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Development of Attention-based Prediction Models for All-cause Mortality, Home Care Need, and Nursing Home Admission in Ageing Adults in Spain Using Longitudinal Electronic Health Record Data
Get PDFPredicting health-related outcomes can help with proactive healthcare planning and resource management. This is especially important on the older population, an age group growing in the coming decades. Considering longitudinal rather than cross-sectional information from primary care electronic health records (EHRs) can contribute to more informed predictions. In this work, we developed prediction models using longitudinal EHRs to inform resource allocation. In this study, we developed deep-learning-based prognostic models to predict 1-year and 5-year all-cause mortality, nursing home admission, and home care need in people over 65 years old using all the longitudinal information from EHRs. The models included attention mechanisms to increase their transparency. EHRs were drawn from SIDIAP (primary care, Catalonia (Spain)) from 2010-2019. Performance on the test set was compared to that from baseline models using cross-sectional one-year history only. Data from 1,456,052 individuals over 65 years old were considered. Cohen’s kappa obtained using longitudinal data was 3.4-fold (1-year all-cause mortality), 10.3-fold (5-year all-cause mortality), 1.1-fold (5-year nursing home admission), and 1.2-fold (5-year home care need) higher than that obtained by the one-year history baseline models. Our models performed better than those not considering longitudinal data, especially when predicting further into the future. However, nursing home admission and home care need in the long term were harder to predict, suggesting their dependence on more abrupt changes. The attention maps helped to understand the predictions, enhancing model transparency. These prediction models can contribute to improve resource allocation in the general population of aging adults
Identifying novel neuromodulator targets of human cognition
No full textImpaired cognition is often overlooked in the clinical management of depression, despite being a principal modulator of perceived disability and quality of life within depression (Knight, Air, & Baune, 2018; Knight, Lyrtzis, & Baune, 2020; Koenig, Bhalla, & Butters, 2014; Naismith, Longley, Scott, & Hickie, 2007). There is an outstanding need for new treatments to address this unmet clinical need: this thesis focuses on the identification of novel neuromodulator targets of human cognition which offer therapeutic promise for cognitive impairment in depression. Chapter 1 of this thesis reviews the evidence which supports the pharmacological targeting of impaired cognition in individuals with depression. This review was informed by interviews (PPI consultations) with individuals with lived experience of depression, helping shape research priorities within this thesis. As a result of this review, promising targets of cognitive function in humans were identified for investigation, including the serotoninergic and histaminergic system. In Chapters 2 and 3, we use a unique approach to increasing synaptic serotonin levels in humans – a selective serotonin releasing agent – to examine its effect on human cognition and emotional processing. In Chapters 4 and 5, the effects of histamine autoreceptor blockade on cognition and neural dynamics in humans are explored. The research covered in Chapters 2–5 employs an experimental medicine approach, where healthy volunteers are used to model the cognitive effects of pharmacological interventions to assess their viability for clinical translation. Chapter 6, the final chapter, unifies the research findings reported within this thesis, placing them in a broader literature context, with suggestions for potential directions of travel for future research. The experimental findings presented in this thesis provide a foundation for future translational research to explore the therapeutic potential of these drug mechanisms within clinical populations
Identifying antifungal resistance mechanisms and modes of action using SAturated Transposon Analysis in Yeast (SATAY)
No full textFungal pathogens are a serious burden for public health and global food security. This problem is exacerbated by the rapid emergence of resistance to our limited armamentarium of antifungal compounds. The future control of fungal diseases therefore depends on the discovery of antifungals with novel modes of action and the development of robust resistance management strategies. These strategies require a comprehensive understanding of the molecular mechanisms governing antifungal resistance, yet our knowledge is incomplete.
Recently, a powerful transposon sequencing method was developed in Saccharomyces cerevisiae, called SAturated Transposon Analysis in Yeast (SATAY). SATAY couples saturated transposon mutagenesis to next-generation sequencing, allowing the genome-wide identification of growth-affecting loci in a straightforward and time-efficient manner. Importantly, SATAY can identify loss- and gain-of-function mutations conferring antifungal resistance, as well as the direct targets of antifungal compounds.
This thesis applies SATAY to uncover novel antifungal resistance mechanisms and to examine the modes of action of nine antifungal compounds. These screens reveal antifungal drug targets, transporters responsible for drug uptake or efflux, as well as metabolic, signalling and trafficking pathways affecting antifungal susceptibility. The most novel and interesting findings in these screens are characterised further. This includes the discovery of Hol1 as the transporter that concentrates the potent antifungal ATI-2307 within yeast, a finding that unveils a straightforward evolutionary path to ATI-2307 resistance with minimal fitness cost. SATAY is also performed in drug-sensitive strains to examine antifungals that lack activity against conventional laboratory strains. This approach is utilised to test a previously proposed model for the mode of action of Fludioxonil, and identifies cell wall mannosylphosphate as the target for the natural antifungal Chitosan. Together, this thesis improves our understanding of several antifungal modes of action and unveils a diverse array of resistance mechanisms, supporting efforts to address the increasing threats posed by multidrug-resistant fungal pathogens
Rethinking the evidence on COVID-19 in Africa
Get PDFThe COVID-19 pandemic was predicted to cause substantial mortality in Africa. However, some countries in Africa had a striking absence of overwhelmed hospitals and low reported mortality. The marked contrast with the overwhelmed hospitals and high mortality seen in Europe and other high-income settings was regarded as puzzling and a paradox. In this Review, we reflect on possible explanations for the paradox with particular reference to observations made on the ground in Kenya. The evidence is inconsistent with reduced viral transmission or poor surveillance as primary explanations for the discrepancy. Population age structure is an important but incomplete explanation of the epidemiology. Due to the high prevalence of asymptomatic infection, low mortality, and evidence of reduced inflammatory responses, we hypothesise that some populations in Africa might have reduced susceptibility to symptomatic COVID-19. The reduced inflammatory responses might result from immunoregulation or cross-reactive, pre-pandemic cellular immunity, although the evidence is not definitive. Local data are essential to develop public health policies that align with the reality on the ground rather than external perceptions
Climate change mitigation policies for developing countries
Get PDFFollowing the Paris Agreement, many low- and middle-income countries (LMICs) have adopted climate change targets. They will need climate policies that are suited to their socioeconomic and institutional contexts. Conventional policy prescriptions are geared toward high-income countries with entrenched high-carbon structures, universal energy access, deep financial markets, formal economies, privatized power markets, a capable public sector, and relative macroeconomic stability. Not all of these assumptions generalize to LMICs. Here, we synthesize what is known about emissions reduction policies in LMICs. We find a strong emphasis on finance interventions and regulatory measures, including the need for power sector reform. Current scholarship focuses heavily on removing existing price distortions, with less emphasis on carbon pricing. Carbon pricing is discussed mostly for middle-income countries, where some pilot schemes exist and institutional capacity constraints are less severe. Prescriptions for skills-related policies focus on capacity building and preparing a young population for a changing labor market rather than reskilling the existing workforce
Sleep and circadian difficulties in schizophrenia: presentations, understanding, and treatment
Get PDFIt is common in mental health care to ask about people’s days but comparatively rare to ask about their nights. Most patients diagnosed with schizophrenia struggle at nighttime. The next-day effects can include a worsening of psychotic experiences, affective disturbances, and inactivity, which in turn affect the next night’s sleep. Objective and subjective cognitive abilities may be affected too. Patients commonly experience a mix of sleep difficulties in a night and across a week. These difficulties include trouble falling asleep, staying asleep, or sleeping at all; nightmares and other awakenings; poor-quality sleep; oversleeping; tiredness; sleeping at the wrong times; and problems establishing a regular sleep pattern. The patient group is also more vulnerable to obstructive sleep apnea and restless legs syndrome. We describe in this article how the complex presentation of non-respiratory sleep difficulties arises from variation across five factors: timing, mental state, need for sleep, self-care, and environment. We set out 10 illustrative patterns of such difficulties experienced by patients with non-affective psychosis. These sleep problems are eminently treatable with intensive psychological therapy delivered over approximately eight sessions. We describe key techniques and their typical order of implementation by presentation. Sleep problems are an important issue for patients. Giving them the therapeutic attention patients often desire brings both real clinical benefits and improves views of services. Treatment is also very likely to lessen psychotic experiences and mood disturbances while improving daytime functioning and quality of life. Tackling sleep difficulties can be a route toward the successful treatment of psychosis
Development of fibrin applications in tissue engineering: design, fabrication and characterisation
No full textThis thesis investigates the use of fibrin as a scaffold material in tissue engineering applications. Fibrin is a glycoprotein critical to a range of physiological processes. As a result of its unique combination of natural biological and mechanical properties, fibrin has been considered a highly promising potential biomaterial for use in a range of tissue engineering applications. However, certain properties of fibrin make it a particularly difficult material to work with. Especially, low mechanical strength, rapid rate of degradation, high shrinkage and dense microstructure in gel form have given rise to significant challenges. The primary aim of this study is to propose functional solutions to these challenges, accelerating the use of fibrin in a range of tissue engineering applications. In doing so, it seeks to establish and optimise effective strategies for processing fibrin as a key component in both soft and hard tissue scaffolds.
The first experimental chapter introduces fibrin as a biofunctionalisation coating on polycaprolactone sheets, employing a chemical modification technique to improve cell attachment and cell response. The results demonstrated significant improvement across cell attachment and proliferation, as well as in osteoblast activity.
