Understanding and modelling of surface and groundwater interactions

The connections between surface water and groundwater systems remain poorly understood in many catchments throughout the world and yet they are fundamental to effectively managing water resources. Managing water resources in an integrated manner is not straightforward, particularly if both resources are being utilised, and especially in those regions that suffer problems of data scarcity. This study explores some of the principle issues associated with understanding and practically modelling surface and groundwater interactions. In South Africa, there remains much controversy over the most appropriate type of integrated model to be used and the way forward in terms of the development of the discipline; part of the disagreement stems from the fact that we cannot validate models adequately. This is largely due to traditional forms of model testing having limited power as it is difficult to differentiate between the uncertainties within different model structures, different sets of alternative parameter values and in the input data used to run the model. While model structural uncertainties are important to consider, the uncertainty from input data error together with parameter estimation error are often more significant to the overall residual error, and essential to consider if we want to achieve reliable predictions for water resource decisions. While new philosophies and theories on modelling and results validation have been developed (Beven, 2002; Gupta et al., 2008), in many cases models are not only still being validated and compared using sparse and uncertain datasets, but also expected to produce reliable predictions based on the flawed data. The approach in this study is focused on fundamental understanding of hydrological systems rather than calibration based modelling and promotes the use of all the available 'hard' and 'soft' data together with thoughtful conceptual examination of the processes occurring in an environment to ensure as far as possible that a model is generating sensible results by simulating the correct processes. The first part of the thesis focuses on characterising the 'typical' interaction environments found in South Africa. It was found that many traditional perceptual models are not necessarily applicable to South African conditions, largely due to the relative importance of unsaturated zone processes and the complexity of the dominantly fractured rock environments. The interaction environments were categorised into four main 'types' of environment. These include karst, primary, fractured rock (secondary), and alluvial environments. Processes critical to Integrated Water Resource Management (IWRM) were defined within each interaction type as a guideline to setting a model up to realistically represent the dominant processes in the respective settings. The second part of the thesis addressed the application and evaluation of the modified Pitman model (Hughes, 2004), which allows for surface and groundwater interaction behaviour at the catchment scale to be simulated. The issue is whether, given the different sources of uncertainty in the modelling process, we can differentiate one conceptual flow path from another in trying to refine the understanding and consequently have more faith in model predictions. Seven example catchments were selected from around South Africa to assess whether reliable integrated assessments can be carried out given the existing data. Specific catchment perceptual models were used to identify the critical processes occurring in each setting and the Pitman model was assessed on whether it could represent them (structural uncertainty). The available knowledge of specific environments or catchments was then examined in an attempt to resolve the parameter uncertainty present within each catchment and ensure the subsequent model setup was correctly representing the process understanding as far as possible. The confidence in the quantitative results inevitably varied with the amount and quality of the data available. While the model was deemed to be robust based on the behavioural results obtained in the majority of the case studies, in many cases a quantitative validation of the outputs was just not possible based on the available data. In these cases, the model was judged on its ability to represent the conceptualisation of the processes occurring in the catchments. While the lack of appropriate data means there will always be considerable uncertainty surrounding model validation, it can be argued that improved process understanding in an environment can be used to validate model outcomes to a degree, by assessing whether a model is getting the right results for the right reasons. Many water resource decisions are still made without adequate account being taken of the uncertainties inherent in assessing the response of hydrological systems. Certainly, with all the possible sources of uncertainty in a data scarce country such as South Africa, pure calibration based modelling is unlikely to produce reliable information for water resource managers as it can produce the right results for the wrong reasons. Thus it becomes essential to incorporate conceptual thinking into the modelling process, so that at the very least we are able to conclude that a model generates estimates that are consistent with, and reflect, our understanding (however limited) of the catchment processes. It is fairly clear that achieving the optimum model of a hydrological system may be fraught with difficulty, if not impossible. This makes it very difficult from a practitioner's point of view to decide which model and uncertainty estimation method to use. According to Beven (2009), this may be a transitional problem and in the future it may become clearer as we learn more about how to estimate the uncertainties associated with hydrological systems. Until then, a better understanding of the fundamental and most critical hydrogeological processes should be used to critically test and improve model predictions as far as possible. A major focus of the study was to identify whether the modified Pitman model could provide a practical tool for water resource managers by reliably determining the available water resource. The incorporation of surface and groundwater interaction routines seems to have resulted in a more robust and realistic model of basin hydrology. The overall conclusion is that the model, although simplified, is capable of representing the catchment scale processes that occur under most South African conditions

Powered mobility interventions for very young children with mobility limitations to aid participation and positive development:the EMPoWER evidence synthesis

