Comparison of socio-economic determinants of COVID-19 testing and positivity in Canada: A multi-provincial analysis.

BACKGROUND: The effects of the COVID-19 pandemic have been more pronounced for socially disadvantaged populations. We sought to determine how access to SARS-CoV-2 testing and the likelihood of testing positive for COVID-19 were associated with demographic factors, socioeconomic status (SES) and social determinants of health (SDH) in three Canadian provinces. METHODS: An observational population-based cross-sectional study was conducted for the provinces of Ontario, Manitoba and New Brunswick between March 1, 2020 and April 27, 2021, using provincial health administrative data. After excluding residents of long-term care homes, those without current provincial health insurance and those who were tested for COVID-19 out of province, records from provincial healthcare administrative databases were reviewed for 16,900,661 healthcare users. Data was modelled separately for each province in accordance to a prespecified protocol and follow-up consultations among provincial statisticians and collaborators. We employed univariate and multivariate regression models to examine determinants of testing and test results. RESULTS: After adjustment for other variables, female sex and urban residency were positively associated with testing, while female sex was negatively associated with test positivity. In New Brunswick and Ontario, individuals living in higher income areas were more likely to be tested, whereas in Manitoba higher income was negatively associated with both testing and positivity. High ethnocultural composition was associated with lower testing rates. Both high ethnocultural composition and high situational vulnerability increased the odds of testing positive for SARS-CoV-2. DISCUSSION: We observed that multiple demographic, income and SDH factors were associated with SARS-CoV-2 testing and test positivity. Barriers to healthcare access identified in this study specifically relate to COVID-19 testing but may reflect broader inequities for certain at-risk groups.

Multivariable models for advanced colorectal neoplasms in screen-eligible individuals at low-to-moderate risk of colorectal cancer: towards improving colonoscopy prioritization.

BACKGROUND: Advanced colorectal neoplasms (ACNs), including colorectal cancers (CRC) and high-risk adenomas (HRA), are detected in less than 20% of persons aged 50 years or older who undergo colonoscopy. We sought to derive personalized predictive models of risk of harbouring ACNs to improve colonoscopy wait times for high-risk patients and allocation of colonoscopy resources. METHODS: We characterized colonoscopy indications, neoplasia risk factors and colonoscopy findings through chart review for consecutive individuals aged 50 years or older who underwent outpatient colonoscopy at The Ottawa Hospital (Ottawa, Canada) between April 1, 2008 and March 31, 2012 for non-life threatening indications. We linked patients to population-level health administrative datasets to ascertain additional historical predictor variables and derive multivariable logistic regression models for risk of harboring ACNs at colonoscopy. We assessed model discriminatory capacity and calibration and the ability of the models to improve colonoscopy specificity while maintaining excellent sensitivity for ACN capture. RESULTS: We modelled 17 candidate predictors in 11,724 individuals who met eligibility criteria. The final CRC model comprised 8 variables and had a c-statistic value of 0.957 and a goodness-of-fit p-value of 0.527. Application of the models to our cohort permitted 100% sensitivity for identifying persons with CRC and > 90% sensitivity for identifying persons with HRA, while improving colonoscopy specificity for ACNs by 23.8%. CONCLUSIONS: Our multivariable models show excellent discriminatory capacity for persons with ACNs and could significantly increase colonoscopy specificity without overly sacrificing sensitivity. If validated, these models could allow more efficient allocation of colonoscopy resources, potentially reducing wait times for those at higher risk while deferring unnecessary colonoscopies in low-risk individuals.

Long-term outcomes of liver transplant recipients followed up in non-transplant centres: Care closer to home.

