Fetal Hemodynamics, Early Survival, and Neurodevelopment in Patients With Cyanotic Congenital Heart Disease.

BACKGROUND: Fetuses with cyanotic congenital heart disease (CHD) exhibit profound fetal circulatory disturbances that may affect early outcomes. OBJECTIVES: This study sought to investigate the relationship between fetal hemodynamics and early survival and neurodevelopmental (ND) outcomes in patients with cyanotic CHD. METHODS: In this longitudinal observational study, fetuses with cyanotic CHD underwent late gestational fetal cardiovascular magnetic resonance (CMR) to measure vessel blood flow and oxygen content. Superior vena cava (SVC) flow was used as a proxy for cerebral blood flow. Primary outcomes were 18-month mortality and Bayley Scales of Infant Development-III assessment. RESULTS: A total of 144 fetuses with cyanotic CHD were assessed. By 18 months, 18 patients (12.5%) died. Early mortality was associated with reduced combined ventricular output (P = 0.01), descending aortic flow (P = 0.04), and umbilical vein flow (P = 0.03). Of the surviving patients, 71 had ND outcomes assessed. Cerebral oxygen delivery was the fetal hemodynamic variable most strongly associated with cognitive, language, and motor outcomes (P < 0.05). Fetal SVC flow was also associated with cognitive, language, and motor outcomes (P < 0.01), and it remained an independent predictor of cognitive (P = 0.002) and language (P = 0.04) outcomes after adjusting for diagnosis. Diminished SVC flow also performed better than other fetal CMR and echocardiographic predictors of cognitive ND delay (receiver-operating characteristic curve area: 0.85; SE 0.05). CONCLUSIONS: Among fetuses with cyanotic CHD, diminished fetal combined ventricular output is associated with mortality, whereas cerebral blood flow and oxygen delivery are associated with early cognitive, language, and motor development at 18 months of age. These results support the inclusion of fetal CMR to help identify patients at risk of adverse ND outcomes.

A method for measuring the bioaccessibility of polycyclic aromatic hydrocarbons in cell culture media.

Airborne polycyclic aromatic hydrocarbons (PAHs) and their derivatives are of particular concern for population health due to their abundance and toxicity via inhalation. Lung toxicity testing includes exposing lung epithelial cell lines to PAHs in a culture medium containing inorganic species, lipids, proteins, and other biochemicals where the cell response is influenced among others by the toxic chemical accessibility in the medium. While inhalation bioaccessibility of PAHs and other toxicants was previously studied in surrogate lung fluids, studies measuring bioaccessibility in cell culture media are rare. In this work, a method was developed to characterize PAH bioaccessibility in a culture medium used for mouse lung epithelial (FE1) cells. Further, the optimised method was tested using commercially available standard reference material of urban particulate matter (PM) as well as polyurethane foam passive air samplers (PUF-PAS). The method provided a high precision and recovery of analytes, indicating no losses during sample processing and analysis. PAHs had non-linear concentration-responses, with the culture medium approaching saturation with PM concentration of 500 µg mL-1. The results showed that phenanthrene, a 3-ring PAH, was significantly more bioaccessible than ≥4-ring congeners in the culture medium (up to ∼2.5 folds; p < 0.05). Finally, using pre-deployed PUF-PAS from a residential and an industrial site, five PAHs were found in the culture medium, including naphthalene, phenanthrene, anthracene, fluoranthene, and pyrene. This work provides a proof of concept to enable future studies to assess the inhalation bioaccessibility of polycyclic aromatic compounds and other airborne pollutants collected using PUF-PAS.

Characterizing the Movement of Per- and Polyfluoroalkyl Substances in an Avian Aquatic-Terrestrial Food Web.

The movement of per- and polyfluoroalkyl substances (PFAS) through linked aquatic-terrestrial food webs is not well understood. Tree swallows (Tachycineta bicolor) in such systems may be exposed to PFAS from multiple abiotic and/or biotic compartments. We show from fatty acid signatures and carbon stable isotopes that tree swallow nestlings in southwestern Ontario fed on both terrestrial and aquatic macroinvertebrates. The PFAS profiles of air, terrestrial invertebrates, and swallows were dominated by perfluorooctanesulfonic acid (PFOS). Short-chain perfluoroalkyl acids (PFAAs) were largely restricted to air, surface water, and sediment, and long-chain PFAAs were mainly found in aquatic invertebrates and tree swallows. PFOS, multiple long-chain perfluorocarboxylic acids [perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorotridecanoic acid (PFTrDA)] and perfluorooctane sulfonamide precursors were estimated to bioaccumulate from air to tree swallows. PFOS bioaccumulated from air to terrestrial invertebrates, and PFOS, PFDA, and perfluorooctane sulfonamidoacetic acids (FOSAAs) bioaccumulated from water to aquatic invertebrates. PFOS showed biomagnification from both terrestrial and aquatic invertebrates to tree swallows, and PFDA and FOSAAs were also biomagnified from aquatic invertebrates to tree swallows. The movement of PFAS through aquatic-terrestrial food webs appears congener- and compartment-specific, challenging the understanding of PFAS exposure routes for multiple species involved in these food webs.

Trace Metals in Global Air: First Results from the GAPS and GAPS Megacities Networks.

Trace metals, as constituents of ambient air, can have impacts on human and environmental health. The Global Atmospheric Passive Sampling (GAPS) and GAPS Megacities (GAPS-MC) networks investigated trace metals in the air at 51 global locations by deploying polyurethane foam disk passive air samplers (PUF-PAS) for periods of 3-12 months. Aluminum and iron exhibited the highest concentrations in air (x̅ = 3400 and 4630 ng/m3, respectively), with notably elevated values at a rural site in Argentina thought to be impacted by resuspended soil. Urban sites had the highest levels of toxic Pb and Cd, with enrichment factors suggesting primarily anthropogenic influences. High levels of As at rural sites were also observed. Elevated trace metal concentrations in cities are associated with local emissions and higher PM2.5 and PM10 concentrations. Brake and tire wear-associated metals Sb, Cu, and Zn are significantly correlated and elevated at urban locations relative to those at background sites. These data demonstrate the versatility of PUF-PAS for measuring trace metals and other particle-associated pollutants in ambient air in a cost-effective and simple manner. The data presented here will serve as a global baseline for assessing future changes in ambient air associated with industrialization, urbanization, and population growth.

Emissions and fate of organophosphate esters in outdoor urban environments.

Cities are drivers of the global economy, containing products and industries that emit many chemicals. Here, we use the Multimedia Urban Model (MUM) to estimate atmospheric emissions and fate of organophosphate esters (OPEs) from 19 global mega or major cities, finding that they collectively emitted ~81,000 kg yr-1 of ∑10OPEs in 2018. Typically, polar "mobile" compounds tend to partition to and be advected by water, while non-polar "bioaccumulative" chemicals do not. Depending on the built environment and climate of the city considered, the same compound behaves like either a mobile or a bioaccumulative chemical. Cities with large impervious surface areas, such as Kolkata, mobilize even bioaccumulative contaminants to aquatic ecosystems. By contrast, cities with large areas of vegetation fix and transform contaminants, reducing loadings to aquatic ecosystems. Our results therefore suggest that urban design choices could support policies aimed at reducing chemical releases to the broader environment without increasing exposure for urban residents.

Per- and polyfluoroalkyl substances and volatile methyl siloxanes in global air: Spatial and temporal trends.

