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Spatial frequency domain imaging of 5-aminolevulinic acid induced protoporphyrin IX was used to recover absorption, scattering, and fluorescence properties of glioblastoma multiforme in tissue-simulating phantoms and in vivo in a mouse model. © 2012.

Longitudinal cohort study. [ABSTRACT FROM AUTHOR]

It has long been recognized that skin sensitizers either are electrophilic or can be activated to electrophilic species. Several nonanimal assays for skin sensitization are based on this premise. In the course of a project to update dermal sensitization thresholds (DST), we found a substantial number of sensitizers, with no electrophilic or pro-electrophilic alerts, that could be simply explained in terms of the sensitizer acting as a nucleophile. In some cases, the nucleophilic center is a sulfur or phosphorus atom, while in others, it is an aromatic carbon atom. For carbon-centered nucleophiles, a quantitative mechanistic model based on a combination of Hammett σ + and logP values has been derived. This has been applied to rationalize several groups of known sensitizers with no electrophilic or pro-electrophilic alerts, including anacardic acids and cardols, which are known human sensitizers associated with, inter alia, cashew nut oil, mango, and Ginkgo biloba . The possibility of nucleophilic sensitization needs to be considered when evaluating new chemicals for skin sensitization potential and potency by nonanimal assays, particularly those based on the premise that skin sensitization is dependent upon reactions of electrophiles with skin protein-based nucleophiles.

Significance: ALA-PpIX and second-window indocyanine green (ICG) have been studied widely for guiding the resection of high-grade gliomas. These agents have different mechanisms of action and uptake characteristics, which can affect their performance as surgical guidance agents. Elucidating these differences in animal models that approach the size and anatomy of the human brain would help guide the use of these agents. Herein, we report on the use of a new pig glioma model and fluorescence cryotomography to evaluate the 3D distributions of both agents throughout the whole brain., Aim: We aim to assess and compare the 3D spatial distributions of ALA-PpIX and second-window ICG in a glioma-bearing pig brain using fluorescence cryotomography., Approach: A glioma was induced in the brain of a transgenic Oncopig via adeno-associated virus delivery of Cre-recombinase plasmids. After tumor induction, the pro-drug 5-ALA and ICG were administered to the animal 3 and 24 h prior to brain harvest, respectively. The harvested brain was imaged using fluorescence cryotomography. The fluorescence distributions of both agents were evaluated in 3D in the whole brain using various spatial distribution and contrast performance metrics., Results: Significant differences in the spatial distributions of both agents were observed. Indocyanine green accumulated within the tumor core, whereas ALA-PpIX appeared more toward the tumor periphery. Both ALA-PpIX and second-window ICG provided elevated tumor-to-background contrast (13 and 23, respectively)., Conclusions: This study is the first to demonstrate the use of a new glioma model and large-specimen fluorescence cryotomography to evaluate and compare imaging agent distribution at high resolution in 3D., (© 2024 The Authors.)

Aims: The purpose of reporting on selected cases is to increase the recognition and treatment of mechanical joint dysfunction (restrictions in movement at the joint level) in pediatric patients., Methods: The selected cases demonstrate a variety of clinical outcomes that are possible using manual therapy to improve mechanical joint dysfunction and chronic pain. The techniques used for these patents were performed by a physical therapist without formal manual therapy training to encourage more physical therapists to use manual therapy as an intervention to improve outcomes in pediatric patients., Results: The hands-on treatment used to treat mechanical joint dysfunction improved participation and function in children of various ages with a variety of clinical issues., Conclusions: : Recognizing and treating mechanical joint restrictions that interfere with active movement in children may result in decreased pain and improved motor skills, balance, self-regulation, sleep hygiene, and social interactions. Clinicians should consider manual therapy as an intervention strategy for pediatric patients with mechanical joint restrictions.

Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest form is provided with the online version of the article (http://links.lww.com/JBJS/H747).

The surfactant sodium lauryl sulfate (SLS), although consistently positive in the murine local lymph node assay (LLNA) for skin sensitization, shows no evidence of being a human sensitizer and is often described as a false positive, lacking structural alerts for sensitization. However, there is evidence of the cinnamyl sulfate anion being the metabolite responsible for the sensitization potential of cinnamyl alcohol to humans and in animal tests. Here, manufacturing chemistry data and physical organic chemistry principles are applied to confirm that SLS is not reactive enough to sensitize, whereas sensitization to cinnamyl alcohol via cinnamyl sulfate is plausible. Sensitization data for several other primary alcohols, including geraniol, farnesol, and possibly hydrocortisone, are also consistent with this mechanism. It seems possible that biosulfation may play a wider role than has previously been recognized in skin sensitization.

Background: Several methyl esters of sulphonic acids are listed in murine local lymph node assay (LLNA) databases, with dose-response data and EC3 values. However, some of these entries are questionable-in one case the chemical tested is not the chemical named in the databases and in others the EC3 value has been derived by extrapolation from data that do not meet the applicability criteria for the approved extrapolation method., Objectives: To consider how LLNA data came to be attributed to the wrong chemical and to address the inappropriate extrapolated EC3 values., Methods: Dose-response data for methyl hexadec-3-enesulphonate (wrongly named as methyl hexadec-1-enesulphonate), two other methyl sulphonates and hexadec-1-ene-1,3-sultone are re-evaluated using the single dose probit extrapolation method (SDPEM). The different reaction chemistry profiles of methyl hexadec-3-enesulphonate and methyl hexadec-1-enesulphonate are discussed., Results: Extrapolated EC3 values for hexadec-1-ene-1,3-sultone are the same by both methods but for the methyl sulphonates the differences are substantial., Conclusions: Current databases should be corrected and further analysed to identify other cases where EC3 values are likely to be unreliable due to inappropriate estimation by extrapolation., (© 2023 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

We investigated conidial mass production of eight isolates of six entomopathogenic fungi (EPF), Aphanocladium album (ARSEF 1329), Beauveria bassiana (ARSEF 252 and 3462), Lecanicillium aphanocladii (ARSEF 6433), Metarhizium anisopliae sensu lato (ARSEF 2341), Metarhizium pingshaense (ARSEF 1545), and Simplicillium lanosoniveum (ARSEF 6430 and 6651) on white or brown rice at four moisture conditions (75-100%). The tolerance of mass-produced conidia of the eight fungal isolates to UV-B radiation and heat (45 °C) were also evaluated. For each moisture content compared, a 20-g sample of rice in a polypropylene bag was inoculated with each fungal isolate in three replicates and incubated at 28 ± 1 °C for 14 days. Conidia were then harvested by washing the substrate, and conidial concentrations determined by haemocytometer counts. Conidial suspensions were inoculated on PDAY with 0.002% benomyl in Petri plates and exposed to 978 mW m -2 of Quaite-weighted UV-B for 2 h. Additionally, conidial suspensions were exposed to 45 °C for 3 h, and aliquots inoculated on PDAY with benomyl. The plates were incubated at 28 ± 1 °C, and germination was assessed at 400 × magnification after 48 h. Conidial production was generally higher on white rice than on brown rice for all fungal species, except for L. aphanocladii ARSEF 6433, regardless of moisture combinations. The 100% moisture condition provided higher conidial production for B. bassiana (ARSEF 252 and ARSEF 3462) and M. anisopliae (ARSEF 2341) isolates, while the addition of 10% peanut oil enhanced conidial yield for S. lanosoniveum isolate ARSEF 6430. B. bassiana ARSEF 3462 on white rice with 100% water yielded the highest conidial production (approximately 1.3 × 10 10 conidia g -1 of substrate). Conidia produced on white rice with the different moisture conditions did not differ in tolerance to UV-B radiation or heat. However, high tolerance to UV-B radiation and heat was observed for B. bassiana, M. anisopliae, and A. album isolates. Heat-treated conidia of S. lanosoniveum and L. aphanocladii did not germinate., (Copyright © 2023 British Mycological Society. Published by Elsevier Ltd. All rights reserved.)

A 12-year-old girl developed a distal femoral shaft fracture treated with lateral trochanteric entry intramedullary nail fixation. The nail was retained after union because of a persistent nonossifying fibroma at the previous fracture site. At 16 months after surgery, marked valgus deformity was noted at the distal femur, with signs of implant haloing and loosening, suggesting repetitive motion and stress concentration of forces at the distal femur. Owing to recognition before skeletal maturity, the valgus was corrected with hemiepiphysiodesis. This finding illustrates the importance of follow-up up to skeletal maturity for pediatric femoral shaft fractures and consideration of routine removal of implants after fracture union to avoid this previously unreported complication., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Climate's effect on global biodiversity is typically viewed through the lens of temperature, humidity and resulting ecosystem productivity 1-6 . However, it is not known whether biodiversity depends solely on these climate conditions, or whether the size and fragmentation of these climates are also crucial. Here we shift the common perspective in global biodiversity studies, transitioning from geographic space to a climate-defined multidimensional space. Our findings suggest that larger and more isolated climate conditions tend to harbour higher diversity and species turnover among terrestrial tetrapods, encompassing more than 30,000 species. By considering both the characteristics of climate itself and its geographic attributes, we can explain almost 90% of the variation in global species richness. Half of the explanatory power (45%) may be attributed either to climate itself or to the geography of climate, suggesting a nuanced interplay between them. Our work evolves the conventional idea that larger climate regions, such as the tropics, host more species primarily because of their size 7,8 . Instead, we underscore the integral roles of both the geographic extent and degree of isolation of climates. This refined understanding presents a more intricate picture of biodiversity distribution, which can guide our approach to biodiversity conservation in an ever-changing world., (© 2023. The Author(s).)

Little is known about the impact of hypoxia and anoxia during mycelial growth on tolerance to different stress conditions of developing fungal conidia. Conidia of the insect-pathogenic fungus Metarhizium robertsii were produced on potato dextrose agar (PDA) medium under normoxia (control = normal oxygen concentrations), continuous hypoxia, and transient anoxia, as well as minimal medium under normoxia. The tolerance of the conidia produced under these different conditions was evaluated in relation to wet heat (heat stress), menadione (oxidative stress), potassium chloride (osmotic stress), UV radiation, and 4-nitroquinoline-1-oxide (=4-NQO genotoxic stress). Growth under hypoxic condition induced higher conidial tolerance of M. robertsii to menadione, KCl, and UV radiation. Transient anoxic condition induced higher conidial tolerance to KCl and UV radiation. Nutritional stress (i.e., minimal medium) induced higher conidial tolerance to heat, menadione, KCl, and UV radiation. However, neither of these treatments induced higher tolerance to 4-NQO. The gene hsp30 and hsp101 encoding a heat shock protein was upregulated under anoxic condition. In conclusion, growth under hypoxia and anoxia produced conidia with higher stress tolerances than conidia produced in normoxic condition. The nutritive stress generated by minimal medium, however, induced much higher stress tolerances. This condition also caused the highest level of gene expression in the hsp30 and hsp101 genes. Thus, the conidia produced under nutritive stress, hypoxia, and anoxia had greater adaptation to stress., Competing Interests: Declaration of competing interest The manuscript has been prepared in accordance with the formatting guidelines for Fungal Biology. The work is not under consideration for publication in any form elsewhere, the manuscript does not infringe any personal or other copyright or property rights, and has been approved for publication by all authors, all of whom declare that they have no conflicting interests., (Copyright © 2023 British Mycological Society. Published by Elsevier Ltd. All rights reserved.)

