Dosimetric validation of SmART-RAD Monte Carlo modelling for x-ray cabinet radiobiology irradiators.

Objective. Accuracy and reproducibility in the measurement of radiation dose and associated reporting are critically important for the validity of basic and preclinical radiobiological studies performed with kilovolt x-ray radiation cabinets. This is essential to enable results of radiobiological studies to be repeated, as well as enable valid comparisons between laboratories. In addition, the commonly used single point dose value hides the 3D dose heterogeneity across the irradiated sample. This is particularly true for preclinical rodent models, and is generally difficult to measure directly. Radiation transport simulations integrated in an easy to use application could help researchers improve quality of dosimetry and reporting.Approach. This paper describes the use and dosimetric validation of a newly-developed Monte Carlo (MC) tool, SmART-RAD, to simulate the x-ray field in a range of standard commercial x-ray cabinet irradiators used for preclinical irradiations. Comparisons are made between simulated and experimentally determined dose distributions for a range of configurations to assess the potential use of this tool in determining dose distributions through samples, based on more readily available air-kerma calibration point measurements.Main results. Simulations gave very good dosimetric agreement with measured depth dose distributions in phantoms containing both water and bone equivalent materials. Good spatial and dosimetric agreement between simulated and measured dose distributions was obtained when using beam-shaping shielding.Significance. The MC simulations provided by SmART-RAD provide a useful tool to go from a limited number of dosimetry measurements to detailed 3D dose distributions through a non-homogeneous irradiated sample. This is particularly important when trying to determine the dose distribution in more complex geometries. The use of such a tool can improve reproducibility and dosimetry reporting in preclinical radiobiological research.

Endothelial cell death after ionizing radiation does not impair vascular structure in mouse tumor models.

The effect of radiation therapy on tumor vasculature has long been a subject of debate. Increased oxygenation and perfusion have been documented during radiation therapy. Conversely, apoptosis of endothelial cells in irradiated tumors has been proposed as a major contributor to tumor control. To examine these contradictions, we use multiphoton microscopy in two murine tumor models: MC38, a highly vascularized, and B16F10, a moderately vascularized model, grown in transgenic mice with tdTomato-labeled endothelium before and after a single (15 Gy) or fractionated (5 × 3 Gy) dose of radiation. Unexpectedly, even these high doses lead to little structural change of the perfused vasculature. Conversely, non-perfused vessels and blind ends are substantially impaired after radiation accompanied by apoptosis and reduced proliferation of their endothelium. RNAseq analysis of tumor endothelial cells confirms the modification of gene expression in apoptotic and cell cycle regulation pathways after irradiation. Therefore, we conclude that apoptosis of tumor endothelial cells after radiation does not impair vascular structure.

Associations between courses of posttraumatic stress disorder and physical health conditions among Canadian military personnel.

BACKGROUND: Posttraumatic stress disorder (PTSD) and physical health conditions commonly co-occur and are both prevalent among military personnel. This study examined how courses of PTSD (no PTSD, remitted, new onset, persistent/recurrent) are associated with physical health conditions, among a population-based sample of Canadian military personnel. METHOD: We analyzed data from the 2002 Canadian Community Health Survey-Mental Health and Well-being-Canadian Forces supplement (CCHS-CF) and the 2018 Canadian Armed Forces Members and Veterans Mental Health Follow-Up Survey (CAFVMHS; N = 2941). Multivariable logistic regressions examined associations between PTSD courses (reference = no PTSD) and physical health conditions. RESULTS: In general, physical health conditions were more prevalent among symptomatic PTSD courses compared to no PTSD. After adjustment, new onset PTSD was associated with increased odds of all physical health conditions with the exception of ulcers and cancer (AOR range: 1.41-2.31) and remitted PTSD was associated with increased odds of diabetes (AOR = 2.31). CONCLUSION: Results suggest that new onset PTSD may be most strongly associated with physical health conditions. Findings may inform targeted screening and intervention methods among military personnel with PTSD and physical health conditions.

Cluster analysis of Canadian Armed Forces veterans living with chronic pain: Life After Service Studies 2016.

