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The value of electronic patient records for determining the prevalence and prognosis of cognitive and physical frailty in a large hospital-based cohort
Get PDFOlder people with frailty account for an increasing proportion of hospital admissions but access to specialised geriatric care varies. Data on the burden of cognitive and physical frailty hospital-wide and by specialty are currently limited but such data are necessary for informing clinical guidance, service-planning and policy. Routine clinical data captured in hospital electronic patient records (EPRs) offers an alternative to existing prospective and administrative coding data study designs but the value of these data for measuring frailty has not yet been studied. Therefore, my thesis aimed to evaluate ‘the value of hospital EPRs for determining the prevalence and prognosis of cognitive and physical frailty’ primarily using data from a large hospital-based cohort, i.e., the Oxford Cognitive Comorbidity, Ageing and Frailty Research Database-Electronic Patient Records (ORCHARD-EPR) study.First, in a systematic review/meta-analysis of 45 hospital-wide and general medicine cohorts, I showed that global frailty, measured using validated tools, was prevalent in older people with unplanned hospital admissions although heterogeneity was high and not explained by frailty tool, setting, or risk of bias. Despite variation in prevalence, frailty was consistently associated with mortality, length of stay (LoS) and discharge destination including after adjustment for confounders, although findings on readmissions were mixed. Notably, cognitive impairment, and in particular delirium, was poorly ascertained by all the frailty measures used in included studies and therefore prevalence of cognitive frailty and the degree of overlap with physical frailty was uncertain. In addition, all studies were either small prospective studies or large administrative datasets based on ICD-10 diagnostic coding except for three which used EPR data but were not validated.Second, I assembled, cleaned and validated data from the Oxford and Reading Cognitive Comorbidity, Frailty and Ageing Research Database-Electronic Patient Record (ORCHARD-EPR) 2017-2019 dataset which contains pseudo-anonymised Oxfordshire University Hospital NHS Foundation Trust EPR data for >=100,000 unplanned hospital admissions. Importantly, ORCHARD-EPR includes the results of mandatory cognitive screening in those >=70 years (existing dementia diagnosis, delirium diagnosis informed by the Confusion Assessment Methods-CAM and recorded as “certain” or “uncertain”, Abbreviated Mental Test-AMT). I validated cognitive frailty data from the cognitive screen for general medicine admissions in ORCHARD-EPR against a reference cohort. The prevalence of cognitive frailty (certain delirium, dementia, AMT<8) in general medicine admissions was 35% in ORCHARD-EPR (increasing to 41% when uncertain delirium diagnosis was included) compared to 50% in the reference data with the difference in prevalence largely explained by lower rates of delirium diagnosis in ORCHARD-EPR.Third, I determined that cognitive frailty (certain+uncertain delirium, dementia, AMT<8) was present in 35% of all ORCHARD-EPR admissions (n=51,202) across 29 specialties, with delirium the most common diagnosis. I also showed that any cognitive frailty predicted survival over up to four years of follow-up as well as LoS, delayed discharge, and discharge destination over and above age, sex, comorbidity and illness severity, with associations strongest for delirium. Additionally, only delirium in non-care home residents predicted readmission.Fourth, using a modified version of the Hospital Frailty Risk Score to measure physical frailty from ICD-10 codes, I found that moderate/severe physical frailty was present in 73% of individuals with cognitive frailty, but only 46% with physical frailty were cognitively frail. Despite being independently associated with survival, physical frailty added little to mortality risk in those with cognitive frailty but added markedly to LoS and risks of delayed discharge and discharge to a destination other than home.In conclusion, routinely acquired clinical frailty data is a valuable tool for research, capable of combining large, inclusive, hospital-wide sampling with accurate ascertainment as shown using ORCHARD-EPR. Similar approaches could be adopted at other centres but will likely only be useful if routine screening is embedded into the EPR and shown to reliably identify frail patients. Moreover, findings of high frailty prevalence across multiple specialties and impact on outcomes supports more widespread implementation of routine cognitive and physical frailty screening in older people with unplanned hospital admission in line with current guidance. Additionally, findings support increased emphasis on delirium in policy and research
DiffBED: scaling Bayesian experimental design to high-dimensions
