Investigation of aneuploidy in preimplantation embryos

Aneuploidy is common in human preimplantation embryos. This thesis examines aneuploidy detection using an array platform, aneuploidy in embryos from fertile couples and recombination in gametes through the detection of cross-over events in embryos. The first aim of this project was the optimisation of array comparative genomic hybridisation (aCGH) to examine all chromosomes in single blastomeres and trophectoderm samples from embryos, prior to clinical implementation. Accurate detection of errors was possible on single cells from epithelial cell lines of known chromosomal status. The same cell lines were used to mimic mosaic trophectoderm samples to examine the effect of mosaicism on aCGH. Aneuploidy could be confidently detected when more than 50% of the cells in the sample were abnormal. Aneuploidy studies have been mainly performed on embryos, from couples undergoing preimplantation genetic screening (PGS), which are expected to be highly abnormal. The second aim was to determine the aneuploidy level in embryos from couples undergoing preimplantation genetic diagnosis (PGD) for monogenic disorders. Fluorescence in situ hybridisation (FISH) was used to examine five chromosomes in 86 embryos from 19 couples and all chromosomes were examined in 53 embryos from six couples by aCGH. Diploid mosaic embryos were the most predominant group when FISH analysis was carried out, whereas the majority of embryos were euploid after aCGH. Post-zygotic rather than meiotic errors were more common in embryos from PGD cycles when compared to embryos from PGS cycles. Aneuploidy is known to associate with aberrant recombination. The third aim was to examine meiotic recombination. Polymorphic markers on five chromosomes were used to detect cross-over events in 77 embryos from 10 couples. Female recombination was higher than male. Increasing age had a negative effect on recombination. No significant effect of recombination on morphology and aneuploidy was observed, however euploid embryos had more recombination than aneuploid

Excess mortality in England and Wales during the first wave of the COVID-19 pandemic

Background: Deaths during the COVID-19 pandemic result directly from infection and exacerbation of other diseases and indirectly from deferment of care for other conditions, and are socially and geographically patterned. We quantified excess mortality in regions of England and Wales during the pandemic, for all causes and for non-COVID-19-associated deaths. Methods: Weekly mortality data for 1 January 2010 to 1 May 2020 for England and Wales were obtained from the Office of National Statistics. Mean-dispersion negative binomial regressions were used to model death counts based on pre-pandemic trends and exponentiated linear predictions were subtracted from: (i) all-cause deaths and (ii) all-cause deaths minus COVID-19 related deaths for the pandemic period (week starting 7 March, to week ending 8 May). Findings: Between 7 March and 8 May 2020, there were 47 243 (95% CI: 46 671 to 47 815) excess deaths in England and Wales, of which 9948 (95% CI: 9376 to 10 520) were not associated with COVID-19. Overall excess mortality rates varied from 49 per 100 000 (95% CI: 49 to 50) in the South West to 102 per 100 000 (95% CI: 102 to 103) in London. Non-COVID-19 associated excess mortality rates ranged from −1 per 100 000 (95% CI: −1 to 0) in Wales (ie, mortality rates were no higher than expected) to 26 per 100 000 (95% CI: 25 to 26) in the West Midlands. Interpretation: The COVID-19 pandemic has had markedly different impacts on the regions of England and Wales, both for deaths directly attributable to COVID-19 infection and for d

The effect of pre-procedure sublingual nitroglycerin on radial artery diameter and Allen’s test outcome - relevance to transradial catheterization

