Table builder problem - confidentiality for linked tables

The aim of this project is to investigate solutions to the problem of improving access to detailed survey data, while ensuring no person or organisation is likely to be identified, or otherwise put at risk of having their data disclosed, and to link general findings back to the ABS Table Builder problem. We focussed on making contributions in two main areas, namely: 1. Identification of sensitive cells in a table, 2. Maximizing data utility and minimising information loss - ensuring the table provides useful information

A MICROFLUIDIC DIGITAL MELT PLATFORM FOR SENSITIVE BIOMARKER ANALYSIS AND PARALLELIZED PROFILING OF MOLECULAR HETEROGENEITY

Variability in gene regulation is a fundamental characteristic of biology, allowing cellular adaptation in many states, such as development, stress response, and survival. In early disease onset, genetic and epigenetic variability permit the formation of multiple cellular phenotypes. In cancer, increased cellular plasticity ultimately results in the foundation of a tumor with the phenotypic alterations necessary to dynamically adapt, proliferate, metastasize, and acquire therapeutic resistance throughout the course of the disease. One prominent form of cellular regulation is DNA methylation, an epigenetic chemical modification that can alter gene expression. Hypermethylation-induced silencing is known to occur early on in tumorigenesis, often in precursor phases of the disease. Furthermore, tumors have been shown to undergo epigenetic reprogramming throughout progression of the disease. In light of these observations, methylation heterogeneity may serve as a novel biomarker for early cancer detection. Early detection of cancer remains challenging, as symptoms often manifest in later stages and current screening techniques often lack the requisite sensitivity and specificity. To maximize effectiveness, routine screening techniques should be noninvasive, simple, and unbiased. To this end, liquid biopsies (e.g. blood samples) containing cellular debris, such as tumor-derived cell-free DNA in the plasma, are ideally suited towards routine screening. However, detection of tumor-derived molecules in plasma is challenging, as they are often rare and may be eclipsed by a high background of molecules from healthy cells. Thus a sensitive platform capable of quantifying epigenetic heterogeneity could uncover new insights and improve early detection. In this dissertation, I present a microfluidic digital melt platform for facile, highly-sensitive detection and molecule-by-molecule profiling. The platform is applied towards the quantification of epiallelic heterogeneity. Digitization of rare molecules into thousands of microchambers followed by parallelized sequencing interrogation through high resolution melt enables order of magnitude higher sensitivity than current techniques and insight into new intermolecular characteristics. I also demonstrate how this platform may be modified to complement and improve the sensing capabilities of existing commercial technologies. Finally, I validate the potential clinical utility of this platform through detection of methylation heterogeneity in complex clinical samples towards noninvasive screening applications. The technical capabilities along with the operational simplicity of this platform facilitate adoption by other laboratories and offer potential clinical utility. This system may offer new insights into the mechanisms of epigenetic regulation in pathogenesis, and potentially improve early diagnosis

Hyperovals in Hall planes

AbstractIn this paper we construct two classes of translation hyperovals in any Hall plane of even orderq2 ≥ 16. Two hyperovals constructed in the same Hall plane are equivalent under the action of the automorphism group of that Hall plane iff they are in the same class

Functional anonymisation: Personal data and the data environment

Anonymisation of personal data has a long history stemming from the expansion of the types of data products routinely provided by National Statistical Institutes. Variants on anonymisation have received serious criticism reinforced by much-publicised apparent failures. We argue that both the operators of such schemes and their critics have become confused by being overly focused on the properties of the data themselves. We claim that, far from being able to determine whether data are anonymous (and therefore non-personal) by looking at the data alone, any anonymisation technique worthy of the name must take account of not only the data but also their environment. This paper proposes an alternative formulation called functional anonymisation that focuses on the relationship between the data and the environment within which the data exist (their data environment). We provide a formulation for describing the relationship between the data and their environment that links the legal notion of personal data with the statistical notion of disclosure control. Anonymisation, properly conceived and effectively conducted, can be a critical part of the toolkit of the privacy-respecting data controller and the wider remit of providing accurate and usable data

Temporary epicardial cardiac resynchronisation versus conventional right ventricular pacing after cardiac surgery: study protocol for a randomised control trial

Background: Heart failure patients with stable angina, acute coronary syndromes and valvular heart disease may benefit from revascularisation and/or valve surgery. However, the mortality rate is increased- 5-30%. Biventricular pacing using temporary epicardial wires after surgery is a potential mechanism to improve cardiac function and clinical endpoints. Method/design: A multi-centred, prospective, randomised, single-blinded, intervention-control trial of temporary biventricular pacing versus standard pacing. Patients with ischaemic cardiomyopathy, valvular heart disease or both, an ejection fraction ≤ 35% and a conventional indication for cardiac surgery will be recruited from 2 cardiac centres. Baseline investigations will include: an electrocardiogram to confirm sinus rhythm and measure QRS duration; echocardiogram to evaluate left ventricular function and markers of mechanical dyssynchrony; dobutamine echocardiogram for viability and blood tests for renal function and biomarkers of myocardial injury- troponin T and brain naturetic peptide. Blood tests will be repeated at 18, 48 and 72 hours. The principal exclusions will be subjects with permanent atrial arrhythmias, permanent pacemakers, infective endocarditis or end-stage renal disease. After surgery, temporary pacing wires will be attached to the postero-lateral wall of the left ventricle, the right atrium and right ventricle and connected to a triple chamber temporary pacemaker. Subjects will be randomised to receive either temporary biventricular pacing or standard pacing (atrial inhibited pacing or atrial-synchronous right ventricular pacing) for 48 hours. The primary endpoint will be the duration of level 3 care. In brief, this is the requirement for invasive ventilation, multi-organ support or more than one inotrope/vasoconstrictor. Haemodynamic studies will be performed at baseline, 6, 18 and 24 hours after surgery using a pulmonary arterial catheter. Measurements will be taken in the following pacing modes: atrial inhibited; right ventricular only; atrial synchronous-right ventricular; atrial synchronous-left ventricular and biventricular pacing. Optimisation of the atrioventricular and interventricular delay will be performed in the biventricular pacing group at 18 hours. The effect of biventricular pacing on myocardial injury, post operative arrhythmias and renal function will also be quantified

