Final Protocol and Statistical Analysis Plan for the SNAP Trial - a randomised, double-blind, placebo-controlled trial of nicotine replacement therapy in pregnancy

This NIHR HTA-funded smoking, nicotine and pregnancy (SNAP) trial investigated whether or not nicotine replacement therapy (NRT) is effective, cost-effective and safe when used for smoking cessation by pregnant women. We randomised 1050 women who were between 12 and 24 weeks pregnant as they attended hospital for ante-natal ultrasound scans. Women received either nicotine or placebo transdermal patches with behavioural support. The primary outcome measure was biochemically-validated, self-reported, prolonged and total abstinence from smoking between a quit date (defined before randomisation and set within 2 weeks of this) and delivery. At 6 months after childbirth self-reported maternal smoking status was ascertained and 2 years after childbirth, self-reported maternal smoking status and the behaviour, cognitive development and respiratory symptoms of children born in the trial were compared in both groups. This repository contains the final approved version of the protocol plus the statistical analysis plan (SAP) for both outcomes at delivery and following the 2 year follow up period after birth

Protocol for the Smoking, Nicotine and Pregnancy (SNAP) trial: double-blind, placebo-randomised, controlled trial of nicotine replacement therapy in pregnancy

Background: Smoking in pregnancy remains a public health challenge. Nicotine replacement therapy (NRT) is effective for smoking cessation in non-pregnant people, but because women metabolise nicotine and cotinine much faster in pregnancy, it is unclear whether this will be effective for smoking cessation in pregnancy. The NHS Health Technology Assessment Programme (HTA)-funded smoking, nicotine and pregnancy ( SNAP) trial will investigate whether or not nicotine replacement therapy ( NRT) is effective, cost-effective and safe when used for smoking cessation by pregnant women. Methods/Design: Over two years, in 5 trial centres, 1050 pregnant women who are between 12 and 24 weeks pregnant will be randomised as they attend hospital for ante-natal ultrasound scans. Women will receive either nicotine or placebo transdermal patches with behavioural support. The primary outcome measure is biochemically-validated, self-reported, prolonged and total abstinence from smoking between a quit date ( defined before randomisation and set within two weeks of this) and delivery. At six months after childbirth self-reported maternal smoking status will be ascertained and two years after childbirth, self-reported maternal smoking status and the behaviour, cognitive development and respiratory symptoms of children born in the trial will be compared in both groups. Discussion: This trial is designed to ascertain whether or not standard doses of NRT ( as transdermal patches) are effective and safe when used for smoking cessation during pregnancy

Piscine UDP-glucuronosyltransferase 1B

Glucuronidation is an important detoxification pathway for organic pollutants in fish. We report here the isolation and characterisation of UDP-glucuronosyltransferases (UGT) genes from the closely related marine flatfish, plaice (Pleuronectes platessa) and flounder (Platichthys flesus). The deduced amino acid sequences share greater similarity with mammalian UGT1 family genes than UGT2 genes (44-47% and 39-40% amino acid identity respectively) and have been designated UGT1B. Both plaice and flounder UGT1B mRNAs are most highly expressed in liver, but are also expressed in intestine, gill, kidney and adipose tissue to a greater extent than muscle, heart or brain. Plaice UGT1B mRNA was undetectable in gametes or fertilised eggs and there was a large increase in expression between gastrulation and myotome formation after which levels declined some 5-10 fold. Flounder UGT1B mRNA was increased in liver after intraperitoneal injection of Arochlor 1254 or lindane, but not after perflourooctanoic acid or 3-methylcholanthrene. In isolated flounder hepatocytes UGT1B mRNA was increased by benzo(a)pyrene but not by ethynylestradiol. Expression of a cDNA for plaice UGT1B in cos7 cells resulted in higher 1-naphthol conjugation in cell homogenates compared to steroid conjugation, whilst bilirubin and bile acid conjugation undetectable. This indicates that the plaice gene codes for the phenol-conjugating UGT previously purified in our laboratory from this species and that it is likely to play a major role in the detoxification of polyaromatic hydrocarbons in flatfish. Its role in development is unknown. UGT1B genes are also present in pufferfish (Tetraodon nigroviridis) and zebrafish (Danio rerio) genomes, but that they differ in their genic organisation. Pufferfish possess multiple (repeated) complete UGT1 genes and Southern blots indicate that the homologous plaice UGT1B gene may also be organised in this way. In contrast, zebrafish appear to have two UGT1 loci whose sequences and intron/exon structures are closely related to that of plaice, however, the organisation of these genes is similar to the mammalian UGT1 family since each has multiple repeated exon 1’s which are alternatively spliced to a common set of exons encoding the aglycone binding domain. Taken together with evidence from phylogenetic comparison of fish sequences with UGT1 and UGT2 families in mammals, we suggest these homologous fish UGTs should all be included within the vertebrate UGT1 family and designated as UGT1B

Final Protocol and Statistical Analysis Plan for the SNAP Trial - a randomised, double-blind, placebo-controlled trial of nicotine replacement therapy in pregnancy

This NIHR HTA-funded smoking, nicotine and pregnancy (SNAP) trial investigated whether or not nicotine replacement therapy (NRT) is effective, cost-effective and safe when used for smoking cessation by pregnant women. We randomised 1050 women who were between 12 and 24 weeks pregnant as they attended hospital for ante-natal ultrasound scans. Women received either nicotine or placebo transdermal patches with behavioural support. The primary outcome measure was biochemically-validated, self-reported, prolonged and total abstinence from smoking between a quit date (defined before randomisation and set within 2 weeks of this) and delivery. At 6 months after childbirth self-reported maternal smoking status was ascertained and 2 years after childbirth, self-reported maternal smoking status and the behaviour, cognitive development and respiratory symptoms of children born in the trial were compared in both groups. This repository contains the final approved version of the protocol plus the statistical analysis plan (SAP) for both outcomes at delivery and following the 2 year follow up period after birth

A GPU-accelerated immersive audio-visual framework for interaction with molecular dynamics using consumer depth sensors

© the Partner Organisations 2014. With advances in computational power, the rapidly growing role of computational/simulation methodologies in the physical sciences, and the development of new human-computer interaction technologies, the field of interactive molecular dynamics seems destined to expand. In this paper, we describe and benchmark the software algorithms and hardware setup for carrying out interactive molecular dynamics utilizing an array of consumer depth sensors. The system works by interpreting the human form as an energy landscape, and superimposing this landscape on a molecular dynamics simulation to chaperone the motion of the simulated atoms, affecting both graphics and sonified simulation data. GPU acceleration has been key to achieving our target of 60 frames per second (FPS), giving an extremely fluid interactive experience. GPU acceleration has also allowed us to scale the system for use in immersive 360° spaces with an array of up to ten depth sensors, allowing several users to simultaneously chaperone the dynamics. The flexibility of our platform for carrying out molecular dynamics simulations has been considerably enhanced by wrappers that facilitate fast communication with a portable selection of GPU-accelerated molecular force evaluation routines. In this paper, we describe a 360°atmospheric molecular dynamics simulation we have run in a chemistry/physics education context. We also describe initial tests in which users have been able to chaperone the dynamics of 10-alanine peptide embedded in an explicit water solvent. Using this system, both expert and novice users have been able to accelerate peptide rare event dynamics by 3-4 orders of magnitude. This journal i

The association between treatment adherence to nicotine patches and smoking cessation in pregnancy: a secondary analysis of a randomised controlled trial

IntroductionIn non-pregnant ‘quitters’, adherence to nicotine replacement therapy (NRT) increases smoking cessation. We investigated relationships between adherence to placebo or NRT patches and cessation in pregnancy, including an assessment of reverse causation and whether any adherence: cessation relationship is moderated when using nicotine or placebo patches. MethodsUsing data from 1050 pregnant trial participants, regression models investigated associations between maternal characteristics, adherence and smoking cessation. ResultsAdherence during the first month was associated with lower baseline cotinine concentrations (beta -0.08, 95%CI -0.15 to -0.01) and randomisation to NRT (beta 2.59, 95%CI 1.50 to 3.68). Adherence during both treatment months was associated with being randomised to NRT (beta 0.51, 95%CI 0.29 to 0.72) and inversely associated with higher nicotine dependence. Adherence with either NRT or placebo was associated with cessation at one month (OR 1.11, 95%CI 1.08 to 1.13) and delivery (OR 1.06, 95%CI 1.03 to 1.09), but no such association was observed in the subgroup where reverse causation was not possible. Amongst all women, greater adherence to nicotine patches was associated with increased cessation (OR 2.47, 95%CI 1.32 to 4.63) but greater adherence to placebo was not (OR 0.98, 95%CI: 0.44 to 2.18). ConclusionWomen who were more adherent to NRT were more likely to achieve abstinence; more nicotine dependent women probably showed lower adherence to NRT because they relapsed to smoking more quickly. The interaction between nicotine-containing patches and adherence for cessation suggests that the association between adherence with nicotine patches and cessation may be partly causal

Revisiting the Latency of Uridine Diphosphate-Glucuronosyltransferases (UGTs)—How Does the Endoplasmic Reticulum Membrane Influence Their Function?

Uridine diphosphate-glucuronosyltransferases (UGTs) are phase 2 conjugation enzymes mainly located in the endoplasmic reticulum (ER) of the liver and many other tissues, and can be recovered in artificial ER membrane preparations (microsomes). They catalyze glucuronidation reactions in various aglycone substrates, contributing significantly to the body’s chemical defense mechanism. There has been controversy over the last 50 years in the UGT field with respect to the explanation for the phenomenon of latency: full UGT activity revealed by chemical or physical disruption of the microsomal membrane. Because latency can lead to inaccurate measurements of UGT activity in vitro, and subsequent underprediction of drug clearance in vivo, it is important to understand the mechanisms behind this phenomenon. Three major hypotheses have been advanced to explain UGT latency: compartmentation, conformation, and adenine nucleotide inhibition. In this review, we discuss the evidence behind each hypothesis in depth, and suggest some additional studies that may reveal more information on this intriguing phenomenon.Pharmaceutical Sciences, Faculty ofReviewedFacult