Social inequalities in COVID-19 mortality by area and individual-level characteristics in Canada, January to July/August 2020: Results from two national data integrations.

Background: Despite early reports of social determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) burden, national Canadian reporting on COVID-19 inequalities has been limited. The objective of this study is to describe inequalities in COVID-19 mortality in Canada using preliminary data, as part of the Pan-Canadian Health Inequalities Reporting Initiative. Methods: Two provisional Canadian Vital Statistics Death Database integrations were used. Data concerning deaths between January 1 and July 4, 2020, among private-dwelling residents were linked to individual-level data from the 2016 short-form Census, and disaggregated by sex and low-income status, dwelling type, household type and size. Data concerning deaths between January 1 and August 31, 2020 linked to 2016 Census area data were disaggregated by sex and neighbourhood ethno-cultural composition quintiles (based on the proportion of residents who are recent immigrants, visible minorities, born outside of Canada, with no knowledge of English or French), income quintiles and urban residence. The COVID-19 age-standardized mortality rate (per 100,000 population) differences and ratios between groups were estimated. Results: As of July/August 2020, apartment dwellers, residents of urban centres, neighbourhoods with the highest ethno-cultural composition or lowest income experienced 14 to 30 more COVID-19-related deaths/100,000 compared with reference groups (residents of single-detached homes, outside of urban centres, with lowest ethno-cultural concentration or highest income, respectively). Per 100,000 population, sex/gender inequalities were also larger in these four groups (11 to 18 more male than female deaths) than in the reference groups (two to four more male than female deaths). Conclusion: These findings highlight how populations facing socioeconomic disadvantage have experienced a higher overall burden of deaths. Areas for future research are discussed to guide health equity-informed pandemic response.

Does geography matter in mortality? An analysis of potentially avoidable mortality by remoteness index in Canada.

BACKGROUND: The avoidable mortality rate is a key indicator of overall health and health care utilization. However, the avoidable mortality rate may differ by the relative remoteness of a community. Avoidable mortality rates specific to remote areas cannot be investigated unless there is a clear geographic classification of remoteness. Therefore, this research uses a newly developed remoteness index to explore the geographic variability of avoidable mortality in Canada. DATA AND METHODS: The remoteness index, Canadian Vital Statistics-Death Database (2011 to 2015), and the 2016 Census of Population are used to understand the geographic variability of preventable and treatable mortality rates in Canada. Descriptive and multivariate data analysis techniques are used to test the hypothesis that remoteness is one of the statistically significant predictors of avoidable mortality rates in Canada. RESULTS: There is a clear gradient of preventable and treatable mortality rates by relative remoteness. The preventable and treatable mortality rates are significantly higher in more remote areas than in easily accessible areas. The remoteness index is a good predictor of both preventable and treatable causes of mortality for low-Aboriginal census subdivisions but not for high-Aboriginal census subdivisions in Canada. DISCUSSION: Both preventable and treatable mortality rates vary significantly by remoteness, despite Canada's universal health care system. The remoteness of Canadian communities may have affected health care delivery and utilization.

Determinants of the variations in self-reported health status among recent and more established immigrants in Canada.

Studies have shown that immigrants are normally in better health on arrival compared to their Canadian-born counterparts. However, the health conditions of new immigrants deteriorate after a few years of their arrival in Canada. This phenomenon is popularly termed the "healthy immigrant effect" (HIE) in the immigrant health literature. Although different hypotheses have been proposed to understand HIE, the causes are subject to ongoing discussion. Unlike previous studies, this study explored the possible causes behind the variations in the health status of recent and more established immigrants comparing 2001 and 2010 Canadian Community Health Surveys (CCHS). Four different hypotheses - namely lifestyle change, barriers to health care services, poor social determinants of health, and work related stress - were tested to understand variations in health status. The study concludes that there is a statistically significant difference in the socioeconomic characteristics and health outcomes of immigrants having less than and more than 10 years of residency in Canada. Logistic regression models show that the health conditions of immigrants are associated with age, sex, ethnic origin, smoking habit, Body Mass Index (BMI), total household income, number of consultations made with a family doctor per year and work related stress.

Discovery of a novel class of boron-based antibacterials with activity against gram-negative bacteria.

Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, including Enterobacteriaceae bearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.

Vulnerability, risk perception, and health profile of marginalized people exposed to multiple built-environment stressors in Worcester, Massachusetts: a pilot project.

Millions of low-income people of diverse ethnicities inhabit stressful old urban industrial neighborhoods. Yet we know little about the health impacts of built-environment stressors and risk perceptions in such settings; we lack even basic health profiles. Difficult access is one reason (it took us 30 months to survey 80 households); the lack of multifaceted survey tools is another. We designed and implemented a pilot vulnerability assessment tool in Worcester, Massachusetts. We answer: (1) How can we assess vulnerability to multiple stressors? (2) What is the nature of complex vulnerability-including risk perceptions and health profiles? (3) How can findings be used by our wider community, and what lessons did we learn? (4) What implications arise for science and policy? We sought a holistic picture of neighborhood life. A reasonably representative sample of 80 respondents captured data for 254 people about: demographics, community concerns and resources, time-activity patterns, health information, risk/stress perceptions, and resources/capacities for coping. Our key findings derive partly from the survey data and partly from our experience in obtaining those data. Data strongly suggest complex vulnerability dominated by psychosocial stress. Unexpected significant gender and ethnic disease disparities emerged: notably, females have twice the disease burden of males, and white females twice the burden of females of color (p < 0.01). Self-reported depression differentiated by gender and age is illustrative. Community based participatory research (CBPR) approaches require active engagement with marginalized populations, including representatives as funded partners. Complex vulnerability necessitates holistic, participatory approaches to improve scientific understanding and societal responses.

Design, synthesis, and pharmacological evaluation of phenoxy pyridyl derivatives as dual norepinephrine reuptake inhibitors and 5-HT1A partial agonists.

Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT(1A) partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT(1A) partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.

Complexities of holistic community-based participatory research for a low income, multi-ethnic population exposed to multiple built-environment stressors in Worcester, Massachusetts.

Low income, multi-ethnic communities in Main South/Piedmont neighborhoods of Worcester, Massachusetts are exposed to cumulative, chronic built-environment stressors, and have limited capacity to respond, magnifying their vulnerability to adverse health outcomes. "Neighborhood STRENGTH", our community-based participatory research (CBPR) project, comprised four partners: a youth center; an environmental non-profit; a community-based health center; and a university. Unlike most CBPR projects that are single topic-focused, our 'holistic', systems-based project targeted five priorities. The three research-focused/action-oriented components were: (1) participatory monitoring of indoor and outdoor pollution; (2) learning about health needs and concerns of residents through community-based listening sessions; (3) engaging in collaborative survey work, including a household vulnerability survey and an asthma prevalence survey for schoolchildren. The two action-focused/research-informed components were: (4) tackling persistent street trash and illegal dumping strategically; and (5) educating and empowering youth to promote environmental justice. We used a coupled CBPR-capacity building approach to design, vulnerability theory to frame, and mixed methods: quantitative environmental testing and qualitative surveys. Process and outcomes yielded important lessons: vulnerability theory helps frame issues holistically; having several topic-based projects yielded useful information, but was hard to manage and articulate to the public; access to, and engagement with, the target population was very difficult and would have benefited greatly from having representative residents who were paid at the partners' table. Engagement with residents and conflict burden varied highly across components. Notwithstanding, we built enabling capacity, strengthened our understanding of vulnerability, and are able to share valuable experiential knowledge.

Discovery of 6-ethyl-2,4-diaminopyrimidine-based small molecule renin inhibitors.

Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC(50): 91-650 nM) against renin while remaining 'Rule-of-five' compliant.

Carbocyclization by radical closure onto O-trityl oximes: dramatic effect of diphenyl diselenide.

O-Trityl oximes of 5- and 6-iodoaldehydes undergo radical cyclization to produce oximes when treated in refluxing tetrahydrofuran (THF) with Bu3SnH, 1,1'-azobis(cyclohexanecarbonitrile), i-Pr2NEt, and diphenyl diselenide (PhSeSePh).

Ketopiperazine-based renin inhibitors: optimization of the "C" ring.

A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.