XE7: A novel splicing factor that interacts with ASF/SF2 and ZNF265

Pre-mRNA splicing is performed by the spliceosome. SR proteins in this macromolecular complex are essential for both constitutive and alternative splicing. By using the SR-related protein ZNF265 as bait in a yeast two-hybrid screen, we pulled out the uncharacterized human protein XE7, which is encoded by a pseudoautosomal gene. XE7 had been identified in a large-scale proteomic analysis of the human spliceosome. It consists of two different isoforms produced by alternative splicing. The arginine/serine (RS)-rich region in the larger of these suggests a role in mRNA processing. Herein we show for the first time that XE7 is an alternative splicing regulator. XE7 interacts with ZNF265, as well as with the essential SR protein ASF/SF2. The RS-rich region of XE7 dictates both interactions. We show that XE7 localizes in the nucleus of human cells, where it colocalizes with both ZNF265 and ASF/SF2, as well as with other SR proteins, in speckles. We also demonstrate that XE7 influences alternative splice site selection of pre-mRNAs from CD44, Tra2-β1 and SRp20 minigenes. We have thus shown that the spliceosomal component XE7 resembles an SR-related splicing protein, and can influence alternative splicing

Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons

Feature-selective firing allows networks to produce representations of the external and internal environments. Despite its importance, the mechanisms generating neuronal feature selectivity are incompletely understood. In many cortical microcircuits the integration of two functionally distinct inputs occurs nonlinearly through generation of active dendritic signals that drive burst firing and robust plasticity. To examine the role of this processing in feature selectivity, we recorded CA1 pyramidal neuron membrane potential and local field potential in mice running on a linear treadmill. We found that dendritic plateau potentials were produced by an interaction between properly timed input from entorhinal cortex and hippocampal CA3. These conjunctive signals positively modulated the firing of previously established place fields and rapidly induced new place field formation to produce feature selectivity in CA1 that is a function of both entorhinal cortex and CA3 input. Such selectivity could allow mixed network level representations that support context-dependent spatial maps.Howard Hughes Medical InstituteRikagaku Kenkyūjo (Japan

Group B <em>Streptococcus </em>engages an inhibitory siglec through sialic acid mimicry to blunt innate immune and inflammatory responses <em>in vivo</em>

Group B Streptococcus (GBS) is a common agent of bacterial sepsis and meningitis in newborns. The GBS surface capsule contains sialic acids (Sia) that engage Sia-binding immunoglobulin-like lectins (Siglecs) on leukocytes. Here we use mice lacking Siglec-E, an inhibitory Siglec of myelomonocytic cells, to study the significance of GBS Siglec engagement during in vivo infection. We found GBS bound to Siglec-E in a Sia-specific fashion to blunt NF-κB and MAPK activation. As a consequence, Siglec-E-deficient macrophages had enhanced pro-inflammatory cytokine secretion, phagocytosis and bactericidal activity against the pathogen. Following pulmonary or low-dose intravenous GBS challenge, Siglec-E KO mice produced more pro-inflammatory cytokines and exhibited reduced GBS invasion of the central nervous system. In contrast, upon high dose lethal challenges, cytokine storm in Siglec-E KO mice was associated with accelerated mortality. We conclude that GBS Sia mimicry influences host innate immune and inflammatory responses in vivo through engagement of an inhibitory Siglec, with the ultimate outcome of the host response varying depending upon the site, stage and magnitude of infection

A randomized, controlled trial of 3.0 mg of liraglutide in weight management

BACKGROUND Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagonlike peptide-1 analogue, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously. METHODS We conducted a 56-week, double-blind trial involving 3731 patients who did not have type 2 diabetes and who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 30 or a BMI of at least 27 if they had treated or untreated dyslipidemia or hypertension. We randomly assigned patients in a 2:1 ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients); both groups received counseling on lifestyle modification. The coprimary end points were the change in body weight and the proportions of patients losing at least 5% and more than 10% of their initial body weight. RESULTS At baseline, the mean (±SD) age of the patients was 45.1±12.0 years, the mean weight was 106.2±21.4 kg, and the mean BMI was 38.3±6.4; a total of 78.5% of the patients were women and 61.2% had prediabetes. At week 56, patients in the liraglutide group had lost a mean of 8.4±7.3 kg of body weight, and those in the placebo group had lost a mean of 2.8±6.5 kg (a difference of -5.6 kg; 95% confidence interval, -6.0 to -5.1; P&lt;0.001, with last-observation-carried-forward imputation). A total of 63.2% of the patients in the liraglutide group as compared with 27.1% in the placebo group lost at least 5% of their body weight (P&lt;0.001), and 33.1% and 10.6%, respectively, lost more than 10% of their body weight (P&lt;0.001). The most frequently reported adverse events with liraglutide were mild or moderate nausea and diarrhea. Serious events occurred in 6.2% of the patients in the liraglutide group and in 5.0% of the patients in the placebo group. CONCLUSIONS In this study, 3.0 mg of liraglutide, as an adjunct to diet and exercise, was associated with reduced body weight and improved metabolic control. (Funded by Novo Nordisk; SCALE Obesity and Prediabetes NN8022-1839 ClinicalTrials.gov number, NCT01272219.)