A developmental approach to fear, worry and rituals among typically developing children

The aim of the studies reported in this thesis was to take a developmental psycho-pathological approach to fear, worry and ritualistic behaviour in typical childhood. The first study examined developmental trends in, and interrelations between, fear, worry and ritualistic behaviour in childhood and adolescence. Content and intensity of fear, worry and ritualistic behaviour were assessed through a semi-structured interview administered to 142 typically developing children aged 7 to 16 years. In line with predictions, fear, worry and ritualistic behaviour decreased in intensity with age, although this decline was only significant between 7 and 10 years. Worry was found to be a particularly strong predictor of ritualistic behaviour across this age range. The second study followed up a sub-sample of these participants (N=80) in examining children's cognitive appraisals of anxiety-related thoughts, and showed predictable age-related decreases in strength of appraisals forethought-Action Fusion and Intolerance of Uncertainty, but not Responsibility. In support of the cognitive model of OCD, the previously observed relation between worry and ritualistic behaviour was mediated by biased cognitive appraisals, particularly Intolerance of Uncertainty. In the third study, a separate sample of 83 typically developing children aged 11 to 16 years reported on fear, worry and ritualistic behaviour, and also completed tasks designed to assess executive functioning in the orbitofrontal ('hot') and dorsolateral ('cool') neural systems. Predicted patterns of impaired 'hot' task performance combined with intact 'cool' task performance in high-anxiety participants were not observed, suggesting that characterisations of OCD in these terms may not apply to anxiety in typical childhood. Against prediction, performance was not impaired when personally salient versions of the orbitofrontal tasks were presented. However, there was a trend towards high levels of ritualistic behaviour being associated with impaired orbitofrontal task performance in the salience manipulation condition in boys only. Taken together, these studies demonstrate the value of taking a developmental psychopathological approach to anxiety processes in typical childhood. Theoretical considerations and implications for future research are discussed

The Mystery That Prevails: Drawing Fragmented Worlds

The body of work I have made for my thesis exhibition is built from organic imagery that hints at diagrammatic filtering of information, but repeats, contorts and layers to become an unsettling conversation between the known and the unknown. In this essay, I discuss my use of repetitive drawing and the rendering of strange, shifting landscapes as a means to describe the uncanny nature of my surroundings as I move from one place and experience to the next. At the same time, I discuss indirect concerns of shared displacement and discontent within a world of unforeseeable changes

Safeguarding People Living with Dementia: How Social Workers Can Use Supported Decision-making Strategies to Support the Human Rights of Individuals during Adult Safeguarding Enquiries.

Dementia may make adults more susceptible to abuse and neglect and such mistreatment is recognised as a human rights violation. This article focusses on how the rights of people living with dementia might be protected through the use of supported decision-making within safeguarding work. The article begins by reviewing the aims and scope of adult safeguarding services. It then describes how the concept of ‘legal capacity’ is set out in the UN Convention on the Rights of Persons with Disabilities (CRPD) and how this differs from the concept of ‘mental capacity’ in the Mental Capacity Act 2005. Focussing on practice in England, it is argued that tensions between the CRPD and domestic law exist, but these can be brought into closer alignment by finding ways to maximise supported decision-making within existing legal and policy frameworks. The article concludes with suggested practice strategies which involve: (i) providing clear and accessible information about safeguarding; (ii) thinking about the location of safeguarding meetings; (iii) building relationships with people living with dementia; (iv) using flexible timescales; (v) tailoring information to meet the needs of people living with dementia and (v) respecting the person’s will and preferences in emergency situations

Past Tense Formation in Williams Syndrome

It has been claimed that in the language systems of people with Williams syndrome (WS), syntax is intact but lexical memory is impaired. Evidence has come from past tense elicitation tasks with a small number of participants where individuals with WS are said to have a specific deficit in forming irregular past tenses. However, typically developing children also show poorer performance on irregulars than regulars in these tasks, and one of the central features of WS language development is that it is delayed. We compared the performance of 21 participants with WS on two past tense elicitation tasks with that of four typically developing control groups, at ages 6, 8, 10, and adult. When verbal mental age was controlled for, participants in the WS group displayed no selective deficit in irregular past tense performance. However, there was evidence for lower levels of generalisation to novel strings. This is consistent with the hypothesis that the WS language system is delayed because it has developed under different constraints, constraints that perhaps include atypical phonological representations. The results are discussed in relation to dual-mechanism and connectionist computational models of language development, and to the possible differential weight given to phonology versus semantics in WS development

