elderly patients with COPD, even when in a stable clinical condition, may be unable to gain optimum benefit from their inhaler.

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OBJECTIVES:Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19).METHODS:ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case–control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitage's trend test.RESULTS:Cochran–Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10−4 (rs3815676) and for ABCB4 it was 4.6×10−7(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings.CONCLUSIONS:Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility.

Objective To estimate the incidence of multiple repeat caesarean section (MRCS) (five or more) in the UK and to describe the outcomes for women and their babies relative to women having fewer repeat caesarean sections.Design A national population-based prospective cohort study using the UK Obstetric Surveillance System (UKOSS).Setting All UK hospitals with consultant-led maternity units. Methods Prospective cohort and comparison identification through the UKOSS monthly mailing system.Main outcome measures Incidence, maternal and neonatal complications. Relative risk, unadjusted (OR) and adjusted (aOR) odds ratio estimates.Results The estimated UK incidence of MRCS was 1.20 per 10 000 maternities [95% confidence interval (CI), 0.97-1.47]. Women with MRCS had significantly more major obstetric haemorrhages (>1500 ml) (aOR, 18.6; 95% CI, 3.89-88.8), visceral damage (aOR, 17.6; 95% CI, 1.85-167.1) and critical care admissions (aOR, 15.5; 95% CI, 3.16-76.0), than women with lower order repeat caesarean sections. These risks were greatest in the 18% of women with MRCS who also had placenta praevia or accreta. Neonates of mothers having MRCS were significantly more likely to be born prior to 37 weeks of gestation (OR, 6.15; 95% CI, 2.56-15.78) and therefore had higher rates of complications and admissions.Conclusions MRCS is associated with greater maternal and neonatal morbidity than fewer caesarean sections. The associated maternal morbidity is largely secondary to placenta praevia and accreta, whereas higher rates of preterm delivery are most likely a response to antepartum haemorrhage.Keywords Multiple repeat caesarean section, placenta praevia, postpartum haemorrhage.Please cite this paper as: Cook J, Jarvis S, Knight M, Dhanjal M. Multiple repeat caesarean section in the UK: incidence and consequences to mother and child. A national, prospective, cohort study. BJOG 2013;120:85-91.

Technical variant techniques expand the pediatric donor pool and reduce time from listing to transplant, but they are associated with increased morbidity and mortality.

Objective To assess the differences in fetal body compartments between fetuses with normal growth and those with reduced intrauterine growth, during the third trimester, through ultrasonographic determination of subcutaneous tissue thickness (SCTT). Methods

Liver diseases is a growing epidemic worldwide. If unresolved, liver fibrosis develops and can lead to cirrhosis and clinical decompensation. Around 5% of cirrhotic liver diseased patients develop hepatocellular carcinoma (HCC), which in its advanced stages has limited therapeutic options and negative survival outcomes. CEPBA is a master regulator of hepatic function where its expression is known to be suppressed in many forms of liver disease including HCC. Injection of MTL-CEBPA, a small activating RNA oligonucleotide therapy (CEBPA-51) formulated in liposomal nanoparticles (NOV340- SMARTICLES®) upregulates hepatic CEBPA expression. Here we show how MTL-CEBPA therapy promotes disease reversal in rodent models of cirrhosis, fibrosis, hepatosteatosis and significantly reduces tumour burden in cirrhotic HCC. Restoration of liver function markers were observed in a carbon-tetrachloride induced rat model of fibrosis following 2-weeks of MTL-CEBPA therapy. At 14-weeks animals showed reduction in ascites and enhanced survival rates. MTL-CEBPA reversed changes associated with hepatosteatosis in non-alcoholic methionine and cholic deficient diet induced steaotic liver disease. In diethylnitrosamine induced cirrhotic HCC rats, MTL-CEBPA treatment led to a significant reduction in tumour burden. The data included here and the rapid adoption of MTL-CEBPA into a Phase 1 study may lead to new therapeutic oligonucleotides for undruggable diseases.

ObjectiveTo determine maternal, obstetric and neonatal outcomes in a cohort of women with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).DesignRetrospective cohort study.SettingTen specialist centres managing pregnant women with liver disease.PopulationWomen with a diagnosis of PBC and PSC and a pregnancy of ≥20 completed weeks of gestation.MethodsRetrospective case notes review.Main outcome measuresAdverse outcomes were defined as: maternal – development of ascites, variceal bleeding, encephalopathy and jaundice; obstetric events – gestational hypertension, pre‐eclampsia and postpartum haemorrhage; and neonatal – stillbirth, preterm delivery and admission to neonatal unit. The relationship of alanine transferase (ALT) and bile acid levels with gestation at delivery was studied.ResultsThe first recorded pregnancies of 34 women with PSC and 27 women with PBC were analysed. There were 60 live births and one intrapartum stillbirth that did not occur in the context of maternal cholestasis. The overall median gestation of delivery was 38 weeks but the rate of preterm birth was 28% (17/61 deliveries), 76% (13/17) of which were spontaneous. Gestation at birth negatively correlated with maternal serum ALT concentration at booking (P = 0.017) and serum bile acid concentration during pregnancy (P = 0.016). There were no other significant correlations and maternal and neonatal outcomes were good.ConclusionsPregnancy in PBC and PSC is well tolerated, but women should be counselled regarding the increased risk of preterm birth. Measurement of maternal ALT and bile acids may help identify women at risk of preterm delivery.Tweetable abstractPregnancy in women with PBC and PSC is well tolerated; however, rates of preterm birth are high and are related to maternal bile acid levels.