Endometriosis is a common complex inflammatory condition characterised by the presence of endometrium-like tissue outside the uterus, mainly in the pelvic area. It is associated with chronic pelvic pain and infertility, and its pathogenesis remains poorly understood. The disease is typically classified according to the revised American Fertility Society (rAFS) 4-stage surgical assessment system, although stage does not correlate well with symptomatology or prognosis. Previously identified genetic variants mainly are associated with stage III/IV disease, highlighting the need for further phenotype-stratified analysis that requires larger datasets. We conducted a meta-analysis of 15 genome-wide association studies (GWAS) and a replication analysis, including 58,115 cases and 733,480 controls in total, and sub-phenotype analyses of stage I/II, stage III/IV and infertility-associated endometriosis cases. This revealed 27 genetic loci associated with endometriosis at the genome-wide p-value threshold (P<5×10−8), 13 of which are novel and an additional 8 novel genes identified from gene-based association analyses. Of the 27 loci, 21 (78%) had greater effect sizes in stage III/IV disease compared to stage I/II, 1 (4%) had greater effect size in stage I/II compared to stage III/IV and 17 (63%) had greater effect sizes when restricted to infertility-associated endometriosis cases compared to overall endometriosis. These results suggest that specific variants may confer risk for different sub-types of endometriosis through distinct pathways. Analyses of genetic variants underlying different pain symptoms reported in the UK Biobank showed that 7/9 had positive significant (p<1.28×103) positive genetic correlations with endometriosis, suggesting a genetic basis for sensitivity to pain in general. Additional conditions with significant positive genetic correlations with endometriosis included uterine fibroids, excessive and irregular menstrual bleeding, osteoarthritis, diabetes as well as menstrual cycle length and age at menarche. These results provide a basis for fine-mapping of the causal variants at these 27 loci, and for functional follow-up to understand their contribution to endometriosis and its potential subtypes.

SituationJJ is a neonate born with diabetes due to a suspected KCNJ11 mutation which was later confirmed by genetic testing. The KCNJ11 mutation results in the patient being unable to produce insulin due to an inability to close a potassium dependent ATP channel required for the process. Prior to the administration of an intravenous (IV) insulin infusion JJ’s blood glucose levels reached 17 mmol/L. A plan for long term management of this patient’s condition was required before discharge.BackgroundUntreated or uncontrolled neonatal diabetes can result in severe complications such as reduced renal function or intra-ventricular haemorrhage therefore prompt and continued management of blood glucose levels is essential.OutcomeOptions for JJ’s long term management were considered by the paediatric diabetes multi-disciplinary team (MDT) following the suggestion of use of a sulphonylurea. Prior experience of its use had been found to be the most effective therapy in patients with KCNJ11 mutations.1 Continuation of IV therapy was unsuitable because of poor IV access and challenging monitoring requirements. Subcutaneous therapy was dismissed due to variability and unpredictability of pharmacokinetics and pain on injection in a neonate. Expert advice was sought from Exeter University specialists who recommended the use of glibenclamide specifically. A literature search described its use in a 3 month old at a dose of 0.1 mg/kg/day.1 A reference discussed 3 extemporaneous formulations and demonstrated chemical stability2 but with rapid settling and poor dose uniformity. It was decided that an extemporaneous product was also unsuitable due to potential for variation of formulation between primary and secondary care. As glibenclamide is insoluble in water a suspension was required to ensure uniformity of distribution of the drug and therefore reliable dosing. An acceptable product manufactured by a specials company as a suspension was identified and product information requested to determine potential suitability for use in neonates with regards to excipients.JJ was discharged at 2 weeks of age with frequent planned review by the MDT. His blood glucose levels were stable, although there were some instances of hypoglycaemia post-dose and hyperglycaemia pre-dose therefore the dose was eventually reduced to 0.04 mg/kg/day and split into 3 divided doses to prevent this. He remains well, is showing normal growth and development with stable blood glucose results since the dose amendment.Lessons learntSulphonylureas close the potassium dependent channel independently of ATP that patients with KCNJ11 mutations cannot. This results in the ability of these patients to produce insulin endogenously whereas previously they would have required full insulin supplementation. Prompt and clear MDT communication and the use of glibenclamide in a neonate enabled discharge due to improved blood glucose levels within 48 hours of initiation.ReferencesPearson ER, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6....

Background Anticoagulation to prevent stroke is a mainstay of atrial fibrillation (AF) management. Patients with established cardiovascular disease (CVD) may have conditions that fulfil Virchow's triad for thrombogenesis even in sinus rhythm. Previous investigation into the benefit of warfarin compared to placebo or antiplatelet drug in sinus rhythm found a reduction in stroke rates, but with an increase in bleeding. The efficacy and safety of non-vitamin K oral anticoagulant (NOAC) agents has not been studied. Purpose To assess the safety and efficacy of NOAC agents in patients without AF. Methods An electronic database search for randomized controlled trials that evaluated a NOAC and control drug (placebo or antiplatelet) in non-AF patients with CVD was conducted up until 1 September 2019. The primary efficacy and safety outcomes were ischemic stroke and major bleeding, respectively. The net clinical benefit (NCB) was calculated as a weighted sum of rate differences of ischemic stroke and major bleeding. Groups were stratified according to intensity of anticoagulation (full vs. low dose NOAC). Results Twelve randomized controlled trials were identified with a total of 83,008 patients (50,617 on NOAC, 32391 on control drug; mean age 66±2.7 years). CVD included coronary artery disease (78.3%), hypertension (73.7%), diabetes mellitus (34.7%), peripheral arterial disease (30.3%), previous stroke (21.7%), renal disease (22.9%) and heart failure (18.4%). Over a mean follow-up of 17.3 months, 1347 (1.6%) ischemic strokes occurred. Use of NOAC was associated with 28% reduction in ischemic stroke (odds-ratio [OR] 0.72, 95% confidence-interval [CI] 0.60 to 0.87; 1.1 vs. 1.8 events per 100-person years), with numbers needed to treat of 145 patients to prevent one stroke. Major bleeding was increased nearly 2-fold (OR 1.83, 95% CI 1.46 to 2.29; 2.1 vs. 1.0 events per 100-person years). The NCB demonstrated overall harm with the use of NOAC agents in this patient population (NCB = −0.28, 95% CI: −0.79 to 0.23). Use of full dose NOAC was widely unsafe (NCB = −0.35, 95% CI: −1.25 to 0.54) and low dose NOAC approached null therapeutic safety advantage (NCB = −0.06, 95% CI: −0.47 to 0.35). Conclusion Patients with CVD are at increased of ischemic stroke in the absence of AF. The use of NOAC agents in this non-AF population reduces rate of ischemic stroke however overall risk of bleeding exceeds antithrombotic benefit. Low-dose NOACs demonstrate a neutral NCB suggesting a point of clinical equipoise and deserve further scrutiny. Ischemic stroke vs major bleeding Funding Acknowledgement Type of funding source: None