Get PDFBayesian experimental design (BED) is a principled framework for intelligent data acquisition. However, current approaches do not scale to problems with high–dimensional designs, impeding its uptake. We show that this limitation arises predominantly from the difficulty in specifying a likelihood model that remains accurate throughout the design space, and that without this, standard design optimisation procedures lead to a reward-hacking-like behaviour that exploits deficiencies in the likelihood, producing implausible or unrealistic designs. To overcome this, we introduce DiffBED, an approach based on a novel BED objective that explicitly rewards realistic designs. Realism is captured by a diffusion model, which we guide using information-theoretic experimental design criteria to generate highly informative yet realistic designs. This enables BED at an unprecedented scale: while existing applications of BED have been restricted to design spaces with a handful of dimensions, we show that DiffBED can successfully scale to designing high–resolution images
Do music and language help? The influence of musicianship and language background on tonal perception
Get PDFThe interaction between musicianship and language background has attracted attention in the academic research field. The OPERA hypothesis suggests that since music processing requires higher neural sensitivity, together with its overlapping neural network with speech processing and the existence of neural plasticity, the music training enhances speech processing. In education and neurolinguistics, there have been numerous investigations providing neural and behavioural evidence on how musical training could significantly improve sensitivity to pitch procession. The co-existence of the concept of pitch in music and language has poses a question about how musical aptitude and language background (specifically focus on whether one’s first language is tonal) influence tonal perception. This study aims to address this question. 167 participants (97 with a tonal L1 and 70 with a non-tonal L1) participated in a musical aptitude test (which included a melody perception and a rhythm perception component) and assessed a tonal discrimination task which included 20 pairs Thai words. The results showed that, for both groups, the participants’ overall musical skills, their rhythmic perception, and their melodic perception in particular had a statistically significant and positive correlation with performance in the tonal discrimination task. These correlations did not present significant difference between tonal and non-tonal L1 groups, indicating that regardless of native (non-)tonal language experience, higher musical aptitudes facilitated tonal perception performance. This echoed the OPERA hypothesis by supporting the music-language effect. The musical aptitudes and (non-)tonal L1 backgrounds were both found as significant predictors of tonal discrimination task scores. When musical aptitudes were controlled as covariate, there was significant difference in tonal discrimination task scores between native tonal and non-tonal speakers. The tonal L1 group scored significantly higher than the non-tonal L1 group. This study had several limitations. The uncontrolled environmental factors, lack of break between tests, and unfamiliar of the tests might undermine participants’ performance on musical aptitudes. The categorisation of participants ignored their proficiencies in languages other than L1, which might influence the investigation of their relationship with tonal perception. For future studies, it is suggested to facilitate participants in test familiarisation, carefully control and measure between-subject and within subject factors if possible. Moreover, since this study only utilised discrimination task for tonal perception measurement, future studies can involve tonal identification task to evaluate the ability of tonal perception more comprehensively
Enhancing photoluminescence in perovskite nanostructures with metal nanoparticles and nanocavities
Get PDFEnhancing photoluminescence (PL) is central to advancing optoelectronic and quantum photonic technologies. Low-dimensional CsPbX3 perovskite nanomaterials have emerged as outstanding emitters due to their large exciton binding energies, high oscillator strength, and the ability to sustain excitons at room temperature. Strategies such as cavity-induced Purcell enhancement and plasmonic local-field amplification offer powerful means to modulate their optical response, markedly boosting PL intensity. This thesis investigates the coupling between metal nanoparticles (NPs), optical nanocavities, and lead-halide perovskite nanostructures to actively control and enhance emission, establishing both mechanisms and design principles for hybrid light–matter architectures.Pronounced plasmon-enhanced emission was demonstrated in Ag/CsPbBr3 nanowire hybrids. A two-step process combining superfluid helium droplet deposition with wet-chemical growth enables precise NP sizing and tunable plasmon resonances, while minimizing damping from chemical residues. Within a tailored four-layer geometry, this approach yields an 8.5-fold PL intensity increase at 4 K, with time-resolved measurements confirming accelerated recombination from plasmon– exciton coupling.Magnesium is further introduced as an alternative plasmonic material to conventional noble metals. Benefiting from earth abundance and low cost, Mg supports competitive plasmonic resonances and is