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Objective: Conventional randomized controlled trials (RCTs) have long served as the foundation of research in clinical psychology; however, most treatments for eating disorders show only modest effects on reduction of symptoms and maintenance of long‐term remission. New options for psychotherapy treatment development research, beyond continuing to pursue additive or subpopulation approaches, are needed. Methods: One option is to apply dose–response designs, which are commonplace in studies of pharmacology, toxicology, and medical research, and characterized by the evaluation of the amount of exposure (dose) to an intervention, and the resulting changes in body function or health (response). Results: Eating disorder interventions are particularly well‐suited for dose–response treatment designs. The deadly nature of eating disorders makes it imperative that patients are not turned away for not being "ready" to engage with treatment. By identifying optimal doses, research will likely yield a more parsimonious course of treatment, which will lend itself to reduced costs, greater uptake, and reduced drop‐out. Discussion: Limited use of within‐subject designs in trials for patients with eating disorders has produced fast‐track efficacy studies and omitted key elements in the treatment development pathway. To decrease reliance on RCT's, dose–response methods should be applied as an alternative study design. Public Significance: Eating disorders are associated with medical and psychiatric comorbidities, poor quality of life, and high mortality. Access to evidence‐based services for patients with eating disorders is limited, and identifying additional effective treatment options can be difficult because of challenges inherent to randomized‐controlled trials. This manuscript describes an alternative trial methodology to maximize the information that can be gathered prior to utilizing a standard large‐scale efficacy design. [ABSTRACT FROM AUTHOR]

Background: Predicting biological responses to mixed radiation types is of considerable importance when combining radiation therapies that use multiple radiation types and delivery regimens. These may include the use of both low‐ and high‐linear energy transfer (LET) radiations. A number of theoretical models have been developed to address this issue. However, model predictions do not consistently match published experimental data for mixed radiation exposures. Furthermore, the models are often computationally intensive. Accordingly, there is a need for efficient analytical models that can predict responses to mixtures of low‐ and high‐LET radiations. Additionally, a general formalism to calculate equieffective dose (EQDX) for mixed radiations is needed. Purpose: To develop a computationally efficient analytical model that can predict responses to complex mixtures of low‐ and high‐LET radiations as a function of either absorbed dose or EQDX. Methods: The Zaider‐Rossi model (ZRM) was modified by replacing the geometric mean of the quadratic coefficients in the interaction term with the arithmetic mean. This modified ZRM model (mZRM) was then further generalized to any number of radiation types and its validity was tested against published experimental observations. Comparisons between the predictions of the ZRM and mZRM, and other models, were made using two and three radiation types. In addition, a generalized formalism for calculating EQDX for mixed radiations was developed within the context of mZRM and validated with published experimental results. Results: The predictions of biological responses to mixed‐LET radiations calculated with the mZRM are in better agreement with experimental observations than ZRM, especially when high‐ and low‐LET radiations are mixed. In these situations, the ZRM overestimated the surviving fraction. Furthermore, the EQDX calculated with mZRM are in better agreement with experimental observations. Conclusion: The mZRM is a computationally efficient model that can be used to predict biological response to mixed radiations that have low‐ and high‐LET characteristics. Importantly, interaction terms are retained in the calculation of EQDX for mixed radiation exposures within the mZRM framework. The mZRM has application in a wide range of radiation therapies, including radiopharmaceutical therapy. [ABSTRACT FROM AUTHOR]

Elizabethkingia spp. are common environmental pathogens responsible for infections in more vulnerable populations. Although the exposure routes of concern are not well understood, some hospital‐associated outbreaks have indicated possible waterborne transmission. In order to facilitate quantitative microbial risk assessment (QMRA) for Elizabethkingia spp., this study fit dose–response models to frog and mice datasets that evaluated intramuscular and intraperitoneal exposure to Elizabethkingia spp. The frog datasets could be pooled, and the exact beta‐Poisson model was the best fitting model with optimized parameters α = 0.52 and β = 86,351. Using the exact beta‐Poisson model, the dose of Elizabethkingia miricola resulting in a 50% morbidity response (LD50) was estimated to be approximately 237,000 CFU. The model developed herein was used to estimate the probability of infection for a hospital patient under a modeled exposure scenario involving a contaminated medical device and reported Elizabethkingia spp. concentrations isolated from hospital sinks after an outbreak. The median exposure dose was approximately 3 CFU/insertion event, and the corresponding median risk of infection was 3.4E‐05. The median risk estimated in this case study was lower than the 3% attack rate observed in a previous outbreak, however, there are noted gaps pertaining to the possible concentrations of Elizabethkingia spp. in tap water and the most likely exposure routes. This is the first dose–response model developed for Elizabethkingia spp. thus enabling future risk assessments to help determine levels of risk and potential effective risk management strategies. [ABSTRACT FROM AUTHOR]

Background: Functional lung avoidance radiation therapy (RT) is a technique being investigated to preferentially avoid specific regions of the lung that are predicted to be more susceptible to radiation‐induced damage. Reducing the dose delivered to high functioning regions may reduce the occurrence radiation‐induced lung injuries (RILIs) and toxicities. However, in order to develop effective lung function‐sparing plans, accurate predictions of post‐RT ventilation change are needed to determine which regions of the lung should be spared. Purpose: To predict pulmonary ventilation change following RT for nonsmall cell lung cancer using machine learning. Methods: A conditional generative adversarial network (cGAN) was developed with data from 82 human subjects enrolled in a randomized clinical trial approved by the institution's IRB to predict post‐RT pulmonary ventilation change. The inputs to the network were the pre‐RT pulmonary ventilation map and radiation dose distribution. The loss function was a combination of the binary cross‐entropy loss and an asymmetrical structural similarity index measure (aSSIM) function designed to increase penalization of under‐prediction of ventilation damage. Network performance was evaluated against a previously developed polynomial regression model using a paired sample t‐test for comparison. Evaluation was performed using eight‐fold cross‐validation. Results: From the eight‐fold cross‐validation, we found that relative to the polynomial model, the cGAN model significantly improved predicting regions of ventilation damage following radiotherapy based on true positive rate (TPR), 0.14±0.15 to 0.72±0.21, and Dice similarity coefficient (DSC), 0.19±0.16 to 0.46±0.14, but significantly declined in true negative rate, 0.97±0.05 to 0.62±0.21, and accuracy, 0.79±0.08 to 0.65±0.14. Additionally, the average true positive volume increased from 104±119 cc in the POLY model to 565±332 cc in the cGAN model, and the average false negative volume decreased from 654±361 cc in the POLY model to 193±163 cc in the cGAN model. Conclusions: The proposed cGAN model demonstrated significant improvement in TPR and DSC. The higher sensitivity of the cGAN model can improve the clinical utility of functional lung avoidance RT by identifying larger volumes of functional lung that can be spared and thus decrease the probability of the patient developing RILIs. [ABSTRACT FROM AUTHOR]

Cereal aphids, including the bird cherry‐oat aphid, Rhopalosiphum padi, and the grain aphid, Sitobion avenae, can transmit viruses that significantly reduce crop yields. To mitigate against yield losses, insecticides are routinely used to manage aphid populations.Aphids can form relationships with endosymbionts that confer fitness benefits or consequences to the aphid. Recent artificial inoculation experiments indicate that endosymbionts could increase aphid susceptibility to insecticides, but this has not been explored using aphid populations naturally infected with endosymbionts.Here, we sampled aphids from an important cereal production region in Lower Saxony, Germany. We characterized the endosymbiont profile of these aphid populations and conducted pyrethroid dose–response assays to test the hypothesis that facultative endosymbionts increase aphid susceptibility to insecticides.We find that the level of insecticide susceptibility is highly variable in S. avenae and we identify populations that are sensitive and tolerant to pyrethroids, including populations collected from the same field. For R. padi, we find evidence for decreased sensitivity to pyrethroids, representing the first report of reduced sensitivity to pyrethroids in R. padi sampled from Central Europe.We detected high endosymbiont infection frequencies in the aphid populations. 84% of aphids carry one facultative endosymbiont and 9% of aphids carry two facultative endosymbionts. We detected associations with Regiella insecticola, Fukatsia symbiotica, and Hamiltonella defensa. However, we do not identify a link between endosymbiont infection and insecticide susceptibility, indicating that other factors may govern the development of insecticide resistance and the need for alternative management strategies. [ABSTRACT FROM AUTHOR]

While a number of phase I dose‐finding designs in oncology exist, the commonly used ones are either algorithmic or empirical model‐based. We propose a new framework for modeling the dose–response relationship, by systematically incorporating the pharmacokinetic (PK) data collected in the trial and the hypothesized mechanisms of the drug effects, via dynamic PK/PD modeling, as well as modeling of the relationship between a latent cumulative pharmacologic effect and a binary toxicity outcome. This modeling framework naturally incorporates the information on the impact of dose, schedule and method of administration (e.g., drug formulation and route of administration) on toxicity. The resulting design is an extension of existing designs that make use of pre‐specified summary PK information (such as the area under the concentration‐time curve [AUC] or maximum serum concentration [Cmax]). Our simulation studies show, with moderate departure from the hypothesized mechanisms of the drug action, that the performance of the proposed design on average improves upon those of the common designs, including the continual reassessment method (CRM), Bayesian optimal interval (BOIN) design, modified toxicity probability interval (mTPI) method, and a design called PKLOGIT that models the effect of the AUC on toxicity. In case of considerable departure from the underlying drug effect mechanism, the performance of the design is shown to be comparable with that of the other designs. We illustrate the proposed design by applying it to the setting of a phase I trial of a γ‐secretase inhibitor in metastatic or locally advanced solid tumors. We also provide R code to implement the proposed design. [ABSTRACT FROM AUTHOR]

Tests for dose–response trend may be used to support conclusions on the toxicity of a substance in a range of doses evaluated in a comparative experiment. Criteria are proposed for evaluating and comparing alternative tests, and are applied in a comparison of certain tests applicable with continuous responses, namely, a multiplicity‐adjusted pairwise comparison procedure, a trend test based on a single contrast, and four multiple‐contrast trend tests. Methods considered treat dose as ordinal information. A particular focus was comparison of the simple test of a single contrast, with coefficients proportional to dose rank, with the multiple‐contrast methods available with modern computing. To explore the role of the dose–response curve shape, regular dose–response shapes (or profiles), defined by the mean response for each dose level, using a simple grid‐based algorithm were generated. Power for individual profiles may be used to illustrate the effect of curve shape on the power of alternative tests. To facilitate selection of tests, we report average power over profiles, averaging at different levels of granularity, first separately for each of several curve shape categories, and then over all profiles, weighting shape categories equally. Power results for the six tests evaluated at least provide clear distinctions between some procedures that are more‐preferred, versus less‐preferred. Our analyses expand the comparisons of tests available and contribute a methodology for choice of statistical methods for toxicological data analysis. Environ Toxicol Chem 2022;41:1754–1764. Published 2022. This article is a U.S. Government work and is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Background: Field experiments were conducted across multiple sites in 2012 and 2013 to describe sensitivity of soybean to 2,4‐D (six doses) and dicamba (seven doses) at V3 and R1 growth stages. Further experiments were conducted under greenhouse conditions in 2017 and 2018 to compare soybean response to several dicamba herbicides across a broader range of doses than those tested in the field. Results: Soybean yield loss was 6.1‐fold greater from 2,4‐D exposure at V3 compared to R1 and 1.4 times greater from dicamba exposure at R1 than at V3. In V3 exposures, soybean was 15.4 times more sensitive to dicamba than 2,4‐D and 134.4‐fold more sensitive to dicamba when exposed at R1. Plant injury and height correlations to grain yield resulted in coefficients ranging from 0.65 to 0.91. In greenhouse experiments, five dicamba products were tested at up to 19 doses and as low as 0.002 g ae ha−1 (3.6 × 10−6% of maximum single use‐rate); however, no differences were observed among formulations used in dicamba‐resistant crops versus traditional formulations. A no observable effects dose was not identified due to responses observed even at the lowest doses tested, although hormesis effects were observed in plant height. Conclusion: These data suggest that the sensitivity of soybean to dicamba is much greater than what has previously been reported. However, as has been indicated by previous work, that injury does not always result in yield loss. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

This article tells the story of hormesis from its conceptual and experimental origins, its dismissal by the scientific and medical communities in the first half of the 20th century, and its rediscovery over the past several decades to be a fundamental evolutionary adaptive strategy. The upregulation of hormetic adaptive mechanisms has the capacity to decelerate the onset and reduce the severity of a broad spectrum of common age‐related health, behavioral, and performance decrements and debilitating diseases, thereby significantly enhancing the human health span. Incorporation of hormetic‐based lifestyle options within the human population would have profoundly positive impacts on the public health, significantly reducing health care costs. [ABSTRACT FROM AUTHOR]

Aims: High resting heart rate (RHR), one abnormal manifestation of autonomic nervous system, is associated with metabolic disorders. However, the association between RHR and metabolic syndrome (MetS) and its components remains controversial. We aimed to explore the link between these two parameters. Materials and Methods: The study included 6589 Dong adults (1434 cases of MetS) from the cross‐sectional survey of the China Multi‐Ethnic Cohort Study. Logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) and assess the association between RHR and MetS, clustered metabolic risk, and MetS components. Restricted cubic splines model was used to evaluate the dose response association. Results: A positive association existed between RHR and MetS, and people in the highest RHR quartile had a higher MetS risk (OR 1.75 [95% CI 1.42–2.15]) than those in the lowest quartile. The clustered metabolic risk associated with RHR (p < 0.05). Furthermore, RHR was related to elevated blood pressure (BP), elevated triglycerides (TG) and elevated fasting plasma glucose (FPG); the ORs (95% CIs) for the highest versus lowest RHR quartile were 2.06 (1.75–2.43), 1.37 (1.17–1.62) and 2.53 (2.04–3.14), respectively. Similar results were found in sensitivity and subgroup analyses. Also, non‐linear dose response association existed between RHR and MetS and elevated levels of BP, TG and FPG (p < 0.001). Conclusions: RHR was related to increased risk of MetS, three MetS components (elevated BP, elevated TG and elevated FPG) and the clustered metabolic risk. RHR may be a useful indicator for MetS. [ABSTRACT FROM AUTHOR]

Insect meals are a group of promising feed materials and sources of nutrients. Their production does not entail deforestation, global warming, environmental pollution or decreased biodiversity. One of the most important farmed insect species is mealworm, which is allowed to be used in aquafeeds by the European Commission Regulation no. 2017/893. The aim of this study was to examine four doses of mealworm meal (TM10 = 10%, TM20 = 20%, TM30 = 30% and TM40 = 40%) in sea trout (Salmo trutta m. trutta) fingerling diets and their effects on growth performance, somatic and condition indices, blood parameters, histomorphological characteristics and body composition. Our results showed the most satisfactory growth performance results with 10% mealworm meal. The feed conversion ratio (FCR), protein efficiency ratio (PER), relative growth rate (RGR) and specific growth rate (SGR) was similar in the control and TM10 group. The lowest fish survival (95%) was occurred in the group of fish fed TM40, and the highest (98.33%) in fish fed control or TM10 diets. The fish condition and the hepatosomatic index were similar among treatments. The histomorphological structures of the intestine and liver were not negatively affected by the experimental diets. The inclusion of up to 40% mealworm meal did not negatively affect growth performance, feed utilization, fish health or survival. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association between lactation and maternal risk of type 2 diabetes, including a potential graded association according to lactation duration. Methods: A systematic review and meta‐analysis of observational studies that investigated the reported association between lactation (irrespective of duration, intensity or mode) and maternal risk of type 2 diabetes was conducted. Results: A total of 22 studies (17 cohort studies and five cross‐sectional studies) were included in this systematic review, and 16 contributed to the meta‐analysis. Studies that investigated the association of lactation with risk of type 2 diabetes in the first months after birth in women with gestational diabetes reported conflicting results. Studies with a longer follow‐up showed a graded protective association for lactation and the risk of type 2 diabetes, with a potentially larger risk reduction in women with gestational diabetes than in those without gestational diabetes. Overall, ever versus never lactation was associated with a 27% lower risk of type 2 diabetes (RR 0.73, 95% CI [0.65, 0.83]). Each additional month of lactation was associated with a 1% lower risk of type 2 diabetes (RR 0.99, 95% CI [0.98, 0.99]). However, the overall quality of the studies was modest. Conclusions: Lactation is associated with a significantly reduced risk of maternal type 2 diabetes over the life course, particularly in women with gestational diabetes. The protective effect seems to increase with longer duration of lactation. Further research is warranted to understand whether this association is modified by exposure to other risk factors. [ABSTRACT FROM AUTHOR]

Inhaled corticosteroids (ICS) are a mainstay of treatment in eosinophilic asthma. Many studies have explored the dose‐response effect of different formulations of ICS through direct or indirect bronchoprovocation testing. Such studies are important for investigating efficacy and identifying the relative potency between formulations. However, lack of consistency in methods and designs has hindered the comparability of study findings. This review discusses current knowledge of the dose‐response, or lack thereof, of different formulations of ICS through direct and indirect bronchoprovocation testing. The strengths and weaknesses of past studies inform recommendations for future methodological considerations in this field, such as utilizing a randomized double‐blind crossover design, enrolling participants likely to respond to ICS therapy, and carefully selecting treatment durations and washout periods to assess incremental improvement in airway hyperresponsiveness while reducing the likelihood of a carryover effect. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the use of commercial‐grade strontium aluminate phosphorescent powder as a thermoluminescent (TL) dosimeter for clinical radiotherapy beams. Materials and Method: Commercially available Eu2+, Dy3+ co‐doped strontium aluminate powder (SrAl2O4:Eu, Dy) was annealed and then irradiated using 20 × 20 cm2 field size, with 6‐MV (PDD10 = 70.7) and 18‐MV (PDD10 = 79.4) photon beams and and 9‐MeV (R50 = 3.6), 15 MeV (R50 = 5.9) and 18‐MeV (R50 = 7.2) electron beams. To calibrate the relationship between the TL readings and the irradiated doses, TL glow curves were acquired for doses up to 600 cGy at all beam energies. For the percentage depth dose (PDD) measurement, the SrAl2O4:Eu, Dy powder was sandwiched by solid water phantoms, with varying thickness of solid water placed above to determine the depth. PDDs were measured at four representative depths and compared against the commissioning depth dose data for each beam energy. Results: Linear dose response models of doses up to 200 cGy were created for all beam energies. Superlinearity was observed with doses greater than 200 cGy. The PDD measurement acquired experimentally agrees well with the commissioning data of the medical linear accelerator. Trapping parameters such as order of kinetics, activation energy and frequency factor have been obtained via TL glow curve analysis. Conclusion: The linear dose response demonstrates that SrAl2O4:Eu, Dy is a potential TLD dosimeter for both electron beams and photon beams at different beam energies. The PDD measurements further support its potential use in quality assurance and radiation dosimetry. [ABSTRACT FROM AUTHOR]

This study developed dose response models for determining the probability of eye or central nervous system infections from previously conducted studies using different strains of Acanthamoeba spp. The data were a result of animal experiments using mice and rats exposed corneally and intranasally to the pathogens. The corneal inoculations of Acanthamoeba isolate Ac 118 included varied amounts of Corynebacterium xerosis and were best fit by the exponential model. Virulence increased with higher levels of C. xerosis. The Acanthamoeba culbertsoni intranasal study with death as an endpoint of response was best fit by the beta‐Poisson model. The HN‐3 strain of A. castellanii was studied with an intranasal exposure and three different endpoints of response. For all three studies, the exponential model was the best fit. A model based on pooling data sets of the intranasal exposure and death endpoint resulted in an LD50 of 19,357 amebae. The dose response models developed in this study are an important step towards characterizing the risk associated with free‐living amoeba like Acanthamoeba in drinking water distribution systems. Understanding the human health risk posed by free‐living amoeba will allow for quantitative microbial risk assessments that support building design decisions to minimize opportunities for pathogen growth and survival. [ABSTRACT FROM AUTHOR]

Uncertainty in model predictions of exposure response at low exposures is a problem for risk assessment. A particular interest is the internal concentration of an agent in biological systems as a function of external exposure concentrations. Physiologically based pharmacokinetic (PBPK) models permit estimation of internal exposure concentrations in target tissues but most assume that model parameters are either fixed or instantaneously dose‐dependent. Taking into account response times for biological regulatory mechanisms introduces new dynamic behaviors that have implications for low‐dose exposure response in chronic exposure. A simple one‐compartment simulation model is described in which internal concentrations summed over time exhibit significant nonlinearity and nonmonotonicity in relation to external concentrations due to delayed up‐ or downregulation of a metabolic pathway. These behaviors could be the mechanistic basis for homeostasis and for some apparent hormetic effects. [ABSTRACT FROM AUTHOR]

Protection and safety authorities recommend the use of model averaging to determine the benchmark dose approach as a scientifically more advanced method compared with the no‐observed‐adverse‐effect‐level approach for obtaining a reference point and deriving health‐based guidance values. Model averaging however highly depends on the set of candidate dose–response models and such a set should be rich enough to ensure that a well‐fitting model is included. The currently applied set of candidate models for continuous endpoints is typically limited to two models, the exponential and Hill model, and differs completely from the richer set of candidate models currently used for binary endpoints. The objective of this article is to propose a general and wide framework of dose response models, which can be applied both to continuous and binary endpoints and covers the current models for both type of endpoints. In combination with the bootstrap, this framework offers a unified approach to benchmark dose estimation. The methodology is illustrated using two data sets, one with a continuous and another with a binary endpoint. [ABSTRACT FROM AUTHOR]

Complex ecological relationships, such as host–parasite interactions, are often modeled with laboratory experiments. However, some experimental laboratory conditions, such as temperature or infection dose, are regularly chosen based on convenience or convention, and it is unclear how these decisions systematically affect experimental outcomes. Here, we conducted a meta‐analysis of 58 laboratory studies that exposed amphibians to the pathogenic fungus Batrachochytrium dendrobatidis (Bd) to understand better how laboratory temperature, host life stage, infection dose, and host species affect host mortality. We found that host mortality was driven by thermal mismatches: hosts native to cooler environments experienced greater Bd‐induced mortality at relatively warm experimental temperatures and vice versa. We also found that Bd dose positively predicted Bd‐induced host mortality and that the superfamilies Bufonoidea and Hyloidea were especially susceptible to Bd. Finally, the effect of Bd on host mortality varied across host life stages, with larval amphibians experiencing lower risk of Bd‐induced mortality than adults or metamorphs. Metamorphs were especially susceptible and experienced mortality when inoculated with much smaller Bd doses than the average dose used by researchers. Our results suggest that when designing experiments on species interactions, researchers should carefully consider the experimental temperature, inoculum dose, and life stage, and taxonomy of the host species. [ABSTRACT FROM AUTHOR]

Medium‐chain fatty acids (MCFAs) and their derivatives are important chemicals that can be used in lubricants, detergents, and cosmetics. MCFAs can be produced in several microbes, although production is not high. Dynamic regulation by synthetic biology is a good method of improving production of chemicals that avoids toxic intermediates, but chemical‐responsive promoters are required. Several MCFA sensors or promoters have been reported in Saccharomyces cerevisiae. In this study, by using transcriptomic analysis of S. cerevisiae exposed to fatty acids with 6‐, 12‐, and 16‐carbon chains, we identified 58 candidate genes that may be responsive to MCFAs. Using a fluorescence‐based screening method, we identified MCFA‐responsive promoters, four that upregulated gene expression, and three that downregulated gene expression. Dose–response analysis revealed that some of the promoters were sensitive to fatty acid concentrations as low as 0.02–0.06 mM. The MCFA‐responsive promoters reported in this study could be used in dynamic regulation of fatty acids and fatty acid‐derived products in S. cerevisiae. [ABSTRACT FROM AUTHOR]

Genetic toxicology data have traditionally been utilized for hazard identification to provide a binary call for a compound's risk. Recent advances in the scientific field, especially with the development of high‐throughput methods to quantify DNA damage, have influenced a change of approach in genotoxicity assessment. The in vitro MultiFlow® DNA Damage Assay is one such method which multiplexes γH2AX, p53, phospho‐histone H3 biomarkers into a single‐flow cytometric analysis (Bryce et al., [2016]: Environ Mol Mutagen 57:546–558). This assay was used to study human TK6 cells exposed to each of eight topoisomerase II poisons for 4 and 24 hr. Using PROAST v65.5, the Benchmark Dose approach was applied to the resulting flow cytometric datasets. With "compound" serving as covariate, all eight compounds were combined into a single analysis, per time point and endpoint. The resulting 90% confidence intervals, plotted in Log scale, were considered as the potency rank for the eight compounds. The in vitro MultiFlow data showed a maximum confidence interval span of 1Log, which indicates data of good quality. Patterns observed in the compound potency rank were scrutinized by using the expert rule‐based software program Derek Nexus, developed by Lhasa Limited. Compound sub‐classification and structural alerts were considered contributory to the potencies observed for the topoisomerase II poisons studied herein. The Topo II poison Adverse Outcome Pathway was evaluated with MultiFlow endpoints serving as Key Events. The step‐wise approach described herein can be considered as a foundation for risk assessment of compounds within a specific mode of action of interest. Environ. Mol. Mutagen. 2020. © 2020 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The whitefly Bemisia tabaci Middle East‐Asia Minor 1 (MEAM1), previously known as B biotype, is a major agricultural pest with a reputation for developing resistance to insecticides. DNA‐based identification revealed that B. tabaci MEAM1 is the dominant species within Australian cotton cropping. Discriminating doses of 10 mg/L for pyriproxyfen and 300 mg/L for both diafenthiuron and bifenthrin were determined from bioassay data collected in 2010–2015. Resistance to these insecticides was tested in whitefly populations collected in 2017 from cotton crops in Queensland and New South Wales. This study reports on the presence of pyriproxyfen resistance in B. tabaci MEAM1 at seven locations in Queensland and New South Wales. One population from Goondiwindi was resistant to bifenthrin, whereas no populations tested had resistance to diafenthiuron. To determine the presence of resistance alleles to organophosphates and pyrethroids, reference populations of susceptible and resistant whiteflies (pyriproxyfen, bifenthrin and neonicotinoid) were tested. The resistance mutation L925I was found in a pyrethroid‐resistant population and in some individuals from the pyriproxyfen‐resistant population. The mutation F331W that confers organophosphate and carbamate resistance was found in all individuals tested including the susceptible reference population, indicative of a widespread distribution in Australian B. tabaci MEAM1. The cotton industry has revised the insecticide resistance management strategy for B. tabaci, to restrict the usage of pyriproxyfen to a single application within a 30‐day window. Our results argue against the use of organophosphate and carbamate insecticides in Australian cotton, because B. tabaci MEAM1 populations show significant resistance levels. Furthermore, both pesticide groups are highly disruptive to a diverse range of natural enemy populations, and as such, widespread use likely contributes to pest outbreaks. [ABSTRACT FROM AUTHOR]

In the quest to model various phenomena, the foundational importance of parameter identifiability to sound statistical modeling may be less well appreciated than goodness of fit. Identifiability concerns the quality of objective information in data to facilitate estimation of a parameter, while nonidentifiability means there are parameters in a model about which the data provide little or no information. In purely empirical models where parsimonious good fit is the chief concern, nonidentifiability (or parameter redundancy) implies overparameterization of the model. In contrast, nonidentifiability implies underinformativeness of available data in mechanistically derived models where parameters are interpreted as having strong practical meaning. This study explores illustrative examples of structural nonidentifiability and its implications using mechanistically derived models (for repeated presence/absence analyses and dose–response of Escherichia coli O157:H7 and norovirus) drawn from quantitative microbial risk assessment. Following algebraic proof of nonidentifiability in these examples, profile likelihood analysis and Bayesian Markov Chain Monte Carlo with uniform priors are illustrated as tools to help detect model parameters that are not strongly identifiable. It is shown that identifiability should be considered during experimental design and ethics approval to ensure generated data can yield strong objective information about all mechanistic parameters of interest. When Bayesian methods are applied to a nonidentifiable model, the subjective prior effectively fabricates information about any parameters about which the data carry no objective information. Finally, structural nonidentifiability can lead to spurious models that fit data well but can yield severely flawed inferences and predictions when they are interpreted or used inappropriately. [ABSTRACT FROM AUTHOR]

Some viruses cause tumor regression and can be used to treat cancer patients; these viruses are called oncolytic viruses. To assess whether oncolytic viruses from animal origin excreted by patients pose a health risk for livestock, a quantitative risk assessment (QRA) was performed to estimate the risk for the Dutch pig industry after environmental release of Seneca Valley virus (SVV). The QRA assumed SVV excretion in stool by one cancer patient on Day 1 in the Netherlands, discharge of SVV with treated wastewater into the river Meuse, downstream intake of river water for drinking water production, and consumption of this drinking water by pigs. Dose–response curves for SVV infection and clinical disease in pigs were constructed from experimental data. In the worst scenario (four log10 virus reduction by drinking water treatment and a farm with 10,000 pigs), the infection risk is less than 1% with 95% certainty. The risk of clinical disease is almost seven orders of magnitude lower. Risks may increase proportionally with the numbers of treated patients and days of virus excretion. These data indicate that application of wild‐type oncolytic animal viruses may infect susceptible livestock. A QRA regarding the use of oncolytic animal virus is, therefore, highly recommended. For this, data on excretion by patients, and dose–response parameters for infection and clinical disease in livestock, should be studied. [ABSTRACT FROM AUTHOR]

Background: Paediatric cancer survivors have a high risk of developing cardiac diseases, and the most frequent cardiac disease is heart failure (HF). The radiation dose-volume effects in the heart and cardiac substructures have not been explored in childhood cancer survivors (CCS). Therefore, the role of irradiated heart volume in the occurrence of HF among this population remains unclear. The aims of this study were to determine the doses and irradiated volumes of the heart and left ventricle (LV) related to the risk of HF in CCS and to investigate the impact of anthracycline exposure on this risk.Methods and Results: A case-control study nested in the French Childhood Cancer Survivors Study cohort. The mean heart and left ventricular doses and volumes indicators were estimated by reconstruction of individual treatments. A total of 239 HF cases and 1042 matched controls were included. The median age of HF diagnosis was 25.1 years. The median volume of the heart that received ≥ 30 Gy was 61.1% for cases and 16.9% for controls. In patients who did not receive anthracycline, the risk of HF was increased 3.6-fold when less than 10% of the LV received ≥ 30 Gy when compared to patients who were not exposed to any cardiac radiation and anthracycline.Conclusions: Small irradiated volumes of the heart or LV were significantly associated with HF risk. To the author's knowledge, this is the first study to report a dose-response relationship based on dose-volume indicators in CCS, which can be translated efficiently into current clinical practice. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mosquito mortality has been documented in numerous studies of spatial repellents but the concentration‐dependent toxicity of spatial repellent vapors has not been documented. To address this issue, prallethrin, flumethrin, metofluthrin, transfluthrin, and meperfluthrin were selected for comparative study against Aedes albopictus (Skuse), Ae. aegypti (L.), Culex quinquefasciatus Say, and Anopheles quadrimaculatus Say. Mosquito were exposed to vapors of each chemical for 2, 4, and 24 h with mortality recorded at each time point. A second experiment involved exposing mosquitoes to vapors for 2 h, then transferring them to untreated holding containers and held for 24 h. For these mosquitoes, readings were only taken after 24 h to allow for metabolic detoxification and recovery. RESULTS: LC50 and LC90 data indicated that transfluthrin and meperfluthrin had the greatest toxicity across all species, followed by metofluthrin, prallethrin, and flumethrin. CONCLUSION: Our findings, through the direct comparison of these compounds, suggest that transfluthrin, meperfluthrin, and metofluthrin be considered for further development. The vapor toxicity for the aforementioned compounds significantly exceeds prallethrin, which is currently market available as an adulticidal active ingredient in public health pest control. © 2018 Society of Chemical Industry Volatile pyrethroids are effective as spatial repellents. In vapor screening, transfluthrin and meperfluthrin were most toxic to mosquitoes, followed by metofluthrin (spatial repellent), prallethrin (mosquito adulticide), and flumethrin (tick preventative). [ABSTRACT FROM AUTHOR]

Summary: Objective: Fructose consumption is a risk factor for metabolic disease. We recently demonstrated that fibroblast growth factor 21 (FGF21), a metabolic hormone involved in lipid and glucose metabolism, is acutely stimulated in humans by 75 g oral fructose, with peak levels occurring 2 h after consumption. This study reports on the dose dependency and reproducibility of the FGF21 response to fructose. Methods: Lean, healthy adults drank either five different doses of fructose dissolved in water, each separated by 2 weeks, or the same dose on three occasions, each separated by 1 week. Results: Fibroblast growth factor 21 levels peaked at 2 h in a dose‐dependent manner. No significant increase in FGF21 was seen after consumption of 10 g fructose, while robust increases were seen after drinking solutions containing 30, 50 and 75 g. At 2 h, the minimal fold change of FGF21 was highest following a 75 g fructose drink, and all subjects demonstrated at least a doubling of FGF21 levels following consumption of this dose. Conclusions: The increase in FGF21 following an oral fructose challenge is dose dependent, with levels peaking at 2 h independent of dose. The FGF21 response to 75 g fructose is also highly reproducible within individuals. Clinical Implications: By demonstrating that the FGF21 response to fructose is dose dependent and reproducible, this study deepens current understanding of FGF21 fructose dynamics and physiology in humans. This is an important area of clinical interest given associations between fructose intake and a wide variety of metabolic derangements. [ABSTRACT FROM AUTHOR]

Abstract: BACKGROUND: A field‐evolved herbicide‐resistant weed population can represent a heterogeneous composite of subpopulations that differ in their susceptibility and responsiveness to herbicide hormesis. Variable hormesis responsiveness can result in selection for and against certain subpopulations under low herbicide doses, and this has the potential to contribute to the evolution of resistance. The relevance of this hypothesis at practical field rates was studied for two field‐collected acetyl‐coenzyme A carboxylase (ACCase) target‐site resistant (TSR) biotypes of Alopecurus myosuroides Huds. (haplotype Leu1781) exposed to three ACCase inhibitors. Herbicide dose responses were evaluated at the population level and at different subpopulation levels after the dissection of individual plants by herbicide selection and genotyping. RESULTS: The practical field rates of fenoxaprop‐P were lower than the observed hormetic doses in the resistant subpopulation, whereas the field rates of clodinafop and cycloxydim stimulated the shoot biomass in different resistant subpopulations by 21–38% above that of the control. Because variable dose levels induced hormesis in the different subpopulations, the practical field rates showed a significant potential to selectively enhance parts of a resistant field population, but did not impact or adversely affect other parts of the population. CONCLUSION: As a consequence of population heterogeneity, herbicide hormesis may impact resistance evolution in weeds at realistic use rates via the selective promotion of individual genotypes. However, the practical relevance of this phenomenon may be influenced by many factors, such as the herbicidal active ingredient used, as indicated in this study. © 2018 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Background: Subcutaneous immunotherapy is an effective allergy treatment only if properly dosed. In this article we review the data on the probable effective dose range for subcutaneous immunotherapy and convert the recommended doses into a clinically relevant format. Methods: A comprehensive literature search of dose‐response subcutaneous immunotherapy studies was done of EBM databases, Medline database, PreMedline, and the National Guideline Clearinghouse for the period 1980–2016. Recommended doses were converted to the volume of allergen extract that should be added to a 5‐mL maintenance vial. Results: A safe and effective dose for subcutaneous immunotherapy is likely 5–20 μg of major allergen per injection. A 0.5‐mL injection from a 5‐mL maintenance vial containing 0.2 mL of manufacturer's extract of each allergen should reach the lower end of the probable effective dose range for most allergens. A larger volume of extract is required to reach that range when treatment includes cat, dog, or only 1 dust mite. Increasing beyond the commonly prescribed 0.2 mL of manufacturer's extract added to a 5‐mL treatment vial is reasonable for nearly all allergens to achieve a maintenance dose higher in the probable effective dose range. Conclusion: Current otolaryngic allergy practice usually escalates patients to 0.5‐mL injections from 5‐mL maintenance vials containing 0.2 mL of manufacturer's extract of each allergen. With the main exceptions of cat and dog, those injections administered 1 or 2 times per month likely provide an efficacious dose of allergen and are consistent with published guidelines. A larger volume of extract should be considered in certain clinical situations. [ABSTRACT FROM AUTHOR]

Abstract: Statin doses around estimated effective dose 50 (ED50) can reduce myocardial infarction by over 25% and mortality by around 10%. Being a competitive enzyme inhibitor, statin efficacy plateaus at doses that are multiples above the ED50, whilst on‐ and off‐target adverse events increase in number and severity with increasing dose. For example, myopathy has been shown to increase by up to 29‐fold and liver dysfunction by up to nine‐fold as statin dose is increased. Doses of up to 40‐fold ED50 have been promoted, but above five‐fold ED50, for example 10 mg of atorvastatin, there is no randomized controlled clinical trial evidence that coronary mortality is lowered, or that survival is increased. [ABSTRACT FROM AUTHOR]

Abstract: BACKGROUND: Five glyphosate‐resistant populations of Chloris truncata originally collected from New South Wales were compared with one susceptible (S) population from South Australia to confirm glyphosate resistance and elucidate possible mechanisms of resistance. RESULTS: Based on the amounts of glyphosate required to kill 50% of treated plants (LD50), glyphosate resistance (GR) was confirmed in five populations of C. truncata (A536, A528, T27, A534 and A535.1). GR plants were 2.4–8.7‐fold more resistant and accumulated less shikimate after glyphosate treatment than S plants. There was no difference in glyphosate absorption and translocation between GR and S plants. The EPSPS gene did not contain any point mutation that had previously been associated with resistance to glyphosate. The resistant plants (A528 and A536) contained up to 32–48 more copies of the EPSPS gene than the susceptible plants. CONCLUSION: This study has identified EPSPS gene amplification contributing to glyphosate resistance in C. truncata. In addition, a Glu‐91‐Ala mutation within EPSPS was identified that may contribute to glyphosate resistance in this species. © 2017 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Abstract: Risks of allergic contact dermatitis (ACD) from consumer products intended for extended (nonpiercing) dermal contact are regulated by E.U. Directive EN 1811 that limits released Ni to a weekly equivalent dermal load of ≤0.5 μg/cm2. Similar approaches for thousands of known organic sensitizers are hampered by inability to quantify respective ACD‐elicitation risk levels. To help address this gap, normalized values of cumulative risk for eliciting a positive (“≥+”) clinical patch test response reported in 12 studies for a total of n = 625 Ni‐sensitized patients were modeled in relation to observed ACD‐eliciting Ni loads, yielding an approximate lognormal (LN) distribution with a geometric mean and standard deviation of GMNi = 15 μg/cm2 and GSDNi = 8.0, respectively. Such data for five sensitizers (including formaldehyde and 2‐hydroxyethyl methacrylate) were also ∼LN distributed, but with a common GSD value equal to GSDNi and with heterogeneous sensitizer‐specific GM values each defining a respective ACD‐eliciting potency GMNi/GM relative to Ni. Such potencies were also estimated for nine (meth)acrylates by applying this general LN ACD‐elicitation risk model to respective sets of fewer data. ACD‐elicitation risk patterns observed for Cr(VI) (n = 417) and Cr(III) (n = 78) were fit to mixed‐LN models in which ∼30% and ∼40% of the most sensitive responders, respectively, were estimated to exhibit a LN response also governed by GSDNi. The observed common LN‐response shape parameter GSDNi may reflect a common underlying ACD mechanism and suggests a common interim approach to quantitative ACD‐elicitation risk assessment based on available clinical data. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To determine the human dose‐response relationship between a stepwise increase in arterial oxygen tension and its associated changes in DO2 and sublingual microcirculatory perfusion. Methods: Fifteen healthy volunteers breathed increasing oxygen fractions for 10 minutes to reach arterial oxygen tensions of baseline (breathing air), 20, 40, 60 kPa, and max kPa (breathing oxygen). Systemic hemodynamics were measured continuously by the volume‐clamp method. At the end of each period, the sublingual microcirculation was assessed by SDF. Results: Systemic DO2 was unchanged throughout the study (Pslope = .8). PVD decreased in a sigmoidal fashion (max −15% while breathing oxygen, SD18, Pslope = .001). CI decreased linearly (max −10%, SD10, Pslope < .001) due to a reduction in HR (max −10%, SD7, Pslope = .009). There were no changes in stroke volume or MAP. Most changes became apparent above an arterial oxygen tension of 20 kPa. Conclusions: In healthy volunteers, supraphysiological arterial oxygen tensions have no effect on systemic DO2. Sublingual microcirculatory PVD decreased in a dose‐dependent fashion. All hemodynamic changes appear negligible up to an arterial oxygen tension of 20 kPa. [ABSTRACT FROM AUTHOR]

MCP-MOD is a testing and model selection approach for clinical dose finding studies. During testing, contrasts of dose group means are derived from candidate dose response models. A multiple-comparison procedure is applied that controls the alpha level for the family of null hypotheses associated with the contrasts. Provided at least one contrast is significant, a corresponding set of "good" candidate models is identified. The model generating the most significant contrast is typically selected. There have been numerous publications on the method. It was endorsed by the European Medicines Agency. The MCP-MOD procedure can be alternatively represented as a method based on simple linear regression, where "simple" refers to the inclusion of an intercept and a single predictor variable, which is a transformation of dose. It is shown that the contrasts are equal to least squares linear regression slope estimates after a rescaling of the predictor variables. The test for each contrast is the usual t statistic for a null slope parameter, except that a variance estimate with fewer degrees of freedom is used in the standard error. Selecting the model corresponding to the most significant contrast P value is equivalent to selecting the predictor variable yielding the smallest residual sum of squares. This criteria orders the models like a common goodness-of-fit test, but it does not assure a good fit. Common inferential methods applied to the selected model are subject to distortions that are often present following data-based model selection. [ABSTRACT FROM AUTHOR]

In an article recently published in this journal, Bogen(1) concluded that an NRC committee's recommendations that default linear, nonthreshold (LNT) assumptions be applied to dose- response assessment for noncarcinogens and nonlinear mode of action carcinogens are not justified. Bogen criticized two arguments used by the committee for LNT: when any new dose adds to a background dose that explains background levels of risk (additivity to background or AB), or when there is substantial interindividual heterogeneity in susceptibility (SIH) in the exposed human population. Bogen showed by examples that SIH can be false. Herein is outlined a general proof that confirms Bogen's claim. However, it is also noted that SIH leads to a nonthreshold population distribution even if individual distributions all have thresholds, and that small changes to SIH assumptions can result in LNT. Bogen criticizes AB because it only applies when there is additivity to background, but offers no help in deciding when or how often AB holds. Bogen does not contradict the fact that AB can lead to LNT but notes that, even if low-dose linearity results, the response at higher doses may not be useful in predicting the amount of low-dose linearity. Although this is theoretically true, it seems reasonable to assume that generally there is some quantitative relationship between the low-dose slope and the slope suggested at higher doses. Several incorrect or misleading statements by Bogen are noted. [ABSTRACT FROM AUTHOR]

Crump's response in this issue to my critique of linear-no-threshold (LNT) default assumptions for noncancer and nongenotoxic cancer risks ( Risk Analysis 2016; 36(3):589-604) is rebutted herein. Crump maintains that distinguishing between a low-dose linear dose response and a threshold dose response on the basis of dose-response data is impossible even for endpoints involving increased cytotoxicity. My rebuttal relies on descriptions and specific illustrations of two well-characterized ultrasensitive molecular switches that govern two key cytoprotective responses to cellular stress-heat shock response and antioxidant response element activation, respectively-each of which serve to suppress stress-induced apoptotic cell death unless overwhelmed. Because detailed dose-response data for each endpoint is shown to be J- or inverted-J-shaped with high confidence, and because independent pathways can explain background rates of apoptosis, LNT assumptions for this cytotoxic endpoint are unwarranted, at least in some cases and perhaps generally. [ABSTRACT FROM AUTHOR]

Aims The currently licensed seasonal trivalent influenza vaccines contain 15 μg haemagglutinin per strain for adult, and up to 60 μg for elderly patients. However, due to recent shortages, dose sparing to increase production capacity would be highly desirable. In the present study, we attempted to find a dose-response relationship for immunogenicity and, thus, the optimal dose for seasonal influenza vaccines in adult and elderly patients. Methods A total of 256 subjects, including adult (aged 18-60 years) and elderly (aged over 60 years) individuals, were enrolled. Subjects were randomly assigned in a 1:1:1:1 ratio to receive a whole-virion, aluminium-adjuvanted trivalent influenza vaccine containing 3.5, 6, 9 or 15 μg haemagglutinin of seasonal A/H1N1, A/H3N2 and B influenza antigens manufactured by Omninvest Ltd., Hungary. Serum antibody titres against the vaccine virus strains were measured by haemagglutination inhibition. Result All vaccines were well tolerated. All four vaccines fulfilled all three immunogenicity licensing criteria, as determined by the European Committee for Proprietary Medicinal Products (CPMP)/Biotechnology Working Party (BWP)/214/96 guideline for all three virus strains and both age groups. The 3.5 μg vaccine showed 28% less seroconversion compared to the 15 μg dose in terms of influenza AH3N2 in the adult group (95% confidence interval -51, −3; P < 0.05). All other doses showed no significant difference in immunogenicity compared with the licensed vaccine containing 15 μg haemagglutinin. Conclusions Our data suggested that significant dose sparing is possible with the use of whole-virion vaccines and aluminium adjuvants, without compromising safety. This could have significant economic and public health impacts. [ABSTRACT FROM AUTHOR]

BIA 10-2474 (a fatty acid amide hydrolase inhibitor) was evaluated in a first-in-human phase 1 study in normal volunteers to assess safety/tolerability, pharmacokinetics, pharmacodynamics, and food effect. The dose-escalation process consisted of a single-ascending-dose phase (SAD) and multiple-ascending-dose phase (MAD). Prospective determination of the starting dose and maximal escalated dose was consistent with the usual clinical pharmacology principles for extrapolation of preclinical toxicology data to human equivalent doses. After only 5-6 days of multiple-dose administration of 50 mg daily in the MAD phase, several subjects became quite ill with central nervous system symptoms. One subject progressed to brain death within several days of symptom onset. Magnetic resonance imaging scans demonstrated signal abnormalities consistent with microbleeds affecting the hippocampus and pons, suggestive of possible cytotoxic or vasogenic edema compatible with a toxic/metabolic process. There were no findings at lower MAD doses or during the SAD phase. The toxicology program carried out in 4 preclinical species (mouse, rat, dog, and monkey) did not demonstrate significant neurotoxicity. The probable mechanism of neurologic toxicity demonstrated in humans at the 50-mg daily dose was inhibition of off-target cerebral receptors or through another mechanism. Additional recommendations have been proposed for future first-in-human studies to maximize subject safety. However, one must also accept the basic premise that, in general, first-in-human phase 1 studies are remarkably safe, and these rare events are not 100% avoidable during the drug development process. [ABSTRACT FROM AUTHOR]

Dose-response analysis of binary developmental data (e.g., implant loss, fetal abnormalities) is best done using individual fetus data (identified to litter) or litter-specific statistics such as number of offspring per litter and proportion abnormal. However, such data are not often available to risk assessors. Scientific articles usually present only dose-group summaries for the number or average proportion abnormal and the total number of fetuses. Without litter-specific data, it is not possible to estimate variances correctly (often characterized as a problem of overdispersion, intralitter correlation, or 'litter effect'). However, it is possible to use group summary data when the design effect has been estimated for each dose group. Previous studies have demonstrated useful dose-response and trend test analyses based on design effect estimates using litter-specific data from the same study. This simplifies the analysis but does not help when litter-specific data are unavailable. In the present study, we show that summary data on fetal malformations can be adjusted satisfactorily using estimates of the design effect based on historical data. When adjusted data are then analyzed with models designed for binomial responses, the resulting benchmark doses are similar to those obtained from analyzing litter-level data with nested dichotomous models. [ABSTRACT FROM AUTHOR]

Purpose Separating the scatter from the primary component of a MV beam to study detector response separately in each case for a better understanding of the role of different effects influencing the response in nonstandard fields. Methods Detector response in three different experimental setups was investigated for a variety of different types (diamond, shielded and unshielded diodes, ionization chamber and film): (a). Detectors positioned in water under a thin steel pole blocking the central part of the beam, yielding only the response to the scatter part of the beam. (b). Detectors positioned in air under a PMMA cap to approximate the contribution of the primary beam without scatter. (c). Detectors positioned in water in the standard open field configuration to obtain a superposition of both. Results Detector differences became more clearly observable when the primary beam was blocked and detector behavior heavily depended on the construction type. It was possible to calculate the response in the open fields from the values measured in the blocked configuration with 1% accuracy for all studied field sizes between 0.8 and 10 cm and for all detectors. Conclusions The limitations of clinically used detectors in nonstandard situations were illustrated in the extreme situation of just scattered radiation reaching the detector. By experimentally separating scatter from the primary beam, the roles of different effects on the detector response were observed. [ABSTRACT FROM AUTHOR]

The pharmacokinetic profile, tolerability and efficacy of benzene-poly-carboxylic acids complex with cis-diammineplatinum ( II) dichloride ( BP-C1) were studied in dogs with mammary cancer. A three-level response surface pathway designed trial was performed on seven dogs. At each level BP-C1 was administered subcutaneously daily for 7 days followed by a 7-day rest period in a dose escalating manner. Adverse events according to VCOG-CTCAE, performance status and tumour progression were recorded. The pharmacokinetic profile followed a two-compartment model with rapid absorption, short distribution, and a slow elimination phase. The overall elimination half-life was 125 h. The maximum tolerated dose of BP-C1 was estimated to be above 0.46 mg kg−1. A significant reduction in VCOG-CTCAE toxicity which correlated negatively with increasing dose was found. The dogs' general performance status remained unchanged. No decrease in total tumour burden was found, although temporary tumour reduction was seen in some target tumours. [ABSTRACT FROM AUTHOR]

Summary: Background: The impact of vitamin D status on body composition is not well understood. Objectives: Evaluate how vitamin D supplementation in infancy affects body composition at 3 years of age. Methods: Double‐blind randomized trial of 132, 1‐month‐old healthy, breastfed infants randomly assigned to receive oral vitamin D3 supplements of 400, 800, 1200 or 1600 IU d−1 for 11 months. In the present analysis, 87 (66%) returned at 3 years of age. Body composition was measured using dual‐energy x‐ray absorptiometry and plasma 25‐hydroxyvitamin D [25(OH)D] concentrations by liquid chromatography tandem mass spectrometry. Results: Anthropometry, body composition, diet, activity and demographics were similar across dosage groups at 3 years. Mean 25(OH)D concentration from 1 month to 3 years was higher (P < 0.001) in the 1200 IU group than 800 and 400 IU groups. Children with 25(OH)D concentrations above 75 nmol L−1 had lower fat mass (~450 g; P = 0.049). In multiple linear regression, mean 25(OH)D was associated with lean mass percent (β = 0.06; CI: 0.00, 0.12; P = 0.042), fat mass (β = −11.29; CI: −22.06, −0.52; P = 0.048) and body fat percent (β = −0.06; CI: −0.12, −0.01; P = 0.045). Conclusions: Higher vitamin D status from infancy through to 3 years of age associates with leaner body composition. [ABSTRACT FROM AUTHOR]

The application of quantitative microbial risk assessments (QMRAs) to understand and mitigate risks associated with norovirus is increasingly common as there is a high frequency of outbreaks worldwide. A key component of QMRA is the dose-response analysis, which is the mathematical characterization of the association between dose and outcome. For Norovirus, multiple dose-response models are available that assume either a disaggregated or an aggregated intake dose. This work reviewed the dose-response models currently used in QMRA, and compared predicted risks from waterborne exposures (recreational and drinking) using all available dose-response models. The results found that the majority of published QMRAs of norovirus use the 1 F1 hypergeometric dose-response model with α = 0.04, β = 0.055. This dose-response model predicted relatively high risk estimates compared to other dose-response models for doses in the range of 1-1,000 genomic equivalent copies. The difference in predicted risk among dose-response models was largest for small doses, which has implications for drinking water QMRAs where the concentration of norovirus is low. Based on the review, a set of best practices was proposed to encourage the careful consideration and reporting of important assumptions in the selection and use of dose-response models in QMRA of norovirus. Finally, in the absence of one best norovirus dose-response model, multiple models should be used to provide a range of predicted outcomes for probability of infection. [ABSTRACT FROM AUTHOR]

There is a need to advance our ability to characterize the risk of inhalational anthrax following a low-dose exposure. The exposure scenario most often considered is a single exposure that occurs during an attack. However, long-term daily low-dose exposures also represent a realistic exposure scenario, such as what may be encountered by people occupying areas for longer periods. Given this, the objective of the current work was to model two rabbit inhalational anthrax dose-response data sets. One data set was from single exposures to aerosolized Bacillus anthracis Ames spores. The second data set exposed rabbits repeatedly to aerosols of B. anthracis Ames spores. For the multiple exposure data the cumulative dose (i.e., the sum of the individual daily doses) was used for the model. Lethality was the response for both. Modeling was performed using Benchmark Dose Software evaluating six models: logprobit, loglogistic, Weibull, exponential, gamma, and dichotomous-Hill. All models produced acceptable fits to either data set. The exponential model was identified as the best fitting model for both data sets. Statistical tests suggested there was no significant difference between the single exposure exponential model results and the multiple exposure exponential model results, which suggests the risk of disease is similar between the two data sets. The dose expected to cause 10% lethality was 15,600 inhaled spores and 18,200 inhaled spores for the single exposure and multiple exposure exponential dose-response model, respectively, and the 95% lower confidence intervals were 9,800 inhaled spores and 9,200 inhaled spores, respectively. [ABSTRACT FROM AUTHOR]

Exposures of brain tissue to ionizing radiation can lead to persistent deficits in cognitive functions and behaviors. However, little is known about the quantitative relationships between exposure dose and neurological risks, especially for lower doses and among genetically diverse individuals. We investigated the dose relationship for spatial memory learning among genetically outbred male Wistar rats exposed to graded doses of 56Fe particles (sham, 5, 10, 15, and 20 cGy; 1 GeV/n). Spatial memory learning was assessed on a Barnes maze using REL3 ratios measured at three months after exposure. Irradiated animals showed dose-dependent declines in spatial memory learning that were fit by a linear regression ( P for slope <0.0002). The irradiated animals showed significantly impaired learning at 10 cGy exposures, no detectable learning between 10 and 15 cGy, and worsened performances between 15 and 20 cGy. The proportions of poor learners and the magnitude of their impairment were fit by linear regressions with doubling doses of ∼10 cGy. In contrast, there were no detectable deficits in learning among the good learners in this dose range. Our findings suggest that genetically diverse individuals can vary substantially in their spatial memory learning, and that exposures at low doses appear to preferentially impact poor learners. This hypothesis invites future investigations of the genetic and physiological mechanisms of inter-individual variations in brain function related to spatial memory learning after low-dose HZE radiation exposures and to determine whether it also applies to physical trauma to brain tissue and exposures to chemical neurotoxicants. Environ. Mol. Mutagen. 57:331-340, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose: USsimComputed tomography(CT)radiation dose reduction is frequently achieved by applying lower tube voltages and using iterative reconstruction (IR). For calcium scoring, the reference protocol at 120 kVp with filtered back projection (FBP) is still used, because kVp and IR may influence the Agatston score (AS) and volume score (VS). The authors present a two-step method to optimize dose: first, to determine the lowest feasible exposure and highest noise thresholds; second, to define a calibration method that ensures that the AS and VS are similar to the reference protocol. Methods: USsimAS and VS were measured for an anthropomorphic thoracic phantom that includes a calciumcalibration module. The phantom was scanned on a 320-row CT scanner, at tube voltages of 120 kVp using FBP, and 120, 100, and 80 kVp using adaptive iterative dose reduction (AIDR 3D)reconstruction. The minimum CTDIs were determined based on three objective quality criteria. Calibration was performed to estimate adjusted CT number thresholds for the lower kVp acquisitions. Finally, the accuracies of the total and individual insert scores at dose level close to the minimum CTDI level were investigated and compared to low (FBPLD - 120) and high (FBPHD - 120) dose reference protocols (based on ten repeated acquisitions for each group). Results: USsimIR allows the exposure to be reduced by 69% at 120 kVp, with no significant effect on the total scores when averaged over all included dose steps and compared to FBP-120 (AS: 693 vs 699, p = 0.182; VS: 588 vs 587 mm³, p = 0.569). Also when averaged over ten repeated scans and compared to FBPHD - 120 (AS: 709 vs 704, p = 0.435; VS: 604 vs 601 mm³, p = 0.479), there is no statistical significant effect. Reducing the peak tube voltage allows even greater dose reductions: 73% at 100 kVp and 76% at 80 kVp. The calibrated CT number thresholds for analysis at 120, 100, and 80 kVp were, respectively, 130, 133, and 160 HU for the Agatston score, and 130, 132, and 140 HU for the volume score. Following the calibration, the mean scores of the four groups with dose variation were not significantly different from the reference protocol, at 100 kVp (AS: 698 vs 699, p = 0.818; VS: 584 vs 587 mm³, p = 0.365) or at 80 kVp (AS: 698 vs 699, p = 0.996; VS: 586 vs 587 mm³, p = 0.827). Similarly, there was no significant score difference with FBPLD - 120 during repeated scanning: 100 kVp (AS: 690 vs 694, p = 0.394; VS: 579 vs 585 mm³, p = 0.168) and 80 kVp (AS: 703 vs 694, p = 0.115; VS: 588 vs 585 mm³, p = 0.613). Compared to FBPHD - 120 group, the relative score deviation for the accuracy of the 400 and 800 mg/cm³ HA inserts with 3 and 5 mm diameter is less than 7%. However, the relative deviation of the smaller 1 mm inserts is poorer (up to 41% deviations for scores <3). Conclusions: USsimWith iterative reconstruction using AIDR 3D, deviations of the total Agatston and volume scores remain within 4% of the reference protocol. The 1 mm inserts were detected as calcification, but scores less than ten tend to be underestimated. Following the calibration process, the application of IR in combination with reduced tube voltages allows up to 76% lower radiation dose. [ABSTRACT FROM AUTHOR]

To improve U.S. Environmental Protection Agency (EPA) dose-response (DR) assessments for noncarcinogens and for nonlinear mode of action (MOA) carcinogens, the 2009 NRC Science and Decisions Panel recommended that the adjustment-factor approach traditionally applied to these endpoints should be replaced by a new default assumption that both endpoints have linear-no-threshold (LNT) population-wide DR relationships. The panel claimed this new approach is warranted because population DR is LNT when any new dose adds to a background dose that explains background levels of risk, and/or when there is substantial interindividual heterogeneity in susceptibility in the exposed human population. Mathematically, however, the first claim is either false or effectively meaningless and the second claim is false. Any dose-and population-response relationship that is statistically consistent with an LNT relationship may instead be an additive mixture of just two quasi-threshold DR relationships, which jointly exhibit low-dose S-shaped, quasi-threshold nonlinearity just below the lower end of the observed 'linear' dose range. In this case, LNT extrapolation would necessarily overestimate increased risk by increasingly large relative magnitudes at diminishing values of above-background dose. The fact that chemically-induced apoptotic cell death occurs by unambiguously nonlinear, quasi-threshold DR mechanisms is apparent from recent data concerning this quintessential toxicity endpoint. The 2009 NRC Science and Decisions Panel claims and recommendations that default LNT assumptions be applied to DR assessment for noncarcinogens and nonlinear MOA carcinogens are therefore not justified either mathematically or biologically. [ABSTRACT FROM AUTHOR]

Dose-response models are essential to quantitative microbial risk assessment (QMRA), providing a link between levels of human exposure to pathogens and the probability of negative health outcomes. In drinking water studies, the class of semi-mechanistic models known as single-hit models, such as the exponential and the exact beta-Poisson, has seen widespread use. In this work, an attempt is made to carefully develop the general mathematical single-hit framework while explicitly accounting for variation in (1) host susceptibility and (2) pathogen infectivity. This allows a precise interpretation of the so-called single-hit probability and precise identification of a set of statistical independence assumptions that are sufficient to arrive at single-hit models. Further analysis of the model framework is facilitated by formulating the single-hit models compactly using probability generating and moment generating functions. Among the more practically relevant conclusions drawn are: (1) for any dose distribution, variation in host susceptibility always reduces the single-hit risk compared to a constant host susceptibility (assuming equal mean susceptibilities), (2) the model-consistent representation of complete host immunity is formally demonstrated to be a simple scaling of the response, (3) the model-consistent expression for the total risk from repeated exposures deviates (gives lower risk) from the conventional expression used in applications, and (4) a model-consistent expression for the mean per-exposure dose that produces the correct total risk from repeated exposures is developed. [ABSTRACT FROM AUTHOR]

At early drug discovery, purified protein‐based assays are often used to characterise compound potency. In the context of dose response, it is often perceived that a time‐independent inhibitor is reversible and a time‐dependent inhibitor is irreversible. The legitimacy of this argument is investigated using a simple kinetics model, where it is revealed by model‐based analytical analysis and numerical studies that dose response of an irreversible inhibitor may appear time‐independent under certain parametric conditions. Hence, the observation of time‐independence cannot be used as sole evidence for identification of inhibitor reversibility. It has also been discussed how the synthesis and degradation of a target receptor affect drug inhibition in an in vitro cell‐based assay setting. These processes may also influence dose response of an irreversible inhibitor in such a way that it appears time‐independent under certain conditions. Furthermore, model‐based steady‐state analysis reveals the complexity nature of the drug–receptor process. [ABSTRACT FROM AUTHOR]

Over the last decade the health and environmental research communities have made significant progress in collecting and improving access to genomic, toxicology, exposure, health, and disease data useful to health risk assessment. One of the barriers to applying these growing volumes of information in fields such as risk assessment is the lack of informatics tools to organize, curate, and evaluate thousands of journal publications and hundreds of databases to provide new insights on relationships among exposure, hazard, and disease burden. Many fields are developing ontologies as a way of organizing and analyzing large amounts of complex information from multiple scientific disciplines. Ontologies include a vocabulary of terms and concepts with defined logical relationships to each other. Building from the recently published exposure ontology and other relevant health and environmental ontologies, this article proposes an ontology for health risk assessment (RsO) that provides a structural framework for organizing risk assessment information and methods. The RsO is anchored by eight major concepts that were either identified by exploratory curations of the risk literature or the exposure-ontology working group as key for describing the risk assessment domain. These concepts are: (1) stressor, (2) receptor, (3) outcome, (4) exposure event, (5) dose-response approach, (6) dose-response metric, (7) uncertainty, and (8) measure of risk. We illustrate the utility of these concepts for the RsO with example curations of published risk assessments for ionizing radiation, arsenic in drinking water, and persistent pollutants in salmon. [ABSTRACT FROM AUTHOR]

The objective of this study was to model and quantify the level of Listeria monocytogenes in raw milk cheese (RMc) and pasteurized milk cheese (PMc) from farm to fork using a Bayesian inference approach combined with a quantitative risk assessment. The modeling approach included a prediction of contamination arising from the farm environment as well from cross-contamination within the cheese-processing facility through storage and subsequent human exposure. The model predicted a high concentration of L. monocytogenes in contaminated RMc (mean 2.19 log10 CFU/g) compared to PMc (mean −1.73 log10 CFU/g). The mean probability of illness (P1 for low-risk population, LR) and (P2 for high-risk population, HR, e.g., immunocompromised) adult Irish consumers following exposure to contaminated cheese was 7 × 10−8 (P1) and 9 × 10−4 (P2) for RMc and 7 × 10−10 (P1) and 8 × 10−6 (P2) for PMc, respectively. In addition, the model was used to evaluate performance objectives at various stages, namely, the cheese making and ripening stages, and to set a food safety objective at the time of consumption. A scenario analysis predicted various probabilities of L. monocytogenes contamination along the cheese-processing chain for both RMc and PMc. The sensitivity analysis showed the critical factors for both cheeses were the serving size of the cheese, storage time, and temperature at the distribution stage. The developed model will allow food processors and policymakers to identify the possible routes of contamination along the cheese-processing chain and to reduce the risk posed to human health. [ABSTRACT FROM AUTHOR]