The Gigii-Bapiimin Study: resilience and the impacts of COVID-19 on health and wellbeing of Indigenous people living with HIV in Manitoba and Saskatchewan.

The Gigii-Bapiimin study explored the impacts of the COVID-19 pandemic on the health and wellbeing of First Nations, Inuit, and Métis people living with HIV in Manitoba and Saskatchewan, two provinces in Canada with alarmingly high rates of HIV infections. Participants (n = 28 in Manitoba and n = 23 in Saskatchewan) were recruited using various methods, including flyers, community organizations, peers, and social media. The qualitative interviews focused on the pandemic's impact on health, access to services, and ceremonies. The data were analyzed using inductive thematic analysis. The study identified three key themes: (a) resilience and coping; (b) negative impacts on health and substance use; (c) decreased access to health services, HIV care and harm reduction. The participants shared their experiences of social isolation and the loss of community support, which had deleterious effects on their mental health and substance use. The impacts on access to HIV care were exacerbated by poverty, homelessness, and distress over inadvertent disclosure of HIV status. Participants mitigated these impacts by relying on Indigenous knowledges, ceremonies, and resilience within their communities. Service providers must address the impacts of the COVID-19 pandemic on Indigenous people living with HIV and their access to HIV services and ceremonies.

A Three-Step Method for the Preparation of N-Substituted 3,4-Dihydroisoquinolin-1(2H)-ones and Heteroaryl-Fused 3,4-Dihydropyridin-2(1H)-ones from 2-Bromobenzoate Precursors.

We demonstrate a general method for the preparation of diverse N-substituted 3,4-dihydroisoquinolin-1(2H)-one compounds through an overall three-step cross-coupling/cyclization/N-deprotection/N-alkylation sequence. In the first step, ethyl 2-bromobenzoates and 2-bromo-1-carboxyethyl heterocycles are cross-coupled with commercially available potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate to produce (hetero)aryl-substituted 3-[(N-Boc-2-carboxyethyl)phenyl]ethylamines. In a subsequent two-stage process, these (hetero)arylethylamines undergo base-mediated ring closure followed by N-deprotection and N-alkylation to produce N-substituted 3,4-dihydroisoquinolin-1(2H)-ones and heteroaryl-fused N-benzyl 3,4-dihydropyridin-2(1H)-ones. Mechanistic work was performed to elucidate the order of transformations for the latter two-stage process. The method was also extended to the production of N-benzyl isoindolin-1-one and N-benzyl 2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one.

The impact of a stress management intervention including cultural components on stress biomarker levels and mental health indicators among indigenous women.

We examined the effectiveness of a 26-week culture-inclusive intervention on reducing salivary stress biomarker levels, and perceived stress, depressive, and post-traumatic stress disorder (PTSD) symptoms measured using scales in 53 Indigenous women in Ontario, Canada. Statistical analyses compared the average biomarker levels, and the area under the curve (AUC) of biomarkers. Differences in biomarkers and mental health scale scores pre- and post-intervention were compared using mixed models with a random intercept. Interaction terms were included between the intervention and age, education, disability, and HIV status, individually, to test for sub-group differences. Cortisol AUC post-intervention was decreased compared to pre-intervention (ß -1.29 µg/dL; 95%CI -2.35, -0.23). There was a slight decrease in perceived stress levels (aOR: -2.80; 95%CI -5.09, -0.50). The associations were stronger among women of younger age, higher education, and no disabilities. These interventions can be effective, but future interventions should target Indigenous population sub-groups to address individual needs.

Impacts of COVID-19 on trans and non-binary people in Canada: a qualitative analysis of responses to a national survey.

