The genetic and functional significance of non-HLA polymorphisms in haematopoietic stem cell transplantation

PhD ThesisHaematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for many patients with malignant and non-malignant haematological diseases. However, its success is greatly reduced by the development of complications, including graft-versus-host disease (GVHD), infection and relapse. Human leukocyte antigen (HLA)-matching of patients and donors is essential in HSCT, but does not completely prevent such complications. Thus, it is extremely likely that non-HLA genes also have an impact. Naturally occurring polymorphisms within non-HLA genes have been suggested to contribute to some of the genetic disparity that exists between transplant patients and donors, consequently, they may have the potential to influence HSCT outcome. As a result, this study investigated the significance of non-HLA polymorphisms in HSCT. Polymorphisms in the genes of interleukin (IL) 2 (IL2, -330 T/G), 4 (IL4, -590 C/T), 6 (IL6, -174 G/C) and 10 (IL10, -592 A/C, -1082 G/A), IL-1 receptor antagonist (IL-1Ra (IL1RN), intron 2 VNTR), tumour necrosis factor α (TNFα (TNFA), intron 3 (GA)n), TNF receptor II (TNFRII (TNFRSF1B), -196 M/R), interferon γ (IFNγ (IFNG), intron 1 (CA)n), vitamin D receptor (VDR, intron 8 A/C, exon 9 T/C) and oestrogen receptor (ESR1, intron 1 A/G, intron 1 C/T) have been studied extensively in HLA-matched sibling transplantation, however, relatively little is known about their role in unrelated donor HSCT. This study therefore examined these polymorphisms in the unrelated donor setting. VDR intron 8 A/C, IFNG intron 1 (CA)n and IL6 -174 G/C were found to associate with GVHD in our cohort. The VDR intron 8 A,A and IFNG intron 1 3,3 genotypes correlated with severe acute GVHD (grades III-IV), whilst the IL6 -174 G,G genotype correlated with chronic GVHD. No genetic associations were demonstrated with any other clinical outcome. This study also examined the +2044 G/A polymorphism in the gene encoding IL-13 (IL13), an immunoregulatory cytokine that has been implicated in GVHD. This polymorphism has been widely studied for disease associations; however, its role in HLA-matched sibling and unrelated donor HSCT is currently unknown. In our transplant cohort the IL13 +2044 A allele was found to correlate significantly with both acute and chronic GVHD. Higher IL-13 expression was also observed in patients with these conditions, although this altered expression could not be directly attributed to IL13 +2044 G/A. The prognostic significance of pre-transplant IL-13 serum levels was also investigated. No associations were observed between IL-13 expression and GVHD. Elevated pre-transplant IL-13 serum levels did, however, correlate with post-transplant relapse and Hodgkin disease in two independent cohorts. Again, this altered expression could not be directly attributed to the IL13 +2044 G/A polymorphism. This study clearly demonstrates that non-HLA polymorphisms influence the outcome of both HLA-matched sibling and unrelated donor HSCT. Thus, in the future, genotyping with respect to a panel of non-HLA polymorphisms may be used to complement HLA typing, increase the ability to predict the risk of transplant complications and allow post-transplant treatment strategies to be tailored to an individual.European Commissio

State building: the case of the European Union's common foreign and security policy

The aim of the thesis is to provide an understanding of the practical and conceptual significance of foreign, security and defence policies within the changing epistemology of the state, and the impact of the development of such policies upon the process of European integration. In order to achieve this analysis the thesis proceeds by examining the linkage made in traditional International Relations and Strategic Studies discourse between the state and security before considering alternative concepts whereby the state is becoming detached from its role as the primary provider of security in the international system. This is followed by an examination and assessment of the man theories of integration International Relations. An historical bridging chapter then highlights the relationship between foreign and security policy and the process of European integration. The two core empirical chapters focus upon the Common Foreign and Security Policy (CFSP) and the European Security and Defence Identity (ESDI) and are linked by a short chapter assessing the significant of the second Treaty on European Union, concluded at Amsterdam. The former traces factors leading to the inclusion of CFSP into the Treaty on European Union (TEU) at Maastricht followed by an outline of the institutional structures established and an assessment of CFSP in operation. The latter considers the factors promoting and preventing the EU’s acquisition of a defence capability. In particular attention is drawn to the significance of reform within the Atlantic Alliance, the future of the Western European Union (WEU) and the national positions of the British and French governments. The content of these chapters has required constant updating as circumstances change. A great deal of information for these chapters is, therefore, based two series of elite interviews, the first with British officials and Members of the European Parliament conducted during the summer of 1997; the second with personnel from EU, WEU and NATO institutions, conducted in March 1999. Finally a conclusion is reached as to the significance of such developments in assessing the nature of the European Union

School nurse perspectives of working with children and young people in the United Kingdom during the Covid-19 pandemic: An online survey study

