The case for early use of rapid whole-genome sequencing in management of critically ill infants: late diagnosis of Coffin-Siris syndrome in an infant with left congenital diaphragmatic hernia, congenital heart disease, and recurrent infections.

Congenital diaphragmatic hernia (CDH) results from incomplete formation of the diaphragm leading to herniation of abdominal organs into the thoracic cavity. CDH is associated with pulmonary hypoplasia, congenital heart disease, and pulmonary hypertension. Genetically, it is associated with aneuploidies, chromosomal copy-number variants, and single gene mutations. CDH is the most expensive noncardiac congenital defect. Management frequently requires implementation of extracorporeal membrane oxygenation (ECMO), which increases management expenditures 2.4-3.5-fold. The cost of management of CDH has been estimated to exceed $250 million per year. Despite in-hospital survival of 80%-90%, current management is imperfect, as a great proportion of surviving children have long-term functional deficits. We report the case of a premature infant prenatally diagnosed with CDH and congenital heart disease, who had a protracted and complicated course in the intensive care unit with multiple surgical interventions, including postcardiac surgery ECMO, gastrostomy tube placement with Nissen fundoplication, tracheostomy for respiratory failure, recurrent infections, and developmental delay. Rapid whole-genome sequencing (rWGS) identified a de novo, likely pathogenic, c.3096_ 3100delCAAAG (p.Lys1033Argfs*32) variant in ARID1B, providing a diagnosis of Coffin-Siris syndrome. Her parents elected palliative care and she died later that day

Potentially Diagnostic Electron Paramagnetic Resonance Spectra Elucidate the Underlying Mechanism of Mitochondrial Dysfunction in the Deoxyguanosine Kinase Deficient Rat Model of a Genetic Mitochondrial DNA Depletion Syndrome

A novel rat model for a well-characterized human mitochondrial disease, mitochondrial DNA depletion syndrome with associated deoxyguanosine kinase (DGUOK) deficiency, is described. The rat model recapitulates the pathologic and biochemical signatures of the human disease. The application of electron paramagnetic (spin) resonance (EPR) spectroscopy to the identification and characterization of respiratory chain abnormalities in the mitochondria from freshly frozen tissue of the mitochondrial disease model rat is introduced. EPR is shown to be a sensitive technique for detecting mitochondrial functional abnormalities in situ and, here, is particularly useful in characterizing the redox state changes and oxidative stress that can result from depressed expression and/or diminished specific activity of the distinct respiratory chain complexes. As EPR requires no sample preparation or non-physiological reagents, it provides information on the status of the mitochondrion as it was in the functioning state. On its own, this information is of use in identifying respiratory chain dysfunction; in conjunction with other techniques, the information from EPR shows how the respiratory chain is affected at the molecular level by the dysfunction. It is proposed that EPR has a role in mechanistic pathophysiological studies of mitochondrial disease and could be used to study the impact of new treatment modalities or as an additional diagnostic tool

Optimisation of spray dryer with nebulisation head

The use of nanotechnology in the food industry has grown significantly in the last decade. As part of a wider project investigating the novel technology Carbon Dioxide Assisted Spray Nebulisation Drying (CASND), this thesis examines two particular dryer models used to produce nanoparticles and analyses their functionality from a mechanical engineering perspective. After providing a broad background in dehydration and nanoparticle technology, the dryer design is outlined, followed by the mass flow balance and numerical simulations of airflow. The results are discussed and recommendations for further developments are proposed.The use of nanotechnology in the food industry has grown significantly in the last decade. As part of a wider project investigating the novel technology Carbon Dioxide Assisted Spray Nebulisation Drying (CASND), this thesis examines two particular dryer models used to produce nanoparticles and analyses their functionality from a mechanical engineering perspective. After providing a broad background in dehydration and nanoparticle technology, the dryer design is outlined, followed by the mass flow balance and numerical simulations of airflow. The results are discussed and recommendations for further developments are proposed

Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes

Case Studies on various approaches to using Technology as a driver for African Development

