Experimental evidence for neonicotinoid driven decline in aquatic emerging insects.

There is an ongoing unprecedented loss in insects, both in terms of richness and biomass. The usage of pesticides, especially neonicotinoid insecticides, has been widely suggested to be a contributor to this decline. However, the risks of neonicotinoids to natural insect populations have remained largely unknown due to a lack of field-realistic experiments. Here, we used an outdoor experiment to determine effects of field-realistic concentrations of the commonly applied neonicotinoid thiacloprid on the emergence of naturally assembled aquatic insect populations. Following application, all major orders of emerging aquatic insects (Coleoptera, Diptera, Ephemeroptera, Odonata, and Trichoptera) declined strongly in both abundance and biomass. At the highest concentration (10 µg/L), emergence of most orders was nearly absent. Diversity of the most species-rich family, Chironomidae, decreased by 50% at more commonly observed concentrations (1 µg/L) and was generally reduced to a single species at the highest concentration. Our experimental findings thereby showcase a causal link of neonicotinoids and the ongoing insect decline. Given the urgency of the insect decline, our results highlight the need to reconsider the mass usage of neonicotinoids to preserve freshwater insects as well as the life and services depending on them.

Response of Chlorella vulgaris to exposure to CuO NPs: Contributions of particulate and dissolved metal forms as modulated by tannic acid and pH.

A suspension of copper oxide nanoparticles (CuO NPs) is a mixture of dissolved and particulate Cu, the relative proportions of which highly depend on the water chemistry. However, the relationship between different proportions of particulate and dissolved Cu and the overall toxicity of CuO NPs is still unknown. This study investigated the response of Chlorella vulgaris to CuO NPs at varying solution pH and at different tannic acid (TA) additions, with a focus on exploring whether and how dissolved and particulate Cu contribute to the overall toxicity of CuO NPs. The results of the exposure experiments demonstrated the involvement of both dissolved and particulate Cu in inducing toxicity of CuO NPs, and the inhibition of CuO NPs on cell density of Chlorella vulgaris was found to be significantly (p < 0.05) alleviated with increased levels of TA and pH (< 8). Using the independent action model, the contribution to toxicity of particulate Cu was found to be enhanced with increasing pH values and TA concentrations. The toxic unit indicator better (R2 = 0.86, p < 0.001) explained impacts of CuO NPs on micro-algae cells than commonly used mass concentrations (R2 = 0.27-0.77, p < 0.05) across different levels of pH and TA. Overall, our study provides an additivity-based method to improve the accuracy of toxicity prediction through including contributions to toxicity of both dissolved and particulate Cu and through eliminating the uneven distribution of data due to large variations in total Cu, particulate Cu, dissolved Cu, Cu2+ activities, Cu-TA complexes and other Cu-complexes concentrations with varying water chemistry conditions.

Using Machine Learning to Predict Adverse Effects of Metallic Nanomaterials to Various Aquatic Organisms.

The wide production and use of metallic nanomaterials (MNMs) leads to increased emissions into the aquatic environments and induces high potential risks. Experimentally evaluating the (eco)toxicity of MNMs is time-consuming and expensive due to the multiple environmental factors, the complexity of material properties, and the species diversity. Machine learning (ML) models provide an option to deal with heterogeneous data sets and complex relationships. The present study established an in silico model based on a machine learning properties-environmental conditions-multi species-toxicity prediction model (ML-PEMST) that can be applied to predict the toxicity of different MNMs toward multiple aquatic species. Feature importance and interaction analysis based on the random forest method indicated that exposure duration, illumination, primary size, and hydrodynamic diameter were the main factors affecting the ecotoxicity of MNMs to a variety of aquatic organisms. Illumination was demonstrated to have the most interaction with the other features. Moreover, incorporating additional detailed information on the ecological traits of the test species will allow us to further optimize and improve the predictive performance of the model. This study provides a new approach for ecotoxicity predictions for organisms in the aquatic environment and will help us to further explore exposure pathways and the risk assessment of MNMs.

Toxicokinetics and Particle Number-Based Trophic Transfer of a Metallic Nanoparticle Mixture in a Terrestrial Food Chain.

Herein, we investigated to which extent metallic nanoparticles (MNPs) affect the trophic transfer of other coexisting MNPs from lettuce to terrestrial snails and the associated tissue-specific distribution using toxicokinetic (TK) modeling and single-particle inductively coupled plasma mass spectrometry. During a period of 22 days, snails were fed with lettuce leaves that were root exposed to AgNO3 (0.05 mg/L), AgNPs (0.75 mg/L), TiO2NPs (200 mg/L), and a mixture of AgNPs and TiO2NPs (equivalent doses as for single NPs). The uptake rate constants (ku) were 0.08 and 0.11 kg leaves/kg snail/d for Ag and 1.63 and 1.79 kg leaves/kg snail/d for Ti in snails fed with NPs single- and mixture-exposed lettuce, respectively. The elimination rate constants (ke) of Ag in snails exposed to single AgNPs and mixed AgNPs were comparable to the corresponding ku, while the ke for Ti were lower than the corresponding ku. As a result, single TiO2NP treatments as well as exposure to mixtures containing TiO2NPs induced significant biomagnification from lettuce to snails with kinetic trophic transfer factors (TTFk) of 7.99 and 6.46. The TTFk of Ag in the single AgNPs treatment (1.15 kg leaves/kg snail) was significantly greater than the TTFk in the mixture treatment (0.85 kg leaves/kg snail), while the fraction of Ag remaining in the body of snails after AgNPs exposure (36%) was lower than the Ag fraction remaining after mixture exposure (50%). These results indicated that the presence of TiO2NPs inhibited the trophic transfer of AgNPs from lettuce to snails but enhanced the retention of AgNPs in snails. Biomagnification of AgNPs from lettuce to snails was observed in an AgNPs single treatment using AgNPs number as the dose metric, which was reflected by the particle number-based TTFs of AgNPs in snails (1.67, i.e., higher than 1). The size distribution of AgNPs was shifted across the lettuce-snail food chain. By making use of particle-specific measurements and fitting TK processes, this research provides important implications for potential risks associated with the trophic transfer of MNP mixtures.

Good scientific practice in EEG and MEG research: Progress and perspectives.

Good scientific practice (GSP) refers to both explicit and implicit rules, recommendations, and guidelines that help scientists to produce work that is of the highest quality at any given time, and to efficiently share that work with the community for further scrutiny or utilization. For experimental research using magneto- and electroencephalography (MEEG), GSP includes specific standards and guidelines for technical competence, which are periodically updated and adapted to new findings. However, GSP also needs to be regularly revisited in a broader light. At the LiveMEEG 2020 conference, a reflection on GSP was fostered that included explicitly documented guidelines and technical advances, but also emphasized intangible GSP: a general awareness of personal, organizational, and societal realities and how they can influence MEEG research. This article provides an extensive report on most of the LiveMEEG contributions and new literature, with the additional aim to synthesize ongoing cultural changes in GSP. It first covers GSP with respect to cognitive biases and logical fallacies, pre-registration as a tool to avoid those and other early pitfalls, and a number of resources to enable collaborative and reproducible research as a general approach to minimize misconceptions. Second, it covers GSP with respect to data acquisition, analysis, reporting, and sharing, including new tools and frameworks to support collaborative work. Finally, GSP is considered in light of ethical implications of MEEG research and the resulting responsibility that scientists have to engage with societal challenges. Considering among other things the benefits of peer review and open access at all stages, the need to coordinate larger international projects, the complexity of MEEG subject matter, and today's prioritization of fairness, privacy, and the environment, we find that current GSP tends to favor collective and cooperative work, for both scientific and for societal reasons.

ZZS similarity tool: The online tool for similarity screening to identify chemicals of potential concern.

Screening and prioritization of chemicals is essential to ensure that available evaluation capacity is invested in those substances that are of highest concern. We, therefore, recently developed structural similarity models that evaluate the structural similarity of substances with unknown properties to known Substances of Very High Concern (SVHC), which could be an indication of comparable effects. In the current study the performance of these models is improved by (1) separating known SVHCs in more specific subgroups, (2) (re-)optimizing similarity models for the various SVHC-subgroups, and (3) improving interpretability of the predicted outcomes by providing a confidence score. The improvements are directly incorporated in a freely accessible web-based tool, named the ZZS similarity tool: https://rvszoeksysteem.rivm.nl/ZzsSimilarityTool. Accordingly, this tool can be used by risk assessors, academia and industrial partners to screen and prioritize chemicals for further action and evaluation within varying frameworks, and could support the identification of tomorrow's substances of concern.

The Road to Achieving the European Commission's Chemicals Strategy for Nanomaterial Sustainability-A PATROLS Perspective on New Approach Methodologies.

The European Green Deal outlines ambitions to build a more sustainable, climate neutral, and circular economy by 2050. To achieve this, the European Commission has published the Chemicals Strategy for Sustainability: Towards a Toxic-Free Environment, which provides targets for innovation to better protect human and environmental health, including challenges posed by hazardous chemicals and animal testing. The European project PATROLS (Physiologically Anchored Tools for Realistic nanOmateriaL hazard aSsessment) has addressed multiple aspects of the Chemicals Strategy for Sustainability by establishing a battery of new approach methodologies, including physiologically anchored human and environmental hazard assessment tools to evaluate the safety of engineered nanomaterials. PATROLS has delivered and improved innovative tools to support regulatory decision-making processes. These tools also support the need for reducing regulated vertebrate animal testing; when used at an early stage of the innovation pipeline, the PATROLS tools facilitate the safe and sustainable development of new nano-enabled products before they reach the market.

Predicted Adsorption Affinity for Enteric Microbial Metabolites to Metal and Carbon Nanomaterials.

Ingested nanomaterials are exposed to many metabolites that are produced, modified, or regulated by members of the enteric microbiota. The adsorption of these metabolites potentially affects the identity, fate, and biodistribution of nanomaterials passing the gastrointestinal tract. Here, we explore these interactions using in silico methods, focusing on a concise overview of 170 unique enteric microbial metabolites which we compiled from the literature. First, we construct quantitative structure-activity relationship (QSAR) models to predict their adsorption affinity to 13 metal nanomaterials, 5 carbon nanotubes, and 1 fullerene. The models could be applied to predict log k values for 60 metabolites and were particularly applicable to 'phenolic, benzoyl and phenyl derivatives', 'tryptophan precursors and metabolites', 'short-chain fatty acids', and 'choline metabolites'. The correlations of these predictions to biological surface adsorption index descriptors indicated that hydrophobicity-driven interactions contribute most to the overall adsorption affinity, while hydrogen-bond interactions and polarity/polarizability-driven interactions differentiate the affinity to metal and carbon nanomaterials. Next, we use molecular dynamics (MD) simulations to obtain direct molecular information for a selection of vitamins that could not be assessed quantitatively using QSAR models. This showed how large and flexible metabolites can gain stability on the nanomaterial surface via conformational changes. Additionally, unconstrained MD simulations provided excellent support for the main interaction types identified by QSAR analysis. Combined, these results enable assessing the adsorption affinity for many enteric microbial metabolites quantitatively and support the qualitative assessment of an even larger set of complex and biologically relevant microbial metabolites to carbon and metal nanomaterials.

Review and Prospects on the Ecotoxicity of Mixtures of Nanoparticles and Hybrid Nanomaterials.

The rapid development of nanomaterials (NMs) and the emergence of new multicomponent NMs will inevitably lead to simultaneous exposure of organisms to multiple engineered nanoparticles (ENPs) at varying exposure levels. Understanding the joint impacts of multiple ENPs and predicting the toxicity of mixtures of ENPs are therefore evidently of importance. We reviewed the toxicity of mixtures of ENPs to a variety of different species, covering algae, bacteria, daphnia, fish, fungi, insects, and plants. Most studies used the independent-action (IA)-based model to assess the type of joint effects. Using co-occurrence networks, it was revealed that 53% of the cases with specific joint response showed antagonistic, 25% synergistic, and 22% additive effects. The combination of nCuO and nZnO exhibited the strongest interactions in each type of joint interaction. Compared with other species, plants exposed to multiple ENPs were more likely to experience antagonistic effects. The main factors influencing the joint response type of the mixtures were (1) the chemical composition of individual components in mixtures, (2) the stability of suspensions of mixed ENPs, (3) the type and trophic level of the individual organisms tested, (4) the biological level of organization (population, communities, ecosystems), (5) the exposure concentrations and time, (6) the endpoint of toxicity, and (7) the abiotic field conditions (e.g., pH, ionic strength, natural organic matter). This knowledge is critical in developing efficient strategies for the assessment of the hazards induced by combined exposure to multiple ENPs in complex environments. In addition, this knowledge of the joint effects of multiple ENPs assists in the effective prediction of hybrid NMs.

