CONservative TReatment of Appendicitis in Children – a randomised controlled feasibility Trial (CONTRACT)

Objective To establish the feasibility of a multicentre randomised controlled trial to assess the effectiveness and cost-effectiveness of a non-operative treatment pathway compared with appendicectomy in children with uncomplicated acute appendicitis.Design Feasibility randomised controlled trial with embedded qualitative study to inform recruiter training to optimise recruitment and the design of a future definitive trial.Setting Three specialist paediatric surgery centres in the UK.Patients Children (aged 4–15 years) with a clinical diagnosis of uncomplicated acute appendicitis.Interventions Appendicectomy or a non-operative treatment pathway (comprising broad-spectrum antibiotics and active observation).Main outcome measures Primary outcome measure was the proportion of eligible patients recruited. Secondary outcomes evaluated adherence to interventions, data collection during follow-up, safety of treatment pathways and clinical course.Results Fifty per cent of eligible participants (95% CI 40 to 59) approached about the trial agreed to participate and were randomised. Repeated bespoke recruiter training was associated with an increase in recruitment rate over the course of the trial from 38% to 72%. There was high acceptance of randomisation, good patient and surgeon adherence to trial procedures and satisfactory completion of follow-up. Although more participants had perforated appendicitis than had been anticipated, treatment pathways were found to be safe and adverse event profiles acceptable.Conclusion Recruitment to a randomised controlled trial examining the effectiveness and cost-effectiveness of a non-operative treatment pathway compared with appendicectomy for the treatment of uncomplicated acute appendicitis in children is feasible.Trial registration number ISRCTN15830435

Conservative treatment for uncomplicated appendicitis in children:the CONTRACT feasibility study, including feasibility RCT

Background Whilst non-operative treatment is known to be effective for the treatment of uncomplicated acute appendicitis in children, comparative randomised trial data reporting important outcomes compared to appendicectomy are lacking.ObjectivesTo ascertain the feasibility of conducting a multi-centre randomised controlled trial (RCT) testing the effectiveness and cost-effectiveness of a non-operative treatment pathway compared to appendicectomy for the treatment of uncomplicated acute appendicitis in children.•DesignMixed methods study including: a feasibility RCT; embedded and parallel qualitative and survey studies; parallel health economic feasibility study; development of a core outcome set.Setting Three specialist NHS Paediatric Surgical Units in EnglandParticipants Children (aged 4-15 years) clinically diagnosed with uncomplicated acute appendicitis participated in the feasibility RCT. Children, their families, recruiting clinicians and other healthcare professionals involved in caring for children with appendicitis took part in the qualitative study. UK Specialist Paediatric Surgeons took part in the survey. Specialist Paediatric Surgeons, Adult General Surgeons who treat children, and children and young people who previously had appendicitis along with their families took part in the core outcomes set development.Interventions Participants in the feasibility RCT were randomised to a non-operative treatment pathway (broad-spectrum antibiotics and active observation) or appendicectomy.Main outcome measures Primary outcome measure was the proportion of eligible patients recruited to the feasibility trial.Data sourcesNHS casenotes, questionnaire responses, transcribed audio recordings of recruitment discussions and qualitative interviewsResults Overall, 50% (95%CI 40-59) of 115 eligible participants approached about the trial agreed to participate and were randomised. There was high acceptance of randomisation and good adherence to trial procedures and follow-up (follow rates of 89%, 85% and 85% at six weeks, three months and six months respectively). More participants had perforated appendicitis than had been anticipated.Qualitative work enabled us to: communicate about the trial effectively with patients and families; design and deliver bespoke training to optimise recruitment; and understand how to optimise design and delivery of a future trial.The health economic study, indicated that the main cost drivers are the ward stay cost and the cost of the operation, and has informed quality of life assessment methods for future work.A core outcome set for the treatment of uncomplicated acute appendicitis in children and young people was developed, containing 14 outcomes.There is adequate surgeon interest to justify proceeding to an effectiveness trial with 51% of those surveyed expressing a willingness to recruit with an unchanged trial protocol.LimitationsSince the feasibility RCT was only performed in three centres we cannot guarantee successful recruitment across a larger number of sites. However, our qualitative work has informed a bespoke training package to facilitate this. Although survey results suggest adequate clinician interest to make a larger trial possible, actual participation may differ, and equipoise may have moved over time.Conclusions A future effectiveness trial is feasible following limited additional preparation to establish appropriate outcome measures and case identification. We recommend a limited package of qualitative work be included to optimise recruitment at new centres in particular.Future work Prior to proceeding to an effectiveness trial we need to: develop a robust method for distinguishing children with uncomplicated acute appendicitis from those with more advanced appendicitis; reach agreement on a primary outcome measure and effect size that is acceptable to all stakeholder groups involved.Study registration ISRCTN15830435.Funding detailsNIHR HTA programm

