Deriving research-quality phenotypes from national electronic health records to advance precision medicine: a UK Biobank case-study

High-throughput genotyping and increased availability of electronic health records (EHR) are giving scientists the unprecedented opportunity to exploit routinely generated clinical data to advance precision medicine. The extent to which national structured EHR in the United Kingdom can be utilized in genome-wide association studies (GWAS) has not been systematically examined. In this study, we evaluate the performance of an EHR-derived acute myocardial infarction phenotype (AMI) for performing GWAS in the UK Biobank

Computational prediction of the refinement of oxide agglomerates in a physical conditioning process for molten aluminium alloy

Physically conditioning molten scrap aluminium alloys using high shear processing (HSP) was recently found to be a promising technology for purification of contaminated alloys. HSP refines the solid oxide agglomerates in molten alloys, so that they can act as sites for the nucleation of Fe-rich intermetallic phases which can subsequently be removed by the downstream de-drossing process. In this paper, a computational modelling for predicting the evolution of size of oxide clusters during HSP is presented. We used CFD to predict the macroscopic flow features of the melt, and the resultant field predictions of temperature and melt shear rate were transferred to a population balance model (PBM) as its key inputs. The PBM is a macroscopic model that formulates the microscopic agglomeration and breakage of a population of a dispersed phase. Although it has been widely used to study conventional deoxidation of liquid metal, this is the first time that PBM has been used to simulate the melt conditioning process within a rotor/stator HSP device. We employed a method which discretizes the continuous profile of size of the dispersed phase into a collection of discrete bins of size, to solve the governing population balance equation for the size of agglomerates. A finite volume method was used to solve the continuity equation, the energy equation and the momentum equation. The overall computation was implemented mainly using the FLUENT module of ANSYS. The simulations showed that there is a relatively high melt shear rate between the stator and sweeping tips of the rotor blades. This high shear rate leads directly to significant fragmentation of the initially large oxide aggregates. Because the process of agglomeration is significantly slower than the breakage processes at the beginning of HSP, the mean size of oxide clusters decreases very rapidly. As the process of agglomeration gradually balances the process of breakage, the mean size of oxide clusters converges to a steady value. The model enables formulation of the quantitative relationship between the macroscopic flow features of liquid metal and the change of size of dispersed oxide clusters, during HSP. It predicted the variation in size of the dispersed phased with operational parameters (including the geometry and, particularly, the speed of the rotor), which is of direct use to experimentalists optimising the design of the HSP device and its implementation.This research is financially supported by the EC FP7 project “High Shear Processing of Recycled Aluminium Scrap for Manufacturing High Performance Aluminium Alloys” (Grant No. 603577)

Modeling of Trapped Fields by Stacked (RE)BCO Tape Using Angular Transversal Field Dependence

Stacks of superconducting (RE)BCO tape are gaining popularity as a potential alternative for superconducting bulks for trapped field applications. This is partly due to versatility and uniformity of the starting material, allowing for more deterministic prediction of field profile and magnitude. However, most FEM models of trapped field magnets do not incorporate parameters such as critical current and n-value dependence on the angle of applied magnetic field, leading to only qualitative modeling results. More quantitative results can be obtained from incorporating more data for superconductivity and thermal properties of the material. Such models can be used as a starting point for most geometries and both trapped field and current transport modeling problems. An FEM model of a stack of tapes was constructed using the H formulation, incorporating goniometric critical current and n-value measurements. The modeling results were compared to field cooling experiments for stacks of different heights. The experiment and modeling show good agreement.This work was supported in part by the Engineering and Physical Sciences Research Council, U.K., and in part by SKF S2M, France

Magnetic levitation using a stack of high temperature superconducting tape annuli

Stacks of large width superconducting tape can carry persistent currents over similar length scales to bulk superconductors, therefore giving them potential for trapped field magnets and magnetic levitation. 46 mm wide high temperature superconducting tape has previously been cut into square annuli to create a 3.5 T persistent mode magnet. The same tape pieces were used here to form a composite bulk hollow cylinder with an inner bore of 26 mm. Magnetic levitation was achieved by field cooling with a pair of rare-earth magnets. This paper reports the axial levitation force properties of the stack of annuli, showing that the same axial forces expected for a uniform bulk cylinder of infinite $\textit{J c}$ can be generated at 20 K. Levitation forces up to 550 N were measured between the rare-earth magnets and stack. Finite element modelling in COMSOL Multiphysics using the H-formulation was also performed including a full critical state model for induced currents, with temperature and field dependent properties as well as the influence of the ferromagnetic substrate which enhances the force. Spark erosion was used for the first time to machine the stack of tapes proving that large stacks can be easily machined to high geometric tolerance. The stack geometry tested is a possible candidate for a rotary superconducting bearing.The authors would like to acknowledge the financial support of SKF S2M, the magnetic bearing division of SKF, the Isaac Newton Trust, Cambridge and EPSRC

RAD51 Is a Selective DNA Repair Target to Radiosensitize Glioma Stem Cells.