INTRODUCTION: Increasing rates of liver transplantation and improved outcomes have led to greater numbers of transplant recipients followed up in non-transplant centres. Our aim was to document long-term clinical outcomes of liver transplant recipients managed in this 'hub-and-spoke' healthcare model. METHODS: A retrospective analysis of all adult patients who underwent liver transplantation between 1987 and 2016, with post-transplant follow-up in two non-transplant centres in the UK (Nottingham) and Canada (Ottawa), was performed. RESULTS: The 1-, 5-, 10- and 20-year patient survival rates were 98%, 95%, 87% and 62%, and 100%, 96%, 88% and 62% in the Nottingham and Ottawa groups, respectively (p=0.87). There were no significant differences between the two centres in 1-, 5-, 10- and 20-year cumulative incidence of death-censored graft-survival (p=0.10), end-stage renal disease (p=0.29) or de novo cancer (p=0.22). Nottingham had a lower incidence of major cardiovascular events (p=0.008). CONCLUSION: Adopting a new model of healthcare provides a means of delivering post-transplant patient care close to home without compromising patient survival and long-term clinical outcomes.

Impact of Bacterial Translocation on Sarcopenia in Patients with Decompensated Cirrhosis.

Advanced liver disease is associated with a persistent inflammatory state, derived from abnormal bacterial translocation from the gut, which may contribute to the development of sarcopenia in cirrhosis. We aim to document the association of chronic inflammation and bacterial translocation with the presence of sarcopenia in cirrhosis. We prospectively followed cirrhotic patients aged 18-70 years with medically refractory ascites at a single tertiary care center in Toronto, Canada. The baseline data included patient demographic variables, the presence of bacterial DNA in serum/ascitic fluid, systemic inflammatory response syndrome (SIRS) status, and nutritional assessment. Thirty-one patients were enrolled, 18 (58.1%) were sarcopenic, 9 (29%) had bacterial DNA in serum and ascites fluid. The mean MELD score was 11.5 ± 4.0 (6-23). Sarcopenic and non-sarcopenic patients did not differ significantly in their baseline MELD scores, caloric intake, resting energy expenditure, the incidence of bacterial translocation, or SIRS. While sarcopenia was not linked to increased hospital admissions or death, it was strongly associated with increased episodes of acute kidney injury (3 vs. 0, p = 0.05). This pilot study did not demonstrate an association between sarcopenia and SIRS or bacterial translocation. These results should be confirmed in future larger studies, encompassing a greater number of chronic inflammation events and quantifying levels of bacterial DNA.

A randomized clinical prospective trial comparing split-dose picosulfate/ magnesium citrate and polyethylene glycol for colonoscopy preparation.

BACKGROUND: Colonoscopy remains the gold standard for the investigation of abnormalities within the colon. However, its success is highly dependent on the quality of bowel preparation. The objective of this study was to compare the bowel preparation efficacy of picosulfate/magnesium citrate (PMC) vs polyethylene glycol (PEG) in a one-day vs two-day split dose regimen. METHODS: A prospective, randomized, controlled trial was conducted at the Forzani & MacPhail Colon Cancer Screening Centre in Calgary, Canada. 171 colonoscopy outpatients were randomized to split-dose PMC or PEG lavage as well as into one-day split or two-day split regimens in blocks of eight. Bowel preparation quality was recorded in a blinded manner by the endoscopist using the Ottawa Bowel Preparation Scale (OBPS) prior to washing or suctioning. The scale results were analyzed using a two-factor analysis of variance. RESULTS: 141 patients received complete colonoscopies (PMC-71; PEG-70). PEG was found to be superior to PMC (mean OBPS: 4.14 ± 2.64 vs 5.11 ± 3.44, p = 0.019), when adjusted for administration regimen, leading to significantly more adequate bowel preparations (79.7% vs 59.7%, p = 0.007). A two-day split dose was superior to a one-day split dose regimen (mean OBPS: 3.68± 2.82 vs 5.69 ± 3.06, p<0.001). Two-day split dosing also resulted in a better right colon cleanliness score (right bowel OBPS 1.27±0.11 vs 2.10±0.12 for one-day split, P<0.001). CONCLUSIONS: Optimal bowel preparation was achieved with the use of PEG lavage when administered in a two-day split dose regimen. This trial is registered with ClinicalTrials.gov under identifier NCT01415687.

Health Care Utilization and Costs for Patients With End-Stage Liver Disease Are Significantly Higher at the End of Life Compared to Those of Other Decedents.

BACKGROUND & AIMS: Patients with end-stage liver disease (ESLD) have progressively complex medical needs. However, little is known about their end-of-life health care utilization or associated costs. We performed a population-based study to evaluate the end-of-life direct utilization and costs for patients with ESLD among health care sectors in the province of Ontario. METHODS: We used linked Ontario health administrative databases to conduct a population-based retrospective cohort study of all decedents from April 1, 2010, through March 31, 2013. Patients with ESLD were compared with patients without ESLD with regard to total health care utilization and costs in the last year and last 90 days of life. RESULTS: The median age at death was significantly lower for ESLD decedents (65 y; interquartile range, 56-75 y) than for individuals without ESLD (80 y; interquartile range, 68-88 y). The median cost in the last year of life was significantly greater for patients with ESLD ($51,235 vs $44,456 without ESLD) (P < .001). Median ESLD end-of-life care costs also significantly exceeded those associated with 4 of the 5 most resource-intensive chronic conditions ($69,040 for ESLD vs $59,088 for non-ESLD) (P < .001). Cost differences were most pronounced in the final 90 days of life. During this period, patients with ESLD spent 4.7 more days in the hospital (95% CI, 4.3-5.1 d) than patients without ESLD (P < .0001), had significantly higher odds of dying in an institutional setting (odds ratio, 1.8; 95% CI, 1.7-1.9) (P < .0001), and incurred an additional $4201 in costs (95% CI, $3384-$5019; P < .0001). CONCLUSIONS: In a population-based study in Canada, we found that patients with ESLD incur significantly higher end-of-life care costs than decedents without ESLD, predominantly owing to increased time in the hospital during the final 90 days of life.

Predictive models of disease burden at diagnosis in persons with adult-onset ulcerative colitis using health administrative data.

BACKGROUND: Health administrative data is increasingly used to conduct population-based health services research. A major limitation of these data for the study of inflammatory bowel diseases is the absence of detailed clinical information relating to disease burden. We used Ontario health administrative data to develop predictive models of disease burden at diagnosis in ulcerative colitis (UC) patients for future use in population-based studies of incident UC cohorts. METHODS: Through chart review, we characterized macroscopic colitis activity and extent at diagnosis in consecutive adult-onset UC patients diagnosed at The Ottawa Hospital between 2001 and 2012. We linked this cohort to Ontario health administrative data to test the capacity of administrative variables to discriminate different levels of disease activity, disease extent and the disease burden (a composite of disease extent and activity). We modelled outcomes as binary (using logistic regression) and ordinal (using proportional odds regression) variables and performed bootstrap validation of our final models. RESULTS: We tested 20 administrative variables in 587 eligible patients. The logistic model of total disease burden (severe and extensive colitis vs. all other phenotypes) showed moderate discriminatory capacity (optimism-corrected c-statistic value 0.729). Individual models of disease extent and disease activity showed poorer discriminatory capacity (c-statistic value < 0.7 for 3 of 4 models). CONCLUSIONS: Ontario health administrative data may reasonably discriminate levels of total disease burden at diagnosis in adult-onset UC patients. Our models should be externally validated before their widespread application in future population-based studies of incident UC cohorts to adjust for the confounding effects of differences in disease burden.

Variable Endoscopist performance in proximal and distal adenoma detection during colonoscopy: a retrospective cohort study.

BACKGROUND: Adenoma Detection Rate (ADR) is a validated colonoscopy quality indicator. In addition to overall ADR, Distal and Proximal Adenoma Detection Rates may provide important colonoscopy quality information. The goal of this study is to determine the association between distal and proximal adenoma detection (AD) and to identify factors contributing to overall, distal, and proximal AD. METHODS: This is a retrospective cohort study of patients with a noted family history of CRC or positive fecal occult blood test who underwent a screening colonoscopy at a regional colorectal cancer (CRC) screening center between May 2009 and December 2011. Data regarding patient demographics, procedure details, endoscopist characteristics and polyp histology were captured. The main outcomes measured were overall, distal, and proximal AD. RESULTS: 1907 patients were included. The median age was 60 years and 42% were male. Endoscopist median overall ADR was 25% (30% male, 21% female). Endoscopist distal ADR was only modestly associated with their proximal ADR (Spearman Rank: 0.51 p = 0.11). Highest overall ADR (29 to 45%) was found for endoscopists whose distal and proximal ADRs were above the group median. In multivariate analysis, factors associated with overall, distal, and proximal AD included age, sex, and endoscopist practicing experience. CONCLUSION: Inclusion of distal and proximal ADRs, in addition to overall ADR, in colonoscopy quality assessment provides the more accurate feedback on endoscopist performance.

Repeated faecal occult blood testing is associated with decreased advanced colorectal cancer risk: A population-based study.

OBJECTIVE: To evaluate the association between repeated faecal occult blood testing and advanced colorectal cancer risk at population level in Canada. METHODS: A retrospective cohort study of all Ontario residents aged 56-74 diagnosed with colorectal cancer from 1 April 2007 to 31 March 2010, identified using health administrative data. The primary outcome was stage IV colorectal cancer, and primary exposure was faecal occult blood testing use within five years prior to colorectal cancer diagnosis. Patients were categorized into four mutually exclusive groups based on their exposure to faecal occult blood testing in the five years prior to colorectal cancer diagnosis: none, pre-diagnostic, repeated, and sporadic. Logistic regression was utilized to adjust for confounders. RESULTS: Of 7753 patients (median age 66, interquartile range 61-70, 62% male) identified, 1694 (22%) presented with stage I, 2056 (27%) with stage II, 2428 (31%) with stage III, and 1575 (20%) with stage IV colorectal cancer. There were 4092 (53%) with no record of prior faecal occult blood testing, 1485 (19%) classified as pre-diagnostic, 1693 (22%) as sporadic, and 483 (6%) as repeated faecal occult blood testing. After adjusting for confounders, patients who had repeated faecal occult blood testing were significantly less likely to present with stage IV colorectal cancer at diagnosis (Odds ratio 0.46, 95% Confidence Interval 0.34-0.62) than those with no prior faecal occult blood testing. CONCLUSIONS: Repeated faecal occult blood testing is associated with a decreased risk of advanced colorectal cancer. Our findings support the use of organized screening programmes that employ repeated faecal occult blood testing to improve colorectal cancer outcomes at population level.

Regional differences in use of endoscopic ultrasonography in Ontario: a population-based retrospective cohort study.

BACKGROUND: Endoscopic ultrasonography is a safe and accurate modality for evaluating and managing hepatobiliary and gastrointestinal conditions (malignant and nonmalignant); its use is increasing. The aim of this study was to describe regional trends in the use of endoscopic ultrasonography in Ontario. METHODS: We conducted a population-based retrospective cohort study using health administrative databases. We identified all patients who underwent an endoscopic ultrasound procedure in Ontario from 2003 to 2011 using physician billing data. Patient, physician and institution characteristics were examined. The primary outcome was use of endoscopic ultrasonography. RESULTS: We identified 9076 endoscopic ultrasound procedures performed in 8001 patients (3858 women [48.2%]; median patient age at first procedure 59 years). A total of 3066 procedures (33.8%) involved fine-needle aspiration. Use of endoscopic ultrasonography increased 17-fold over the study period. In 2011, people living in the health region with the highest rate of use of endoscopic ultrasonography were more than 4 times more likely to undergo the procedure than people living in the health region with the lowest rate of use (standardized rate 61.6 v. 12.9 per 100 000). About 7 in 10 endoscopic ultrasound procedures were performed in an academic institution or regional cancer centre. All 17 endoscopists performing endoscopic ultrasonography during the study period practised in urban areas. INTERPRETATION: Although the use of endoscopic ultrasonography increased over time in Ontario, there were marked regional differences in use. Provincial needs- and evidence-based initiatives may be needed to narrow the regional gaps in provision of endoscopic ultrasound services in the province.

