Pre-pregnancy obesity, pre-existing diabetes, and the risks of serious adverse fetal outcomes

PhD ThesisThe epidemics of obesity and diabetes are two of the leading threats to health in the 21st century. Maternal obesity complicates a large and increasing minority of pregnancies, and pre-existing diabetes is one of the most common maternal chronic health complications of pregnancy. This Doctoral Statement presents a portfolio of six published articles that draw on the North of England’s long-standing population-based registries of maternal and perinatal health to investigate the effects of pre-pregnancy obesity and diabetes on a range of serious adverse pregnancy outcomes. The first two articles examined a cohort of pregnant women who delivered in five of the region’s hospitals during 2003-2005 to explore the associations between maternal body mass index and the risks of, 1) congenital anomaly and 2) fetal and infant death. The next three examined a cohort of pregnant women with pre-existing diabetes who delivered during 1996-2008 to explore the effects of the condition on, 1) congenital anomaly, 2) birth weight, and 3) fetal and infant death. The final article examined women with pre-existing diabetes who had delivered two successive pregnancies to explore the influences of recurrent adverse pregnancy outcome. Maternal pre-pregnancy obesity and diabetes were both associated with increased risks of congenital anomaly, stillbirth, and infant death, with stronger effects for diabetes than obesity. In diabetes, peri-conception glycaemic control was strongly associated with birthweight and the risks of congenital anomaly, stillbirth, and infant death, and previous adverse outcome was associated with a doubled risk in the second pregnancy. For each article I provide a contemporary analysis of its contribution to the literature and critique of the methodology. The wider relevance of the research is also considered by discussing the evidence for causality, potential mechanisms, and implications for public health. Finally, I reflect on my individual contributions and my development towards an independent epidemiologist.the Newlife Foundation, NHS North of Tyne, Diabetes UK, and the South Tees Hospitals NHS Foundation Trust

Subformula and separation properties in natural deduction via small Kripke models

Various natural deduction formulations of classical, minimal, intuitionist, and intermediate propositional and first-order logics are presented and investigated with respect to satisfaction of the separation and subformula properties. The technique employed is, for the most part, semantic, based on general versions of the Lindenbaum and Lindenbaum–Henkin constructions. Careful attention is paid (i) to which properties of theories result in the presence of which rules of inference, and (ii) to restrictions on the sets of formulas to which the rules may be employed, restrictions determined by the formulas occurring as premises and conclusion of the invalid inference for which a counterexample is to be constructed. We obtain an elegant formulation of classical propositional logic with the subformula property and a singularly inelegant formulation of classical first-order logic with the subformula property, the latter, unfortunately, not a product of the strategy otherwise used throughout the article. Along the way, we arrive at an optimal strengthening of the subformula results for classical first-order logic obtained as consequences of normalization theorems by Dag Prawitz and Gunnar Stalmarck

Genome editing using site-specific nucleases: targeting highly expressed genomic regions for robust transgene expression and genetic analysis

Integration and expression of exogenous genetic material – in particular, transgenes – into the genomes of model organisms, cell lines or patients is widely used for the creation of genetically modified experimental systems and gene therapy. However, loss of transgene expression due to silencing is still a major hurdle which remains to be overcome. Judicious selection of integration loci can help alleviate the risk of silencing; in recent years the ability to efficiently and specifically target transgene integration has been improved by the advent of site-specific nucleases (SSNs). SSNs can be used to generate double strand breaks (DSBs) in a targeted manner, which increases the efficiency of homologous recombination (HR) mediated transgene integration into predetermined loci. In this work I investigate four human genomic loci for their potential to act as transgene integration sites which will support robust long term expression: the adeno-associated virus (AAV) integration site 1 (AAVS1); the human homologue of the mouse Rosa26 locus (hROSA26); the inosine monophosphate dehydrogenase 2 (IMPDH2) gene and the eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) gene. I also investigate the potential of creating a novel drug-selectable transgene integration system at the IMPDH2 locus to allow for rapid and specific selection of correctly inserted transgenes. In addition to their ability to drive targeted transgene integration, SSNs can be harnessed to specifically disrupt gene function through indel formation following erroneous repair of the induced DSB. Using this strategy, I aimed to answer some important biological questions about eukaryotic translation elongation factor 1 alpha (eEF1A); eEF1A is responsible for providing aminoacylated tRNAs to the ribosome during the elongation phase of protein synthesis. Humans and other vertebrates express two isoforms, eEF1A1 and eEF1A2 (encoded by EEF1A1 and EEF1A2 respectively). During development eEF1A1 is replaced by eEF1A2 in some tissues. The reasons for this remain elusive, but one explanation may lie in the moonlighting functions of eEF1A1, which may not be shared by eEF1A2. Additionally, eEF1A2 can act as an oncogene, while there is no evidence that eEF1A1 is overexpressed in tumours. To begin to untangle these issues I targeted EEF1A1 using SSNs with the aim of making a cell line expressing only the eEF1A2 isoform. This work suggests that eEF1A1 may be essential even in the presence of eEF1A2, though further studies will be required to confirm this