Assessing the Impact of Substandard and Falsified Antimalarials in Benin

Substandard and falsified antimalarials contribute to the global malaria burden by increasing the risk of treatment failures, adverse events, unnecessary health expenditures, and avertable deaths. Yet no study has examined this impact in Western Francophone Africa to date. In Benin, where malaria remains endemic and is the leading cause of mortality among children under age five, there is a lack of robust data to combat the issue effectively and inform policy decisions. We adapted the Substandard and Falsified Antimalarial Research Impact (SAFARI) model to assess the health and economic impact of poor-quality antimalarials in this population. The model simulated population characteristics, malaria infection, care-seeking behavior, disease progression, treatment outcomes, and associated costs of malaria. We estimated approximately 1.8 million cases of malaria in Benin among children under age five, which cost $177 million (95$176 – $178 million) in treatment costs and productivity losses annually. Substandard and falsified antimalarials were responsible for 2.8$4.9 million in annual costs. Moreover, we found that replacing all antimalarials with quality-assured artemisinin combination therapies (ACTs) could result in $13.6 million in cost-savings, and increasing pediatric malaria care-seeking by 20$19.4 million in cost-savings. These results highlight the value of improving access to quality-assured ACTs for malaria treatment and increasing care-seeking in Benin. Policymakers and key stakeholders should use these findings to advocate for increased access to quality-assured antimalarials, inform policies and interventions to improve healthcare access and quality, and reduce the burden of malaria.Doctor of Pharmac

One health for neglected tropical diseases

The forthcoming World Health Organization road map for neglected tropical diseases (NTDs) 2021–2030 recognises the complexity surrounding control and elimination of these 20 diseases of poverty. It emphasises the need for a paradigm shift from disease-specific interventions to holistic cross-cutting approaches coordinating with adjacent disciplines. The One Health approach exemplifies this shift, extending beyond a conventional model of zoonotic disease control to consider the interactions of human and animal health systems within their shared environment and the wider social and economic context. This approach can also promote sustainability and resilience within these systems. To achieve the global ambition on NTD elimination and control, political will, along with contextualised innovative scientific strategies, is required.http://trstmh.oxfordjournals.orghj2021Veterinary Tropical Disease

Cost savings of paper analytical devices (PADs) to detect substandard and falsified antibiotics: Kenya case study

Background: Over 10% of antibiotics in low- and middle-income countries (LMICs) are substandard or falsified. Detection of poor-quality antibiotics via the gold standard method, high-performance liquid chromatography (HPLC), is slow and costly. Paper analytical devices (PADs) and antibiotic paper analytical devices (aPADs) have been developed as an inexpensive way to estimate antibiotic quality in LMICs. Aim: To model the impact of using a rapid screening tools, PADs/aPADs, to improve the quality of amoxicillin used for treatment of childhood pneumonia in Kenya. Methods: We developed an agent-based model, ESTEEM (Examining Screening Technologies with Economic Evaluations for Medicines), to estimate the effectiveness and cost savings of incorporating PADs and aPADs in amoxicillin quality surveillance in Kenya. We compared the current testing scenario (batches of entire samples tested by HPLC) with an expedited HPLC scenario (testing smaller batches at a time), as well as a screening scenario using PADs/aPADs to identify poor-quality amoxicillin followed by confirmatory analysis with HPLC. Results: Scenarios using PADs/aPADs or expedited HPLC yielded greater incremental benefits than the current testing scenario by annually averting 586 (90% uncertainty range (UR) 364-874) and 221 (90% UR 126-332) child pneumonia deaths, respectively. The PADs/aPADs screening scenario identified and removed poor-quality antibiotics faster than the expedited or regular HPLC scenarios, and reduced costs significantly. The PADs/aPADs scenario resulted in an incremental return of $14.9 million annually compared with the reference scenario of only using HPLC. Conclusion: This analysis shows the significant value of PADs/aPADs as a medicine quality screening and testing tool in LMICs with limited resources

