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Delineating biallelic PI4KA variants as a cause of a complex neurological, gastrointestinal and immunological syndromic disorder
No full textThis thesis documents clinical, genomic and functional studies of a novel, highly variable and mechanistically complex syndrome associated with biallelic PI4KA variants (PI4KA-related disorder), which encodes phosphatidylinositol 4-kinase alpha (PI4KIIIa), a protein central to multiple cellular signalling pathways and the maintenance of cell polarity, actin dynamics and plasma membrane identity. Chapter three describes the discovery of PI4KA-related disorder. This finding, stemming from investigations in an extended Amish pedigree with a distinct, severe neonatally lethal multiple intestinal atresia (MIA), entailed clinical and molecular studies. Nine additional affected individuals from seven unrelated families were subsequently identified with phenotypes ranging from a severe antenatal neurodevelopmental presentation to a complex neurodevelopmental disorder of varying severity with/without an associated immunodeficiency and/or gastrointestinal symptomatology. These clinical presentations exhibit significant overlap to disorders associated with biallelic variants in PI4KIIIα’s molecular binding partners; TTC7A-related gastrointestinal defects and immunodeficiency syndrome, and HYCC1-related hypomyelinating leukodystrophy 5. Protein modelling and in vitro functional studies presented in this chapter identify a likely pathomechanism for the extensive clinical variability. Chapter four documents studies that further delineate the phenotypic spectrum and genetic basis of PI4KA-related disorder in 44 affected individuals, and enable development of clinical management guidelines. Four overlapping clinical subtypes that are characteristic of the condition were identified, with onset ranging from foetal to adult life. Protein modelling studies show utility in variant classification when combined with detailed clinical phenotyping. Whilst genotype-phenotype correlations cannot be comprehensively ascribed due to the inherent molecular complexities of PI4KIIIa function, correlations were identified associated with both gastrointestinal and neurological presentations. Chapter five describes data from collaborative studies of the immunological aspects of PI4KA-related disorder. These define B-cell anomalies, with failure of B-cell differentiation, as the predominate immunopathology alongside treatment options that may improve morbidity and mortality. This chapter also documents the development of the PI4KA-Community support group, website and establishment of a patient registry in partnership with parents of a child with the condition. In combination, these will enable ongoing investigations into the natural history of this rare disorder and dissemination of translational research findings. Together these studies provide important new scientific and clinical insights into the complex pathomolecular basis and diverse phenotypic spectrum of PI4KA-related disorder. In turn this facilitates improved diagnostic provision and provides an exceptional opportunity to develop therapeutic interventions, ultimately improving healthcare outcomes
Design of a web-based intervention for the rehabilitation of balance following traumatic brain injury in military personnel
No full textTraumatic Brain Injury (TBI) is the most common neurological injury treated at the Defence Medical Rehabilitation Centre accounting for approximately 80% of referrals to the Neurological Rehabilitation Team (Dharm-Datta et al. 2015). TBI is associated with a range of deficits including physical, cognitive, behavioural and those effecting executive function (Jaeger et al. 2014). Balance problems have been shown to be present long-term in 43% of persons with TBI, and dizziness symptoms are present in up to 80% of TBI patients in the first 24 hours (Jourdan et al. 2016, Maskell et al. 2007). ‘Balance Retraining’, is a web-supported programme, that assists older people to overcome balance problems and dizziness symptoms (Essery et al. 2015), but it has not been designed for use by people with TBI, taking into consideration their potential range of deficits. Gaining an understanding of the target population is vital to create an intervention that is accessible to people with TBI. This study aimed to design an online balance rehabilitation programme for military personnel with TBI. The objective was to conduct FGs with HCPs that have experience of working military personnel who have sustained a TBI. The FGs aimed to discover their