An Assessment of the Quality of Competence Restoration Research.

A systematic review of the literature on restoration of competence to stand trial identified a predominance of retrospective case studies using descriptive and correlational statistics. Guided by National Institutes of Health (NIH) quality metrics and emphasizing study design, sample size, and statistical methods, the authors categorized a large majority of studies as fair in quality, underscoring the need for controlled designs, larger representative samples, and more sophisticated statistical analyses. Implications for the state of forensic research include the need to use large databases within jurisdictions and the importance of reliable methods that can be applied across jurisdictions and aggregated for meta-analysis. More sophisticated research methods can be advanced in forensic fellowship training where coordinated projects and curricula can encourage systematic approaches to forensic research.

Sizing Up General Practice Environments for Big-Bodied Patients: An Environmental Assessment of Three Facilities in Aotearoa New Zealand.

OBJECTIVES: This research describes the physical environments of and equipment in Aotearoa New Zealand (NZ) general practices in relation to available standards for big-bodied people (BBP) seeking healthcare. BACKGROUND: The prevalence of BBP both in NZ and globally has increased over the last 30 years and is expected to increase further. As the first and most utilized point of contact for patients in NZ and many countries, it is essential that general practices provide suitable environments to cater for and meet the needs of big-bodied patients seeking healthcare. METHODS: An exploratory study utilizing an environmental investigation was undertaken in three diverse general practices. Data collection consisted of direct observation and physical measurements of practice layout and equipment. Findings were compared to the existing guidelines or standards for the healthcare of BBP. RESULTS: The analysis identified most environmental facets and equipment in all three general practices did not meet published guidelines for the care of BBP. CONCLUSIONS: In the global context of increasing and sustained prevalence of BBP, this exploratory study highlights it is crucial that general practices and similar community-based facilities review their physical environments and equipment and consider modifications to improve accessibility, inclusivity, and comfort for BBP.

Developing a transgender and non-binary inclusive obstetrics and gynaecology undergraduate medical curriculum in Aotearoa/New Zealand: Where are we at, and where do we need to be?

Internationally, undergraduate medical education is not currently enabling early career doctors to meet the needs of trans and gender diverse (TGD) people as healthcare consumers. This review outlines inclusion of TGD education in undergraduate medical education more broadly to contextualise curriculum development needs in obstetrics, gynaecology and reproductive medicine in Aotearoa/New Zealand. Limited, and lack of integrated content, teaching capability and current absence of TGD health knowledge as graduate outcomes, compounded by pedagogy (biomedical/binary framing) and more appropriate learning resources are indicators for curricula, and workforce, development.

New Zealand hospice staff perspectives on 'Xcellent Gowns' for big bodied palliative care patients: a qualitative study.

Introduction A handful of reports detail efforts to redesign traditional hospital gowns to address common concerns related to patient comfort and privacy for big bodied patients. Results suggest that improving gown design has the potential to improve both the patient and carer experience and satisfaction of care. Aim This study aimed to ascertain the utility of gowns purposely designed for big bodied patients (named Xcellent Gowns) from a staff perspective. Methods Qualitative semi-structured interviews were conducted in 2022 with 14 hospice staff members. Interview transcripts were uploaded to DedooseTM . Data were analysed utilising reflexive thematic analysis according to a six-phase process including data familiarisation, iterative data coding, and theme development and refinement. Results The qualitative analysis of the interview data identified four main themes: (1) the gown experience, (2) fit-for-purpose, (3) love and dignity, (4) design principles. Each theme is presented and discussed with illustrative quotes from participants' interview transcripts. Discussion The perspectives of the staff participants in this study confirm research findings from other healthcare settings, that the patient and carer experience may be improved through focused redesign of this vital item of patient clothing.

Features of Congenital Arthrogryposis Due to Abnormalities in Collagen Homeostasis, a Scoping Review.

Congenital arthrogryposis (CA) refers to the presence of multiple contractures at birth. It is a feature of several inherited syndromes, notable amongst them are disorders of collagen formation. This review aims to characterize disorders that directly or indirectly impact collagen structure and function leading to CA in search for common phenotypic or pathophysiological features, possible genotype-phenotype correlation, and potential novel treatment approaches based on a better understanding of the underlying pathomechanism. Nine genes, corresponding to five clinical phenotypes, were identified after a literature search. The most notable trend was the extreme phenotype variability. Clinical features across all syndromes ranged from subtle with minimal congenital contractures, to severe with multiple congenital contractures and extra-articular features including skin, respiratory, or other manifestations. Five of the identified genes were involved in the function of the Lysyl Hydroxylase 2 or 3 enzymes, which enable the hydroxylation and/or glycosylation of lysyl residues to allow the formation of the collagen superstructure. Whilst current treatment approaches are post-natal surgical correction, there are also potential in-utero therapies being developed. Cyclosporin A showed promise in treating collagen VI disorders although there is an associated risk of immunosuppression. The treatments that could be in the clinical trials soon are the splice correction therapies in collagen VI-related disorders.

Development of a robust induced pluripotent stem cell atrial cardiomyocyte differentiation protocol to model atrial arrhythmia.

BACKGROUND: Atrial fibrillation is the most common arrhythmia syndrome and causes significant morbidity and mortality. Current therapeutics, however, have limited efficacy. Notably, many therapeutics shown to be efficacious in animal models have not proved effective in humans. Thus, there is a need for a drug screening platform based on human tissue. The aim of this study was to develop a robust protocol for generating atrial cardiomyocytes from human-induced pluripotent stem cells. METHODS: A novel protocol for atrial differentiation, with optimized timing of retinoic acid during mesoderm formation, was compared to two previously published methods. Each differentiation method was assessed for successful formation of a contractile syncytium, electrical properties assayed by optical action potential recordings and multi-electrode array electrophysiology, and response to the G-protein-gated potassium channel activator, carbamylcholine. Atrial myocyte monolayers, derived using the new differentiation protocol, were further assessed for cardiomyocyte purity, gene expression, and the ability to form arrhythmic rotors in response to burst pacing. RESULTS: Application of retinoic acid at day 1 of mesoderm formation resulted in a robust differentiation of atrial myocytes with contractile syncytium forming in 16/18 differentiations across two cell lines. Atrial-like myocytes produced have shortened action potentials and field potentials, when compared to standard application of retinoic acid at the cardiac mesoderm stage. Day 1 retinoic acid produced atrial cardiomyocytes are also carbamylcholine sensitive, indicative of active Ikach currents, which was distinct from ventricular myocytes and standard retinoic addition in matched differentiations. A current protocol utilizing reduced Activin A and BMP4 can produce atrial cardiomyocytes with equivalent functionality but with reduced robustness of differentiation; only 8/17 differentiations produced a contractile syncytium. The day 1 retinoic acid protocol was successfully applied to 6 iPSC lines (3 male and 3 female) without additional optimization or modification. Atrial myocytes produced could also generate syncytia with rapid conduction velocities, > 40 cm s-1, and form rotor style arrhythmia in response to burst pacing. CONCLUSIONS: This method combines an enhanced atrial-like phenotype with robustness of differentiation, which will facilitate further research in human atrial arrhythmia and myopathies, while being economically viable for larger anti-arrhythmic drug screens.

"I felt like I had no options": Navigating an ultrasound prediction of a large baby in pregnancy.

BACKGROUND: Pregnancy ultrasound is deeply embedded in maternity care worldwide, undertaken routinely and in response to clinical indicators. Though ultrasound fetal size predictions can be inaccurate, they heavily influence clinical decision-making. As a result, women with a scan prediction of a 'large' baby may be more likely to have unnecessary interventions. AIM: This study aimed to explore the implications of an ultrasound prediction of a 'large' baby on birthing women's experiences of their pregnancies and births. METHODS: The study was underpinned by feminist poststructural theory. Semi-structured interviews were undertaken with women who had an ultrasound prediction of a 'large' baby. Transcripts were analysed using reflexive thematic analysis, with particular attention to discourse. FINDINGS: Dominant medicalising discourses prioritised surveillance and risk-centric care, and problematised large babies. Engagement with these produced oppressive effects on women including loss of control as they were directed towards high intervention care, and the experience of fear and guilt. DISCUSSION: A 'large' baby prediction has a negative impact on women's experiences. Women take up dominant discourses that frame predicted large babies as a medical problem to be managed, with little tangible improvement in outcomes. They struggle with fear and guilt as they experience their pregnancies as sites of risk and are constituted as failed mothers who are responsible for their large babies. CONCLUSION: The prediction of a 'large' baby in pregnancy has undeniably negative impacts on women. We encourage midwives to scrutinise the dominant discourses of authoritative scans and problematic large babies, becoming vectors for critical thinking and resistance.

Taking up the challenge of trans and non-binary inclusion in midwifery education: Reflections from educators in Aotearoa and Ontario Canada.

Perinatal services are being challenged to acknowledge that not all pregnant and birthing people are women and to ensure the design and delivery of services that are inclusive of, and deliver equitable outcomes for, trans, non-binary, and other gender diverse people. This is posing unique challenges for midwifery with its women-centred philosophy and professional frameworks. This paper presents the critical reflections of midwifery educators located in two midwifery programmes in Aotearoa1 and Ontario Canada, who are engaged in taking up the challenge of trans and non-binary inclusion in their local contexts. The need to progress trans and non-binary inclusion in midwifery education to secure the human rights of gender diverse people to safe midwifery care and equitable perinatal outcomes is affirmed. We respond to an existing lack of research or guidance on how to progress trans and non-binary inclusion in midwifery education. We offer our insights and reflections organised as four themes located within the frameworks of cultural humility and safety. These themes address midwifery leadership for inclusion, inclusive language, a broader holistic approach, and the importance of positioning this work intersectionally. We conclude by affirming the critical role of midwifery education/educators in taking up the challenge of trans and non-binary inclusion to ensure a future midwifery workforce skilled and supported in the provision of care to the growing gender diverse population.

Teeth are for chewing: a critical review of the conceptualisation and ethics of a controversial intraoral weight-loss device.

We are a diverse collective of researchers who are committed to improving the health and wellbeing of marginalised individuals. This article is a response to, and critique of, the DentalSlim Diet Control research. This device revises a controversial 1970s weight-loss technology connected to poor health outcomes, which is indicative of a culture that consistently promotes harm to fat and other marginalised communities.We address the historical context in which unruly bodies, particularly fat, and Indigenous bodies have been the site of unethical investigation conducted under the auspices of medical research. Existence outside the normative white, male, cis physical ideal demands regulation, and disciplinary measures. We demonstrate how Brunton et al.'s research is underpinned by anti-fat attitudes and assumptions which impose this punitive physical intervention onto healthy people in a way that should not be acceptable in medical research.Further, we address a range of harms, giving attention to Maori and to individuals with eating disorders, along with issues of research integrity. We argue that no ethics committee should have approved this research, no academic journal should have published it, and no member of the dental and medical community should promote or prescribe this device.

Resisting the problematisation of fatness in COVID-19: In pursuit of health justice.

The purpose of this paper is to explore the problematisation of fatness in contemporary responses to the COVID-19 pandemic. This paper draws from the catalogue of reports from journalists informed largely by an array of non-peer reviewed scientific literature documenting the relationship between fatness and COVID-19. Our method of enquiry is to examine fatness and COVID-19 through a problematisation lens that enables us to interrogate the scientific, political, and economic processes implicated in the production of fat bodies as problems. Fatness has been problematised in the COVID-19 pandemic. This has diverted responsibility for preparedness and well-being away from health systems and governments and onto the back of fat people and communities. This is unjust and unethical. In juxtaposition, fat activists around the world have challenged the problematisation of fatness and its effects, finding ways for fat people to subvert fat phobic institutions in the midst of the COVID-19 pandemic by collectively organising to support one another. The ways in which fatness is being taken up in current COVID-19 pandemic responses diverts responsibility for health system preparedness and community resiliency to fat individuals. This is both unjust and also obstructs meaningful action to address the health inequities laid bare by COVID-19. This paper is believed to be the first to analyse the problematisation of fatness in COVID-19, highlighting that lessons can be learned about health justice in disasters from the work of fat activists during this COVID-19 pandemic.

The Natural History of Acute Radiation-induced H-ARS and Concomitant Multi-organ Injury in the Non-human Primate: The MCART Experience.

ABSTRACT: The dose response relationship and corresponding values for mid-lethal dose and slope are used to define the dose- and time-dependent parameters of the hematopoietic acute radiation syndrome. The characteristic time course of mortality, morbidity, and secondary endpoints are well defined. The concomitant comorbidities, potential mortality, and other multi-organ injuries that are similarly dose- and time-dependent are less defined. Determination of the natural history or pathophysiology associated with the lethal hematopoietic acute radiation syndrome is a significant gap in knowledge, especially when considered in the context of a nuclear weapon scenario. In this regard, the exposure is likely ill-defined, heterogenous, and nonuniform. These conditions forecast sparing of bone marrow and increased survival from the acute radiation syndrome consequent to threshold doses for the delayed effects of acute radiation exposure due to marrow sparing, medical management, and use of approved medical countermeasures. The intent herein is to provide a composite natural history of the pathophysiology concomitant with the evolution of the potentially lethal hematopoietic acute radiation syndrome derived from studies that focused on total body irradiation and partial body irradiation with bone marrow sparing. The marked differential in estimated LD50/60 from 7.5 Gy to 10.88 Gy for the total body irradiation and partial body irradiation with 5% bone marrow sparing models, respectively, provided a clear distinction between the attendant multiple organ injury and natural history of the two models that included medical management. Total body irradiation was focused on equivalent LD50/60 exposures. The 10 Gy and 11 Gy partial body with 5% bone marrow sparing exposures bracketed the LD50/60 (10.88 Gy). The incidence, progression, and duration of multiple organ injury was described for each exposure protocol within the hematopoietic acute radiation syndrome. The higher threshold doses for the partial body irradiation with bone marrow sparing protocol induced a marked degree of multiple organ injury to include lethal gastrointestinal acute radiation syndrome, prolonged crypt loss and mucosal damage, immune suppression, acute kidney injury, body weight loss, and added clinical comorbidities that defined a complex timeline of organ injury through the acute hematopoietic acute radiation syndrome. The natural history of the acute radiation syndrome presents a 60-d time segment of multi-organ sequelae that is concomitant with the latent period or time to onset of the evolving multi-organ injury of the delayed effects of acute radiation exposure.

Scientific and Regulatory Policy Committee Best Practices: Documentation of Sexual Maturity by Microscopic Evaluation in Nonclinical Safety Studies.

The sexual maturity status of animals in nonclinical safety studies can have a significant impact on the microscopic assessment of the reproductive system, the interpretation of potential test article-related findings, and ultimately the assessment of potential risk to humans. However, the assessment and documentation of sexual maturity for animals in nonclinical safety studies is not conducted in a consistent manner across the pharmaceutical and chemical industries. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology convened an international working group of pathologists and nonclinical safety scientists with expertise in the reproductive system, pathology nomenclature, and Standard for Exchange of Nonclinical Data requirements. This article describes the best practices for documentation of the light microscopic assessment of sexual maturity in males and females for both rodent and nonrodent nonclinical safety studies. In addition, a review of the microscopic features of the immature, peripubertal, and mature male and female reproductive system and general considerations for study types and reporting are provided to aid the study pathologist tasked with documentation of sexual maturity.

Acute Radiation-induced Lung Injury in the Non-human Primate: A Review and Comparison of Mortality and Co-morbidities Using Models of Partial-body Irradiation with Marginal Bone Marrow Sparing and Whole Thorax Lung Irradiation.

The nonhuman primate, rhesus macaque, is a relevant animal model that has been used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality of radiation-induced lung injury. Herein, a literature review of published studies showing the evolution of lethal lung injury characteristic of the delayed effects of acute radiation exposure between the two significantly different exposure protocols, whole thorax lung irradiation and partial-body irradiation with bone marrow sparing in the nonhuman primate, is provided. The selection of published data was made from the open literature. The primary studies conducted at two research sites benefitted from the similarity of major variables; namely, both sites used rhesus macaques of approximate age and body weight and radiation exposure by LINAC-derived 6 MV photons at dose rates of 0.80 Gy min and 1.00 Gy min delivered to the midline tissue via bilateral, anterior/posterior, posterior/anterior geometry. An advantage relative to sex difference resulted from the use of male and female macaques by the Maryland and the Washington sites, respectively. Subject-based medical management was used for all macaques. The primary studies (6) provided adequate data to establish dose response relationships within 180 d for the radiation-induced lung injury consequent to whole thorax lung irradiation (male vs. female) and partial-body irradiation with bone marrow sparing exposure protocols (male). The dose response relationships established by probit analyses vs. linear dose relationships were characterized by two main parameters or dependent variables, a slope and LD50/180. Respective LD50/180 values for the primary studies that used whole thorax lung irradiation for respective male and female nonhuman primates were 10.24 Gy [9.87, 10.52] (n = 76, male) and 10.28 Gy [9.68, 10.92] (n = 40, female) at two different research sites. The respective slopes were steep at 1.73 [0.841, 2.604] and 1.15 [0.65, 1.65] probits per linear dose. The LD50/180 value and slope derived from the dose response relationships for the partial-body irradiation with bone marrow sparing exposure was 9.94 Gy [9.35, 10.29] (n = 87) and 1.21 [0.70, 1.73] probits per linear dose. A secondary study (1) provided data on limited control cohort of nonhuman primates exposed to whole thorax lung irradiation. The data supported the incidence of clinical, radiographic, and histological indices of the dose-dependent lung injury in the nonhuman primates. Tertiary studies (6) provided data derived from collaboration with the noted primary and secondary studies on control cohorts of nonhuman primates exposed to whole thorax lung irradiation and partial-body irradiation with bone marrow sparing exposure. These studies provided a summary of histological evidence of fibrosis, inflammation and reactive/proliferative changes in pneumonocytes characteristic of lung injury and data on biomarkers for radiation-induced lung injury based on matrix-assisted laser desorption ionization-mass spectrometry imaging and gene expression approaches. The available database in young rhesus macaques exposed to whole thorax lung irradiation or partial-body irradiation with bone marrow sparing using 6 MV LINAC-derived radiation with medical management showed that the dose response relationships were equivalent relative to the primary endpoint all-cause mortality. Additionally, the latency, incidence, severity, and progression of the clinical, radiographic, and histological indices of lung injury were comparable. However, the differences between the exposure protocols are remarkable relative to the demonstrated time course between the multiple organ injury of the acute radiation syndrome and that of the delayed effects of acute radiation exposure, respectively.

Lack of Cellular Inflammation in a Non-human Primate Model of Radiation Nephropathy.

Inflammation is commonly cited as a mechanism of delayed effects of acute radiation exposure (DEARE). Confirmation of its presence could provide significant insight to targeted use of treatments or mitigators of DEARE. We sought to quantify the presence of cellular inflammation in kidneys of non-human primates that developed acute and chronic kidney injury after a partial body irradiation exposure. We show herein that cellular inflammation is not found as a component of either acute or chronic kidney injury. Other mechanistic pathways of injury must be sought.

MALDI-MSI spatially maps N-glycan alterations to histologically distinct pulmonary pathologies following irradiation.

Radiation-induced lung injury is a highly complex combination of pathological alterations that develop over time and severity of disease development is dose-dependent. Following exposures to lethal doses of irradiation, morbidity and mortality can occur due to a combination of edema, pneumonitis and fibrosis. Protein glycosylation has essential roles in a plethora of biological and immunological processes. Alterations in glycosylation profiles have been detected in diseases ranging from infection, inflammation and cancer. We utilized mass spectrometry imaging to spatially map N-glycans to distinct pathological alterations during the clinically latent period and at 180 days post-exposure to irradiation. Results identified alterations in a number of high mannose, hybrid and complex N-glycans that were localized to regions of mucus and alveolar-bronchiolar hyperplasia, proliferations of type 2 epithelial cells, accumulations of macrophages, edema and fibrosis. The glycosylation profiles indicate most alterations occur prior to the onset of clinical symptoms as a result of pathological manifestations. Alterations in five N-glycans were identified as a function of time post-exposure. Understanding the functional roles N-glycans play in the development of these pathologies, particularly in the accumulation of macrophages and their phenotype, may lead to new therapeutic avenues for the treatment of radiation-induced lung injury.

A Pathology Review of the Lower Gastrointestinal Tract in Relation to Ulcerative Colitis in Rats and Cynomolgus Macaques Treated With Ammonium Perfluorooctanoate.

Among many short-term, subchronic, and chronic toxicology studies with ammonium perfluorooctanoate (PFOA), the gastrointestinal tract has not been identified as a target organ for PFOA-related toxicity in laboratory animals where the corresponding serum PFOA concentrations typically approach several orders of magnitude higher than the general human population. These lack of gastrointestinal tract-related findings were in direct contrast to an epidemiological observation where a positive trend was observed for ulcerative colitis, an idiopathic chronic inflammatory condition of the gut, in a Mid-Ohio River community whose drinking water contained higher levels of PFOA. This study was conducted to perform a histological reevaluation of large intestine sections in laboratory animals from 2 long-term toxicological studies: one was with Sprague Dawley rats that received ammonium PFOA in their diet for 2 years and the other one was with cynomolgus macaques that received daily capsules of ammonium PFOA for 6 months. In both studies, there was a lack of histological evidence of treatment-related inflammatory lesions that was suggestive of the occurrence of ulcerative colitis in these laboratory animals even under the most rigorous treatment schedules. These findings do not offer support for the biological plausibility of the epidemiological associations reported.

