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Fenscapes: archaeology, natural heritage and environmental change in the Fens of eastern England
Get PDFDiagnosis of paediatric infectious diseases and the utility of host immune signatures
Get PDFBackground: It can be difficult to distinguish between bacterial and viral infections in children. Current diagnostics lack the sensitivity to confidently rule out serious bacterial infections. The aims of this thesis include discovery of novel host biomarkers to identify bacterial infections, and evaluation of the role of expanded molecular testing in detecting pathogens. Methods: The data in this thesis come from two prospective cohort studies recruiting children admitted to Patan Hospital, a tertiary-level hospital in the Kathmandu Valley, Nepal. The first cohort study recruited children with lower respiratory tract infections (LRTIs). Whole blood samples from these children were sent for RNA-sequencing and plasma samples were sent for mass spectrometry proteomics and cytokine analysis. The LRTI cases were grouped together based on aetiology; RNA and protein levels were compared between different LRTI groups. Data were divided into training and test datasets; using a partial least squares approach, signatures were identified to differentiate between bacterial and viral LRTIs. The data in the RNA and protein platforms were integrated to identify a multi-platform signature. The second cohort study recruited children with any signs of infection. Causes of infection were described using routine diagnostics; samples were tested using four additional research molecular panels. Results: In the LRTI study, samples from 258 LRTI cases were tested. The median age was 2 years and 38% were female. The most common pathogens detected were RSV, influenza and Streptococcus pneumoniae. Using a training subset of cases classified as bacterial, n = 47, or viral, n = 53, a three-gene RNA signature was identified; this signature identified bacterial infections, in the test dataset, with a sensitivity of 89% and a specificity of 100%. Integrating data from the RNA and protein platforms identified a signature with 100% sensitivity and 94% specificity for identifying bacterial LRTIs. In the second cohort study, 574 cases were enrolled, median age was 3 years and 35% were female, 498 cases had additional molecular testing. Using routine diagnostics only, 28.7% (143/498) of cases were classified as having a confirmed bacterial or viral aetiology. After additional molecular testing, 45.6% (227/498) of cases had a likely pathogen identified. Molecular testing for RSV infection, influenza virus infection, Neisseria meningitidis, enterovirus infection and dengue fever showed potential diagnostic utility. Conclusions: The signatures identified in this thesis have the potential to improve the identification of serious bacterial infections. A small number of molecular tests which had the potential to alter clinical management were identified
Observation of the doubly-charmed-baryon decay Ξ cc + + → Ξ c 0 π + π +
Get PDFA search for the doubly-charmed-baryon decay Ξcc++→Ξc0π+π+ is performed using proton-proton collision data collected by the LHCb experiment at a centre-of-mass energy of 13 TeV and corresponding to an integrated luminosity of 5.4 fb−1. A significant structure consistent with the Ξcc++ baryon is observed in the Ξc0π+π+ invariant-mass spectrum. Using the Ξcc++→Λc+K−π+π+ decay as the normalisation channel, the branching fraction ratio, BΞcc++→Ξc0π+π+BΞcc++→Λc+K−π+π+, is measured to be 1.37 ± 0.18 (stat) ± 0.09 (syst) ± 0.35 (ext). This measurement provides critical input for testing QCD factorisation methods in the weak decays of doubly-heavy baryons, particularly in quantifying nonperturbative effects such as final-state interactions and resonance contributions to the hadronisation process
Lowering the Cu-O bond energy in CuO nanocatalysts enhances the efficiency of NH 3 oxidation
Get PDFTuning the electronic properties of nanocatalysts via doping with monodispersed hetero-metal atoms is an effective method used to enhance catalytic properties. Doping CuO nanoparticles with monodispersed Co atoms using different reductants affords catalysts (CoBCu/Al2O3 and CoHCu/Al2O3) with strikingly different electronic structures. Compared to CoHCu/Al2O3, the CuO nanoparticles in CoBCu/Al2O3 have longer and weaker Cu-O bonds, with a lower 1s → 4pz antibonding transition and higher 4p → 1s bonding transition (as demonstrated from HERFD-XANES and valence-to-core X-ray emission spectroscopy). The weaker Cu-O bonds in CoBCu/Al2O3 lead to superior redox activity of the CuO nanoparticles, evidenced from operando XAFS and in-situ near ambient pressure-near edge X-ray absorption fine structures studies. Such superior redox properties of CuO in CoBCu/Al2O3 result in a much reduced activation energy of CoBCu/Al2O3 compared to CoHCu/Al2O3 (40.0 vs. 63.5 kJ/mol), thus leading to an enhancement in catalytic performance in the selective catalytic oxidation of NH3 to N2
Reconstructing the first COVID-19 pandemic wave with minimal data in England
Get PDFAccurate measurement of exposure to SARS-CoV-2 in the population is crucial for understanding the dynamics of disease transmission and evaluating the impacts of interventions. However, it was particularly challenging to achieve this in the early phase of a pandemic because of the sparsity of epidemiological data. We previously developed an early pandemic diagnostic tool that linked minimum datasets: seroprevalence, mortality and infection testing data to estimate the true exposure in different regions of England and found levels of SARS-CoV-2 population exposure to be considerably higher than suggested by seroprevalence surveys. Here, we re-examine and evaluate the model in the context of reconstructing the first COVID-19 epidemic wave in England from three perspectives: validation against the Office for National Statistics (ONS) Coronavirus Infection Survey, relationship among model performance and data abundance and time-varying case detection ratios. We find that our model can recover the first, unobserved, epidemic wave of COVID-19 in England from March 2020 to June 2020 if two or three serological measurements are given as additional model inputs, while the second wave during winter of 2020 is validated by estimates from the ONS Coronavirus Infection Survey. Moreover, the model estimates that by the end of October in 2020 the UK government's official COVID-9 online dashboard reported COVID-19 cases only accounted for 9.1 % of cumulative exposure, dramatically varying across the two epidemic waves in England in 2020, 4.3 % vs 43.7 %
Autophagy acts as a brake on obesity-related fibrosis by controlling purine nucleoside signalling
Get PDFA hallmark of obesity is a pathological expansion of white adipose tissue (WAT), accompanied by marked tissue dysfunction and fibrosis. Autophagy promotes adipocyte differentiation and lipid homeostasis, but its role in obese adipocytes and adipose tissue dysfunction remains incompletely understood. Using a mouse model, we demonstrate that autophagy is a key tissue-specific regulator of WAT remodelling in diet-induced obesity. Importantly, loss of adipocyte autophagy substantially exacerbates pericellular fibrosis in visceral WAT. Change in WAT architecture correlates with increased infiltration of macrophages with tissue-reparative, fibrotic features. We uncover that autophagy restrains purine nucleoside metabolism in obese adipocytes. This ultimately leads to a reduced release of the purine catabolites xanthine and hypoxanthine. Purines signal cell-extrinsically for fibrosis by driving macrophage polarisation towards a tissue reparative phenotype. Our findings in mice reveal a role for adipocyte autophagy in regulating tissue purine nucleoside metabolism, thereby limiting obesity-associated fibrosis and maintaining the functional integrity of visceral WAT. Purine signals may serve as a critical balance checkpoint and therapeutic target in fibrotic diseases
Co-design and implementation of nursing handover improvement tool in Kenyan newborn units: a pilot study
Get PDFBackground: Transfer of care and responsibility for patients from one healthcare provider to another during hospitalisation is critical to them receiving the right interventions and overall quality and safety of care, and is dependent on the accurate transfer of patient information. Sick newborns are particularly dependent on health workers being able to meet their needs, but previous work suggests that nursing handovers in newborn units (NBUs) may be poor in Kenya. Initiatives aimed at improving nursing handovers have mainly been tested and implemented in High-Income Countries (HICs), with very little happening in Low- and Middle-Income Countries (LMICs), especially in the context of sick and hospitalised newborn nursing care. In this study, we sought to co-design, implement, and assess a nursing handover tool’s effect on the communication of patient information, teamwork, and coordination of care among nurses in selected newborn units. Methods: We adopted a co-design approach where nurses were involved in the design of a nursing handover improvement tool, i.e., the ESBAR tool. To pilot and assess the effects of this tool, a prospective before-and-after study was conducted in three county referral hospitals in Kenya. We utilised both in-depth qualitative interviews (pre = 15, post = 22), observation of nursing handover sessions (pre = 48 sessions, post = 48 sessions) and a survey using a structured self-administered questionnaire (pre = 43, post = 37). The study participants were all nurses working in selected NBUs. The qualitative data were thematically coded in NVivo, and for the quantitative data, descriptive statistics and paired t-tests analysis were conducted in STATA 15. Results: Our qualitative findings showed a positive influence of ESBAR on nursing handovers, i.e., completeness of information, improvements in the handover process and nursing team interactions. However, quantitatively, we observed no differences in means for all three indicators before and after the use of ESBAR. Implementation challenges included: a lack of interest among staff to adopt new changes and high patient-to-staff ratios. Enabling factors were user involvement in tool design, teamwork, and support of champions. Conclusions: Standardised handover tools can improve information exchange during handovers in low-resource settings; however, due to contextual challenges, there is potential to integrate these tools more as a communication guide. We recommend adopting a co-design approach with healthcare workers to ensure such initiatives meet their needs and to encourage adoption