The study reports on the atmospheric concentrations of per- and polyfluoroalkyl substances (PFAS) and volatile methyl siloxanes (VMS) measured using sorbent-impregnated polyurethane foam disks (SIPs) passive air samplers. New results are reported for samples collected in 2017, which extends temporal trend information to the period 2009-2017, for 21 sites where SIPs have been deployed since 2009. Among neutral PFAS, fluorotelomer alcohols (FTOHs) had higher concentrations than perfluoroalkane sulfonamides (FOSAs) and perfluoroalkane sulfonamido ethanols (FOSEs) with levels of ND‒228, ND‒15.8, ND‒10.4 pg/m3, respectively. Among ionizable PFAS, the sum of perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkyl sulfonic acids (PFSAs) in air were 0.128-781 and 6.85-124 pg/m3, respectively. Longer-chain i.e. C9-C14 PFAS, which are relevant to the recent proposal by Canada for a listing of long-chain (C9-C21) PFCAs to the Stockholm Convention, were also detected in the environment at all site categories including Arctic sites. Cyclic and linear VMS ranged between 1.34‒452 and 0.01-12.1 ng/m3, respectively, showing dominance in urban areas. Despite the wide range of levels observed across different site categories, geometric means of the PFAS and VMS groups were fairly similar when grouped according to the five United Nations regions. Variable temporal trends in air (2009-2017) were observed for both PFAS and VMS. PFOS, which has been listed in the Stockholm Convention since 2009, is still showing increasing tendencies at several sites, indicating constant input from direct and/or indirect sources. These new data inform international chemicals management for PFAS and VMS.

Genomic landscape of the DHA1 family in Candida auris and mapping substrate repertoire of CauMdr1.

The last decade has witnessed the rise of an extremely threatening healthcare-associated multidrug-resistant non-albicans Candida (NAC) species, Candida auris. Since besides target alterations, efflux mechanisms contribute maximally to antifungal resistance, it is imperative to investigate their contributions in this pathogen. Of note, within the major facilitator superfamily (MFS) of efflux pumps, drug/H+ antiporter family 1 (DHA1) has been established as a predominant contributor towards xenobiotic efflux. Our study provides a complete landscape of DHA1 transporters encoded in the genome of C. auris. This study identifies 14 DHA1 transporters encoded in the genome of the pathogen. We also construct deletion and heterologous overexpression strains for the most important DHA1 drug transporter, viz., CauMdr1 to map the spectrum of its substrates. While the knockout strain did not show any significant changes in the resistance patterns against most of the tested substrates, the ortholog when overexpressed in a minimal background Saccharomyces cerevisiae strain, AD1-8u-, showed significant enhancement in the minimum inhibitory concentrations (MICs) against a large panel of antifungal molecules. Altogether, the present study provides a comprehensive template for investigating the role of DHA1 members of C. auris in antifungal resistance mechanisms. KEY POINTS: • Fourteen putative DHA1 transporters are encoded in the Candida auris genome. • Deletion of the CauMDR1 gene does not lead to major changes in drug resistance. • CauMdr1 recognizes and effluxes numerous xenobiotics, including prominent azoles.

Air monitoring of tire-derived chemicals in global megacities using passive samplers.

Pollution from vehicle tires has received world-wide research attention due to its ubiquity and toxicity. In this study, we measured various tire-derived contaminants semi-quantitatively in archived extracts of passive air samplers deployed in 18 major cities that comprise the Global Atmospheric Passive Sampling (GAPS) Network (GAPS-Megacities). Analysis was done on archived samples, which represent one-time weighted passive air samples from each of the 18 monitoring sites. The target analytes included cyclic amines, benzotriazoles, benzothiazoles, and p-phenylenediamine (PPD) derivatives. Of the analyzed tire-derived contaminants, diphenylguanidine was the most frequently detected analyte across the globe, with estimated concentrations ranging from 45.0 pg/m3 in Beijing, China to 199 pg/m3 in Kolkata, India. The estimated concentrations of 6PPD-quinone and total benzothiazoles (including benzothiazole, 2-methylthio-benzothiazole, 2-methyl-benzothiazole, 2-hydroxy-benzothiazole) peaked in the Latin American and the Caribbean region at 1 pg/m3 and 100 pg/m3, respectively. In addition, other known tire-derived compounds, such as hexa(methoxymethyl)melamine, phenylguanidine, and various transformation products of 6PPD, were also monitored and characterized semi-quantitatively or qualitatively. This study presents some of the earliest data on airborne concentrations of chemicals associated with tire-wear and shows that passive sampling is a viable techniquefor monitoring airborne tire-wear contamination. Due to the presence of many tire-derived contaminants in urban air across the globe as highlighted by this study, there is a need to determine the associated exposure and toxicity of these chemicals to humans.

Medium- and long-chain chlorinated paraffins in air: A review of levels, physicochemical properties, and analytical considerations.

Chlorinated paraffins (CPs) are synthetic chemicals that are produced at high volumes and have a global presence. CPs are generally divided into three groups based on their carbon chain lengths: short-chain CPs (SCCPs, C10-13), medium-chain CPs (MCCPs, C14-17), and long-chain CPs (LCCPs, C≥18). SCCPs have been formally recognized as persistent organic pollutants (POPs) and have been listed under the Stockholm Convention on POPs. Concerns about increases in MCCP and LCCP production as replacements for SCCP products are rising, given their similar properties to SCCPs and the fact that they remain relatively understudied with only a few reported measurements in air. Passive air samplers with polyurethane foam disks (PUF-PAS), which have been successfully applied to SCCPs, provide an opportunity to expand the existing body of data on MCCP and LCCP air concentrations, as they are inexpensive and require little maintenance. The uptake of MCCPs and LCCPs by PUF disk samplers is characterized in this paper based on newly derived PUF-air partitioning coefficients using COSMOtherm. The ability of PUF disk samplers to capture both gas-phase and particle fractions is important because MCCPs and LCCPs have reduced volatility compared to SCCPs and therefore are mainly associated with particulate matter in air. In addition, due to their use as additives in plastics and rubber products, they are associated with micro- and nanoplastics, which are considered to be potential vectors for the long-range atmospheric transport (LRAT) of these chemicals. The review has highlighted other limitations to reporting of MCCPs and LCCPs in air, including the lack of suitable analytical standards and the requirement for advanced analytical methods to detect and resolve these complex mixtures. Overall, this review indicates that further research is needed in many areas for medium- and long-chain chlorinated paraffins in order to better understand their occurrence, transport and fate in air.

High-flow nasal cannula and noninvasive ventilation: effects on alveolar recruitment and overdistension.

Both high-flow nasal cannula and noninvasive ventilation are subject to pulmonary complications https://bit.ly/3jFCSG9.

Cytotoxic and Transcriptomic Effects in Avian Hepatocytes Exposed to a Complex Mixture from Air Samples, and Their Relation to the Organic Flame Retardant Signature.

Assessing complex environmental mixtures and their effects is challenging. In this study, we evaluate the utility of an avian in vitro screening approach to determine the effects of passive air sampler extracts collected from different global megacities on cytotoxicity and gene expression. Concentrations of a suite of organic flame retardants (OFRs) were quantified in extracts from a total of 19 megacities/major cities in an earlier study, and levels were highly variable across sites. Chicken embryonic hepatocytes were exposed to serial dilutions of extracts from the 19 cities for 24 h. Cell viability results indicate a high level of variability in cytotoxicity, with extracts from Toronto, Canada, having the lowest LC50 value. Partial least squares (PLS) regression analysis was used to estimate LC50 values from OFR concentrations. PLS modeling of OFRs was moderately predictive of LC50 (p-value = 0.0003, r2 = 0.66, slope = 0.76, when comparing predicted LC50 to actual values), although only after one outlier city was removed from the analysis. A chicken ToxChip PCR array, comprising 43 target genes, was used to determine effects on gene expression, and similar to results for cell viability, gene expression profiles were highly variable among the megacities. PLS modeling was used to determine if gene expression was related to the OFR profiles of the extracts. Weak relationships to the ToxChip expression profiles could be detected for only three of the 35 OFRs (indicated by regression slopes between 0.6 and 0.5 when comparing predicted to actual OFR concentrations). While this in vitro approach shows promise in terms of evaluating effects of complex mixtures, we also identified several limitations that, if addressed in future studies, might improve its performance.