High end of life health care costs and hospitalization burden in inflammatory bowel disease patients: A population-based study.

BACKGROUND: End of life (EOL) care is associated with greater costs, particularly for acute care services. In patients with inflammatory bowel disease (IBD), EOL costs may be accentuated due to reliance on hospital-based services and expensive diagnostic tests and treatments. We aimed to compare EOL health care use and costs between IBD and non-IBD decedents. METHODS: We conducted a retrospective cohort study of all decedents of Ontario, Canada between 2010 and 2013 using linked health administrative data. IBD (N = 2,214) and non-IBD (N = 262,540) decedents were compared on total direct health care costs in the last year of life and hospitalization time during the last 90 days of life. RESULTS: During the last 90 days of life, IBD patients spent an average of 16 days in hospital, equal to 2.1 greater adjusted hospital days (95% confidence interval [CI] 1.5-2.8 days) than non-IBD patients. IBD diagnosis was associated with $7,210 CAD (95% CI $5,005 - $9,464) higher adjusted per-patient cost in the last year of life, of which 76% was due to excess hospitalization costs. EOL cost of IBD care was higher than 15 of 16 studied chronic conditions. Health care costs rose sharply in the last 90 days of life, primarily due to escalating hospitalization costs. CONCLUSIONS: IBD patients spend more time in hospital and incur substantially greater health care costs than other decedents as they approach the EOL. These excess costs could be curtailed through avoidance of unnecessary hospitalizations and expensive treatments in the setting of irreversible deterioration.

Loss of periostin/OSF-2 in ErbB2/Neu-driven tumors results in androgen receptor-positive molecular apocrine-like tumors with reduced Notch1 activity.

INTRODUCTION: Periostin (Postn) is a secreted cell adhesion protein that activates signaling pathways to promote cancer cell survival, angiogenesis, invasion, and metastasis. Interestingly, Postn is frequently overexpressed in numerous human cancers, including breast, lung, colon, pancreatic, and ovarian cancer. METHODS: Using transgenic mice expressing the Neu oncogene in the mammary epithelium crossed into Postn-deficient animals, we have assessed the effect of Postn gene deletion on Neu-driven mammary tumorigenesis. RESULTS: Although Postn is exclusively expressed in the stromal fibroblasts of the mammary gland, Postn deletion does not affect mammary gland outgrowth during development or pregnancy. Furthermore, we find that loss of Postn in the mammary epithelium does not alter breast tumor initiation or growth in mouse mammary tumor virus (MMTV)-Neu expressing mice but results in an apocrine-like tumor phenotype. Surprisingly, we find that tumors derived from Postn-null animals express low levels of Notch protein and Hey1 mRNA but increased expression of androgen receptor (AR) and AR target genes. We show that tumor cells derived from wild-type animals do not proliferate when transplanted in a Postn-null environment but that this growth defect is rescued by the overexpression of active Notch or the AR target gene prolactin-induced protein (PIP/GCDFP-15). CONCLUSIONS: Together our data suggest that loss of Postn in an ErbB2/Neu/HER2 overexpression model results in apocrine-like tumors that activate an AR-dependent pathway. This may have important implications for the treatment of breast cancers involving the therapeutic targeting of periostin or Notch signaling.

Impaired c-src activation and motility defects in PEA3-null fibroblasts.

Null mutations in the pea3 allele compromise the capacity of mammary tumors to metastasize in MMTV-Neu/ErbB2/HER2 transgenic mice, indicating a motility defect in PEA3-null cells. Cellular and biochemical analyses of established PEA3-null fibroblasts show impaired motility and aberrant localization of adhesion proteins in spreading cells. Our results show that PEA3-/- cells express normal levels of key adhesion components, but that spreading PEA3-null cells fail to activate c-src and to downregulate phospho-FAK(Y397), suggesting that focal adhesion signaling is impaired. Supporting this, biochemical analysis revealed that adhesion complex-associated proteins such as p130Cas failed to undergo tyrosine phosphorylation and dissociated from the adhesion complex with delayed kinetics. Overall our data show that the motility defects observed in PEA3-null cells are due to altered adhesion signaling.

The unliganded glucocorticoid receptor positively regulates the tumor suppressor gene BRCA1 through GABP beta.

Loss of BRCA1 tumor suppressor function is a critical event in breast tumorigenesis. We have previously identified the stress hormone hydrocortisone as a negative regulator of BRCA1 expression in nonmalignant mammary cells. Here, we have identified a direct role for the unliganded glucocorticoid receptor (GR) in BRCA1 upregulation in the absence of hydrocortisone. The positive regulatory effect of GR is lost upon the addition of hydrocortisone. We have shown that GR interacts with the BRCA1 promoter only in the absence of hydrocortisone, and that this interaction is mediated through the ß-subunit of the ets transcription factor GA-binding protein (GABP) at the RIBS promoter element. GR and GABPß interact in both coimmunoprecipitation and mammalian two-hybrid assays, and this interaction involves the N-terminal to central regions of both proteins. This work presents the first evidence of a ligand-independent role for GR as a positive regulator of gene expression, and loss of GR from the BRCA1 promoter in response to stress hormones leads to decreased BRCA1 expression. Because low levels of BRCA1 have been implicated in the development of sporadic breast cancer, this may represent a novel mechanism through which prolonged stress signaling increases breast cancer risk.

Stress and breast cancer: from epidemiology to molecular biology.

Stress exposure has been proposed to contribute to the etiology of breast cancer. However, the validity of this assertion and the possible mechanisms involved are not well established. Epidemiologic studies differ in their assessment of the relative contribution of stress to breast cancer risk, while physiological studies propose a clear connection but lack the knowledge of intracellular pathways involved. The present review aims to consolidate the findings from different fields of research (including epidemiology, physiology, and molecular biology) in order to present a comprehensive picture of what we know to date about the role of stress in breast cancer development.

Hydrocortisone down-regulates the tumor suppressor gene BRCA1 in mammary cells: a possible molecular link between stress and breast cancer.

Psychological stress has been correlated with breast cancer development in numerous epidemiological studies. However, physiological and molecular models which may account for this association are not readily available. We have found that the stress hormone hydrocortisone (cortisol) down-regulates the expression of the breast cancer susceptibility gene BRCA1 in the nonmalignant mouse mammary cell line EPH4. This effect is concentration-dependent, is reliant on the continuous presence of hydrocortisone, and is not affected by the addition of lactogenic hormones, or growth conditions. Hydrocortisone was also found to negate a known positive effect of estrogen on BRCA1 expression and, therefore, may interfere with estrogen-related signaling in mammary epithelial cells. The repressive effect of hydrocortisone is diminished or lost in the mouse mammary lines HC-11 and SP1, respectively, suggesting regulation of the BRCA1 may differ between lines. We have uncovered two promoter regulatory sites, which are involved in BRCA1 regulation by hydrocortisone, namely the RIBS and UP regulatory elements. Binding of the transcription factor GABP to both sites is lost upon hydrocortisone addition, though the levels of these factors are not altered by hydrocortisone treatment. Because BRCA1 activity is important for a number of intracellular pathways involved in prevention of tumorigenesis, its observed down-regulation may represent a novel molecular mechanism for cortisol's involvement in breast cancer development.