Acute Impacts of Ionizing Radiation Exposure on the Gastrointestinal Tract and Gut Microbiome in Mice.

Radiation therapy for abdominopelvic malignancies often results in damage to the gastrointestinal tract (GIT) and permanent changes in bowel function. An overlooked component of the pathophysiology of radiation-induced bowel injury is the role of the gut microbiome. The goal of this research was to identify the impacts of acute radiation exposure on the GIT and gut microbiome. C57BL/6 mice exposed to whole-body X-rays (0.1-3 Gy) were assessed for histological and microbiome changes 48 h post-radiation exposure. Within the ileum, a dose of 3 Gy significantly decreased crypt depth as well as the number of goblet cells, but increased overall goblet cell size. Overall, radiation altered the microbial distribution within each of the main phyla in a dose- and tissue-dependent manner. Within the Firmicutes phylum, high dose irradiation resulted in significant alterations in bacteria from the class Bacilli within the small bowels, and from the class Clostridia in the large bowels. The 3 Gy radiation also significantly increased the abundance of bacterial families from the Bacteroidetes phylum in the colon and feces. Overall, we identified various alterations in microbiome composition following acute radiation exposure, which could potentially lead to novel biomarkers for tracking patient toxicities or could be used as targets for mitigation strategies against radiation damage.

Absence of Depressive and Anxious Behavior with Genetic Dysregulation in Adult C57Bl/6J Mice after Prenatal Exposure to Ionizing Radiation.

The exposure of ionizing radiation during early gestation often leads to deleterious and even lethal effects; however, few extensive studies have been conducted on late gestational exposures. This research examined the behavior al effects of C57Bl/6J mouse offspring exposed to low dose ionizing gamma irradiation during the equivalent third trimester. Pregnant dams were randomly assigned to sham or exposed groups to either low dose or sublethal dose radiation (50, 300, or 1000 mGy) at gestational day 15. Adult offspring underwent a behavioral and genetic analysis after being raised under normal murine housing conditions. Our results indicate very little change in the behavioral tasks measuring general anxiety, social anxiety, and stress-management in animals exposed prenatally across the low dose radiation conditions. Quantitative real-time polymerase chain reactions were conducted on the cerebral cortex, hippocampus, and cerebellum of each animal; results indicate some dysregulation in markers of DNA damage, synaptic activity, reactive oxygen species (ROS) regulation, and methylation pathways in the offspring. Together, our results provide evidence in the C57Bl/6J strain, that exposure to sublethal dose radiation (<1000 mGy) during the last period of gestation leads to no observable changes in behaviour when assessed as adults, although some changes in gene expression were observed for specific brain regions. These results indicate that the level of oxidative stress occurring during late gestation for this mouse strain is not sufficient for a change in the assessed behavioral phenotype, but results in some modest dysregulation of the genetic profile of the brain.

The REPAIR Project, a Deep-Underground Radiobiology Experiment Investigating the Biological Effects of Natural Background Radiation: The First 6 Years.

In 2017, a special edition of Radiation Research was published [Oct; Vol. 188 4.2 (https://bioone.org/journals/radiation-research/volume-188/issue-4.2)] which focused on a recently established radiobiology project within SNOLAB, a unique deep-underground research facility. This special edition included original articles, reviews and commentaries relevant to the research goals of this new project which was titled Researching the Effects of the Presence and Absence of Ionizing Radiation (REPAIR). These research goals were founded in understanding the biological effects of terrestrial and cosmic natural background radiation (NBR). Since 2017, REPAIR has evolved into a sub-NBR radiobiology research program which investigates these effects using multiple model systems and various biological endpoints. This paper summarizes the evolution of the REPAIR project over the first 6-years including its experimental scope and capabilities as well as research accomplishments.

Gene Dysregulation in the Adult Rat Paraventricular Nucleus and Amygdala by Prenatal Exposure to Dexamethasone.

Fetal programming is the concept that maternal stressors during critical periods of fetal development can alter offspring phenotypes postnatally. Excess glucocorticoids can interact with the fetus to effect genetic and epigenetic changes implicated in adverse developmental outcomes. The present study investigates how chronic exposure to the synthetic glucocorticoid dexamethasone during late gestation alters the expression of genes related to behavior in brain areas relevant to the regulation and function of the hypothalamic-pituitary-adrenal axis. Pregnant Wistar Kyoto rats received subcutaneous injections of dexamethasone (100 µg/kg) daily from gestational day 15-21 or vehicle only as sham controls. The amygdala and paraventricular nucleus (PVN) were micro-punched to extract mRNA for reverse transcription and quantitative polymerase chain reaction for the analysis of the expression of specific genes. In the PVN, the expression of the glucocorticoid receptor NR3C1 was downregulated in female rats in response to programming. The expression of CACNA1C encoding the Cav1.2 pore subunit of L-type voltage-gated calcium channels was downregulated in male and female rats prenatally exposed to dexamethasone. Collectively, the results suggest that prenatal exposure to elevated levels of glucocorticoids plays a role in the dysregulation of the hypothalamic-pituitary-adrenal axis and potentially learning and memory by altering the expression of specific genes within the amygdala and PVN.

