileptic treatment and several clinical factors influence the risk of seizure recurrence.Results At six months after the index seizure the risk of recurrence in the next 12 months for those who start antiepileptic drugs was significantly below 20% (unadjusted risk 14%, 95% confidence interval 10% to 18%). For patients who did not start treatment the risk estimate was less than 20% but the upper limit of the confidence interval was greater than 20% (18%, 13% to 23%). Multivariable analyses identified subgroups with a significantly greater than 20% risk of seizure recurrence in the 12 months after a six month seizure-free period, such as those with a remote symptomatic seizure with abnormal electroencephalogram results.Conclusion After a single unprovoked seizure this reanalysis of MESS provides estimates of seizure recurrence risks that will inform policy and guidance about regaining an ordinary driving licence. Further guidance is needed as to how such data should be utilised; in particular, whether a population approach should be taken with a focuson the unadjusted results or whether attempts should be made to individualise risk. Guidance is also required as to whether the focus should be on risk estimates only or on the confidence interval as well. If the focus is on the estimate only our unadjusted estimates suggest that treated and untreated patients are eligible to drive after being seizure-free for six months. If the focus is also on confidence intervals, direction is needed as to whether a conservative or liberal approach should be taken.3. Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study卡马西平的宫内暴露和先天畸形：系统回顾和病例对照研究Objective To identify specific major congenital malformations associated with use of carbamazepine in the first trimester of pregnancy.Design A review of all published cohort studies to identify key indications and a population based case-control study to test these indications.Setting Review of PubMed, Web of Science, and Embase for papers about carbamazepine exposure in the first trimester of pregnancy and specific malformations, and the EUROCAT Antiepileptic Study Database, including data from 19 European population based congenital anomaly registries, 1995-2005.Participants The literature review covered eight cohort studies of 2680 pregnancies with carbamazepine monotherapy exposure, and the EUROCAT dataset included 98 075 registrations of malformations covering over 3.8 million births.Main outcome measures Overall prevalence for a major congenital malformation after exposure to carbamazepine monotherapy in the first trimester. Odds ratios for malformations with exposure to carbamazepine among cases (five types of malformation identified in the literature review) compared with two groups of controls: other non-chromosomal registrations of malformations and chromosomal syndromes.Results The literature review yielded an overall prevalence for a major congenital malformation of 3.3% (95% confidence interval 2.7 to 4.2) after exposure to carbamazepine monotherapy in the first trimester. In 131 registrations of malformations, the fetus had been exposed to carbamazepine monotherapy. Spina bifida was the only specific major congenital malformation significantly associated with exposure to carbamazepine monotherapy (odds ratio 2.6 (95% confidence interval 1.2 to 5.3) compared with no antiepileptic drug), but the risk was smaller for carbamazepine than for valproic acid (0.2, 0.1 to 0.6). There was no evidence for an association with total anomalous pulmonary venous return (no cases with carbamazepine exposure), cleft lip (with or without palate) (0.2, 0.0 to 1.3), diaphragmatic hernia (0.9, 0.1 to 6.6), or hypospadias (0.7, 0.3 to 1.6) compared with no exposure to antiepileptic drugs. Further exploratory analysis suggested a higher risk of single ventricle and atrioventricular septal defect.Conclusion Carbamazepine teratogenicity is relatively specific to spina bifida, though the risk is less than with valproic acid. Despite the large dataset, there was not enough power to detect moderate risks for some rare major congenital malformations.4. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial在4.5-9个月时接种标准麻疹疫苗对儿童死亡率的非特异性效果：随机对照试验Objective To examine in a randomised trial whether a 25% difference in mortality exists between 4.5 months and 3 years of age for children given two standard doses of Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age (current policy).Design Randomised controlled trial.Setting The Bandim Health Project, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area.Participants 6648 children aged 4.5 months of age who had received three doses of diphtheria-tetanus-pertussis vaccine at least four weeks before enrolment. A large proportion of the children (80%) had previously taken part in randomised trials of neonatal vitamin A supplementation.Intervention Children were randomised to receive Edmonston-Zagreb measles vaccine at 4.5 and 9 months of age (group A), no vaccine at 4.5 months and Edmonston-Zagreb measles vaccine at 9 months of age (group B), or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months of age (group C).Main outcome measure Mortality rate ratio between 4.5 and 36 months of age for group A compared with groups B and C. Secondary outcomes tested the hypothesis that the beneficial effect was stronger in the 4.5 to 9 months age group, in girls, and in the dry season, but the study was not powered to test whether effects differed significantly between subgroups.Results In the intention to treat analysis of mortality between 4.5 and 36 months of age the mortality rate ratio of children who received two doses of Edmonston-Zagreb vaccine at 4.5 and 9 months of age compared with those who received a single dose of Edmonston-Zagreb vaccine or Schwarz vaccine at 9 months of age was 0.78 (95% confidence interval 0.59 to 1.05). In the analyses of secondary outcomes, the intention to treat mortality rate ratio was 0.67 (0.38 to 1.19) between 4.5 and 9 months and 0.83 (0.83 to 1.16) between 9 and 36 months of age. The effect on mortality between 4.5 and 36 months of age was significant for girls (intention to treat mortality rate ratio 0.64 (0.42 to 0.98)), although this was not significantly different from the effect in boys (0.95 (0.64 to 1.42)) (interaction test, P=0.18). The effect did not differ between the dry season and the rainy season. As neonatal vitamin A supplementation is not WHO policy, the analyses were done separately for the 3402 children who did not receive neonatal vitamin A. In these children, the two dose Edmonston-Zagreb measles vaccine schedule was associated with a significantly lower mortality between 4.5 and 36 months of age (intention to treat mortality rateratio 0.59 (0.39 to 0.89)). The effect was again significant for girls but not statistically significant from the effect in boys. When measles cases were censored, the intention to treat mortality rate ratio was 0.65 (0.43 to 0.99).Conclusions Although the overall effect did not reach statistical significance, the results may indicate that a two dose schedule with Edmonston-Zagreb measles vaccine given at 4.5 and 9 months of age has beneficial non-specific effects on children’s survival, partic ularly for girls and for children who have not received neonatal vitamin A. This should be tested in future studies in different locations.。