End-to-End Ensemble Modelling for Water Resources Planning Under Uncertainty

A hydrological model ensemble, considering two model structures (CatchMOD and PDM), parameter uncertainty and two contrasting methods for estimating potential evapotranspiration (PET), is developed to investigate the relative significance of different sources of uncertainty for water resources planning in the Thames basin. This model ensemble is driven by an ensemble of UKCP09 probabilistic and Future Flows climate change projections, for the 2030s, 2050s and 2080s, to quantify the projected impacts on a range of metrics of relevance to water resources planners using a water resources system model of London. These sources of supply-side uncertainty are shown to be significant, with the uncertainty associated with the climate change scenarios the largest but hydrological modelling uncertainty, and the method used to estimate PET also shown to be considerable. In terms of overall impacts, the central estimates for the 2030s, 2050s and 2080s are reductions in available resource of around 7%, 11% and 14% respectively. These impacts are shown to equate to economic costs of the order of £360m, £610m and £735m respectively to mitigate such reductions in supply. The range of uncertainty within each time-horizon is large, greater than the differences between the time-horizons, presenting a significant challenge in deciding the level and timing of investments to mitigate emerging risks. As an example, impacts considered reasonably likely by the 2080s (e.g. a central estimate of 14% impact on deployable output using both PET methods) may be as likely by the 2030s (e. g. using only the modified Penman-Monteith PET method). The estimates of future supply reliability are contrasted with demand forecasts and whilst the pressure associated with the latter is shown to be greater, both are significant and subject to large degrees of uncertainty. This thesis also highlights the need for detailed examination of hydrological model structures to provide evidence as to their strengths and weaknesses in their representation of key processes, particularly during droughts. The limitations of the climate change products currently used in the industry, particularly with regards to droughts and estimating changes in PET, are also explored. Significant ongoing research is developing decision-making approaches to support the planning of robust and resilient systems under an uncertain future. This thesis demonstrates that alongside this development, more research is needed to understand, identify and quantify the significant sources of uncertainty that need to be considered as part of the decision-making process

Functional thalamocortical connectivity at term equivalent age and outcome at 2 years in infants born preterm

Contains fulltext : 231088.pdf (Publisher’s version ) (Open Access

Use of Two Self-referral Reminders and a Theory-Based Leaflet to Increase the Uptake of Flexible Sigmoidoscopy in the English Bowel Scope Screening Program: Results From a Randomized Controlled Trial in London

Background We previously initiated a randomized controlled trial to test the effectiveness of two self-referral reminders and a theory-based leaflet (sent 12 and 24 months after the initial invitation) to increase participation within the English Bowel Scope Screening program. Purpose This study reports the results following the second reminder. Methods Men and women included in the initial sample (n = 1,383) were re-assessed for eligibility 24 months after their invitation (12 months after the first reminder) and excluded if they had attended screening, moved away, or died. Eligible adults received the same treatment they were allocated 12 months previous, that is, no reminder (“control”), or a self-referral reminder with either the standard information booklet (“Reminder and Standard Information Booklet”) or theory-based leaflet designed using the Behavior Change Wheel (“Reminder and Theory-Based Leaflet”). The primary outcome was the proportion screened within each group 12 weeks after the second reminder. Results In total, 1,218 (88.1%) individuals were eligible. Additional uptake following the second reminder was 0.4% (2/460), 4.8% (19/399), and 7.9% (29/366) in the control, Reminder and Standard Information Booklet, and Reminder and Theory-Based Leaflet groups, respectively. When combined with the first reminder, the overall uptake for each group was 0.7% (3/461), 14.5% (67/461), and 21.5% (99/461). Overall uptake was significantly higher in the Reminder and Standard Information Booklet and Reminder and Theory-Based Leaflet groups than in the control (odds ratio [OR] = 26.1, 95% confidence interval [CI] = 8.1–84.0, p < .001 and OR = 46.9, 95% CI = 14.7–149.9, p < .001, respectively), and significantly higher in the Reminder and Theory-Based Leaflet group than in the Reminder and Standard Information Booklet group (OR = 1.8, 95% CI = 1.3–2.6, p < .001). Conclusion A second reminder increased uptake among former nonparticipants. The added value of the theory-based leaflet highlights a potential benefit to reviewing the current information booklet. Trials Registry Number ISRCTN44293755

Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases

Background: Median survival of non-small cell lung cancer (NSCLC) patients with brain metastases is poor. We examined concurrent erlotinib and whole brain radiotherapy (WBRT) followed by maintenance erlotinib in patients with untreated brain metastases, given the potential radiosensitizing properties of erlotinib and its direct effect on brain metastases and systemic activity.Methods: Eighty NSCLC patients with KPS of 70 and greater and multiple brain metastases were randomly assigned to placebo (n = 40) or erlotinib (100mg, n = 40) given concurrently with WBRT (20 Gy in 5 fractions). Following WBRT, patients continued with placebo or erlotinib (150mg) until disease progression. The primary end point was neurological progression-free survival (nPFS); hazard ratios (HRs) were calculated using Cox regression. All P values were two-sided.Results: Fifteen patients (37.5%) from each arm were alive and without neurological progression 2 months after WBRT. Median nPFS was 1.6 months in both arms; nPFS HR 0.95 (95% CI = 0.59 to1.54; P = .84). Median overall survival (OS) was 2.9 and 3.4 months in the placebo and erlotinib arms; HR 0.95 (95% CI = 0.58 to 1.55; P = .83). The frequency of epidermal growth factor receptor (EGFR) mutations was low with only 1 of 35 (2.9%) patients with available samples had activating EGFR-mutations. Grade 3/4 adverse event rates were similar between the two groups (70.0% in each arm), except for rash 20.0% (erlotinib) vs 5.0% (placebo), and fatigue 17.5% vs 35.0%. No statistically significant quality of life differences were found.Conclusions: Our study showed no advantage in nPFS or OS for concurrent erlotinib and WBRT followed by maintenance erlotinib in patients with predominantly EGFR wild-type NSCLC and multiple brain metastases compared to placebo. Future studies should focus on the role of erlotinib with or without WBRT in patients with EGFR mutations.Up to 40% of patients with non-small cell lung cancer (NSCLC) develop brain metastases (BM), which are associated with poor outcome (median survival &lt;5 months) (1–3). Treatment options include whole-brain radiotherapy (WBRT) with or without corticosteroids. Modifying the radiation dose or fractionation or combining radiotherapy with radiosensitizers have not substantially improved prognosis (4–10). More than half of patients treated with WBRT ultimately die of progressive systemic disease (11–13).Erlotinib, an epidermal growth factor receptor (EGFR) pathway inhibitor, is currently approved as first-line treatment for advanced NSCLC patients harboring EGFR mutations, and, as maintenance, second-line or third-line treatments following chemotherapy (14–17). Pre-clinical data show that erlotinib enhances the inhibitory effect of ionizing radiation in lung cancer, and it crosses the blood-brain barrier, so it could be used to provide sufficient radiosensitizing and therapeutic level in the brain (18–22).To exploit the potential radiosensitizing properties, the direct effect on brain metastases, and systemic activity of erlotinib, we examined the role of erlotinib given concurrently with WBRT, then as maintenance

Improving uptake of flexible sigmoidoscopy screening: a randomized trial of nonparticipant reminders in the English Screening Programme

Background and study aims Uptake of flexible sigmoidoscopy screening in the English Bowel Scope Screening (BSS) Programme is low. The aim of this study was to test the impact of a nonparticipant reminder and theory-based leaflet to promote uptake among former nonresponders (previously did not confirm their appointment) and nonattenders (previously confirmed their appointment but did not attend). Patients and methods Eligible adults were men and women in London who had not attended a BSS appointment within 12 months of their invitation. Individuals were randomized (1:1:1) to receive no reminder (control), a 12-month reminder plus standard information booklet (TMR-SIB), or a 12-month reminder plus bespoke theory-based leaflet (TMR-TBL) designed to address barriers to screening. The primary outcome of the study was the proportion of individuals screened within each group 12 weeks after the delivery of the reminder. Results A total of 1383 men and women were randomized and analyzed as allocated (n = 461 per trial arm). Uptake was 0.2 % (n = 1), 10.4 % (n = 48), and 15.2 % (n = 70) in the control, TMR-SIB, and TMR-TBL groups, respectively. Individuals in the TMR-SIB and TMR-TBL groups were significantly more likely to attend screening than individuals in the control group (adjusted odds ratio [OR] 53.7, 95 % confidence interval [CI] 7.4 – 391.4, P

