Optimal locations of groundwater extractions in coastal aquifers

A regional water supply management model for coastal aquifers was developed. One of its outcomes is the definition of the optimized locations for groundwater withdrawal. Such a tool permits the analysis of alternative plans for groundwater extraction and the sustainable use of water resources in a coastal aquifer subject to saltwater intrusion. The principal components are the evolutionary optimization and the analytical/numerical simulation models. The optimization technique looks for the best well locations taking into consideration the economic results and the satisfaction of the societal water demand. However these two concerns are conditioned by trying to control the saltwater intrusion, i.e., preserving the environmental equilibrium. The simulation model uses the governing mathematical equations for groundwater movement to find the interface between freshwater and saltwater. Because of the non-linearity in the system and the possibility of a jumping interface, a security distance was defined. This is a controlling variable which can be set by the decision makers. The model was applied to a typical case with interesting results. For example, diagrams showing the relationship between the location of the wells and the security distance(s) are of importance to the managers. It was also crucial to have an understanding of the tradeoffs between groundwater withdrawals, positions of the wells from the coast line, and the security distance. The model was also applied to a real case in order to relate the extractions, distances and artificial recharge (not presented in this paper).Civil Engineering Research Centre of the University of Minho.Science and Technology Foundation -POCTI/ECM/2512/9

Protein kinase Cε and protein kinase Cθ double-deficient mice have a bleeding diathesis.

In comparison to the classical isoforms of protein kinase C (PKC), the novel isoforms are thought to play minor or inhibitory roles in the regulation of platelet activation and thrombosis.To measure the levels of PKCθ and PKCε and to investigate the phenotype of mice deficient in both novel PKC isoforms.Tail bleeding and platelet activation assays were monitored in mice and platelets from mice deficient in both PKCθ and PKCε.PKCε plays a minor role in supporting aggregation and secretion following stimulation of the collagen receptor GPVI in mouse platelets but has no apparent role in spreading on fibrinogen. PKCθ, in contrast, plays a minor role in supporting adhesion and filopodial generation on fibrinogen but has no apparent role in aggregation and secretion induced by GPVI despite being expressed at over 10 times the level of PKCε. Platelets deficient in both novel isoforms have a similar pattern of aggregation downstream of GPVI and spreading on fibrinogen as the single null mutants. Strikingly, a marked reduction in aggregation on collagen under arteriolar shear conditions is observed in blood from the double but not single-deficient mice along with a significant increase in tail bleeding.These results reveal a greater than additive role for PKCθ and PKCε in supporting platelet activation under shear conditions and demonstrate that, in combination, the two novel PKCs support platelet activation

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Design of Experiments for Screening

The aim of this paper is to review methods of designing screening experiments, ranging from designs originally developed for physical experiments to those especially tailored to experiments on numerical models. The strengths and weaknesses of the various designs for screening variables in numerical models are discussed. First, classes of factorial designs for experiments to estimate main effects and interactions through a linear statistical model are described, specifically regular and nonregular fractional factorial designs, supersaturated designs and systematic fractional replicate designs. Generic issues of aliasing, bias and cancellation of factorial effects are discussed. Second, group screening experiments are considered including factorial group screening and sequential bifurcation. Third, random sampling plans are discussed including Latin hypercube sampling and sampling plans to estimate elementary effects. Fourth, a variety of modelling methods commonly employed with screening designs are briefly described. Finally, a novel study demonstrates six screening methods on two frequently-used exemplars, and their performances are compared

Design and implementation of GRIP: a computerized glucose control system at a surgical intensive care unit

BACKGROUND: Tight glucose control by intensive insulin therapy has become a key part of critical care and is an important field of study in acute coronary care. A balance has to be found between frequency of measurements and the risk of hypoglycemia. Current nurse-driven protocols are paper-based and, therefore, rely on simple rules. For safety and efficiency a computer decision support system that employs complex logic may be superior to paper protocols. METHODS: We designed and implemented GRIP, a stand-alone Java computer program. Our implementation of GRIP will be released as free software. Blood glucose values measured by a point-of-care analyzer were automatically retrieved from the central laboratory database. Additional clinical information was asked from the nurse and the program subsequently advised a new insulin pump rate and glucose sampling interval. RESULTS: Implementation of the computer program was uneventful and successful. GRIP treated 179 patients for a total of 957 patient-days. Severe hypoglycemia (< 2.2 mmol/L) only occurred once due to human error. With a median (IQR) of 4.9 (4.2 – 6.2) glucose measurements per day the median percentage of time in which glucose fell in the target range was 78%. Nurses rated the program as easy to work with and as an improvement over the preceding paper protocol. They reported no increase in time spent on glucose control. CONCLUSION: A computer driven protocol is a safe and effective means of glucose control at a surgical ICU. Future improvements in the recommendation algorithm may further improve safety and efficiency

Psychosocial work factors, job stress and strain at the wheel: Validation of the Copenhagen Psychosocial Questionnaire (COPSOQ) in professional drivers

Psychosocial work environment has been related to many negative health outcomes in different workforces. However, evidence in this regard is still limited in the case of transport workers, and most of the tools used in research, often excessively generic, do not fully consider the specific key stressors, and adverse issues present in the psychosocial environment of professional driving. Objective: Thus, the purpose of this study was to obtain a complete description of the validation of measurement applied to psychosocial factors at work in professional drivers, using the Enterprise version (2018) of COPSOQ-III. Methods: The data was collected from 726 Spanish professional drivers, and the analyses were conducted using the competitive Confirmatory Factor Analysis or CFA, obtaining basic psychometric properties and an optimized structure for the instrument applied to active transport workers. Results: The results suggest a clear factorial structure, high factorial weights, internal consistency, and an improved adjustment to the psychosocial conditions of this group, excluding a set of items with low psychometrical adjustment and keeping the five-factor structure of the questionnaire: demands, influence and development, interpersonal relationships and leadership, job insecurity, and strain-effects and outcomes. Conclusion: Overall, what was found in this study supports the hypothesis that the validated version of COPSOQ in professional drivers, together with complementary information sources specific for their work environment, may have a relevant research value and some important practical implications for the improvement of the occupational safety, and health within the typically vulnerable industry of transportatio

Temperature Dependence of the Extrinsic Incubation Period of Orbiviruses in Culicoides Biting Midges

The rate at which viruses replicate and disseminate in competent arthropod vectors is limited by the temperature of their environment, and this can be an important determinant of geographical and seasonal limits to their transmission by arthropods in temperate regions.Here, we present a novel statistical methodology for estimating the relationship between temperature and the extrinsic incubation period (EIP) and apply it to both published and novel data on virus replication for three internationally important orbiviruses (African horse sickness virus (AHSV), bluetongue virus (BTV) and epizootic haemorrhagic disease virus (EHDV)) in their Culicoides vectors. Our analyses show that there can be differences in vector competence for different orbiviruses in the same vector species and for the same orbivirus in different vector species. Both the rate of virus replication (approximately 0.017-0.021 per degree-day) and the minimum temperature required for replication (11-13°C), however, were generally consistent for different orbiviruses and across different Culicoides vector species. The estimates obtained in the present study suggest that previous publications have underestimated the replication rate and threshold temperature because the statistical methods they used included an implicit assumption that all negative vectors were infected.Robust estimates of the temperature dependence of arbovirus replication are essential for building accurate models of transmission and for informing policy decisions about seasonal relaxations to movement restrictions. The methodology developed in this study provides the required robustness and is superior to methods used previously. Importantly, the methods are generic and can readily be applied to other arbovirus-vector systems, as long as the assumptions described in the text are valid

Changes in Early Cortical Visual Processing Predict Enhanced Reactivity in Deaf Individuals

Individuals with profound deafness rely critically on vision to interact with their environment. Improvement of visual performance as a consequence of auditory deprivation is assumed to result from cross-modal changes occurring in late stages of visual processing. Here we measured reaction times and event-related potentials (ERPs) in profoundly deaf adults and hearing controls during a speeded visual detection task, to assess to what extent the enhanced reactivity of deaf individuals could reflect plastic changes in the early cortical processing of the stimulus. We found that deaf subjects were faster than hearing controls at detecting the visual targets, regardless of their location in the visual field (peripheral or peri-foveal). This behavioural facilitation was associated with ERP changes starting from the first detectable response in the striate cortex (C1 component) at about 80 ms after stimulus onset, and in the P1 complex (100–150 ms). In addition, we found that P1 peak amplitudes predicted the response times in deaf subjects, whereas in hearing individuals visual reactivity and ERP amplitudes correlated only at later stages of processing. These findings show that long-term auditory deprivation can profoundly alter visual processing from the earliest cortical stages. Furthermore, our results provide the first evidence of a co-variation between modified brain activity (cortical plasticity) and behavioural enhancement in this sensory-deprived population

Insecticide resistance in Anopheles gambiae from south-western Chad, Central Africa

<p>Abstract</p> <p>Background</p> <p>Indoor residual spraying and insecticide-treated nets (ITN) are essential components of malaria vector control in Africa. Pyrethroids are the only recommended compounds for nets treatment because they are fast-acting insecticides with low mammalian toxicity. However, there is growing concern that pyrethroid resistance may threaten the sustainability of ITN scaling-up programmes. Here, insecticide susceptibility was investigated in <it>Anopheles gambiae </it>sensu lato from an area of large scale ITN distribution programme in south-western Chad.</p> <p>Methods</p> <p>Susceptibility to 4% DDT, 0.05% deltamethrin, 0.75% permethrin, 0.1% bendiocarb and 5% malathion was assessed using the WHO standard procedures for adult mosquitoes. Tests were carried out with two to four days-old, non-engorged female mosquitoes. The <it>An. gambiae </it>Kisumu strain was used as a reference. Knockdown effect was recorded every 5 min and mortality scored 24 h after exposure. Mosquitoes were identified to species and molecular form by PCR-RFLP and genotypes at the <it>kdr </it>locus were determined in surviving specimens by Hot Oligonucleotide Ligation Assay (HOLA).</p> <p>Results</p> <p>During this survey, full susceptibility to malathion was recorded in all samples. Reduced susceptibility to bendiocarb (mortality rate of 96.1%) was found in one sample out of nine assayed. Increased tolerance to pyrethroids was detected in most samples (8/9) with mortality rates ranging from 70.2 to 96.6% for deltamethrin and from 26.7 to 96.3% for permethrin. Pyrethroid tolerance was not associated with a significant increase of knock-down times. <it>Anopheles arabiensis </it>was the predominant species of the <it>An. gambiae </it>complex in the study area, representing 75 to 100% of the samples. Screening for <it>kdr </it>mutations detected the L1014F mutation in 88.6% (N = 35) of surviving <it>An</it>. <it>gambiae </it>sensu stricto S form mosquitoes. All surviving <it>An. arabiensis </it>(N = 49) and M form <it>An</it>. <it>gambiae </it>s.s. (N = 1) carried the susceptible allele.</p> <p>Conclusion</p> <p>This first investigation of malaria vector susceptibility to insecticides in Chad revealed variable levels of resistance to pyrethroid insecticides (permethrin and deltamethrin) in most <it>An</it>. <it>gambiae </it>s.l. populations. Resistance was associated with the L1014F <it>kdr </it>mutation in the S form of <it>An. gambiae </it>s.s.. Alternative mechanisms, probably of metabolic origin are involved in <it>An. arabiensis</it>. These results emphasize the crucial need for insecticide resistance monitoring and in-depth investigation of resistance mechanisms in malaria vectors in Chad. The impact of reduced susceptibility to pyrethroids on ITN efficacy should be further assessed.</p

Support for e-cigarette regulations among Australian young adults

Background: Surveying support for various regulatory options relating to e-cigarettes can assist policymakers to identify those that have broad support and are therefore likely to be easier to implement. However, data on support for potential e-cigarette regulations in Australia are limited. To inform regulatory efforts, the present study assessed attitudes to the regulation of e-cigarettes among Australian young adults, the most prevalent users of e-cigarettes and therefore the most likely population segment to be affected by e-cigarette regulations. Methods: A total of 1116 Australians aged 18 to 25 years (59% female) completed an online survey where they were presented with various statements relating to the regulation of e-cigarettes and asked to report on the extent to which they agreed or disagreed with each. Statements presented either a restrictive or non-restrictive approach to e-cigarette regulation. Results: Across all statements, 10-22% of respondents responded "don't know" while 23-35% neither agreed nor disagreed, indicating general ambivalence. There was a moderate level of support (33-37%) for regulating e-cigarette sales/use and treating e-cigarettes like tobacco products. Only 20% of respondents were in favour of allowing the use of e-cigarettes in smoke-free areas. Smokers, e-cigarette users, and those who did not believe in the harms associated with e-cigarettes were typically less likely than other respondents to support restrictive approaches. Conclusions: The young Australian adults surveyed were somewhat supportive of restrictions around the sale and use of e-cigarettes, but generally opposed outright bans and any need for a prescription from a medical practitioner. Increasing awareness of the harms associated with the use of e-cigarettes represents a potential strategy to gaining regulatory support