Background One-fifth of all disabled children have mobility limitations. Early provision of powered mobility for very young children (aged < 5 years) is hypothesised to trigger positive developmental changes. However, the optimum age at which to introduce powered mobility is unknown. Objective The aim of this project was to synthesise existing evidence regarding the effectiveness and cost-effectiveness of powered mobility for very young children, compared with the more common practice of powered mobility provision from the age of 5 years. Review methods The study was planned as a mixed-methods evidence synthesis and economic modelling study. First, evidence relating to the effectiveness, cost-effectiveness, acceptability, feasibility and anticipated outcomes of paediatric powered mobility interventions was reviewed. A convergent mixed-methods evidence synthesis was undertaken using framework synthesis, and a separate qualitative evidence synthesis was undertaken using thematic synthesis. The two syntheses were subsequently compared and contrasted to develop a logic model for evaluating the outcomes of powered mobility interventions for children. Because there were insufficient published data, it was not possible to develop a robust economic model. Instead, a budget impact analysis was conducted to estimate the cost of increased powered mobility provision for very young children, using cost data from publicly available sources. Data sources A range of bibliographic databases [Cumulative Index to Nursing and Allied Health Literature (CINHAL), MEDLINE, EMBASE™ (Elsevier, Amsterdam, the Netherlands), Physiotherapy Evidence Database (PEDro), Occupational Therapy Systematic Evaluation of Evidence (OTseeker), Applied Social Sciences Index and Abstracts (ASSIA), PsycINFO, Science Citation Index (SCI; Clarivate Analytics, Philadelphia, PA, USA), Social Sciences Citation Index™ (SSCI; Clarivate Analytics), Conference Proceedings Citation Index – Science (CPCI-S; Clarivate Analytics), Conference Proceedings Citation Index – Social Science & Humanities (CPCI-SSH; Clarivate Analytics), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED), Health Technology Assessment (HTA) Database and OpenGrey] was systematically searched and the included studies were quality appraised. Searches were carried out in June 2018 and updated in October 2019. The date ranges searched covered from 1946 to September 2019. Results In total, 89 studies were included in the review. Only two randomised controlled trials were identified. The overall quality of the evidence was low. No conclusive evidence was found about the effectiveness or cost-effectiveness of powered mobility in children aged either < 5 or ≥ 5 years. However, strong support was found that powered mobility interventions have a positive impact on children’s movement and mobility, and moderate support was found for the impact on children’s participation, play and social interactions and on the safety outcome of accidents and pain. ‘Fit’ between the child, the equipment and the environment was found to be important, as were the outcomes related to a child’s independence, freedom and self-expression. The evidence supported two distinct conceptualisations of the primary powered mobility outcome, movement and mobility: the former is ‘movement for movement’s sake’ and the latter destination-focused mobility. Powered mobility should be focused on ‘movement for movement’s sake’ in the first instance. From the budget impact analysis, it was estimated that, annually, the NHS spends £1.89M on the provision of powered mobility for very young children, which is < 2% of total wheelchair service expenditure. Limitations The original research question could not be answered because there was a lack of appropriately powered published research. Conclusions Early powered mobility is likely to have multiple benefits for very young children, despite the lack of robust evidence to demonstrate this. Age is not the key factor; instead, the focus should be on providing developmentally appropriate interventions and focusing on ‘movement for movement’s sake’. Future work Future research should focus on developing, implementing, evaluating and comparing different approaches to early powered mobility. Study registration This study is registered as PROSPERO CRD42018096449. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology programme and will be published in full in Health Technology Assessment; Vol. 24, No. 50. See the NIHR Journals Library website for further project information

Inhibitors of trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease.

Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease. Sirtuins, also called Silent information regulator 2 (Sir2) proteins have long been suggested as interesting targets to treat different diseases, including parasitic infections. Recent studies on Trypanosoma cruzi sirtuins have hinted at the possibility to exploit these enzymes as a possible drug targets. In the present work, the T. cruzi Sir2 related protein 1 (TcSir2rp1) is genetically validated as a drug target and biochemically characterized for its NAD+-dependent deacetylase activity and its inhibition by the classic sirtuin inhibitor nicotinamide, as well as by bisnaphthalimidopropyl (BNIP) derivatives, a class of parasite sirtuin inhibitors. BNIPs ability to inhibit TcSir2rp1, and anti-parasitic activity against T. cruzi amastigotes in vitro were investigated. The compound BNIP Spermidine (BNIPSpd) (9), was found to be the most potent inhibitor of TcSir2rp1. Moreover, this compound showed altered trypanocidal activity against TcSir2rp1 overexpressing epimastigotes and anti-parasitic activity similar to the reference drug benznidazole against the medically important amastigotes, while having the highest selectivity index amongst the compounds tested. Unfortunately, BNIPSpd failed to treat a mouse model of Chagas disease, possibly due to its pharmacokinetic profile. Medicinal chemistry modifications of the compound, as well as alternative formulations may improve activity and pharmacokinetics in the future. Additionally, an initial TcSIR2rp1 model in complex with p53 peptide substrate was obtained from low resolution X-ray data (3.5 Å) to gain insight into the potential specificity of the interaction with the BNIP compounds. In conclusion, the search for TcSir2rp1 specific inhibitors may represent a valuable strategy for drug discovery against T. cruzi

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.

BACKGROUND: The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. METHODS: We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18-55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. FINDINGS: Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493-1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96-317; n=127), and were boosted following a second dose (639 EU, 360-792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R2=0·67 by Marburg VN; p<0·001). INTERPRETATION: ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. FUNDING: UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen