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Background: Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer mortality. Acute adverse effects (AEs) from CRC treatments (surgery, chemotherapy, radiation therapy) may cause dose limitations and/or treatment discontinuation. Chronic AEs may include bowel symptoms, fatigue, anxiety, depression, and sarcopenic obesity. These acute and chronic AEs significantly impact quality of life (QoL). A comprehensive understanding of the pathophysiological mechanism(s) driving these AEs is lacking. Evidence supports the hypothesis that the gut microbiota may be an integrative point in the pathogenesis of several AEs. Dysbiosis alters the normal function of the gut and gut-brain-axis. CRC treatments can lead to dysbiosis and in turn may drive acute and chronic AEs. Our aims are to explore how CRC treatment affects the microbiota and the further path to recovery. Methods: A prospective feasibility study of n=35 participants in Calgary, Alberta of stage I-III CRC patients to evaluate: 1) The feasibility of collecting microbiota samples at diagnosis to one-year post diagnosis; 2) Longitudinal changes to microbiota over a 1-year period; and 3) Preliminary associations between changes in the microbiota and treatment completion, treatment AEs, clinical and tumor characteristics, and changes to patient reported outcomes (PROs). Inclusion: Newly diagnosed stage I-III CRC, aged ≥18, English speaking, and willing to provide 4 fecal samples. Exclusion: Inflammatory bowel disease, hereditary CRC syndromes, or stage IV. Convenience sampling will be used. Feasibility will include recruitment and retention rates, adherence to specimen collection protocols, specimen quality, and patient satisfaction. Microbiota will be evaluated using longitudinal fecal sampling for metabolomics, culture, and mechanistic studies to examine intra-individual differences in microbiota (α and b diversity). Shotgun sequencing libraries will be prepared to generate approximately 4M 150 bp read pairs/sample. Clinical data on tumor characteristics, treatments, and treatment AEs will be abstracted from medical records. Demographic data and a battery of PROs (diet, physical activity, depression, anxiety, QoL, CRC symptoms, cognitive function, and fatigue using validated questionnaires) will be collected. Results: This study will determine the feasibility of longitudinal prospective collection of biospecimen, clinical, and PROs in newly diagnosed stage I-III CRC patients. This study will also provide preliminary data on changes to the gut microbiota as a result of treatments and how these changes may in turn impact clinical and PROs. Conclusions: This novel investigation into dysbiosis as an integrative point driving CRC treatment AEs is timely and warranted given the persistence of debilitating problems post CRC treatment. Building on data from this project we plan to conduct a population-based cohort study. Our goal is to ultimately inform interventions to manage treatment AEs, improve clinical outcomes, and improve QoL for CRC survivors. Citation Format: Colleen Ann Cuthbert, Kathy McCoy, Anthony MacLean, Lin Yang, May Lynn Quan, Donald Buie. Investigating the effects of cancer treatment on gut microbiota in colorectal cancer patients: Study protocol [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B005.

Brain injury, resulting from stroke and traumatic brain injury, is a common occurrence in Australia, with Aboriginal people affected at a significant rate and impact felt by individuals, families and communities. Access to brain injury rehabilitation services for Aboriginal people is reported to be often limited, with very little support outside the hospital environment. Our research involving Aboriginal brain injury survivors and their families to date has revealed that people often manage ‘on their own’ following such events. Following recommendations from survivors and their families, the Healing Right Way clinical trial, currently underway in Western Australia, has created the role of Aboriginal Brain Injury Coordinator (ABIC) to assist in navigating information and services, particularly after discharge from hospital. Eight positions for this role have been instigated across metropolitan and rural regions in the state. Healing Right Way’s aim is to enhance rehabilitation services and improve quality of life for Aboriginal Australians after brain injury. The ABIC’s role is to provide education, support, liaison and advocacy services to participants and their families over a six-month period, commencing soon after the participant’s stroke or injury has occurred. This paper outlines the development of this role, the partnerships involved, experiences to date and identifies some facilitators and barriers encountered that may impact the role’s ongoing sustainability. Details of components of the planned full Process Evaluation of Healing Right Way related to the ABIC role and the partnerships surrounding it are also provided. In combination with the trial’s ultimate results, this detail will assist in future service planning and provide a model of culturally secure care for stroke and brain injury services that can also inform other sub-acute and primary care models.

During systemic bacterial infections and sepsis, neutrophils are recruited en mass into the microcirculation of the liver and lungs as part of a coordinated intravascular response to defend the bloodstream against bacterial pathogens. The mechanisms that program this response have not been elucidated. The gut microbiota regulates immune cell development and function. In extra-intestinal organs, the microbiota conducts long-distance communication with immune cells through the release of metabolites into the bloodstream. While gut microbes augment granulopoiesis in the bone marrow, the role the microbiota and commensal-derived metabolites on neutrophil trafficking is poorly understood. Using confocal intravital microscopy, we observed that germ-free (GF) mice had impaired neutrophil recruitment to the liver, but not the lungs, during sepsis. Analysis of microbial metabolites in the gut, portal circulation (between gut and liver), and systemic circulation revealed that commensal-derived D-lactate levels are high in the gut and portal circulation, but nearly absent in the systemic circulation. Reconstitution of gut-to-liver D-lactate signalling by enteral administration restored neutrophil trafficking to the liver. In contrast, D-lactate did not impact neutrophil infiltration to the lungs, systemic levels of pro-inflammatory mediators or granulopoiesis. Instead, commensal D-lactate primed liver endothelium to express adhesion molecules required for neutrophil adhesion and crawling. Taken together, we show that compartmentalized molecular communication between gut microbes and the liver primes the microvascular endothelium for neutrophil recruitment in response to systemic bacterial infection and sepsis.

