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"Miller, Neil"
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Modeling
Modeling is coming to the fore as it is now widely accepted and indeed expected during drug discovery and development. Modeling integrates knowledge, increases understanding and provides the ability to predict an outcome either before it occurs or when it is not possible to measure. This makes modeling an attractive option for inhaled drugs as it is not possible to routinely measure what is occurring to the drug (pharmacokinetics) and what effect the drug is having (pharmacodynamics) at local microscopic sites of such a diverse and complex organ as the lung. Many pieces of information (data and knowledge) exist like the pieces of a jigsaw puzzle and modeling brings the pieces together in a scientific and mechanistically coherent manner to increase understanding of both the efficacy and safety of inhaled drugs.
Journal Article
Physiologically Based Pharmacokinetic Modelling for First-In-Human Predictions: An Updated Model Building Strategy Illustrated with Challenging Industry Case Studies
Physiologically based pharmacokinetic modelling is well established in the pharmaceutical industry and is accepted by regulatory agencies for the prediction of drug–drug interactions. However, physiologically based pharmacokinetic modelling is valuable to address a much wider range of pharmaceutical applications, and new regulatory impact is expected as its full power is leveraged. As one example, physiologically based pharmacokinetic modelling is already routinely used during drug discovery for in-vitro to in-vivo translation and pharmacokinetic modelling in preclinical species, and this leads to the application of verified models for first-in-human pharmacokinetic predictions. A consistent cross-industry strategy in this application area would increase confidence in the approach and facilitate further learning. With this in mind, this article aims to enhance a previously published first-in-human physiologically based pharmacokinetic model-building strategy. Based on the experience of scientists from multiple companies participating in the GastroPlus™ User Group Steering Committee, new Absorption, Distribution, Metabolism and Excretion knowledge is integrated and decision trees proposed for each essential component of a first-in-human prediction. We have reviewed many relevant scientific publications to identify new findings and highlight gaps that need to be addressed. Finally, four industry case studies for more challenging compounds illustrate and highlight key components of the strategy.
Journal Article
Investigating the diverse potential of a multi-purpose legume, Lablab purpureus (L.) Sweet, for smallholder production in East Africa
Climate change is posing severe challenges in Africa, where resilient crops are urgently needed to withstand drought periods and unreliable rainfall. Multi-purpose legume species, such as lablab (Lablab purpureus (L.) Sweet), have been under-utilized yet have the potential to overcome climate challenges. While lablab is native to Africa, there are few characterized varieties and it is under-utilized by smallholder farmers due to a lack of information and access to varieties. Knowledge is especially lacking on the performance of this crop by genotype, management, and environment. We conducted a two-year field study at two sites to evaluate 29 lablab cultivars under sole and maize intercrop management, with 14 cultivars selected for in-depth study. Cultivars were evaluated on vegetative biomass and grain yield production, with N fixation assessed for one site year. Biomass and grain production differed across environments and cultivars, with only biomass affected by intercropping. Average grain yield was substantially reduced to only 37 kg ha-1 in environments with maximum temperatures greater than 33°C, but biomass production yielded comparable amounts across high temperatures and in dry (<500 mm rainfall) environments. Tradeoffs were found between biomass and grain yield across high yielding cultivars, with the top three grain accessions averaging 612 kg ha-1 of grain and 1.97 Mg ha-1 biomass whereas the top three biomass accessions produced 327 kg ha-1 grain and 2.52 Mg ha-1 biomass across all environments. In a comparison of production and N fixation measurements, cultivars were identified which may have high performance in both. Suitability of lablab for grain and biomass production were visualized across Tanzania in a map comparing max temperature thresholds for grain and biomass against average regional livestock populations. This provides a way forward for identifying potential areas for lablab cultivation as a novel means to enhance fodder and pulse production with smallholder farmers.
Journal Article
Implications of monocular vision for racing drivers
We performed two experiments to investigate how monocular vision and a monocular generalized reduction in vision (MRV) impact driving performance during racing. A total of 75 visually normal students or professional racing drivers, were recruited for the two experiments. Driving performance was evaluated under three visual conditions: normal vision, simulated monocularity and simulated monocular reduction in vision. During the driving scenario, the drivers had to detect and react to the sudden intrusion of an opponent's racing car into their trajectory when entering a turn. Generalized Linear Mixed Models (GLMMs) and ANOVA were then used to explore how monocular vision and monocular reduction in vision affect drivers' performance (crash and reaction time) while confronting them with critical situations. The results show that drivers under monocular condition are from 2.1 (95% CI 1.11-4.11, p = .024) to 6.5 (95% CI 3.91-11.13; p = .0001) times more likely to collide with target vehicles compared with their baseline (binocular) condition, depending on the driving situation. Furthermore, there was an average increase in reaction time from 64 ms (p = .029) to 126 ms (p = .015) under monocular condition, depending on the critical driving situation configuration. This study objectively demonstrates that monocularity has a significant impact on driving performance and safety during car racing, whereas performance under monocular reduction in vision conditions is less affected.
Journal Article
Horner syndrome: clinical perspectives
Horner syndrome consists of unilateral ptosis, an ipsilateral miotic but normally reactive pupil, and in some cases, ipsilateral facial anhidrosis, all resulting from damage to the ipsilateral oculosympathetic pathway. Herein, we review the clinical signs and symptoms that can aid in the diagnosis and localization of a Horner syndrome as well as the causes of the condition. We emphasize that pharmacologic testing can confirm its presence and direct further testing and management.
Journal Article
Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair
Processes that damage the optic nerve, including elevated intraocular pressure, trauma, ischemia, and compression, often cause visual loss for which there is no current treatment [...].Processes that damage the optic nerve, including elevated intraocular pressure, trauma, ischemia, and compression, often cause visual loss for which there is no current treatment [...].
Journal Article
Biomarkers of lesion severity in a rodent model of nonarteritic anterior ischemic optic neuropathy (rNAION)
The rodent model of nonarteritic anterior ischemic optic neuropathy (rNAION) is similar in many of its pathophysiological responses to clinical NAION. Like human NAION, there is significant variability in the severity of the lesion produced, and little is known of the parameters associated with rNAION induction severity or if pre- or early post-induction biomarkers can be identified that enable prediction of lesion severity and ultimate loss of retinal ganglion cells (RGCs). Adult male Sprague-Dawley outbred rats were evaluated for various parameters including physiological characteristics (heart rate, respiratory rate, temperature, hematocrit [Hct]), optic nerve head (ONH) appearance, pre- and post-induction mean diameter, and intravenous fluorescein and indocyanine green angiographic patterns of vascular leakage at 5 hours post-induction, performed using a spectral domain-optical coherence tomography (SD-OCT) instrument. Early changes were correlated with ultimate RGC loss by Brn3a (+) immunohistology. RGC loss also was correlated with the relative level of laser exposure. The severity of ONH edema 2d, but not 5hr, post induction was most closely associated with the degree of RGC loss, revealing a threshold effect, and consistent with a compartment syndrome where a minimum level of capillary compression within a tight space is responsible for damage. RGC loss increased dramatically as the degree of laser exposure increased. Neither physiological parameters nor the degree of capillary leakage 5hr post induction were informative as to the ultimate degree of RGC loss. Similar to human NAION, the rNAION model exhibits marked variability in lesion severity. Unlike clinical NAION, pre-induction ONH diameter likely does not contribute to ultimate lesion severity; however, cross-sectional ONH edema can be used as a biomarker 2d post-induction to determine randomization of subjects prior to inclusion in specific neuroprotection or neuroregeneration studies.
Journal Article
C6/36 Aedes albopictus Cells Have a Dysfunctional Antiviral RNA Interference Response
Mosquitoes rely on RNA interference (RNAi) as their primary defense against viral infections. To this end, the combination of RNAi and invertebrate cell culture systems has become an invaluable tool in studying virus-vector interactions. Nevertheless, a recent study failed to detect an active RNAi response to West Nile virus (WNV) infection in C6/36 (Aedes albopictus) cells, a mosquito cell line frequently used to study arthropod-borne viruses (arboviruses). Therefore, we sought to determine if WNV actively evades the host's RNAi response or if C6/36 cells have a dysfunctional RNAi pathway. C6/36 and Drosophila melanogaster S2 cells were infected with WNV (Flaviviridae), Sindbis virus (SINV, Togaviridae) and La Crosse virus (LACV, Bunyaviridae) and total RNA recovered from cell lysates. Small RNA (sRNA) libraries were constructed and subjected to high-throughput sequencing. In S2 cells, virus-derived small interfering RNAs (viRNAs) from all three viruses were predominantly 21 nt in length, a hallmark of the RNAi pathway. However, in C6/36 cells, viRNAs were primarily 17 nt in length from WNV infected cells and 26-27 nt in length in SINV and LACV infected cells. Furthermore, the origin (positive or negative viral strand) and distribution (position along viral genome) of S2 cell generated viRNA populations was consistent with previously published studies, but the profile of sRNAs isolated from C6/36 cells was altered. In total, these results suggest that C6/36 cells lack a functional antiviral RNAi response. These findings are analogous to the type-I interferon deficiency described in Vero (African green monkey kidney) cells and suggest that C6/36 cells may fail to accurately model mosquito-arbovirus interactions at the molecular level.
Journal Article