Investigating penetrance of rare genetic variants using population cohorts

The same genetic variant found in different individuals can cause a spectrum of phenotypes, with some individuals showing no signs of any clinical illness, and some displaying severe illness. Variants that cause this can be said to show incomplete penetrance, where the related genotype either causes clinical disease or not, or they can be said to display variable expressivity, in which the clinical symptoms can vary across a spectrum. Incomplete penetrance and variable expressivity are both thought to be influenced by a large number of factors, including genetic modifiers, epigenetics, and environmental factors. Many thousands of genetic variants have been identified as causal of monogenic disorders, mostly determined through small clinical studies, and thus the penetrance and expressivity of these variants may be overestimated when compared to their effect in the general population. With the wealth of population cohort data currently available, the penetrance and expressivity of such genetic variants can be investigated across a much wider contingent, potentially helping to reclassify variants that were previously thought to be completely penetrant. This thesis aims to investigate the penetrance and expressivity of rare genetic variants in large population cohorts, and to potentially identify any genetic modifiers that could also affect the phenotypic effect of these variants, including the presence of other rare variants, and the aggregation of small effect common variants. We show that putatively damaging variants in a large number of genes are present at a higher rate than previously expected in healthy population cohorts. Furthermore, we show that as an aggregate, individuals who carry one of these variants have sub-clinical phenotypes related to the traits seen in clinical disease cases with variants in similar genes. We also show that the penetrance and expressivity of these rare variants can be modified by the presence of other rare variants in similar genes, and through common genetic variant, aggregated as polygenic scores. We then investigate methods of identifying rare non-coding variants that could be potential genetic modifiers

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis

BACKGROUND: The body of knowledge regarding rhinosinusitis (RS) continues to expand, with rapid growth in number of publications yet substantial variability in the quality of those presentations. In an effort to both consolidate and critically appraise this information, rhinologic experts from around the world have produced the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR:RS). This executive summary consolidates the findings of the ICAR:RS document. METHODS: ICAR:RS presents over 140 topics in the forms of evidence-based reviews with recommendations (EBRRs) and evidence-based reviews (EBR). The structured recommendations of the EBRR sections are summarized in this executive summary. RESULTS: This summary compiles the EBRRs regarding medical and surgical management of acute RS (ARS) and chronic RS with and without nasal polyps (CRSwNP and CRSsNP). CONCLUSION: This ICAR:RS Executive Summary provides a compilation of the evidence-based recommendations for medical and surgical treatment of the most common forms of RS

Pathways into services for offenders with intellectual disabilities : childhood experience, diagnostic information and offence variables

The patterns and pathways into intellectual disability (ID) offender services were studied through case file review for 477 participants referred in one calendar year to community generic, community forensic, and low, medium, and maximum secure services. Data were gathered on referral source, demographic information, index behavior, prior problem behaviors, diagnostic information, and abuse or deprivation. Community referrers tended to refer to community services and secure service referrers to secure services. Physical and verbal violence were the most frequent index behaviors, whereas contact sexual offenses were more prominent in maximum security. Age at first incident varied with security, with the youngest in maximum secure services. Attention-deficit/hyperactivity disorder or conduct disorder was the most frequently recorded diagnosis, and severe deprivation was the most frequent adverse developmental experience. Fire starting, theft, and road traffic offenses did not feature prominently. Generic community services accepted a number of referrals with forensic-type behavior and had higher proportions of both women and people with moderate or severe ID

Effects of glycol-split low molecular weight heparin on placental, endothelial, and anti-inflammatory pathways relevant to preeclampsia

The authors thank the donors, the Research Centre for Women’s and Infants’ Health BioBank program, the Lunenfeld-Tanenbaum Research Institute and the MSH/University Health Network Department of Obstetrics & Gynaecology for the human specimens used in this study.Peer reviewedPublisher PD

Commercials, careers and culture: travelling salesmen in Britain 1890s-1930s

Within the lower middle-class, British commercial travellers established a strong fraternal culture before 1914. This article examines their interwar experiences in terms of income, careers, and associational culture. It demonstrates how internal labour markets operated, identifies the ways in which commercial travellers interpreted their role, and explores their social and political attitudes

Can Linear Regression Modeling Help Clinicians in the Interpretation of Genotypic Resistance Data? An Application to Derive a Lopinavir-Score

The question of whether a score for a specific antiretroviral (e.g. lopinavir/r in this analysis) that improves prediction of viral load response given by existing expert-based interpretation systems (IS) could be derived from analyzing the correlation between genotypic data and virological response using statistical methods remains largely unanswered.We used the data of the patients from the UK Collaborative HIV Cohort (UK CHIC) Study for whom genotypic data were stored in the UK HIV Drug Resistance Database (UK HDRD) to construct a training/validation dataset of treatment change episodes (TCE). We used the average square error (ASE) on a 10-fold cross-validation and on a test dataset (the EuroSIDA TCE database) to compare the performance of a newly derived lopinavir/r score with that of the 3 most widely used expert-based interpretation rules (ANRS, HIVDB and Rega). Our analysis identified mutations V82A, I54V, K20I and I62V, which were associated with reduced viral response and mutations I15V and V91S which determined lopinavir/r hypersensitivity. All models performed equally well (ASE on test ranging between 1.1 and 1.3, p = 0.34).We fully explored the potential of linear regression to construct a simple predictive model for lopinavir/r-based TCE. Although, the performance of our proposed score was similar to that of already existing IS, previously unrecognized lopinavir/r-associated mutations were identified. The analysis illustrates an approach of validation of expert-based IS that could be used in the future for other antiretrovirals and in other settings outside HIV research

Secondary education reform in Lesotho and Zimbabwe and the needs of rural girls: Pronouncements, policy and practice

Analysis of the educational needs of rural girls in Lesotho and Zimbabwe suggests a number of shortcomings in the current form of secondary education, and ways in which it might be modified so as to serve this sizeable group of students better. Several of the shortcomings, notably in relation to curricular irrelevance and excessive focus on examinations, have long been recognised, including by politicians. Yet political pronouncements are seldom translated into policy, and even where policy is formulated, reforms are seldom implemented in schools. This paper makes use of interviews with educational decision-makers in the two southern African countries and a range of documentary sources to explore why, despite the considerable differences between the two contexts, much needed educational reforms have been implemented in neither

Reflections on a 'virtual' practice development unit: changing practice through identity development

Aims. This paper draws together the personal thoughts and critical reflections of key people involved in the establishment of a ‘virtual’ practice development unit of clinical nurse specialists in the south of England. Background. This practice development unit is ‘virtual’ in that it is not constrained by physical or specialty boundaries. It became the first group of Trust-wide clinical nurse specialists to be accredited in the UK as a practice development unit in 2004. Design and methods. The local university was asked to facilitate the accreditation process via 11 two-hour audio-recorded learning sessions. Critical reflections from practice development unit members, leaders and university staff were written 12 months after successful accreditation, and the framework of their content analysed. Findings and discussion. Practice development was seen as a way for the clinical nurse specialists to realize their potential for improving patient care by transforming care practice in a collaborative, interprofessional and evolutionary manner. The practice development unit provided a means for these nurses to analyse their role and function within the Trust. Roberts’ identity development model for nursing serves as a useful theoretical underpinning for the reflections contained in this paper. Conclusions. These narratives provide another example of nurses making the effort to shape and contribute to patient care through organizational redesign. This group of nurses began to realize that the structure of the practice development unit process provided them with the means to analyse their role and function within the organization and, as they reflected on this structure, their behaviour began to change. Relevance to clinical practice. Evidence from these reflections supports the view that practice development unit participants have secured a positive and professional identity and are, therefore, better able to improve the patient experience

A generation apart? Youth and political participation in Britain

Conventional wisdom holds that young people in Britain are alienated from politics, with some claiming that this reflects a wider crisis of legitimacy that should be met by initiatives to increase citizenship. This article addresses these areas, presenting both panel survey and focus group data from first-time voters. It concludes that, contrary to the findings from many predominantly quantitative studies of political participation, young people are interested in political matters, and do support the democratic process. However they feel a sense of anti-climax having voted for the first time, and are critical of those who have been elected to positions of political power. If they are a generation apart, this is less to do with apathy, and more to do with their engaged scepticism about ‘formal’ politics in Britain

The politics of the teaching of reading

Historically, political debates have broken out over how to teach reading in primary schools and infant classrooms. These debates and “reading wars” have often resulted from public concerns and media reportage of a fall in reading standards. They also reflect the importance placed on learning to read by parents, teachers, employers, and politicians. Public and media-driven controversies over the teaching of reading have resulted in intense public and professional debates over which specific methods and materials to use with beginning readers and with children who have reading difficulties. Recently, such debates have led to a renewed emphasis on reading proficiency and “standardized” approaches to teaching reading and engaging with literacy. The universal acceptance of the importance of learning to read has also led to vested interests in specific methods, reading programmes, and early literacy assessments amongst professional, business, commercial, and parental lobbying groups. This article traces these debates and the resulting growing support for a quantitative reductionist approach to early-reading programmes