CONTRACT Study - CONservative TReatment of Appendicitis in Children (feasibility):study protocol for a randomised controlled Trial

BackgroundCurrently, the routine treatment for acute appendicitis in the United Kingdom is an appendicectomy. However, there is increasing scientific interest and research into non-operative treatment of appendicitis in adults and children. While a number of studies have investigated non-operative treatment of appendicitis in adults, this research cannot be applied to the paediatric population. Ultimately, we aim to perform a UK-based multicentre randomised controlled trial (RCT) to test the clinical and cost effectiveness of non-operative treatment of acute uncomplicated appendicitis in children, as compared with appendicectomy. First, we will undertake a feasibility study to assess the feasibility of performing such a trial.Methods/designThe study involves a feasibility RCT with a nested qualitative research to optimise recruitment as well as a health economic substudy. Children (aged 4–15 years inclusive) diagnosed with acute uncomplicated appendicitis that would normally be treated with an appendicectomy are eligible for the RCT. Exclusion criteria include clinical/radiological suspicion of perforated appendicitis, appendix mass or previous non-operative treatment of appendicitis. Participants will be randomised into one of two arms. Participants in the intervention arm are treated with antibiotics and regular clinical assessment to ensure clinical improvement. Participants in the control arm will receive appendicectomy. Randomisation will be minimised by age, sex, duration of symptoms and centre. Children and families who are approached for the RCT will be invited to participate in the embedded qualitative substudy, which includes recording of recruitment consultants and subsequent interviews with participants and non-participants and their families and recruiters. Analyses of these will inform interventions to optimise recruitment. The main study outcomes include recruitment rate (primary outcome), identification of strategies to optimise recruitment, performance of trial treatment pathways, clinical outcomes and safety of non-operative treatment. We have involved children, young people and parents in study design and delivery.DiscussionIn this study we will explore the feasibility of performing a full efficacy RCT comparing non-operative treatment with appendicectomy in children with acute uncomplicated appendicitis. Factors determining success of the present study include recruitment rate, safety of non-operative treatment and adequate interest in the future RCT. Ultimately this feasibility study will form the foundation of the main RCT and reinforce its design.Trial registrationISRCTN15830435. Registered on 8 February 2017

H5N1 and 1918 Pandemic Influenza Virus Infection Results in Early and Excessive Infiltration of Macrophages and Neutrophils in the Lungs of Mice

Fatal human respiratory disease associated with the 1918 pandemic influenza virus and potentially pandemic H5N1 viruses is characterized by severe lung pathology, including pulmonary edema and extensive inflammatory infiltrate. Here, we quantified the cellular immune response to infection in the mouse lung by flow cytometry and demonstrate that mice infected with highly pathogenic (HP) H1N1 and H5N1 influenza viruses exhibit significantly high numbers of macrophages and neutrophils in the lungs compared to mice infected with low pathogenic (LP) viruses. Mice infected with the 1918 pandemic virus and a recent H5N1 human isolate show considerable similarities in overall lung cellularity, lung immune cell sub-population composition and cellular immune temporal dynamics. Interestingly, while these similarities were observed, the HP H5N1 virus consistently elicited significantly higher levels of pro-inflammatory cytokines in whole lungs and primary human macrophages, revealing a potentially critical difference in the pathogenesis of H5N1 infections. These results together show that infection with HP influenza viruses such as H5N1 and the 1918 pandemic virus leads to a rapid cell recruitment of macrophages and neutrophils into the lungs, suggesting that these cells play a role in acute lung inflammation associated with HP influenza virus infection. In addition, primary macrophages and dendritic cells were also susceptible to 1918 and H5N1 influenza virus infection in vitro and in infected mouse lung tissue

Groundwater pathways for nutrient transport from agricultural land to the Great Barrier Reef