readily synthesized via colloidal routes into spheroidal Mg/MgO core–shell NPs. Near-field coupling between their dipolar modes and CsPbBr3 nanowire emission delivers PL enhancement factors of 1.7× and 4.1× for different sub-100 nm particles at room temperature. Although weaker than Ag in analogous designs, Mg’s self-limiting oxide shell provides improved ambient stability, highlighting a sustainable pathway for plasmonic integration.Finally, micro-PL studies on CsPbI3 nanoplatelets reveal pronounced quantum confinement, with excitonic energies and recombination dynamics tuned by thickness. Cavity-assisted measurements show brighter and more symmetric emission spectra relative to off-cavity references, though without significant lifetime shortening. These results indicate that excitation/collection efficiency and spectral filtering dominate the observed enhancements, while Purcell acceleration remains weak under the current cavity design.Collectively, this work establishes new routes to control and amplify light emission in perovskite nanostructures through plasmonic and cavity coupling, providing insights for the rational design of scalable hybrid architectures for optoelectronics and quantum photonics
Robust triboelectric energy harvesters engineered from electrochemically deposited films of HKUST-1 polycrystals
Get PDFTriboelectric nanogenerators (TENGs) offer a potential power source for compact electronics and self-powered portable devices, with increasing interest in integrating metal-organic frameworks (MOFs) due to their tunable physical and chemical properties. However, the direct incorporation of MOF powders in TENG is hindered by their weak and unstable attachment to the underlying conductive substrates. Herein, we show that electrochemical MOF deposition offers a facile approach to deposit hydrophilic HKUST-1 films on a copper electrode, yielding a robust tribopositive layer after a growth time of 2 h. When this surface was impacted against a tribonegative layer such as Kapton under contact-separation mode, the optimal output of the TENG device reached the highest voltage output of ~99 V with a power density of 771.8 ± 0.3 mW m-2. The device exhibits extended stability, with a negligible voltage decay under ambient environment and exposed to relative humidity from 10% to 70%. This study demonstrates a feasible strategy to generate mechanically resilient MOF-based TENGs with reproducible output for real-world environmental conditions
Peripheral and CSF protein quantification in Parkinson’s disease and multiple system atrophy—the nucleic acid-linked immuno-sandwich assay
Get PDFThere are currently no validated peripheral biomarkers for the diagnosis, differentiation or progression of the neurodegenerative synucleinopathies, Parkinson’s disease and multiple system atrophy. Diagnostic biomarkers that reflect the disease mechanisms or progression biomarkers that change with disease severity would be extremely valuable for assessing disease-modifying therapies. Our objective was to explore putative protein biomarkers of Parkinson’s disease and multiple system atrophy, in relation to clinical disease severity, using the nucleic acid-linked immuno-sandwich assay central nervous system disease panel for biomarker quantification. We used the nucleic acid-linked immuno-sandwich assay CNS disease panel to test plasma from 161 Parkinson’s disease patients collected at three time points (0, 48, 96 weeks) and serum from 43 multiple system atrophy patients at three time points (0, 24, 48 weeks) and compared results to paired plasma and serum samples collected from (n = 39) age-matched healthy control individuals at a single time point. We also tested paired CSF samples collected on two occasions, separated by 96 weeks from a subgroup of Parkinson’s disease participants (n = 51) and after an interval of 48 weeks in a subgroup of multiple system atrophy participants (n = 23). All samples were taken contemporaneously with objective clinical assessments of disease severity. Biomarker comparisons were made across disease status and in relation to disease severity using linear modelling. Multiple proteins showed significantly different quantitative levels (false discovery rate-corrected P value < 0.05) between peripheral samples from Parkinson’s disease and healthy controls and multiple system atrophy and healthy controls. For Parkinson’s disease, we identified three key classes of proteins that showed significant differences between Parkinson’s disease and controls: (i) amyloidogenic proteins, specifically, oligomeric alpha-synuclein was significantly higher in Parkinson’s disease compared to controls. A number of other aggregating proteins also exhibited differences. (ii) Metabolic pathways, including the adipokine (chemokine-like protein TAFA-5), were associated with Parkinson’s disease diagnosis, and (iii) inflammatory pathways (interleukin-7) were associated with Parkinson’s disease diagnosis. Importantly, some of these same proteins were significantly associated with Parkinson’s disease severity including oligomeric and phosphorylated forms of alpha-synuclein and insulin-like growth factor-1 receptor. We also confirmed as expected that neurofilament light levels strongly distinguish multiple system atrophy patients from healthy controls, while also demonstrating that serum inflammatory proteins (interleukin-6) as well as the phosphorylated alpha-synuclein ratio are strongly associated with multiple system atrophy severity. These results from the nucleic acid-linked immuno-sandwich assay multiplex platform provide additional insights into the complex pathogenetic mechanisms associated with alpha-synucleinopathy related neurodegeneration. Individual protein levels or the combination of multiple protein candidates may usefully serve as diagnostic biomarkers, or as biomarkers for disease progression in trials of potential disease-modifying interventions
