Development and implementation of a vehicle-pedestrian conflict analysis method: Adaptation of a vehicle-vehicle technique

This paper examines the development, use, and evaluation of a new traffic conflict analysis technique that specifically addresses pedestrian-vehicle conflicts with the intention of being applicable to shared-space environments. The method is based on an existing, well-established, and widely used vehicle-vehicle conflict analysis technique, but is adapted to consider the movement of pedestrians, which differs significantly from that of vehicles. The new method is then implemented on the Exhibition Road site of West London with the use of video data collected from locations with a potentially high concentration of vehicle-pedestrian conflicts, and the results of the analysis are presented. Finally, the results are compared with those obtained by other conflict analysis techniques and also against accident data to assess not only the accuracy but also the functionality of the new technique

Analysis of pedestrian-vehicle traffic conflicts in street designs with elements of shared space

This paper investigates changes in pedestrian-vehicle traffic conflicts in urban streets redesigned according to the principles of shared space, using a recently developed Pedestrian-Vehicle Conflicts Analysis (PVCA) method. In a first step, the PVCA method is revised to more accurately reflect the features of shared space: this includes the definition of a systematic process for identifying conflict occurrences on one hand, and the full quantification of the conflict severity grading process on the other. Then, the refined PVCA method is applied to a case study in London, using video data from periods before and after the redevelopment of the Exhibition Road site from a conventional dual carriageway to a modern design with some elements of shared space. The results of the comparative analysis carried out indicate a general decrease in traffic conflict rates as a result of the redesign, but also highlight specific issues that may require additional analysis

On equity risk prediction and tail spillovers

This paper studies the impact of modelling time-varying variances of stock returns in terms of risk measurement and extreme risk spillover. Using a general class of regime-dependent models, we find that volatility can be disaggregated into distinct components: a persistent stable process with low sensitivity to shocks and a high volatility process capturing rather short-lived rare events. Out-of-sample forecasts show that, once regime shifts are accounted for, accuracy is improved compared to the standard GARCH or the historical volatility model. Volatility plays an important role in controlling and monitoring financial risks. Therefore, by means of a risk management application, we illustrate the economic value and the practical implications of risk control ability of the models in terms of value-at-risk. Finally, tests for predictability in co-movements in the tails of stock index returns suggest that large losses are strongly correlated, supporting asymmetric transmission processes for financial contagion in the left tail of return distributions whereas contagion in reverse direction (gains) is weak

Mitochondrial Dysfunction and Insulin Resistance: The Contribution of Dioxin-Like Substances

Persistent organic pollutants (POPs) are known to cause mitochondrial dysfunction and this in turn is linked to insulin resistance, a key biochemical abnormality underlying the metabolic syndrome. To establish the cause and effect relationship between exposure to POPs and the development of the metabolic syndrome, Koch's postulates were considered. Problems arising from this approach were discussed and possible solutions were suggested. In particular, the difficulty of establishing a cause and effect relationship due to the vagueness of the metabolic syndrome as a disease entity was discussed. Recently a bioassay, aryl-hydrocarbon receptor (AhR) trans-activation activity using a cell line expressing AhR-luciferase, showed that its activity is linearly related with the parameters of the metabolic syndrome in a population. This finding suggests the possible role of bioassays in the analysis of multiple pollutants of similar kinds in the pathogenesis of several closely related diseases, such as type 2 diabetes and the metabolic syndrome. Understanding the effects of POPs on mitochondrial function will be very useful in understanding the integration of various factors involved in this process, such as genes, fetal malnutrition and environmental toxins and their protectors, as mitochondria act as a unit according to the metabolic scaling law

Uptake of synthetic low density lipoprotein by leukemic stem cells — a potential stem cell targeted drug delivery strategy

Chronic Myeloid Leukemia (CML) stem/progenitor cells, which over-express Bcr-Abl, respond to imatinib by a reversible block in proliferation without significant apoptosis. As a result, patients are unlikely to be cured owing to the persistence of leukemic quiescent stem cells (QSC) capable of initiating relapse. Previously, we have reported that intracellular levels of imatinib in primary primitive CML cells (CD34<sup>+</sup>38<sup>lo/−</sup>), are significantly lower than in CML progenitor cells (total CD34<sup>+</sup>) and leukemic cell lines. The aim of this study was to determine if potentially sub-therapeutic intracellular drug concentrations in persistent leukemic QSC may be overcome by targeted drug delivery using synthetic Low Density Lipoprotein (sLDL) particles. As a first step towards this goal, however, the extent of uptake of sLDL by leukemic cell lines and CML patient stem/progenitor cells was investigated. Results with non-drug loaded particles have shown an increased and preferential uptake of sLDL by Bcr-Abl positive cell lines in comparison to Bcr-Abl negative. Furthermore, CML CD34<sup>+</sup> and primitive CD34<sup>+</sup>38<sup>lo/−</sup> cells accumulated significantly higher levels of sLDL when compared with non-CML CD34<sup>+</sup> cells. Thus, drug-loading the sLDL nanoparticles could potentially enhance intracellular drug concentrations in primitive CML cells and thus aid their eradication

Palliative care in a rural subdistrict in South Africa: A 4-year critical review

Background: Palliative care (PC) is a priority in South Africa, focussing on integrating PC into primary health care. Few examples exist showing how this is done. In 2018, a rural PC project was implemented, which subsequently evolved into an integrated service between the hospital and the community. Aim: The aim was to review the PC project over 4 years. Setting: The setting was the George subdistrict of the Garden Route district in South Africa. Community-based services were offered to all patients with PC needs by three non-governmental organisations who deliver home community-based care via community health workers. They were supplemented by primary health care clinics, an intermediate care facility and two hospitals. Methods: This was a retrospective descriptive study. Inpatient ward round data and patient referrals between 2018 and 2022 were analysed using descriptive statistics. Variables included patient demographics, diagnosis, home visits and place of death. Results: A total of 819 patients were referred. Inpatients were reviewed on weekly ward rounds by a multidisciplinary team. The most common diagnosis was cancer (57%). Home visits enabled patient follow-ups, of which 152 were recorded. Conclusion: The programme has become sustainable and integrated in the public healthcare system. Contributing factors included dedicated staff, using simple tools and continuous training. The findings may be useful to PC programmes in similar contexts elsewhere. Contribution: This work adds new knowledge to the field of PC in an underresourced rural healthcare environment in sub-Saharan Africa, by describing how system-wide integration of a new service was navigated to become sustainable

Cardiac hypertrophy is inhibited by a local pool of cAMP regulated by phosphodiesterase 2

Rationale: Chronic elevation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels has been associated with cardiac remodelling and cardiac hypertrophy. However, enhancement of particular aspects of cAMP/protein kinase A (PKA) signalling appears to be beneficial for the failing heart. cAMP is a pleiotropic second messenger with the ability to generate multiple functional outcomes in response to different extracellular stimuli with strict fidelity, a feature that relies on the spatial segregation of the cAMP pathway components in signalling microdomains. Objective: How individual cAMP microdomains impact on cardiac pathophysiology remains largely to be established. The cAMP-degrading enzymes phosphodiesterases (PDEs) play a key role in shaping local changes in cAMP. Here we investigated the effect of specific inhibition of selected PDEs on cardiac myocyte hypertrophic growth. Methods and Results: Using pharmacological and genetic manipulation of PDE activity we found that the rise in cAMP resulting from inhibition of PDE3 and PDE4 induces hypertrophy whereas increasing cAMP levels via PDE2 inhibition is anti-hypertrophic. By real-time imaging of cAMP levels in intact myocytes and selective displacement of PKA isoforms we demonstrate that the anti-hypertrophic effect of PDE2 inhibition involves the generation of a local pool of cAMP and activation of a PKA type II subset leading to phosphorylation of the nuclear factor of activated T cells (NFAT). Conclusions: Different cAMP pools have opposing effects on cardiac myocyte cell size. PDE2 emerges as a novel key regulator of cardiac hypertrophy in vitro and in vivo and its inhibition may have therapeutic applications

Measuring the hedging effectiveness of index futures contracts: Do dynamic models outperform static models? A regime-switching approach

This paper estimates linear and non-linear GARCH models to find optimal hedge ratios with futures contracts for some of the main European stock indexes. By introducing non-linearities through a regime-switching model, we can obtain more efficient hedge ratios and superior hedging performance in both in-sample and out-sample analysis compared with other methodologies (constant hedge ratios and linear GARCH). Moreover, non-linear models also reflect different patterns followed by the dynamic relationship between the volatility of spot and futures returns during low and high volatility periods