The local lymph node assay (LLNA) has provided a large dataset against which performance of non-animal approaches for prediction of skin sensitisation potential and potency can be assessed. However, a recent comparison of LLNA results with human data has argued that LLNA specificity is low, with many human non-sensitisers, particularly hydrophobic chemicals, being false positives. It has been suggested that such putative false positives result from hydrophobic chemicals causing cytotoxicity, which induces irritancy, in turn driving non-specific lymphocyte proliferation. This paper finds that the apparent reduced specificity of the LLNA largely reflects differences in definitions of the boundaries between weak skin sensitisers and non-sensitisers. A small number of LLNA false positives may be due to lymphocyte proliferation without skin sensitisation, but most alleged 'false' positives are in fact very weak sensitisers predictable from structure-activity considerations. The evidence does not support the hypothesis for hydrophobicity-induced false positives. Moreover, the mechanistic basis is untenable. Sound LLNA data, appropriately interpreted, remain a good measure of sensitisation potency, applicable across a wide hydrophilicity-hydrophobicity range. The standard data interpretation protocol enables detection of very low levels of sensitisation, irrespective of regulatory significance, but there is scope to interpret the data to give focus on regulatory significance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Structurally similar phytochemical compounds may elicit markedly different skin sensitization responses. Eugenol and isoeugenol are natural phenylpropanoids found in various essential oils are frequently used as fragrance ingredients in consumer products due to their pleasing aromatic properties. Both compounds are also skin sensitizers with isoeugenol being a stronger sensitizer than eugenol. The most commonly accepted mechanisms for haptenation by eugenol involve formation of a quinone methide or an ortho -quinone intermediate. The mechanism for the increased skin response to isoeugenol remains elusive, although quinone methide intermediates have been proposed. The recent identification of diastereomeric 7,4'-oxyneolignans as electrophilic, thiol-depleting isoeugenol derivatives has revived interest in the possible role of elusive reactive intermediates associated with the isoeugenol's haptenation process. In the present work, integrated non-animal skin sensitization methods were performed to determine the ability of syn -7,4'-oxyneolignan to promote haptenation and activation of further molecular pathways in keratinocytes and dendritic cells, confirming it as a candidate skin sensitizer. Kinetic NMR spectroscopic studies using dansyl cysteamine (DCYA) confirmed the first ordered nature of the nucleophilic addition for the syn -7,4'-oxyneolignan. Computational studies reaffirmed the " syn " stereochemistry of the isolated 7,4'-oxyneolignans along with that of their corresponding DCYA adducts and provided evidence for the preferential stereoselectivity. A plausible rationale for isoeugenol's strong skin sensitization is proposed based on the formation of a hydroxy quinone methide as a reactive intermediate rather than the previously assumed quinone methide.

Hyperspectral imaging and spectral analysis quantifies fluorophore concentration during fluorescence-guided surgery 1-6 . However, acquisition of the multiple wavelengths required to implement these methods can be time-consuming and hinder surgical workflow. To this end, a snapshot hyperspectral imaging system capable of acquiring 64 channels of spectral data simultaneously was developed for rapid hyperspectral imaging during neurosurgery. The system uses a birefringent spectral demultiplexer to split incoming light and redirect wavelengths to different sections of a large format microscope sensor. Its configuration achieves high optical throughput, accepts unpolarized input light and exceeds channel count of prior image-replicating imaging spectrometers by 4-fold. Tissue-simulating phantoms consisting of serial dilutions of the fluorescent agent characterize system linearity and sensitivity, and comparisons to performance of a liquid crystal tunable filter based hyperspectral imaging device are favorable. The new instrument showed comparable, if not improved, sensitivity at low fluorophore concentrations; yet, acquired wide-field images at more than 70-fold increase in frame rate. Image data acquired in the operating room during human brain tumor resection confirm these findings. The new device is an important advance in achieving real-time quantitative imaging of fluorophore concentration for guiding surgery., (© 2023. The Author(s).)

Background: Direct cortical stimulation of the mesial frontal premotor cortex, including the supplementary motor area (SMA), is challenging in humans. Limited access to these brain regions impedes understanding of human premotor cortex functional organization and somatotopy., Objective: To test whether seizure onset within the SMA was associated with functional remapping of mesial frontal premotor areas in a cohort of patients with epilepsy who underwent awake brain mapping after implantation of interhemispheric subdural electrodes., Methods: Stimulation trials from 646 interhemispheric subdural electrodes were analyzed and compared between patients who had seizure onset in the SMA (n = 13) vs patients who had seizure onset outside of the SMA (n = 12). 1:1 matching with replacement between SMA and non-SMA data sets was used to ensure similar spatial distribution of electrodes. Centroids and 95% confidence regions were computed for clustered head, trunk, upper extremity, lower extremity, and vision responses. A generalized linear mixed-effects model was used to test for significant differences in the resulting functional maps. Clinical, radiographic, and histopathologic data were reviewed., Results: After analyzing direct cortical stimulation trials from interhemispheric electrodes, we found significant displacement of the head and trunk responses in SMA compared with non-SMA patients ( P < .01 for both). These differences remained significant after accounting for structural lesions, preexisting motor deficits, and seizure outcome., Conclusion: The somatotopy of the mesial frontal premotor regions is significantly altered in patients who have SMA-onset seizures compared with patients who have seizure onset outside of the SMA, suggesting that functional remapping can occur in these brain regions., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Purpose: Increased oxygen levels may enhance the radiosensitivity of brain metastases treated with stereotactic radiosurgery (SRS). This project administered hyperbaric oxygen (HBO) prior to SRS to assess feasibility, safety, and response., Methods: 38 patients were studied, 19 with 25 brain metastases treated with HBO prior to SRS, and 19 historical controls with 27 metastases, matched for histology, GPA, resection status, and lesion size. Outcomes included time from HBO to SRS, quality-of-life (QOL) measures, local control, distant (brain) metastases, radionecrosis, and overall survival., Results: The average time from HBO chamber to SRS beam-on was 8.3 ± 1.7 minutes. Solicited adverse events (AEs) were comparable between HBO and control patients; no grade III or IV serious AEs were observed. Radionecrosis-free survival (RNFS), radionecrosis-free survival before whole-brain radiation therapy (WBRT) (RNBWFS), local recurrence-free survival before WBRT (LRBWFS), distant recurrence-free survival before WBRT (DRBWFS), and overall survival (OS) were not significantly different for HBO patients and controls on Kaplan-Meier analysis, though at 1-year estimated survival rates trended in favor of SRS + HBO: RNFS - 83% vs 60%; RNBWFS - 78% vs 60%; LRBWFS - 95% vs 78%; DRBWFS - 61% vs 57%; and OS - 73% vs 56%. Multivariate Cox models indicated no significant association between HBO treatment and hazards of RN, local or distant recurrence, or mortality; however, these did show statistically significant associations (p < 0.05) for: local recurrence with higher volume, radionecrosis with tumor resection, overall survival with resection, and overall survival with higher GPA., Conclusion: Addition of HBO to SRS for brain metastases is feasible without evident decrement in radiation necrosis and other clinical outcomes., (Copyright © 2022. Published by Elsevier B.V.)

The Dermal Sensitisation Thresholds (DST) are Thresholds of Toxicological Concern, which can be used to justify exposure-based waiving when conducting a skin sensitisation risk assessment. This study aimed to update the published DST values by expanding the size of the Local Lymph Node Assay dataset upon which they are based, whilst assigning chemical reactivity using an in silico expert system (Derek Nexus). The potency values within the expanded dataset fitted a similar gamma distribution to that observed for the original dataset. Derek Nexus was used to classify the sensitisation activity of the 1152 chemicals in the expanded dataset and to predict which chemicals belonged to a High Potency Category (HPC). This two-step classification led to three updated thresholds: a non-reactive DST of 710 μg/cm 2 (based on 79 sensitisers), a reactive (non-HPC) DST of 73 μg/cm 2 (based on 331 sensitisers) and an HPC DST of 1.0 μg/cm 2 (based on 146 sensitisers). Despite the dataset containing twice as many sensitisers, these values are similar to the previously published thresholds, highlighting their robustness and increasing confidence in their use. By classifying reactivity in silico the updated DSTs can be applied within a skin sensitisation risk assessment in a reproducible, scalable and accessible manner., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The direct peptide reactivity assay (DPRA) is an OECD test guideline method that aims to determine if a chemical is reactive enough to be a skin sensitiser. It involves incubation of the test chemical at 5 mMolar concentration for 24 h with a cysteine-based peptide at 0.5 mMolar concentration and measurement of the percentage depletion (DP) of the peptide. The kinetic direct peptide reactivity assay (kDPRA) is derived from the DPRA and involves incubating the peptide with the test chemical at a range of concentrations and incubation times to produce a data matrix of DP values, which is analysed to give a reactivity parameter log k max that assigns chemicals to the 1A potency class (high potency) if log k max reaches the threshold value of -2. Here the DPRA, with a threshold of 47% DP, is compared against the kDPRA for their abilities to distinguish between the 1A and non-1A potency classes. It is found that they perform very similarly against a dataset of 157 chemicals with known potency, with only marginal differences in predictive performance. The thresholds of -2.0 (kDPRA) and 47% DP (DPRA) to distinguish 1A sensitisers are not scientific absolutes but the best compromises for a heterogenous set of data containing classes of chemicals for which different thresholds would be applicable. It is concluded that although the kDPRA represents a major advance towards predicting skin sensitisation potency on a continuous basis without animal testing, it offers no significant advantage over the DPRA for the purpose of 1A classification.

Understanding the reliability and relevance of a toxicological assessment is important for gauging the overall confidence and communicating the degree of uncertainty related to it. The process involved in assessing reliability and relevance is well defined for experimental data. Similar criteria need to be established for in silico predictions, as they become increasingly more important to fill data gaps and need to be reasonably integrated as additional lines of evidence. Thus, in silico assessments could be communicated with greater confidence and in a more harmonized manner. The current work expands on previous definitions of reliability, relevance, and confidence and establishes a conceptional framework to apply those to in silico data. The approach is used in two case studies: 1) phthalic anhydride, where experimental data are readily available and 2) 4-hydroxy-3-propoxybenzaldehyde, a data poor case which relies predominantly on in silico methods, showing that reliability, relevance, and confidence of in silico assessments can be effectively communicated within Integrated approaches to testing and assessment (IATA)., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease in which extraskeletal (heterotopic) bone forms within tissues such as skeletal muscles, often in response to injury. Mutations in the BMP type I receptor ACVR1/ALK2 cause FOP by increasing BMP pathway signaling. In contrast to the growing understanding of the inappropriate formation of bone tissue within the muscle in FOP, much is still unknown about the regenerative capacity of adult diseased muscles. Utilizing an inducible ACVR1 R206H knock-in mouse, we found that injured Acvr1 R206H/+ skeletal muscle tissue regenerates poorly. We demonstrated that while two resident stem cell populations, muscle stem cells (MuSCs) and fibro/adipogenic progenitors (FAPs), have similar proliferation rates after injury, the differentiation potential of mutant MuSCs is compromised. Although MuSC-specific deletion of the ACVR1 R206H mutation does not alter the regenerative potential of skeletal muscles in vivo, Acvr1 R206H/+ MuSCs form underdeveloped fibers that fail to fuse in vitro. We further determined that FAPs from Acvr1 R206H/+ mice repress the MuSC-mediated formation of Acvr1 R206H/+ myotubes in vitro. These results identify a previously unrecognized role for ACVR1 R206H in myogenesis in FOP, via improper interaction of tissue-resident stem cells during skeletal muscle regeneration., (© 2022. The Author(s).)

White light during mycelial growth influences high conidial stress tolerance of the insect-pathogenic fungus Metarhizium robertsii, but little is known if low- or high-white light irradiances induce different stress tolerances. The fungus was grown either in the dark using two culture media: on minimal medium (Czapek medium without sucrose = MM) or on potato dextrose agar (PDA) or PDA medium under five different continuous white light irradiances. The stress tolerances of conidia produced on all treatments were evaluated by conidial germination on PDA supplemented with KCl for osmotic stress or on PDA supplemented with menadione for oxidative stress. Conidia produced on MM in the dark were more tolerant to osmotic and oxidative stress than conidia produced on PDA in the dark or under the light. For osmotic stress, growth under the lower to higher irradiances produced conidia with similar tolerances but more tolerant than conidia produced in the dark. For oxidative stress, conidia produced under the white light irradiances were generally more tolerant to menadione than conidia produced in the dark. Moreover, conidia produced in the dark germinated at the same speed when incubated in the dark or under lower irradiance treatment. However, at higher irradiance, conidial germination was delayed compared to germination in the dark, which germinated faster. Therefore, growth under light from low to high irradiances induces similar conidial higher stress tolerances; however, higher white light irradiances cause a delay in germination speed., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

It is widely recognized that the ability of chemicals to sensitize, and the potency of those chemicals that are sensitizers, is related to their ability to covalently modify protein in the skin. With the object of putting non-animal-based prediction of skin sensitization on a more quantitative footing, a recent paper describes the development of the kinetic Direct Protein Reactivity Assay (kDPRA), in which a matrix of peptide depletion values for different reaction times and test chemical concentrations is generated and analyzed so as to derive a reactivity parameter, log k max , which is used to classify chemicals into one of two potency categories. The present paper demonstrates that the reaction chemistry is not always consistent with the mathematical analysis of the data matrix and the kDPRA protocol does not identify such cases. Consequently the derived log k max value is not always mechanistically meaningful and its application to predict potency can lead to misleading conclusions. It is shown that by adopting a data analysis protocol based on conventional kinetics practice, the kDPRA can be made to provide more reliably meaningful and more extensive information that can be used for purposes such as potency estimation for deriving No Expected Sensitization Induction Level (NESILs) required for quantitative risk assessment (QRA), deriving quality specifications in terms of acceptable impurity levels, and development of structure-activity relationships. Secondly, the paper addresses applicability domain issues, in particular the problem of deciding whether or not the kDPRA is applicable for a given chemical.

The Mormon cricket (MC), Anabrus simplex Haldeman, 1852 (Orthoptera: Tettigoniidae), has a long and negative history with agriculture in Utah and other western states of the USA. Most A. simplex populations migrate in large groups, and their feeding can cause significant damage to forage plants and cultivated crops. Chemical pesticides are often applied, but some settings (e.g. habitats of threatened and endangered species) call for non-chemical control measures. Studies in Africa, South America, and Australia have assessed certain isolates of Metarhizium acridum as very promising pathogens for Orthoptera: Acrididae (locust) biocontrol. In the current study, two isolates of Metarhizium robertsii, one isolate of Metarhizium brunneum, one isolate of Metarhizium guizhouense, and three isolates of M. acridum were tested for infectivity to MC nymphs and adults of either sex. Based on the speed of mortality, M. robertsii (ARSEF 23 and ARSEF 2575) and M. brunneum (ARSEF 7711) were the most virulent to instars 2 to 5 MC nymphs. M. guizhouense (ARSEF 7847) from Arizona was intermediate and the M. acridum isolates (ARSEF 324, 3341, and 3609) were the slowest killers. ARSEF 2575 was also the most virulent to instar 6 and 7 nymphs and adults of MC. All of the isolates at the conidial concentration of 1 × 107 conidia ml-1 induced approximately 100% mortality by 6 days post application of fungal conidia. In conclusion, isolates ARSEF 23, ARSEF 2575, and ARSEF 7711 acted most rapidly to kill MC under laboratory conditions. The M. acridum isolates, however, have much higher tolerance to heat and UV-B radiation, which may be critical to their successful use in field application.

Background: Tumors that take up and metabolize 5-aminolevulinic acid emit bright pink fluorescence when illuminated with blue light, aiding surgeons in identifying the margin of resection. The adoption of this method is hindered by the blue light illumination, which is too dim to safely operate under and therefore necessitates switching back and forth from white-light mode. The aim of this study was to examine the addition of an optimized secondary illuminant adapter to improve usability of blue-light mode without degrading tumor contrast., Methods: Color science methods were used to evaluate the color of the secondary illuminant and its impact on color rendering index as well as the tumor-to-background color contrast in data collected from 7 patients with high-grade gliomas (World Health Organization grade III and IV). A secondary illuminant adapter was built to provide 475-600 nm light the intensity of which can be controlled by the surgeon and was evaluated in 2 additional patients., Results: Secondary illuminant color had opposing effects on color rendering index and tumor-to-background color contrast; providing surgeon control of intensity allows this trade-off to be balanced in real time. Demonstration in 2 high-grade glioma cases confirms this, showing that additional visibility adds value when intensity can be controlled by the surgeon., Conclusions: Addition of a secondary illuminant may mitigate surgeon complaints that the operative field is too dark under the blue light illumination required for 5-aminolevulinic acid fluorescence guidance by providing improved color rendering index without completely sacrificing tumor-to-background color contrast., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hypothesis: The α-sulfo alkyl ester, AES, surfactants are a class of anionic surfactants which have potential for improved sustainable performance in a range of applications, and an important feature is their enhanced tolerance to precipitation in the presence of multivalent counterions. It is proposed that their adsorption properties can be adjusted substantially by changing the length of the shorter alkyl chain, that of the alkanol group in the ester., Experiments: Surface tension and neutron reflectivity have been used to investigate the variation in the adsorption properties with the shorter alkyl chain length (methyl, ethyl and propyl), the impact of NaCl on the adsorption, the tendency to form surface multilayer structures in the presence of AlCl 3 , and the effects of mixing the methyl ester sulfonate with the ethyl and propyl ester sulfonates on the adsorption., Findings: The variations in the critical micelle concentration, CMC, the adsorption isotherms, the saturation adsorption values, and the impact of NaCl illustrate the subtle influence of varying the shorter alkyl chain length of the surfactant. The non-ideal mixing of pairs of AES surfactants with different alkanol group lengths of the ester show that the extent of the non-ideality changes as the difference in the alkanol length increases. The surface multilayer formation observed in the presence of AlCl 3 varies in a complex manner with the length of the short chain and for mixtures of surfactants with different chains lengths., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

There is a large body of information on testing of chemicals for skin sensitization in the murine local lymph node assay (LLNA), in which potency is quantified by the EC3 value, derived from dose-response data. This information finds use in risk assessment and regulatory classification, and also in assessing the performance of non-animal methods. However, some LLNA results are not straightforward to interpret, and in some cases published EC3 values are questionable. These cases usually arise where the dose-response does not show a monotonic increasing pattern but is bell-shaped, or shows a decrease in response with increasing dose over the whole dose range tested. By analogy with a long-recognised phenomenon in guinea pig sensitization, this is referred to as the overload effect. Here a mechanistic rationale is presented to explain the overload effect, and at the same time to explain the production of danger signals even when the sensitizer is non-irritant. Some illustrative examples are presented where the overload effect can lead to misinterpretation of LLNA results, and chemistry-based read-across is applied to reinterpret the data., Competing Interests: The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

The aim of the present study was to analyze ten native Metarhizium spp. isolates as to their UV-B tolerances. Comparisons included: different fungal propagules (conidia, blastospores, or microsclerotia [MS]); conidia in aqueous suspensions or in 10% mineral oil-in-water emulsions; and conidia mixed with different types of soil. The UV-B effect was expressed as the germination of conidia or culturability of blastospores and MS relative to nongerminated propagules. Metarhizium anisopliae LCM S05 exhibited high tolerance as blastospores and/or MS, but not as conidia; LCM S10 and LCM S08 had positive results with MS or conidia but not blastospores. The formulations with 10% mineral oil did not always protect Metarhizium conidia against UV-B. Conidia of LCM S07, LCM S08, and LCM S10 exhibited the best results when in aqueous suspensions, 24 h after UV-B exposure. In general, conidia mixed with soil and exposed to UV-B yielded similar number of colony forming units as conidia from unexposed soil, regardless the soil type. It was not possible to predict which type of propagule would be the most UV-B tolerant for each fungal isolate; in conclusion, many formulations and propagule types should be investigated early in the development of new fungal biocontrol products., (© 2020 Wiley‐VCH GmbH.)

Objective: The efficacy of deep brain stimulation (DBS) depends on accurate placement of electrodes. Although stereotactic frames enable co-registration of image-based surgical planning and the operative field, the accuracy of electrode placement can be degraded by intra-operative brain shift. In this study, we adapted a biomechanical model to estimate whole brain displacements from which we deformed preoperative CT (preCT) to generate an updated CT (uCT) that compensates for brain shift., Methods: We drove the deformation model using displacement data derived from deformation in the frontal cortical surface that occurred during the DBS intervention. We evaluated 15 patients, retrospectively, who underwent bilateral DBS surgery, and assessed the accuracy of uCT in terms of target registration error (TRE) relative to a CT acquired post-placement (postCT). We further divided subjects into large (Group L) and small (Group S) deformation groups based on a TRE threshold of 1.6mm. Anterior commissure (AC), posterior commissure (PC) and pineal gland (PG) were identified on preCT and postCT and used to quantify TREs in preCT and uCT., Results: In the group of large brain deformation, average TREs for uCT were 1.11 ± 0.13 and 1.07 ± 0.38 mm at AC and PC, respectively, compared to 1.85 ± 0.17 and 0.92 ± 0.52 mm for preCT. The model updating approach improved AC localization but did not alter TREs at PC., Conclusion: This preliminary study suggests that our image updating method may compensate for brain shift around surgical targets of importance during DBS surgery, although further investigation is warranted before conclusive evidence will be available., Significance: With further development and evaluation, our model-based image updating method using intraoperative sparse data may compensate for brain shift in DBS surgery efficiently, and have utility in updating targeting coordinates.