The purpose of this paper is to explore the pragmatic issue of when to use pre-constructed utterances by discussing a research project investigating messages that fail to meet either conventional standards of contextual appropriateness or timing. The use of pragmatic theory to systematically examine pre-constructed messages will be discussed, along with the outcomes of using messages that do not seem to follow pragmatic rules. The development of a hierarchy of types of rule violations will be described and the clinical implications of the hierarchy will be explored.

Novel 1,3-diarylcycloalkanopyrazoles 1, and diphenyl hydrazides 2 were identified as selective inhibitors of cyclooxygenase-2. The 1,3-diaryl substitution pattern of the pyrazole ring in 1 differentiates these compounds from most of the known selective COX-2 inhibitors that contain two aryl rings at the adjacent positions on a heterocyclic or a phenyl ring. Similarly, the two phenyl rings in 2 are also separated by three atoms. SAR of both phenyl rings in 1 and 2, and the aliphatic ring in 1 will be discussed.

Novel 1,3-diarylcycloalkanopyrazoles 1, and diphenyl hydrazides 2 were identified as selective inhibitors of cyclooxygenase-2. The 1,3-diaryl substitution pattern of the pyrazole ring in 1 differentiates these compounds from most of the known selective COX-2 inhibitors that contain two aryl rings at the adjacent positions on a heterocyclic or a phenyl ring. Similarly, the two phenyl rings in 2 are also separated by three atoms. SAR of both phenyl rings in 1 and 2, and the aliphatic ring in 1 will be discussed.

Environmentally-induced alterations in the commensal microbiome have been implicated in the increasing prevalence of food allergy. We found that antibiotic treatment of neonatal mice leads to reduced proportions of regulatory T cells(Tregs) in the colonic lamina propria(LP), impaired production of intestinal IgA, and elevated peanut (PN) specific IgE/IgG1 in response to sensitization. Selective colonization of gnotobiotic mice linked the Treg/IgA inducing capacity to a consortium of bacteria within the Clostridia class. Introduction of either a conventional SPF microbiota or a mixture of Clostridia strains to antibiotic-treated mice restored the Treg and IgA compartments and blocked the induction of a food allergic response. Clostridia colonized gnotobiotic mice displayed increased expression of IL-23 and IL-22 in the colonic LP compartment and the induction of anti-microbial REG3β expression in the epithelium. Collectively, these results suggest that the maintenance of oral tolerance to dietary antigens relies on bacterial populations that induce a barrier protective response, which includes activation of the IL-23/IL22 axis and the expansion of intestinal Tregs and IgA secreting B cells. Our findings hold promise for the development of approaches to prevent or treat food allergy based on modulation of the composition of intestinal microbiota.

Representatives of national organizations private foundations and agencies concerned with adolescent sexuality as well as health care practitioners and educators media representatives and authorities on sex education and adolescent behavior met at Wingspread in Racine Wisconsin for a conference on "Adolescent sexuality and health care: an affirmation of purpose." Rising rates of pregnancy and venereal disease among teenagers were seen as symptoms of deeper problems including 1) the low priority of the adolescent in our society and the generational double standard; 2) the lack of candor and accurate information in regard to human sexuality; 3) the lack of access to medical services including contraceptives; and 4) the influence of a negative attitude toward sex in our society. Affirmative plans of action toward education in the rights and responsibilities for human sexuality were worked out in committees representing vital elements in society: the home schools community churches health services and business and foundations. All can combine in upgrading the dignity of human sexuality.

(1974). What teen readers are asking about sex … and what we're telling them. Journal of Clinical Child Psychology: Vol. 3, Adolescent Sexuality, pp. 34-36.

Food allergies are immune system-driven diseases that lead to reproducible adverse reactions which can be fatal. These severe systemic reactions are primary mediated by immunoglobulin E (IgE) that is derived from B cells which have been activated by T helper type 2 (Th2) cells. While much work has advanced the clinical and pharmacological management of patients with allergic diseases, much remains to be elucidated about how individuals initially acquire allergy. This Thesis details a mechanism linking initial gastrointestinal exposure to peanut (PN) allergen, to the generation of Th2 cells: PN allergen activates epithelial cell secretion of interleukin (IL)-33 and eosinophil degranulation of eosinophil peroxidase, which causes CD103+ dendritic cell (DC) activation and migration to mesenteric lymph nodes where DC OX40L engages naïve T cells to secrete IL-4 in an autocrine/paracrine manner to promote and consolidate Th2 cell differentiation. These events are followed by B cell activation and PN-specific IgE production, which sensitizes mast cells to be hypersensitive to PN re-exposure by causing immediate allergic reactions including anaphylaxis. This is later followed by eosinophilic inflammation that is partially mediated by innate lymphoid cells. As food allergy also serves as a unique model to better understand mechanisms of adaptive immunity, especially Th2 immunobiology, both basic science and clinical implications are discussed in this Thesis. Major themes include Th2 and disease heterogeneity, identification of ‘the original source of IL-4’, an unprecedented in vivo requirement for eosinophils in priming adaptive immune responses, and the need to weigh basic science findings against the human disease in natura litmus test. Looking forward, many questions remain to be answered in the field of food allergy research, but the findings of this Thesis may be one step towards the prevention, management or cure of a disease with growing public concern, potentially fatal consequences, and an unmet need in understanding its pathogenesis. Doctor of Philosophy (Medical Science)