Uncovering global-scale risks from commercial chemicals in air.

Commercial chemicals are used extensively across urban centres worldwide1, posing a potential exposure risk to 4.2 billion people2. Harmful chemicals are often assessed on the basis of their environmental persistence, accumulation in biological organisms and toxic properties, under international and national initiatives such as the Stockholm Convention3. However, existing regulatory frameworks rely largely upon knowledge of the properties of the parent chemicals, with minimal consideration given to the products of their transformation in the atmosphere. This is mainly due to a dearth of experimental data, as identifying transformation products in complex mixtures of airborne chemicals is an immense analytical challenge4. Here we develop a new framework-combining laboratory and field experiments, advanced techniques for screening suspect chemicals, and in silico modelling-to assess the risks of airborne chemicals, while accounting for atmospheric chemical reactions. By applying this framework to organophosphate flame retardants, as representative chemicals of emerging concern5, we find that their transformation products are globally distributed across 18 megacities, representing a previously unrecognized exposure risk for the world's urban populations. More importantly, individual transformation products can be more toxic and up to an order-of-magnitude more persistent than the parent chemicals, such that the overall risks associated with the mixture of transformation products are also higher than those of the parent flame retardants. Together our results highlight the need to consider atmospheric transformations when assessing the risks of commercial chemicals.

Fugacity-Based Trophic Magnification Factors Characterize Bioaccumulation of Cyclic Methyl Siloxanes within an Urban Terrestrial Avian Food Web: Importance of Organism Body Temperature and Composition.

Trophic magnification of cyclic volatile methyl siloxanes (cVMS) in a terrestrial food web was investigated by measuring concentrations of octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6) and two reference chemicals within air and biota samples from an avian food web located in a mixed urban-agricultural landscape. Terrestrial trophic magnification factors derived from lipid normalized concentrations (TMFLs) for D5 and D6 were 0.94 (0.17 SE) and 1.1 (0.23 SE) and not statistically different from 1 (p > 0.05); however, the TMFL of D4 was 0.62 (0.11 SE) and statistically less than 1 (p < 0.001). TMFLs of PCB-153 and p,p'-DDE were 5.6 (2.2 SE) and 6.1 (2.8 SE) and statistically greater than 1 (p < 0.001). TMFLs of cVMS in this terrestrial system were similar to those reported in aquatic systems. However, trophic magnification factors derived on a fugacity basis (TMFFs), which recognize differences in body temperature and lipid composition between organisms, were greater than corresponding TMFLs primarily because a temperature-induced thermodynamic biomagnification of hydrophobic chemicals occurs when endothermic organisms consume poikilothermic organisms. Therefore, we recommend that biomagnification studies of food webs including endothermic and poikilothermic organisms incorporate differences in body temperature and tissue composition to accurately characterize the biomagnification potential of chemicals.

Guidance on the Application of Polyurethane Foam Disk Passive Air Samplers for Measuring Nonane and Short-Chain Chlorinated Paraffins in Air: Results from a Screening Study in Urban Air.

This study provides guidance on using polyurethane foam-based passive air samplers (PUF-PASs) for atmospheric nonane chlorinated paraffins (C9-CPs) and short-chain CPs (SCCPs) and reports SCCP concentrations in air in the Greater Toronto Area (GTA), Canada. We estimated the partition coefficients between PUF and air (KPUF-A) and between octanol and air (KOA) for C9-CP and SCCP congeners using the COSMO-RS method, so that PUF disk uptake profiles for each formula group could be calculated. We then measured SCCP concentrations in PUF disk samples collected from distinct source sectors in urban air across the GTA. Concentrations in samplers were used to calculate C9-CP and SCCP concentrations in air and the PUF disk uptake profiles revealed that time-weighted linear phase sampling was possible for congeners having log KOA values greater than 8.5. The highest SCCP concentrations, with an annual average concentration of 35.3 ng/m3, were measured at the industrial site, whereas lower but comparable SCCP concentrations were found in residential and background sites, with annual averages of 7.73 and 10.5 ng/m3, respectively. No consistent seasonal variation in SCCP concentrations was found in the six distinct source sectors. Direct measurements of KPUF-A and KOA values as a function of temperature could be used to increase accuracy in future studies.

Metabolic Enzyme DLST Promotes Tumor Aggression and Reveals a Vulnerability to OXPHOS Inhibition in High-Risk Neuroblastoma.

High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here, we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in patients with neuroblastoma. DLST is an E2 component of the α-ketoglutarate (αKG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, αKG is converted into succinyl-CoA, producing NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven neuroblastoma, we demonstrate that even modest increases in DLST expression promote tumor aggression, while monoallelic dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified neuroblastoma cells minimally affected glutamine anaplerosis and did not alter TCA cycle metabolites other than αKG. However, DLST loss significantly suppressed NADH production and impaired OXPHOS, leading to growth arrest and apoptosis of neuroblastoma cells. In addition, multiple inhibitors targeting the electron transport chain, including the potent IACS-010759 that is currently in clinical testing for other cancers, efficiently reduced neuroblastoma proliferation in vitro. IACS-010759 also suppressed tumor growth in zebrafish and mouse xenograft models of high-risk neuroblastoma. Together, these results demonstrate that DLST promotes neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk neuroblastoma. SIGNIFICANCE: These findings demonstrate a novel role for DLST in neuroblastoma aggression and identify the OXPHOS inhibitor IACS-010759 as a potential therapeutic strategy for this deadly disease.

Characterization of Opalescence in low Volume Monoclonal Antibody Solutions Enabled by Microscale Nephelometry.

Monoclonal antibody (mAb)-based drugs are often prone to unfavorable solution behaviors including high viscosity, opalescence, phase separation, and aggregation at the high concentrations needed to enable patient-centric subcutaneous dosage forms. Given that these can have a detrimental impact on manufacturability, stability, and delivery, approaches to identifying, monitoring, and controlling these behaviors during drug development are critical. Opalescence presents a significant challenge due to its relationship to liquid-liquid phase separation. Quantitative characterization of opalescence via turbidimetry is often restrictive due to large volume requirements (>2 mL) and alternative microscale approaches based on light transmittance (Eckhardt et al., J Pharm Sci Technol. 1994, 48: 64-70) may pose challenging with respect to accuracy. To address the need for accurate and quantitative microscale opalescence measurements, we have evaluated the use of a 'de-tuned' static light scattering detector which requires <10 µL sample per measurement. We show that tuning of the laser power to a range far below that of traditional light scattering measurements results in a stable detector response that can be accurately calibrated to the nephelometric turbidity unit (NTU) scale using appropriate standards. The calibrated detector signal yields NTU values for mAbs and other protein solutions that are comparable to a commercial turbidimeter. We used this microscale approach to characterize the opalescence of 48 commercial mAb drug products and found that the majority have opalescence below 15 NTU. However, in products with mAb concentrations greater than 75 mg/mL, a broad range of opalescence was observed, in a few cases greater than 20 NTU. These measurements as well as nephelometric characterization of several IgG1 and IgG4 mAbs across a broad pH range highlight subclass-specific tendencies toward opalescence in high concentration solutions.

Cholic-Acid-Derived Amphiphiles Can Prevent and Degrade Fungal Biofilms.

Infections caused by fungal species via their existence as biofilms on medical devices can cause organ damage via candidiasis and candidemia. Different Candida species like Candida albicans can pose a serious threat by resisting host's immune system and by developing drug resistance against existing antimycotic agents. Therefore, targeting of fungal membranes can be used as an alternative strategy to combat the fungal infections. Here, we present screening of different amphiphiles based on cholic acid against different Candida strains as these amphiphiles can act as potent membrane-targeting antimycotic agents. Structure-activity correlations, biochemical assays and electron microscopy studies showed that amphiphiles having 4 and 6 carbon chains are most potent, safe and can act on the fungal membranes. Candida albicans did not show emergence of drug resistance on repeated usage of these amphiphiles unlike fluconazole. We show that these amphiphiles can prevent the formation of biofilms and also have the ability to degrade preformed biofilms on different substrates including acrylic teeth. We further demonstrate that amphiphiles 4 and 6 can clear the Candida albicans wound infections and prevent the biofilm formation on indwelling devices in murine models. Therefore, amphiphiles derived from cholic acid and their coatings provide suitable alternatives for inhibiting the fungal infections.

A single molecular descriptor to predict solution behavior of therapeutic antibodies.

Despite the therapeutic success of monoclonal antibodies (mAbs), early identification of developable mAb drug candidates with optimal manufacturability, stability, and delivery attributes remains elusive. Poor solution behavior, which manifests as high solution viscosity or opalescence, profoundly affects the developability of mAb drugs. Using a diverse dataset of 59 mAbs, including 43 approved products, and an array of molecular descriptors spanning colloidal, conformational, charge-based, hydrodynamic, and hydrophobic properties, we show that poor solution behavior is prevalent (>30%) in mAbs and is singularly predicted (>90%) by the diffusion interaction parameter (k D), a dilute-solution measure of colloidal self-interaction. No other descriptor, individually or in combination, was found to be as effective as k D. We also show that well-behaved mAbs, a substantial subset of which bear high positive charge and pI, present no disadvantages with respect to pharmacokinetics in humans. Here, we provide a systematic framework with quantitative thresholds for selecting well-behaved therapeutic mAbs during drug discovery.

GAPS-megacities: A new global platform for investigating persistent organic pollutants and chemicals of emerging concern in urban air.

A pilot study was initiated in 2018 under the Global Atmospheric Passive Sampling (GAPS) Network named GAPS-Megacities. This study included 20 megacities/major cities across the globe with the goal of better understanding and comparing ambient air levels of persistent organic pollutants and other chemicals of emerging concern, to which humans residing in large cities are exposed. The first results from the initial period of sampling are reported for 19 cities for several classes of flame retardants (FRs) including organophosphate esters (OPEs), polybrominated diphenyl ethers (PBDEs), and halogenated flame retardants (HFRs) including new flame retardants (NFRs), tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCDD). The two cities, New York (USA) and London (UK) stood out with ∼3.5 to 30 times higher total FR concentrations as compared to other major cities, with total concentrations of OPEs of 15,100 and 14,100 pg/m3, respectively. Atmospheric concentrations of OPEs significantly dominated the FR profile at all sites, with total concentrations in air that were 2-5 orders of magnitude higher compared to other targeted chemical classes. A moderately strong and significant correlation (r = 0.625, p < 0.001) was observed for Gross Domestic Product index of the cities with total OPEs levels. Although large differences in FR levels were observed between some cities, when averaged across the five United Nations regions, the FR classes were more evenly distributed and varied by less than a factor of five. Results for Toronto, which is a 'reference city' for this study, agreed well with a more in-depth investigation of the level of FRs over different seasons and across eight sites representing different urban source sectors (e.g. traffic, industrial, residential and background). Future sampling periods under this project will investigate trace metals and other contaminant classes, linkages to toxicology, non-targeted analysis, and eventually temporal trends. The study provides a unique urban platform for evaluating global exposome.