Applicability of nanomaterial-specific guidelines within long-term Daphnia magna toxicity assays: A case study on multigenerational effects of nTiO2 and nCeO2 exposure in the presence of artificial daylight.

In recent years, various ecotoxicological test guidelines and (technical) guidance documents have been evaluated and updated with regard to their applicability to nanomaterials (NMs). Several of these have currently reached official regulatory status. Ensuring their harmonized implementation with previously recognized methods for ecotoxicity testing of chemicals is a crucial next step towards effective and efficient regulation of NMs. In the present study, we evaluated the feasibility of assessing multigenerational effects in the first generation of offspring derived from exposed Daphnia magna whilst maintaining test conditions in accordance with regulatory test guidelines and guidance documents for NMs. To do so, we integrated the recommendations for ecotoxicological testing of NMs as defined in OECD Guidance Document 317 into an extended long-term D. magna reproduction test method (OECD Test Guideline 211) and assessed effects of two poorly soluble NMs (nTiO2 and nCeO2). Our results show adverse effects on life-history parameters of D. magna exposed to the selected nanomaterials within the range of reported environmental concentrations. We argue that conforming to OECD test guidelines and accompanying guidance for nanomaterials is feasible when performing D. magna reproduction tests and can minimize unnecessary duplication of similar experiments, even when extensions to the standardized test setup are added.

Endobronchial Intubation to Facilitate Extraluminal Bronchial Blocker Placement in Young Children: A Retrospective Case Series.

OBJECTIVES: Extraluminal bronchial blocker placement has become a well-accepted approach to one-lung ventilation in young children. In some cases, technical issues with placement may require alternative approaches to correct bronchial blocker positioning. The primary aim of this study was to review the authors' experience with using endobronchial intubation to facilitate extraluminal bronchial blocker placement in young children. DESIGN: Single-center case series of pediatric patients undergoing thoracic surgery and one-lung ventilation using a bronchial blocker. SETTING: Tertiary academic medical center. PARTICIPANTS: Pediatric patients < three years of age undergoing thoracic surgery and one-lung ventilation who underwent bronchial blocker placement using endobronchial intubation to facilitate blocker placement. In all patients, the bronchial blocker was inserted through a selectively mainstemmed endotracheal tube to facilitate blocker positioning. INTERVENTIONS: No interventions were performed. MEASUREMENTS AND MAIN RESULTS: Fifteen patients were identified after a query of the local electronic health record. There were five right-sided and ten left-sided placements in this cohort. Bronchial blocker placement was successful in 14 of 15 patients using endobronchial intubation to facilitate bronchial blocker placement. In one patient, the bronchial blocker was discovered in the nonsurgical bronchus, following placement with this technique. The bronchial blocker was repositioned manually into the desired mainstem bronchus prior to lateral positioning. CONCLUSIONS: Mainstem intubation can be used to facilitate bronchial blocker placement in young children and represents an alternative approach to extraluminal bronchial blocker placement.

Microbiota-dependent TLR2 signaling reduces silver nanoparticle toxicity to zebrafish larvae.

Many host-microbiota interactions depend on the recognition of microbial constituents by toll-like receptors of the host. The impacts of these interactions on host health can shape the hosts response to environmental pollutants such as nanomaterials. Here, we assess the role of toll-like receptor 2 (TLR2) signaling in the protective effects of colonizing microbiota against silver nanoparticle (nAg) toxicity to zebrafish larvae. Zebrafish larvae were exposed to nAg for two days, from 3 to 5 days post-fertilization. Using an il1ß-reporter line, we first characterized the accumulation and particle-specific inflammatory effects of nAg in the total body and intestinal tissues of the larvae. This showed that silver gradually accumulated in both the total body and intestinal tissues, yet specifically caused particle-specific inflammation on the skin of larvae. Subsequently, we assessed the effects of microbiota-dependent TLR2 signaling on nAg toxicity. This was done by comparing the sensitivity of loss-of-function zebrafish mutants for TLR2, and each of the TLR2-adaptor proteins MyD88 and TIRAP (Mal), under germ-free and microbially-colonized conditions. Irrespective of their genotype, microbially-colonized larvae were less sensitive to nAg than their germ-free siblings, supporting the previously identified protective effect of microbiota against nAg toxicity. Under germ-free conditions, tlr2, myd88 and tirap mutants were equally sensitive to nAg as their wildtype siblings. However, when colonized by microbiota, tlr2 and tirap mutants were more sensitive to nAg than their wildtype siblings. The sensitivity of microbially-colonized myd88 mutants did not differ significantly from that of wildtype siblings. These results indicate that the protective effect of colonizing microbiota against nAg-toxicity to zebrafish larvae involves TIRAP-dependent TLR2 signaling. Overall, this supports the conclusion that host-microbiota interactions affect nanomaterial toxicity to zebrafish larvae.

Correlation analysis of single- and multigenerational endpoints in Daphnia magna toxicity tests: A case-study using TiO2 nanoparticles.

Multigenerational toxicity tests provide more sensitive measures of population-level effects than conventional single-generation tests. Particularly for stressors which exhibit slow uptake rates (e.g. nanomaterials), multigenerational tests may also provide a more realistic representation of natural exposure scenarios. To date, the inherently high costs and labor intensity have however limited the use of multigenerational toxicity tests and thereby their incorporation in environmental risk assessment. The aim of the present study was therefore to determine to what extent short(er) term endpoints which are conventionally measured in Daphnia magna toxicity tests hold predictive capacity towards reproduction measured over longer timescales, including multiple generations. To assess this, a case-study was performed in which effects of TiO2 nanoparticles (0, 0.02, 0.2, 2 and 5 mg L-1) on D. magna life-history traits were assessed over five generations. Additionally, it was determined whether offspring derived from exposed parents exhibited sustained adverse effects when rearing them in clean (non-exposed) media after each generation of exposure. The present study showed that although various life-history traits correlate with the total reproductive output in the same- and subsequent generation under non-exposed conditions, these correlations were decoupled in presence of exposure to nTiO2. In addition, it was found that nTiO2 can induce adverse effects on population relevant endpoints at concentrations 1-2 orders of magnitude lower than previously found (i.e. 0.02 mg L-1), and close to the range of concentrations occurring in natural freshwater ecosystems.

Trophic transfer of Cu nanoparticles in a simulated aquatic food chain.

The goal of the current study was to quantify the trophic transfer of copper nanoparticles (CuNPs) in a food chain consisting of the microalga Pseudokirchneriella subcapitata as the representative of primary producer, the grazer Daphnia magna, and the omnivorous mysid Limnomysis benedeni. To quantify the size and number concentration of CuNPs in the biota, tissue extraction with tetramethylammonium hydroxide (TMAH) was performed and quantification was done by single particle inductively coupled plasma mass spectrometry (sp-ICP-MS). The bioconcentration factor (BCF) of the test species for CuNPs varied between 102 - 103 L/kg dry weight when expressing the internal concentration on a mass basis, which was lower than BCF values reported for Cu2+ (103 - 104 L/kg dry weight). The particle size of CuNPs determined by sp-ICP-MS ranged from 22 to 40 nm in the species. No significant changes in the particle size were measured throughout the food chain. Moreover, the measured number of CuNPs in each trophic level was in the order of 1013 particles/kg wet weight. The calculated trophic transfer factor (mass concentration basis) was > 1. This indicates biomagnification of particulate Cu from P. subcapitata to L. benedeni. It was also found that the uptake of particulate Cu (based on the particle number concentration) was mainly from the dietary route rather than from direct aqueous exposure. Furthermore, dietary exposure to CuNPs had a significant effect on the feeding rate of mysid during their transfer from daphnia to mysid and from alga through daphnia to mysid. This work emphasizes the importance of tracing the particulate fraction of metal-based engineered nanoparticles when studying their uptake and trophic transfer.

Pelvic organ prolapse and anal incontinence in women: screening with a validated epidemiology survey.

PURPOSE: The primary objective of this study was to determine the prevalence of pelvic organ prolapse (POP) and anal incontinence (AI) in a Minnesota population using the Epidemiology of Prolapse and Incontinence Questionnaire (EPIQ). The secondary objective of this study was to determine the association of POP and AI with parity, age, smoking status, body mass index (BMI), and co-morbidities. METHODS: Women ≥ 18 years old attending the 2018 Minnesota State Fair were asked to fill out a web-based version of the EPIQ. Multivariable logistic regression models were used to investigate the association of POP and AI with the variables of interest. RESULTS: A total of 1426 women were included in the analysis. There was a 4.9% prevalence of POP and 14.9% prevalence of AI. POP was significantly associated with parity and higher BMI (p < 0.01 and p = 0.02, respectively). In this cohort, POP was not associated with older age, smoking, or presence of co-morbid conditions. Anal incontinence was associated with older age (p < 0.01), smoking status (p = 0.01), and presence of co-morbid conditions (p = 0.01) but was not associated with parity or higher BMI. CONCLUSION: POP and AI were associated with some, but not all, of the variables tested, which differs from prior studies. In addition, the prevalence of POP and AI were different than rates reported in similar studies. This may suggest regional differences in prevalence of POP and AI.

Prediction of the Joint Toxicity of Multiple Engineered Nanoparticles: The Integration of Classic Mixture Models and In Silico Methods.

An approach to solve the emerging need of prediction of the toxicity of mixtures of engineered nanoparticles (ENPs) is presented. The integration of classic approaches to mixture toxicity assessment and computational toxicology approaches is proposed to be a smart strategy for forecasting the toxicity of a mixture of ENPs.

Trophic Transfer and Toxicity of (Mixtures of) Ag and TiO2 Nanoparticles in the Lettuce-Terrestrial Snail Food Chain.

The increasing application of biosolids and agrochemicals containing silver nanoparticles (AgNPs) and titanium dioxide nanoparticles (TiO2NPs) results in their inevitable accumulation in soil, with unknown implications along terrestrial food chains. Here, the trophic transfer of single NPs and a mixture of AgNPs and TiO2NPs from lettuce to snails and their associated impacts on snails were investigated. Both AgNPs and TiO2NPs were transferred from lettuce to snails with trophic transfer factors (defined as the ratio of the Ag/Ti concentration in snail tissues to the Ag/Ti concentration in lettuce leaves) of 0.2-1.1 for Ag and 3.8-47 for Ti. Moreover, the majority of Ag captured by snails in the AgNP-containing treatments was excreted via feces, whereas more than 70% of Ti was distributed in the digestive gland of snails in the TiO2NP-containing treatments. Additionally, AgNP-containing treatments significantly inhibited the activity of snails, while TiO2NP-containing treatments significantly reduced feces excretion of snails. Furthermore, the concurrent application of AgNPs and TiO2NPs did not affect the biomagnification and distribution patterns of Ag and Ti in snails, whereas their co-existence exhibited more severe inhibition of the growth and activity of snails than in the case of applying AgNPs or TiO2NPs alone. This highlights the possibility of nanoparticle transfer to organisms of higher trophic levels via food chains and the associated risks to ecosystem health.

Current understanding of and emerging treatment options for spinal muscular atrophy with respiratory distress type 1 (SMARD1).

Spinal muscular atrophy (SMA) with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease that is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, infants with the severe form of the disease die before 2 years of age. SMARD1 is caused by mutations in the IGHMBP2 gene that determine a deficiency in the encoded IGHMBP2 protein, which plays a critical role in motor neuron survival because of its functions in mRNA processing and maturation. Although it is rare, SMARD1 is the second most common motor neuron disease of infancy, and currently, treatment is primarily supportive. No effective therapy is available for this devastating disease, although multidisciplinary care has been an essential element of the improved quality of life and life span extension in these patients in recent years. The objectives of this review are to discuss the current understanding of SMARD1 through a summary of the presently known information regarding its clinical presentation and pathogenesis and to discuss emerging therapeutic approaches. Advances in clinical care management have significantly extended the lives of individuals affected by SMARD1 and research into the molecular mechanisms that lead to the disease has identified potential strategies for intervention that target the underlying causes of SMARD1. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to halt or possibly prevent neurodegenerative disease in SMARD1 patients. The recent approval of the first gene therapy approach for SMA associated with mutations in the SMN1 gene may be a turning point for the application of this strategy for SMARD1 and other genetic neurological diseases.

Evaluating chemical similarity as a measure to identify potential substances of very high concern.

Due to the large amount of chemical substances on the market, fast and reproducible screening is essential to prioritize chemicals for further evaluation according to highest concern. We here evaluate the performance of structural similarity models that are developed to identify potential substances of very high concern (SVHC) based on structural similarity to known SVHCs. These models were developed following a systematic analysis of the performance of 112 different similarity measures for varying SVHC-subgroups. The final models consist of the best combinations of fingerprint, similarity coefficient and similarity threshold, and suggested a high predictive performance (≥80%) on an internal dataset consisting of SVHC and non-SVHC substances. However, the application performance on an external dataset was not evaluated. Here, we evaluated the application performance of the developed similarity models with a 'pseudo-external assessment' on a set of substances (n = 60-100 for the varying SVHC-subgroups) that were putatively assessed as SVHC or non-SVHC based upon consensus scoring using expert elicitations (n = 30 experts). Expert scores were direct evaluations based on structural similarity to the most similar SVHCs according to the similarity models, and did not consider an extensive evaluation of available data. The use of expert opinions is particularly suitable as this is exactly the intended purpose of the chemical similarity models: a quick, reproducible and automated screening tool that mimics the expert judgement that is frequently applied in various screening applications. In addition, model predictions were analyzed via qualitative approaches and discussed via specific examples, to identify the model's strengths and limitations. The results indicate a good statistical performance for carcinogenic, mutagenic or reprotoxic (CMR) and endocrine disrupting (ED) substances, whereas a moderate performance was observed for (very) persistent, (very) bioaccumulative and toxic (PBT/vPvB) substances when compared to expert opinions. For the PBT/vPvB model, particularly false positive substances were identified, indicating the necessity of outcome interpretation. The developed similarity models are made available as a freely-accessible online tool. In general, the structural similarity models showed great potential for screening and prioritization purposes. The models proved to be effective in identifying groups of substances of potential concern, and could be used to identify follow-up directions for substances of potential concern.

A Retrospective Evaluation of Airway Anatomy in Young Children and Implications for One-Lung Ventilation.

OBJECTIVE: One-lung ventilation (OLV) in children remains a niche practice with few studies to guide best practices. The objective of this study was to describe lower airway anatomy relevant to establishment of OLV in young children. DESIGN: Retrospective, observational study using pre-existing studies in the electronic health record. SETTING: Single institution, academic medical center, tertiary-care hospital. PARTICIPANTS: Pediatric patients <8 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Chest computed tomographic scans of 111 children 4 days to 8 years of age were reviewed. Measurements were taken from the thyroid isthmus to the carina, carina to first lobar branch on the left and right, diameter of the trachea at the carina, and diameter of the left and right mainstem bronchi. Dimensions were correlated with the outer diameter of endotracheal tubes and bronchial blockers. The left mainstem bronchus is consistently smaller than the right. Lung isolation using a mainstem technique on the left should use an endotracheal tube a half size smaller than would be used for tracheal intubation. The length from the carina to the first lobar branch on the left is consistently 3 times longer than on the right. Further, age-delineated bronchial diameters suggest that the clinician should transition from a 5F to a 7F Arndt bronchial blocker at 3-to-4 years of age. CONCLUSION: A more detailed and accurate understanding of pediatric lower airway anatomy may assist the clinician in successfully performing OLV in young children.