Behavioural models of penguins and krill in the Southern Ocean

The thesis applies state of the art ecological modelling methods to predict optimal behavioural patterns in two key Southern Ocean species, macaroni penguins, Eudyptes chrysolophus, and Antarctic krill, Euphausia superba. The work is divided into three main parts. The first considers how female macaroni penguins allocate their time between searching, foraging and feeding their chick during the guard stage. The model is forced by the availability of their main prey, Antarctic krill, and the increasing demands of the chick. The second part focuses on the behaviour of Antarctic krill at South Georgia, a hotspot in the Southern Ocean. This model predicts the most likely distribution of krill between 3 main environments that relate to bathymetry, resulting from an individual's choice of depth, density of swarm and swimming behaviour, which has some influence on their advection. The model is forced by the availability of phytoplankton and by the prevailing advection regime. The third part takes a similar approach, determining the optimal behaviour of krill as they are transported from the Antarctic Peninsula to South Georgia, except in this model, krill do not have any influence on their horizontal location. The first main finding of the thesis is that macaroni penguins will travel further to obtain a more reliable meal of krill, even if the krill reward does not change with distance from nest. A second important finding is that krill are able to increase their overall concentration in favourable areas simply by altering their swimming speed and tum rate. The third major finding describes the likely existence of a threshold availability of krill to penguins, below which the chick dies and above which there is no change to chick growth. The thesis discusses the suitability of the modelling technique and proposes future fieldwork for better model parameterisation and validation. The models provide a framework for predicting the responses of these organisms to future changes in their environment

SemEHR:A general-purpose semantic search system to surface semantic data from clinical notes for tailored care, trial recruitment, and clinical research

OBJECTIVE: Unlocking the data contained within both structured and unstructured components of electronic health records (EHRs) has the potential to provide a step change in data available for secondary research use, generation of actionable medical insights, hospital management, and trial recruitment. To achieve this, we implemented SemEHR, an open source semantic search and analytics tool for EHRs. METHODS: SemEHR implements a generic information extraction (IE) and retrieval infrastructure by identifying contextualized mentions of a wide range of biomedical concepts within EHRs. Natural language processing annotations are further assembled at the patient level and extended with EHR-specific knowledge to generate a timeline for each patient. The semantic data are serviced via ontology-based search and analytics interfaces. RESULTS: SemEHR has been deployed at a number of UK hospitals, including the Clinical Record Interactive Search, an anonymized replica of the EHR of the UK South London and Maudsley National Health Service Foundation Trust, one of Europe's largest providers of mental health services. In 2 Clinical Record Interactive Search-based studies, SemEHR achieved 93% (hepatitis C) and 99% (HIV) F-measure results in identifying true positive patients. At King's College Hospital in London, as part of the CogStack program (github.com/cogstack), SemEHR is being used to recruit patients into the UK Department of Health 100 000 Genomes Project (genomicsengland.co.uk). The validation study suggests that the tool can validate previously recruited cases and is very fast at searching phenotypes; time for recruitment criteria checking was reduced from days to minutes. Validated on open intensive care EHR data, Medical Information Mart for Intensive Care III, the vital signs extracted by SemEHR can achieve around 97% accuracy. CONCLUSION: Results from the multiple case studies demonstrate SemEHR's efficiency: weeks or months of work can be done within hours or minutes in some cases. SemEHR provides a more comprehensive view of patients, bringing in more and unexpected insight compared to study-oriented bespoke IE systems. SemEHR is open source, available at https://github.com/CogStack/SemEHR

Protecting an ecosystem service: approaches to understanding and mitigating threats to wild insect pollinators

Insect pollination constitutes an ecosystem service of global importance, providing significant economic and aesthetic benefits as well as cultural value to human society, alongside vital ecological processes in terrestrial ecosystems. It is therefore important to understand how insect pollinator populations and communities respond to rapidly changing environments if we are to maintain healthy and effective pollinator services. This paper considers the importance of conserving pollinator diversity to maintain a suite of functional traits to provide a diverse set of pollinator services. We explore how we can better understand and mitigate the factors that threaten insect pollinator richness, placing our discussion within the context of populations in predominantly agricultural landscapes in addition to urban environments. We highlight a selection of important evidence gaps, with a number of complementary research steps that can be taken to better understand: i) the stability of pollinator communities in different landscapes in order to provide diverse pollinator services; ii) how we can study the drivers of population change to mitigate the effects and support stable sources of pollinator services; and, iii) how we can manage habitats in complex landscapes to support insect pollinators and provide sustainable pollinator services for the future. We advocate a collaborative effort to gain higher quality abundance data to understand the stability of pollinator populations and predict future trends. In addition, for effective mitigation strategies to be adopted, researchers need to conduct rigorous field-testing of outcomes under different landscape settings, acknowledge the needs of end-users when developing research proposals and consider effective methods of knowledge transfer to ensure effective uptake of actions

