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Pain arising from trigeminal systems such as headache is common, debilitating, and current treatments (e.g., sumatriptan) are limited. New treatments that target novel mechanisms of action may be required to innovate both short- and long-term pain therapy. Fatty acid amide hydrolase and soluble epoxide hydrolase are two pain-related enzymes that regulate pain and inflammation via independent pathways. We have previously demonstrated that simultaneous inhibition of these enzymes using a novel dual inhibitor alleviates acute inflammatory pain in the hindpaw and does not depress wheel running in rats. Here, we expanded on these findings and performed structure-activity relationships of our lead compound, the 4-phenyl-thiazole-based dual inhibitor SW-17, to generate 18 analogs and tested them for their inhibition at both enzymes. Conversion of the sulfonamide group to a tertiary amine led to a general decrease in the potency for the sEH enzyme, while this change was well-tolerated at the FAAH enzyme yielding several strong inhibitors. Six selected inhibitors were evaluated in mouse and rat sEH inhibition assays and results showed a species difference, i.e. 4-phenyl-thiazole-based analogs are significantly less or not active in mouse sEH compared to human and rat enzymes. The most potent inhibitor, SW-17, was evaluated in a plasma stability assay in human and rat plasma and showed moderate stability. However, SW-17 did not alleviate orofacial inflammatory pain in female rats compared to the traditional anti-migraine agent sumatriptan. Although modification of 4-phenyl-thiazole-based dual inhibitor SW-17 changes potencies at both FAAH and sEH, these approaches may not produce antinociception against trigeminal pain. Key Words: polypharmacology, formalin, inflammation, enzyme inhibition, structure-activity relationship studies

This paper presents a numerical study on the hydrodynamic coefficients of the DARPA SUBOFF hull when deeply submerged and near the seabed. The CFD-based model was validated with experimental data, namely experiments involving the SUBOFF and BB2 undergoing straight-ahead motion near the free surface and the SUBOFF only when deeply submerged at drift angles without the influence of either the free surface or the seabed. The validated model was used to investigate the effects of the seabed's effect on the hydrodynamic behaviour of the SUBOFF across a range of speeds, drift angles, and submergence depths. The results were then compared to operations near the free surface. The results show that the seabed has a smaller influence on the hydrodynamic coefficients compared to the free surface. Also, the hydrodynamic coefficients do not vary with Froude number when near the seabed but do vary with Froude number when near the free surface.

Foldable containers have the potential to enhance the cost efficiency of the logistics industry and improve the problem of space allocation at seaports. Using primary and secondary data sources the pros and cons of using foldable containers as compared to standard containers are identified, and it is shown that a port can gain cost efficiencies by using foldable containers. A simulation for the Port of Melbourne (Australia) demonstrates that using foldable containers would reduce the projected total number of containers handled by the port in 2035 from 7.057 million to 5.817 million, with an 80% decrease in the number of empty containers. Foldable containers can therefore have a significant impact on the reformation of the transport and logistics systems.

The increasing adoption of solar photovoltaic systems has brought attention to performance degradation factors, such as soiling, that hinder their efficiency. This study investigates the impact of dust particle thermophysical properties on solar cell temperature and energy losses, using transient thermal analysis and computational fluid dynamics simulations to analyse the complex interactions between dust and solar panels specifically focusing on solar cell temperature. By analyzing dust particle thermophysical characteristics and their interaction with solar collectors, this study provides a comprehensive understanding of performance degradation in solar energy systems. Simulation results reveal that velocity distributions around the solar panel, particularly in low-pressure zones and regions of high turbulence, significantly affect dust dispersion and deposition. Thermal emissions from the panel further influence dust accumulation through thermophoresis. Response surface methodology and contour analysis identified dust particle size as the most critical factor affecting cell temperature, followed by density and specific heat capacity. Thermal conductivity exhibited an inverse relationship with cell temperature, acting as an insulator at lower values. The developed response surface model demonstrated high accuracy (R2 = 0.9964) and statistical significance (p-value = 0.0001), predicting temperature variations based on different dust thermophysical parameters. Energy computations, extrapolated from the computational fluid dynamics and thermal simulations for a 50 kW grid-tied solar system over six months, indicated an overall energy loss of 18.93 %, due to transmittance loss (14.89 %), normal cell temperature rise (3.31 %), and temperature rise due to soiling (0.73 %). The study further revealed an overall revenue loss of 4.3 %, with 0.83 % attributed to thermal losses due to soiling. By understanding the influence of dust particle characteristics on solar cell temperature and performance, the findings can inform better maintenance practices and improve long-term energy yield predictions for solar installations.

Introducción: El ensayo clínico PROWESS ha demostrado que el tratamiento con drotrecogina alfa (activada) en pacientes con sepsis grave se asocia a una reducción del riesgo absoluto de muerte en comparación con el tratamiento estándar. El objetivo del estudio fue evaluar el coste-efectividad de drotrecogina alfa (activada), frente a tratamiento estándar, en el tratamiento de la sepsis grave en España. Pacientes y métodos: Se elaboró un modelo de análisis de decisión en el que se compararon los costes hasta el alta hospitalaria y la eficacia a largo plazo de drotrecogina alfa (activada) frente a tratamiento estándar de pacientes con sepsis grave en España, desde la perspectiva del financiador de los servicios sanitarios. La mayoría de la información para realizar el modelo se obtuvo del ensayo clínico PROWESS. El análisis basal fue doble: a) para todos los pacientes incluidos en el ensayo clínico PROWESS, y b) para los pacientes con 2 o más fallos orgánicos. Las variables principales de valoración clínica fueron la reducción de la mortalidad hospitalaria y los años de vida ganados (AVG). El coste-efectividad se expresó como coste por AVG. Se realizó un análisis de sensibilidad utilizando tasas de descuento del 3 y el 5% para los AVG y modificando los patrones de atención sanitaria, los costes de la unidad de cuidados intensivos, la esperanza de vida según la comorbilidad inicial y la eficacia terapéutica de drotrecogina alfa (activada). Resultados: El tratamiento con drotrecogina alfa (activada) se asoció a un descenso del riesgo absoluto de mortalidad hospitalaria del 6,0% (p = 0,005) cuando se incluyeron todos los pacientes del estudio PROWESS, y una reducción del 7,3% (p = 0,005) cuando sólo se incluyeron los pacientes con 2 o más fracasos orgánicos. El coste-efectividad de drotrecogina alfa (activada) fue de 13.550 euros por AVG respecto a placebo cuando se analizó el total de pacientes, y de 9.800 euros por AVG en el grupo de pacientes con 2 o más fallos orgánicos. En el análisis de sensibilidad, los resultados oscilaron desde 7.322 a 16.493 euros por AVG. Los factores que más influyeron en los resultados fueron la modificación de la eficacia de drotrecogina alfa (activada), el ajuste de la supervivencia según la comorbilidad inicial y la aplicación de descuento a los AVG. Conclusiones: El tratamiento con drotrecogina alfa (activada) presenta una relación coste-efectividad favorable en comparación con otras intervenciones sanitarias comúnmente utilizadas en España.Introduction: The PROWESS clinical trial has shown that treatment with drotrecogin alpha (activated) in patients with severe sepsis is associated with a reduction in the absolute risk of death compared with standard treatment. The aim of the present study was to assess the cost-effectiveness of drotrecogin alpha (activated) versus that of standard care in the treatment of severe sepsis in Spain. Patients and methods: A decision analysis model was drawn up to compare costs to hospital discharge and the long-term efficacy of drotrecogin alpha (activated) versus those of standard care in the treatment of severe sepsis in Spain from the perspective of the health care payer. Most of the information for creating the model was obtained from the PROWESS clinical trial. A two-fold baseline analysis was performed: a) for all patients included in the PROWESS clinical trial and b) for the patients with two or more organ failures. The major variables for clinical assessment were the reduction in mortality and years of life gained (YLG). Cost-effectiveness was expressed as cost per YLG. A sensitivity analysis was applied using 3% and 5% discount rates for YLG and by modifying the patterns of health care, intensive care unit costs, and life expectancy by initial co-morbidity and therapeutic efficacy of drotrecogin alpha (activated). Results: Treatment with drotrecogin alfa (activated) was associated with a 6.0% drop in the absolute risk of death (p = 0.005) when all of the patients from the PROWESS trial were included and with a 7.3% reduction (p = 0.005) when the analysis was restricted to patients with two or more organ failures. The cost-effectiveness of drotrecogin alfa (activated) was euros 13,550 per YLG with respect to standard care after analysing all of the patients and euros 9,800 per YLG in the group of patients with two or more organ failures. In the sensitivity analysis, the results ranged from 7,322 to euros 16,493 per YLG. The factors with the greatest impact on the results were the change in the efficacy of drotrecogin alfa (activated), adjustment of survival by initial co-morbidity and the application of discount rates to YLG. Conclusions: Treatment with drotrecogin alfa (activated) presents a favorable cost-effectiveness ratio compared with other health care interventions commonly used in Spain.