BACKGROUND: Emerging international evidence indicates the COVID-19 pandemic has exacerbated socioeconomic and health challenges faced by transgender (trans) and non-binary populations globally. This qualitative study is among the first to characterize impacts of the pandemic on these groups in Canada. METHODS: Drawing on data from the Trans PULSE Canada survey (N = 820), we used thematic analysis to examine the free-form responses of 697 participants to one open-ended question on impacts of the pandemic. We first organized responses into descriptive themes, and then used this preliminary analytical process to construct more refined, higher order themes that provided a rich account of the pandemic's impacts. RESULTS: Our results are organized into five themes that highlight the pandemic's impacts on trans and non-binary populations in Canada. These include: (1) reduced access to both gender-affirming and other healthcare, (2) heightened financial, employment, and housing precarity, (3) strained social networks in an era of physical distancing and virtual communication, (4) an intensification of safety concerns, and (5) changes in experiences of gender affirmation. CONCLUSION: Our findings highlight the pandemic's systemic impacts on the lives of trans and non-binary people in domains such as healthcare, employment, and housing, and on the social networks of these groups, many of which reflect an exacerbation of pre-existing inequities. Based on our analysis, we recommend that public health researchers, policymakers, and practitioners attend to the structural impacts of the pandemic on these groups as primary sites of inquiry and intervention.

Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable ß-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes.

A major antimicrobial resistance mechanism in Gram-negative bacteria is the production of ß-lactamase enzymes. The increasing emergence of ß-lactamase-producing multi-drug-resistant "superbugs" has resulted in increases in costly hospital Emergency Department (ED) visits and hospitalizations due to the requirement for parenteral antibiotic therapy for infections caused by these difficult-to-treat bacteria. To address the lack of outpatient treatment, we initiated an iterative program combining medicinal chemistry, biochemical testing, microbiological profiling, and evaluation of oral pharmacokinetics. Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing ß-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum ß-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.

Diagnosis of cyanide poisoning using an automated, field-portable sensor for rapid analysis of blood cyanide concentrations.

Cyanide (both HCN and CN- are represented by CN) has multiple industrial applications, is commonly found in some foods, and is a component of fire smoke. Upon exposure, CN blocks production of adenosine triphosphate, causing cellular hypoxia and cytotoxic anoxia, which can eventually result in death. Considering CN's quick onset of action and the long analysis times associated with current techniques, the objective of this study was to develop and validate a rapid and field-portable sensor to detect blood CN concentrations focusing on both concentration and diagnostic accuracy. The sensor takes advantage of the chemical properties of CN by converting it exclusively to HCN via acidification of whole blood. High-speed headspace transfer is used to deliver HCN to a capture solution where it is reacted with naphthalene dialdehyde and taurine to produce a fluorescent ß-isoindole product. Simple spectrofluorometric analysis of the product provides quantitative analysis of CN from whole blood in 60 s and requires only 25 µL of blood (obtainable via fingerstick). A limit of detection of 5 µM, a linear range of 10-200 µM (with ≥15 µM considered CN exposed), and excellent accuracy (100 ± 15%) and precision (≤15.2% relative standard deviation) were obtained. To evaluate the diagnostic accuracy of the sensor, rabbit blood samples (N = 190, including 24 blinded samples) were analyzed by both the sensor and a lab-based spectrophotometric method. An excellent positive correlation was obtained between the sensor and the lab-based method (R2 ˃ 0.995) confirming the concentration accuracy of the CN sensor. Moreover, the sensor produced no false positives or negatives when diagnosing CN poisoning.

Building Bridges: Describing a Process for Indigenous Engagement in Epidemiology.

BACKGROUND: Processes for epidemiology embedded with Indigenous methodology are needed. Building Bridges was developed to engage Indigenous peoples in epidemiology to address health issues relevant to them. OBJECTIVES: We describe our process for meaningfully engaging Indigenous leaders and peoples living with human immunodeficiency virus (HIV) in epidemiology research. METHODS: As a community-based research (CBR) project, Indigenous methodologies and leadership ensured the quality and relevance of findings. Study phases included 1) advisory board formation, 2) recruitment, 3) research question identification, 4) data analysis from the Canadian HIV Observational Cohort (CANOC) collaboration, 5) data interpretation and contextualization, and 6) knowledge translation and exchange. LESSONS LEARNED: Support and guidance from Indigenous team members, Spiritual Leaders and Elders along with meaningful relationships with allied academic researchers were pivotal. Expertise and lived experiences in Indigenous culture, HIV, epidemiology and services enabled multidirectional learning. CONCLUSIONS: Building Bridges' success hinged on ongoing co-learning and engagement of Indigenous peoples, service providers and researchers.

The Impact of Indigenous Youth Sharing Digital Stories About HIV Activism.

INTRODUCTION: This article reports on the micro-, meso-, and macro-level impacts of sharing digital stories created by Indigenous youth leaders about HIV prevention activism in Canada. METHOD: Eighteen participants created digital stories and hosted screenings in their own communities to foster dialogue. Data for this article are drawn from individual semistructured interviews with the youth leaders, audio-recordings of audience reflections, and research team member's field notes collected between 2012 and 2015 across Canada. Data were coded using NVivo. A content analysis approach guided analysis. RESULTS: The process of sharing their digital stories had a positive impact on the youth themselves and their communities. Stories also reached policymakers. They challenged conventional public health messaging by situating HIV in the context of Indigenous holistic conceptions of health. DISCUSSION: The impact(s) of sharing digital stories were felt most strongly by their creators but rippled out to create waves of change for many touched by them. More research is warranted to examine the ways that the products of participatory visual methodologies can be powerful tools in creating social change and reducing health disparities.

Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-ß-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections.

A major resistance mechanism in Gram-negative bacteria is the production of ß-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent ß-lactamases can now confer resistance to other ß-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of ß-lactamase-producing multi-drug-resistant "superbugs" has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-ß-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided 20 (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum ß-lactamase inhibitor. In vitro and in vivo studies demonstrated that 20 restored the activity of ß-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum ß-lactamase inhibitor to enter clinical development.

VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-ß-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa.

As shifts in the epidemiology of ß-lactamase-mediated resistance continue, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are the most urgent threats. Although approved ß-lactam (BL)-ß-lactamase inhibitor (BLI) combinations address widespread serine ß-lactamases (SBLs), such as CTX-M-15, none provide broad coverage against either clinically important serine-ß-lactamases (KPC, OXA-48) or clinically important metallo-ß-lactamases (MBLs; e.g., NDM-1). VNRX-5133 (taniborbactam) is a new cyclic boronate BLI that is in clinical development combined with cefepime for the treatment of infections caused by ß-lactamase-producing CRE and CRPA. Taniborbactam is the first BLI with direct inhibitory activity against Ambler class A, B, C, and D enzymes. From biochemical and structural analyses, taniborbactam exploits substrate mimicry while employing distinct mechanisms to inhibit both SBLs and MBLs. It is a reversible covalent inhibitor of SBLs with slow dissociation and a prolonged active-site residence time (half-life, 30 to 105 min), while in MBLs, it behaves as a competitive inhibitor, with inhibitor constant (Ki ) values ranging from 0.019 to 0.081 µM. Inhibition is achieved by mimicking the transition state structure and exploiting interactions with highly conserved active-site residues. In microbiological testing, taniborbactam restored cefepime activity in 33/34 engineered Escherichia coli strains overproducing individual enzymes covering Ambler classes A, B, C, and D, providing up to a 1,024-fold shift in the MIC. Addition of taniborbactam restored the antibacterial activity of cefepime against all 102 Enterobacterales clinical isolates tested and 38/41 P. aeruginosa clinical isolates tested with MIC90s of 1 and 4 µg/ml, respectively, representing ≥256- and ≥32-fold improvements, respectively, in antibacterial activity over that of cefepime alone. The data demonstrate the potent, broad-spectrum rescue of cefepime activity by taniborbactam against clinical isolates of CRE and CRPA.

Decolonizing Scoping Review Methodologies for Literature With, for, and by Indigenous Peoples and the African Diaspora: Dialoguing With the Tensions.

This article summarizes our deepened understanding of decolonizing research with, for, and by Indigenous peoples and peoples of African descent that emerged from conducting a scoping review of the methodological literature and reflecting on our review process. Although our review identified decolonizing methodologies as a promising approach, we questioned if our scoping review process engaged in decolonizing knowing. To unpack the epistemological tensions between decolonizing knowing and Western ways of doing scoping reviews, we engaged in individual and collective reflective processes- dialoguing with the tensions-moving from individual immersion in the literature to transformative dialogues among the team. In reflecting upon our tensions with the scoping review process, themes that emerged included (a) ontological/epistemological disjunctures, (b) tensions with concepts and language, and (c) relationships with the literature and beyond. This reflexive process provides valuable insight into ways in which review methods might be made a decolonizing research experience.

Increased mortality among Indigenous persons in a multisite cohort of people living with HIV in Canada.

OBJECTIVE: Compare all-cause mortality between Indigenous participants and participants of other ethnicities living with HIV initiating combination antiretroviral therapy (cART) in an interprovincial multi-site cohort. METHODS: The Canadian Observational Cohort is a collaboration of 8 cohorts of treatment-naïve persons with HIV initiating cART after January 1, 2000. Participants were followed from the cART initiation date until death or last viral load (VL) test date on or before December 31, 2012. Cox proportional hazard models were used to estimate the effect of ethnicity on time until death after adjusting for age, gender, injection drug use, being a man who has sex with men, hepatitis C, province of origin, baseline VL and CD4 count, year of cART initiation and class of antiretroviral medication. RESULTS: The study sample consisted of 7080 participants (497 Indigenous, 2471 Caucasian, 787 African/Caribbean/Black (ACB), 629 other, and 2696 unknown ethnicity). Most Indigenous persons were from British Columbia (BC) (83%), with smaller numbers from Ontario (13%) and Québec (4%). During the study period, 714 (10%) participants died. The five-year survival probability was lower for Indigenous persons (0.77) than for Caucasian (0.94), ACB (0.98), other ethnicities (0.96) and unknown ethnicities (0.85) (p < 0.0001). In an adjusted proportional hazard model for which missing data were imputed, Indigenous persons were more likely to die than Caucasian participants (hazard ratio = 2.69, p < 0.0001). CONCLUSION: The mortality rate for Indigenous persons was higher than for other ethnicities and is largely reflective of the BC population. Addressing treatment challenges and identifying HIV- and non-HIV-related causes for mortality among Indigenous persons is required to optimize their clinical management.

A review of rapid and field-portable analytical techniques for the diagnosis of cyanide exposure.

Although commonly known as a highly toxic chemical, cyanide is also an essential reagent for many industrial processes in areas such as mining, electroplating and synthetic fiber production. The "heavy" use of cyanide in these industries, along with its necessary transportation, increases the possibility of human exposure. Another relatively common, but consistently overlooked, mode of cyanide exposure is inhalation of fire smoke. Both civilians and fire rescue personnel risk exposure during the unfortunate event of a structure fire. Additionally, fire rescue personnel risk long-term effects of habitual exposure throughout their careers in fire rescue. The relatively rapid onset of cyanide toxicity and the fact that cyanide exposure symptoms mimic other medical conditions necessitate a rapid, sensitive, portable, and accurate method for the diagnosis of cyanide exposure. This review focuses on the important issues concerning accurate point-of-care diagnosis of cyanide exposure and cyanide detection technologies that may allow a commercial cyanide exposure diagnostic to become a reality.

A comparison of virological suppression and rebound between Indigenous and non-Indigenous persons initiating combination antiretroviral therapy in a multisite cohort of individuals living with HIV in Canada.

BACKGROUND: This study compared time to virological suppression and rebound between Indigenous and non-Indigenous individuals living with HIV in Canada initiating combination antiretroviral therapy (cART). METHODS: Data were from the Canadian Observational Cohort collaboration; eight studies of treatment-naive persons with HIV initiating cART after 1/1/2000. Fine and Gray models were used to estimate the effect of ethnicity on time to virological suppression (two consecutive viral loads [VLs] <50 copies/ml at least 3 months apart) after adjusting for the competing risk of death and time until virological rebound (two consecutive VLs >200 copies/ml at least 3 months apart) following suppression. RESULTS: Among 7,080 participants were 497 Indigenous persons of whom 413 (83%) were from British Columbia. The cumulative incidence of suppression 1 year after cART initiation was 54% for Indigenous persons, 77% for Caucasian and 80% for African, Caribbean or Black (ACB) persons. The cumulative incidence of rebound 1 year after suppression was 13% for Indigenous persons, 6% for Caucasian and 7% for ACB persons. Indigenous persons were less likely to achieve suppression than Caucasian participants (aHR=0.58, 95% CI 0.50, 0.68), but not more likely to experience rebound (aHR=1.03, 95% CI 0.84, 1.27) after adjusting for age, gender, injection drug use, men having sex with men status, province of residence, baseline VL and CD4+ T-cell count, antiretroviral class and year of cART initiation. CONCLUSIONS: Lower suppression rates among Indigenous persons suggest a need for targeted interventions to improve HIV health outcomes during the first year of treatment when suppression is usually achieved.

