The SNAP trial: a randomised placebo-controlled trial of nicotine replacement therapy in pregnancy – clinical effectiveness and safety until 2 years after delivery, with economic evaluation

BACKGROUND: Smoking during pregnancy causes many adverse pregnancy and birth outcomes. Nicotine replacement therapy (NRT) is effective for cessation outside pregnancy but efficacy and safety in pregnancy are unknown. We hypothesised that NRT would increase smoking cessation in pregnancy without adversely affecting infants. OBJECTIVES: To compare (1) at delivery, the clinical effectiveness and cost-effectiveness for achieving biochemically validated smoking cessation of NRT patches with placebo patches in pregnancy and (2) in infants at 2 years of age, the effects of maternal NRT patch use with placebo patch use in pregnancy on behaviour, development and disability. DESIGN: Randomised, placebo-controlled, parallel-group trial and economic evaluation with follow-up at 4 weeks after randomisation, delivery and until infants were 2 years old. Randomisation was stratified by centre and a computer-generated sequence was used to allocate participants using a 1 : 1 ratio. Participants, site pharmacies and all study staff were blind to treatment allocation. SETTING: Seven antenatal hospitals in the Midlands and north-west England. PARTICIPANTS: Women between 12 and 24 weeks' gestation who smoked ≥ 10 cigarettes a day before and ≥ 5 during pregnancy, with an exhaled carbon monoxide (CO) reading of ≥ 8 parts per million (p.p.m.). INTERVENTIONS: NRT patches (15 mg per 16 hours) or matched placebo as an 8-week course issued in two equal batches. A second batch was dispensed at 4 weeks to those abstinent from smoking. MAIN OUTCOME MEASURES: PARTICIPANTS: self-reported, prolonged abstinence from smoking between a quit date and childbirth, validated at delivery by CO measurement and/or salivary cotinine (COT) (primary outcome). Infants, at 2 years: absence of impairment, defined as no disability or problems with behaviour and development. Economic: cost per 'quitter'. RESULTS: One thousand and fifty women enrolled (521 NRT, 529 placebo). There were 1010 live singleton births and 12 participants had live twins, while there were 14 fetal deaths and no birth data for 14 participants. Numbers of adverse pregnancy and birth outcomes were similar in trial groups, except for a greater number of caesarean deliveries in the NRT group. Smoking: all participants were included in the intention-to-treat (ITT) analyses; those lost to follow-up (7% for primary outcome) were assumed to be smoking. At 1 month after randomisation, the validated cessation rate was higher in the NRT group {21.3% vs. 11.7%, odds ratio [OR], [95% confidence interval (CI)] for cessation with NRT, 2.05 [1.46 to 2.88]}. At delivery, there was no difference between groups' smoking cessation rates: 9.4% in the NRT and 7.6% in the placebo group [OR (95% CI), 1.26 (0.82 to 1.96)]. Infants: at 2 years, analyses were based on data from 888 out of 1010 (87.9%) singleton infants (including four postnatal infant deaths) [445/503 (88.5%) NRT, 443/507 (87.4%) placebo] and used multiple imputation. In the NRT group, 72.6% (323/445) had no impairment compared with 65.5% (290/443) in placebo (OR 1.40, 95% CI 1.05 to 1.86). The incremental cost-effectiveness ratio for NRT use was £4156 per quitter (£4926 including twins), but there was substantial uncertainty around these estimates. CONCLUSIONS: Nicotine replacement therapy patches had no enduring, significant effect on smoking in pregnancy; however, 2-year-olds born to women who used NRT were more likely to have survived without any developmental impairment. Further studies should investigate the clinical effectiveness and safety of higher doses of NRT. TRIAL REGISTRATION: Current Controlled Trials ISRCTN07249128. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 54. See the NIHR Journals Library programme website for further project information

The London exercise and pregnant smokers (LEAP) trial: A randomised controlled trial of physical activity for smoking cessation in pregnancy with an economic evaluation