Telecommunications Act of 1996: 704 of the Act and Protections Afforded the Telecommunications Provider in the Facilities Sitting Context, The

The Telecommunications Act of 1996, signed into law by President Clinton in February, addresses, among many other important subjects, some of the technical problems that have arisen from the increasing popularity of mobile communications. This article will provide an overview of the Act and will focus specifically on the protections afforded a telecommunications provider in § 704 of the Act

Telecommunications Act of 1996: 704 of the Act and Protections Afforded the Telecommunications Provider in the Facilities Sitting Context, The

The Telecommunications Act of 1996, signed into law by President Clinton in February, addresses, among many other important subjects, some of the technical problems that have arisen from the increasing popularity of mobile communications. This article will provide an overview of the Act and will focus specifically on the protections afforded a telecommunications provider in § 704 of the Act

Mask or mirror? : a study of Juvenal's Satires as a reflection of authorial personality and perspective.

Thesis (Ph.D.)-University of Natal, Durban, 1999.This study aims to present Juvenal's Satires as a whole as the fundamentally coherent and plausible product of the author's own personality, convictions and circumstanceswhere the latter may be reasonably inferred. It therefore questions the view that the dichotomy which the persona theory creates between the author and his notional 'speaker' provides the basis for a better insight into Juvenal's Satires. There is no compelling reason to reject the impression that in his earlier Books Juvenal was genuinely writing from the standpoint of a disaffected client; and an examination of the Epigrams of Juvenal's contemporary, Martial, suggests that complaints of paupertas should not be dismissed as a merely conventional literary facade. Juvenal's own resentment as a neglected dependant and his contempt for the corrupt Roman elite give the first three Books their basic coherence. However, while Satires 7, 8 and 9 are not characterised to the same extent by the strident invective which is the hallmark of the earlier poems, the notion that the image of the 'indignant' satirist is deliberately abandoned, albeit tentatively, after Book 2 is less convincing , if one gives due weight to the types of themes treated in the third Book and to the nature of the satirical vehicle used in each instance. Juvenal's empathy with the plight of the neglected intellectuals in Satire 7 and his condemnation of the effete and corrupt elite in Satires 8 and 9 are clear and forthright: the shift in satirical technique away from aggressive invective towards a more analytical treatment of the themes in Satires 7 and 8, as indeed befits the subject matter, and towards wryly ironic 'humour in the sordid dialogue with Naevolus in Satire 9 are not to be interpreted as the manifestation of a refashioned authorial persona. The importance of theme as a major determinant of the satirical method or technique employed is equally evident in the fourth Book. Here, the themes lend themselves, in general, to a more consistently didactic approach, reminiscent of Horace's Sermones. From the outset of Book 1, Juvenal focuses perSistently on avaritia, in all its manifestations, as a root cause of the malaise in Roman society; and this vice continues to playa dominant role in Book 3 (particularly in Satires 7 and 9). Not only does avaritia come under further attack in Satires 11 , 12 and 13, but the prominence given to it in Satire 14 provides cogent evidence of the extent to which the satirist is preoccupied with this most pernicious of social evils. These poems also illustrate the fact that, even when Juvenal adopts a more didactic or reflective approach, his urge towards acerbic satire is far from suppressed; and, as in the cases of Satires 7 and 8, he shows his predilection for using ostensibly positive themes as platforms for attacks on vice and depravity. Similarly. when other themes congenial to his prejudices and convictions present themselves - such as an appalling act of barbarism perpetrated by the Egyptians - that urge can readily find expression through the poet's innate propensity towards ira and indignatio. Furthermore, Books 4 and 5 provide ample evidence of the very qualities which characterize the so-called 'angry' satirist of the first two Books: vigorous and persistent denunciation of contemporary greed and other vices, strong moral convictions, brooding pessimism and cynicism and , not least, an acerbic wit and a genius for crafting powerfully evocative images. The evidence is tenuous, but sufficient to suggest that the shifts in tone and focus in Books 4 and 5 could also be attributed , in part, to Juvenal's circumstances and state of mind at that time. In Satires 10-14 Juvenal shows a particular interest in the Epicurean virtue of tranquillitas. This is perhaps to be attributed to a realization that angry protests could effect no real changes for the better and that some solace could be derived from a more detached perspective, and to the comforting conviction that ultimately wickedness finds its nemesis in the torture of a guilty conscience. For one steadfastly convinced that he lived in an age of unsurpassed and incorrigible vice, in which the gods were apparently ineffectual, it was probably both satisfying and logical to cultivate such a perspective. One should also not lose sight of the fact that the poet's age could well have contributed to shifts of both attitude and interest. Satire 15 provides strong corroboration of the view that Juvenal's personality and attitudes remain basically consistent and that theme is a major determinant of the satirical manner adopted. The merciless attack on the Egyptians is not to be seen as a consciously contrived return to the 'old style' or, more fancifully, as an exercise in selfii mockery. Rather, it is clear proof that Juvenal has not forsaken his inherently aggressive xenophobia, which was so prominent in Books 1 and 2. Similarly, what remains of Satire 16 suggests the same character traits which are so powerfully conveyed in the first Satire. Thatone can still feel the presence of the bitter and acerbic pessimist of that first Satire is not the effect of calculated mask-changing , but a further indication that the Satires as a whole should be seen as a reflection of the author's own personality and perspective

