Severe primary immune thrombocytopenia in Pregnancy UK Obstetric Surveillance System (UKOSS) Study

This is the largest reported population cohort of severe ITP in pregnancy. Current incidence of severe ITP in the UK is approximately 0.1/1000 pregnancies. With current treatment strategies the incidence of serious maternal and neonatal outcomes is extremely low

Identification of the additional mitochondrial liabilities of 2-hydroxyflutamide when compared to its parent compound, flutamide in HepG2 cells

The androgen receptor antagonist, flutamide, is strongly associated with idiosyncratic drug-induced liver injury (DILI). Following administration, flutamide undergoes extensive first-pass metabolism to its primary metabolite, 2-hydroxyflutamide. Flutamide is a known mitochondrial toxicant; however there has been limited investigation into the potential mitochondrial toxicity of 2-hydroxyflutamide and its contribution to flutamide-induced liver injury. In this study we have used the acute glucose or galactose-conditioning of HepG2 cells to compare the mitochondrial toxicity of flutamide, 2-hydroxyflutamide and the structurally-related, non-hepatotoxic androgen receptor antagonist, bicalutamide. Compound-induced changes in mitochondrial oxygen consumption rate were assessed using Seahorse technology. Permeabilization of cells and delivery of specific substrates and inhibitors of the various respiratory complexes provided more detailed information on the origin of mitochondrial perturbations. These analyses were supported by assessment of downstream impacts including changes in cellular NAD+/NADH ratio. Bicalutamide was not found to be a mitochondrial toxicant, yet flutamide and 2-hydroxyflutamide significantly reduced basal and maximal respiration. Both flutamide and 2-hydroxyflutamide significantly reduced respiratory complex I-linked respiration, though 2-hydroxyflutamide also significantly decreased complex II and V-linked respiration; liabilities not demonstrated by the parent compound. This study has identified for the first time, the additional mitochondrial liabilities of the major metabolite, 2-hydroxyflutamide compared with its parent drug, flutamide. Given the rapid production of this metabolite upon administration of flutamide, but not bicalutamide, we propose that the additional mitochondrial toxicity of 2-hydroxyflutamide may fundamentally contribute to the idiosyncratic DILI seen in flutamide-treated, but not bicalutamide-treated patients

Treatment for primary postpartum haemorrhage.

BACKGROUND: Primary postpartum haemorrhage (PPH) is one of the top five causes of maternal mortality in both developed and developing countries. OBJECTIVES: To assess the effectiveness and safety of any intervention used for the treatment of primary PPH. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2013). SELECTION CRITERIA: Randomised controlled trials comparing any interventions for the treatment of primary PPH. DATA COLLECTION AND ANALYSIS: We assessed studies for eligibility and quality and extracted data independently. We contacted authors of the included studies to request more information. MAIN RESULTS: Ten randomised clinical trials (RCTs) with a total of 4052 participants fulfilled our inclusion criteria and were included in this review.Four RCTs (1881 participants) compared misoprostol with placebo given in addition to conventional uterotonics. Adjunctive use of misoprostol (in the dose of 600 to 1000 mcg) with simultaneous administration of additional uterotonics did not provide additional benefit for our primary outcomes including maternal mortality (risk ratio (RR) 6.16, 95% confidence interval (CI) 0.75 to 50.85), serious maternal morbidity (RR 0.34, 95% CI 0.01 to 8.31), admission to intensive care (RR 0.79, 95% CI 0.30 to 2.11) or hysterectomy (RR 0.93, 95% CI 0.16 to 5.41).  Two RCTs (1787 participants) compared 800 mcg sublingual misoprostol versus oxytocin infusion as primary PPH treatment; one trial included women who had received prophylactic uterotonics, and the other did not. Primary outcomes did not differ between the two groups, although women given sublingual misoprostol were more likely to have additional blood loss of at least 1000 mL (RR 2.65, 95% CI 1.04 to 6.75). Misoprostol was associated with a significant increase in vomiting and shivering.Two trials attempted to test the effectiveness of estrogen and tranexamic acid, respectively, but were too small for any meaningful comparisons of pre-specified outcomes.One study compared lower segment compression but was too small to assess impact on primary outcomes.We did not identify any trials evaluating surgical techniques or radiological interventions for women with primary PPH unresponsive to uterotonics and/or haemostatics. AUTHORS' CONCLUSIONS: Clinical trials included in the current review were not adequately powered to assess impact on the primary outcome measures. Compared with misoprostol, oxytocin infusion is more effective and causes fewer side effects when used as first-line therapy for the treatment of primary PPH. When used after prophylactic uterotonics, misoprostol and oxytocin infusion worked similarly. The review suggests that among women who received oxytocin for the treatment of primary PPH, adjunctive use of misoprostol confers no added benefit.The role of tranexamic acid and compression methods requires further evaluation. Furthermore, future studies should focus on the best way to treat women who fail to respond to uterotonic therapy

Phenotype standardization for statin-induced myotoxicity

Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.</p

Screening and Management of the Small for Gestational Age Fetus in the UK: A Survey of Practice

Background Antenatal detection of the small for gestational (SGA) fetus has become an important indicator of quality of antenatal care in the UK. This has been driven by a desire to reduce stillbirth in this at risk group. Methods We conducted a postal survey of 187 NHS consultant units within the UK to determine what the current practice for the detection and subsequent management of the suspected SGA fetus was following the guidance from the Royal College of Obstetricians and Gynaecologists (RCOG) in 2013. Results The survey was performed in 3 rounds between 2016 and 2017 with a response rate of 65%. 85% of units assessed risk factors for SGA at booking. 81% of units used a customized symphysis fundal height (SFH) chart to screen for SGA with 95% of them using a cut off of <10th centile to refer for ultrasound assessment. When ultrasound is used to detect SGA, 80% of units used estimated fetal weight (EFW), with 89% of these using a cut off of <10th centile to diagnose SGA. Umbilical artery (UA) Doppler monitoring was undertaken in 97% of management and 94% delivered after 37 weeks. Only 24% of units had a dedicated fetal growth clinic, whilst 48% of units were able to offer computerised CTG to monitor the SGA fetus. Conclusions Overall there is consistency in the screening methods for SGA (customised SFH charts) and identification of suspected SGA (SFH <10th centile, EFW <10th centile, UA monitoring and induction of labour at term). There was a low uptake of computerized CTG to monitor SGA babies and a low number of specialised fetal growth clinics

Mortality in the UK STRIDER trial of sildenafil therapy for the treatment of severe early-onset fetal growth restriction.

Severe early-onset fetal growth restriction (FGR) is an untreatable condition associated with significant mortality and morbidity for the fetus and neonate. There has been growing interest in novel therapies such as nitic oxide donors/promotors to improve placental function and outcomes for these high-risk pregnancies. The recently published STRIDER UK trial was designed to test the effectiveness of sildenafil (25mg three times a day) versus placebo at prolonging gestation in severe early-onset

Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genomewide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P = 4.7 x 10(-14), odds ratio (OR) = 0.19, 95% confidence interval (CI) = 0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P = 6.4 x 10(-10), OR = 3.3, 95% CI = 2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG