Virtual clinical QT exposure-response studies - A translational computational approach.

BACKGROUND AND PURPOSE: A recent paradigm shift in proarrhythmic risk assessment suggests that the integration of clinical, non-clinical, and computational evidence can be used to reach a comprehensive understanding of the proarrhythmic potential of drug candidates. While current computational methodologies focus on predicting the incidence of proarrhythmic events after drug administration, the objective of this study is to predict concentration-response relationships of QTc as a clinical endpoint. EXPERIMENTAL APPROACH: Full heart computational models reproducing human cardiac populations were created to predict the concentration-response relationship of changes in the QT interval as recommended for clinical trials. The concentration-response relationship of the QT-interval prolongation obtained from the computational cardiac population was compared against the relationship from clinical trial data for a set of well-characterized compounds: moxifloxacin, dofetilide, verapamil, and ondansetron. KEY RESULTS: Computationally derived concentration-response relationships of QT interval changes for three of the four drugs had slopes within the confidence interval of clinical trials (dofetilide, moxifloxacin and verapamil) when compared to placebo-corrected concentration-ΔQT and concentration-ΔQT regressions. Moxifloxacin showed a higher intercept, outside the confidence interval of the clinical data, demonstrating that in this example, the standard linear regression does not appropriately capture the concentration-response results at very low concentrations. The concentrations corresponding to a mean QTc prolongation of 10 ms were consistently lower in the computational model than in clinical data. The critical concentration varied within an approximate ratio of 0.5 (moxifloxacin and ondansetron) and 1 times (dofetilide, verapamil) the critical concentration observed in human clinical trials. Notably, no other in silico methodology can approximate the human critical concentration values for a QT interval prolongation of 10 ms. CONCLUSION AND IMPLICATIONS: Computational concentration-response modelling of a virtual population of high-resolution, 3-dimensional cardiac models can provide comparable information to clinical data and could be used to complement pre-clinical and clinical safety packages. It provides access to an unlimited exposure range to support trial design and can improve the understanding of pre-clinical-clinical translation.

Assessing groundwater denitrification spatially is the key to targeted agricultural nitrogen regulation.

Globally, food production for an ever-growing population is a well-known threat to the environment due to losses of excess reactive nitrogen (N) from agriculture. Since the 1980s, many countries of the Global North, such as Denmark, have successfully combatted N pollution in the aquatic environment by regulation and introduction of national agricultural one-size-fits-all mitigation measures. Despite this success, further reduction of the N load is required to meet the EU water directives demands, and implementation of additional targeted N regulation of agriculture has scientifically and politically been found to be a way forward. In this paper, we present a comprehensive concept to make future targeted N regulation successful environmentally and economically. The concept focus is on how and where to establish detailed maps of the groundwater denitrification potential (N retention) in areas, such as Denmark, covered by Quaternary deposits. Quaternary deposits are abundant in many parts of the world, and often feature very complex geological and geochemical architectures. We show that this subsurface complexity results in large local differences in groundwater N retention. Prioritization of the most complex areas for implementation of the new concept can be a cost-efficient way to achieve lower N impact on the aquatic environment.

Scanning electron microscopy of damage caused by Mesocyclops thermocyclopoides (Copepoda: Cyclopoidea) on larvae of the Dengue fever vector Aedes aegypti (Diptera: Culicidae)

Dengue fever is a mosquito-borne viral disease, whose main biological vector is Aedes aegypti. This mosquito colonizes tropical areas where the disease is endemic. The most obvious action against dengue is attacking its vector. Biological control appears to be an alternative approach, using natural enemies of the mosquitoes, such as predatory copepods. Thus, the morphological study of the damage caused by copepods is important to understand its predatory capacity. Twenty-five A. aegypti larvae were exposed to the copepod Mesocyclops thermocyclopoides and the damage caused by the copepods was evaluated using scanning electron microscopy. The larvae showed damage mainly at the anal segment, the siphon and the abdomen; only three attacks to the head were observed. The size of the siphon might be of importance in determining whether or not a copepod will attack a mosquito larva.

El dengue es una enfermedad viral transmitida por mosquitos, cuyo principal vector es Aedes aegypti. Este mosquito coloniza muchas áreas tropicales donde la enfermedad es endémica. La acción más obvia contra el dengue es el ataque a su vector. El control biológico parece una buena alternativa, empleando enemigos naturales de los mosquitos, como los copépodos. Por lo tanto, es importante el estudio morfológico del daño causado por los copépodos para comprender su capacidad depredadora. Veinticinco larvas de A. aegypti fueron expuestas a la actividad depredadora del copépodo Mesocyclops thermocyclopoides. Mediante microscopia electrónica de rastreo se evaluó el daño causado por los copépodos. Éstos atacaron principalmente el segmento anal, el sifón y el abdomen de las larvas; sólo vimos tres ataques a la cabeza. El tamaño del sifón podría ser de importancia para predecir si los copépodos pudiesen atacar larvas de determinado mosquito.

Scanning electron microscopy of the four larval instars of the Dengue fever vector Aedes aegypti (Diptera: Culicidae)

Aedes aegypti is the main insect vector of Dengue fever and dengue hemorrhagic fever/dengue shock syndrome and represents the only vulnerable element in the control of this disease. Therefore, the identification and quantification of this mosquito is an important task; however, the majority of taxonomic keys are based on the 4th larval instar. For that reason, this study describes the four larval instars ofA. aegypti using scanning electron microscopy. Morphological changes during larval development were observed at the pecten, comb scales and the ventral brush of the abdominal segment X; however, the 3rd and 4th instars showed similar structures with only a slight variation. The structures described in this study will be helpful in the identification of the four instars of A. aegypti, a fundamental task for comprehending the natural history of dengue mainly in new territories affected.

Aedes aegypti es el principal insecto vector de la fiebre del dengue y del dengue hemorrágico/síndrome del choque por dengue y es el único elemento atacable para el control de esta virosis. La identificación y cuantificación de éste es una tarea importante; no obstante, la mayoría de las llaves taxonómicas se basan en el cuarto estadio larval. Por esta razón, en este trabajo se describen los cuatro estadios larvales de A. aegypti los cuales fueron examinados mediante microscopia electrónica de rastreo. Los cambios morfológicos ocurridos durante el desarrollo larval fueron observados en el pecten, las escamas del peine, el cepillo ventral del décimo segmento. El 3ero y 4to estadios larvales mostraron estructuras similares con sólo ligeras variaciones. Las estructuras descritas en este artículo permiten identificar cualquiera de los cuatro estadios larvales de A. aegypti, lo cual representa una tarea importante en la comprensión de la historia natural del dengue en los nuevos territorios afectados.

Scanning electron microscopy of damage caused by Mesocyclops thermocyclopoides (Copepoda: Cyclopoidea) on larvae of the Dengue fever vector Aedes aegypti (Diptera: Culicidae).

Dengue fever is a mosquito-borne viral disease, whose main biological vector is Aedes aegypti. This mosquito colonizes tropical areas where the disease is endemic. The most obvious action against dengue is attacking its vector. Biological control appears to be an alternative approach, using natural enemies of the mosquitoes, such as predatory copepods. Thus, the morphological study of the damage caused by copepods is important to understand its predatory capacity. Twenty-five A. aegypti larvae were exposed to the copepod Mesocyclops thermocyclopoides and the damage caused by the copepods was evaluated using scanning electron microscopy. The larvae showed damage mainly at the anal segment, the siphon and the abdomen; only three attacks to the head were observed. The size of the siphon might be of importance in determining whether or not a copepod will attack a mosquito larva.

Scanning electron microscopy of the four larval instars of the Dengue fever vector Aedes aegypti (Diptera: Culicidae).

Aedes aegypti is the main insect vector of Dengue fever and dengue hemorrhagic fever/dengue shock syndrome and represents the only vulnerable element in the control of this disease. Therefore, the identification and quantification of this mosquito is an important task; however, the majority of taxonomic keys are based on the 4th larval instar. For that reason, this study describes the four larval instars ofA. aegypti using scanning electron microscopy. Morphological changes during larval development were observed at the pecten, comb scales and the ventral brush of the abdominal segment X; however, the 3rd and 4th instars showed similar structures with only a slight variation. The structures described in this study will be helpful in the identification of the four instars of A. aegypti, a fundamental task for comprehending the natural history of dengue mainly in new territories affected.

La lucha contra el dengue: control biológico de larvas de aedes aegypti empleando mesocyclops thermocyclopoides (crustacea) / The fight against dengue: biological control of aedes aegypti larvas using mesocyclops thermocyclopoides (crustacea)

La medida más eficaz contra el dengue es el control de su insecto vector Aedes Aegypti. Para tal propósito la acción más común es el uso de insecticidas, lo cual es controversial, porque es caro, sólo afecta a los adultos, induce resistencia y contamina el ambiente. No obstante, el control biológico con predadores naturales de Aedes Aegypti, como los copépodos (microcrustáceos) ha sido exitoso en varios países. Uno de los géneros más grandes de copépodos de ríos y lagunas de Costa Rica es mesocyclops thermocyclopoides. El objetivo de este trabajo es la evaluación de la acción depredadora de este microcrustáceo en contra de las larvas de A. aegypti. En experimentos de laboratorio realizados en la Universidad Nacional y en la Unidad de Microscopía Electrónica se demostró que un copépodo es capaz de eliminar aproximadamente 7 larvas por día. Después de 7 semanas de observación, la población de mosquitos fue eliminada de una jaula donde se habían puesto 40 larvas de cuarto estadio junto con un recipiente plástico con agua y copépodos. En la Jaula control, bajo condiciones similares, pero sin copépodos, a las 7 semanas de observación el número de adultos prácticamente se duplicó y en el agua había unas 40 pupas. El análisis al microscopio electrónico de rastreo de las larvas atacadas por los copépodos mostraron lesiones en sus segmentos abdominales y el sifón siempre había sido cortado. Estos datos promisorios muestran que el copépodo mesocyclops thermocyclopoides puede ser usado satisfactoriamente como control biológico de Aedes aegypti