Mathematical modelling of the Germasogeia aquifer

Two challenges related to improving the management of the Germasogeia aquifer were presented to the Study Group by the Cyprus Water Development Department (WDD), the public organisation responsible for managing the water resources in Cyprus. The first challenge was how to optimally recharge the aquifer in order to compensate for the extraction of drinking and irrigation water whilst preventing sea water intrusion. In order to address this challenge we developed model for the water in the aquifer. Note that by exploiting the long, thin nature of the aquifer we only develop two-dimensional models in this work. We first develop a simple model based on Darcy flows for porous media which gives the water table height for given dam seepage rate, recharge and extraction rates; we neglect seawater intrusion. We then use the steady version of this model to develop an optimized recharge strategy with which we can identify minimal recharge required for a desired extracted water volume such that the minimum prescribed water table is respected. We explore 4 different scenarios and we find that in certain cases there can be a considerable reduction in the amount of recharged water compared to the current empirical strategy the Water Development Department is employing, where water is recharged and extracted in equal proportions. To incorporate the effects of seawater intrusion, which can be very damaging to the water quality, we next develop transient twodimensional models of saturated-unsaturated groundwater flow and solve them numerically using the open source software SUTRASuite and the commercial package ANSYS FLUENT; the position of the water table and the seawaterfreshwater interface are determined for various extraction/recharge strategies. Data from the WDD are used in some of the simulations. The second important challenge we were asked to look at was to predict the transport of pollutants in the aquifer in the case of an accidental leakage. An advection-diffusion equation for the contaminant concentration is introduced and simulations are undertaken using the commercial package COMSOL. The concentration profiles of the contaminant are studied and we find that the effect of contamination varies depending on where the contamination site is; the closer the contamination site is to the dam, the larger the extent of contamination will be

Mathematical modelling of the Germasogeia aquifer

Two challenges related to improving the management of the Germasogeia aquifer were presented to the Study Group by the Cyprus Water Development Department (WDD), the public organisation responsible for managing the wa- ter resources in Cyprus. The rst challenge was how to optimally recharge the aquifer in order to compensate for the extraction of drinking and irrigation water whilst preventing sea water intrusion. In order to address this challenge we developed model for the water in the aquifer. Note that by exploiting the long, thin nature of the aquifer we only develop two-dimensional models in this work. We rst develop a simple model based on Darcy ows for porous media which gives the water table height for given dam seepage rate, recharge and extraction rates; we neglect seawater intrusion. We then use the steady version of this model to develop an optimized recharge strategy with which we can identify minimal recharge required for a desired extracted water volume such that the minimum prescribed water table is respected. We explore 4 di erent scenarios and we nd that in certain cases there can be a considerable reduction in the amount of recharged water compared to the current empirical strategy the Water Development Department is employing, where water is recharged and extracted in equal proportions. To incorporate the e ects of seawater intrusion, which can be very damaging to the water quality, we next develop transient two- dimensional models of saturated-unsaturated groundwater ow and solve them numerically using the open source software SUTRASuite and the commercial package ANSYS FLUENT; the position of the water table and the seawater- freshwater interface are determined for various extraction/recharge strategies. Data from the WDD are used in some of the simulations. The second important challenge we were asked to look at was to predict the transport of pollutants in the aquifer in the case of an accidental leakage. An advection-difusion equation for the contaminant concentration is introduced and simulations are under- taken using the commercial package COMSOL. The concentration pro les of the contaminant are studied and we nd that the e ect of contamination varies depending on where the contamination site is; the closer the contamination site is to the dam, the larger the extent of contamination will be

Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain

BACKGROUND: Breast pain and tenderness affects 70% of women at some time. These symptoms have been attributed to stretching of the nerves with increase in breast size, but tissue mechanisms are poorly understood. METHODS: Eighteen patients (n = 12 breast reduction and n = 6 breast reconstruction) were recruited and assessed for breast pain by clinical questionnaire. Breast skin biopsies from each patient were examined using immunohistological methods with specific antibodies to the capsaicin receptor TRPV1, related vanilloid thermoreceptors TRPV3 and TRPV4, and nerve growth factor (NGF). RESULTS: TRPV1-positive intra-epidermal nerve fibres were significantly increased in patients with breast pain and tenderness (TRPV1 fibres / mm epidermis, median [range] – no pain group, n = 8, 0.69 [0–1.27]; pain group, n = 10, 2.15 [0.77–4.38]; p = 0.0009). Nerve Growth Factor, which up-regulates TRPV1 and induces nerve sprouting, was present basal keratinocytes: some breast pain specimens also showed NGF staining in supra-basal keratinocytes. TRPV4-immunoreactive fibres were present in sub-epidermis but not significantly changed in painful breast tissue. Both TRPV3 and TRPV4 were significantly increased in keratinocytes in breast pain tissues; TRPV3, median [range] – no pain group, n = 6, 0.75 [0–2]; pain group, n = 11, 2 [1-3], p = 0.008; TRPV4, median [range] – no pain group, n = 6, [0–1]; pain group, n = 11, 1 [0.5–2], p = 0.014). CONCLUSION: Increased TRPV1 intra-epidermal nerve fibres could represent collateral sprouts, or re-innervation following nerve stretch and damage by polymodal nociceptors. Selective TRPV1-blockers may provide new therapy in breast pain. The role of TRPV3 and TRPV4 changes in keratinocytes deserve further study

Optimisation of Fluid Mixing in a Hydrosacc⃝ Growing Module

A mathematical model is sought for the flow of nutrients in the Hydrosac⃝c growing module being developed by Phytoponics. The basic operation involves long fluid-filled bags with periodic growing zones from which root systems emerge into the bulk fluid. The system is periodically perturbed via two main processes: partial drainage and refilling of each bag with nutrient infused water, with inlet and outlet at opposite ends of the bag; and a more violent oxygenation of the water through bubbles that rise from the pores of an aeration tube that runs underneath the central long axis of the bag. The aim of the modelling is to determine the key parameters and fluid regimes underlying the nutrient mixing process, to ensure that required nutrient levels are maintained through- out the root zones, and to enable optimal scheduling of the nutrient and bubble flow. Simple experiments were performed via the injection of dye into an operating Hydrosac⃝c that contained semi-mature plants. This enabled a basic understanding of the time and lengthscales of nutrient flow, and also the extent to which mixing occurs in different zones within the bag. Four different flow regimes are identified. At the scale of a single root, a Stokes-flow approximation may be used. At the scale of the individual plant, a so-called Brinkman flow regime may be employed which is describes a transition between slow porous- medium flow and fast channel flow. These equations may be homogenised into a 1D model that can be used to estimate the macro-scale flow of nutrients along the length of the bag. A shear flow model is used to predict the extent to which this flow permeates into regions dominated by plant roots. This leads to the requirement to model the bubble-driven flow within a bag cross-section containing a plant. Simplified two-phase flow equations are de- rived and solved within the software COMSOL. The results suggest that the bubble flow is sufficient to drive recirculating flow, which is also found to be consistent with previous literature. The overall conclusion is that both the periodic flow of nutrients and the aeration are re- quired in order to enable even nutrient spread in the Hydrosac⃝c . Wave effects can be ignored, as can the effect of stagnated nutrient diffusion. The longitudinal nutrient flow enables the whole sack to be reached on the time scale of several cycles of the main inlet flow, while the recirculation from the bubble flow enables enables nutrients to spread within the plant roots. Nevertheless, regions of stagnation can occur via this process near any sharp corners of the bag. It is recommend that the various analyses are combined into a a reduced-order mathemat- ical model that can be used to optimise the dynamic operation of the Hydrosac⃝c , which can also be adaptable to other geometries and growing conditions

Th17 cells are more protective than Th1 cells against the intracellular parasite Trypanosoma cruzi

Th17 cells are a subset of CD4+ T cells known to play a central role in the pathogenesis of many autoimmune diseases, as well as in the defense against some extracellular bacteria and fungi. However, Th17 cells are not believed to have a significant function against intracellular infections. In contrast to this paradigm, we have discovered that Th17 cells provide robust protection against Trypanosoma cruzi, the intracellular protozoan parasite that causes Chagas disease. Th17 cells confer significantly stronger protection against T. cruzi-related mortality than even Th1 cells, traditionally thought to be the CD4+ T cell subset most important for immunity to T. cruzi and other intracellular microorganisms. Mechanistically, Th17 cells can directly protect infected cells through the IL-17A-dependent induction of NADPH oxidase, involved in the phagocyte respiratory burst response, and provide indirect help through IL-21-dependent activation of CD8+ T cells. The discovery of these novel Th17 cell-mediated direct protective and indirect helper effects important for intracellular immunity highlights the diversity of Th17 cell roles, and increases understanding of protective T. cruzi immunity, aiding the development of therapeutics and vaccines for Chagas disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Expert Leadership and Hidden Inequalities in Community Projets

This chapter explores the development of a mid-range theory that can be used in organisations when considering how to engage multiple stakeholders in a project that requires expert input. The case study presented here is concerned with a ground-breaking approach to integrate heritage, culture and social benefit through the medium of archaeology and heritage. The findings indicated that the ‘expert’ as a leader of the project created hidden inequalities in the team, preventing the longer-term social outcomes of the project from materialising. A Realist Evaluation (Pawson and Tilley, 1997a) protocol was developed which created an ‘intervention’, permitting the non-linear complex interactions between multiple groups and multiple stakeholders to be observed and evaluated. This allowed for the political, strategic, organisational, operational and individual perspectives to be addressed making it a suited evaluative approach to this type of multiple stakeholder project

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication