Radiation Adverse Outcome pathways (AOPs): examining priority questions from an international horizon-style exercise.

PURPOSE: The Organisation for Economic Co-operation and Development (OECD) Adverse Outcome Pathway (AOP) Development Programme is being explored in the radiation field, as an overarching framework to identify and prioritize research needs that best support strengthening of radiation risk assessment and risk management strategies. To advance the use of AOPs, an international horizon-style exercise (HSE) was initiated through the Radiation/Chemical AOP Joint Topical Group (JTG) formed by the OECD Nuclear Energy Agency (NEA) High-Level Group on Low Dose Research (HLG-LDR) under the auspices of the Committee on Radiological Protection and Public Health (CRPPH). The intent of the HSE was to identify key research questions for consideration in AOP development that would help to reduce uncertainties in estimating the health risks following exposures to low dose and low dose-rate ionizing radiation. The HSE was conducted in several phases involving the solicitation of relevant questions, a collaborative review of open-ended candidate questions and an elimination exercise that led to the selection of 25 highest priority questions for the stated purpose. These questions were further ranked by over 100 respondents through an international survey. This final set of questions was judged to provide insights into how the OECD's AOP approach can be put into practice to meet the needs of hazard and risk assessors, regulators, and researchers. This paper examines the 25 priority questions in the context of hazard/risk assessment framework for ionizing radiation. CONCLUSION: By addressing the 25 priority questions, it is anticipated that constructed AOPs will have a high level of specificity, making them valuable tools for simplifying and prioritizing complex biological processes for use in developing revised radiation hazard and risk assessment strategies.

Leadership education as democracy-in-action: In pursuit of the United Nations Sustainable Development Goals.

With the world growing in complexity and interconnectedness, the demand for leaders equipped to solve compound problems will only increase. Higher education is called upon to develop leadership in students and needs to engage relevant tools and techniques to prepare students for the tasks ahead. Democratic engagement-from voter education and engagement to critical service learning-and leadership development are powerful vehicles for student development. The United Nations Sustainable Development Goals are effective and compelling tools to support student learning in academic and cocurricular arenas as part of democratic engagement and leadership education and development. The authors will explore some of the implications and considerations in advancing these initiatives and using these means to advance our local and global communities.

Considerations for application of benchmark dose modeling in radiation research: workshop highlights.

BACKGROUND: Exposure to different forms of ionizing radiation occurs in diverse occupational, medical, and environmental settings. Improving the accuracy of the estimated health risks associated with exposure is therefore, essential for protecting the public, particularly as it relates to chronic low dose exposures. A key aspect to understanding health risks is precise and accurate modeling of the dose-response relationship. Toward this vision, benchmark dose (BMD) modeling may be a suitable approach for consideration in the radiation field. BMD modeling is already extensively used for chemical hazard assessments and is considered statistically preferable to identifying low and no observed adverse effects levels. BMD modeling involves fitting mathematical models to dose-response data for a relevant biological endpoint and identifying a point of departure (the BMD, or its lower bound). Recent examples in chemical toxicology show that when applied to molecular endpoints (e.g. genotoxic and transcriptional endpoints), BMDs correlate to points of departure for more apical endpoints such as phenotypic changes (e.g. adverse effects) of interest to regulatory decisions. This use of BMD modeling may be valuable to explore in the radiation field, specifically in combination with adverse outcome pathways, and may facilitate better interpretation of relevant in vivo and in vitro dose-response data. To advance this application, a workshop was organized on June 3rd, 2022, in Ottawa, Ontario that brought together BMD experts in chemical toxicology and the radiation scientific community of researchers, regulators, and policy-makers. The workshop's objective was to introduce radiation scientists to BMD modeling and its practical application using case examples from the chemical toxicity field and demonstrate the BMDExpress software using a radiation dataset. Discussions focused on the BMD approach, the importance of experimental design, regulatory applications, its use in supporting the development of adverse outcome pathways, and specific radiation-relevant examples. CONCLUSIONS: Although further deliberations are needed to advance the use of BMD modeling in the radiation field, these initial discussions and partnerships highlight some key steps to guide future undertakings related to new experimental work.

Ethical Issues in Research: Perceptions of Researchers, Research Ethics Board Members and Research Ethics Experts.

In the context of academic research, a diversity of ethical issues, conditioned by the different roles of members within these institutions, arise. Previous studies on this topic addressed mainly the perceptions of researchers. However, to our knowledge, no studies have explored the transversal ethical issues from a wider spectrum, including other members of academic institutions as the research ethics board (REB) members, and the research ethics experts. The present study used a descriptive phenomenological approach to document the ethical issues experienced by a heterogeneous group of Canadian researchers, REB members, and research ethics experts. Data collection involved socio-demographic questionnaires and individual semi-structured interviews. Following the triangulation of different perspectives (researchers, REB members and ethics experts), emerging ethical issues were synthesized in ten units of meaning: (1) research integrity, (2) conflicts of interest, (3) respect for research participants, (4) lack of supervision and power imbalances, (5) individualism and performance, (6) inadequate ethical guidance, (7) social injustices, (8) distributive injustices, (9) epistemic injustices, and (10) ethical distress. This study highlighted several problematic elements that can support the identification of future solutions to resolve transversal ethical issues in research that affect the heterogeneous members of the academic community.

Radiation adverse outcome pathways (AOPs) are on the horizon: advancing radiation protection through an international Horizon-Style exercise.

PURPOSE: The Adverse Outcome Pathway (AOP) framework, a systematic tool that can link available mechanistic data with phenotypic outcomes of relevance to regulatory decision-making, is being explored in areas related to radiation risk assessment. To examine the challenges including the use of AOPs to support the radiation protection community, an international horizon-style exercise was initiated through the Organisation for Economic Co-operation and Development Nuclear Energy Agency High-Level Group on Low Dose Research Radiation/Chemical AOP Joint Topical Group. The objective of the HSE was to facilitate the collection of ideas from a range of experts, to short-list a set of priority research questions that could, if answered, improve the description of the radiation dose-response relationship for low dose/dose-rate exposures, as well as reduce uncertainties in estimating the risk of developing adverse health outcomes following such exposures. MATERIALS AND METHODS: The HSE was guided by an international steering committee of radiation risk experts. In the first phase, research questions were solicited on areas that can be supported by the AOP framework, or challenges on the use of AOPs in radiation risk assessment. In the second phase, questions received were refined and sorted by the SC using a best-worst scaling method. During a virtual 3-day workshop, the list of questions was further narrowed. In the third phase, an international survey of the broader radiation protection community led to an orderly ranking of the top questions. RESULTS: Of the 271 questions solicited, 254 were accepted and categorized into 9 themes. These were further refined to the top 25 prioritized questions. Among these, the higher ranked questions will be considered as 'important' to drive future initiatives in the low dose radiation protection community. These included questions on the ability of AOPs to delineate responses across different levels of biological organization, and how AOPs could be applied to address research questions on radiation quality, doses or dose-rates, exposure time patterns and deliveries, and uncertainties in low dose/dose-rate effects. A better understanding of these concepts is required to support the use of the AOP framework in radiation risk assessment. CONCLUSION: Through dissemination of these results and considerations on next steps, the JTG will address select priority questions to advance the development and use of AOPs in the radiation protection community. The major themes observed will be discussed in the context of their relevance to areas of research that support the system of radiation protection.

A localized calcium transient and polar body abscission.

Polar body emission is a special form of cytokinesis in oocyte meiosis that ensures the correct number of chromosomes in reproduction-competent eggs. The molecular mechanism of the last step, polar body abscission, is poorly understood. While it has been proposed that Ca2+ signaling plays important roles in embryonic cytokinesis, to date transient increases in intracellular free Ca2+ have been difficult to document in oocyte meiosis except for the global Ca2+ wave induced by sperm at fertilization. Here, we find that microinjection of the calcium chelator dibromo-BAPTA inhibits polar body abscission in Xenopus laevis oocytes. Using a novel, microtubule-targeted ratio-metric calcium sensor, we detected a calcium transient that is focused at the contractile ring-associated plasma membrane and which occurred after anaphase and constriction of the contractile ring but prior to abscission. This calcium transient was confirmed by mobile calcium probes. Further, the Ca2+-sensitive protein kinase Cß C2 domain transiently translocated to the contractile ring-associated membrane simultaneously with the calcium transient. Collectively, these results demonstrate that a calcium transient, apparently originating at the contractile ring-associated plasma membrane, promotes polar body abscission.

Adverse outcome pathway: a path toward better data consolidation and global co-ordination of radiation research.

BACKGROUND: The purpose of toxicology is to protect human health and the environment. To support this, the Organisation for Economic Co-operation and Development (OECD), operating via its Extended Advisory Group for Molecular Screening and Toxicogenomics (EAGMST), has been developing the Adverse Outcome Pathway (AOP) approach to consolidate evidence for chemical toxicity spanning multiple levels of biological organization. The knowledge transcribed into AOPs provides a structured framework to transparently organize data, examine the weight of evidence of the AOP, and identify causal relationships between exposure to stressors and adverse effects of regulatory relevance. The AOP framework has undergone substantial maturation in the field of hazard characterization of chemicals over the last decade, and has also recently gained attention from the radiation community as a means to advance the mechanistic understanding of human and ecological health effects from exposure to ionizing radiation at low dose and low dose-rates. To fully exploit the value of such approaches for facilitating risk assessment and management in the field of radiation protection, solicitation of experiences and active cooperation between chemical and radiation communities are needed. As a result, the Radiation and Chemical (Rad/Chem) AOP joint topical group was formed on June 1, 2021 as part of the initiative from the High Level Group on Low Dose Research (HLG-LDR). HLG-LDR is overseen by the OECD Nuclear Energy Agency (NEA) Committee on Radiation Protection and Public Health (CRPPH). The main aims of the joint AOP topical group are to advance the use of AOPs in radiation research and foster broader implementation of AOPs into hazard and risk assessment. With global representation, it serves as a forum to discuss, identify and develop joint initiatives that support research and take on regulatory challenges. CONCLUSION: The Rad/Chem AOP joint topical group will specifically engage, promote, and implement the use of the AOP framework to: (a) organize and evaluate mechanistic knowledge relevant to the protection of human and ecosystem health from radiation; (b) identify data gaps and research needs pertinent to expanding knowledge of low dose and low dose-rate radiation effects; and (c) demonstrate utility to support risk assessment by developing radiation-relevant case studies. It is envisioned that the Rad/Chem AOP joint topical group will actively liaise with the OECD EAGMST AOP developmental program to collectively advance areas of common interest and, specifically, provide recommendations for harmonization of the AOP framework to accommodate non-chemical stressors, such as radiation.

Delirium and Inflammation in Older Adults Hospitalized for COVID-19: A Cohort Study.

PURPOSE: The occurrence and predictors of delirium in older adults hospitalized for coronavirus disease 2019 (COVID-19) have not been well described. Highlighting the association with inflammatory markers may be useful for identifying delirium. This study aimed to determine the prevalence and incidence of delirium and explore its association with the C-reactive protein (CRP). PATIENTS AND METHODS: This cohort study of adults aged 65 and older with a COVID-19 diagnosis took place at an academic healthcare institution between April and May 2020. COVID-19 was diagnosed by positive nasopharyngeal swab. Serum levels of CRP were collected as a marker of systemic inflammation. The primary outcome was the prevalence and incidence of delirium. Delirium was diagnosed primarily during a patient's stay in hospital based on the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5). To ensure that no delirium diagnosis was missed during hospital stay, clinical records were reviewed by clinicians with geriatric medicine training for retrospective diagnoses. RESULTS: A total of 127 patients aged 65 and older were hospitalized with a diagnosis of COVID-19. The median age was 82 years (IQR: 74-88), with 54 (43%) females. Overall, delirium was present in 62 (49%) patients: manifestations of delirium were present on the first day of hospitalization in 53 of these cases (86%), while 9 cases (14%) developed delirium during hospitalization. After controlling for age and sex, the mean CRP value over the first 3 days since arrival was associated with a higher risk of delirium (OR 1.35; 95% CI: 1.01-1.85) for every 50 mg/L increase. CONCLUSION: In this cohort of older adults hospitalized for COVID-19, delirium was highly prevalent. An early increase in CRP levels should raise suspicion about the occurrence of delirium and could improve its diagnosis.

COHERE - strengthening cooperation within the Canadian government on radiation research.

PURPOSE: Canadian Organization on Health Effects from Radiation Exposure (COHERE) is a government initiative to better understand biological and human health risks from ionizing radiation exposures relevant to occupational and environmental settings (<100 mGy, <6 mGy/h). It is currently a partnership between two federal agencies, Health Canada (HC) and the Canadian Nuclear Safety Commission (CNSC). COHERE's vision is to contribute knowledge to reduce scientific uncertainties from low dose and dose-rate exposures. COHERE will advance our understanding by bridging the knowledge gap between human health risks and linkages to molecular- and cellular-level responses to radiation. Research focuses on identifying sensitive, early, and key molecular events of relevance to risk assessment. CONCLUSIONS: The initiative will address questions of relevance to better apprize Canadians, including radiation workers and members of the public and Indigenous peoples, on health risks from low dose radiation exposure and inform radiation protection frameworks at a national and international level. Furthermore, it will support global efforts to conduct collaborative undertakings and better coordinate research. Here, we describe a historical overview of the research conducted, the strategic research agenda that outlines the scientific framework, stakeholders, opportunities to harmonize internationally, and how research outcomes will better inform communication of risk to Canadians.

Bringing together scientific disciplines for collaborative undertakings: a vision for advancing the adverse outcome pathway framework.

BACKGROUND: Decades of research to understand the impacts of various types of environmental occupational and medical stressors on human health have produced a vast amount of data across many scientific disciplines. Organizing these data in a meaningful way to support risk assessment has been a significant challenge. To address this and other challenges in modernizing chemical health risk assessment, the Organisation for Economic Cooperation and Development (OECD) formalized the adverse outcome pathway (AOP) framework, an approach to consolidate knowledge into measurable key events (KEs) at various levels of biological organisation causally linked to disease based on the weight of scientific evidence (http://oe.cd/aops). Currently, AOPs have been considered predominantly in chemical safety but are relevant to radiation. In this context, the Nuclear Energy Agency's (NEA's) High-Level Group on Low Dose Research (HLG-LDR) is working to improve research co-ordination, including radiological research with chemical research, identify synergies between the fields and to avoid duplication of efforts and resource investments. To this end, a virtual workshop was held on 7 and 8 October 2020 with experts from the OECD AOP Programme together with the radiation and chemical research/regulation communities. The workshop was a coordinated effort of Health Canada, the Electric Power Research Institute (EPRI), and the Nuclear Energy Agency (NEA). The AOP approach was discussed including key issues to fully embrace its value and catalyze implementation in areas of radiation risk assessment. CONCLUSIONS: A joint chemical and radiological expert group was proposed as a means to encourage cooperation between risk assessors and an initial vision was discussed on a path forward. A global survey was suggested as a way to identify priority health outcomes of regulatory interest for AOP development. Multidisciplinary teams are needed to address the challenge of producing the appropriate data for risk assessments. Data management and machine learning tools were highlighted as a way to progress from weight of evidence to computational causal inference.

Celiac Disease After Administration of Immune Checkpoint Inhibitors: A Case Report.

Immune checkpoint inhibitors (ICI) reinvigorate the immune system to recognize and destroy tumor cells. Because of this biological mechanism, patients might develop autoimmune toxicities, notably in the digestive tract (most frequently, hepatitis or colitis). A 70-year-old man with relapsed mesothelioma was treated with nivolumab in 3rd line. He was hospitalized for watery and foul-smelling diarrhea. He underwent gastrointestinal endoscopy, showing duodenitis and villous atrophy and measurement of serum IgA antibodies to tissue transglutaminase (tTG-IgA+), leading to the diagnosis of ICI-induced celiac disease. He was treated with steroids, proton pump inhibitors, and a gluten-free diet. If ICI-induced celiac disease is rare in the literature, increasing reports suggest that celiac disease might represent an underestimated ICI toxicity. This case highlights the necessity of complementary investigation (including tTG-IgA and endoscopic biopsies) in patients with atypical digestive symptoms during immunotherapy.

Diffusive gradients in thin films (DGT): A suitable tool for metals/metalloids monitoring in continental waterbodies at the large network scale.

The contribution of Diffusive Gradients in Thin films (DGT) passive sampling to continental water quality monitoring was assessed in a real measurement network (6 sampling campaigns, 17 stations). Ten metals/metalloids (Al, Zn, Ni, Cd, Cu, Pb, Cr, As, Se and Sb) were studied using the control laboratory's working conditions with grab and DGT passive sampling. The DGT field deployments were robust, with a 3% sampler loss rate and a <65% average relative deviation between duplicates. Compared to grab sampling, DGT showed a similar quantification frequency for half of the targeted elements but showed a higher frequency for the other half (e.g., Cd quantification at 20% with grab sampling vs. 97% with DGT). Similar concentration trends were established using DGT and grab sampling at most sites throughout the year. Notably, for some elements, trends were only provided by DGT sampling. A study of several DGT blanks showed that the device contamination was occasional and originated primarily from cross-contamination during the disassembly step. Considering this contamination, the operational sensitivity by DGT was at least between 1 and 5 times greater in comparison to that by grab sampling. Estimations of the economic cost revealed that measurement networks cost 2 to 3 times more when monitored by DGT compared to standard grab monitoring. However, the information obtained based on each type of sampling method is different. Grab sampling is easy to implement and can highlight high contamination peaks. The DGT concentrations are averaged over time and are relevant to chronic exposure evaluations. Considering the good performance of the DGT sampling highlighted in this study and its complementarity with grab sampling in terms of water quality assessments, a combination of these two types of sampling, which can be affordable, should improve the water quality evaluation within monitoring networks.

Agranulocytosis Induced by Tamoxifen in a Breast Cancer Patient.

BACKGROUND: The main side effects of tamoxifen are menopausal symptoms. We report a case of agranulocytosis induced by tamoxifen in a 33-year-old woman treated in the adjuvant setting. CASE PRESENTATION: Ten days after the beginning of tamoxifen treatment, the patient complained of asthenia and mucositis. Blood testing showed a grade 4 neutropenia (0.06 G/L) without any other major hematologic disorder. Tamoxifen was discontinued, and the patient received granulocyte colony-stimulating factor. Within 2 days, she recovered to a normal granulocyte count. Tamoxifen was then switched to the combination of ovarian suppression (triptorelin) and aromatase inhibitor (anastrozole). CONCLUSION: Agranulocytosis is a very rare adverse event of tamoxifen.

Fulvestrant and palbociclib combination in heavily pretreated hormone receptor-positive, HER2-negative metastatic breast cancer patients.

PURPOSE: We report the results of a retrospective analysis of the fulvestrant and palbociclib combination within a temporary authorization of use (TAU) program in 77 heavily pretreated patients with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. METHODS: All patients who received the fulvestrant and palbociclib combination within this TAU program were included. Toxicities were graded using the CTCAE v5 scale. RESULTS: The majority of patients (62.3%) were previously treated with the mTOR inhibitor everolimus. The median number of previous treatments for their metastatic disease was 4. With a median follow-up of 14 months, the median progression-free survival (PFS) was 7.6 months. The median PFS significantly (p < 0.0001) decreased with the number of previous treatment lines in the metastatic setting. The median PFS was 5.5 months in patients who had previously progressed on everolimus compared to 9.3 months in the everolimus non-pretreated subgroup. No significant difference in median PFS was detected in patients according to age. The median overall survival rate was not reached. The clinical benefit rate was 64%, including 4% of complete responses, 26% partial responses, and 34% stable diseases for the entire cohort. CONCLUSIONS: The fulvestrant and palbociclib combination exerts an appreciable effect on metastatic heavily pretreated patients with a tolerable toxicity profile.

Measles Hospitalizations at a United States Children's Hospital 2011-2017.

BACKGROUND: There are no recent descriptions of measles hospitalizations and complications in US children despite outbreaks within the past decade-including 2 in Minnesota (2011 and 2017). The objective of our study was to describe complications, hospital management and resource utilization for children hospitalized for measles at a US children's hospital. METHODS: Retrospective case series of children (0-18 years of age) hospitalized for measles (observation/inpatient diagnosis code for measles) at Children's Minnesota, January 1, 2011, to September 1, 2017. Descriptive statistics were performed. RESULTS: Thirty-three patients were included (7 from 2011 and 21 from 2017 outbreaks). Median age was 27 months (range, 6-95 months), 94% were Black or African American (73% Somali ethnicity), 88% had medical assistance and 91% were unvaccinated to measles. Poor feeding was a primary reason for admission (97%); additional complications included otitis media (42%), pneumonia (30%), tracheitis (6%) and keratitis (3%). Additional testing was common [chest radiographs (70%), blood cultures (64%), nonmeasles viral testing (42%)]. Seventy-three percent received antibiotics, 30% required oxygen and 21% received vitamin A. Median length of stay was 3.7 days (range, 1.1-26.2 days); 1 patient was readmitted. Median direct cost in 2017 was $5291 (interquartile range : $3907-$7519), and estimated total cost to the hospital for the 2017 outbreak was $1.3 million. CONCLUSIONS: Clinicians should be aware of measles complications and treatment. Public and private health efforts should continue to focus on immunization, given significant implications of measles infections for patients and healthcare systems. Future studies may assess complications of measles across the United States as individual outbreaks often occur in specific populations, making generalization of results challenging.

Radiation Biology and Its Role in the Canadian Radiation Protection Framework.

The linear no-threshold (linear-non-threshold) model is a dose-response model that has long served as the foundation of the international radiation protection framework, which includes the Canadian regulatory framework. Its purpose is to inform the choice of appropriate dose limits and subsequent as low as reasonably achievable requirements, social and economic factors taken into account. The linear no-threshold model assumes that the risk of developing cancer increases proportionately with increasing radiation dose. The linear no-threshold model has historically been applied by extrapolating the risk of cancer at high doses (>1,000 mSv) down to low doses in a linear manner. As the health effects of radiation exposure at low doses remain ambiguous, reducing uncertainties found in cancer risk dose-response models can be achieved through in vitro and animal-based studies. The purpose of this critical review is to analyze whether the linear no-threshold model is still applicable for use by modern nuclear regulators for radiation protection purposes, or if there is sufficient scientific evidence supporting an alternate model from which to derive regulatory dose limits.

Is there a role for the adverse outcome pathway framework to support radiation protection?

PURPOSE: In 2012, the Organization for Economic Cooperation and Development (OECD) formally launched the Adverse Outcome Pathway (AOP) Programme. The AOP framework has the potential for predictive utility in identifying early biological endpoints linked to adverse effects. It uses the weight of correlative evidence to identify a minimal set of measurable key events that link molecular initiating events to an adverse outcome. AOPs have the capability to identify knowledge gaps and priority areas for future research based on relevance to an adverse outcome. In addition, AOPs can identify pathways that are common among multiple stressors, thereby allowing for the possibility of refined risk assessments based on co-exposure considerations. The AOP framework is increasingly being used in chemical and ecological risk assessment; however, its use in the development of radiation-specific pathways has yet to be fully explored. To bring awareness of the AOP framework to the Canadian radiation community, a workshop was held in Canada in June 2018 that brought together radiation experts from Health Canada, the Canadian Nuclear Laboratories, and the Canadian Nuclear Safety Commission. METHODS: The purpose of the workshop was to share knowledge on the AOP framework, specifically (1) to introduce the concept of the AOP framework and its possible utility to Canadian radiation experts; (2) to provide examples on how it has advanced risk assessment; (3) to discuss an illustrative example specific to ionizing radiation; and lastly (4) to identify the broad benefits and challenges of the AOP framework to the radiation community. RESULTS: The participants showed interest in the framework, case examples were described and areas of challenge were identified. Herein, we summarize the outcomes of the workshop. CONCLUSIONS: Overall, participants agreed that by building AOPs in the radiation field, a network of data-sharing initiatives will enhance our interpretation of existing knowledge where current scientific evidence is minimal. They would provide new avenues to understand effects at low-dose and dose-rates and help to quantify the combined effect of multiple stressors on shared mechanistic pathways.

In vivo animal studies help achieve international consensus on standards and guidelines for health risk estimates for chronic exposure to low levels of tritium in drinking water.

Existing and future nuclear fusion technologies involve the production and use of large quantities of tritium, a highly volatile, but low toxicity beta-emitting isotope of hydrogen. Tritium has received international attention because of public and scientific concerns over its release to the environment and the potential health impact of its internalization. This article provides a brief summary of the current state of knowledge of both the biological and regulatory aspects of tritium exposure; it also explores the gaps in this knowledge and provides recommendations on the best ways forward for improving our understanding of the health effects of low-level exposure to it. Linking health effects specifically to tritium exposure is challenging in epidemiological studies due to high uncertainty in tritium dosimetry and often suboptimal cohort sizes. We therefore argued that limits for tritium in drinking water should be based on evidence derived from controlled in vivo animal tritium toxicity studies that use realistically low levels of tritium. This article presents one such mouse study, undertaken within an international collaboration, and discusses the implications of its main findings, such as the similarity of the biokinetics of tritiated water (HTO) and organically bound tritium (OBT) and the higher biological effectiveness of OBT. This discussion is consistent with the position expressed in this article that in vivo animal tritium toxicity studies carried out within large, multi-partner collaborations allow evaluation of a great variety of health-related endpoints and essential to the development of international consensus on the regulation of tritium levels in the environment. Environ. Mol. Mutagen. 59:586-594, 2018. © 2018 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

Practice Patterns in the Treatment and Monitoring of Acute T Cell-Mediated Kidney Graft Rejection in Canada.

BACKGROUND: One of the goals of the Canadian National Transplant Research Program (CNTRP) is to develop novel therapies for acute rejection that could positively affect graft outcomes with greater efficacy or less toxicity. To develop innovative management strategies for kidney graft rejection, new modalities need to be compared with current clinical practices. However, there are no standardized practices concerning the management of acute T cell-mediated rejection (TCMR). OBJECTIVES: To describe clinicians' practice patterns in the diagnosis, treatment, and monitoring of acute TCMR in Canada. DESIGN: Survey. SETTING PATIENTS/PARTICIPANTS: Canadian transplant nephrologists and transplant surgeons involved in the management of acute TCMR. METHODS AND MEASUREMENTS: We developed an anonymous, web-based survey consisting of questions related to the diagnosis, treatment, and monitoring of TCMR. The survey was disseminated on 3 occasions between June and October 2016 through the Canadian Society of Transplantation (CST) kidney group electronic mailing list. RESULTS: Forty-seven respondents, mostly transplant nephrologists (97%), originating from at least 18 of the 25 Canadian centers offering adult or pediatric kidney transplantation, participated in the study. Surveillance biopsies were used by 28% of respondents to screen for kidney graft rejection. High-dose steroids were used by most of the respondents to treat clinical and subclinical Banff grade 1A and 1B rejections. Nine percent (95% confidence interval [CI]: 1-17) of practitioners used lymphocyte-depleting agents as the first-line approach for the treatment of Banff grade 1B acute rejection. Eighteen percent (95% CI: 7-29) and 36% (95% CI: 8-65) of respondents reported that they would not use high-dose steroids for treating clinical and subclinical borderline rejections, respectively. Seventy percent (95% CI: 54-83) of respondents answered that there was no indication to assess histological response to treatment independent of the change in kidney function. LIMITATIONS: The limitations of this study are its limited sample size and the low representation of pediatric specialists. CONCLUSIONS: There is heterogeneity regarding the use of surveillance biopsies, treatment of borderline rejection, and modalities to monitor treatment response among transplant physicians. Our results illustrate the current state of practice patterns across Canada and can be used to inform the design of future trials.

CONTEXTE: Un des objectifs du Programme national de recherche en transplantation rénale du Canada (PNRTC) est de développer des traitements plus efficaces et moins toxiques en vue d'améliorer l'issue des greffes. Il est impératif de comparer ces nouvelles modalités aux pratiques cliniques existantes si l'on veut élaborer des stratégies de prise en charge thérapeutiques innovantes. Cependant, en contexte de greffe rénale, il n'existe aucune pratique standardisée pour la prise en charge thérapeutique du rejet aigu à médiation cellulaire (RAMC) provoqué par la cytotoxicité des lymphocytes T. OBJECTIF: Décrire le schéma de pratique des médecins canadiens en matière de diagnostic, de traitement et de monitorage du RAMC. TYPE D'ÉTUDE: Il s'agit d'une étude menée sous forme de sondage. PARTICIPANTS: Les chirurgiens et néphrologues en transplantologie impliqués dans la prise en charge du RAMC au Canada. MÉTHODOLOGIE: Nous avons préparé un sondage Web anonyme constitué de questions relatives au diagnostic et au monitorage du RAMC. Les répondants visés étaient les abonnés à la liste d'envoi du groupe de transplantation rénale de la Société canadienne de transplantation (SCT). Ils ont reçu le sondage à trois reprises entre juin et octobre 2016. RÉSULTATS: Les répondants, au nombre de 47, étaient en grande majorité des néphrologues transplantologues (97 %). Ils provenaient d'au moins 18 des 25 centres hospitaliers canadiens dans lesquels on pratique des greffes rénales (adultes ou pédiatriques). Vingt-huit pour cent (28 %) des répondants ont recours aux biopsies de surveillance pour évaluer le risque de rejet du greffon. Les stéroïdes administrés à fortes doses sont employés par la plupart des répondants pour traiter les rejets cliniques et infracliniques de stade 1A et 1B (classification de Banff). Les agents de déplétion des lymphocytes sont utilisés par 9 % (IC 95 % : 1-17) des praticiens comme approche thérapeutique de première ligne pour les rejets aigus de stade 1B de Banff. En matière de traitement des cas rejets limites cliniques et infracliniques, 18% (IC 95 % : 7-29) et 36 % (IC 95 % : 8-65) des répondants ont indiqués qu'ils n'emploieraient pas de stéroïdes à forte dose. Enfin, 70 % (IC 95 % : 54-83) des spécialistes sondés jugeaient qu'il n'y avait pas d'indication d'évaluer la réponse histologique au traitement indépendamment de la réponse au traitement en terme de fonction rénale. LIMITES DE L'ÉTUDE: Les résultats du sondage sont limités par le faible nombre de répondants et par la sous-représentation des spécialistes en pédiatrie. CONCLUSION: Chez les médecins sondés, on a constaté des différences dans trois aspects de la prise en charge de la greffe rénale : la fréquence du recours aux biopsies de surveillance, le traitement des cas limites de rejet et les modalités employées pour mesurer la réponse au traitement. Nos résultats témoignent de l'hétérogénéité actuelle des schémas de pratique au Canada et pourraient servir à orienter la conception d'études ultérieures.