Range of the perfluorooctanoate (PFOA) safe dose for human health: An international collaboration.

Many government agencies and expert groups have estimated a dose-rate of perfluorooctanoate (PFOA) that would protect human health. Most of these evaluations are based on the same studies (whether of humans, laboratory animals, or both), and all note various uncertainties in our existing knowledge. Nonetheless, the values of these various, estimated, safe-doses vary widely, with some being more than 100,000 fold different. This sort of discrepancy invites scrutiny and explanation. Otherwise what is the lay public to make of this disparity? The Steering Committee of the Alliance for Risk Assessment (2022) called for scientists interested in attempting to understand and narrow these disparities. An advisory committee of nine scientists from four countries was selected from nominations received, and a subsequent invitation to scientists internationally led to the formation of three technical teams (for a total of 24 scientists from 8 countries). The teams reviewed relevant information and independently developed ranges for estimated PFOA safe doses. All three teams determined that the available epidemiologic information could not form a reliable basis for a PFOA safe dose-assessment in the absence of mechanistic data that are relevant for humans at serum concentrations seen in the general population. Based instead on dose-response data from five studies of PFOA-exposed laboratory animals, we estimated that PFOA dose-rates 10-70 ng/kg-day are protective of human health.

The Conundrum of the PFOA human half-life, an international collaboration.

The Steering Committee of the Alliance for Risk Assessment (ARA) opened a call for scientists interested in resolving what appeared to be a conundrum in estimating of the half-life of perfluorooctanoate (PFOA) in humans. An Advisory Committee was formed from nominations received and a subsequent invitation led to the development of three small independent working groups to review appropriate information and attempt a resolution. Initial findings were shared among these groups and a conclusion developed from the ensuing discussions. Many human observational studies have estimated the PFOA half-life. Most of these studies note the likely occurrence of unmonitored PFOA exposures, which could inflate values of the estimated PFOA half-life. Also, few of these studies estimated the half-life of PFOA isomers, the branched chains of which likely have shorter half-lives. This could deflate values of the estimated linear PFOA half-life. Fortunately, several studies informed both of these potential problems. The majority opinion of this international collaboration is that the studies striking the best balance in addressing some of these uncertainties indicate the likely central tendency of the human PFOA half-life is less than 2 years. The single best value appears to be the geometric mean (GM) of 1.3 years (Zhang et al., 2013, Table 3), based on a GM = 1.7 years in young females (n = 20) and GM = 1.2 years in males of all ages and older females (n = 66). However, a combined median value from Zhang et al. (2013) of 1.8 years also adds value to this range of central tendency. While the Collaboration found this study to be the least encumbered with unmonitored PFOA exposures and branched isomers, more studies of similar design would be valuable. Also valuable would be clarification around background exposures in other existing studies in case adjustments to half-life estimates are attempted.

Real-world comparison of healthcare resource utilization and costs of [177Lu]Lu-DOTA-TATE in patients with progressive neuroendocrine tumors in England: a matched cohort analysis using data from the hospital episode statistics dataset.

OBJECTIVE: To explore the healthcare resource utilization (HCRU) and costs for patients with progressive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with [177Lu]Lu-DOTA-TATE and matched patients treated with somatostatin analogs (SSAs), chemotherapy, or targeted therapies. METHODS: Hospital Episode Statistics (HES) dataset 2016-2018 was used to compare HCRU and costs between the two cohorts. The [177Lu]Lu-DOTA-TATE cohort included patients assigned with a diagnosis code relevant to GEP-NET, a procedure code for imaging or SSAs, and a subsequent code for radionuclide therapy. The non-[177Lu]Lu-DOTA-TATE cohort included patients assigned with a diagnosis code relevant to GEP-NET who had an increased frequency of SSAs or switched from SSAs to chemotherapy or targeted therapies. Cohorts were matched on propensity scores with sex, age at disease progression, and Charlson Comorbidity Index as parameters. Healthcare Resource Group codes were used for costing. RESULTS: A total of 199 matched patients were included. The [177Lu]Lu-DOTA-TATE cohort had lower overall costs (£1,882,028 vs. £3,016,321; p < .0001), non-elective inpatient spells (289 vs. 611 days) and costs (£849,569 vs. £1,707,109; p < .0001 for both), Accident & Emergency costs (£41,978 vs. £62,480; p = .0013), and average length of stay for overall inpatient spells (14.2 vs. 23.3 days; p = .1092) compared with the non-[177Lu]Lu-DOTA-TATE cohort. CONCLUSIONS: These analyses indicate significantly lower overall costs and HCRU for progressive GEP-NET patients treated with [177Lu]Lu-DOTA-TATE. Current research reveals that future real-world analyses would further benefit from using additional databases linked to the HES dataset such as the Clinical Practice Research Datalink and/or National Cancer Registration and Analysis Service database.

Neuroendocrine neoplasms (NENs) are uncommon cancers involving the body's neuroendocrine cells. One type of NEN that is less aggressive with more favorable characteristics and prognosis is known as neuroendocrine tumor (NET). Somatostatin receptors (SSTR) are expressed by most NETs and are important treatment targets. Two-thirds of NETs originate in the body's gastroenteropancreatic system (GEP-NETs). GEP-NET is typically treated in the first instance with somatostatin analogs (SSAs), while other treatments such as chemotherapy, biologic targeted therapy, or Radio Ligand Therapy (RLT), can be offered to patients who have progressed. [¹⁷⁷Lu]Lu-DOTA-TATE is a form of RLT that has recently been approved for use in England, Wales, and Scotland.The purpose of this study is to analyze the utilization of healthcare resources and the costs associated with the management of GEP-NETs patients who have progressed on SSAs. This study is based on hospital data from England as available in the Hospital Episode Statistics dataset 2016­2018.The utilization and costs of healthcare resources were compared between two groups of patients. Following progression, one group received [¹⁷⁷Lu]Lu-DOTA-TATE, while the other group received other therapies (chemotherapy, biologic targeted therapy, or SSA with escalated or more frequent dosing). Statistical techniques were applied to enhance the comparability of analyzed groups of patients.The results revealed that the [¹⁷⁷Lu]Lu-DOTA-TATE group had lower inpatient admissions, outpatient appointments, and Accident & Emergency attendances compared with the non-[¹⁷⁷Lu]Lu-DOTA-TATE group. Furthermore, the overall costs in the [¹⁷⁷Lu]Lu-DOTA-TATE group were lower by 37.6%. This study indicated that patients and hospitals in England and other parts of the United Kingdom may benefit from the use of [¹⁷⁷Lu]Lu-DOTA-TATE. Further research is foreseen involving additional and linked databases, including further clinical outcomes as well.

Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial.

BACKGROUND: A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19 disease in the UK from November, 2020. We report a post-hoc analysis of the efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19 (AZD1222), against this variant. METHODS: Volunteers (aged ≥18 years) who were enrolled in phase 2/3 vaccine efficacy studies in the UK, and who were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 or a meningococcal conjugate control (MenACWY) vaccine, provided upper airway swabs on a weekly basis and also if they developed symptoms of COVID-19 disease (a cough, a fever of 37·8°C or higher, shortness of breath, anosmia, or ageusia). Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2 and positive samples were sequenced through the COVID-19 Genomics UK consortium. Neutralising antibody responses were measured using a live-virus microneutralisation assay against the B.1.1.7 lineage and a canonical non-B.1.1.7 lineage (Victoria). The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to vaccine received. Vaccine efficacy was calculated as 1 - relative risk (ChAdOx1 nCoV-19 vs MenACWY groups) derived from a robust Poisson regression model. This study is continuing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. FINDINGS: Participants in efficacy cohorts were recruited between May 31 and Nov 13, 2020, and received booster doses between Aug 3 and Dec 30, 2020. Of 8534 participants in the primary efficacy cohort, 6636 (78%) were aged 18-55 years and 5065 (59%) were female. Between Oct 1, 2020, and Jan 14, 2021, 520 participants developed SARS-CoV-2 infection. 1466 NAAT positive nose and throat swabs were collected from these participants during the trial. Of these, 401 swabs from 311 participants were successfully sequenced. Laboratory virus neutralisation activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9, 95% CI 7·2-11·0). Clinical vaccine efficacy against symptomatic NAAT positive infection was 70·4% (95% CI 43·6-84·5) for B.1.1.7 and 81·5% (67·9-89·4) for non-B.1.1.7 lineages. INTERPRETATION: ChAdOx1 nCoV-19 showed reduced neutralisation activity against the B.1.1.7 variant compared with a non-B.1.1.7 variant in vitro, but the vaccine showed efficacy against the B.1.1.7 variant of SARS-CoV-2. FUNDING: UK Research and Innovation, National Institute for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

On the changes in surface ozone over the twenty-first century: sensitivity to changes in surface temperature and chemical mechanisms.

In this study, we show using a state-of-the-art Earth system model, UKESM1, that emissions and climate scenario depending, there could be large changes in surface ozone by the end of the twenty-first century, with unprecedentedly large increases over South and East Asia. We also show that statistical modelling of the trends in future ozone works well in reproducing the model output between 1900 and 2050. However, beyond 2050, and especially under large climate change scenarios, the statistical model results are in poorer agreement with the fully interactive Earth system model output. This suggests that additional processes occurring in the Earth system model such as changes in the production of ozone at higher temperatures or changes in the influx of ozone from the stratosphere, which are not captured by the statistical model, have a first order impact on the evolution of surface ozone over the twenty-first century. We show in a series of idealized box model simulations, with two different chemical schemes, that changes in temperature lead to diverging responses between the schemes. This points at the chemical mechanisms as being a source of uncertainty in the response of ozone to changes in temperature, and so climate, in the future. This underscores the need for more work to be performed to better understand the response of ozone to changes in temperature and constrain how well this relationship is simulated in models. This article is part of a discussion meeting issue 'Air quality, past present and future'.