The ERBB network facilitates KRAS-driven lung tumorigenesis

KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of the lung. There are presently no clinically proven strategies for treatment of KRAS-driven lung cancer. Activating mutations in KRAS are thought to confer independence from upstream signaling; however, recent data suggest that this independence may not be absolute. We show that initiation and progression of KRAS-driven lung tumors require input from ERBB family receptor tyrosine kinases (RTKs): Multiple ERBB RTKs are expressed and active from the earliest stages of KRAS-driven lung tumor development, and treatment with a multi-ERBB inhibitor suppresses formation of KRASG12D-driven lung tumors. We present evidence that ERBB activity amplifies signaling through the core RAS pathway, supporting proliferation of KRAS-mutant tumor cells in culture and progression to invasive disease in vivo. Brief pharmacological inhibition of the ERBB network enhances the therapeutic benefit of MEK (mitogen-activated protein kinase kinase) inhibition in an autochthonous tumor setting. Our data suggest that lung cancer patients with KRAS-driven disease may benefit from inclusion of multi-ERBB inhibitors in rationally designed treatment strategies

Development of an agent-based model to assess the impact of substandard and falsified anti-malarials: Uganda case study

Background Global efforts to address the burden of malaria have stagnated in recent years with malaria cases beginning to rise. Substandard and falsified anti-malarial treatments contribute to this stagnation. Poor quality anti-malarials directly affect health outcomes by increasing malaria morbidity and mortality, as well as threaten the effectiveness of treatment by contributing to artemisinin resistance. Research to assess the scope and impact of poor quality anti-malarials is essential to raise awareness and allocate resources to improve the quality of treatment. A probabilistic agent-based model was developed to provide country-specific estimates of the health and economic impact of poor quality anti-malarials on paediatric malaria. This paper presents the methodology and case study of the Substandard and Falsified Antimalarial Research Impact (SAFARI) model developed and applied to Uganda. Results The total annual economic impact of malaria in Ugandan children under age five was estimated at US$614 million. Among children who sought medical care, the total economic impact was estimated at$403 million, including $57.7 million in direct costs. Substandard and falsified anti-malarials were a significant contributor to this annual burden, accounting for$31 million (8% of care-seeking children) in total economic impact involving $5.2 million in direct costs. Further, 9$48.5 million in additional economic impact annually. Conclusions Improving the quality of treatment is essential to combat the burden of malaria and prevent the development of drug resistance. The SAFARI model provides country-specific estimates of the health and economic impact of substandard and falsified anti-malarials to inform governments, policy makers, donors and the malaria community about the threat posed by poor quality medicines. The model findings are useful to illustrate the significance of the issue and inform policy and interventions to improve medicinal quality

Optimisation of sample preparation from primary mouse tissue to maintain RNA integrity for methods examining translational control

The protein output of different mRNAs can vary by two orders of magnitude; therefore, it is critical to understand the processes that control gene expression operating at the level of translation. Translatome-wide techniques, such as polysome profiling and ribosome profiling, are key methods for determining the translation rates occurring on specific mRNAs. These techniques are now widely used in cell lines; however, they are underutilised in tissues and cancer models. Ribonuclease (RNase) expression is often found to be higher in complex primary tissues in comparison to cell lines. Methods used to preserve RNA during lysis often use denaturing conditions, which need to be avoided when maintaining the interaction and position of the ribosome with the mRNA is required. Here, we detail the cell lysis conditions that produce high-quality RNA from several different tissues covering a range of endogenous RNase expression levels. We highlight the importance of RNA integrity for accurate determination of the global translation status of the cell as determined by polysome gradients and discuss key aspects to optimise for accurate assessment of the translatome from primary mouse tissue