COATI: Multimodal Contrastive Pretraining for Representing and Traversing Chemical Space.

Creating a successful small molecule drug is a challenging multiparameter optimization problem in an effectively infinite space of possible molecules. Generative models have emerged as powerful tools for traversing data manifolds composed of images, sounds, and text and offer an opportunity to dramatically improve the drug discovery and design process. To create generative optimization methods that are more useful than brute-force molecular generation and filtering via virtual screening, we propose that four integrated features are necessary: large, quantitative data sets of molecular structure and activity, an invertible vector representation of realistic accessible molecules, smooth and differentiable regressors that quantify uncertainty, and algorithms to simultaneously optimize properties of interest. Over the course of 12 months, Terray Therapeutics has collected a data set of 2 billion quantitative binding measurements of small molecules to therapeutic targets, which directly motivates multiparameter generative optimization of molecules conditioned on these data. To this end, we present contrastive optimization for accelerated therapeutic inference (COATI), a pretrained, multimodal encoder-decoder model of druglike chemical space. COATI is constructed without any human biasing of features, using contrastive learning from text and 3D representations of molecules to allow for downstream use with structural models. We demonstrate that COATI possesses many of the desired properties of universal molecular embedding: fixed-dimension, invertibility, autoencoding, accurate regression, and low computation cost. Finally, we present a novel metadynamics algorithm for generative optimization using a small subset of our proprietary data collected for a model protein, carbonic anhydrase, designing molecules that satisfy the multiparameter optimization task of potency, solubility, and drug likeness. This work sets the stage for fully integrated generative molecular design and optimization for small molecules.

Agrobacterium-mediated transfer of the Fusarium graminearum Tri6 gene into barley using mature seed-derived shoot tips as explants.

KEY MESSAGE: We transferred the Tri6 gene into the elite barley GemCraft via new transformation method through shoot organogenesis and identified the rearrangements of transgenes and phenotypic variations in the transgenic plants. Despite its agronomic and economic importance, barley transformation is still very challenging for many elite varieties. In this study, we used direct shoot organogenesis to transform the elite barley cultivar GemCraft with the RNAi constructs containing Tri6 gene of Fusarium graminearum, which causes fusarium head blight (FHB). We isolated 4432 shoot tips and co-cultured these explants with Agrobacterium tumefaciens. A total of 25 independent T0 transgenic plants were generated including 15 events for which transgene-specific PCR amplicons were observed. To further determine the presence of transgenes, the T1 progenies of all 15 T0 plants were analyzed, and the expected PCR products were obtained in 10 T1 lines. Droplet digital (dd) PCR analysis revealed various copy numbers of transgenes in the transgenic plants. We determined the insertion site of transgenes using long-read sequencing data and observed the rearrangements of transgenes. We found phenotypic variations in both T1 and T2 generation plants. FHB disease was evaluated under growth chamber conditions, but no significant differences in disease severity or deoxynivalenol accumulation were observed between two Tri6 transgenic lines and the wildtype. Our results demonstrate the feasibility of the shoot tip transformation and may open the door for applying this system for genetic improvement and gene function research in other barley genotypes.

Exploring the complexities of drug formulation selection, storage, and shelf-life for exploration spaceflight.

Medications have been a part of space travel dating back to the Apollo missions. Currently, medical kits aboard the International Space Station (ISS) contain medications and supplies to treat a variety of possible medical events. As we prepare for more distant exploration missions to Mars and beyond, risk management planning for astronaut healthcare should include the assembly of a medication formulary that is comprehensive enough to prevent or treat anticipated medical events, remains safe and chemically stable, and retains sufficient potency to last for the duration of the mission. Emerging innovation and technologies in pharmaceutical development, delivery, quality maintenance, and validation offer promise for addressing these challenges. The present editorial will summarize the current state of knowledge regarding innovative formulary optimization strategies, pharmaceutical stability assessment techniques, and storage and packaging solutions that could enhance drug safety and efficacy for future exploration spaceflight missions.

Agrobacterium-mediated direct transformation of wheat mature embryos through organogenesis.

Transgenic plant production in monocotyledonous species has primarily relied on embryogenic callus induction from both immature and mature embryos as the pathway for plant regeneration. We have efficiently regenerated fertile transgenic wheat plants through organogenesis after Agrobacterium-mediated direct transformation of mechanically isolated mature embryos from field-grown seed. Centrifugation of the mature embryos in the presence of Agrobacterium was found to be essential for efficient T-DNA delivery to the relevant regenerable cells. The inoculated mature embryos formed multiple buds/shoots on high-cytokinin medium, which directly regenerated into transgenic shoots on hormone-free medium containing glyphosate for selection. Rooted transgenic plantlets were obtained within 10-12 weeks after inoculation. Further optimization of this transformation protocol resulted in significant reduction of chimeric plants to below 5%, as indicated by leaf GUS staining and T1 transgene segregation analysis. Direct transformation of wheat mature embryos has substantial advantages over traditional immature embryo-based transformation systems, including long-term storability of the mature dry explants, scalability, and greatly improved flexibility and consistency in transformation experiments.

Revisions to Acute/Off-Nominal Limits for Benzene in Spacecraft Air.

BACKGROUND: The previous short-term (1-h and 24-h) Spacecraft Maximal Allowable Concentrations (SMACs) for benzene were established at 10 and 3 ppm by NASA in 1996, based on a study of mice in which no hematological effects were noted following two 6-h exposures to benzene. When the benzene SMACs were updated in 2008, there was no revision to the short-term SMAC limits. Rather, that effort developed a long-term SMAC (1000-d) for Exploration mission scenarios.Acute benzene exposures can cause numerous neurological effects, and long-term exposure to low levels is well-known to cause acute myeloid leukemia. Since publication of the original benzene SMACs, the National Academy of Sciences developed interim Acute Exposure Guideline Limits (AEGLs) for unintentional releases of benzene into the air. Based on the data used to establish the AEGLs, we have increased our short-term, off-nominal limits for benzene in crewed spacecraft to 40 ppm and 6.7 ppm for 1-h and 24-h, respectively.Ryder VE, Williams ES. Revisions to acute/off-nominal limits for benzene in spacecraft air. Aerosp Med Hum Perform. 2023; 94(7):544-545.

Cre-mediated autoexcision of selectable marker genes in soybean, cotton, canola and maize transgenic plants.

KEY MESSAGE: Efficient selectable marker gene autoexcision in transgenic plants of soybean, cotton, canola, and maize is achieved by effective Cre recombinase expression. Selectable marker genes are often required for efficient generation of transgenic plants in plant transformation but are not desired once the transgenic events are obtained. We have developed Cre/loxP autoexcision systems to remove selectable marker genes in soybean, cotton, canola and maize. We tested a set of vectors with diverse promoters and identified promising promoters to drive cre expression for each of the four crops. We evaluated both the efficiency of generating primary transgenic events with low transgene copy numbers, and the frequency of marker-free progeny in the next generation. The best performing vectors gave no obvious decrease in the transformation frequency in each crop and generated homozygous marker-free progeny in the next generation. We found that effective expression of Cre recombinase for marker gene autoexcision can be species dependent. Among the vectors tested, the best autoexcision frequency (41%) in soybean transformation came from using the soybean RSP1 promoter for cre expression. The cre gene expressed by soybean RSP1 promoter with an Arabidopsis AtpE intron delivered the best autoexcision frequency (69%) in cotton transformation. The cre gene expressed by the embryo-specific eUSP88 promoter from Vicia faba conferred the best marker excision frequency (32%) in canola transformation. Finally, the cre gene expressed by the rice CDC45-1 promoter resulted in 44% autoexcision in maize transformation. The Cre/loxP recombinase system enables the generation of selectable marker-free transgenic plants for commercial product development in four agriculturally important crops and provides further improvement opportunities for more specific and better marker excision efficiency.

Commercial scale genetic transformation of mature seed embryo explants in maize.

A novel, efficient maize genetic transformation system was developed using Agrobacterium-mediated transformation of embryo explants from mature seeds. Seeds from field grown plants were sterilized and crushed to isolate embryo explants consisting of the coleoptile, leaf primordia, and shoot apical meristem which were then purified from the ground seed bulk preparation. The infection of relevant tissues of seed embryo explants (SEEs) by Agrobacterium was improved by the centrifugation of the explants. Transgenic plants were obtained by multiple bud induction on high cytokinin media, followed by plant regeneration on hormone-free medium. Three different selectable markers (cp4 epsps, aadA, and nptII) were successfully used for producing transgenic plants. Stable integration of transgenes in the maize genome was demonstrated by molecular analyses and germline transmission of the inserted transgenes to the next generation was confirmed by pollen segregation and progeny analysis. Phenotypic evidence for chimeric transgenic tissue was frequently observed in initial experiments but was significantly reduced by including a second bud induction step with optimized cytokinin concentration. Additional improvements, including culturing explants at an elevated temperature during bud induction led to the development of a revolutionary system for efficient transgenic plant production and genome editing. To our knowledge, this is the first report of successful transgenic plant regeneration through Agrobacterium-mediated transformation of maize mature SEEs. This system starts with mature seed that can be produced in large volumes and the SEEs explants are storable. It has significant advantages in terms of scalability and flexibility over methods that rely on immature explants.

Early Left Ventricular Thrombus Following Ventricular Fibrillation/Ventricular Tachycardia Electrical Storm.

Left ventricular thrombus (LVT) formation is a serious clinical complication of low-flow states that may be seen in an ischaemic, arrhythmic heart. While LVT formation has a poor prognosis, in the setting of myocardial infarction it is usually a result of post-infarct sequelae such as left ventricle aneurysms, and inflammatory changes from damaged tissue, with the LVT taking several days to form. Arrythmias such as ventricular tachycardia (VT) or ventricular fibrillation (VF) may also lead to thrombus formation, as they contribute to stasis due to decreased cardiac output. Large anterolateral myocardial infarctions can cause electrical or arrhythmic storm, characterized by more than three episodes of VT or VF in a 24-hour period. This prolonged state of dyskinesis further increases the risk of thrombosis, creating a compounding effect. Here, we report the case of a patient who had a VF cardiac arrest with electrical storm secondary to anterolateral myocardial infarction complicated with LVT formation found on echocardiogram after the cardiac arrest, which was absent on presentation. This thrombus formation occurred particularly early during the course of the patient's arrest, possibly due to the compounding factors increasing the risk of thrombosis. Herein, we discuss in detail the risk factors for LVT formation, its mechanism and management options. A review of the literature also shows that LVT formation in the acute phase of arrest, as seen in our patient, is rare. LEARNING POINTS: Left ventricular thrombus (LVT) formation occurs 3-14 days after myocardial infarction, but in the setting of concomitant ventricular fibrillation arrest, may occur within the first 24 hours.Risk factors for LVT formation include a large infarct, anterior/anterior apical infarction, decreased ejection fraction (particularly <30-35%), left ventricular aneurysm, and delayed time to revascularization.Although diagnosis is generally made on transthoracic echocardiography with intravenous contrast, cardiac MRI with contrast has better sensitivity and specificity.Treatment consists of anticoagulation with a vitamin K antagonist or heparin for 3-6 months with a repeat echocardiogram to confirm the thrombus has organized or resolved. Further trials are needed to assess the efficacy of direct oral anticoagulants.

Revisions to Limits for Propylene Glycol in Spacecraft Air.

INTRODUCTION: The previous Spacecraft Maximal Allowable Concentrations (SMACs) for propylene glycol were established based on a study of rodents exposed to propylene glycol (PG) aerosol for 6 h/d, 5 d/wk for 90 d. This study has been used as the basis for the few existing limits, but all exposure concentrations were well above the saturated vapor concentration of ∼100 ppm for pure propylene glycol at room temperature. For this reason, the Environmental Protection Agency and the Agency for Toxic Substances and Disease Registry noted that the method used to generate the aerosols for the two published studies of animal exposures are not relevant to exposure conditions for the general public, and most regulatory agencies have not established inhalation limits for propylene glycol, citing lack of data. Since publication of the PG SMACs in 2008, an acute inhalation study was conducted in healthy human subjects which allows us to revise our assessment. This manuscript provides the rationale for increasing the prior limits for PG in spacecraft air from 32 and 17 ppm to 64 and 32 ppm for off-nominal scenarios/releases (1-h and 24-h limits) and from 9, 3, and 1.5 ppm to 32 ppm for all nominal timeframes (7, 30, and 180 d). Due to a lack of longer-term exposure data, NASA has elected to eliminate the 1000-d SMAC limit at this time.Ryder VE, Williams ES. Revisions to limits for propylene glycol in spacecraft air. Aerosp Med Hum Perform. 2022; 93(5):467-469.

Sorafenib is associated with a reduced rate of tumour growth and liver function deterioration in HCV-induced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib has been the standard of care for patients with advanced hepatocellular carcinoma and although immunotherapeutic approaches are now challenging this position, it retains an advantage in HCV-seropositive patients. We aimed to quantify the rate of tumour progression in patients receiving sorafenib and relate this figure to survival, both overall, and according to viral status. METHODS: Using serial data from an international clinical trial we applied a joint model to combine survival and progression over time in order to estimate the rate of tumour growth as assessed by tumour burden and serum alpha-fetoprotein, and the impact of treatment on liver function. RESULTS: High tumour burden at baseline was associated with an increased risk of death. In patients still alive at the end of the study, the progression in relation to tumour burden was very low compared to those who died within the study. Overall, the change in mean tumour burden was 0.12 mm per day or an absolute growth rate of 3.6 mm/month. Median doubling time was 665 days. For those who progressed above 0.12 mm per day or the 12% rate, median survival was 234 days compared to 384 days if the rate was below 12%. Tumour growth rate and serum alpha-fetoprotein rise were significantly lower in those who were HCV seropositive as was the rate of decline in liver function. These results were replicated in 2 independent patient groups. CONCLUSION: Our analysis suggests that sorafenib treatment is associated with improved survival in patients with advanced hepatocellular carcinoma mainly by decreasing the rate of tumour growth and liver function deterioration among patients with HCV infection. LAY SUMMARY: Among patients receiving sorafenib for advanced hepatocellular carcinoma the rate of tumour growth (as assessed by changes in tumour size and the biomarker alpha-fetoprotein) and the deterioration of liver function is less in those who have the hepatitis C virus, than in those who do not.

CamGFR v2: A New Model for Estimating the Glomerular Filtration Rate from Standardized or Non-standardized Creatinine in Patients with Cancer.

PURPOSE: Management of patients with cancer, specifically carboplatin dosing, requires accurate knowledge of glomerular filtration rate (GFR). Direct measurement of GFR is resource limited. Available models for estimated GFR (eGFR) are optimized for patients without cancer and either isotope dilution mass spectrometry (IDMS)- or non-IDMS-standardized creatinine measurements. We present an eGFR model for patients with cancer compatible with both creatinine measurement methods. EXPERIMENTAL DESIGN: GFR measurements, biometrics, and IDMS- or non-IDMS-standardized creatinine values were collected for adult patients from three cancer centers. Using statistical modeling, an IDMS and non-IDMS creatinine-compatible eGFR model (CamGFR v2) was developed. Its performance was compared with that of the existing models Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), Full Age Spectrum (FAS), Lund-Malmö revised, and CamGFR v1, using statistics for bias, precision, accuracy, and clinical robustness. RESULTS: A total of 3,083 IDMS- and 4,612 non-IDMS-standardized creatinine measurements were obtained from 7,240 patients. IDMS-standardized creatinine values were lower than non-IDMS-standardized values in within-center comparisons (13.8% lower in Cambridge; P < 0.0001 and 19.3% lower in Manchester; P < 0.0001), and more consistent between centers. CamGFR v2 was the most accurate [root-mean-squared error for IDMS, 14.97 mL/minute (95% confidence interval, 13.84-16.13) and non-IDMS, 15.74 mL/minute (14.86-16.63)], most clinically robust [proportion with >20% error of calculated carboplatin dose for IDMS, 0.12 (0.09-0.14) and non-IDMS, 0.17 (0.15-0.2)], and least biased [median residual for IDMS, 0.73 mL/minute (-0.68 to 2.2) and non-IDMS, -0.43 mL/minute (-1.48 to 0.91)] eGFR model, particularly when eGFR was larger than 60 ml/minute. CONCLUSIONS: CamGFR v2 can utilize IDMS- and non-IDMS-standardized creatinine measurements and outperforms previous models. CamGFR v2 should be examined prospectively as a practice-changing standard of care for eGFR-based carboplatin dosing.

A GIS-based 3D slope stability analysis method based on the assumed normal stress on the slip surface.

The study proposes a geographic information systems (GIS)-based slope stability analysis method assuming a normal stress distribution acting on the slip surface. Compared with traditional methods, the three-dimensional (3D) safety factor acquired through this method will more closely approximate the actual value. First, a 3D slope stability analysis model is developed using grid column units, and the spatial expression of calculation parameters based on the grid column is given by the spatial analysis capability of GIS. Then, four equilibrium equations are derived under the limit equilibrium condition. The normal stress distribution acting on the slip surface is analyzed to construct a reasonable normal stress distribution approximation function. The 3D safety factor is obtained through the approximation function and the Mohr-Coulomb strength criterion. Moreover, we develop a GIS-based extension module which combines the grid-based data with the 3D slope stability analysis model. The accuracy and feasibility of the module are verified by three typical cases.

Multicenter Validation of the CamGFR Model for Estimated Glomerular Filtration Rate.

Important oncological management decisions rely on kidney function assessed by serum creatinine-based estimated glomerular filtration rate (eGFR). However, no large-scale multicenter comparisons of methods to determine eGFR in patients with cancer are available. To compare the performance of formulas for eGFR based on routine clinical parameters and serum creatinine not calibrated with isotope dilution mass spectrometry, we studied 3620 patients with cancer and 166 without cancer who had their glomerular filtration rate (GFR) measured with an exogenous nuclear tracer at one of seven clinical centers. The mean measured GFR was 86 mL/min. Accuracy of all models was center dependent, reflecting intercenter variability of isotope dilution mass spectrometry-creatinine measurements. CamGFR was the most accurate model for eGFR (root-mean-squared error 17.3 mL/min) followed by the Chronic Kidney Disease Epidemiology Collaboration model (root-mean-squared error 18.2 mL/min).

Relationship Between Methylmercury Contamination and Proportion of Aquatic and Terrestrial Prey in Diets of Shoreline Spiders.

Terrestrial organisms such as shoreline spiders that consume prey from aquatic food webs can be contaminated with methylmercury (MeHg). However, no studies have examined the relationship between MeHg contamination of shoreline spider taxa and the proportion of aquatic and terrestrial prey in their diets. The present study had 2 objectives: 1) determine concentrations of MeHg in 7 taxa of shoreline spiders, and 2) assess the relationship between concentrations of MeHg in spiders and the proportion of aquatic and terrestrial prey in spider diets. We collected shoreline spiders, emergent aquatic insects, and terrestrial insects from in and around 10 experimental ponds. Methylmercury concentrations were greatest in spiders, intermediate in aquatic insects, and lowest in terrestrial insects. The elevated MeHg concentrations in spiders indicate that they were feeding, at least in part, on emergent aquatic insects. However, variability in MeHg concentration observed among spider taxa suggested that the proportion of aquatic and terrestrial prey in spider diets likely varied among taxa. We estimated the proportion of aquatic and terrestrial prey in the diet of each spider taxon from the nitrogen (δ15 N) and carbon (δ13 C) isotope values of spiders and their potential aquatic and terrestrial prey items. The median proportion of aquatic prey in spider diets varied by almost 2-fold, and MeHg concentrations in shoreline spiders were strongly correlated with the proportion of aquatic prey in their diet. In the present study, we demonstrate for the first time that the degree of connectivity to aquatic food webs determines MeHg contamination of shoreline spiders. Environ Toxicol Chem 2019;38:2503-2508. © 2019 SETAC.

Kinetics of Glutathione Depletion and Antioxidant Gene Expression as Indicators of Chemical Modes of Action Assessed in Vitro in Mouse Hepatocytes with Enhanced Glutathione Synthesis.

Here we report a vertically integrated in vitro - in silico study that aims to elucidate the molecular initiating events involved in the induction of oxidative stress (OS) by seven diverse chemicals (cumene hydroperoxide, t-butyl hydroperoxide, hydroquinone, t-butyl hydroquinone, bisphenol A, Dinoseb, and perfluorooctanoic acid). To that end, we probe the relationship between chemical properties, cell viability, glutathione (GSH) depletion, and antioxidant gene expression. Concentration-dependent effects on cell viability were assessed by MTT assay in two Hepa-1 derived mouse liver cell lines: a control plasmid vector transfected cell line (Hepa-V), and a cell line with increased glutamate-cysteine ligase (GCL) activity and GSH content (CR17). Changes to intracellular GSH content and mRNA expression levels for the Nrf2-driven antioxidant genes Gclc, Gclm, heme oxygenase-1 ( Hmox1), and NADPH quinone oxidoreductase-1 ( Nqo1) were monitored after sublethal exposure to the chemicals. In silico models of covalent and redox reactivity were used to rationalize differences in activity of quinones and peroxides. Our findings show CR17 cells were generally more resistant to chemical toxicity and showed markedly attenuated induction of OS biomarkers; however, differences in viability effects between the two cell lines were not the same for all chemicals. The results highlight the vital role of GSH in protecting against oxidative stress-inducing chemicals as well as the importance of probing molecular initiating events in order to identify chemicals with lower potential to cause oxidative stress.

Weight management interventions for youth with autism spectrum disorder: a systematic review.

BACKGROUND AND OBJECTIVE: In response to the elevated levels of overweight and obesity among children with autism spectrum disorder (ASD), this article provides a systematic review of the extant empirical literature reporting the effect of weight management interventions (including exercise, diet, and medication) for youth with ASD. DESIGN: A systematic review of published studies. The databases CINAHL, Web of Science, ERIC, Pubmed, and PsychINFO were searched, revealing 12 studies that were eligible for review. RESULTS: Of the included studies, half (n = 6) demonstrated significant weight loss; including comprehensive (n = 3), pharmaceutical (n = 2), and exercise (n = 1) interventions. Of relevance, and concern, was that only one of the included studies was determined to be of strong research quality, with the majority (n = 8) determined as being of weak study quality. Furthermore, studies included highly heterogeneous treatment approaches, study designs, and sample characteristics. CONCLUSIONS: This review demonstrates the potential of interventions (particularly individualized, comprehensive, and multidisciplinary team- based interventions) to effectively impact on weight among youth with ASD. It is imperative to rigorously test these interventions in individuals with ASD given the rates of obesity in this population and complications that ensue.

"I'm not in this alone" the perspective of parents mediating a physical activity intervention for their children with autism spectrum disorder.

BACKGROUND AND AIMS: Web-based, parent-mediated interventions have shown to be beneficial for children with autism spectrum disorder (ASD) in a variety of domains. We aimed to examine how parents of children with ASD perceive mediating a physical activity intervention delivered via a private Facebook group. METHODS: Thirteen families participated in a four-week trial of Project CHASE. Inductive thematic analysis of semi-structured interviews and interactions within the Facebook group were conducted to elicit the perspective of the parents. OUTCOMES AND RESULTS: Thematic analysis resulted in three themes emerging: (1) 'Remembering to Act' encompassed the participants' perspectives of Project CHASE as being an intervention that reminded them of the importance of physical activity, and served as a prompt for them to take action; (2) 'A sharing community' included the subthemes of 'sharing success and struggles' and 'sharing ideas'; and, (3) 'Taking control: possibilities and problems' encapsulates the dichotomy between participants who spoke of embracing and rising to the challenge of taking control, with the parents who spoke of the need for more support, direction, and guidance. CONCLUSION AND IMPLICATION: The current study suggests parent-mediated, web-based interventions may have the potential for improving the effectiveness of physical activity interventions for children with ASD.

Seasonality of dipteran-mediated methylmercury flux from ponds.

Methylmercury (MeHg) is an aquatic contaminant that can be transferred to terrestrial predators by emergent aquatic insects. We assessed the effects of month and pond permanence on dipteran-mediated MeHg flux (calculated as emergent dipteran biomass × dipteran MeHg concentration) in 10 experimental ponds. Emergent dipterans were collected weekly from permanent ponds with bluegill (Lepomis macrochirus; n = 5) and semipermanent ponds without fish (n = 5) over a 7-mo period (February-August, 2015). We detected a significant effect of month on MeHg flux from 6 dipteran taxa and aggregate MeHg flux, with the highest MeHg flux from herbivorous/detritivorous chironomid midges and predatory midges in March; biting midges, phantom midges and herbivorous/detritivorous orthoclad midges in April; and mosquitoes in August. Aggregate dipteran-mediated MeHg flux peaked in April and then declined throughout the remainder of the summer. We did not detect a significant main effect of pond permanence or a significant month × pond permanence interaction effect on MeHg flux for any of the taxa examined in the present study or for aggregate MeHg flux. Given their ubiquity in aquatic systems and their importance in food webs at the land-water interface, dipterans are important taxa that should not be overlooked as a part of the Hg cycle. Environ Toxicol Chem 2018;37:1846-1851. © 2018 SETAC.

Cancer Immunotherapy Trials Underutilize Immune Response Monitoring.

Immune-related radiological and biomarker monitoring in cancer immunotherapy trials permits interrogation of efficacy and reasons for therapeutic failure. We report the results from a cross-sectional analysis of response monitoring in 685 T-cell checkpoint-targeted cancer immunotherapy trials in solid malignancies, as registered on the U.S. National Institutes of Health trial registry by October 2016. Immune-related radiological response criteria were registered for only 25% of clinical trials. Only 38% of trials registered an exploratory immunological biomarker, and registration of immunological biomarkers has decreased over the last 15 years. We suggest that increasing the utilization of immune-related response monitoring across cancer immunotherapy trials will improve analysis of outcomes and facilitate translational efforts to extend the benefit of immunotherapy to a greater proportion of patients with cancer.

New Model for Estimating Glomerular Filtration Rate in Patients With Cancer.

Purpose The glomerular filtration rate (GFR) is essential for carboplatin chemotherapy dosing; however, the best method to estimate GFR in patients with cancer is unknown. We identify the most accurate and least biased method. Methods We obtained data on age, sex, height, weight, serum creatinine concentrations, and results for GFR from chromium-51 (51Cr) EDTA excretion measurements (51Cr-EDTA GFR) from white patients ≥ 18 years of age with histologically confirmed cancer diagnoses at the Cambridge University Hospital NHS Trust, United Kingdom. We developed a new multivariable linear model for GFR using statistical regression analysis. 51Cr-EDTA GFR was compared with the estimated GFR (eGFR) from seven published models and our new model, using the statistics root-mean-squared-error (RMSE) and median residual and on an internal and external validation data set. We performed a comparison of carboplatin dosing accuracy on the basis of an absolute percentage error > 20%. Results Between August 2006 and January 2013, data from 2,471 patients were obtained. The new model improved the eGFR accuracy (RMSE, 15.00 mL/min; 95% CI, 14.12 to 16.00 mL/min) compared with all published models. Body surface area (BSA)-adjusted chronic kidney disease epidemiology (CKD-EPI) was the most accurate published model for eGFR (RMSE, 16.30 mL/min; 95% CI, 15.34 to 17.38 mL/min) for the internal validation set. Importantly, the new model reduced the fraction of patients with a carboplatin dose absolute percentage error > 20% to 14.17% in contrast to 18.62% for the BSA-adjusted CKD-EPI and 25.51% for the Cockcroft-Gault formula. The results were externally validated. Conclusion In a large data set from patients with cancer, BSA-adjusted CKD-EPI is the most accurate published model to predict GFR. The new model improves this estimation and may present a new standard of care.