An Informatics Consult has been proposed in which clinicians request novel evidence from large scale health data resources, tailored to the treatment of a specific patient, with return of results in clinical timescales. However, the availability of such consultations is lacking. We seek to provide an Informatics Consult for a situation where a treatment indication and contraindication coexist in the same patient, i.e., anti-coagulation use for stroke prevention in a patient with both atrial fibrillation (AF) and liver cirrhosis. We examined four sources of evidence for the effect of warfarin on stroke risk (efficacy) or all-cause mortality (safety) from: (i) randomised controlled trials (RCTs), (ii) meta- analysis of prior observational studies, (iii) trial emulation (using population electronic health records (N = 3,854,710) and (iv) genetic evidence (Mendelian randomisation). We developed prototype forms to request an Informatics Consult and return of results in electronic health record systems. We found 0 RCT reports and 0 trials recruiting for patients with AF and cirrhosis. We found broad concordance across the three new sources of evidence we generated. Meta-analysis of prior observational studies showed that warfarin use was associated with lower stroke risk (hazard ratio [HR] = 0.71). In a target trial emulation, warfarin was associated with lower all-cause mortality (HR = 0.61) and ischaemic stroke (HR = 0.27). Mendelian randomisation served as a drug target validation where we found that lower levels of vitamin K1 (warfarin is a vitamin K1 antagonist) are associated with lower stroke risk. A pilot survey with an independent sample of 34 clinicians revealed that 85% of clinicians found information on prognosis useful and that 79% thought that they should have access to the Informatics Consult as a service within their healthcare systems. We identified candidate steps for automation to scale evidence generation and to accelerate the return of results within clinical timescales.
Poster discussion hub abstracts from biparietal diameter and abdominal circumference using the eSnurra algorithm. Mean fetal weight gain/day was calculated as the difference between birthweight and estimated fetal weight in the second trimester, and thereafter related to the remaining days in pregnancy from the ultrasound examination to delivery. Results: We observed a significant association between mean flow calculated from PixelFlux and weight gain/day (r =0.33; p =0.02) as presented in the Figure. The correlations remained significant after adjusting for maternal age, BMI, parity and systolic blood pressure (p =0.01 and p =0.02, respectively). Conclusions: We found a significant association between total blood flow based on PixelFlux and fetal weight-gain/day. The PixelFlux method might be a promising tool in predicting birthweight.Supporting information can be found in the online version of this abstract P21.08 Diagnosis of metabolic risk during pregnancy by body mass index (BMI): does a better method exist? Preliminary results
AimsABO incompatible renal transplantation has been reported as a successful form of renal replacement therapy in children and adults. Antibody removal is required with options of B lymphocyte depletion with splenectomy, plasma exchange, double filtration plasmapheresis or immunoadsorption.MethodsTo report the successful outcome of ABO incompatible renal transplantation using quadruple immunosuppression (basiliximab at days 0 and 4, mycophenolate mofetil and tacrolimus from one week pretransplantation and corticosteroids) with only B lymphocyte depletion (intravenous rituximab 375 mg/m2 at one month pretransplantation). A 14-year-old young man received a living related renal transplantation from his mother for end-stage renal failure (ESRF) on haemodialysis for steroid resistant nephrotic syndrome due to focal and segmental glomerulosclerosis (FSGS) who had a living related renal transplant from his father 18 months previously, which had failed due to a vascular event.ResultsThe recipient and donor (mother) blood groups were A and B Rhesus positive, respectively, with anti-B titres of one in four rising to one in eight pretransplantation. His renal transplant was performed successfully without further antibody removal or surgical complications and immediate renal allograft function. Three months posttransplant his renal function has stabilised with a plasma creatinine of 114μmol/l giving an estimated glomerular filtration rate of 62 ml/min/1.73 m2. He does not have clinical evidence of recurrent FSGS posttransplantation (normal serum albumin levels without albuminuria) with negative anti-B titres and donor specific antibodies and no evidence of EBV, BK or CMV viraemia (having required oral valganciclovir as CMV mismatch). He had a normal transplant renal biopsy at ten days post-transplant without evidence of acute rejection and one focal segmental sclerotic lesion seen on protocol biopsy at three months.ConclusionIn view of the reported success of ABO incompatible renal transplantation, clinicians must consider this option in ESRF patients whose parents have been excluded as living donors in view of ABO blood group incompatibility.
Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence (HIPKD) in 17 children from 11 unrelated families suggested the existence of a previously unrecognized genetic disorder. Whole genome linkage analysis in 5 informative families identified a single significant (LOD 6.5) locus on chromosome 16p13.2. Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, a promoter mutation (c.-167G>T) in PMM2 was found in all patients, either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has previously been associated with polycystic kidney disease and we show that deglycosylation in pancreatic β-cells alters insulin secretion.Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multi-system disorder with prominent neurological involvement. Yet the typical clinical features of CDG1A were absent in our patients and the diagnostic test of transferrin isoelectric focusing was normal, clearly separating HIPKD from CDG1A and establishing PMM2 pleiotropy. The promoter mutation showed decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggests an important role of ZNF143 for the formation of a chromatin loop including PMM2.We propose that the promoter mutation alters tissue-specific chromatin loop formation with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic 5 causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.
Summary 先天性黑素细胞痣(CMN,通常称为“痣”)由色素细胞组成,色素细胞含有发生了改变(突变)的基因。我们知道不同的痣具有不同的遗传突变(或“基因型”),并且不同的痣在外观和行为上也有所不同,即它们具有不同的“表型”。 CMN 很少会与大脑的问题相关,或者极少会发展成恶性肿瘤(黑色素瘤)。这些伦敦的研究人员回顾了 134 名儿童的 156 个 CMN,以查看特定的基因型是否会引起特定的表型。 这些儿童的表型趋于更严重:76% 出生时有两个或更多的 CMN,大多数 CMN 较大,8 个有恶性黑色素瘤,而 29% 的人脑部 MRI 扫描异常。关于基因型,有 68% 的痣 NRAS 基因发生突变,7% BRAF 基因发生突变,25% 两种基因均未突变。 在同一位患者中研究了两种不同的痣,它们具有相同的基因型。该研究未显示基因型与恶性肿瘤或神经系统疾病之间有任何关系。但是,较大的痣通常有 NRAS 突变,而块状痣大多伴有 BRAF 突变而非 NRAS 突变。 在显微镜下检查块状痣表明,肿块不是由 CMN 细胞组成,而是由脂肪和结缔组织组成,其中 CMN 组织在顶部延伸。 作者得出的结论是,尽管已证明基因检测在恶性黑色素瘤中有用,其中基因型可以指导治疗选择,但没有必要对痣进行基因检测。 本摘要涉及研究:基因是否重要? 先天性黑 素细胞痣的基因型‐表型与基因型结果的相关性
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