Major Histocompatibility Complex (MHC) Markers in Conservation Biology

Human impacts through habitat destruction, introduction of invasive species and climate change are increasing the number of species threatened with extinction. Decreases in population size simultaneously lead to reductions in genetic diversity, ultimately reducing the ability of populations to adapt to a changing environment. In this way, loss of genetic polymorphism is linked with extinction risk. Recent advances in sequencing technologies mean that obtaining measures of genetic diversity at functionally important genes is within reach for conservation programs. A key region of the genome that should be targeted for population genetic studies is the Major Histocompatibility Complex (MHC). MHC genes, found in all jawed vertebrates, are the most polymorphic genes in vertebrate genomes. They play key roles in immune function via immune-recognition and -surveillance and host-parasite interaction. Therefore, measuring levels of polymorphism at these genes can provide indirect measures of the immunological fitness of populations. The MHC has also been linked with mate-choice and pregnancy outcomes and has application for improving mating success in captive breeding programs. The recent discovery that genetic diversity at MHC genes may protect against the spread of contagious cancers provides an added impetus for managing and protecting MHC diversity in wild populations. Here we review the field and focus on the successful applications of MHC-typing for conservation management. We emphasize the importance of using MHC markers when planning and executing wildlife rescue and conservation programs but stress that this should not be done to the detriment of genome-wide diversity

Implementation and evaluation of a multi-level mental health promotion intervention for the workplace (MENTUPP): study protocol for a cluster randomised controlled trial

Background Well-organised and managed workplaces can be a source of wellbeing. The construction, healthcare and information and communication technology sectors are characterised by work-related stressors (e.g. high workloads, tight deadlines) which are associated with poorer mental health and wellbeing. The MENTUPP intervention is a flexibly delivered, multi-level approach to supporting small- and medium-sized enterprises (SMEs) in creating mentally healthy workplaces. The online intervention is tailored to each sector and designed to support employees and leaders dealing with mental health difficulties (e.g. stress), clinical level anxiety and depression, and combatting mental health-related stigma. This paper presents the protocol for the cluster randomised controlled trial (cRCT) of the MENTUPP intervention in eight European countries and Australia. Methods Each intervention country will aim to recruit at least two SMEs in each of the three sectors. The design of the cRCT is based on the experiences of a pilot study and guided by a Theory of Change process that describes how the intervention is assumed to work. SMEs will be randomly assigned to the intervention or control conditions. The aim of the cRCT is to assess whether the MENTUPP intervention is effective in improving mental health and wellbeing (primary outcome) and reducing stigma, depression and suicidal behaviour (secondary outcome) in employees. The study will also involve a process and economic evaluation. Conclusions At present, there is no known multi-level, tailored, flexible and accessible workplace-based intervention for the prevention of non-clinical and clinical symptoms of depression, anxiety and burnout, and the promotion of mental wellbeing. The results of this study will provide a comprehensive overview of the implementation and effectiveness of such an intervention in a variety of contexts, languages and cultures leading to the overall goal of delivering an evidence-based intervention for mental health in the workplace

High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)

Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in >50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events. Protocol: We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment. Discussion: Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia. Trial registration: ISRCTN15668391 (17/06/2019

Health, education, and social care provision after diagnosis of childhood visual disability

Aim: To investigate the health, education, and social care provision for children newly diagnosed with visual disability.Method: This was a national prospective study, the British Childhood Visual Impairment and Blindness Study 2 (BCVIS2), ascertaining new diagnoses of visual impairment or severe visual impairment and blindness (SVIBL), or equivalent vi-sion. Data collection was performed by managing clinicians up to 1-year follow-up, and included health and developmental needs, and health, education, and social care provision.Results: BCVIS2 identified 784 children newly diagnosed with visual impairment/SVIBL (313 with visual impairment, 471 with SVIBL). Most children had associated systemic disorders (559 [71%], 167 [54%] with visual impairment, and 392 [84%] with SVIBL). Care from multidisciplinary teams was provided for 549 children (70%). Two-thirds (515) had not received an Education, Health, and Care Plan (EHCP). Fewer children with visual impairment had seen a specialist teacher (SVIBL 35%, visual impairment 28%, χ2p < 0.001), or had an EHCP (11% vs 7%, χ2p < 0 . 01).Interpretation: Families need additional support from managing clinicians to access recommended complex interventions such as the use of multidisciplinary teams and educational support. This need is pressing, as the population of children with visual impairment/SVIBL is expected to grow in size and complexity.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Towards Sustainable Environmental Quality : Priority Research Questions for the Australasian Region of Oceania

Environmental challenges persist across the world, including the Australasian region of Oceania, where biodiversity hotspots and unique ecosystems such as the Great Barrier Reef are common. These systems are routinely affected by multiple stressors from anthropogenic activities, and increasingly influenced by global megatrends (e.g., the food-energy-water nexus, demographic transitions to cities) and climate change. Here we report priority research questions from the Global Horizon Scanning Project, which aimed to identify, prioritize, and advance environmental quality research needs from an Australasian perspective, within a global context. We employed a transparent and inclusive process of soliciting key questions from Australasian members of the Society of Environmental Toxicology and Chemistry. Following submission of 78 questions, 20 priority research questions were identified during an expert workshop in Nelson, New Zealand. These research questions covered a range of issues of global relevance, including research needed to more closely integrate ecotoxicology and ecology for the protection of ecosystems, increase flexibility for prioritizing chemical substances currently in commerce, understand the impacts of complex mixtures and multiple stressors, and define environmental quality and ecosystem integrity of temporary waters. Some questions have specific relevance to Australasia, particularly the uncertainties associated with using toxicity data from exotic species to protect unique indigenous species. Several related priority questions deal with the theme of how widely international ecotoxicological data and databases can be applied to regional ecosystems. Other timely questions, which focus on improving predictive chemistry and toxicology tools and techniques, will be important to answer several of the priority questions identified here. Another important question raised was how to protect local cultural and social values and maintain indigenous engagement during problem formulation and identification of ecosystem protection goals. Addressing these questions will be challenging, but doing so promises to advance environmental sustainability in Oceania and globally

Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands