Symptomatic, clinical and biomarker associations for mortality in hospitalized COVID-19 patients enriched for African Americans.

BACKGROUND AND AIMS: Initial reports on US COVID-19 showed different outcomes in different races. In this study we use a diverse large cohort of hospitalized COVID-19 patients to determine predictors of mortality. METHODS: We analyzed data from hospitalized COVID-19 patients (n = 5852) between March 2020- August 2020 from 8 hospitals across the US. Demographics, comorbidities, symptoms and laboratory data were collected. RESULTS: The cohort contained 3,662 (61.7%) African Americans (AA), 286 (5%) American Latinx (LAT), 1,407 (23.9%), European Americans (EA), and 93 (1.5%) American Asians (AS). Survivors and non-survivors mean ages in years were 58 and 68 for AA, 58 and 77 for EA, 44 and 61 for LAT, and 51 and 63 for AS. Mortality rates for AA, LAT, EA and AS were 14.8, 7.3, 16.3 and 2.2%. Mortality increased among patients with the following characteristics: age, male gender, New York region, cardiac disease, COPD, diabetes mellitus, hypertension, history of cancer, immunosuppression, elevated lymphocytes, CRP, ferritin, D-Dimer, creatinine, troponin, and procalcitonin. Use of mechanical ventilation (p = 0.001), shortness of breath (SOB) (p < 0.01), fatigue (p = 0.04), diarrhea (p = 0.02), and increased AST (p < 0.01), significantly correlated with death in multivariate analysis. Male sex and EA and AA race/ethnicity had higher frequency of death. Diarrhea was among the most common GI symptom amongst AAs (6.8%). When adjusting for comorbidities, significant variables among the demographics of study population were age (over 45 years old), male sex, EA, and patients hospitalized in New York. When adjusting for disease severity, significant variables were age over 65 years old, male sex, EA as well as having SOB, elevated CRP and D-dimer. Glucocorticoid usage was associated with an increased risk of COVID-19 death in our cohort. CONCLUSION: Among this large cohort of hospitalized COVID-19 patients enriched for African Americans, our study findings may reflect the extent of systemic organ involvement by SARS-CoV-2 and subsequent progression to multi-system organ failure. High mortality in AA in comparison with LAT is likely related to high frequency of comorbidities and older age among AA. Glucocorticoids should be used carefully considering the poor outcomes associated with it. Special focus in treating patients with elevated liver enzymes and other inflammatory biomarkers such as CRP, troponin, ferritin, procalcitonin, and D-dimer are required to prevent poor outcomes.

Integrating cancer care beyond the hospital and across the cancer pathway: a patient-centred approach.

Cancer patients constitute one of the most complex, diverse and growing patient populations in Canada. Like other high-needs patient groups, cancer patients desire a more integrated approach to care delivery that spans organizational and professional boundaries. This article provides an overview of Cancer Care Ontario's experience in fostering a more integrated cancer system, and describes the organization's emerging focus on patient-centred models of integrated care through the whole cancer pathway, from prevention to end-of-life care and survivorship.

IMRT utilization in Ontario: qualitative deployment evaluation.

PURPOSE: The purpose of this paper is to describe a jurisdiction-wide implementation and evaluation of intensity-modulated radiation therapy (IMRT) in Ontario, Canada, highlighting innovative strategies and lessons learned. DESIGN/METHODOLOGY/APPROACH: To obtain an accurate provincial representation, six cancer centres were chosen (based on their IMRT utilization, geography, population, academic affiliation and size) for an in-depth evaluation. At each cancer centre semi-structured, key informant interviews were conducted with senior administrators. An electronic survey, consisting of 40 questions, was also developed and distributed to all cancer centres in Ontario. FINDINGS: In total, 21 respondents participated in the interviews and a total of 266 electronic surveys were returned. Funding allocation, guidelines and utilization targets, expert coaching and educational activities were identified as effective implementation strategies. The implementation allowed for hands-on training, an exchange of knowledge and expertise and the sharing of responsibility. Future implementation initiatives could be improved by creating stronger avenues for clear, continuing and comprehensive communication at all stages to increase awareness, garner support and encourage participation and encouraging expert-based coaching. IMRT utilization for has increased without affecting wait times or safety (from fiscal year 2008/2009 to 2012/2013 absolute increased change: prostate 46, thyroid 36, head and neck 29, sarcoma 30, and CNS 32 per cent). ORIGINALITY/VALUE: This multifaceted, jurisdiction-wide approach has been successful in implementing guideline recommended IMRT into standard practice. The expert based coaching initiative, in particular presents a novel training approach for those who are implementing complex techniques. This paper will be of interest to those exploring ways to fund, implement and sustain complex and evolving technologies.

Nutritional Calorie Labeling and Menu Ordering Practices Among US Adults With Chronic Illnesses.

BACKGROUND: The relationship between diet and the management of chronic illnesses is well established. However, it is unknown the extent to which people with chronic illnesses pay attention to nutritional information and act upon the information obtained. We evaluated the menu ordering practices of adults with chronic illnesses. METHODS: We analyzed the 2018 Health Information National Trends Survey (HINTS 5 Cycle 2). Our analytic cohort included 3,154 respondents (weighted population size=228,464,822) who answered questions regarding a personal history of diabetes, hypertension, heart disease, and obesity. They also answered questions about their nutritional habits regarding whether they noticed caloric information at fast-food or sit-down restaurants and how that information influenced their dietary choices. RESULTS: Among respondents with these chronic illnesses, only obese patients were significantly more likely to pay attention to caloric information (OR=1.56; 95%CI: 1.06-2.31). However, noticing the calorie information was not associated with ordering less calories among all categories of respondents with chronic illnesses. CONCLUSION: US adults with chronic illnesses do not pay sufficient attention to the calorie information of their diet. Furthermore, awareness of the calorie information did not influence their dietary choices. Healthcare professionals should incorporate dietary counseling into the management of chronic illnesses of their patients.

The value of collecting population-based cancer stage data to support decision-making at organizational, regional and population levels.

The stage of a patient's cancer at diagnosis is essential to predict the prognosis and plan the treatment. Since 2008, stage data have been collected on all Ontario patients with breast, colorectal, lung and prostate cancers and are linked to other data collected by Cancer Care Ontario. Here, an analysis of such data is presented. How it can be used to assess the value of screening programs, inform resource allocation, evaluate compliance with treatment guidelines, compare survival trends and enhance the spectrum of cancer control activities across the province is demonstrated. International comparisons can also be made.

The crucial role of clinician engagement in system-wide quality improvement: the Cancer Care Ontario experience.

In 2004, Cancer Care Ontario's (CCO) role changed from providing direct cancer service to oversight, with a mission to improve the performance of the cancer system by driving quality, accountability and innovation in all cancer-related services. Since then, CCO has built a model for province-wide quality improvement and oversight--the Performance Improvement Cycle--that exemplifies the key elements of the Excellent Care for All Act, 2010. While ensuring that quality of the cancer system is by necessity a continuous process, the approach taken thus far has achieved measurable results and will continue to form the basis of CCO's future work. Clinician engagement has been critical to the success of CCO's approach to quality oversight and improvement. CCO uses a variety of formal and informal clinical engagement structures at each step of the Performance Improvement Cycle, and has developed operational processes to support quality improvement, and educational and mentorship programs to build clinician leadership capacity in that area. An example of sustained quality improvement in system performance is illustrated in a case study of the surgical treatment of prostate cancer. The improvement was achieved with strong collaboration across CCO's surgery and pathology clinical programs, with support from informatics staff.

A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response.

The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are closely related orphan nuclear hormone receptors that play a critical role as xenobiotic sensors in mammals. Both receptors regulate the expression of genes involved in the biotransformation of chemicals in a ligand-dependent manner. As the ligand specificity of PXR and CAR have diverged between species, the prediction of in vivo PXR and CAR interactions with a drug are difficult to extrapolate from animals to humans. We report the development of what we believe are novel PXR- and CAR-humanized mice, generated using a knockin strategy, and Pxr- and Car-KO mice as well as a panel of mice including all possible combinations of these genetic alterations. The expression of human CAR and PXR was in the predicted tissues at physiological levels, and splice variants of both human receptors were expressed. The panel of mice will allow the dissection of the crosstalk between PXR and CAR in the response to different drugs. To demonstrate the utility of this panel of mice, we used the mice to show that the in vivo induction of Cyp3a11 and Cyp2b10 by phenobarbital was only mediated by CAR, although this compound is described as a PXR and CAR activator in vitro. This panel of mouse models is a useful tool to evaluate the roles of CAR and PXR in drug bioavailability, toxicity, and efficacy in humans.

COVID-19 among African Americans and Hispanics: Does gastrointestinal symptoms impact the outcome?

BACKGROUND: The coronavirus disease 2019 (COVID-19) disproportionately affected African Americans (AA) and Hispanics (HSP). AIM: To analyze the significant effectors of outcome in African American patient population and make special emphasis on gastrointestinal (GI) symptoms, laboratory values and comorbidities. METHODS: We retrospectively evaluated the medical records of 386 COVID-19 positive patients admitted at Howard University Hospital between March and May 2020. We assessed the symptoms, including the GI manifestations, comorbidities, and mortality, using logistic regression analysis. RESULTS: Of these 386 COVID-19 positive patients, 257 (63.7%) were AAs, 102 (25.3%) HSP, and 26 (6.45%) Whites. There were 257 (63.7%) AA, 102 (25.3%) HSP, 26 (6.45%) Whites. The mean age was 55.6 years (SD = 18.5). However, the mean age of HSP was the lowest (43.7 years vs 61.2 for Whites vs 60 for AAs). The mortality rate was highest among the AAs (20.6%) and lowest among HSP (6.9%). Patients with shortness of breath (SOB) (OR2 = 3.64, CI = 1.73-7.65) and elevated AST (OR2 = 8.01, CI = 3.79-16.9) elevated Procalcitonin (OR2 = 8.27, CI = 3.95-17.3), AST (OR2 = 8.01, CI = 3.79-16.9), ferritin (OR2 = 2.69, CI = 1.24-5.82), and Lymphopenia (OR2 = 2.77, CI = 1.41-5.45) had a high mortality rate. Cough and fever were common but unrelated to the outcome. Hypertension and diabetes mellitus were the most common comorbidities. Glucocorticoid treatment was associated with higher mortality (OR2 = 5.40, CI = 2.72-10.7). Diarrhea was prevalent (18.8%), and GI symptoms did not affect the outcome. CONCLUSION: African Americans in our study had the highest mortality as they consisted of an older population and comorbidities. Age is the most important factor along with SOB in determining the mortality rate. Overall, elevated liver enzymes, ferritin, procalcitonin and C-reactive protein were associated with poor prognosis. GI symptoms did not affect the outcome. Glucocorticoids should be used judiciously, considering the poor outcomes associated with it. Attention should also be paid to monitor liver function during COVID-19, especially in AA and HSP patients with higher disease severity.

In vivo responses of the human and murine pregnane X receptor to dexamethasone in mice.

Dexamethasone (DEX) is a potent and widely used anti-inflammatory and immunosuppressant glucocorticoid. It can bind and activate the pregnane X receptor (PXR), which plays a critical role as xenobiotic sensor in mammals to induce the expression of many enzymes, including cytochromes P450 in the CYP3A family. This induction results in its own metabolism. We have used a series of transgenic mouse lines, including a novel, improved humanized PXR line, to compare the induction profile of PXR-regulated drug-metabolizing enzymes after DEX administration, as well as looking at hepatic responses to rifampicin (RIF). The new humanized PXR model has uncovered further intriguing differences between the human and mouse receptors in that RIF only induced Cyp2b10 in the new humanized model. DEX was found to be a much more potent inducer of Cyp3a proteins in wild-type mice than in mice humanized for PXR. To assess whether PXR is involved in the detoxification of DEX in the liver, we analyzed the consequences of high doses of the glucocorticoid on hepatotoxicity on different PXR genetic backgrounds. We also studied these effects in an additional mouse model in which functional mouse Cyp3a genes have been deleted. These strains exhibited different sensitivities to DEX, indicating a protective role of the PXR and CYP3A proteins against the hepatotoxicity of this compound.

Drug transporters: gatekeepers controlling access of xenobiotics to the cellular interior.

In this paper, we evaluate methodologies and null mouse models used to study drug transporter function in vitro and in vivo. P-glycoprotein and MRP null mice have been used to examine many aspects of xenobiotic distribution and bioavailability. Their advantage over conventional models is that they allow the exclusion of transporters from a particular process; however, they cannot be used to study the activity of the transporter that has been deleted. Use of humanized mice permits a logical progression from phenomena in wild-type mice via the effects of removing the mouse transporter to the consequences of replacing it with its human counterpart.

Standardized synoptic cancer pathology reporting: a population-based approach.

Cancer pathology reports contain information which is critical for patient management and for cancer surveillance, resource planning, and quality purposes. The College of American Pathologists (CAP) has defined scientifically validated content of checklists that form the basis for synoptic cancer pathology reporting. We outline how the CAP standards were implemented in a large Canadian province over a 3-year period resulting in improvements in rates of synoptic reporting and completeness of cancer pathology reporting.

Directional trans-epithelial transport of organic anions in porcine LLC-PK1 cells that co-express human OATP1B1 (OATP-C) and MRP2.

The transcellular transport of many compounds, which cannot readily cross the lipid bilayer, is mediated by drug uptake and efflux transporters. Human OATP1B1 and MRP2 have been implicated in the hepato-biliary transport of many endogenous and exogenous compounds. Here, we have established epithelial porcine kidney LLC-PK1 derived cell lines, that express both transporters in a polarized fashion, as a model to predict hepato-biliary transport. Immunological identification of OATP1B1 in the recombinant cell lines was greatly facilitated by its C-terminal tagging with a peptide sequence derived from hemagglutinin (HA) avoiding the generation of OATP1B1 specific antibodies. Importantly, the tag did not interfere with the functionality of the transporter. Compared to LLC-PK1 cells and cells which expressed only OATP1B1, the cell line that co-expressed MRP2 and OATP1B1 displayed high directional basolateral-to-apical transport of 17 beta-estradiol-17 beta-glucuronide and estrone-3-sulfate. Dehydroepiandrosterone sulfate already displayed a significant basolateral-to-apical transport in the parental cell line, which was further stimulated upon expression of both transporters. Transcellular flux of all steroid conjugates in the opposite direction (apical-to-basolateral) was much lower. By employing this cellular model we were able to demonstrate for the first time that OATP1B1 together with MRP2 mediates the trans-cellular transport of rifampicin. It is anticipated that the models established herein will greatly facilitate the identification of transporters involved in the disposition of novel drug candidates.

The Ontario Cardiac Rehabilitation Pilot Project: Recommendations for health planning and policy.

BACKGROUND: Expansion of cardiac rehabilitation (CR) could save both lives and costs by reducing illness and use of health care services. In February 2001, the Ontario Ministry of Health and Long-Term Care (the Ministry) announced a pilot project (the Pilot) to implement and evaluate a comprehensive, multifactoral model of CR service delivery at 17 centres across Ontario. OBJECTIVES: To design, coordinate and evaluate a coordinated model of CR service delivery, and to collect and evaluate an extensive set of clinical and administrative data. METHODS AND RESULTS: The Pilot was a large, province-wide observational investigation of a health service delivery model for CR and secondary prevention care. The present paper is the third in a three-part, policy-related series. In the present paper, the results of the evaluation of the service delivery model and the final health policy recommendations that were made to the Ministry in September 2002 are presented. CONCLUSIONS: Within approximately one year, 4922 patients were enrolled in the Pilot at participating sites throughout Ontario; 88% of sites implemented all elements of the comprehensive services model, either on-site or through internal/external partnerships, and 94% of sites implemented the multidisciplinary Pilot staffing model. Based on this rapid and near-total implementation of the Pilot model, it was concluded that the Pilot model of care was generalizable. Furthermore, regional coordination was achieved through operationalization of the coordinating centres' roles in quality management, regional planning and program development, education and outreach.

The Ontario Cardiac Rehabilitation Pilot Project.

In February 2001, the Ontario Ministry of Health and Long-Term Care announced a $9.6 million, 15-month pilot project (the Pilot) to implement and evaluate a comprehensive, multifactoral model of cardiac rehabilitation (CR) service delivery at 17 sites across Ontario. This is the second paper in a three-part, policy-related series which provides a summary of the Ontario CR Pilot model and the Pilot implementation and evaluation methodology. The aim of the present paper was to outline the goals of the Pilot, the Pilot model of care, the organizational structure that facilitated implementation of the model, and the operational procedures that were put in place to evaluate patient outcomes and the generalizability of a regional model of CR service delivery. The model was based on the findings and recommendations of the Cardiac Care Network of Ontario's 1999 Consensus Panel on Cardiac Rehabilitation and Secondary Prevention, which was described in part one of this series. An upcoming final paper will describe the outcomes of the project and its recommendations for CR health policy decisions in Ontario.

Closing the quality loop: facilitating improvement in oncology practice through timely access to clinical performance indicators.

PURPOSE: Health care organizations and professionals are being called on to develop clear and transparent measures of quality and to demonstrate the application of the data to performance improvement at the system and provider levels. MATERIALS AND METHODS: Cancer Care Ontario (CCO) initiated a pathology reporting project aimed at improving the quality of cancer pathology by standardizing the content, format, and transmission of reports to a central registry and enabling the information to be available for planning, quality measurement, and quality improvement. This population-based quality-improvement project involved more than 400 Ontario pathologists and more than 100 hospitals. Clinically relevant quality indicators that used the newly available data were developed and shared. Synoptic pathology data were electronically captured at the point of report development and used to automate the timely generation of clinical performance indicators that support quality improvement in surgical oncology. These reports provided comparison data at the organizational, regional, and population levels. RESULTS: Monthly quality indicator reports are generated and distributed to each cancer center and are used to generate dialogue at the professional, organizational, and regional levels regarding evidence-informed quality-improvement opportunities. Since the launch of the project, colorectal lymph node retrieval rates have increased from 76% to 87%, and pT2 prostatectomy margin positivity rates have decreased from 37% to 21%. CONCLUSION: High-quality, complete cancer pathology reports are important not only for contemporary oncological practice, but also for secondary users of pathology information including tumor registries, health planners, epidemiologists, and others involved in quality-improvement activities and research.

Collegiate athletes' experience of the meaning of sport injury: a phenomenological investigation.

AIMS: In this study, a phenomenological approach was used to gain an in-depth understanding of the meaning collegiate athletes derive from their injury experience. The integrated model of sport injury developed by Wiese-Bjornstal and colleagues served as the conceptual framework for the study. METHODS: Elite athletes (n = 5) at one National Collegiate Athletic Association (NCAA) Division I university in the USA participated in phenomenological interviews at three different points postinjury and prior to return to participation in their respective sports. The first interview was conducted within seven days post-injury, while the second and third interviews were conducted 15-20 days post-injury and at least 30 days post-injury, respectively. RESULTS: Inductive analysis of the interview data revealed that while participants' experiences varied somewhat and fluctuated over time, the meaning they derived from the experience was characterized by four major themes: perspective, emotion, coping and relationships. Subsequent deductive analysis indicated a modest fit of each athlete's experience within the integrated model of sport injury and rehabilitation developed by Wiese-Bjornstal et al. CONCLUSION: Participants' psychological responses to sport injury were generally consistent with the Wiese-Bjornstal et al. model but the meaning of the experience was highly individualized and seemed to evolve over the course of the injury and rehabilitation process.

Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo.

Mouse nongenotoxic hepatocarcinogens phenobarbital (PB) and chlordane induce hepatomegaly characterized by hypertrophy and hyperplasia. Increased cell proliferation is implicated in the mechanism of tumor induction. The relevance of these tumors to human health is unclear. The xenoreceptors, constitutive androstane receptors (CARs), and pregnane X receptor (PXR) play key roles in these processes. Novel "humanized" and knockout models for both receptors were developed to investigate potential species differences in hepatomegaly. The effects of PB (80 mg/kg/4 days) and chlordane (10 mg/kg/4 days) were investigated in double humanized PXR and CAR (huPXR/huCAR), double knockout PXR and CAR (PXRKO/CARKO), and wild-type (WT) C57BL/6J mice. In WT mice, both compounds caused increased liver weight, hepatocellular hypertrophy, and cell proliferation. Both compounds caused alterations to a number of cell cycle genes consistent with induction of cell proliferation in WT mice. However, these gene expression changes did not occur in PXRKO/CARKO or huPXR/huCAR mice. Liver hypertrophy without hyperplasia was demonstrated in the huPXR/huCAR animals in response to both compounds. Induction of the CAR and PXR target genes, Cyp2b10 and Cyp3a11, was observed in both WT and huPXR/huCAR mouse lines following treatment with PB or chlordane. In the PXRKO/CARKO mice, neither liver growth nor induction of Cyp2b10 and Cyp3a11 was seen following PB or chlordane treatment, indicating that these effects are CAR/PXR dependent. These data suggest that the human receptors are able to support the chemically induced hypertrophic responses but not the hyperplastic (cell proliferation) responses. At this time, we cannot be certain that hCAR and hPXR when expressed in the mouse can function exactly as the genes do when they are expressed in human cells. However, all parameters investigated to date suggest that much of their functionality is maintained.

PXR and CAR: nuclear receptors which play a pivotal role in drug disposition and chemical toxicity.

Xenobiotic metabolism and detoxification is regulated by receptors (e.g., PXR, CAR) whose characterization has contributed significantly to our understanding of drug responses in humans. Technologies facilitating the screening of compounds for receptor interactions provide valuable tools applicable in drug development. Most use in vitro systems or mice humanized for receptors in vivo. In vitro assays are limited by the reporter systems and cell lines chosen and are uninformative about effects in vivo. Humanized mouse models provide novel, exciting ways of understanding the functions of these genes. This article evaluates these technologies and current knowledge on PXR/CAR-mediated regulation of gene expression.