The World Heritage listed Great Barrier Reef (GBR) off the northeast coast of Australia is the largest reef in the world. Unfortunately, agricultural production in GBR catchments over the past 150 years has contributed to a decline in water quality entering the GBR lagoon. Riverine discharge has been identified as the single largest source of nutrients to inshore areas of the GBR lagoon. However, the contribution of groundwater discharge to nutrient concentrations in rivers and streams in GBR catchments is currently uncertain. One of the GBR catchments of particular interest is the Lower Burdekin catchment. In this catchment, the predominant crop grown is sugarcane and there are ongoing concerns related to soil and water management. A significant body of research has been undertaken in this catchment, focusing mostly on paddock scale monitoring and modeling. In addition to this, a regional scale modeling toolkit has been developed which aims to support decision making for water management by addressing local groundwater management issues including: declining groundwater quality, rising water tables and increased discharge of poor quality groundwater to the environment. In recent years, there has been a significant increase in the monitoring of groundwater nutrient concentrations underlying agricultural land in the Lower Burdekin, including a program of voluntary monitoring by canegrowers where 962 samples were taken over a 12-month period. Around 40% of the groundwater samples from this voluntary monitoring program contained nitrate at concentrations > 5mg nitrate-N/L, the fate of this nitrogen remains unclear. Some preliminary research has been conducted in the Lower Burdekin into nitrogen transport both from aquifers directly to the marine environment and from aquifers to surface water. This research has identified the need to better define; I) groundwater flow paths to the marine environment and the possible role of preferential flow paths ii) spatial and temporal variations in redox conditions in these environments and the processes that underlie them. Further research, incorporating isotopic analyses and geochemical modeling, is required to better understand the processes occurring and to improve estimates of nutrient fluxes to the GBR via groundwater

Impacts of Amelioration on Sodic Soil Hydraulic Conductivity and Potential Consequences for Deep Drainage in the Lower Burdekin, North Queensland

Groundwater tables are rising beneath irrigated fields in the Lower Burdekin in North Queensland, Australia. The soils where this occurs are predominantly sodic clay soils with low hydraulic conductivities. Many of these soils have been treated by applying gypsum or by increasing the salinity of irrigation water by mixing saline groundwater with fresh river water. While the purpose of these treatments is to increase infiltration into the surface soils and improve productivity of the root zone, it is thought that the treatments may have altered the soil hydraulic properties well below the root zone leading to increased groundwater recharge and rising water tables. The objective of this thesis is to assess the potential for sodic soil amelioration treatments to increase soil hydraulic conductivity and hence increase groundwater recharge rates. This research focuses on the impacts of gypsum treatments and increased irrigation water salinity on soil chemistry, soil hydraulic conductivity and deep drainage rates. To determine the current properties of local sodic soils, previous soil surveys were reviewed and field work was conducted to collect soil samples. From the analysis of these soils, it was determined that sodicity levels remain high at some locations even under irrigation and that the high sodicity levels extend below the typically sampled “root zone” Using the samples of the collected sodic soils, experiments were conducted to measure changes in hydraulic conductivity in response to selected treatments. The results of these column experiments showed that gypsum applications can lead to increases in hydraulic conductivity of an order of magnitude when compared with the maximum hydraulic conductivity of a surrogate for good quality irrigation water. Hydraulic conductivity increases occurred when sodic soils were leached continuously with a saturated gypsum solution for at least three weeks. These increases in hydraulic conductivity were positively correlated with decreases in exchangeable sodium and magnesium concentrations. The salt concentration of the applied solution was found to have a significant influence on the maximum hydraulic conductivity; however continued leaching with mixed cation saline waters caused a rapid increase in hydraulic conductivity followed by a gradual decrease. vi Numerical modelling was used to study the expected depth and timing of the impacts of amelioration, compare the impacts of different treatments on deep drainage and to determine the influence of large amounts of rain during the relatively short wet season on soil properties and deep drainage. When the amelioration of ten metre profiles of sodic clays was simulated using HYDRUS-1D, decreases in soil sodicity only occurred close to the soil surface but deep drainage rates still increased. When gypsum applications occurred during the irrigation season, deep drainage rates during the following wet season were at least three times greater than when no gypsum was applied. Gypsum applications and increased irrigation salinity have the potential to increase soil hydraulic conductivity and deep drainage rates. The overall impact of sodic soil amelioration on rising groundwater tables in the Lower Burdekin depends on the initial soil sodicity and soil hydraulic properties of the active crop root zone, the frequency and duration of treatments, the rates of irrigation and rainfall, and the hydraulic conductivity of the materials in the deeper unsaturated zone below the crop root zone