Retroactive skill of multi-tiered forecasts of summer rainfall over southern Africa

Sea‐surface temperature (SST) variations of the oceans surrounding southern Africa are associated with seasonal rainfall variability, especially during austral summer when the tropical atmospheric circulation is dominant over the region. Because of instabilities in the linear association between summer rainfall over southern Africa and SSTs of the tropical Indian Ocean, the skilful prediction of seasonal rainfall may best be achieved using physically based models. A two‐tiered retro‐active forecast procedure for the December–February (DJF) season is employed over a 10‐year period starting from 1987/1988. Rainfall forecasts are produced for a number of homogeneous regions over part of southern Africa. Categorized (below‐normal, near‐normal and above‐normal) statistical DJF rainfall predictions are made for the region to form the baseline skill level that has to be outscored by more elaborate methods involving general circulation models (GCMs). The GCM used here is the Centre for Ocean–Land–Atmosphere Studies (COLA) T30, with predicted global SST fields as boundary forcing and initial conditions derived from the National Centres for Environmental Prediction (NCEP) reanalysis data. Bias‐corrected GCM simulations of circulation and moisture at certain standard pressure levels are downscaled to produce rainfall forecasts at the regional level using the perfect prognosis approach. In the two‐tiered forecasting system, SST predictions for the global oceans are made first. SST anomalies of the equatorial Pacific (NIÑO3.4) and Indian oceans are predicted skilfully at 1‐ and 3‐month lead‐times using a statistical model. These retro‐active SST forecasts are accurate for pre‐1990 conditions, but predictability seems to have weakened during the 1990s. Skilful multi‐tiered rainfall forecasts are obtained when the amplitudes of large events in the global oceans (such as El Niño and La Niña episodes) are described adequately by the predicted SST fields. GCM simulations using persisted August SST anomalies instead of forecast SSTs produce skill levels similar to those of the baseline for longer lead‐times. Given high‐skill SST forecasts, the scheme has the potential to provide climate forecasts that outscore the baseline skill level substantially

Microbiota in exhaled breath condensate and the lung

The lung microbiota is commonly sampled using relatively invasive bronchoscopic procedures. Exhaled breath condensate (EBC) collection potentially offers a less invasive alternative for lung microbiota sampling. We compared lung microbiota samples retrieved by protected specimen brushings (PSB) and exhaled breath condensate collection. We also sought to assess whether aerosolized antibiotic treatment would influence the lung microbiota and whether this change could be detected in EBC. EBC was collected from 6 conscious sheep and then from the same anesthetized sheep during mechanical ventilation. Following the latter EBC collection, PSB samples were collected from separate sites within each sheep lung. On the subsequent day, each sheep was then treated with nebulized colistimethate sodium. Two days after nebulization, EBC and PSB samples were again collected. Bacterial DNA was quantified using 16S rRNA gene quantitative PCR. The V2-V3 region of the 16S rRNA gene was amplified by PCR and sequenced using Illumina MiSeq. Quality control and operational taxonomic unit (OTU) clustering were performed with mothur. The EBC samples contained significantly less bacterial DNA than the PSB samples. The EBC samples from anesthetized animals clustered separately by their bacterial community compositions in comparison to the PSB samples, and 37 bacterial OTUs were identified as differentially abundant between the two sample types. Despite only low concentrations of colistin being detected in bronchoalveolar lavage fluid, PSB samples were found to differ by their bacterial compositions before and after colistimethate sodium treatment. Our findings indicate that microbiota in EBC samples and PSB samples are not equivalent

Precise Localization of the Soft Gamma Repeater SGR 1627-41 and the Anomalous X-ray Pulsar AXP 1E1841-045 with Chandra

We present precise localizations of AXP 1E1841-045 and SGR 1627-41 with Chandra. We obtained new infrared observations of SGR 1627-41 and reanalyzed archival observations of AXP 1E1841-045 in order to refine their positions and search for infrared counterparts. A faint source is detected inside the error circle of AXP 1E1841-045. In the case of SGR 1627-41, several sources are located within the error radius of the X-ray position and we discuss the likelihood of one of them being the counterpart. We compare the properties of our candidates to those of other known AXP and SGR counterparts. We find that the counterpart candidates for SGR 1627-41 and SGR 1806-20 would have to be intrinsically much brighter than AXPs to have detectable counterparts with the observational limits currently available for these sources. To confirm the reported counterpart of SGR 1806-20, we obtained new IR observations during the July 2003 burst activation of the source. No brightening of the suggested counterpart is detected, implying that the counterpart of SGR 1806-20 remains yet to be identified.Comment: 29 pages, 4 figures, accepted for publication in Ap