Atorvastatin Impairs Pathways Associated With Skeletal Muscle Function and Health in Myoblasts From Older Adults
Get PDFBackground: Statins are widely prescribed to reduce low‐density lipoprotein (LDL) cholesterol to decrease the risk of cardiovascular disease. However, there are ongoing concerns surrounding the frequently reported skeletal muscle side effects. These include muscle pain, weakness and reduced function and are defined as statin‐associated muscle symptoms (SAMS). This study aimed to characterise the biological processes, which underlie SAMS through analysing in vitro muscle cell phenotypic and transcriptomic effects of atorvastatin, the most prescribed statin, using human myoblasts from older adults. Methods: Human myoblasts were isolated from vastus lateralis biopsies of 11 female older adult participants (average age 78.4 years) who were not on statin therapy from the Hertfordshire Sarcopenia Study extension (HSSe). Myoblasts were treated with 1, 5, or 10 μM atorvastatin for 4 days in proliferating or differentiating cultures. In proliferating cells, cytotoxicity, senescence and proliferation were measured using LDH cytotoxicity, β‐galactosidase (β‐gal) and 5‐ethynyl‐2′‐deoxyuridine (EdU) assays. To understand the influence of atorvastatin treatment across myoblast differentiation, immunocytochemistry (ICC) was undertaken analysing Myogenic Differentiation 1 (MyoD), Myogenin (MyoG) and Myosin Heavy Chain (MyHC). RNA sequencing (RNA‐seq) was performed on a subset of 10 differentiating myoblast cultures treated with 10 μM atorvastatin followed by gene ontology and protein–protein interaction (PPI) pathway analysis (Metascape). Results: Atorvastatin treatment was not significantly toxic to myoblasts at any of the concentrations tested (1 μM p = 0.32, 5 μM p = 0.21 or 10 μM p = 0.76). Senescence increased with atorvastatin at 5 μM (p = 1.95 × 10−4) and 10 μM (p = 9.77 × 10−4). Myoblast proliferation decreased at all of 1 μM (p = 1.86 × 10−2), 5 μM and 10 μM (p = 9.77 × 10−4) concentrations. In differentiating cells, ICC identified MyoD significantly decreased with 10 μM atorvastatin; decreased MyoG at 1, 5, and 10 μM atorvastatin (p = 9.77 × 10−4); and decreased MyHC at 1 μM (p = 3.2 × 10−2), 5 μM (p = 2.93 × 10−3) and 10 μM atorvastatin (p = 1.37 × 10−2). RNA‐Seq analysis following 10 μM atorvastatin treatment in differentiating myoblast cultures revealed 822 genes upregulated and 888 genes downregulated in expression (false discovery rate [FDR] < 0.05). Pathway and MCODE analysis identified key networks downregulated, including muscle contraction and cell cycle process, and upregulated pathways implicated in cholesterol and fatty acid synthesis. Conclusions: These findings show that atorvastatin treatment negatively impacts skeletal muscle at the cellular level by disrupting many key gene regulatory pathways involved in muscle maintenance, function and health. Identification of such disruption, which likely underpins SAMS, provides novel molecular mechanisms, which could be targeted through pharmaceutical/nutraceutical interventions to reduce the negative effects of statins on skeletal muscle health
From kinds to plural reference: essays on the meaning of generics
Get PDFIn this thesis, I present a range of arguments in support of the hypothesis that generic bare plural noun phrases in English – those which appear in sentences such as ‘Ravens are black’ or ‘Dodos are extinct’ – should be analysed as covert definite descriptions.In Chapter 1, I introduce the topic of generics and provide a critical summary of the extant semantic theories. I propose a novel way of characterising the phenomenon of genericity as the belief that a sentence is true in virtue of a state of affairs which is stable over time.In Chapter 2, I present novel data concerning the availability of collective and distributive readings of generics. These ambiguities are paralleled by the availability of collective and distributive readings for non-generic plurals. I show that extant theories cannot explain the availability of both readings and argue that this evidence weighs heavily in favour of a plural reference theory of generics.In Chapter 3, I present further linguistic parallels between generics and plural definite descriptions and introduce a novel compositional semantic theory which analyses generic bare plurals as covert definite descriptions. I give a lexical entry for a null determiner and show how this predicts both the differences and similarities in the meanings of generic bare plurals and plural definite descriptions.Chapter 4 