Text-message Reminders in Colorectal Cancer Screening (TRICCS): a randomised controlled trial

Background: We investigated the effectiveness of a text-message reminder to improve uptake of the English Bowel Cancer Screening programme in London. Methods: We performed a randomised controlled trial across 141 general practices in London. Eight thousand two hundred sixty-nine screening-eligible adults (aged 60–74 years) were randomised in a 1 : 1 ratio to receive either a text-message reminder (n=4134) or no text-message reminder (n=4135) if they had not returned their faecal occult blood test kit within 8 weeks of initial invitation. The primary outcome was the proportion of adults returning a test kit at the end of an 18-week screening episode (intention-to-treat analysis). A subgroup analysis was conducted for individuals receiving an invitation for the first time. Results: Uptake was 39.9% in the control group and 40.5% in the intervention group. Uptake did not differ significantly between groups for the whole study population of older adults (adjusted odds ratio (OR) 1.03, 95% confidence interval (CI) 0.94–1.12; P=0.56) but did vary between the groups for first-time invitees (uptake was 34.9% in the control and 40.5% in the intervention; adjusted OR 1.29, 95% CI 1.04–1.58; P=0.02). Conclusions: Although text-message reminders did not significantly increase uptake of the overall population, the improvement among first-time invitees is encouraging

Impact of general practice endorsement on the social gradient in uptake in bowel cancer screening

This is a summary of independent research funded by the National Institute for Health. Research (NIHR)’s Programme Grants for Applied Research Programme (RP-PG-0609–10106

The enhanced future Flows and Groundwater dataset: development and evaluation of nationally consistent hydrological projections based on UKCP18

This paper details the development and evaluation of the enhanced future FLows and Groundwater (eFLaG) dataset of nationally consistent hydrological projections for the UK, based on the latest UK Climate Projections (UKCP18). The projections are derived from a range of hydrological models. For river flows, multiple models (Grid-to-Grid, PDM (Probability Distributed Model) and GR (Génie Rural; both four- and six-parameter versions, GR4J and GR6J)) are used to provide an indication of hydrological model uncertainty. For groundwater, two models are used, a groundwater level model (AquiMod) and a groundwater recharge model (ZOODRM: zooming object-oriented distributed-recharge model). A 12-member ensemble of transient projections of present and future (up to 2080) daily river flows, groundwater levels and groundwater recharge was produced using bias-corrected data from the UKCP18 regional (12 km) climate ensemble. Projections are provided for 200 river catchments, 54 groundwater level boreholes and 558 groundwater bodies, all sampling across the diverse hydrological and geological conditions of the UK. An evaluation was carried out to appraise the quality of hydrological model simulations against observations and also to appraise the reliability of hydrological models driven by the regional climate model (RCM) ensemble in terms of their capacity to reproduce hydrological regimes in the current period. The dataset was originally conceived as a prototype climate service for drought planning for the UK water sector and so has been developed with drought, low river flow and low groundwater level applications as the primary objectives. The evaluation metrics show that river flows and groundwater levels are, for the majority of catchments and boreholes, well simulated across the flow and level regime, meaning that the eFLaG dataset could be applied to a wider range of water resources research and management contexts, pending a full evaluation for the designated purpose. Only a single climate model and one emissions scenario are used, so any applications should ideally contextualise the outcomes with other climate model–scenario combinations. The dataset can be accessed in Hannaford et al. (2022): https://doi.org/10.5285/1bb90673-ad37-4679-90b9-0126109639a9

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation