Project FATIMA Final Report: Part 1.

EXECUTIVE SUMMARY This Final Report covers the results of the EU-funded research project FATIMA (Financial Assistance for Transport Integration in Metropolitan Areas) which had the following objectives: (i) to identify the benefits to the private sector of optimal urban transport strategies, and the potential for obtaining private sector funding to reflect those benefits; (ii) to determine the differences between strategies optimised using public funds and those optimised within the constraints imposed by private funding initiatives; (iii) to propose mechanisms by which private sector funding can be provided so as to achieve appropriately optimal transport strategies while maintaining quality of operation; and (iv) to use the results to provide more general guidance on the role of private sector funding for urban transport in the EU. The project adopted an approach which involved the application of the same study method to nine cities, chosen to reflect a range of urban transport policy contexts in Europe: Edinburgh, Eisenstadt, Helsinki, Merseyside, Oslo, Salerno, Torino, Tromsø and Vienna. This method involved specifying appropriate policy objective functions against which transport strategies could be assessed, and finding the specific strategy that optimised each of these functions. The objective functions covered a range of differing regimes with respect to constraints on public finance and the involvement of the private sector. It was found that, in a majority of the case study cities, optimal socio-economic policies could be funded by road pricing or increased parking charges, considered over a 30 year time horizon. Such measures would typically be used to make it feasible to increase public transport frequency levels or decrease public transport fares. In general it was found to be important that the city transport planning authority had complete control over all transport measures, affecting both private and public transport. However, such strategies are likely to require significant levels of investment and, given current attitudes towards constraints on public spending, it might be politically awkward for the public sector to raise such finance. There is thus a potentially useful role for private finance to be used to help overcome such (short term) financing problems. However, it must be appreciated that the private sector will expect to make a profit on such investment. In cities where optimal policies are funded by travellers, the private sector can be reimbursed by travellers. In cities where it is unfeasible for travellers to fund all the costs of optimal policies, it will be necessary for the private sector to be reimbursed from public funds (raised from taxes). An important issue here is that the use of private finance should not be allowed to replace optimal policies with sub-optimal policies. Whether or not the private sector is involved in financing a strategy, there may be interest in private sector operation of the public transport service. However, evidence on the scale of benefits or losses from such operation is unclear. If, though, a city authority decides that private operation is beneficial, it should use, where legally possible, a franchising model in which it specifies optimal public transport service levels and fares. On the other hand, if a deregulation model is required (in order to comply with national law), private operators should not be given complete freedom to determine the operating conditions which meet their profitability target, even if the level of profitability is itself constrained as a result. There are typically a number of combinations (e.g. of fares and frequency) which achieve a given level of profitability, and not all will be equally effective in terms of public policy objectives

Project FATIMA Final Report: Part 2

The final report of project FATIMA is presented in two parts. Part 1 contains a summary of the FATIMA method and sets out the key recommendations in terms of policies and optimisation methodology from both project OPTIMA and project FATIMA. Part 1 is thus directed particularly towards policy makers. Part 2 contains the details of the methodology, including the formulation of the objective functions, the optimisation process, the resulting optimal strategies under the various objective function regimes and a summary of the feasibility and acceptability of the optimal strategies based on consultations with the city authorities. This part is thus mainly aimed at the professional in transport planning and modelling

Shock Deformation in Zircon, a Comparison of Results from Shock-Reverberation and Single-Shock Experiments

The utility of the mineral zircon, ZrSiO4, as a shock-metamorphic geobarometer and geochronometer, has been steadily growing within the planetary science community. Zircon is an accessory phase found in many terrestrial rock types, lunar samples, lunar meteorites, martian meteorites and various other achondrites. Because zircon is refractory and has a high closure temperature for Pb diffusion, it has been used to determine the ages of some of the oldest material on Earth and elsewhere in the Solar System. Furthermore, major (O) and trace-element (REE, Ti, Hf) abundances and isotope compositions of zircon help characterize the petrogenetic environments and sources from which they crystallized. The response of zircon to impact-induced shock deformation is predominantly crystallographic, including dislocation creep and the formation of planar and sub-planar, low-angle grain boundaries; the formation of mechanical {112} twins; transformation to the high pressure polymorph reidite; the development of polycrystalline microtextures; and dissociation to the oxide constituents SiO2 and ZrO2. Shock microstructures can also variably affect the U- Pb isotope systematics of zircon and, in some instances, be used to constrain the impact age. While numerous studies have characterized shock deformation in zircon recovered from a variety of terrestrial impact craters and ejecta deposits and Apollo samples, experimental studies of shock deformation in zircon are limited to a handful of examples in the literature. In addition, the formation conditions (e.g., P, T) of various shock microstructures, such as planar-deformation bands, twins, and reidite lamellae, remain poorly con-strained. Furthermore, previous shocked-zircon experimental charges have not been analyzed using modern analytical equipment. This study will therefore under-take an new set of zircon shock experiments, which will then be microstructurally characterized using state-of-the-art instrumentation within the Astromaterials Research and Exploration Science Division (ARES), NASA Johnson Space Center

Implications of deep drainage through saline clay for groundwater recharge and sustainable cropping in a semi-arid catchment, Australia

The magnitude and timing of deep drainage and salt leaching through clay soils is a critical issue for dryland agriculture in semi-arid regions (<500 mm yr<sup>−1</sup> rainfall, potential evapotranspiration >2000 mm yr<sup>−1</sup>) such as parts of Australia's Murray-Darling Basin (MDB). In this rare study, hydrogeological measurements and estimations of the historic water balance of crops grown on overlying Grey Vertosols were combined to estimate the contribution of deep drainage below crop roots to recharge and salinization of shallow groundwater. Soil sampling at two sites on the alluvial flood plain of the Lower Namoi catchment revealed significant peaks in chloride concentrations at 0.8–1.2 m depth under perennial vegetation and at 2.0–2.5 m depth under continuous cropping indicating deep drainage and salt leaching since conversion to cropping. Total salt loads of 91–229 t ha<sup>−1</sup> NaCl equivalent were measured for perennial vegetation and cropping, with salinity to ≥ 10 m depth that was not detected by shallow soil surveys. Groundwater salinity varied spatially from 910 to 2430 mS m<sup>−1</sup> at 21 to 37 m depth (<i>N</i> = 5), whereas deeper groundwater was less saline (290 mS m<sup>−1</sup>) with use restricted to livestock and rural domestic supplies in this area. The Agricultural Production Systems Simulator (APSIM) software package predicted deep drainage of 3.3–9.5 mm yr<sup>−1</sup> (0.7–2.1% rainfall) based on site records of grain yields, rainfall, salt leaching and soil properties. Predicted deep drainage was highly episodic, dependent on rainfall and antecedent soil water content, and over a 39 yr period was restricted mainly to the record wet winter of 1998. During the study period, groundwater levels were unresponsive to major rainfall events (70 and 190 mm total), and most piezometers at about 18 m depth remained dry. In this area, at this time, recharge appears to be negligible due to low rainfall and large potential evapotranspiration, transient hydrological conditions after changes in land use and a thick clay dominated vadose zone. <br><br> This is in contrast to regional groundwater modelling that assumes annual recharge of 0.5% of rainfall. Importantly, it was found that leaching from episodic deep drainage could not cause discharge of saline groundwater in the area, since the water table was several meters below the incised river bed

Chlamydia trachomatis Genital Tract Infections: When Host Immune Response and the Microbiome Collide

© 2016 Genital infections with Chlamydia trachomatis continue to be a major health problem worldwide. While some individuals clear their infection (presumed to be the result of an effective Th1/interferon-γ response), others develop chronic infections and some are prone to repeat infections. In females in particular, chronic asymptomatic infections are common and can lead to pelvic inflammatory disease and infertility. Recent studies suggest that the genital tract microbiota could be a significant factor and explain person-to-person variation in C. trachomatis infections. One hypothesis suggests that C. trachomatis can use its trpBA genes to rescue tryptophan from indole, which is a product of anaerobic members of the genital tract microbiota. Women with particular microbiota types, such as seen in bacterial vaginosis, have increased numbers of anaerobes, and this would enable the chlamydia in these individuals to overcome the host's interferon-γ attempts to eliminate it, resulting in more repeat and/or chronic infections

Molar incisor hypomineralisation: current knowledge and practice

Background Molar incisor hypomineralisation (MIH) is a common developmental dental condition that presents in childhood. Areas of poorly formed enamel affect one or more first permanent molars and can cause opacities on the anterior teeth. MIH presents a variety of challenges for the dental team as well as functional and social impacts for affected children. Objectives Here, we provide an up‐to‐date review of the epidemiology, aetiology, diagnosis and clinical management of MIH. Materials and methods A review of the contemporary basic science and clinical literature, relating to MIH, was undertaken using information obtained (up to 10 April 2020) from the electronic databases PubMed, Scopus, Web of Science and the Cochrane Library. Results There is a growing body of evidence relating to the aetiology, presentation and clinical management of MIH. Current knowledge appears to be focused on potential genetic aspects, as well as the development and validation of indices for the diagnosis and management of MIH. There has also been increasing recognition of the global and individual burden of this common condition. Conclusions Dental health professionals should regularly appraise the basic science and clinical MIH literature to ensure that they provide the best possible short‐ and long‐term care for their young patients

High expression of IDO1 and TGF-?1 during recurrence and post infection clearance with Chlamydia trachomatis, are independent of host IFN-? response

© 2019 The Author(s). Background: Chlamydia trachomatis infections in women continue to be a major public health concern due to their high prevalence and consequent reproductive morbidities. While antibiotics are usually efficient to clear the Chlamydia, repeat infections are common and may contribute to pathological outcomes. Interferon-gamma (IFN-γ)-mediated immunity has been suggested to be protective against reinfection, and represent an important anti-chlamydial agent, primarily via the induction of indoleamine-2,3 dioxygenase 1 (IDO1) enzyme. IDO1 catalyzes the degradation of tryptophan, which can eliminate C. trachomatis infection in vitro. Here, we sought to measure IDO1 expression levels and related immune markers during different C. trachomatis infection statuses (repeated vs single infection vs post antibiotic treatment), in vitro and in vivo. Methods: In this study, we measured the expression levels of IDO1 and immune regulatory markers, transforming growth factor β1 (TGF-β1) and forkhead box P3 (FoxP3), in vaginal swab samples of C. trachomatis-infected women, with either single or repeated infection. In addition, we used an in vitro co-culture model of endometrial carcinoma cell-line and peripheral blood mononuclear cells (PBMCs) to measure the same immune markers. Results: We found that in women with repeated C. trachomatis infections vaginal IDO1 and TGF-β1 expression levels were significantly increased. Whereas, women who cleared their infection post antibiotic treatment, had increased levels of IDO1 and TGF-β1, as well as FoxP3. Similarly, using the in vitro model, we found significant upregulation of IDO1 and TGF-β1 levels in the co-culture infected with C. trachomatis. Furthermore, we found that in PBMCs infected with C. trachomatis there was a significant upregulation in IDO1 levels, which was independent of IFN-γ. In fact, C. trachomatis infection in PBMCs failed to induce IFN-γ levels in comparison to the uninfected culture. Conclusions: Our data provide evidence for a regulatory immune response comprised of IDO1, TGF-β1 and FoxP3 in women post antibiotic treatment. In this study, we demonstrated a significant increase in IDO1 expression levels in response to C. trachomatis infection, both in vivo and in vitro, without elevated IFN-γ levels. This study implicates IDO1 and TGF-β1 as part of the immune response to repeated C. trachomatis infections, independently of IFN-γ

Identification of a serum biomarker panel for the differential diagnosis of cholangiocarcinoma and primary sclerosing cholagnitis

The non-invasive differentiation of malignant and benign biliary disease is a clinical challenge. Carbohydrate antigen 19-9 (CA19-9), leucine-rich α2-glycoprotein (LRG1), interleukin 6 (IL6), pyruvate kinase M2 (PKM2), cytokeratin 19 fragment (CYFRA21.1) and mucin 5AC (MUC5AC) have reported utility for differentiating cholangiocarcinoma (CCA) from benign biliary disease. Herein, serum levels of these markers were tested in 66 cases of CCA and 62 cases of primary sclerosing cholangitis (PSC) and compared with markers of liver function and inflammation. Markers panels were assessed for their ability to discriminate malignant and benign disease. Several of the markers were also assessed in pre-diagnosis biliary tract cancer (BTC) samples with performances evaluated at different times prior to diagnosis. We show that LRG1 and IL6 were unable to accurately distinguish CCA from PSC, whereas CA19-9, PKM2, CYFRA21.1 and MUC5AC were significantly elevated in malignancy. Area under the receiver operating characteristic curves for these individual markers ranged from 0.73–0.84, with the best single marker (PKM2) providing 61% sensitivity at 90% specificity. A panel combining PKM2, CYFRA21.1 and MUC5AC gave 76% sensitivity at 90% specificity, which increased to 82% sensitivity by adding gamma-glutamyltransferase (GGT). In the pre-diagnosis setting, LRG1, IL6 and PKM2 were poor predictors of BTC, whilst CA19-9 and C-reactive protein were elevated up to 2 years before diagnosis. In conclusion, LRG1, IL6 and PKM2 were not useful for early detection of BTC, whilst a model combining PKM2, CYFRA21.1, MUC5AC and GGT was beneficial in differentiating malignant from benign biliary disease, warranting validation in a prospective trial

In vitro rescue of genital strains of Chlamydia trachomatis from interferon-γ and tryptophan depletion with indole-positive, but not indole-negative Prevotella spp.

© 2016 The Author(s). Background: The natural course of sexually transmitted infections caused by Chlamydia trachomatis varies between individuals. In addition to parasite and host effects, the vaginal microbiota might play a key role in the outcome of C. trachomatis infections. Interferon-gamma (IFN-γ), known for its anti-chlamydial properties, activates the expression of indoleamine 2,3-dioxygenase (IDO1) in epithelial cells, an enzyme that catabolizes the amino acid L- tryptophan into N-formylkynurenine, depleting the host cell's pool of tryptophan. Although C. trachomatis is a tryptophan auxotroph, urogenital strains (but not ocular strains) have been shown in vitro to have the ability to produce tryptophan from indole using the tryptophan synthase (trpBA) gene. It has been suggested that indole producing bacteria from the vaginal microbiota could influence the outcome of Chlamydia infection. Results: We used two in vitro models (treatment with IFN-γ or direct limitation of tryptophan), to study the effects of direct rescue by the addition of exogenous indole, or by the addition of culture supernatant from indole-positive versus indole-negative Prevotella strains, on the growth and infectivity of C. trachomatis. We found that only supernatants from the indole-positive strains, P. intermedia and P. nigrescens, were able to rescue tryptophan-starved C. trachomatis. In addition, we analyzed vaginal secretion samples to determine physiological indole concentrations. In spite of the complexity of vaginal secretions, we demonstrated that for some vaginal specimens with higher indole levels, there was a link to higher recovery of the Chlamydia under tryptophan-starved conditions, lending preliminary support to the critical role of the IFN-γ-tryptophan-indole axis in vivo. Conclusions: Our data provide evidence for the ability of both exogenous indole as well as supernatant from indole producing bacteria such as Prevotella, to rescue genital C. trachomatis from tryptophan starvation. This adds weight to the hypothesis that the vaginal microbiota (particularly from women with lower levels of lactobacilli and higher levels of indole producing anaerobes) may be intrinsically linked to the outcome of chlamydial infections in some women

Dysbiosis of the vaginal microbiota and higher vaginal kynurenine/tryptophan ratio reveals an association with Chlamydia trachomatis genital infections

© 2018 Ziklo, Vidgen, Taing, Huston and Timms. The natural course of Chlamydia trachomatis urogenital tract infections varies between individuals. While protective immunity can occur, some women can become reinfected, contributing to the development of severe pathology. While the reasons for these differences are unknown, an individual's response to induced interferon-γ (IFN-γ) is suggested to be critical. IFN-γ induction of the enzyme indoleamine 2,3-dioxygenase, which depletes tryptophan, may be the key. One hypothesis suggests that indole-producing bacteria in the vaginal microbiota can provide a substrate for the Chlamydia to synthesize tryptophan, rescuing the Chlamydia from host IFN-γ attack. We studied a cohort of 25 women who were either, Chlamydia negative, Chlamydia positive with a single infection, or Chlamydia positive with repeated infection, to test our hypothesis. We characterized their vaginal microbiota, cytokine response, as well as their tryptophan, kynurenine and indole concentrations directly in vaginal secretions. We found that C. trachomatis urogenital tract infections either initial or repeat infections, were associated with elevated vaginal kynurenine/tryptophan ratios, primarily as a result of elevated kynurenine levels. In addition, vaginal microbiota of community state type (CST) IV showed significantly lower vaginal tryptophan levels compared to CST I and III, which might be related to a higher abundance of indole producers found within this group. Furthermore, we found a higher abundance of indole producers in women who cleared their Chlamydia infection post antibiotic treatment. This study demonstrates for the first time in vivo, the association between high vaginal kynurenine/tryptophan ratios and C. trachomatis infections. In addition, tryptophan depletion was associated with vaginal microbiota of CST IV