Criminal Justice and Suicide Outcomes with Indiana's Risk-Based Gun Seizure Law.

This article examines the application and effectiveness of a 2006 Indiana law designed to prevent gun violence by authorizing police officers to separate firearms from persons who present imminent or future risk of injury to self or others, or display a propensity for violent or emotionally unstable conduct. A court hearing is held to determine ongoing risk in these cases; a judge decides whether to return the seized firearms or retain them for up to five years. The study examines the frequency of criminal arrest as well as suicide outcomes for 395 gun-removal actions in Indiana. Fourteen individuals (3.5%) died from suicide, seven (1.8%) using a firearm. The study population's annualized suicide rate was about 31 times higher than that of the general adult population in Indiana, demonstrating that the law is being applied to a population genuinely at high risk. By extrapolating information on the case fatality rate for different methods of suicide, we calculated that one life was saved for every 10 gun-removal actions, similar to results of a previous study in Connecticut. Perspectives from key stakeholders are also presented along with implications for gun policy reform and implementation.

Radiation Nephropathy in a Nonhuman Primate Model of Partial-body Irradiation with Minimal Bone Marrow Sparing-Part 1: Acute and Chronic Kidney Injury and the Influence of Neupogen.

Acute and chronic kidney injury may occur after accidental prompt radiation exposures. We have modeled their occurrence in a nonhuman primate model. Subjects who are exposed to more than 5-Gy prompt irradiation are apt to show blood cell cytopenias and be treated with granulocyte colony-stimulating factors such as Neupogen® or Neulasta® to mitigate the hematologic injury of the acute radiation syndrome. Neupogen or Neulasta are now approved by the US Food and Drug Administration for this indication. This will significantly increase the number of survivors of acute radiation exposures who will be at risk for delayed effects of radiation exposure, which includes acute and chronic kidney injury. The primary objectives of the present two companion manuscripts were to assess natural history of delayed radiation-induced renal injury in a nonhuman primate model of acute, high-dose, partial-body irradiation with 5% bone marrow sparing to include the clinical and histopathological evidence and the effect of Neupogen administration on morbidity and mortality. In this study, 88 nonhuman primates underwent 10- or 11-Gy partial-body irradiation with 5% bone marrow sparing, of which 36 were treated with Neupogen within 1, 3, or 5 d postirradiation. All animals were followed up to 180 d after irradiation. Renal function and histology end points showed early acute and later chronic kidney injury. These end points were not affected by use of Neupogen. We conclude that use of Neupogen to mitigate against the hematopoietic acute radiation syndrome has no impact on acute or chronic kidney injury.

Radiation Nephropathy in a Nonhuman Primate Model of Partial-Body Irradiation With Minimal Bone Marrow Sparing-Part 2: Histopathology, Mediators, and Mechanisms.

Male rhesus macaques were subjected to partial-body irradiation at 10, 11, or 12 Gy with 5% bone marrow protection. Animals were euthanized when dictated by prospectively determined clinical parameters or at approximately 180 d following irradiation. Histological sections of kidney were stained with hematoxylin and eosin as well as a battery of histochemical and immunohistochemical stains. Histopathological alterations were centered on glomerular changes and fibrosis of glomeruli and the interstitial compartment. These changes were first noted in animals necropsied approximately 100 d postirradiation and continued in animals necropsied through the observation period. Glomerular changes included congestion, thrombosis, erythrocyte degeneration, capillary tuft dilation, fibrin deposition, altered quantity and dispersion pattern of von Willebrand factor, increased mesangial matrix, and mesangial deposits of material that stained positively with periodic acid-Schiff staining. Areas of interstitial and glomerular fibrosis, as demonstrated by Masson's trichrome staining, were topographically associated with increased immunohistochemical staining for connective tissue growth factor, alpha smooth muscle actin, and collagen 1, but there was little staining for transforming growth factor beta. Fibrotic glomeruli had reduced microvascularity as demonstrated by reduced CD31 immunohistochemical staining. Vascular congestion was commonly noted in the region of the corticomedullary junction, and proteinaceous casts were commonly noted in cortical and medullary tubules. Longitudinal analysis of histopathological alterations provided evidence defining the latency, severity, and progression of delayed radiation-induced kidney injury.