"They're all struggling as well": social and economic barriers and facilitators to self-managing chronic illness among marginalized people who use drugs.

PURPOSE: Self-management is recommended for addressing chronic conditions, and self-management programmes improve health behaviours and outcomes. However, social and economic factors have been neglected in self-management research, despite their relevance for marginalized groups. Thus, we aimed to explore barriers and facilitators that influence self-management among socioeconomically marginalized people who use drugs (PWUD). METHODS: Using community-based participatory methods, we developed a qualitative interview guide and conducted peer-led recruitment. Participants were admitted into the study after self-identifying as using non-prescribed drugs, having a chronic health issue, and experiencing socioeconomic marginalization. Data were analysed using reflexive thematic analysis, taking a relational autonomy lens. RESULTS: Participants highlighted substantial barriers to managing their health issues, mostly stemming from their social and economic environments, such as unstable housing, low income, lack of supportive social networks, and negative healthcare experiences. Participants also described how their ability to self-manage their chronic conditions benefited from specific aspects of social interactions, including close relationships, community connectedness, and engaging in peer support. CONCLUSIONS: Our findings suggest that structural interventions are needed to support self-management among marginalized PWUD, especially stable housing. Self-management supports for PWUD would benefit from including a range of low-barrier community-based options, peer work opportunities, and advocacy for needs.

Effect of Prenatal Glucocorticoid Exposure on Circadian Rhythm Gene Expression in the Brains of Adult Rat Offspring.

Circadian clocks control many vital aspects of physiology from the sleep-wake cycle to metabolism. The circadian clock operates through transcriptional-translational feedback loops. The normal circadian signaling relies on a 'master clock', located in the suprachiasmatic nucleus (SCN), which synchronizes peripheral oscillators. Glucocorticoid receptor (GR) signaling has the ability to reset the phase of peripheral clocks. It has been shown that maternal exposure to glucocorticoids (GCs) can lead to modification of hypothalamic-pituitary-adrenal (HPA) function, impact stress-related behaviors, and result in a hypertensive state via GR activation. We previously demonstrated altered circadian rhythm signaling in the adrenal glands of offspring exposed to the synthetic GC, dexamethasone (Dex). Results from the current study show that prenatal exposure to Dex affects circadian rhythm gene expression in a brain region-specific and a sex-specific manner within molecular oscillators of the amygdala, hippocampus, paraventricular nucleus, and prefrontal cortex, as well as the main oscillator in the SCN. Results also show that spontaneously hypertensive rats (SHR) exhibited dysregulated circadian rhythm gene expression in these same brain regions compared with normotensive Wistar-Kyoto rats (WKY), although the pattern of dysregulation was markedly different from that seen in adult offspring prenatally exposed to GCs.

"The Drug Use Unfortunately isn't all Bad": Chronic Disease Self-Management Complexity and Strategy Among Marginalized People Who Use Drugs.

Self-management programs improve health outcomes and self-management is recommended for chronic conditions. Yet chronic disease self-management supports have rarely been applied to people who use drugs (PWUD). Thus, our objective was to explore self-management experiences among marginalized PWUD. We used community-based participatory methods and conducted qualitative interviews. Participants self-identified as having long-term and past year experience using non-prescribed drugs, one other chronic condition, and socioeconomic marginalization. We analyzed the data using reflexive thematic analysis. Although many participants considered drug use a chronic health issue, self-medicating with non-prescribed drugs was also a key self-management strategy to address other health issues. Participants also described numerous other strategies, including cognitive and behavioral tactics. These findings highlight the need for a safe supply of pharmaceutical-grade drugs to support self-management among marginalized PWUD. Self-management supports should also be tailored to address relevant topics (e.g., harm reduction, withdrawal), include creative activities, and not hinder PWUD's agency.

Late gestational exposure to dexamethasone and fetal programming of abnormal behavior in Wistar Kyoto rats.