Background The radial artery is increasingly used for cardiac procedures, but is a relatively small vessel that is prone to spasm when instrumented. Intra-arterial nitroglycerine has been shown to reduce radial spasm but first requires arterial access. We investigated the effect of pre-procedure sublingual nitroglycerin (NTG) on the diameter of the radial artery in a large cohort of patients. Methods 305 subjects underwent ultrasound measurement of their radial and ulnar arteries in both arms before and after the administration of 800 μg of sublingual NTG. The Allen's test was also performed in the subjects prior to and after NTG. Results Radial artery diameter in this Caucasian study group is larger than that reported for other populations. The administration of sublingual NTG significantly increased the size of the right radial artery from 2.88 ± 0.36 mm to 3.36 ± 0.40 mm in men and from 2.23 ± 0.37 up to 2.74 ± 0.36 mm in women. There were also significant increases in left radial, right and left ulnar artery diameters in males and females with NTG. There was no significant effect of NTG on blood pressure. In all patients with an unfavourable Allen's test, retesting following sublingual NTG resulted in transition to a favourable Allen's. Conclusion Caucasian populations have larger calibre radial arteries compared to other geographic areas. Sublingual NTG is effective at dilating the radial artery in both men and women. This may make radial artery puncture and cannulation less challenging and should be considered in all patients in the absence of contraindications. The results of Allen's testing are dynamic and its usefulness for screening prior to transradial access is undetermined

Cancer event rate and mortality with thienopyridines: a systematic review and meta-analysis

Introduction Thienopyridines are a class of antiplatelet drugs widely used in cardiovascular disease prevention and treatment. A recent concern has come to light regarding the safety of thienopyridines because of the possible risk of malignancy. We therefore performed a systematic review and meta-analysis to evaluate the association between thienopyridine exposure and malignancy. Methods We searched the MEDLINE and EMBASE databases in March 2016 for studies that evaluated incident cancer and cancer mortality with and without exposure to thienopyridines. Relevant studies were identified, and data were extracted and analysed using random-effects meta-analysis. Results A total of nine studies (six randomised controlled trials and three cohort studies) that included 282,084 participants were included. The cancer event rate with clopidogrel and prasugrel was 3.25% and 1.58% respectively. When compared with standard aspirin or placebo, thienopyridines are not significantly associated with cancer mortality and event rate (odds ratio [OR] 1.12, 95% confidence interval [CI] 0.80–1.56, n = 3; and OR 0.92, 95% CI 0.52–1.64, n = 2, respectively. Further analyses examining clopidogrel showed no significant association with cancer event rate or malignancy-related death. When comparing prasugrel with clopidogrel, no significant association was noted for cancer event rate (OR 1.10, 95% CI 0.89–1.37, n = 2]. Subanalyses according to cancer location showed that thienopyridines are not significantly associated with malignancy mortality and/or incidence. Conclusions Our results suggest that there is currently insufficient evidence to suggest that thienopyridine exposure is associated with an increased risk of cancer event rate or mortality

Does prior antithrombotic therapy influence recurrence and bleeding risk in stroke patients with atrial fibrillation or atrial flutter?

The authors would like to thank the patients of the NNUH Stroke Register cohort and the data team of the Norfolk and Norwich University Stroke Services. NNUH Stroke Register is maintained by the NNUH Stroke Services.Peer reviewedPostprin

Long Term Prognostic Impact of Sex-specific Longitudinal Changes in Blood Pressure. The EPIC-Norfolk Prospective Population Cohort Study

AIMS: We aimed to determine the sex differences in longitudinal systolic and diastolic blood pressure (SBP and DBP) trajectories in mid-life and delineate the associations between these and mortality (all-cause, cardiovascular, and non-cardiovascular) and incident cardiovascular disease (CVD) in old age. METHODS AND RESULTS: Participants were selected from the European Prospective Investigation into Cancer, Norfolk (EPIC-Norfolk) cohort study. Sex-specific trajectories were determined using group-based trajectory models using three clinic BP measurements acquired between 1993 and 2012 (mean exposure ∼12.9 years). Multivariable Cox regressions determined the associations between trajectories and incident outcomes over the follow-up (median follow-up 9.4 years). A total of 2897 men (M) and 3819 women (F) were included. At baseline, women were younger (F-55.5, M-57.1), had a worse cardiometabolic profile and were less likely to receive primary CVD prevention including antihypertensive treatment (F-36.0%, M-42.0%). Over the exposure period, women had lower SBP trajectories while men exhibited more pronounced SBP decreases over this period. Over the follow-up period, women had lower mortality (F-11.9%, M-20.5%) and CVD incidence (F-19.8%, M-29.6%). Compared to optimal SBP (≤120 mmHg) and DBP (≤70 mmHg) trajectories, hypertensive trajectories were associated with increased mortality and incident CVD in both men and women during follow-up at univariable level. These associations were nevertheless not maintained upon extensive confounder adjustment including antihypertensive therapies. CONCLUSION: We report sex disparities in CVD prevention which may relate to worse cardiometabolic profiles and less pronounced longitudinal SBP decreases in women. Effective anti-hypertensivetherapy may offset the adverse outcomes associated with prolonged exposure to high blood pressure