Sub-Saharan Africa (SSA) has been largely left behind in the last century's race for development. This thesis explores the connection between innovation and standard of living in the context of technology. We address the question: What can be learned from current efforts to use technology to resolve real-life issues encountered by Africans, and how can this be applied in new contexts?Sub-Saharan Africa (SSA) has been largely left behind in the last century's race for development. This thesis explores the connection between innovation and standard of living in the context of technology. We address the question: What can be learned from current efforts to use technology to resolve real-life issues encountered by Africans, and how can this be applied in new contexts? Initially we conduct a broad overview of the situation in SSA, concentrating on the areas of health, clean water, power and transport infrastructure. By studying two specific companies, Zipline and Desert Rose working respectively in the fields of drone distribution and water filtration, we examine their approaches to the African market, the needs which they address and their chosen solutions to meet those needs. Finally, we propose our own project, to establish a solar panel factory using the principles which we have discovered, selecting the optimum country and conducting a brief study into feasibility. The principles established in the paper relate to the need for innovation, a careful choice of country in which to locate, the use of robust designs and the importance of working closely with Africans. These are of value to investors in the continent, and those considering humanitarian work through the medium of business. Taking them into consideration can help challenge the way we approach sustainable development, prioritising the inclusion of Africans in the process

Common data elements for clinical research in mitochondrial disease: a National Institute for Neurological Disorders and Stroke project

Objectives The common data elements (CDE) project was developed by the National Institute of Neurological Disorders and Stroke (NINDS) to provide clinical researchers with tools to improve data quality and allow for harmonization of data collected in different research studies. CDEs have been created for several neurological diseases; the aim of this project was to develop CDEs specifically curated for mitochondrial disease (Mito) to enhance clinical research. Methods Nine working groups (WGs), composed of international mitochondrial disease experts, provided recommendations for Mito clinical research. They initially reviewed existing NINDS CDEs and instruments, and developed new data elements or instruments when needed. Recommendations were organized, internally reviewed by the Mito WGs, and posted online for external public comment for a period of eight weeks. The final version was again reviewed by all WGs and the NINDS CDE team prior to posting for public use

The effect of men's body attitudes and motivation for gym attendance

The current study integrates men's body attitudes with implicitly and explicitly measured motivation to investigate the role of these factors in predicting gym attendance. Male participants (N = 99) who regularly attended a gym were recruited to participate in an online questionnaire. Participants completed implicit and explicit measures of motivation, explicitly-measured men's body attitudes, and reported the average number of gym visits per week. Attitudes related to body fat and explicitly-measured autonomous motivation significantly predicted typical gym attendance. Implicitly-measured motivation significantly and negatively predicted gym attendance. Results indicate some support for a dual-systems account of gym attendance. Men's body attitudes and autonomous motivation influences gym attendance; however, implicitly-measured motivation showed antagonistic effects. While individuals may explicitly state their autonomous motivation for gym attendance, attendance may be influenced at the explicit level. Health and fitness professionals may improve gym attendance by focusing on people's reasons for attending a gym, facilitating autonomous motivation in clients, and minimising the influence of controlled reasons for exercise

Contesting the psychiatric framing of ME / CFS

ME/CFS is a medically contested illness and its understanding, framing and treatment has been the subject of heated debate. This paper examines why framing the condition as a psychiatric issue—what we refer to as ‘psychiatrisation’—has been so heavily contested by patients and activists. We argue that this contestation is not simply about stigmatising mental health conditions, as some have suggested, but relates to how people diagnosed with mental illness are treated in society, psychiatry and the law. We highlight the potentially harmful consequences of psychiatrisation which can lead to people’s experiential knowledge being discredited. This stems, in part, from a psychiatric-specific form of ‘epistemic injustice’ which can result in unhelpful, unwanted and forced treatments. This understanding helps explain why the psychiatrisation of ME/CFS has become the focus of such bitter debate and why psychiatry itself has become such a significant field of contention, for both ME/CFS patients and mental health service users/survivors. Notwithstanding important differences, both reject the way psychiatry denies patient explanations and understandings, and therefore share a collective struggle for justice and legitimation. Reasons why this shared struggle has not resulted in alliances between ME and mental health activists are noted