INTRODUCTION: Fetal programming was characterized a few decades ago, explaining the correlation of physiological phenotypes of offspring exposed to early-life stress. High acute or chronic prenatal stress can overwhelm the enzymatic placental barrier, inducing transcriptional changes in the fetus that can result in different adverse behavioral and physiological phenotypes. The current study investigates the impact of exposure to the synthetic glucocorticoid, dexamethasone, during late gestation on behavioral outcomes. METHODS: Pregnant Wistar Kyoto rats were given daily subcutaneous injections from gestational days 15-21 of either dexamethasone (0.9% NaCl, 4% EtOH, 100 µg kg-1  day-1 ) or were physically manipulated as naïve controls. Pups were raised normally until 17 weeks of age and underwent the Porsolt swim task and elevated plus maze for depressive and anxiety-like behaviors, respectively. Neural tissue was preserved for genetic analysis using quantitative real-time polymerase chain reaction. RESULTS: Statistical analyses show significant disruption of behavior and genetic profiles of offspring exposed to dexamethasone in-utero. Exposed animals spent more time immobile on the swim task and entered open arms of the elevated plus maze more often than their naïve counterparts. In the prefrontal cortex, there was a sex by treatment interaction on gene expression relevant to neural transmission in ryanodine receptor 2, as well as increased gene expression in SNAP25, COMT, and LSAMP in males prenatally exposed to dexamethasone compared with controls. Both dysregulated genes and behavior are linked to decreased anxiety and fear inhibition. CONCLUSION: Our results indicate adult offspring exposed to dexamethasone in-utero have a tendency toward passive stress-coping strategies and an inhibition of anxiety on behavioral tasks. Methyltransferase activity, synaptic activity, and cellular processes were disrupted in the prefrontal cortices of these animals. Specifically, genes involved in emotional response pathways were overexpressed, supporting the link between the behavioral and genetic profiles. Combined, we determine that dexamethasone offspring have adaptive predispositions when faced with novel situations, with increased immobility in the swim task and increased exploration on the elevated plus maze.

Establishing need and population priorities to improve the health of homeless and vulnerably housed women, youth, and men: A Delphi consensus study.

BACKGROUND: Homelessness is one of the most disabling and precarious living conditions. The objective of this Delphi consensus study was to identify priority needs and at-risk population subgroups among homeless and vulnerably housed people to guide the development of a more responsive and person-centred clinical practice guideline. METHODS: We used a literature review and expert working group to produce an initial list of needs and at-risk subgroups of homeless and vulnerably housed populations. We then followed a modified Delphi consensus method, asking expert health professionals, using electronic surveys, and persons with lived experience of homelessness, using oral surveys, to prioritize needs and at-risk sub-populations across Canada. Criteria for ranking included potential for impact, extent of inequities and burden of illness. We set ratings of ≥ 60% to determine consensus over three rounds of surveys. FINDINGS: Eighty four health professionals and 76 persons with lived experience of homelessness participated from across Canada, achieving an overall 73% response rate. The participants identified priority needs including mental health and addiction care, facilitating access to permanent housing, facilitating access to income support and case management/care coordination. Participants also ranked specific homeless sub-populations in need of additional research including: Indigenous Peoples (First Nations, Métis, and Inuit); youth, women and families; people with acquired brain injury, intellectual or physical disabilities; and refugees and other migrants. INTERPRETATION: The inclusion of the perspectives of both expert health professionals and people with lived experience of homelessness provided validity in identifying real-world needs to guide systematic reviews in four key areas according to priority needs, as well as launch a number of working groups to explore how to adapt interventions for specific at-risk populations, to create evidence-based guidelines.

Uptake of Community-Based Peer Administered HIV Point-of-Care Testing: Findings from the PROUD Study.

OBJECTIVES: HIV prevalence among people who inject drugs (PWID) in Ottawa is estimated at about 10%. The successful integration of peers into outreach efforts and wider access to HIV point-of-care testing (POCT) create opportunities to explore the role of peers in providing HIV testing. The PROUD study, in partnership with Ottawa Public Health (OPH), sought to develop a model for community-based peer-administered HIV POCT. METHODS: PROUD draws on community-based participatory research methods to better understand the HIV risk environment of people who use drugs in Ottawa. From March-October 2013, 593 people who reported injecting drugs or smoking crack cocaine were enrolled through street-based recruitment. Trained peer or medical student researchers administered a quantitative survey and offered an HIV POCT (bioLytical INSTI test) to participants who did not self-report as HIV positive. RESULTS: 550 (92.7%) of the 593 participants were offered a POCT, of which 458 (83.3%) consented to testing. Of those participants, 74 (16.2%) had never been tested for HIV. There was no difference in uptake between testing offered by a peer versus a non-peer interviewer (OR = 1.05; 95% CI = 0.67-1.66). Despite testing those at high risk for HIV, only one new reactive test was identified. CONCLUSION: The findings from PROUD demonstrate high uptake of community-based HIV POCT. Peers were able to successfully provide HIV POCT and reach participants who had not previously been tested for HIV. Community-based and peer testing models provide important insights on ways to scale-up HIV prevention and testing among people who use drugs.