Objective: This study explored the heterogeneity of Canadian Armed Forces veterans living with chronic pain to inform service needs planning and research using cluster analysis. Design: We used a national cross-sectional Statistics Canada population survey. Participants: Participants included 2754 Canadian Armed Forces (CAF) Regular Force veterans released from service between 1998 and 2015 and surveyed in 2016. Methods: We used cluster analysis of veterans with chronic pain based on pain severity, mental health, and activity limitation characteristics. We compared clusters for sociodemographic, health, and service utilization characteristics. Results: Of 2754 veterans, 1126 (41%) reported chronic pain. Veterans in cluster I (47%) rarely had severe pain (2%) or severe mental health problems (8%), and none had severe activity limitations. Veterans in cluster II (26%) more often than veterans in cluster I but less often than veterans in cluster III endorsed severe pain (27%) and severe mental health problems (22%) and were most likely to report severe activity limitation (91%). Veterans in cluster III (27%) were most likely to report severe pain (36%) and severe mental health problems (96%), and a majority reported severe activity limitations (72%). There was evidence of considerable heterogeneity among individuals in terms of socioeconomic characteristics, pain characteristics, mental and physical health status, activity limitations, social integration, and service utilization indicators. Conclusions: About half of Canadian veterans living with chronic pain infrequently endorse severe pain or serious mental health issues without severe activity limitations. The other half had more complex characteristics. The heterogeneity of CAF veterans with chronic pain emphasizes the need for support systems that can address variability of needs.

Objectif: Cette étude portait sur l'hétérogénéité des anciens combattants des Forces armées canadiennes vivant avec la douleur chronique pour éclairer la planification et la recherche en matière de besoins de services à l'aide de l'analyse par groupes.Devis: Nous avons utilisé une enquête nationale transversale sur la population de Statistique Canada.Participants: Les participants comprenaient 2 754 anciens combattants de la Force régulière des Forces armées canadiennes (FAC) libéré du service entre 1998 et 2015 et enquêtés en 2016.Méthodes: Nous avons utilisé une analyse par groupes d'anciens combattants souffrant de douleur chronique fondée sur l'intensité de la douleur, la santé mentale et les caractéristiques en matière de limitation d'activité. Nous avons comparé les caractéristiques sociodémographiques, de santé et d'utilisation des services des groupes.Résultats: Sur 2 754 anciens combattants, 1 126 (41 %) ont fait état d'une douleur chronique. Les anciens combattants du groupe I (47 %) avaient rarement une douleur intense (2 %) ou de graves problèmes de santé mentale (8 %), et aucun d'entre eux n'avait de limitation d'activité sévère. Les anciens combattants du groupe II (26%) souffraient de douleur intense (27 %) et de problèmes de santé mentale graves (22 %) plus souvent que les anciens combattants du groupe I mais moins souvent que les anciens combattants du groupe III et étaient plus susceptibles de déclarer une limitation d'activité sévère (91 %). Les anciens combattants du groupe III (27 %) étaient les plus susceptibles de déclarer une douleur intense (36 %) et des problèmes de santé mentale graves (96 %), et la majorité d'entre eux a signalé une limitation d'activité grave (72%). Les données probantes ont révélé une hétérogénéité considérable parmi les individus en ce qui concerne les indicateurs relatifs aux caractéristiques socioéconomiques, aux caractéristiques de la douleur, à l'état de santé mentale et physique, à la limitation d'activité, à l'intégration sociale et à l'utilisation des services.Conclusions: Environ la moitié des anciens combattants canadiens vivant avec une douleur chronique souffrent rarement de douleur intense ou de problèmes de santé mentale graves sans avoir de limitations d'activité graves. L'autre moitié avait des caractéristiques plus complexes. L'hétérogénéité des vétérans des FAC souffrant de douleur chronique souligne l'importance que des systèmes de soutien capables de répondre à la diversité des besoins soient disponibles.

Chronic pain experience and health inequities during the COVID-19 pandemic in Canada: qualitative findings from the chronic pain & COVID-19 pan-Canadian study.

BACKGROUND: Chronic pain affects about 20 % of the Canadian population and can lead to physical, psychological and social vulnerabilities. However, this condition remains poorly recognized and undertreated. During 2020, as the COVID-19 pandemic disrupted daily living and health care systems, the situation of people with chronic pain has drawn little public attention. METHODS: This qualitative study was part of a pan-Canadian mixed-methods project and aimed to understand the experiences and challenges of people living with chronic pain during the COVID-19 pandemic in Canada. Between May and August 2020, we conducted in-depth semi-structured interviews with 22 individuals living with chronic pain across the country. We used reflexive thematic analysis to interpret data. RESULTS: Our findings underscored four dimensions of the chronic pain experience during the pandemic: (1) Reinforced vulnerability due to uncertainties regarding pain and its management; (2) Social network as a determinant of pain and psychological condition; (3) Increasing systemic inequities intermingling with the chronic pain experience; (4) More viable living conditions due to confinement measures. Though several participants reported improvements in their quality of life and reduced social pressure in the context of stay-at-home orders, participants from socio-economically deprived groups and minorities reported more challenges in accessing pain relief, health care services, and psychosocial support. CONCLUSIONS: The COVID-19 pandemic has revealed and intensified pre-existing disparities and challenges among people living with chronic pain in terms of material resources, psychosocial condition, social support, and access to care. In post-pandemic times, it will be essential to address flaws in health and welfare policies to foster equity and social inclusiveness of people with chronic pain.

Ongoing repair of migration-coupled DNA damage allows planarian adult stem cells to reach wound sites.

Mechanical stress during cell migration may be a previously unappreciated source of genome instability, but the extent to which this happens in any animal in vivo remains unknown. We consider an in vivo system where the adult stem cells of planarian flatworms are required to migrate to a distal wound site. We observe a relationship between adult stem cell migration and ongoing DNA damage and repair during tissue regeneration. Migrating planarian stem cells undergo changes in nuclear shape and exhibit increased levels of DNA damage. Increased DNA damage levels reduce once stem cells reach the wound site. Stem cells in which DNA damage is induced prior to wounding take longer to initiate migration and migrating stem cell populations are more sensitive to further DNA damage than stationary stem cells. RNAi-mediated knockdown of DNA repair pathway components blocks normal stem cell migration, confirming that active DNA repair pathways are required to allow successful migration to a distal wound site. Together these findings provide evidence that levels of migration-coupled-DNA-damage are significant in adult stem cells and that ongoing migration requires DNA repair mechanisms. Our findings reveal that migration of normal stem cells in vivo represents an unappreciated source of damage, which could be a significant source of mutations in animals during development or during long-term tissue homeostasis.

Lifetime Prevalence and Comorbidity of Mental Disorders in the Two-wave 2002-2018 Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (CAFVMHS): Prévalence et Comorbidité de Durée de vie Des Troubles Mentaux Dans l'Enquête de Suivi Sur la Santé Mentale Auprès des Membres des Forces Armées Canadiennes et Des ex-Militaires (ESSMFACM) en Deux Cycles de 2002 à 2018.

OBJECTIVE: The current study used the Canadian Armed Forces Members and Veterans Mental Health Follow-up Survey (CAFVMHS) to (1) examine the incidence and prevalence of mental disorders and (2) estimate the comorbidity of mental disorders over the follow-up period. METHOD: The CAFVMHS (2018) is a longitudinal study with two time points of assessment. The sample is comprised of 2,941 Canadian Forces members and veterans who participated in the 2002 Canadian Community Health Survey: Canadian Forces Supplement. The World Health Organization Composite International Diagnostic Interview (WHO-CIDI) was utilized to diagnose Diagnostic and Statistical Manual-IV post-traumatic stress disorder (PTSD), major depressive episode (MDE), generalized anxiety disorder, social anxiety disorder (SAD), and alcohol abuse and dependence. Self-report health professional diagnoses were assessed for attention deficit hyperactivity disorder (ADHD), mania, obsessive compulsive disorder (OCD), and personality disorder. We established weighted prevalence of mental disorders and examined the association between mental disorders using logistic regression. RESULTS: In 2018, lifetime prevalence of any WHO-CIDI-based or self-reported mental disorder was 58.1%. Lifetime prevalence of any mood or anxiety disorder or PTSD was 54.0% in 2018. MDE (39.9%), SAD (25.7%), and PTSD (21.4%) were the most common mental disorders. There was a substantial increase in new onset or recurrence/persistence of mental disorders between the two measurement points (16-year assessment gap); 2002-2018 period prevalences were 43.5% for mood and anxiety disorder and 16.8% for alcohol abuse or dependence. The prevalence of self-reported ADHD, OCD, any personality disorder, and mania were 3.3%, 3.0%, 0.8%, and 0.8%, respectively. Comorbidity between mental disorders increased over the follow-up. CONCLUSIONS: This study demonstrates a high burden of mental disorders among a large Canadian military and veteran cohort. These findings underscore the importance of prevention and intervention strategies to reduce the burden of mental disorders and alcohol use disorders in these populations.

Olaparib increases the therapeutic index of hemithoracic irradiation compared with hemithoracic irradiation alone in a mouse lung cancer model.

BACKGROUND: The radiosensitising effect of the poly(ADP-ribose) polymerase inhibitor olaparib on tumours has been reported. However, its effect on normal tissues in combination with radiation has not been well studied. Herein, we investigated the therapeutic index of olaparib combined with hemithoracic radiation in a urethane-induced mouse lung cancer model. METHODS: To assess tolerability, A/J mice were treated with olaparib plus whole thorax radiation (13 Gy), body weight changes were monitored and normal tissue effects were assessed by histology. In anti-tumour (intervention) studies, A/J mice were injected with urethane to induce lung tumours, and were then treated with olaparib alone, left thorax radiation alone or the combination of olaparib plus left thorax radiation at 8 weeks (early intervention) or 18 weeks (late intervention) after urethane injection. Anti-tumour efficacy and normal tissue effects were assessed by visual inspection, magnetic resonance imaging and histology. RESULTS: Enhanced body weight loss and oesophageal toxicity were observed when olaparib was combined with whole thorax but not hemithorax radiation. In both the early and late intervention studies, olaparib increased the anti-tumour effects of hemithoracic irradiation without increasing lung toxicity. CONCLUSIONS: The addition of olaparib increased the therapeutic index of hemithoracic radiation in a mouse model of lung cancer.

Impact of the COVID-19 pandemic on the pharmacological, physical, and psychological treatments of pain: findings from the Chronic Pain & COVID-19 Pan-Canadian Study.

INTRODUCTION: Multimodal treatment is recognized as the optimal paradigm for the management of chronic pain (CP). Careful balance between pharmacological and physical/psychological approaches is thus desirable but can be easily disrupted. OBJECTIVES: This study aimed at exploring the impact of the COVID-19 pandemic on pharmacological and physical/psychological treatments of CP. METHODS: A Pan-Canadian cross-sectional web-based study was conducted between April 16th and May 31st 2020 among adults living with CP when the country was in the ascending slope of the first COVID-19 pandemic wave. RESULTS: A total of 2864 participants shared their treatment experience (mean age: 49.7 years and women: 83.5%). Among medication users (n = 2533), 38.3% reported changes in their pharmacological pain treatment. The main reasons were as follows: (1) changes in pain symptoms, (2) lack of access to prescribers/cancellation of medical appointments, and (3) increased medication intake in compensation for stopping physical/psychological treatments because of the pandemic. Among participants who used physical/psychological pain management approaches before the pandemic (n = 2467), 68.3% had to modify their treatments or self-management strategies. Common reasons were lack of access to clinics/exercise facilities and the need to compensate for having to stop another type of physical/psychological treatment because of the pandemic-related public health safety measures. CONCLUSIONS: Our study underlines the negative impact of the COVID-19 pandemic on access to pain relief, which is considered a fundamental human right. Results will help to justify resource allocation and inform the development of interventions to be better prepared for waves to come and future health crises.

A cross-sectional study of pain status and psychological distress among individuals living with chronic pain: the Chronic Pain & COVID-19 Pan-Canadian Study. / Une étude transversale sur l'évolution de la douleur et la détresse psychologique chez les personnes atteintes de douleur chronique : l'étude pancanadienne « Douleur chronique et COVID-19.

BACKGROUND: The COVID-19 pandemic has had a disproportionate impact on vulnerable populations, including individuals with chronic pain. We examined associations between geographical variations in COVID-19 infection rates, stress and pain severity, and investigated factors associated with changes in pain status and psychological distress among individuals living with chronic pain during the pandemic. METHODS: This investigation is part of a larger initiative, the Chronic Pain & COVID-19 Pan-Canadian Study, which adopted a cross-sectional observational design. A total of 3159 individuals living with chronic pain completed a quantitative survey between 16 April and 31 May 2020. RESULTS: Two-thirds (68.1%) of participants were between 40 and 69 years old, and 83.5% were women. Two-thirds (68.9%) of individuals reported worsened pain since pandemic onset. Higher levels of perceived pandemic-related risks (adjusted odds ratio: 1.27; 95% confidence interval: 1.03-1.56) and stress (1.21; 1.05-1.41), changes in pharmacological (3.17; 2.49-4.05) and physical/psychological (2.04; 1.62-2.58) pain treatments and being employed at the beginning of the pandemic (1.42; 1.09-1.86) were associated with increased likelihood of reporting worsened pain. Job loss (34.9% of individuals were employed pre-pandemic) was associated with lower likelihood (0.67; 0.48-0.94) of reporting worsened pain. Almost half (43.2%) of individuals reported moderate/severe levels of psychological distress. Negative emotions toward the pandemic (2.14; 1.78-2.57) and overall stress (1.43; 1.36-1.50) were associated with moderate/severe psychological distress. CONCLUSIONS: Study results identified psychosocial factors to consider in addition to biomedical factors in monitoring patients' status and facilitating treatment access for chronic pain patients during a pandemic.

Density compensated diodes for small field dosimetry: comprehensive testing and implications for design.

PURPOSE: In small megavoltage photon fields, the accuracies of an unmodified PTW 60017-type diode dosimeter and six diodes modified by adding airgaps of thickness 0.6-1.6 mm and diameter 3.6 mm have been comprehensively characterized experimentally and computationally. The optimally thick airgap for density compensation was determined, and detectors were micro-CT imaged to investigate differences between experimentally measured radiation responses and those predicted computationally. METHODS: Detectors were tested on- and off-axis, at 5 and 15 cm depths in 6 and 15 MV fields ≥ 0.5 × 0.5 cm2. Computational studies were carried out using the EGSnrc/BEAMnrc Monte Carlo radiation transport code. Experimentally, radiation was delivered using a Varian TrueBeam linac and doses absorbed by water were measured using Gafchromic EBT3 film and ionization chambers, and compared with diode readings. Detector response was characterized via the [Formula: see text] formalism, choosing a 4 × 4 cm2 reference field. RESULTS: For the unmodified 60017 diode, the maximum error in small field doses obtained from diode readings uncorrected by [Formula: see text] factors was determined as 11.9% computationally at +0.25 mm off-axis and 5 cm depth in a 15 MV 0.5 × 0.5 cm2 field, and 11.7% experimentally at -0.30 mm off-axis and 5 cm depth in the same field. A detector modified to include a 1.6 mm thick airgap performed best, with maximum computationally and experimentally determined errors of 2.2% and 4.1%. The 1.6 mm airgap deepened the modified dosimeter's effective point of measurement by 0.5 mm. For some detectors significant differences existed between responses in small fields determined computationally and experimentally, micro-CT imaging indicating that these differences were due to within-tolerance variations in the thickness of an epoxy resin layer. CONCLUSIONS: The dosimetric performance of a 60017 diode detector was comprehensively improved throughout 6 and 15 MV small photon fields via density compensation. For this approach to work well with good detector-to-detector reproducibility, tolerances on dense component dimensions should be reduced to limit associated variations of response in small fields, or these components should be modified to have more water-like densities.

Out of the shadows: Chronic pain in Canadian Armed Forces veterans - Proceedings of a workshop at the 2019 Forum of the Canadian Institute for Military and Veteran Health Research.

This commentary summarizes proceedings of a workshop on chronic pain in military personnel and veterans (released personnel) at the Annual Forum of the Canadian Institute for Military and Veteran Health Research in Gatineau and Ottawa on October 22, 2019. The extent and impact of chronic pain among Canadian Armed Forces (CAF) veterans and their families is significant and has been underappreciated, largely due to limited disclosure by serving and veteran military personnel, stemming from a fear of stigmatization. Living with pain is seen as a fact of life in military cultures, something to be endured and not discussed. Though progress is being made in reducing the stigma of mental illness, the discourse on chronic pain remains censored. This workshop's goal was to bring the discussion of chronic pain out of the shadows in the search for ways to help veterans and active service personnel living with chronic pain. Many points of view were brought forward at this first national Canadian multidisciplinary gathering of researchers, veterans with lived experience, clinicians, and policymakers. A CAF member described his lived experience with constant chronic pain. Clinicians described aspects of chronic pain in military personnel and veterans whom they treat in their clinics. Dr. Ramesh Zacharias described the new Chronic Pain Center of Excellence for Canadian Veterans that will be established with funding from Veterans Affairs Canada. Dr. Norman Buckley highlighted collaboration with the existing Chronic Pain Network funded by the Canadian Institute for Health Research. Audience members identified a diverse variety of issues.

Ce commentaire résume les actes d'un atelier sur la douleur chronique chez le personnel militaire et les anciens combattants (personnel libéré) tenu dans le cadre du Forum annuel de l'Institut canadien de recherche sur la santé des militaires et des vétérans à Gatineau et Ottawa le 22 octobre 2019. L'étendue et l'effet de la douleur chronique chez les anciens combattants des Forces armées canadiennes (FAC) et leurs familles sont importantes et ont été sous-estimées, en grande partie en raison de la divulgation limitée par le personnel militaire en service et les anciens combattants, découlant de la peur de la stigmatisation. Le fait de vivre avec la douleur est considéré comme faisant partie de la vie dans les cultures militaires, quelque chose qu'il faut endurer et dont il ne faut pas discuter. Bien que des progrès aient été réalisés dans la réduction de la stigmatisation de la maladie mentale, le discours sur la douleur chronique continue d'être censuré. L'objectif de cet atelier était de faire sortir de l'ombre la discussion sur la douleur chronique afin de chercher des moyens d'aider les anciens combattants et le personnel de service actif vivant avec la douleur chronique. De nombreux points de vue ont été exprimés lors de cette première rencontre multidisciplinaire nationale canadienne réunissant des chercheurs, des anciens combattants ayant vécu l'expérience de la douleur chronique, des cliniciens et des décideurs. Un membre des FAC a décrit l'expérience de douleur chronique qu'il a vécue. Les cliniciens ont décrit les aspects de la douleur chronique chez le personnel militaire et les anciens combattants qu'ils traitent dans leurs cliniques. Le Dr Ramesh Zacharias a décrit le nouveau Centre d'excellence sur la douleur chronique pour les vétérans canadiens qui sera établi grâce au financement d'Anciens Combattants Canada. Le Dr Norman Buckley a souligné la collaboration avec le Réseau de douleur chronique existant financé par l'Institut canadien de la recherche en santé. Les membres de l'audience ont relevé divers problèmes.

Treatment of military-related post-traumatic stress disorder: challenges, innovations, and the way forward.

Post-traumatic stress disorder (PTSD) is one of the common mental disorders in military and veteran populations. Considerable research and clinical opinion has been focused on understanding the relationship between PTSD and military service and the implications for prevention, treatment, and management. This paper examines factors associated with the development of PTSD in this population, considers issues relating to engagement in treatment, and discusses the empirical support for best practice evidence-based treatment. The paper goes on to explore the challenges in those areas, with particular reference to treatment engagement and barriers to care, as well as treatment non-response. The final section addresses innovative solutions to these challenges through improvements in agreed terminology and definitions, strategies to increase engagement, early identification approaches, understanding predictors of treatment outcome, and innovations in treatment. Treatment innovations include enhancing existing treatments, emerging non-trauma-focused interventions, novel pharmacotherapy, personalized medicine approaches, advancing functional outcomes, family intervention and support, and attention to physical health.

Radiosensitivity of colorectal cancer to 90Y and the radiobiological implications for radioembolisation therapy.

Approximately 50% of all colorectal cancer (CRC) patients will develop metastasis to the liver. 90Y selective internal radiation therapy (SIRT) is an established treatment for metastatic CRC. There is still a fundamental lack of understanding regarding the radiobiology underlying the dose response. This study was designed to determine the radiosensitivity of two CRC cell lines (DLD-1 and HT-29) to 90Y ß - radiation exposure, and thus the relative effectiveness of 90Y SIRT in relation to external beam radiotherapy (EBRT). A 90Y-source dish was sandwiched between culture dishes to irradiate DLD-1 or HT-29 cells for a period of 6 d. Cell survival was determined by clonogenic assay. Dose absorbed per 90Y disintegration was calculated using the PENELOPE Monte Carlo code. PENELOPE simulations were benchmarked against relative dose measurements using EBT3 GAFchromic™ film. Statistical regression based on the linear-quadratic model was used to determine the radiosensitivity parameters [Formula: see text] and [Formula: see text] using R. These results were compared to radiosensitivity parameters determined for 6 MV clinical x-rays and 137Cs γ-ray exposure. Equivalent dose of EBRT in 2 Gy ([Formula: see text]) and 10 Gy ([Formula: see text]) fractions were derived for 90Y dose. HT-29 cells were more radioresistant than DLD-1 for all treatment modalities. Radiosensitivity parameters determined for 6 MV x-rays and 137Cs γ-ray were equivalent for both cell lines. The [Formula: see text] ratio for 90Y ß --particle exposure was over an order of magnitude higher than the other two modalities due to protraction of dose delivery. Consequently, an 90Y SIRT absorbed dose of 60 Gy equates to an [Formula: see text] of 28.7 and 54.5 Gy and an [Formula: see text] of 17.6 and 19.3 Gy for DLD-1 and HT-29 cell lines, respectively. We derived radiosensitivity parameters for two CRC cell lines exposed to 90Y ß --particles, 6 MV x-rays, and 137Cs γ-ray irradiation. These radiobiological parameters are critical to understanding the dose response of CRC lesions and ultimately informs the efficacy of 90Y SIRT relative to other radiation therapy modalities.

Characterisation of Deubiquitylating Enzymes in the Cellular Response to High-LET Ionizing Radiation and Complex DNA Damage.

PURPOSE: Ionizing radiation, particular high-linear energy transfer (LET) radiation, can induce complex DNA damage (CDD) wherein 2 or more DNA lesions are induced in close proximity, which contributes significantly to the cell killing effects. However, knowledge of the enzymes and mechanisms involved in coordinating the recognition and processing of CDD in cellular DNA are currently lacking. METHODS AND MATERIALS: A small interfering RNA screen of deubiquitylation enzymes was conducted in HeLa cells irradiated with high-LET α-particles or protons, versus low-LET protons and x-rays, and cell survival was monitored by clonogenic assays. Candidates whose depletion led to decreased cell survival specifically in response to high-LET radiation were validated in both HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells, and the association with CDD repair was confirmed using an enzyme modified neutral comet assay. RESULTS: Depletion of USP6 decreased cell survival specifically after high-LET α-particles and protons, but not low-LET protons or x-rays. USP6 depletion caused cell cycle arrest and a deficiency in CDD repair mediated through instability of poly(ADP-ribose) polymerase-1 (PARP-1) protein. Increased radiosensitivity of cells to high-LET protons as a consequence of defective CDD repair was furthermore mimicked using the PARP inhibitor olaparib, and through PARP-1 small interfering RNA. CONCLUSIONS: USP6 controls cell survival in response to high-LET radiation by stabilizing PARP-1 protein levels, which is essential for CDD repair. We also describe synergy between CDD induced by high-LET protons and PARP inhibition, or PARP-1 depletion, in effective cancer cell killing.

Effects of variations in overall treatment time on the clonogenic survival of V79-4 cells: Implications for radiosurgery.

The importance of effects related to the repair of sublethal radiation damage as treatment duration varies, partly a function of dose-rate, is a current controversy in clinical radiosurgery. Cell survival studies have been performed to verify the importance of this effect in relation to established models. Mammalian V79-4 cells were irradiated in vitro with γ-rays, either as an acute exposure in a few minutes, where the effects of sublethal irradiation damage repair over the period of exposure can be ignored, or as protracted exposures delivered over 15-120 min. Protraction was achieved either by introducing a variable time gap between two doses of 7 Gy, or as a continuous exposure at lower dose rates so that a range of doses were delivered in fixed times of 30, 60 or 120 min. For all doses there was a progressive reduction in efficacy with increasing overall treatment time. This was illustrated by the progressive increase in clonogenic cell survival with a resulting right shift of the survival curves. Cell survival curves for irradiations given either as an acute exposure (6.1 Gy/min), over fixed times (30, 60 and 120 min) or for a fixed low dose-rate (0.2 Gy/min) were well fitted by the Linear Quadratic (LQ) model giving an α/ß ratio of 4.0 Gy and a single repair half-time of 31.5 min. The present results are consistent with published data with respect to the response of solid tumors and normal tissues, whose response to both continuous and fractionated irradiation is also well described by the LQ model. This suggests the need for dose compensation in radiosurgical treatments, and other forms of radiotherapy, where dose is delivered over a similar range of protracted overall treatment times, perhaps as a prerequisite to full biological effective dose treatment planning.

TRACKING DOWN ALPHA-PARTICLES: THE DESIGN, CHARACTERISATION AND TESTING OF A SHALLOW-ANGLED ALPHA-PARTICLE IRRADIATOR.