experiences of working with this population and gain their opinions on the existing ‘Balance Retraining’ programme to discover if changes were necessary so that it could be used by people in the military with TBI. This was an Interpretative Phenomenological Analysis study. A combination of previously described IPA methods were used to analyse the FG data. These findings were then used to inform design changes for a prototype website. Findings from the FGs discovered that TBI is a complex and multi-faceted disorder and each TBI patient is unique. To meet these individual needs HCPs described the importance of a specialist MDT and the need to consider each patients’ complexities when conducting balance rehabilitation. Being in the military is described as resulting in different challenges and demands from their rehabilitation. These complexities all effect the design of a web-based programme for this population and these factors were described in five categories, visual presentation, military concepts, programme features, communicating information and getting patient buy in. Subsequent research should focus on creating a prototype website using the findings from this study. Think-aloud studies with TBI patients in the military followed by a series of case studies and a feasibility study should be considered to develop and create the prototype website programme
Multi-objective pareto optimal power quality improvement in distribution systems
No full textThe present study proposes a multi-objective optimized Electric Spring (ES) operation to improve the voltage regulation and overall power quality in a distribution system. A suitable controller has been designed for the ES implementing the Multi-objective artificial cooperative search (MOACS) optimization algorithm. The objectives are to enhance the system power factor, regulate the critical load voltage, and minimize the neutral current. The proposed technique provides satisfactory results with intermittent energy source also. The performance of MOACS has been compared with particle swarm optimization (PSO) and harmony search (HS) algorithms. It has been observed that the improvement in power factor and reduction of neutral current is much more with MOACS compared to PSO and HS. The power quality factors obtained with PSO are 0.9136, 0.9257, and 0.9146 for three different sets of loads, whereas, with HS, these values are 0.9072, 0.9324, and 0.8985. The same index improves to 0.9465, 0.9392, and 0.9307 with MOACS, which proves the efficacy of MOACS algorithm. The validation of the proposed scheme through real-time simulation confirms the reliability of this scheme
Injury and local injection and the risk of foot/ankle osteoarthritis: a case-control study in retired UK male professional footballers
No full textObjectives: to examine whether foot/ankle injury and injection contribute to the risk of foot/ankle OA in retired UK male professional footballers.Methods: this was a case-control study within retired UK male footballers, where cases reported General Practitioner diagnosed foot/ankle OA or forefoot/ankle surgery after retirement, and controls reported neither. Injury was defined as significant foot/ankle injury with pain for most days over three months during their career. Injection was defined as injection of corticosteroid or other agents into foot/ankle joints during their career. Adjusted odds ratio (aOR) with 95% confidence intervals (CI) were calculated using logistic regression. Area Under the Curve (AUC) and 95% CI were estimated to examine the contribution of injury and/or injection in the context of other available risk factors.Results: of 424 footballers studied, 63 had foot/ankle OA and 361 had neither. Cases had similar mean age (63.2 versus 63.0, p=0.457) and body mass index (27.7 versus 27.0, p=0.240) as controls, but more foot/ankle injury (73.3% versus 42.5%, p<0.001) and injections (75.0% versus 48.4%, p<0.001), with aORs of 4.23 (95% CI 1.88-9.48) and 2.62 (95% CI 1.19-5.78), respectively. AUC was 0.69 (95% CI 0.62-0.77) for injury, 0.74 (95% CI 0.66-0.81) for injury and injection, and 0.78 (95% CI 0.70-0.85) for all risk factors. Similar results were observed in footballers with ankle OA only.Conclusion: injury was a major risk factor for foot/ankle OA in retired UK male professional footballers. The role of injection needs cautious interpretation due to potential confounding by indication
Challenges and opportunities in scaling enhanced weathering for carbon dioxide removal