School nurses are public health specialists with an integral role in the safeguarding of children and young people. This study gathered information about school nurses’ approaches to overcome practice restrictions as a result of COVID-19. A cross-sectional survey was administered to school nurses across the United Kingdom. Quantitative data were analysed descriptively. Qualitative data (free-text responses to open-ended questions) were analysed using reflexive thematic analysis. Seventy-eight participant responses were included in the analysis. Quantitative data highlighted increased workloads; decreased contact with service users; and difficulties in identifying safeguarding needs and working with known vulnerable children. Through qualitative data analysis, five themes were identified: a move from preventive to reactive school nursing; professional challenges of safeguarding in the digital context; the changing nature of inter-professional working; an increasing workload; and reduced visibility and representation of the child. The findings call for advocacy by policymakers and professional organisations representing school nurses to enable this professional group to lead in the evolving public health landscape; for commissioning that recognises the school nurse as a specialist public health practitioner; and for sufficient numbers of school nurses to respond to the emergent and ongoing health needs of children and young people

Protecting children and young people vulnerable to harm and abuse: learning from school nursing practices and new ways of working in the Covid-19 pandemic

This is a report detailing the process and findings of a mixed-methods study, funded by the General Nursing Council England and Wales Trust, aimed to identify changes in school nurse practice working with children and young people, to explore the benefits and challenges in school nurse work to support vulnerable children and young people during the pandemic, map new ways of working, and consider the use of these going forward

Plasma long-chain omega-3 fatty acid status and risk of recurrent early spontaneous preterm birth: a prospective observational study

Introduction A 2018 Cochrane review found that omega-3 supplementation in pregnancy was associated with a risk reduction of early preterm birth of 0.58; prompting calls for universal supplementation. Recent analysis suggests the benefit may be confined to women with a low baseline omega-3 fatty acid status, however the contemporary UK pregnant omega-3 fatty acid status is largely unknown. This is particularly pertinent for women with a previous preterm birth, in whom a small relative risk reduction would have a larger reduction of absolute risk. This study aimed to assess the omega-3 fatty acid status of a UK pregnant population and determine the association between the long-chain omega-3 fatty acids and recurrent spontaneous early preterm birth. Material and methods A total of 283 high-risk women with previous early preterm birth were recruited to the prospective obstervational study in Liverpool, UK. Additionally, 96 pregnant women with previous term births and birth ≥39⁺⁰ weeks in the index pregnancy provided a low-risk population sample. Within the high-risk group we assessed the odds ratio of recurrent early preterm birth compared to birth at ≥37⁺⁰ weeks gestation according to plasma eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) at 15-22 weeks gestation.  RESULTS: Our participants had low EPA+DHA; 62% (143/229) of women with previous preterm birth and 69% (68/96) of the population sample had levels within the lowest two quintiles of a previously published pregnancy cohort. We found no association between long-chain omega-3 status and recurrent early preterm birth (n=51). The crude odds ratio of a recurrent event was 0.91 (95% CI 0.38 to 2.15, p=0.83) for women in the lowest, compared to the highest three quintiles of EPA+DHA. Conclusions In the majority of our participants levels of long-chain omega-3 were low; within the range that may benefit from supplementation. However, levels showed no association with risk of recurrent early spontaneous preterm birth. This could be because our population levels were too low to show benefit in being omega-3 'replete'; or else omega-3 levels may be of lesser importance in recurrent early preterm birth.Laura Goodfellow, Angharad Care, Jane Harrold, Andrew Sharp, Jelena Ivandic, Borna Poljak ... et al

Diagnosis and management of selective fetal growth restriction in monochorionic twin pregnancies: A cross‐sectional international survey

Objective: To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies. Design: Cross‐sectional survey. Setting: International. Population: Clinicians involved in the management of MCDA twin pregnancies with sFGR. Methods: A structured, self‐administered survey. Main Outcome Measures: Clinical practices and attitudes to diagnostic criteria and management strategies. Results: Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of 25% for the diagnosis of sFGR. For early‐onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early‐onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early‐onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early‐onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide. Conclusions: There is significant variation in clinician practices and attitudes towards the management of early‐onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high‐level evidence to guide management

Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial

Background Severe early-onset fetal growth restriction can lead to a range of adverse outcomes including fetal or neonatal death, neurodisability, and lifelong risks to the health of the affected child. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates the actions of nitric oxide, which leads to vasodilatation of the uterine vessels and might improve fetal growth in utero. Methods We did this superiority, placebo-controlled randomised trial in 19 fetal medicine units in the UK. We used random computer allocation (1:1) to assign women with singleton pregnancies between 22 weeks and 0 days' gestation and 29 weeks and 6 days' gestation and severe early-onset fetal growth restriction to receive either sildenafil 25 mg three times daily or placebo until 32 weeks and 0 days' gestation or delivery. We stratified women by site and by their gestational age at randomisation (before week 26 and 0 days or at week 26 and 0 days or later). We defined fetal growth restriction as a combination of estimated fetal weight or abdominal circumference below tenth percentile and absent or reversed end-diastolic blood flow in the umbilical artery on Doppler velocimetry. The primary outcome was the time from randomisation to delivery, measured in days. This study is registered with BioMed Central, number ISRCTN 39133303. Findings Between Nov 21, 2014, and July 6, 2016, we recruited 135 women and randomly assigned 70 women to sildenafil and 65 women to placebo. We found no difference in the median randomisation to delivery interval between women assigned to sildenafil (17 days [IQR 7–24]) and women assigned to placebo (18 days [8–28]; p=0·23). Livebirths (relative risk [RR] 1·06, 95% CI 0·84 to 1·33; p=0·62), fetal deaths (0·89, 0·54 to 1·45; p=0·64), neonatal deaths (1·33, 0·54 to 3·28; p=0·53), and birthweight (−14 g,–100 to 126; p=0·81) did not differ between groups. No differences were found for any other secondary outcomes. Eight serious adverse events were reported during the course of the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil. Interpretation Sildenafil did not prolong pregnancy or improve pregnancy outcomes in severe early-onset fetal growth restriction and therefore it should not be prescribed for this indication outside of research studies with explicit participants' consent. Funding National Institute for Health Research and Medical Research Council

Habitat and Scale Shape the Demographic Fate of the Keystone Sea Urchin Paracentrotus lividus in Mediterranean Macrophyte Communities

Demographic processes exert different degrees of control as individuals grow, and in species that span several habitats and spatial scales, this can influence our ability to predict their population at a particular life-history stage given the previous life stage. In particular, when keystone species are involved, this relative coupling between demographic stages can have significant implications for the functioning of ecosystems. We examined benthic and pelagic abundances of the sea urchin Paracentrotus lividus in order to: 1) understand the main life-history bottlenecks by observing the degree of coupling between demographic stages; and 2) explore the processes driving these linkages. P. lividus is the dominant invertebrate herbivore in the Mediterranean Sea, and has been repeatedly observed to overgraze shallow beds of the seagrass Posidonia oceanica and rocky macroalgal communities. We used a hierarchical sampling design at different spatial scales (100 s, 10 s and <1 km) and habitats (seagrass and rocky macroalgae) to describe the spatial patterns in the abundance of different demographic stages (larvae, settlers, recruits and adults). Our results indicate that large-scale factors (potentially currents, nutrients, temperature, etc.) determine larval availability and settlement in the pelagic stages of urchin life history. In rocky macroalgal habitats, benthic processes (like predation) acting at large or medium scales drive adult abundances. In contrast, adult numbers in seagrass meadows are most likely influenced by factors like local migration (from adjoining rocky habitats) functioning at much smaller scales. The complexity of spatial and habitat-dependent processes shaping urchin populations demands a multiplicity of approaches when addressing habitat conservation actions, yet such actions are currently mostly aimed at managing predation processes and fish numbers. We argue that a more holistic ecosystem management also needs to incorporate the landscape and habitat-quality level processes (eutrophication, fragmentation, etc.) that together regulate the populations of this keystone herbivore

Diagnosis and management of selective fetal growth restriction in monochorionic twin pregnancies: A cross-sectional international survey.

ObjectiveTo identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies.DesignCross-sectional survey.SettingInternational.PopulationClinicians involved in the management of MCDA twin pregnancies with sFGR.MethodsA structured, self-administered survey.Main outcome measuresClinical practices and attitudes to diagnostic criteria and management strategies.ResultsOverall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of 25% for the diagnosis of sFGR. For early-onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early-onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early-onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early-onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide.ConclusionsThere is significant variation in clinician practices and attitudes towards the management of early-onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high-level evidence to guide management

A consensus statement on perinatal mental health during the COVID-19 pandemic and recommendations for post-pandemic recovery and re-build

Introduction: The COVID-19 pandemic posed a significant lifecourse rupture, not least to those who had specific physical vulnerabilities to the virus, but also to those who were suffering with mental ill health. Women and birthing people who were pregnant, experienced a perinatal bereavement, or were in the first post-partum year (i.e., perinatal) were exposed to a number of risk factors for mental ill health, including alterations to the way in which their perinatal care was delivered. Methods: A consensus statement was derived from a cross-disciplinary collaboration of experts, whereby evidence from collaborative work on perinatal mental health during the COVID-19 pandemic was synthesised, and priorities were established as recommendations for research, healthcare practice, and policy. Results: The synthesis of research focused on the effect of the COVID-19 pandemic on perinatal health outcomes and care practices led to three immediate recommendations: what to retain, what to reinstate, and what to remove from perinatal mental healthcare provision. Longer-term recommendations for action were also made, categorised as follows: Equity and Relational Healthcare; Parity of Esteem in Mental and Physical Healthcare with an Emphasis on Specialist Perinatal Services; and Horizon Scanning for Perinatal Mental Health Research, Policy, & Practice. Discussion: The evidence base on the effect of the pandemic on perinatal mental health is growing. This consensus statement synthesises said evidence and makes recommendations for a post-pandemic recovery and re-build of perinatal mental health services and care provision