Integrative Pharmacology in the Treatment of Substance Use Disorders.

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs.

Toxicity of Chlorantraniliprole and it's Formulated Product, Altacor®, to Individuals and Populations of Ceriodaphnia Dubia Richard.

The toxicity of the insecticide chlorantraniliprole and its formulated product Altacor® was determined for the Cladoceran, Ceriodaphnia dubia Richard. Acute toxicity (48 h) and 21 d population studies were conducted. The hypothesis of this study was that these two compounds would have different toxicities. We conducted acute and chronic toxicity studies for each compound and compared the results to test this hypothesis. 48 h LC50s (95% CL) for chlorantraniliprole and Altacor® were 8.5 (6.6-11.5) and 6.0 (3.7-9.0) µg chlorantraniliprole/L water, respectively. Therefore, chlorantraniliprole and Altacor® were equitoxic to C. dubia at LC50 based on overlap of the 95% CL. In the population study, chlorantraniliprole and Altacor® concentrations equivalent to the acute LC5, 10, 25, and 50 for each product were evaluated on populations of C. dubia. Number of individuals after 21 d was the endpoint evaluated. T-tests conducted at each LC value indicated that there was no significant difference in population size between these two products at each LC value evaluated. Previous studies show that toxicity can vary greatly between formulated and technical grade pesticides. However, our results show that chlorantraniliprole and its formulated product, Altacor® were equally toxic to C. dubia. Therefore, making assumptions about the toxicity of formulated and unformulated products is ill advised.

A tale of two metrics: the EPA Risk Quotient Approach versus the delay in Population Growth Index for determination of pesticide risk to aquatic species.

The potential risk that two closely related insecticides, spinetoram and spinosad, posed to three Cladoceran species, Ceriodaphnia dubia, Daphnia pulex, and D. magna was determined using two approaches, the USEPA Risk Quotient method and the Delay in Population Growth Index (DPGI). Results of the RQ method showed that spinetoram posed a risk to all three species, but spinosad posed a risk only to C. dubia. The DPGI analysis showed that exposure to spinetoram resulted in populations of all three species being delayed ≥ 3 generation times. Exposure to the LC50 and the lower 95% CL resulted in delayed populations while exposure to the upper 95% CL concentration of spinetoram resulted in no recovery of any of the three species over the course of the modeling exercise (88 d). Exposure to the lower and upper 95% Cl and the LC50 of spinosad resulted in C. dubia populations being delayed ≥ 3 generations. D. pulex populations were not negatively affected after exposure to spinosad. D. magna populations were delayed ≥ 3 generations, but only after exposure to the upper 95% Cl of spinosad. These results illustrate that although the EPA risk quotient method indicated that spinetoram posed a risk to all three species and that spinosad only posed a risk to C. dubia, the DPGI showed that D. magna would be negatively affected by spinosad and none of the three species would reach a predetermined number of individuals after exposure to the upper 95% CL of spinetoram. Because the DPGI uses the 95% Cl as well as the LC50 in its calculation and produces a measure of population growth it provides more detailed information in terms of the potential risk of pesticides to populations than the RQ method.

Population viability in a host-parasitoid system is mediated by interactions between population stage structure and life stage differential susceptibility to toxicants.

The effects of toxicants, such as pesticides, may be more severe for some life stages of an organism than others. However, in most toxicity studies, data is developed for only one life stage, which may lead to misleading interpretations. Furthermore, population stage-structure may interact with differential susceptibility, especially when populations consist of higher proportions of individuals in more susceptible stages at the time of toxicant exposure. We explore the interaction of differential stage susceptibility and stage distribution using a stage-structured Lefkovitch matrix model. We incorporate lab-derived toxicity data for a common parasitoid, the braconid Diaeretiella rapae (M'Intosh), a common natural enemy of the cabbage aphid (Brevicoryne brassicae L.), exposed to the pesticide imidacloprid. We compare population outcomes of simulations in which we vary both the population stage structure along with the susceptibility of each stage to toxicants. Our results illustrate an interaction between differential susceptibility and initial stage distribution, highlighting the fact that both of these demographic features should be considered in interpreting toxicity data and the development of ecological risk assessments.

Relationship between soil and groundwater salinity in the Western Canada Sedimentary Basin.

Saturated soil paste extracts indicate soluble ions in soil pore water that are available to vegetation. As such, they are thought to accurately describe the relationship between soil and groundwater salinity. To test this assumption, soil and groundwater samples were collected from 575 monitoring wells in saline regions of the Western Canadian Sedimentary Basin (WCSB). Samples were analyzed for electrical conductivity (EC) and Cl-, Na+, Ca2+, Mg2+, K+, SO42-, and HCO- 3 content. We compared groundwater ionic concentrations to paste extracts derived from matching soils, finding that differences from in situ soil porosity cause saturated pastes to underestimate groundwater salinity. Therefore, we provide pedotransfer functions for accurately calculating groundwater quality from soil data. In addition, we discuss the effects of porosity and soil composition on the saturated paste method, as measured through hydraulic conductivity, saturation percent, and sample lithology. Groundwater salinity may also influence further leaching of salts from soil. As produced water (NaCl brine) spills are common across the sulfate-rich soils of the WCSB, we considered the effects of NaCl on leaching of other ions, finding that influx of Na+ into groundwater is associated with increased sulfate leaching from soil. Therefore, considering the secondary effects of produced water on groundwater quality is essential to spill management.

Population model for the decline of Homalodisca vitripennis (Hemiptera: Cicadellidae) over a ten-year period.

The glassy-winged sharpshooter, Homalodisca vitripennis (Germar), is an invasive pest which presents a major economic threat to grape industries in California, because it spreads a disease-causing bacterium, Xylella fastidiosa. In this note we develop a time and temperature dependent mathematical model to analyze aggregate population data for H. vitripennis from a 10-year study consisting of biweekly monitoring of H. vitripennis populations on unsprayed citrus, during which H. vitripennis decreased significantly. This model was fitted to the aggregate H. vitripennis time series data using iterative reweighted weighted least squares (IRWLS) with assumed probability distributions for certain parameter values. Results indicate that the H. vitripennis model fits the phenological and temperature data reasonably well, but the observed population decrease may possibly be attributed to factors other than the abiotic effect of temperature. A key factor responsible for this decline but not analyzed here could be biotic, for example, potentially parasitism of H. vitripennis eggs by Cosmocomoidea ashmeadi. A biological control program targeting H. vitripennis utilizing the mymarid egg parasitoid Cosmocomoidea (formerly Gonatocerus) ashmeadi (Girault) is described.

Ecosystem function in predator-prey food webs-confronting dynamic models with empirical data.

Most ecosystem functions and related services involve species interactions across trophic levels, for example, pollination and biological pest control. Despite this, our understanding of ecosystem function in multitrophic communities is poor, and research has been limited to either manipulation in small communities or statistical descriptions in larger ones. Recent advances in food web ecology may allow us to overcome the trade-off between mechanistic insight and ecological realism. Molecular tools now simplify the detection of feeding interactions, and trait-based approaches allow the application of dynamic food web models to real ecosystems. We performed the first test of an allometric food web model's ability to replicate temporally nonaggregated abundance data from the field and to provide mechanistic insight into the function of predation. We aimed to reproduce and explore the drivers of the population dynamics of the aphid herbivore Rhopalosiphum padi observed in ten Swedish barley fields. We used a dynamic food web model, taking observed interactions and abundances of predators and alternative prey as input data, allowing us to examine the role of predation in aphid population control. The inverse problem methods were used for simultaneous model fit optimization and model parameterization. The model captured >70% of the variation in aphid abundance in five of ten fields, supporting the model-embodied hypothesis that body size can be an important determinant of predation in the arthropod community. We further demonstrate how in-depth model analysis can disentangle the likely drivers of function, such as the community's abundance and trait composition. Analysing the variability in model performance revealed knowledge gaps, such as the source of episodic aphid mortality, and general method development needs that, if addressed, would further increase model success and enable stronger inference about ecosystem function. The results demonstrate that confronting dynamic food web models with abundance data from the field is a viable approach to evaluate ecological theory and to aid our understanding of function in real ecosystems. However, to realize the full potential of food web models, in ecosystem function research and beyond, trait-based parameterization must be refined and extended to include more traits than body size.

The trouble with surrogates in environmental risk assessment: a daphniid case study.

The use of indicator species to test for environmental stability and functioning is a widespread practice. In aquatic systems, several daphniids (Cladocera: Daphniidae) are commonly used as indicator species; registration of new pesticides are mandated by the Environmental Protection Agency to be accompanied by daphniid toxicity data. This reliance upon a few species to infer ecosystem health and function assumes similar responses to toxicants across species with potentially very different life histories and susceptibility. Incorporating lab-derived life-history data into a simple mathematical model, we explore the reliability of three different daphniid species as surrogates for each other by comparing their responses to reductions in survivorship and fecundity after simulated exposure to toxicants. Our results demonstrate that daphniid species' responses to toxicant exposure render them poor surrogates for one another, highlighting that caution should be exercised in using a surrogate approach to the use of indicator species in risk assessment.

Correctly modeling plant-insect-herbivore-pesticide interactions as aggregate data.

We consider a population dynamics model in investigating data from controlled experiments with aphids in broccoli patches surrounded by different margin types (bare or weedy ground) and three levels of insecticide spray (no, light, or heavy spray). The experimental data is clearly aggregate in nature. In previous efforts [1], the aggregate nature of the data was ignored. In this paper, we embrace this aspect of the experiment and correctly model the data as aggregate data, comparing the results to the previous approach. We discuss cases in which the approach may provide similar results as well as cases in which there is a clear difference in the resulting fit to the data.

The evolution of toxicant resistance in daphniids and its role on surrogate species.

Prolonged exposure to a disturbance such as a toxicant has the potential to result in rapid evolution to toxicant resistance in many short-lived species such as daphniids. This evolution may allow a population to persist at higher levels of the toxicant than is possible without evolution. Here we apply evolutionary game theory to a Leslie matrix model for a daphniid population to obtain a Darwinian model that couples population dynamics with the dynamics of an evolving trait. We use the Darwinian model to consider how the evolution of resistance to the lethal or sublethal effects of a disturbance may change the population dynamics. In particular, we determine the conditions under which a daphniid population can persist by evolving toxicant resistance. We then consider the implications of this evolution in terms of the use of daphniids as surrogate species. We show for three species of daphniids that evolution of toxicant resistance means that one species may persist while another does not. These results suggest that toxicant studies that do not consider the potential of a species (or its surrogate) to develop toxicant resistance may not accurately predict the long term persistence of the species.

Sublethal Effects in Pest Management: A Surrogate Species Perspective on Fruit Fly Control.

Tephritid fruit flies are economically important orchard pests globally. While much effort has focused on controlling individual species with a combination of pesticides and biological control, less attention has been paid to managing assemblages of species. Although several tephritid species may co-occur in orchards/cultivated areas, especially in mixed-cropping schemes, their responses to pesticides may be highly variable. Furthermore, predictive efforts about toxicant effects are generally based on acute toxicity, with little or no regard to long-term population effects. Using a simple matrix model parameterized with life history data, we quantified the responses of several tephritid species to the sublethal effects of a toxicant acting on fecundity. Using a critical threshold to determine levels of fecundity reduction below which species are driven to local extinction, we determined that threshold levels vary widely for the three tephritid species. In particular, Bactrocera dorsalis was the most robust of the three species, followed by Ceratitis capitata, and then B. cucurbitae, suggesting individual species responses should be taken into account when planning for area-wide pest control. The rank-order of susceptibility contrasts with results from several field/lab studies testing the same species, suggesting that considering a combination of life history traits and individual species susceptibility is necessary for understanding population responses of species assemblages to toxicant exposure.

British Thoracic Society Guideline for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).

The full guideline for the management of non-tuberculous mycobacterial pulmonary disease is published in Thorax. The following is a summary of the recommendations and good practice points. The sections referred to in the summary refer to the full guideline.

An adaptive feedback methodology for determining information content in stable population studies.

We develop statistical and mathematical based methodologies for determining (as the experiment progresses) the amount of information required to complete the estimation of stable population parameters with pre-specified levels of confidence. We do this in the context of life table models and data for growth/death for three species of Daphniids as investigated by J. Stark and J. Banks [17]. The ideas developed here also have wide application in the health and social sciences where experimental data are often expensive as well as difficult to obtain.

Developing demographic toxicity data: optimizing effort for predicting population outcomes.

Mounting evidence suggests that population endpoints in risk assessment are far more accurate than static assessments. Complete demographic toxicity data based on full life tables are eminently useful in predicting population outcomes in many applications because they capture both lethal and sublethal effects; however, developing these life tables is extremely costly. In this study we investigated the efficiency of partial life cycle tests as a substitute for full life cycles in parameterizing population models. Life table data were developed for three species of Daphniids, Ceriodaphnia dubia, Daphnia magna, and D. pulex, weekly throughout the life span of these species. Population growth rates (λ) and a series of other demographic parameters generated from the complete life cycle were compared to those calculated from cumulative weeks of the life cycle in order to determine the minimum number of weeks needed to generate an accurate population projection. Results showed that for C. dubia and D. pulex, λ values developed at >4 weeks (44.4% of the life cycle) were not significantly different from λ developed for the full life cycle (9 weeks) of each species. For D. magna, λ values developed at >7 weeks (70% of the life cycle) were not significantly different from λ developed for the full life cycle (10 weeks). Furthermore, these cutoff points for λ were not the same for other demographic parameters, with no clear pattern emerging. Our results indicate that for C. dubia, D. magna, and D. pulex, partial life tables can be used to generate population growth rates in lieu of full life tables. However, the implications of differences in cutoff points for different demographic parameters need to be investigated further.

Incorporating variability in point estimates in risk assessment: Bridging the gap between LC50 and population endpoints.

Historically, point estimates such as the median lethal concentration (LC50) have been instrumental in assessing risks associated with toxicants to rare or economically important species. In recent years, growing awareness of the shortcomings of this approach has led to an increased focus on analyses using population endpoints. However, risk assessment of pesticides still relies heavily on large amounts of LC50 data amassed over decades in the laboratory. Despite the fact that these data are generally well replicated, little or no attention has been given to the sometime high levels of variability associated with the generation of point estimates. This is especially important in agroecosystems where arthropod predator-prey interactions are often disrupted by the use of pesticides. Using laboratory derived data of 4 economically important species (2 fruit fly pest species and 2 braconid parasitoid species) and matrix based population models, the authors demonstrate in the present study a method for bridging traditional point estimate risk assessments with population outcomes. The results illustrate that even closely related species can show strikingly divergent responses to the same exposures to pesticides. Furthermore, the authors show that using different values within the 95% confidence intervals of LC50 values can result in very different population outcomes, ranging from quick recovery to extinction for both pest and parasitoid species. The authors discuss the implications of these results and emphasize the need to incorporate variability and uncertainty in point estimates for use in risk assessment.

Deconstructing the surrogate species concept: a life history approach to the protection of ecosystem services.

The use of the surrogate species concept is widespread in environmental risk assessment and in efforts to protect species that provide ecosystem services, yet there are no standard protocols for the choice of surrogates. Surrogates are often chosen on the basis of convenience or vague resemblances in physiology or life history to species of concern. Furthermore, our ability to predict how species of concern will fare when subjected to disturbances such as environmental contaminants or toxicants is often based on woefully misleading comparisons of static toxicity tests. Here we present an alternative approach that features a simple mathematical model parameterized with life history data applied to an assemblage of species that provide an important ecosystem service: a suite of parasitoid wasps that provide biological control of agricultural pests. Our results indicate that these parasitoid wasp species have different population responses to toxic insult--that is, we cannot predict how all four species will react to pesticide exposure simply by extrapolating from the response of any one species. Furthermore, sensitivity analysis of survivorship and reproduction demonstrates that the life stage most sensitive to pesticide disturbance varies among species. Taken together, our results suggest that the ability to predict the fate of a suite of species using the response of just one species (the surrogate species concept) is widely variable and potentially misleading.

The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts.

Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - http://www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.

Spatial dynamics of two oriental fruit fly (Diptera: Tephritidae) parasitoids, Fopius arisanus and Diachasmimorpha longicaudata (Hymenoptera: Braconidae), in a Guava orchard in Hawaii.

We examined spatial patterns of both sexes of oriental fruit fly, Bactrocera dorsalis (Hendel), and its two most abundant parasitoids, Fopius arisanus (Sonan) and Diachasmimorpha longicaudata (Ashmead) in a commercial guava (Psidium guajava L.) orchard. Oriental fruit fly spatial patterns were initially random, but became highly aggregated with host fruit ripening and the subsequent colonization of, first, F. arisanus (egg-pupal parasitoid) and, second, D. longicaudata (larval-pupal parasitoid). There was a significant positive relationship between populations of oriental fruit fly and F. arisanus during each of the F. arisanus increases, a pattern not exhibited between oriental fruit fly and D. longicaudata. Generally, highest total numbers of males and females (oriental fruit fly, F. arisanus, and D. longicaudata) occurred on or about the same date. There was a significant positive correlation between male and female populations of all three species; we measured a lag of 2-4 wk between increases of female F. arisanus and conspecific males. There was a similar trend in one of the two years for the second most abundant species, D. longicaudata, but no sign of a time lag between the sexes for oriental fruit fly. Spatially, we found a significant positive relationship between numbers of F. arisanus in blocks and the average number in adjoining blocks. We did not find the same effect for oriental fruit fly and D. longicaudata, possibly a result of lower overall numbers of the latter two species or less movement of F. arisanus within the field.

Obliterative bronchiolitis in fibreglass workers: a new occupational disease?

RATIONALE AND OBJECTIVES: Obliterative bronchiolitis (OB) is a rare disease with a small number of established occupational aetiologies. We describe a case series of severe OB in workers making glass-reinforced plastics. METHODS: Workplace exposures were the likely cause after the independent diagnosis of OB in two workers laying up the fibreglass hulls of yachts; the second worker took over the job of the first after he left following a lung transplant. Presentation of these two cases at international meetings led to others identifying similar workers. MAIN RESULTS: We identified six workers with good evidence of OB. All were involved in preparing fibreglass with styrene resins, five as boat builders laying up fibreglass hulls and one during cooling-tower fabrication. The disease came on rapidly without unusual acute exposures. Two patients had lung transplants, while another died while waiting for one. Histology confirmed OB in the four with biopsies/post-mortem examinations or explanted lungs. CONCLUSIONS: A rare, potentially fatal disease occurring in six workers laying up fibreglass with styrene resins from five different worksites suggests that work exposures were the cause of their OB. The precise agent responsible awaits identification.