No full textTerrestrial enhanced weathering (EW) on agricultural lands is a proposed carbon dioxide removal (CDR) technology involving the amendment of soils with crushed base cation-rich rocks, such as basalt. Over a quarter of a billion dollars have been raised by commercial EW start-ups across the globe, accelerating the deployment of EW at scale. In this Review, we outline the scientific knowledge and policy requirements for scaling EW. The global CDR potential of EW is 0.5–2 Gt CO 2 year by 2050. Tracking carbon as it is transferred from soils (cradle) to the oceans (grave), fully considering and quantifying lag times in CDR and developing a robust framework of monitoring, reporting and verification of CDR are all important for understanding the performance of EW deployments. Policies aimed at incentivizing responsible deployment and gaining acceptability among directly impacted communities, such as agriculture, are essential to sustainable and long-term growth of EW. High initial prices, the lack of consistent methodology for issuing carbon credits and lifecycle carbon emissions associated with a deployment are the main challenges of scaling EW through the voluntary carbon market. Future research needs to explore the co-deployment of EW and other CDR technologies and utilize long-term (>10 years) instrumented EW field trials to evaluate processes that regulate CDR efficiency and agronomic and economic co-benefits
Low-temperature solution-processed growth of ternary (Bi1−xSbx)2S3 films
No full textThe development of low-temperature deposition methods for ternary metal chalcogenides is significant for advancing electronics and optoelectronic devices, where precise compositional control remains a key challenge. Here, we report a simple, low-temperature, and scalable in situ solvothermal technique for the deposition of ternary (Bi
1−xSb
x)
2S
3 films using structurally compatible single-source precursors, [Bi{S
2P{O(Pr)
2}
3}] and [Sb{S
2P{O(Pr)
2}
3}]. This one-pot chemical route facilitates precise control over composition and film quality without the need for additional processing steps. Compositional and structural characterisation confirmed the successful formation of orthorhombic (Bi
1−xSb
x)
2S
3 phases across the full composition range (x = 0–1). The systematic shift in X-ray diffraction peak positions and lattice parameters with varying Sb content is consistent with Vegard's law, indicating the formation of a homogeneous, compositionally tunable ternary alloy. Scanning electron microscopy revealed pronounced morphology changes correlated with the Sb mole fraction, highlighting the influence of composition on microstructural evolution. UV-vis spectroscopy further demonstrated optical tunability, with bandgaps increasing from 1.82 to 2.04 eV as Sb content increased. These results underscore the effectiveness of precursor ratio adjustment for controlling final film composition and properties, showcasing the versatility of this low-temperature solvothermal approach for synthesising phase-pure, compositionally engineered mixed-metal chalcogenide thin films.</p
Feature extraction tool using temporal landmarks in arterial blood pressure and photoplethysmography waveforms
No full textArterial blood pressure (ABP) and photoplethysmography (PPG) waveforms both contain vital physiological information for the prevention and treatment of cardiovascular diseases. Extracted features from these waveforms have diverse clinical applications, including predicting hyper- and hypo-tension, estimating cardiac output from ABP, and monitoring blood pressure and nociception from PPG. However, the lack of standardized tools for feature extraction limits their exploration and clinical utilization. In this study, we propose an automatic feature extraction tool that first detects temporal location of landmarks within each cardiac cycle of ABP and PPG waveforms, including the systolic phase onset, systolic phase peak, dicrotic notch, and diastolic phase peak using the iterative envelope mean method. Then, based on these landmarks, extracts 852 features per cardiac cycle, encompassing time-, statistical-, and frequency-domains. The tool's ability to detect landmarks was evaluated using ABP and PPG waveforms from a large perioperative dataset (MLORD dataset) comprising 17,327 patients. We analyzed 34,267 cardiac cycles of ABP waveforms and 33,792 cardiac cycles of PPG waveforms. Additionally, to assess the tool's real-time landmark detection capability, we retrospectively analyzed 3,000 cardiac cycles of both ABP and PPG waveforms, collected from a Philips IntelliVue MX800 patient monitor. The tool's detection performance was assessed against markings by an experienced researcher, achieving average F1-scores