The Time Course of Radiation-induced Lung Injury in a Nonhuman Primate Model of Partial-body Irradiation With Minimal Bone Marrow Sparing: Clinical and Radiographic Evidence and the Effect of Neupogen Administration.

The primary objectives of two companion manuscripts were to assess the natural history of delayed radiation-induced lung injury in a nonhuman primate model of acute high-dose, partial-body irradiation with 5% bone marrow sparing, to include the clinical, radiographic, and histopathological evidence and the effect of Neupogen administration on the morbidity and mortality. Nonhuman primates were exposed to 10.0 or 11.0 Gy with 6 MV linac-derived photons at approximately 0.80 Gy min. All nonhuman primates received subject-based, medical management. Subsets of nonhuman primates were administered Neupogen (10 µg kg) starting on day 1, day 3, or day 5 until recovery (absolute neutrophil count ≥ 1,000 cells µL for three consecutive days). Mortality due to multiple organ injury at 180 d study duration: Mortality at 180 d post either 10.0 Gy or 11.0 Gy was the consequence of concurrent injury due to the acute radiation syndrome (gastrointestinal and hematological) and delayed radiation-induced lung injury. The 180-d all-cause mortality observed in the control cohorts at 10.0 Gy (53%) or 11.0 Gy (86%) did not vary from cohorts that received Neupogen at any administration schedule. Mortality ranged from 43-50% (10 Gy) to 75-100% (11.0 Gy) in the Neupogen-treated cohorts. The study, however, was not powered to detect statistical significant differences between mortality in the control and Neupogen-treated cohorts. Clinical and radiographic evidence of radiation-induced lung injury: The mean nonsedated respiratory rate in the control cohorts exposed to 10 or 11 Gy increased from a baseline value of 37 breaths min to >60 breaths min within 103 d and 94 d postexposure, and the incidence of nonsedated respiratory rate > 80 breaths min was 50% and 70%, respectively. The mean duration of latency to development of clinical pneumonitis and/or fibrosis (nonsedated respiratory rate > 80 breaths min) was not significantly different between the 10.0-Gy or 11.0 Gy-cohorts (range 100-107 d). Neupogen (granulocyte colony-stimulating factor) administration had no apparent effect of the latency, incidence, or severity of nonsedated respiratory rate within either radiation dose or administration schedule. Computed tomography scans were obtained and images were analyzed for evidence of lung injury, e.g., pneumonitis and/or fibrosis, pleural and pericardial effusion. A quantitative, semiautomated method was developed based on differences in radiodensity (Hounsfield units) and lung morphology to extract the volume of pneumonitis/fibrosis and pleural effusion as indexed against total lung at each time point obtained. At both irradiation doses, 100% of the nonhuman primates surviving acute radiation syndrome manifested radiographic evidence of radiation-induced lung injury as pneumonitis and/or fibrosis. There was no apparent effect of Neupogen administration on the latency, incidence, severity, or progression of pneumonitis/fibrosis:total lung volume or pleural effusion:total lung volume at either exposure. A comparative review of the data illustrated the concomitant time course of increased mortality, nonsedated respiratory rate, and pneumonitis/fibrosis:total lung volume and pleural effusion:total lung volume consequent to 10.0-Gy or 11.0-Gy partial-body irradiation with 5% bone marrow sparing. All key parameters proceeded from a latent period of approximately 60 d followed by an increase in all three indices of clinical and radiographic evidence of radiation-induced lung injury within the next 60 d to 120 d postexposure. The subsequent time course and longitudinal analysis was influenced by the persistent progression of radiation-induced lung injury, administration of dexamethasone, and loss of nonhuman primates due to lethality. Companion paper: Lung and Heart Injury in a Nonhuman Primate Model of Partial-body Irradiation With Minimal Bone Marrow Sparing: Histopathological Evidence of Lung and Heart Injury (Parker et al. 2019): Note that the computed tomography-based radiodensity data do not permit differentiation of pneumonitis and fibrosis. The companion paper employed Masson's trichrome, collagen 1, and selected staining to identify the key time and incidence parameters relative to excessive collagen deposition indicative of fibrosis and associated histopathology in the lung. This histological database provided valuable longitudinal analysis in support of the clinical and radiographic evidence associated with the time course of radiation-induced lung injury.