Skin sensitization evaluation is a key part of the safety assessment of ingredients in consumer products, which may have skin sensitizing potential. The dermal sensitization threshold (DST) concept, which is based on the concept of the thresholds of toxicological concern, has been proposed for the risk assessment of chemicals to which skin exposure is very low level. There is negligible risk of skin sensitization if a skin exposure level for the substance of interest was below the reactive DST which would protect against 95% of protein-reactive chemicals. For the remaining 5%, the substance with the defined knowledge of chemical structure (i.e., High Potency Category (HPC) rules) needs to be excluded from the application. However, the DST value for HPC chemicals has not yet been proposed. In this study, we calculated the 95th percentile probabilities estimate from distributions of skin sensitization potency data and derived a novel DST for HPC chemicals (HPC DST) of 1.5 μg/cm 2 . This value presents a useful default approach for unidentified substances in ingredients considering, as a worst-case scenario, that the unidentified compound may be a potent skin sensitizer. Finally, we developed a novel risk assessment workflow incorporating the HPC DST along with the previously published DSTs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The assessment of skin sensitization has evolved over the past few years to include in vitro assessments of key events along the adverse outcome pathway and opportunistically capitalize on the strengths of in silico methods to support a weight of evidence assessment without conducting a test in animals. While in silico methods vary greatly in their purpose and format; there is a need to standardize the underlying principles on which such models are developed and to make transparent the implications for the uncertainty in the overall assessment. In this contribution, the relationship between skin sensitization relevant effects, mechanisms, and endpoints are built into a hazard assessment framework. Based on the relevance of the mechanisms and effects as well as the strengths and limitations of the experimental systems used to identify them, rules and principles are defined for deriving skin sensitization in silico assessments. Further, the assignments of reliability and confidence scores that reflect the overall strength of the assessment are discussed. This skin sensitization protocol supports the implementation and acceptance of in silico approaches for the prediction of skin sensitization., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years., Methods: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory., Results: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% ( p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved ( p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators ( p < 0.05, 1-tailed χ 2 )., Conclusions: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low., Clinicaltrialsgov Identifier: NCT00572195., Classification of Evidence: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Fluorescence-guided surgery (FGS) enhances intraoperative visualization of tumors to maximize safe resection, and quantitative fluorescence imaging (qFI) of protoporphyrin IX (PpIX) has provided additional information for guidance during intracranial tumor surgery. Previous developments in fluorescence quantification have demonstrated that the depth of fluorescence signals can be estimated given known optical properties in a lab setting, and now with the work described here that these optical properties can be determined in vivo in human brain tissue in the operating room (OR) during tumor resection procedures. More specifically, we report the first depth estimation of subsurface tumor intraoperatively, achieved with the combination of spatial frequency domain imaging (SFDI) for optical property measurement and red-light excitation of PpIX. We modified a commercial surgical microscope (Zeiss) with a digital light processing module (DLI Austin, TX) to modulate light from a xenon arc lamp to illuminate the field. White-light excitation and a liquid crystal tunable filter (LCTF Verispec) were used to measure diffuse reflectance at discrete wavelengths of 670 nm and 710 nm on a sCMOS camera. An illumination-side filter wheel allowed excitation of PpIX fluorescence at 405 nm and 635 nm, and the LCTF measured fluorescence emissions at 670 nm and 710 nm. Data acquisition and processing generated wide-field images of the depth of PpIX fluorescence within 1 minute in the OR. The ability of the clinical microscope to perform optical property mapping with SFDI and convert these wide-field estimates into images of the depth of fluorescence was tested in tissue simulating phantoms and in vivo during a craniotomy for brain tumor resection. Results indicate that wide-field optical property estimates with SFDI can be combined with depth sensing algorithms to produce maps of the depth of PpIX when exposed to red-light in the OR., Competing Interests: Drs. Roberts, Wilson, and Paulsen have equity in InSight Surgical Technologies LLC., (© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Distance-based ordinations have played a critical role in community ecology for more than half a century, but are still under active development. These methods employ a matrix of pairwise distances or dissimilarities between sample units, and map sample units from the high-dimensional distance or dissimilarity space to a low-dimensional representation for analysis. Distance- or dissimilarity-based methods employ continuum or gradient ecological theory and a variety of statistical models to achieve the mapping. Recently, ecologists have developed model-based ordinations based on latent vectors and individual species response models. These methods employ the individualistic perspective of Gleason as the ecological model, and Bayesian or maximum-likelihood methods to estimate the parameters for the low dimensional space represented by the latent vectors. In this research I compared two distance-based methods (NMDS and t-SNE) with two model-based methods (BORAL and REO) on five data sets to determine which methods are superior for (1) extracting meaningful ecological drivers of variability in community composition, and (2) estimating sample unit locations in ordination space that maximize the goodness-of-fit of individual species response models to the estimated sample unit locations. Environmental variables and species were fitted to the ordinations by generalized additive models (GAMs) with Gaussian, negative binomial, or Poisson distribution models as appropriate. Across the five data sets, 22 models of environmental variability and 449 models of species distributions were calculated for each of the ordination methods. To minimize the effects of stochasticity the entire analysis was replicated three times and results averaged across the replicates. Results were evaluated by deviance explained and AIC for environmental variables and species distributions, averaged by ordination method for each data set, and ranked from best to worst. For the four assessments distance-based methods ranked 1 and 2 in three cases, and 1 and 3 in one case, significantly out performing the model-based methods. t-SNE was the top-performing method, out performing NMDS especially on the more complex data sets. In general the gradient-based theoretical basis and data sufficiency of distance-based methods allowed distance-based methods to outperform model-based methods in every assessment., (© 2019 by the Ecological Society of America.)

Acetaminophen liver injury is the most common cause of acute liver injury in the United States and several other countries. Diagnosis of acetaminophen-induced acute liver injury in the clinic is challenging due to the lack of validated and specific biomarkers. The following chapter provides an overview of recent advances evaluating candidate biomarkers in development for acetaminophen acute liver injury. Relationships of biomarkers to mechanisms of acetaminophen toxicity and their potential role in confirming the diagnosis and/or predicting evolving toxicity are addressed., (© 2020 Elsevier Inc. All rights reserved.)

Variability in ecological community composition is often analyzed by recording the presence or abundance of taxa in sample units, calculating a symmetric matrix of pairwise distances or dissimilarities among sample units and then mapping the resulting matrix to a low-dimensional representation through methods collectively called ordination. Unconstrained ordination only uses taxon composition data, without any environmental or experimental covariates, to infer latent compositional gradients associated with the sampling units. Commonly, such distance-based methods have been used for ordination, but recently there has been a shift toward model-based approaches. Model-based unconstrained ordinations are commonly formulated using a Bayesian latent factor model that permits uncertainty assessment for parameters, including the latent factors that correspond to gradients in community composition. While model-based methods have the additional benefit of addressing uncertainty in the estimated gradients, typically the current practice is to report point estimates without summarizing uncertainty. To demonstrate the uncertainty present in model-based unconstrained ordination, the well-known spider and dune data sets were analyzed and shown to have large uncertainty in the ordination projections. Hence to understand the factors that contribute to the uncertainty, simulation studies were conducted to assess the impact of additional sampling units or species to help inform future ordination studies that seek to minimize variability in the latent factors. Accurate reporting of uncertainty is an important part of transparency in the scientific process; thus, a model-based approach that accounts for uncertainty is valuable. An R package, UncertainOrd, contains visualization tools that accurately represent estimates of the gradients in community composition in the presence of uncertainty., Competing Interests: None declared., (© 2019 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Most solid cancers are treated by surgical resections to reduce the burden of disease. Surgeons often face the challenge of detecting small areas of residual neoplasm after resection or finding small primary tumors for the initial resection. Intraoperative molecular imaging (IMI) is an emerging technology with the potential to dramatically improve cancer surgery operations by allowing surgeons to better visualize areas of neoplasm using fluorescence imaging. Over the last two years, two molecular optical contrast agents received U.S. Food and Drug Administration approval, and several more drugs are now on the horizon. Thus a conference was organized at the University of Pennsylvania to bring together oncologic surgeons from different specialties to discuss the current clinical status of IMI trials with a specific focus on phase 2 and phase 3 studies. In addition, phase 1 and experimental trials were also discussed briefly, to highlight other novel techniques. Our review summarizes the discussions from the conference and delves into the types of cancers discussed, different contrast agents in human trials, and the clinical value being studied.

The ester sulfonate anionic surfactants are a potentially valuable class of sustainable surfactants. The micellar growth, associated rheological changes, and the onset of precipitation are important consequences of the addition of electrolyte and especially multi-valent electrolytes in anionic surfactants. Small angle neutron scattering, SANS, has been used to investigate the self-assembly and the impact of different valence electrolytes on the self-assembly of a range of ester sulfonate surfactants with subtly different molecular structures. The results show that in the absence of electrolyte small globular micelles form, and in the presence of NaCl, and AlCl 3 relatively modest micellar growth occurs before the onset of precipitation. The micellar growth is more pronounced for the longer unbranched and branched alkyl chain lengths. Whereas changing the headgroup geometry from methyl ester to ethyl ester has in general a less profound impact. The study highlights the importance of relative counterion binding strengths and shows how the surfactant structure affects the counterion binding and hence the micelle structure. The results have important consequences for the response of such surfactants to different operational environments., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The molecular initiating event for many mechanisms of toxicological action comprise the reactive, covalent binding between an exogenous electrophile and an endogenous nucleophile. The target sites for electrophiles are typically peptides, proteins, enzymes or DNA. Of these, the formation of covalent adducts with proteins and DNA are perhaps the most established as they are most closely associated with skin sensitisation and genotoxicity endpoints. As such, being able to identify electrophilic features within a chemical structure provides a starting point to characterise its reactivity profile. There are a number of software tools that have been developed to help identify structural features indicative of electrophilic reactive potential to address various purposes, including: 1) to facilitate category formation for read-across of toxicity effects such as skin sensitisation potential, as well as 2) to profile substances to identify potential confounding factors to rationalise their activity in high-throughput screening (HTS) assays. Here, three such schemes that have been published in the literature as collections of SMARTS patterns and their associated chemical-biological reaction domains have been compared. The goals are 1) to better understand their scope and coverage, and 2) to assess their performance relative to a published skin sensitisation dataset where manual annotations to assign likely mechanistic domains based on expert judgement were already available. The 3 schemes were then applied to the Tox21 library and the consensus outcome was reported to highlight the proportion of chemicals likely to exhibit a reactivity response, specific to a mechanistic reaction domain, but non-specific with respect to target-tissue based activity. ToxPrint fingerprints were computed and activity enrichments computed to compare the structural features identified for the skin sensitisation dataset and Tox21 chemicals for each 'consensus' reaction domain. Enriched ToxPrints were also used to identify ToxCast assays potentially informative for reactivity., Competing Interests: Conflict of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Background: Surgery for gliomas is often confounded by difficulties in distinguishing tumor from surrounding normal brain. For better discrimination, intraoperative optical imaging methods using fluorescent dyes are currently being explored. Understandably, such methods require the demonstration of a high degree of diagnostic accuracy and clinical benefit. Currently, clinical utility is determined by tissue biopsies which are correlated to optical signals, and quantified using measures such as sensitivity, specificity, positive predictive values, and negative predictive values. In addition, surgical outcomes, such as extent of resection rates and/or survival (progression-free survival (PFS) and overall survival (OS)) have been measured. These assessments, however, potentially involve multiple biases and confounders, which have to be minimized to ensure reproducibility, generalizability and comparability of test results. Test should aim at having a high internal and external validity. The objective of this article is to analyze how diagnostic accuracy and outcomes are utilized in available studies describing intraoperative imaging and furthermore, to derive recommendations for reliable and reproducible evaluations., Methods: A review of the literature was performed for assessing the use of measures of diagnostic accuracy and outcomes of intraoperative optical imaging methods. From these data, we derive recommendations for designing and reporting future studies., Results: Available literature indicates that potential confounders and biases for reporting the diagnostic accuracy and usefulness of intraoperative optical imaging methods are seldom accounted for. Furthermore, methods for bias reduction are rarely used nor reported., Conclusions: Detailed, transparent, and uniform reporting on diagnostic accuracy of intraoperative imaging methods is necessary. In the absence of such reporting, studies will not be comparable or reproducible. Future studies should consider some of the recommendations given here.