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AIMS: Thrombotic thrombocytopenic purpura (TTP) is an ultra-rare blood disorder, characterized by severe ADAMTS13 deficiency. Affected individuals present with potentially life-threatening acute events and may experience sub-acute and chronic TTP manifestations often resulting in long-term organ damage. Incremental symptom prevalence before, during, and after an acute event as well as healthcare resource utilization (HCRU) and costs during and after an acute event were compared between people with TTP and matched non-TTP controls. METHODS: This retrospective, matched study used data from Merative MarketScan Commercial Database and Medicare Supplemental Database (from January 1, 2008, through September 30, 2021) to identify people with TTP (inpatient diagnosis for "thrombotic microangiopathy (TMA)" or "congenital TTP," and ≥1 claim for plasma exchange or infusion). People with TTP were matched (1:2) with non-TTP controls on age, sex, geographic region, index year, and select Elixhauser comorbidities. RESULTS: 255 people with TTP were matched with 510 non-TTP controls. Both cohorts had a mean age of 43.9 years; 71% were female. Overall, more people with TTP reported symptoms compared with non-TTP controls prior to (51% vs 43%), during (99% vs 52%), and after an acute event (85% vs 50%; p < 0.05 for all periods). Symptom prevalence decreased following an acute event compared with during an acute event, but remained high-85% of people with TTP experienced symptoms compared with 50% of non-TTP controls. HCRU and mean costs per patient per month were significantly higher in all care settings among people with TTP compared with non-TTP controls (p < 0.05). LIMITATIONS: Identification of patient populations may have been limited due to coding errors, as the data were obtained from an administrative claims database. CONCLUSIONS: TTP is associated with a substantial symptom burden and increased costs and HCRU during and up to almost a year after acute events, demonstrating the longitudinal burden of this disease.

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DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Severe ADAMTS13 deficiency (activity <10%) is the diagnostic threshold for thrombotic thrombocytopenic purpura (TTP) and is associated with various clinical symptoms, abnormal laboratory results, and long-term complications. METHODS: This retrospective, noninterventional cohort study used the Premier Healthcare Database to identify patients with ADAMTS13 activity of <10% in US hospitals from January 1, 2016, through March 31, 2020. The objective was to describe patient characteristics, laboratory results, comorbidities (as measured by the Elixhauser comorbidity index), symptoms, length of stay, treatment patterns, mortality, inpatient costs, and readmission rates (summarized descriptively). Inpatient costs were calculated as total cost to the hospital. RESULTS: There were 211 patients with severe ADAMTS13 deficiency; 89% of patients had a TTP-related diagnosis, of whom 62% had a primary diagnosis of thrombotic microangiopathy. Over 80% of patients with available data had a decreased platelet count and elevated lactate dehydrogenase; schistocytes were detected in 99%. The most prevalent symptoms/complications were neurological, bleeding, and pain. Most patients (86%) had 2 or more Elixhauser comorbidities. Over 80% of patients received 1 or more TTP-related treatments, mostly plasma exchange. The mean length of stay was 11.5 days; 5% of patients died during their stay. Readmission rates at 30, 60, and 90 days were 20%, 26%, and 28%, respectively. The median (interquartile range) total inpatient cost to the hospital throughout the index admission was $33,221 ($19,431-$64,901). CONCLUSION: Patients with severe ADAMTS13 deficiency have substantial clinical burden, have high mortality and readmission rates, and generate high costs for hospitals. There is a high need for a therapy that replaces ADAMTS13, thus addressing the root cause of the symptoms and complications caused by this deficiency.

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Per- and polyfluoroalkyl substances (PFAS) receive global attention due to their adverse effects on human health and the environment. Fish consumption is a major source of human PFAS exposure. The aim of this work was to address the lack of harmonization within legislations (in the EU and the USA) and highlight the level of PFAS in fish exposed to pollution from diffuse sources in the context of current safety thresholds. A non-exhaustive literature review was carried out to obtain PFAS concentrations in wild fish from the Norwegian mainland, Svalbard, the Netherlands, the USA, as well as sea regions (North Sea, English Channel, Atlantic Ocean), and farmed fish on the Dutch market. Median sum wet weight concentrations of PFOA, PFNA, PFHxS, and PFOS ranged between 0.1 µg kg-1 (farmed fish) and 22 µg kg-1 (Netherlands eel). Most concentrations fell below the EU environmental quality standard (EQSbiota) for PFOS (9.1 µg kg-1) and would not be defined as polluted in the EU. However, using recent tolerable intake or reference dose values in the EU and the USA revealed that even limited fish consumption would lead to exceedance of these thresholds - possibly posing a challenge for risk communication.

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Limited information is available on the removal of per- and polyfluoroalkyl substances (PFAS) in anaerobic digestion (AD). Τhe fate of six PFAS was studied in thermophilic bioreactors in the presence of granular activated carbon (GAC) and voltage application. Reactors with GAC exhibited lower concentrations of volatile fatty acids and higher methane production compared to those with and without the application of voltage. Analysis of PFAS in dissolved and solid phase showed that their distribution was dependent on perfluorocarbon chain length and functional group. Mass balances showed that PFAS were not removed during conventional AD or after applying voltage; however, significant removal (up to 61 ± 8 %) was observed in bioreactors with GAC for perfluoroheptanoic acid (PFHpA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorooctane sulfonate (PFOS). Biomass characterization showed that in these bioreactors, the relative abundance of Acinetobacter and Pseudomonas was higher, indicating their potential role in PFAS biotransformation.

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Background: Persistent, mobile and toxic (PMT), or very persistent and very mobile (vPvM) substances are a wide class of chemicals that are recalcitrant to degradation, easily transported, and potentially harmful to humans and the environment. Due to their persistence and mobility, these substances are often widespread in the environment once emitted, particularly in water resources, causing increased challenges during water treatment processes. Some PMT/vPvM substances such as GenX and perfluorobutane sulfonic acid have been identified as substances of very high concern (SVHCs) under the European Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulation. With hundreds to thousands of potential PMT/vPvM substances yet to be assessed and managed, effective and efficient approaches that avoid a case-by-case assessment and prevent regrettable substitution are necessary to achieve the European Union's zero-pollution goal for a non-toxic environment by 2050. Main: Substance grouping has helped global regulation of some highly hazardous chemicals, e.g., through the Montreal Protocol and the Stockholm Convention. This article explores the potential of grouping strategies for identifying, assessing and managing PMT/vPvM substances. The aim is to facilitate early identification of lesser-known or new substances that potentially meet PMT/vPvM criteria, prompt additional testing, avoid regrettable use or substitution, and integrate into existing risk management strategies. Thus, this article provides an overview of PMT/vPvM substances and reviews the definition of PMT/vPvM criteria and various lists of PMT/vPvM substances available. It covers the current definition of groups, compares the use of substance grouping for hazard assessment and regulation, and discusses the advantages and disadvantages of grouping substances for regulation. The article then explores strategies for grouping PMT/vPvM substances, including read-across, structural similarity and commonly retained moieties, as well as the potential application of these strategies using cheminformatics to predict P, M and T properties for selected examples. Conclusions: Effective substance grouping can accelerate the assessment and management of PMT/vPvM substances, especially for substances that lack information. Advances to read-across methods and cheminformatics tools are needed to support efficient and effective chemical management, preventing broad entry of hazardous chemicals into the global market and favouring safer and more sustainable alternatives.