Patients with glioblastoma die from local relapse despite surgery and high-dose radiotherapy. Resistance to radiotherapy is thought to be due to efficient DNA double-strand break (DSB) repair in stem-like cells able to survive DNA damage and repopulate the tumor. We used clinical samples and patient-derived glioblastoma stem cells (GSCs) to confirm that the DSB repair protein RAD51 is highly expressed in GSCs, which are reliant on RAD51-dependent DSB repair after radiation. RAD51 expression and RAD51 foci numbers fall when these cells move toward astrocytic differentiation. In GSCs, the small-molecule RAD51 inhibitors RI-1 and B02 prevent RAD51 focus formation, reduce DNA DSB repair, and cause significant radiosensitization. We further demonstrate that treatment with these agents combined with radiation promotes loss of stem cells defined by SOX2 expression. This indicates that RAD51-dependent repair represents an effective and specific target in GSCs

Toward Uniform Trapped Field Magnets Using a Stack of Roebel Cable Offcuts

Stacks of high temperature superconducting tape can be magnetized to produce a variety of different trapped field profiles in addition to the most common conical or pyramidal profiles. Stacks of tape using discarded Roebel cable offcuts were created to investigate various stacking arrangements with the aim of creating a stack that can be magnetized to produce a uniform trapped field for potential applications such as NMR. A new angled stacking arrangement proved to produce the flattest, most uniform field of all the overlapping stacking arrangements and has the potential to be scaled up. FEM modeling in COMSOL was also performed to complement the measurements and explain the limitations and advantages of the stacking arrangements tested.This work was supported in part by the Engineering and Physical Sciences Research Council, U.K., and in part by SKF S2M, France.This is the author accepted manuscript. The final version is available from IEEE via http://dx.doi.org/10.1109/TASC.2016.251899

Laparoscopic cholecystectomy at the Aga Khan Hospital, Nairobi

Objective: To evaluate our experience of laparoscopic cholecystectomies at the Aga Khan Hospital, Nairobi over a three-year period from the inception of the technique, and to assess its value and advantages to the patients.Design: A prospective case series study.Setting: The Aga Khan Hospital, Nairobi.Patients: One hundred and thirty five cases operated from February 1996 to April 1999. All patients were subjected to the American method of laparoscopic cholecystectomy, which is described in detail in this paper. Main outcome measures: Clinical presentation, age and sex demographics, average hospital stay, intraoperative and postoperative complications and outcome.Results: There was a female preponderance with a female to male ratio of 5:1. Mean age was forty nine years. Majority of patients suffered from chronic cholecystitis. The conversion rate to an open procedure was five per cent. There were two cases of significant bile leakage which required laparotomy. No mortality was reported in this series.Conclusion: This technique was found to have distinct advantages such as shorter hospital stay, lesser postoperative pain and very good cosmesis. It is a safe procedure if performed by a well trained surgeon

Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation

A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach

Novel role for the innate immune receptor toll-like receptor 4 (TLR4) in the regulation of the wnt signaling pathway and photoreceptor apoptosis

Recent evidence has implicated innate immunity in regulating neuronal survival in the brain during stroke and other neurodegenerations. Photoreceptors are specialized light-detecting neurons in the retina that are essential for vision. In this study, we investigated the role of the innate immunity receptor TLR4 in photoreceptors. TLR4 activation by lipopolysaccharide (LPS) significantly reduced the survival of cultured mouse photoreceptors exposed to oxidative stress. With respect to mechanism, TLR4 suppressed Wnt signaling, decreased phosphorylation and activation of the Wnt receptor LRP6, and blocked the protective effect of the Wnt3a ligand. Paradoxically, TLR4 activation prior to oxidative injury protected photoreceptors, in a phenomenon known as preconditioning. Expression of TNFα and its receptors TNFR1 and TNFR2 decreased during preconditioning, and preconditioning was mimicked by TNFα antagonists, but was independent of Wnt signaling. Therefore, TLR4 is a novel regulator of photoreceptor survival that acts through the Wnt and TNFα pathways. © 2012 Yi et al