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Competing Interests: Declaration of conflicting interestsThe study diet was provided by the manufacturer for this study. An overview of the study results was shared with the manufacturer, but they did not read, revise, or contribute to the manuscript prior to publication.

Regulation of per- and polyfluorinated substances (PFAS) in surface water is a work-in-progress with relatively few criteria promulgated in the United States and internationally. Surface water quality criteria (SWQC) or screening values derived for perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) by Australia, Canada, the European Union (EU), and four US states (Florida, Michigan, Minnesota, and Wisconsin), and the San Francisco Bay Regional Water Quality Control Board (SFB RWQCB; California) were compared. Across these eight jurisdictions, promulgated numeric criteria for the same compound and receptor span over five orders of magnitude as a result of different approaches and data interpretations. Human health criteria for PFOS range from 0.0047 to 600 ng/L depending on route of exposure (e.g., fish consumption or drinking water) and are lower than most ecological criteria for protection of aquatic and wildlife receptors. Data gaps and uncertainty in chronic toxicity and bioaccumulation of PFOS and PFOA, as well as the use of conservative assumptions regarding intake and exposure, have resulted in some criteria falling at or below ambient background concentrations and current analytical detection limits (around 1 ng/L for commercial laboratories). Some jurisdictions (e.g., Australia, Canada) have deemed uncertainty in quantifying water-fish bioaccumulation too great and set fish tissue action levels in lieu of water criteria. Current dynamics associated with the emerging and evolving science of PFAS toxicity, exposure, and environmental fate (i.e., data gaps and uncertainty), as well as the continuous release of scientific updates, pose a challenge to setting regulatory limits. Integr Environ Assess Manag 2024;20:36-58. © 2023 AECOM Technical Services, Inc and The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)., (© 2023 AECOM Technical Services, Inc and The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)

Background and Aim: While studies continually identify new clinical prognostic factors in stage IV melanoma, the introduction of targeted and immunotherapies have revolutionised the prognosis of advanced melanoma since 2011. The study aims to investigate the prognostic significance of past and newly identified clinical factors in a contemporary cohort., Methods: A retrospective analysis of The Canberra Hospital melanoma database identified 161 patients with Stage IV melanoma between 2011 and 2017. Survival was analysed by demographics and clinical factors with chi-square tests to determine significance. Logistic binary regression was performed to test the independence of the clinical factors on predicting the survival outcome., Results: Overall, the 3-month, 6-month, 9-month, and 12-month stage IV melanoma survival rate of our cohort was 79%, 67%, 55%, and 45%, respectively. Age, sex, and BRAF mutation status were found to have no impact on survival, whereas M1d category of the American Joint Committee on Cancer (AJCC) staging (8th edition), neutrophil-lymphocyte ratio (NLR) >3, elevated serum LDH, more than three metastatic sites, brain metastases, poorer Eastern cooperative oncology group (ECOG) status were associated with poorer survival. Binary logistic regression test identified AJCC staging, NLR (cutoff score 3), LDH, and brain metastases as independent prognostic factors., Conclusion: Most clinical factors investigated in this study were found to have a statistically significant impact on survival, with AJCC (8th edition) staging M1a-M1d, NLR (cutoff score 3), LDH, and brain metastases identified as independent prognostic factors in stage IV melanoma from a contemporary cohort treated with targeted therapies and immunotherapies., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Immune checkpoint inhibitors have become the mainstay of treatment for metastatic melanoma. This article presents a new case of acquired generalised lipodystrophy (AGL) during anti-programmed cell death-1 (anti-PD-1) therapy and a systematic review of the literature with an aim to further understand the pathogenesis. A comprehensive search was conducted using PubMed, Embase, MEDLINE and Cochrane Central databases. We identified four cases of lipodystrophy associated with anti-PD-1 immunotherapy, including our own. Of these, three were associated with nivolumab, and one with pembrolizumab. Body composition changes occurred at a median of 7 months after anti-PD-1 initiation. All cases reported AGL, with subcutaneous fat loss affecting majority of the body. There were three reported cases of insulin resistance associated with AGL. AGL should be a recognised adverse event associated with anti-PD-1 therapy.

Background: Endothelial dysfunction is associated with vascular risk factors such as dyslipidemia, hypertension, and diabetes, leading to coronary atherosclerosis. Sympathetic stress using cold-pressor testing (CPT) has been used to measure coronary endothelial function in humans with positron emission tomography (PET) myocardial blood flow (MBF) imaging, but is not practical in small animal models. This study characterized coronary vasomotor function in mice with [(11)C]acetate micro-PET measurements of nitric-oxide-mediated endothelial flow reserve (EFRNOM) (adrenergic-stress/rest MBF) and myocardial oxygen consumption (MVO2) using salbutamol β2-adrenergic-activation., Methods: [(11)C]acetate PET MBF was performed at rest + salbutamol (SB 0.2, 1.0 μg/kg/min) and norepinephrine (NE 3.2 μg/kg/min) stress to measure an index of MBF response. β-adrenergic specificity of NE was evaluated by pretreatment with α-adrenergic-antagonist phentolamine (PHE), and β2-selectivity was assessed using SB., Results: Adjusting for changes in heart rate × systolic blood pressure product (RPP), the same stress/rest MBF ratio of 1.4 was measured using low-dose SB and NE in normal mice (equivalent to human CPT response). The MBF response was correlated with changes in MVO2 (p = 0.02). Nitric oxide synthase (NOS)-inhibited mice (N(g)-nitro-L-arginine methyl ester (L-NAME) pretreatment and endothelial nitric oxide synthase (eNOS) knockout) were used to assess the EFRNOM, in which the low-dose SB- and NE-stress MBF responses were completely blocked (p = 0.02). With high-dose SB-stress, the MBF ratio was reduced by 0.4 following NOS inhibition (p = 0.03)., Conclusions: Low-dose salbutamol β2-adrenergic-stress [(11)C]acetate micro-PET imaging can be used to measure coronary-specific EFRNOM in mice and may be suitable for assessment of endothelial dysfunction in small animal models of disease and evaluation of new therapies.

The use of lead in military and civilian small arms projectiles is widely acknowledged to have resulted in high soil lead concentrations at many small arms ranges. These ranges are often adjacent to wildlife habitat or have become habitat when no longer used. To assess the potential toxicity of lead to terrestrial amphibians in contaminated areas, we exposed 100 red-backed salamanders (Plethodon cinereus) to either a control soil or one of four soil treatments amended with lead acetate for 28 days. Analytical mean soil concentrations were 14 (control), 553, 1700, 4700, and 9167 mg Pb/kg soil dry weight. An additional 60 salamanders were also exposed for 28 days to one of six field-collected soil samples from a small arms range and a skeet range. The field soil concentrations ranged from 11 (background) to 16,967 mg Pb/kg soil dry weight. Food consisted of uncontaminated flightless Drosophila melanogaster. Salamander survival was reduced in amended soil treatments of 4700 and 9167 mg/kg by 15% and 80%, respectively. Inappetence was observed at 4700 and 9167 mg/kg and growth decreased in the 9167 mg/kg treatment. Total white blood cells decreased 32% at 4700 mg/kg compared to controls and were 22% lower in the 9167 mg/kg treatment. In contrast, survival was 100% for all field-collected soils with no hematological effects. At 16,967 mg/kg there was evidence of soil avoidance and decreased growth. These data suggest marked differences in toxicity and bioavailability of the lead-amended soil in contrast to the field-collected soil containing lead.

Copper (Cu) has widespread military use in munitions and small arms, particularly as a protective jacket for lead projectiles. The distribution of Cu at many US military sites is substantial and sites of contamination include habitats in and around military storage facilities, manufacturing, load and packing plants, open burning/open detonation areas, and firing ranges. Some of these areas include habitat for amphibian species, which generally lack toxicity data for risk assessment purposes. In an effort to ascertain Cu concentrations in soil that are toxic to terrestrial amphibians, 100 red-backed salamanders (Plethodon cinereus) were randomly sorted by weight, assigned to either a control soil or one of four treatments amended with copper acetate in soil, and exposed for 28 days. Analytical mean soil concentrations were 18, 283, 803, 1333, and 2700 mg Cu/kg soil dry weight. Food consisted of uncontaminated flightless Drosophila melanogaster. Survival was reduced in salamanders exposed to 1333 and 2700 mg/kg by 55% and 100%, respectively. Mortality/morbidity occurred within the first 4 days of exposure. These data suggest that a Cu soil concentration of and exceeding 1333.3 +/- 120.2 mg/kg results in reduced survival, whereas hematology analyses suggest that a concentration of and exceeding 803.3 +/- 98.4 mg/kg might result in reduced total white blood cell count. No effects were observed at 283.3 +/- 36.7 mg/kg.