Nitrate dynamics in groundwater under sugarcane in a wet-tropics catchment

The transport of nitrogen (N) to groundwater and surface water in the form of nitrate (NO3-), as a by-product of the application of N-rich fertilisers, has been studied extensively. Yet, in the catchments adjacent to the Great Barrier Reef (GBR) in tropical north Queensland, Australia, NO3- transport in groundwater is not regularly monitored. An assessment of groundwater chemistry in the Liverpool Creek catchment of Queensland's wet-tropics region was conducted by regular sampling and analysis of groundwater over 12 months, through wet and dry seasons. A distinct spatial variability in groundwater chemistry was observed; groundwater aquifers with very low dissolved oxygen (DO) and NO3- consistently displayed relatively higher concentrations of sulphate (SO42-), sulphur (S2-) and ferrous iron (Fe2+) and low concentrations of dissolved organic carbon (DOC) (3- via autotrophic denitrification (DN), while other groundwater aquifers retained NO3 – concentrations just above the acceptable trigger limits defined in regional water quality guidelines. Observations indicate that the naturally heterogeneous structure of the coastal alluvium contributes to the distinct variability in groundwater chemistry over small distances, with NO3- concentrations influenced by a combination of DN, lateral shallow drainage and potential adsorption to clay surfaces within the alluvial sediments.</p

Hydrogeochemical evolution of the shallow and deep basaltic aquifers in Tamborine Mountain, Queensland (Australia) [Evolucion hidrogeoquimica de los acuiferos basalticos someros y profundos de Tamborine Mountain, Queensland (Australia)]

Tamborine Mountain, Queensland (Australia), is a prime example of a basalt fractured-rock aquifer. Yet very little is known about the hydrochemistry of this groundwater system. Both analytical (major ions and stable isotopes) and multivariate (hierarchical cluster analysis, principal component analysis and factor analysis) analyses were used in this study to investigate the factors that interact within this aquifer system, in order to determine groundwater hydrogeochemistry. A new approach was applied to the data by classifying hydrographs by water type to clearly identify differing aquifer zones. Three distinct groundwater chemistry types were identified, and they were differentiated by variations in depth. Shallow bores were dominated by Na–Cl waters, deep bores were dominated by Na–HCO3 and Ca–HCO3 waters, and the two deepest bores were dominated by mixed water types. The evaluation of hydrogeochemical data has determined that both mineral weathering processes and groundwater/surface-water interaction had a strong influence on the hydrogeochemistry. Seasonal effects were minimal in the study area based on physicochemical parameters and ion chemistry. However, stable isotopic data show temporal trends. Increased rainfall events during the wet season produced a depletion in δ18O and increased d-excess values. The opposite is found during the dry season as a result of higher evaporation rates that are not hindered by intense rainfall events.</p

Simulating deep drainage and nitrate leaching on a regional scale: implications for groundwater management in an intensively irrigated area

Groundwater management in irrigation areas requires a comprehensive understanding of the interactions between agricultural management practices and the underlying groundwater resource. Unsaturated zone modelling can be used to predict rates of water and solute movement through the soil profile. By incorporating expert knowledge and measured data, it is possible to investigate the relative influence of management vs environmental factors on water and solute movement. The Agricultural Production Systems sIMulator (APSIM) has been applied to simulate the impacts of both environmental factors and agricultural management factors on deep drainage and nitrate leaching in the Lower Burdekin, North Queensland, Australia. Based on the results of this modelling, predicted annual average deep drainage rates were found to be controlled primarily by soil properties, irrigation scheduling, and, to a lesser extent, annual rainfall. The key factors which were found to control nitrate leaching were: irrigation water quality, fertilizer application rates, soil type, crop management, and irrigation scheduling. However, increases in the concentrations of nitrate in irrigation water resulted in a 64-fold increase in predicted nitrate-leaching rates, compared with a 22-fold increase in predicted nitrate-leaching rates associated with increased fertilizer application rates. As significant quantities of nitrate are predicted to be leached below the root zone, the immediate priority should be to increase monitoring of groundwater quality with a focus on quantifying the transport of nutrients to sensitive receptors

External Engagement Program: Strategic Investment Priorities Report

The aim of this report, the Strategic Investment Priorities Report (SIPR) is to identify, assess and prioritise a set of strategic investment opportunities for the Queensland Water Modelling Network (QWMN) Secretariat (representing the State Government) to consider in planning the work of the QWMN with regards capability and capacity building for water modelling and use across Queensland. The scope of the report and the work behind it:• Focusses on the capability and capacity building activities of the QWMN • Focusses on the next 4 years of operation for the QWMN• Identifies and assesses opportunities for investment by the QWMN based on existing written evidence alone – no primary research was undertaken although it should be noted that the written evidence includes outputs from a workshop with over 60 representatives of the sector that occurred during the QWMN Forum 2020 (Filet, 2020)• Prioritises investment opportunities based on a qualitative assessment rather than on a quantitative approach such as ROI<br/