Human exposure to α-particles from radon and other radionuclides is associated with carcinogenesis, but if well controlled and targeted to cancer cells, α-particles may be used in radiotherapy. Thus, it is important to understand the biological effects of α-particles to predict cancer risk and optimise radiotherapy. To enable studies of α-particles in cells, we developed and characterised an α-particle automated irradiation rig that allows exposures at a shallow angle (70° to the normal) of cell monolayers in a 30 mm diameter dish to complement standard perpendicular irradiations. The measured incident energy of the α-particles was 3.3 ± 0.5 MeV (LET in water = 120 keV µm-1), with a maximum incident dose rate of 1.28 ± 0.02 Gy min-1, which for a 5 µm cell monolayer corresponds to a mean dose rate of 1.57 ± 0.02 Gy min-1 and a mean LET in water of 154 keV µm-1. The feasibility of resolving radiation-induced DNA double-strand breaks (DSB) foci along the track of α-particles was demonstrated using immunofluorescent labelling with γH2AX and 53BP1 in normal MRC-5 human lung cells.

Reflections on recovery, rehabilitation and reintegration of injured service members and veterans from a bio-psychosocial-spiritual perspective

Medical interventions regarding trauma resuscitation have increased survivorship to levels not previously attained. Multiple examples from recent conflicts illustrate the potential return to high-level function of severely injured service members following medical and rehabilitative interventions. This review addresses the goals of rehabilitation, distills hard-won lessons of the last decade of military trauma and rehabilitation, and recommends the use of a bio-psychosocial-spiritual approach to care that can be applied at all tiers of the health care system. Questions on enabling participation in meaningful life activities include the following: Why do some patients do well and others do not? What elements contribute to positive outcomes? What factors relate to suboptimal results? Lessons learned revolve around the importance of considering the physical, psychosocial and spiritual aspects of a person's well-being; empowering patients by fostering self-efficacy; and helping patients find meaning in life events and set high-level goals. A bio-psychosocial-spiritual model from the rehabilitation medicine literature ­ the Canadian Model of Occupational Performance and Engagement ­ is proposed as a guide to the provision of person-centred care and the maximization of a person's functioning posttrauma.

Les interventions médicales de réanimation en traumatologie ont porté les taux de survie à des niveaux encore inégalé. Plusieurs exemples tirés de conflits récents illustrent le retour potentiel à un degré fonctionnel élevé après des interventions médicales et de réadaptation chez des membres des forces armées grièvement blessés. La présente revue expose les objectifs de la réadaptation, résume les dures leçons tirées de la dernière décennie en traumatologie et réadaptation dans le monde militaire et recommande l'utilisation d'une approche de soins bio- et psychosociospirituelle qui peut être appliquée à tous les échelons du système de soins de santé. Les questions concernant la capacité d'un retour à des activités signifiantes incluent : Pourquoi les patients n'obtiennent-ils pas tous les mêmes résultats? Quels éléments contribuent à des résultats positifs? Quels facteurs sont en lien avec des résultats optimaux? Les leçons apprises font ressortir l'importance de tenir compte des dimensions physique, psychosociale et spirituelle des personnes pour assurer leur bien-être, de les rendre autonomes en favorisant une plus grande auto-efficacité et de les aider à trouver du sens dans les événements de la vie et à se fixer des objectifs ambitieux. Un modèle bio- et psychosociospirituel tiré de la littérature en médecine de réadaptation ­ le Modèle canadien de rendement occupationnel et de participation ­ est proposé comme guide pour la prestation de soins centrés sur la personne et la maximisation de son fonctionnement après un traumatisme.

High-resolution µCT of a mouse embryo using a compact laser-driven X-ray betatron source.

In the field of X-ray microcomputed tomography (µCT) there is a growing need to reduce acquisition times at high spatial resolution (approximate micrometers) to facilitate in vivo and high-throughput operations. The state of the art represented by synchrotron light sources is not practical for certain applications, and therefore the development of high-brightness laboratory-scale sources is crucial. We present here imaging of a fixed embryonic mouse sample using a compact laser-plasma-based X-ray light source and compare the results to images obtained using a commercial X-ray µCT scanner. The radiation is generated by the betatron motion of electrons inside a dilute and transient plasma, which circumvents the flux limitations imposed by the solid or liquid anodes used in conventional electron-impact X-ray tubes. This X-ray source is pulsed (duration <30 fs), bright (>1010 photons per pulse), small (diameter <1 µm), and has a critical energy >15 keV. Stable X-ray performance enabled tomographic imaging of equivalent quality to that of the µCT scanner, an important confirmation of the suitability of the laser-driven source for applications. The X-ray flux achievable with this approach scales with the laser repetition rate without compromising the source size, which will allow the recording of high-resolution µCT scans in minutes.