Antithrombotic therapy in patients receiving saphenous vein coronary artery bypass grafts: a protocol for a systematic review and network meta-analysis.

INTRODUCTION: The current evidence for the prevention of saphenous vein graft failure (SVGF) after coronary artery bypass graft (CABG) surgery consists of direct head-to-head comparison of treatments (including placebo) in randomised-controlled trials (RCTs) and observational studies. However, summarising the evidence using traditional pairwise meta-analyses does not allow the inclusion of data from treatments that have not been compared head to head. Exclusion of such comparisons could impact the precision of pooled estimates in a meta-analysis. Hence, to address the challenge of whether aspirin alone or in addition to another antithrombotic agent is a more effective regimen to improve SVG patency, a network meta-analysis (NMA) is necessary. The objectives of this study are to synthesise the available evidence on antithrombotic agents (or their combination) and estimate the treatment effects among direct and indirect treatment comparisons on SVGF and major adverse cardiovascular events, and to generate a treatment ranking according to their efficacy and safety outcomes. METHODS: We will perform a systematic review of RCTs evaluating antithrombotic agents in patients undergoing CABG. A comprehensive English literature search will be conducted using electronic databases and grey literature resources to identify published and unpublished articles. Two individuals will independently and in duplicate screen potential studies, assess the eligibility of potential studies and extract data. Risk of bias and quality of evidence will also be evaluated independently and in duplicate. We will investigate the data to ensure its suitability for NMA, including adequacy of the outcome data and transitivity of treatment effects. We plan to estimate the pooled direct, indirect and the mixed effects for all antithrombotic agents using a NMA. ETHICS AND DISSEMINATION: Due to the nature of the study, there are no ethical concerns nor informed consent required. We anticipate that this NMA will be the first to simultaneously assess the relative effects of multiple antithrombotic agents in patients undergoing CABG. The results of this NMA will inform clinicians, patients and guideline developers the best available evidence on comparative effects benefits of antithrombotic agents after CABG while considering the side effect profile to support future clinical decision-making. We will disseminate the results of our systematic review and NMA through a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42017065678

Association between serum secretory phospholipase A2 and risk of ischaemic stroke

Background and purpose: Previous literature has demonstrated an association between high serum levels of type II secretory phospholipase A2 (sPLA2) concentration and an increased risk of coronary artery disease. However, such association has not been established in terms of ischaemic stroke risk. The aim was to evaluate the association between both sPLA2 concentration and activity as continuous variables with risk of future ischaemic stroke. / Methods: A nested case–control study was conducted using data from the European Prospective Investigation into Cancer—Norfolk study. Cases (n = 145) in the current study were participants who developed ischaemic stroke during follow-up, with controls (n = 290) matched in a 2:1 ratio based on age and sex. Statistical analyses were performed using SPSS (version 25.0) software. Logistic regression was used to determine odds ratios (OR) and corresponding 95% confidence intervals (95% CIs) for ischaemic stroke. / Results: After adjusting for a wide array of cardiovascular confounders, sPLA2 activity was found to be associated with an increased risk of ischaemic stroke using both multiple imputations with chained equations and complete case analysis: OR 1.20 (95% CI 1.01–1.43) and OR 1.23 (95% CI 1.01−1.49), respectively. However, sPLA2 concentration was not found to be associated with increased risk of ischaemic stroke. / Conclusions: The activity of sPLA2, but not sPLA2 concentration, is associated with an increased risk of future ischaemic stroke. This finding may be significant in risk group stratification, allowing targeted prophylactic treatment, or the development of novel therapeutic agents