and error rates for ABP and PPG as follows: (1) On MLORD dataset: systolic phase onset (99.77 %, 0.35 % and 99.52 %, 0.75 %), systolic phase peak (99.80 %, 0.30 % and 99.56 %, 0.70 %), dicrotic notch (98.24 %, 2.63 % and 98.72 %, 1.96 %), and diastolic phase peak (98.59 %, 2.11 % and 98.88 %, 1.73 %); (2) On real time data: systolic phase onset (98.18 %, 3.03 % and 97.94 %, 3.43 %), systolic phase peak (98.22 %, 2.97 % and 97.74 %, 3.77 %), dicrotic notch (97.72 %, 3.80 % and 98.16 %, 3.07 % ), and diastolic phase peak (98.04 %, 3.27 % and 98.08 %, 3.20 %). This tool has significant potential for supporting clinical utilization of ABP and PPG waveform features and for facilitating feature-based machine learning models for various clinical applications where features derived from these waveforms play a critical role
Analysis of the Performance of Beethoven’s Piano Sonatas Composed Between 1798 and 1804 (Op.13 to Op.54)
No full textThis study aims to conduct an in-depth analysis of the performance recordings of 13 piano sonatas composed by Beethoven between 1798 and 1804 (Op. 13 to Op. 54), exploring the evolution over time of the performance styles of eight pianists from the 20th to the early 21st century in terms of tempo. This thesis first introduces the key collected and analytical methods of data used in this study, consisting of Vmus graphs and colour-coded spreadsheets. Subsequently, it explores the historical background of tempo treatment in 19th century performances, providing a context for the following analysis of performance styles. Then, this thesis continues by comparing and analysing the average tempo used by eight pianists in different phrases and segments of these works, providing a comprehensive interpretation of the variation of performance styles during this period. The analysis is mainly focused on three aspects, including the degree of acceleration, treatment of metronome mark, and trend analysis based on colour-coded spreadsheet. Meanwhile, this study investigates the individual characteristics of each pianist regarding tempo treatment. Finally, from the two perspectives, namely integrating historical performance methods with modern practices and innovative performance approaches, the author discusses how to create a Beethoven style that is consistent with contemporary aesthetics for today's audiences, demonstrating the potential for new interpretations of historical works in both the present and future
Miglustat as a treatment for adults with tangier disease neuropathy: The MUSTANG N‑of‑1 Trial with 21 months clinical observation
No full textImportance: Tangier disease (TD) is an ultra- rare disease, characterised by progressive peripheral neuropathy with no established treatment.Objectives: To determine whether miglustat improved the clinical status of a single patient with TD, and to investigate the possible mechanisms of miglustat in this patient.Design, Setting, and Participants: An n-of-1 ABAB study, alternating on and off treatment for 6-month periods, total study duration of 2 years with an additional compassionate-access period of 21 months.Exposure: Miglustat, an orphan drug licenced to treat Gaucher disease and Niemann–Pick disease, was repurposed.Main Outcomes and Measures: The study wasdesigned with two co-primary endpoints: (a) time taken to complete the nine-hole peg test(fine motor control and finger dexterity), and (b) hand strength: grip and three-point pinch strength tests. Secondary endpoints were quality-of-life measures and biomarkers.Results: A 21-year-old (at baseline) left-handed male patient with TD, diagnosed at the age of 6 months, and disabling neuropathy was included in the study. Over 2 years, there was a small signal in our clinical measures that the drug may be beneficial. Compared with the 2 years prior to treatment, the patient had no relapse of neuropathy during his study period and further extension. During the 21-month treatment extension, he showed considerable improvement on primary endpoints. Biomarkers changed as expected based on the mechanism of action of miglustat. Nerve conduction studies showed a mild benefit. Importantly, the patient’s reported experience suggested a meaningful ben efit from miglustat.Conclusions and Relevance: Miglustat may be used to treat neurological complications of TD. This study showed that an n-of-1 study to inform a policy decision is practical and may offer hope to patients with rare diseases.Trial Registration: ClinicalTrials.gov Identifier: ISRCTN17945917. Registration date: 07/06/2021; ‘retrospectively registered’
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