deals with the law-likeness of generics, which seems to present a challenge for my plural reference theory. I present a puzzle concerning the law-like interpretation of generics and show that generics with a temporal restriction wholly located in the past elicit diminished intuitions of law-likeness. I resolve this puzzle by proposing a novel truthmaker semantics for plural predication which explains the law-likeness of generics in terms of the different ways that they can be made true. In Chapter 5, I address Sarah-Jane Leslie’s arguments that generics express a default mode of generalisation. I argue that Leslie’s approach does not represent a genuine alternative to semantic theories of generics, since it ignores the non-semantic factors that affect speakers’ judgments of the truth values of generics and, as a result, overfits the data. I present a reconceptualised version of Leslie’s theory as a theory of how heuristics affect our judgements of the truth values of generics
The dopamine D3 receptor regulates dopamine-induced activation and glycolytic metabolism of synovial fibroblasts in rheumatoid arthritis
Get PDFINTRODUCTION: Increased glycolytic metabolism in synovial fibroblasts contributes to their activated phenotype in rheumatoid arthritis (RA). Our previous results revealed that the activation of the dopamine D3 receptor (D3R) in mast cells reduced inflammation in a mouse model of RA. In this study, we explored the role of D3R in regulating dopamine-induced activation and glycolysis in synovial fibroblasts from patients with RA (RASFs).METHOD: RASFs were cultured in the presence of dopamine. Pharmacological modulation of D3R by D3R agonist (7-OH-DPAT) and antagonist (NGB2904) was used to investigate the regulatory role of D3R in dopamine-induced activation and glycolysis in RASFs. RESULTS: Dopamine stimulation induced a dose-dependent increase in cell viability and α-SMA expression in RASFs. Dopamine also caused significant and dose-dependent upregulation of glycolysis-related enzymes in RASFs. Treatment with 7-OH-DPAT inhibited dopamine-induced increases inα-SMA expression and inflammatory response in RASFs, whereas NGB2904 treatment resulted in the enhancedeffects stimulated by dopamine. NGB2904 treatment upregulated glycolysis and the expression of glycolytic enzymes induced by dopamine, whereas 7-OH-DPAT treatment downregulated glycolysis and glycolytic enzymes in RASFs. NGB2904 attenuated the ability of 7-OH-DPAT to inhibit the dopamine-induced elevation in cAMP levels of RASFs. Involvements of the cAMP pathway was confirmed by findings that H89 (a PKA inhibitor) abrogated the upregulation of activation, glycolysis, and expression of glycolytic enzymes mediated by the D3R antagonist, NGB2904, in RASFs.CONCLUSION: D3R downregulates dopamine induced activation and glycolysis of RASFs by suppressing PKA activity. Therefore, inhibition of glycolysis by manipulating the D3R pathway may provide a novel therapeutic strategy to reduce the activation of RASFs
Serum GFAP and NfL augment a metabolomics-driven strategy for long-term prediction of multiple sclerosis progression
Get PDFBackgroundReliable biomarkers for predicting disease progression in multiple sclerosis (MS) are crucial for advancing precision medicine and optimising treatment strategies. This study evaluates the predictive potential of serum nuclear magnetic resonance (NMR)-based metabolomics, individually and in combination with well-established biomarkers of neuroinflammation (serum glial fibrillary acidic protein, sGFAP) and axonal damage (neurofilament light chain, sNfL), in an extreme-phenotype subset of the Swiss Multiple Sclerosis Cohort (SMSC).MethodsSerum samples were analysed using NMR-based metabolomics, along with quantification of sNfL and sGFAP. Supervised multivariate analysis was performed to differentiate MS phenotypes and identify future progressors. Multivariable receiver operating characteristic (ROC) analysis evaluated predictive performance, with key metabolite findings validated in an independent Oxford MS cohort.ResultsNMR-based metabolomics reliably distinguishes relapsing-remitting MS (RRMS) from secondary-progressive MS (SPMS) and predicts individual transitions. The identified predictive metabolites (lipoproteins, glutamine, alanine, valine, glucose) are also associated with progression independent of relapse activity (PIRA), a clinically relevant marker of sustained disability worsening. This demonstrates that the approach can both stage disease and forecast progression irrespective of stage. ROC analysis shows strong predictive performance (AUC = 0.81, p = 0.001), with external validation confirming robustness. Integration of NMR-metabolomics with sGFAP and sNfL further improves accuracy, yielding AUCs of 0.91 (p < 0.0001) and 0.87 (p = 0.0002), respectively, supported by independent validation.ConclusionsThe integration of metabolic and protein biomarkers enables both accurate staging of RRMS versus SPMS and, critically, early prediction of progression irrespective of stage. This dual capability provides a clinically actionable, serum-based tool that can refine monitoring, improve therapeutic decision-making, and support a shift towards stage-agnostic, progression-focused care in MS