The second experimental chapter documents the development of a novel fibrin bioink formulation for use in the production of 3D bioprinted soft tissue scaffolds. Fibrin inks were combined with emulsions and gelatin to create large pore sizes, and to achieve a balance of the required mechanical and biological properties within the final scaffold structure.
The results are further developed in the third experimental chapter, where the proposed bioink formulation was evaluated through an extensive printing assessment. This qualitative research was critical to the process of optimising the bioink formulation to achieve the qualities required for successful printability. 3D bioprinted scaffolds were structurally, mechanically, and biologically characterised. The results demonstrated fibrous, highly porous scaffolds with suitable mechanical properties, while cell assays revealed robust cell attachment and proliferation on the scaffolds.
In summary, two distinct strategies have been successfully developed to advance the use of fibrin in the production of biologically active structures in tissue applications, offering potential benefits to patients by enhancing tissue regeneration and improving healing outcomes in clinical treatments
CountGD: multi-modal open-world counting
Get PDFThe goal of this paper is to improve the generality and accuracy of open-vocabulary object counting in images. To improve the generality, we repurpose an openvocabulary detection foundation model (GroundingDINO) for the counting task, and also extend its capabilities by introducing modules to enable specifying the target object to count by visual exemplars. In turn, these new capabilities – being able to specify the target object by multi-modalites (text and exemplars) – lead to an improvement in counting accuracy. We make three contributions: first, we introduce the first open-world counting model, COUNTGD, where the prompt can be specified by a text description or visual exemplars or both; second, we show that the performance of the model significantly improves the state of the art on multiple counting benchmarks – when using text only, COUNTGD is comparable to or outperforms all previous text-only works, and when using both text and visual exemplars, we outperform all previous models; third, we carry out a preliminary study into different interactions between the text and visual exemplar prompts, including the cases where they reinforce each other and where one restricts the other. The code and an app to test the model are available at https://www.robots.ox.ac.uk/vgg/research/countgd/
After neonatal care, what next? A qualitative study of mothers’ post-discharge experiences after premature birth in Kenya
Get PDFBackground: Approximately 15 million babies are born prematurely every year worldwide. Sub-Saharan Africa (SSA) and Asia account for more than half of the global preterm deliveries. Prominent healthcare structural and socio-economic factors in SSA, for example poverty and weak health systems, amplify vulnerabilities for mothers and premature babies; often leading to poor outcomes. Post-discharge mortality rates are high, and readmission is common. For mothers of premature babies, the transition home from hospital is marked by challenges and uncertainties. This study explored the post-discharge experiences of mothers of premature babies with the aim of identifying their needs and suggests strategies to strengthen and support their discharge preparation to care for their premature baby at home, and to and reduce mortality and readmission rates. Methods: Narrative interviews were conducted face-to-face in English or Swahili with 34 mothers of premature babies recruited from two public hospitals and a social support group in Nairobi, Kenya between August—November 2021. Interviews were audio and video-recorded and transcribed for analysis. After transcription, the interviews were translated, where applicable, and thematic analysis was undertaken. Results: For mothers of premature babies, discharge from neonatal care and the transition home is a complex process marked with mixed emotions; many reported feeling unprepared and facing stigma while in hospital and in their communities. Mothers described the emotional challenges of discharge from the neonatal unit and their information and support needs. Minimal involvement in their baby’s care while in the neonatal unit appeared to contribute to the mothers’ lack of confidence in caring for their babies independently post-discharge when they no longer had the support of the clinical and nursing staff. Insufficient information provided on discharge hindered a smooth transition to home, highlighting the need for information to support mothers’ confidence after discharge. Stigma relating to beliefs around preterm births was experienced by some of the mothers in the community and within some health clinics. Conclusions: To support transitions home, strengthening the timing and adequacy of information provided to mothers at discharge from the neonatal unit in low-income settings in SSA and Asia – such as Kenya—is essential. Introducing strategies to build and assess mothers’ competencies with skills such as breastfeeding and identifying signs of deterioration before discharge could support their smooth transition home. Targeted engagement interventions at the community level could demystify and address stigma and knowledge gaps about premature deliveries at the community and social levels more broadly and within the health system
A manifesto for a globally diverse, equitable, and inclusive open science
Get PDFThe field of psychology has rapidly transformed its open science practices in recent years. Yet there has been limited progress in integrating principles of diversity, equity and inclusion. In this Perspective, we raise the spectre of Questionable Generalisability Practices and the issue of MASKing (Making Assumptions based on Skewed Knowledge), calling for more responsible practices in generalising study findings and co-authorship to promote global equity in knowledge production. To drive change, researchers must target all four key components of the research process: design, reporting, generalisation, and evaluation. Additionally, macro-level geopolitical factors must be considered to move towards a robust behavioural science that is truly inclusive, representing the voices and experiences of the majority world (i.e., low-and-middle-income countries)