Background: Smoking during pregnancy is the main preventable cause of poor birth outcomes. Improved methods are needed to help women to stop smoking during pregnancy. Pregnancy provides a compelling rationale for physical activity (PA) interventions as cessation medication is contraindicated or ineffective, and an effective PA intervention could be highly cost-effective.  Objective: To examine the effectiveness and cost-effectiveness of a PA intervention plus standard behavioural support for smoking cessation relative to behavioural support alone for achieving smoking cessation at the end of pregnancy.  Design: Multicentre, two-group, pragmatic randomised controlled trial and economic evaluation with follow-up at the end of pregnancy and 6 months postnatally. Randomisation was tratified by centre and a computer-generated sequence was used to allocate participants using a 1: 1 ratio. Setting: 13 hospitals offering antenatal care in the UK.  Participants: Women between 10 and 24 weeks’ gestation smoking five or more cigarettes a day before pregnancy and one or more during pregnancy.  Interventions: Participants were randomised to behavioural support for smoking cessation (control) or behavioural support plus a PA intervention consisting of supervised treadmill exercise plus PA consultations. Neither participants nor researchers were blinded to treatment allocation.  Main outcome measures: The primary outcome was self-reported, continuous smoking abstinence between a quit date and end of pregnancy, validated by expired carbon monoxide and/or salivary cotinine. Secondary outcomes were maternal weight, depression, birth outcomes, withdrawal symptoms and urges to smoke. The economic evaluation investigated the costs of the PA intervention compared with the control intervention.  Results: In total, 789 women were randomised (n = 394 PA, n = 395 control). Four were excluded post randomisation (two had been enrolled twice in sequential pregnancies and two were ineligible and randomised erroneously). The intention-to-treat analysis comprised 785 participants (n = 392 PA, n = 393 control). There was no significant difference in the rate of abstinence at the end of pregnancy between the PA group (7.7%) and the control group (6.4%) [odds ratio for PA group abstinence 1.21, 95% confidence interval (CI) 0.70 to 2.10]. For the PA group compared with the control group, there was a 33% (95% CI 14% to 56%), 28% (95% CI 7% to 52%) and 36% (95% CI 12% to 65%) significantly greater increase in self-reported minutes of moderate- and vigorous-intensity PA from baseline to 1 week, 4 weeks and 6 weeks respectively. Accelerometer data showed that there was no significant difference in PA levels between the groups. There were no significant differences between the groups for change in maternal weight, depression, withdrawal symptoms or urges to smoke. Adverse events and birth outcomes were similar between the groups except for there being significantly more caesarean births in the control group than in the PA group (28.7% vs. 21.3%; p < 0.023). The PA intervention was less costly than the control intervention by £35 per participant. This was mainly attributable to increased health-care usage in the control group. However, there was considerable statistical uncertainty around this estimate.  Conclusions: During pregnancy, offering an intervention combining supervised exercise and PA counselling does not add to the effectiveness of behavioural support for smoking cessation. Only 10% of participants had PA levels accessed by accelerometer and it is, therefore, unclear whether or not the lack of an effect on the primary outcome is the result of insufficient increases in PA. Research is needed to identify the smoking populations most suitable for PA interventions and methods for increasing PA adherence.  Trial registration: Current Controlled Trials ISRCTN48600346

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Search for heavy long-lived charged R-hadrons with the ATLAS detector in 3.2 fb(-1) of proton-proton collision data at root s=13 TeV

A search for heavy long-lived charged R-hadrons is reported using a data sample corresponding to 3.2 fb−1 of proton–proton collisions at √s = 13 TeV collected by the ATLAS experiment at the Large Hadron Collider at CERN. The search is based on observables related to large ionisation losses and slow propagation velocities, which are signatures of heavy charged particles travelling significantly slower than the speed of light. No significant deviations from the expected background are observed. Upper limits at 95% confidence level are provided on the production cross section of long-lived R-hadrons in the mass range from 600 GeV to 2000 GeV and gluino, bottom and top squark masses are excluded up to 1580 GeV, 805 GeV and 890 GeV, respectively

Transmission electron microscopy of a transformation toughened white cast iron

Transmission electron microscopy has been used to study the microstructure of an experimental white cast iran, in which a combination of modified alloy composition and unconventional heat treatment has resulted in a fracture toughness of 40 MPa m(-1/2). Microstructural features of the alloy that contribute to the toughness improvement and hence distinguish it from conventional white irons have been investigated. In the as-cast condition the dendrites are fully austenitic and the eutectic consists of M7C3 carbides and martensite. During heat treatment at 1130 degrees C the austenite is partially destabilized by precipitation of chromium-rich M7C3 carbides. This results in a dendritic microconstituent consisting of bulk retained austenite and secondary carbides which are sheathed with martensite. The martensite sheaths, which contain interlath films of retained austenite, are irregular in shape with some laths extending into the bulk retained austenite. Emphasis has been placed on the morphology, distribution, and stability of the retained austenite and its transformation products in the dendrites. The implications of these findings on the transformation toughening mechanism in this alloy are discussed