CATCH 2024 meeting summary: Collaborate & Address Treatment Challenges in Haemophilia
Get PDFGreater treatment choice and the associated flexibility in regimens has necessitated new conversations with people with haemophilia about their personal goals. Innovations in haemophilia treatment drive the need for innovation in care service delivery. Supported by Sobi™, CATCH (Collaborate & Address Treatment Challenges in Haemophilia) is an annual, non-promotional, medical education meeting that brings together members of the haemophilia multidisciplinary team from across the UK and Ireland to discuss all aspects of haemophilia care and management. This report summarises the key issues that were explored and discussed during the CATCH 2024 meeting, including understanding the personal motivations of people with haemophilia and how these influence treatment choices and support; facilitating behaviour change to improve outcomes; reviewing the practicalities and possibilities for eliminating bleeds and new arthropathy in people with haemophilia; and developing new models of care to elevate haemophilia services
The Continuum Fallacy in Moral Philosophy
Get PDF‘Spectrum arguments’ or ‘continuum arguments’ in moral philosophy are sometimes invalid because they commit a particular fallacy I call the ‘Continuum Fallacy’. An important example is an argument in population ethics described by Derek Parfit, which purports to derive a conclusion that he and others find repugnant on the basis of a weak and plausible premise. Parfit treats this as a paradox, and takes up the challenge of resolving it, looking for a way to avoid the Repugnant Conclusion. The solution he offers depends on the existence of imprecision within the relation of betterness among populations of people. Other philosophers have taken up the same challenge, following Parfit's lead, and offered solutions also based on imprecision or incommensurability. I show that actually the Repugnant Conclusion is not implied by Parfit's appealing premise. There is therefore no paradox and no real challenge. Moreover, the explanation of why this is so has nothing to do with imprecision, incompleteness, incommensurability, indeterminacy or vagueness in betterness. It is consistent with a sharp, complete betterness ordering
Population pharmacokinetics of lumefantrine in pregnant and non‐pregnant women with uncomplicated Plasmodium falciparum malaria in Western Kenya
Get PDFAim: This study intends to assess the pharmacokinetic properties and treatment response of lumefantrine in pregnant and non‐pregnant women with uncomplicated Plasmodium falciparum malaria infection in Western Kenya. Methods: Seventy‐five women with uncomplicated P. falciparum malaria were enrolled, including 25 non‐pregnant, 30 pregnant women in the second trimester and 20 pregnant women in their third trimester. The participants received a standard dose of artemether–lumefantrine (80/480 mg) twice daily for 3 days. Densely venous plasma samples were collected. Nonlinear mixed‐effects modelling was used to characterize the pharmacokinetic properties of lumefantrine, and the effects of pregnancy was assessed on all pharmacokinetic parameters by a full covariate modelling approach. Results: The concentration‐time data of lumefantrine were described adequately by a two‐compartment disposition model, with a flexible transit absorption and first‐order elimination. Covariate modelling results demonstrated that pregnancy status or gestational age had a significant impact on both elimination clearance (CL) and the central volume of distribution (Vc) of lumefantrine. The estimated pregnancy effects on CL and Vc were 23% (95%CI: 10.8–34.8%) and 28% (95%CI: 7.3–51.8%), respectively. Pregnant women exhibited lower drug exposure compared to non‐pregnant women, with the geometric mean ratios (GMRs) of 0.76 (95% CI: 0.57–1.01), 0.79 (95% CI: 0.63–0.99) and 0.69 (95% CI: 0.51–0.94) for area under the concentration‐time curve (AUC), maxinum concentration (Cmax) and Day 7 concentration, respectively. Other covariates did not significantly affect the pharmacokinetics of lumefantrine. The 28‐day polymerase chain reaction (PCR)‐corrected parasitological cure was 100% for both pregnant and non‐pregnant women. Conclusions: The exposure to lumefantrine was lower in pregnant women, compared to non‐pregnant women, with uncomplicated P. falciparum infection. This lower drug exposure might increase the risk of treatment failure with artemether–lumefantrine in pregnant women, especially if susceptibility to either drug is reduced. Continuous assessment and monitoring of the efficacy of artemether–lumefantrine in pregnant women are warranted