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BACKGROUND: Von Willebrand disease (VWD) is underdiagnosed, often delaying treatment. VWD claims coding is limited and includes no severity qualifiers; improved identification methods for VWD are needed. The aim of this study is to identify and characterize undiagnosed symptomatic persons with VWD in the US from medical insurance claims using predictive machine learning (ML) models. RESEARCH DESIGN AND METHODS: Diagnosed and potentially undiagnosed VWD cohorts were defined using Komodo longitudinal US claims data (January 2015-March 2020). ML models were built using key characteristics predictive of VWD diagnosis from the diagnosed cohort. Two ML models predicted VWD diagnosis with the highest accuracy in females (random forest; 84%) and males (gradient boosting machine; 85%). Undiagnosed persons suspected to have VWD were identified using an 80% cutoff probability; profiles of key characteristics were constructed. RESULTS: The trained ML models were applied to the undiagnosed cohort (28,463 females; 20,439 males) with suspected VWD. Fifty-two percent of undiagnosed females had heavy menstrual bleeding, a key pre-diagnosis symptom. Undiagnosed males tended to have more frequent medical procedures, hospitalizations, and emergency room visits compared with undiagnosed females. CONCLUSIONS: ML algorithms successfully identified potentially undiagnosed symptomatic people with VWD, although many may remain undiagnosed and undertreated. External validation of the algorithms is recommended.

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INTRODUCTION: Gastrointestinal (GI) bleeding events (BEs) in von Willebrand disease (VWD) are difficult to diagnose and often recurrent. Limited data from clinical trials has led to lack of consensus on treatment options. AIM: Describe current treatments and outcomes for GI BEs in people with VWD. METHODS: This retrospective, observational, multicentre chart review study was conducted from January 2018 through December 2019 and included patients with inherited VWD with ≥1 GI BE in the preceding 5 years. Baseline characteristics, number and aetiology of BEs, associated GI-specific morbidities/lesions, treatment and outcomes were analysed descriptively. RESULTS: Sixty bleeds were reported in 20 patients with type 1 (20%), type 2 (50%) and type 3 (30%) VWD. During the 5-year study period, 31 (52%) BEs had one identified or suspected cause; multiple causes were reported in 11 (18%). Most GI BEs (72%) were treated with a combination of von Willebrand factor (VWF), antifibrinolytics and/or other haemostatic or non-haemostatic treatments. Time to resolution did not differ by VWF treatment use; however, BEs treated with non-VWF treatments tended to resolve later. In patients with GI-specific morbidities/lesions, 84% resolved with first-line treatment; time to resolution tended to be longer than in patients without such morbidities/lesions. Thirteen BEs occurred in patients receiving prophylaxis and 47 in patients receiving on-demand treatment; 18 BEs resulted in a switch to prophylaxis after bleed resolution. CONCLUSIONS: This study confirms the unmet need for the management of recurrent GI BEs in people with VWD and the need for prospective data, especially on prophylaxis.

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When chemical pollutants enter the environment, they can undergo diverse transformation processes, forming a wide range of transformation products (TPs), some of them benign and others more harmful than their precursors. To date, the majority of TPs remain largely unrecognized and unregulated, particularly as TPs are generally not part of routine chemical risk or hazard assessment. Since many TPs formed from oxidative processes are more polar than their precursors, they may be especially relevant in the context of persistent, mobile, and toxic (PMT) and very persistent and very mobile (vPvM) substances, which are two new hazard classes that have recently been established on a European level. We highlight herein that as a result, TPs deserve more attention in research, chemicals regulation, and chemicals management. This perspective summarizes the main challenges preventing a better integration of TPs in these areas: (1) the lack of reliable high-throughput TP identification methods, (2) uncertainties in TP prediction, (3) inadequately considered TP formation during (advanced) water treatment, and (4) insufficient integration and harmonization of TPs in most regulatory frameworks. A way forward to tackle these challenges and integrate TPs into chemical management is proposed.

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AIMS: Differentiating cardiac amyloidosis (CA) subtypes is important considering the significantly different therapies for transthyretin (ATTR)-CA and light chain (AL)-CA. Therefore, an echocardiographic method to distinguish ATTR-CA from AL-CA would provide significant value. We assessed a novel echocardiographic pixel intensity method to quantify myocardial calcification to differentiate ATTR-CA from phenocopies of CA and from AL-CA, specifically. METHODS AND RESULTS: 167 patients with ATTR-CA (n=53), AL-CA (n=32), hypertrophic cardiomyopathy (n=37), and advanced chronic kidney disease (n=45) were retrospectively evaluated. The septal reflectivity ratio (SRR) was measured as the average pixel intensity of the visible anterior septal wall divided by the average pixel intensity of the visible posterior lateral wall. SRR and other myocardial strain-based echocardiographic measures were evaluated with receiver operator characteristic analysis to evaluate accuracy in distinguishing ATTR-CA from AL-CA and other forms of left ventricular hypertrophy. Mean septal reflectivity ratio (SRR) was significantly higher in the ATTR-CA cohort compared to the other cohorts (p <0.001). SRR demonstrated the largest AUC (0.91, p<0.0001) for distinguishing ATTR from all other cohorts and specifically for distinguishing ATTR-CA from AL-CA (AUC=0.90, p<0.0001, specificity 96%, sensitivity 63%). There was excellent inter- and intra-operator reproducibility with an ICC of 0.91 (p <0.001) and 0.89 (p <0.001), respectively. CONCLUSION: The SRR is a reproducible and robust parameter for differentiating ATTR-CA from other phenocopies of CA and specifically ATTR-CA from AL-CA.

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Proximal radial artery (PRA) access for cardiac catheterization is safe but can jeopardize subsequent use of the artery because of occlusion. Distal radial artery (DRA) access in the anatomical snuffbox preserves the RA but safety and potential detrimental effects on hand function are unknown. We aimed to assess hand function and complications after DRA and PRA. In this single-center trial, 300 patients were randomly allocated 1:1 to cardiac catheterization through DRA or PRA. The primary end point of change in hand function from baseline to 1 year was a composite of the Quick Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire, hand grip test, and thumb-forefinger pinch test. The secondary end points included access feasibility and complications. Of 216 patients with 1-year completed follow-up, 112 were randomly allocated to DRA and 104 to PRA, with balanced demographics and procedural characteristics. Both groups had similar access site bleeding rates (DRA 0% vs PRA 1.4%, p = 0.25). Radial artery occlusion occurred in 1 PRA patient versus 2 in DRA. There was no significant difference in change of hand function, median (interquartile range) hand grip (DRA 0.7 [-3 to 4.5] vs PRA 1.3 [-2 to 4.3] kg, p = 0.57), pinch grip (DRA -0.1 [-1.1 to 1] vs PRA -0.3 [-1 to 0.7] kg, p = 0.66), and Quick DASH (DRA 0 [-6.6 to 2.3] vs PRA 0 [-4.6 to 2.9] points, p = 0.58). The composite of hand function was comparable between PRA and DRA. In conclusion, DRA is a safe strategy for cardiac catheterization, with a low complication rate. Compared with PRA, there is no increased risk of hand dysfunction or radial artery occlusion at 1 year.

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Only a fraction of the total number of per- and polyfluoroalkyl substances (PFAS) are monitored on a routine basis using targeted chemical analyses. We report on an approach toward identifying bioactive substances in environmental samples using effect-directed analysis by combining toxicity testing, targeted chemical analyses, and suspect screening. PFAS compete with the thyroid hormone thyroxin (T4 ) for binding to its distributor protein transthyretin (TTR). Therefore, a TTR-binding bioassay was used to prioritize unknown features for chemical identification in a PFAS-contaminated sediment sample collected downstream of a factory producing PFAS-coated paper. First, the TTR-binding potencies of 31 analytical PFAS standards were determined. Potencies varied between PFAS depending on carbon chain length, functional group, and, for precursors to perfluoroalkyl sulfonic acids (PFSA), the size or number of atoms in the group(s) attached to the nitrogen. The most potent PFAS were the seven- and eight-carbon PFSA, perfluoroheptane sulfonic acid (PFHpS) and perfluorooctane sulfonic acid (PFOS), and the eight-carbon perfluoroalkyl carboxylic acid (PFCA), perfluorooctanoic acid (PFOA), which showed approximately four- and five-times weaker potencies, respectively, compared with the native ligand T4 . For some of the other PFAS tested, TTR-binding potencies were weak or not observed at all. For the environmental sediment sample, not all of the bioactivity observed in the TTR-binding assay could be assigned to the PFAS quantified using targeted chemical analyses. Therefore, suspect screening was applied to the retention times corresponding to observed TTR binding, and five candidates were identified. Targeted analyses showed that the sediment was dominated by the di-substituted phosphate ester of N-ethyl perfluorooctane sulfonamido ethanol (SAmPAP diester), whereas it was not bioactive in the assay. SAmPAP diester has the potential for (bio)transformation into smaller PFAS, including PFOS. Therefore, when it comes to TTR binding, the hazard associated with this substance is likely through (bio)transformation into more potent transformation products. Environ Toxicol Chem 2024;43:245-258. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

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Soil washing is currently attracting attention as a promising remediation strategy for land contaminated with per- and polyfluoroalkyl substances (PFAS). In the soil washing process, the contaminant is transferred from the soil into the liquid phase, producing a PFAS contaminated process water. One way to treat such process water is to use coagulation and flocculation; however, few studies are available on the performance of coagulation and flocculation for removing PFAS from such process water. This study evaluated 6 coagulants and flocculants (polyaluminium chloride (PACl), zirconium oxychloride octahydrate, cationic and anionic polyacrylamide, Polyclay 685 and Perfluor Ad®), for the treatment of a proxy PFAS contaminated washing water, spiked with PFAS concentrations found at typical Aqueous Film Forming Foam (AFFF) contaminated sites. PFAS removal efficiencies (at constant pH) varied greatly depending on the coagulants and flocculants, as well as the dosage used and the targeted PFAS. All tested coagulants and flocculants reduced the turbidity by >95%, depending on the dosage. Perfluor Ad®, a specially designed coagulant, showed the highest removal efficiency for all longer chain (>99%) and shorter chain PFAS (>68%). The cationic polyacrylamide polymer removed longer chain PFAS up to an average of 80%, whereas average shorter chain PFAS removal was lower (<30%). The two metal-based coagulants tested, PACl and zirconium, removed longer chain PFAS by up to an average of 61% and shorter chain PFAS up to 48%. Polyclay 685, a mixture of powdered activated carbon (PAC) and aluminium sulphate, removed longer chain PFAS by 90% and shorter chain PFAS on average by 76%, when very high dosages of the coagulant were used (2,000 mg/L). PFAS removal efficiencies correlated with chain length and headgroup. Shorter chain PFAS removal was dependent on electrostatic interaction with the precipitating flocs, whereas for longer chain PFAS, hydrophobic interactions between apolar functional groups and flocs created by the coagulant/flocculant, dissolved organic matter and suspended solids played a major role. The results of this study showed that by selecting the most efficient coagulant and aqueous conditions, a greater amount of PFAS can be removed from process waters in soil washing facilities, and thus included as part of various treatment trains.

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Background Proximal radial artery (pRA) access for cardiac catheterization is safe but can jeopardize subsequent use of the artery because of occlusion. Distal radial artery (dRA) access in the anatomical snuffbox preserves the radial artery, but safety and potential detrimental effects on hand function are unknown. Methods and Results In the DIPRA (Distal Versus Proximal Radial Artery Access for Cardiac Catheterization and Intervention) study, a single-center trial, 300 patients were randomized 1:1 to cardiac catheterization through dRA or pRA. The primary end point of change in hand function from baseline to 30 days was a composite of the QuickDASH (Quick Disabilities of the Arm, Shoulder and Hand) questionnaire, hand-grip test, and thumb forefinger pinch test. Secondary end points included access feasibility and complications; 254 of 300 patients completed follow-up at 30 days; of these, 128 were randomized to dRA and 126 to pRA with balanced demographic and procedural characteristics. Both groups had similar rates of access site bleeding (dRA 0% versus pRA 1.4%; P=0.25). Six patients with dRA failed access compared with 2 patients with pRA. Radial artery occlusion occurred in 2 pRA versus none in dRA. There were no significant differences in change in hand function, median hand-grip (dRA 0 [-3.2, 3.3] versus pRA 0.7 [-2.3, 3.3] kg; P=0.21), pinch-grip (dRA -0.3 [-1.2, 0.5] versus pRA 0 [-0.9, 0.9] kg; P=0.09), and QuickDASH (dRA 0 [-4.6, 2.3] versus pRA 0 [-4.6, 2.3] points, P=0.96). There was no significant difference in the composite of hand function between pRA and dRA. Conclusions dRA is a safe strategy for cardiac catheterization with a low complication rate. Compared with pRA, there is no increased risk of hand dysfunction at 30 days. Registration URL: https://www.ClinicalTrials.gov. Unique identifier: NCT04318990.

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A soil that was historically contaminated with Aqueous Film Forming Foam (AFFF) was dry sieved into size fractions representative of those produced during soil washing. Batch sorption tests were then conducted to investigate the effect of soil parameters on in situ per- and polyfluoroalkyl substances (PFAS) sorption of these different size fractions: < 0.063 mm, 0.063 to 0.5 mm, 0.5 to 2 mm, 2 to 4 mm, 4 to 8 mm, and soil organic matter residues (SOMR). PFOS (513 ng/g), 6:2 FTS (132 ng/g) and PFHxS (58 ng/g) were the most dominant PFAS in the AFFF contaminated soil. Non-spiked, in situ Kd values for 19 PFAS ranged from 0.2 to 138 L/Kg (log Kd -0.8 to 2.14) for the bulk soil and were dependant on the head group and perfluorinated chain length (spanning C4 to C13). The Kd values increased with decreasing grain size and increasing organic carbon content (OC), which were correlated to each other. For example, the PFOS Kd value for silt and clay (< 0.063 mm, 17.1 L/Kg, log Kd 1.23) were approximately 30 times higher compared to the gravel fraction (4 to 8 mm, 0.6 L/Kg, log Kd -0.25). The highest PFOS Kd value (116.6 L/Kg, log Kd 2.07) was found for the SOMR fraction, which had the highest OC content. Koc values for PFOS ranged from 6.9 L/Kg (log Koc 0.84) for the gravel fraction to 1906 L/Kg (log Koc 3.28) for the silt and clay, indicating that the mineral composition of the different size fractions also influenced sorption. The results here emphasize the need to separate coarse-grained fractions and fine-grained fractions, and in particular the SOMR, to optimize the soil washing process. Higher Kd values for the smaller size fractions indicate that coarser soils are better suited for soil washing.

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BACKGROUND: Excessive or abnormal mucocutaneous bleeding (MCB) may impact all aspects of the physical and psychosocial wellbeing of those who live with it (PWMCB). The evidence base for the optimal diagnosis and management of disorders such as inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD), Ehlers-Danlos syndromes (EDS), and von Willebrand disease (VWD) remains thin with enormous potential for targeted research. RESEARCH DESIGN AND METHODS: National Hemophilia Foundation and American Thrombosis and Hemostasis Network initiated the development of a National Research Blueprint for Inherited Bleeding Disorders with extensive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them. They recruited multidisciplinary expert working groups (WG) to distill community-identified priorities into concrete research questions and score their feasibility, impact, and risk. RESULTS: WG2 detailed 38 high priority research questions concerning the biology of MCB, VWD, inherited qualitative platelet function defects, HDS/EDS, HHT, bleeding disorder of unknown cause, novel therapeutics, and aging. CONCLUSIONS: Improving our understanding of the basic biology of MCB, large cohort longitudinal natural history studies, collaboration, and creative approaches to novel therapeutics will be important in maximizing the benefit of future research for the entire MCB community.

More people experience mucocutaneous bleeding (MCB), affecting tissues like skin and gums, than have hemophilia A or B. MCB is not understood as well as hemophilia. Common types of MCB include nosebleeds, bleeding gums, heavy menstrual bleeding, and digestive tract bleeding. Mucocutaneous inherited bleeding disorders include inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD) and Ehlers-Danlos syndromes (EDS), von Willebrand Disease (VWD), and others. Diagnosing and treating MCB is complicated and sometimes medical providers dismiss the bleeding that patients report when they cannot find a medical explanation for it. Many people with mucocutaneous bleeding (PWMCB) do not receive the care they need; for example, women with VWD live with symptoms for, on average, 16 years before they are diagnosed in the US. This struggle to obtain care has important negative impacts on patients' physical and psychological health and their quality-of-life. The National Hemophilia Foundation (NHF), a large US bleeding disorders patient advocacy organization, set out to develop a National Research Blueprint for Inherited Bleeding Disorders focused on community priorities. They brought together a group of patients, providers, and researchers with MCB expertise to identify the research that would most improve the lives of PWMCB through targeted and accessible diagnostics and therapies. We report in this paper that research is needed to better understand the biology of MCB and to define the mechanisms of disease in these disorders. We also describe high priority research questions for each of the main disorders, novel therapeutics, and aging.

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Cyclic arginyl-glycyl-aspartic acid peptide (cRGD) peptides show a high affinity towards αVß3 integrin, a receptor overexpressed in many cancers. We aimed to combine the versatility of ultrasmall gold nanoparticles (usGNP) with the target selectivity of cRGD peptide for the directed delivery of a cytotoxic payload in a novel design. usGNPs were synthesized with a modified Brust-Schiffrin method and functionalized via amide coupling and ligand exchange and their uptake, intracellular trafficking, and toxicity were characterized. Our cRGD functionalized usGNPs demonstrated increased cellular uptake by αVß3 integrin expressing cells, are internalized via clathrin-dependent endocytosis, accumulated in the lysosomes, and when loaded with mertansine led to increased cytotoxicity. Targeting via cRGD functionalization provides a mechanism to improve the efficacy, tolerability, and retention of therapeutic GNPs.

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Persistent and mobile organic substances are those with the highest propensity to be widely distributed in groundwater and thereby, when emitted at low-levels, to contaminate drinking water extraction points and freshwater environments. To prevent such contamination, the European Commission is in the process of introducing new hazard classes for persistent, mobile, and toxic (PMT) and very persistent and very mobile (vPvM) substances within its key chemical regulations CLP and REACH. The assessment of persistence in these regulations will likely be based on simulated half-life, t 1/2, thresholds; the assessment of mobility will likely be based on organic carbon-water distribution coefficient, K OC, thresholds. This study reviews the use of t 1/2 and K OC to describe persistence and mobility, considering the theory, history, suitability, data limitations, estimation methods, and alternative parameters. For this purpose, t 1/2, K OC, and alternative parameters were compiled for substances registered under REACH, known transformation products, and substances detected in wastewater treatment plant effluent, surface water, bank filtrate, groundwater, raw water, and drinking water. Experimental t 1/2 values were rare and only available for 2.2% of the 14 203 unique chemicals identified. K OC data were only available for a fifth of the substances. Therefore, the usage of alternative screening parameters was investigated to predict t 1/2 and K OC values, to assist weight-of-evidence based PMT/vPvM hazard assessments. Even when considering screening parameters, for 41% of substances, PMT/vPvM assessments could not be made due to data gaps; for 23% of substances, PMT/vPvM assessments were ambiguous. Further effort is needed to close these substantial data gaps. However, when data is available, the use of t 1/2 and K OC is considered fit-for-purpose for defining PMT/vPvM thresholds. Using currently discussed threshold values, between 1.9 and 2.6% of REACH registered substances were identified as PMT/vPvM. Among the REACH registered substances detected in drinking water sources, 24-30% were PMT/vPvM substances.