'Women are supposed to be the leaders': intersections of gender, race and colonisation in HIV prevention with Indigenous young people.

Focusing on gender, race and colonialism, this paper foregrounds the voices of Indigenous young people, their histories of oppression, their legacies of resistance and the continuing strengths rooted in Indigenous peoples, their cultures and their communities. Exploring the relationship between gender and colonialism, the paper speaks to the lived realities of young people from Indigenous communities across Canada. Over 85 young people participated in six different Indigenous community workshops to create artistic pieces that explored the connections between HIV, individual risk and structural inequalities. In the course of the research, Indigenous young people, and young Indigenous women in particular, talked about how gender intersects with race and colonisation to create experiences that are, at times, especially difficult for them. In this paper, young people discuss the ways in which colonialism has demeaned women's roles and degraded women's sexuality, and how continuing cultural erasure and assimilationist policies impact on their lives and on their bodies.

Development of a fluorescence-based sensor for rapid diagnosis of cyanide exposure.

Although commonly known as a highly toxic chemical, cyanide is also an essential reagent for many industrial processes in areas such as mining, electroplating, and synthetic fiber production. The "heavy" use of cyanide in these industries, along with its necessary transportation, increases the possibility of human exposure. Because the onset of cyanide toxicity is fast, a rapid, sensitive, and accurate method for the diagnosis of cyanide exposure is necessary. Therefore, a field sensor for the diagnosis of cyanide exposure was developed based on the reaction of naphthalene dialdehyde, taurine, and cyanide, yielding a fluorescent ß-isoindole. An integrated cyanide capture "apparatus", consisting of sample and cyanide capture chambers, allowed rapid separation of cyanide from blood samples. Rabbit whole blood was added to the sample chamber, acidified, and the HCN gas evolved was actively transferred through a stainless steel channel to the capture chamber containing a basic solution of naphthalene dialdehyde (NDA) and taurine. The overall analysis time (including the addition of the sample) was <3 min, the linear range was 3.13-200 µM, and the limit of detection was 0.78 µM. None of the potential interferents investigated (NaHS, NH4OH, NaSCN, and human serum albumin) produced a signal that could be interpreted as a false positive or a false negative for cyanide exposure. Most importantly, the sensor was 100% accurate in diagnosing cyanide poisoning for acutely exposed rabbits.

Challenges to the involvement of people living with HIV in community-based HIV/AIDS organizations in Ontario, Canada.

The Greater Involvement of People Living with HIV/AIDS Principle (GIPA) has been a core commitment for many people involved in the community-based HIV/AIDS movement. GIPA refers to the inclusion of people living with HIV/AIDS in service delivery and decision-making processes that affect their lives. Despite its central importance to the movement, it has received little attention in the academic literature. Drawing on focus group discussions among staff members and volunteers of AIDS service organizations, activists, and community members, we explore challenges to the implementation of the GIPA principle in community-based HIV/AIDS organizations in Ontario, Canada. Our findings reveal ways in which implementing GIPA has become more complicated over recent years. Challenges relating to health, stigma and disclosure, evolving HIV/AIDS organizations, and GIPA-related tensions are identified. This paper considers our findings in light of previous research, and suggests some implications for practice.

The experience of HIV diagnosis among Aboriginal people living with HIV/AIDS and depression.

In this article, we consider how the broad context of Aboriginal people's lives can shape their experience and understanding of their HIV diagnosis. We conducted interviews across Canada with 72 Aboriginal people living with HIV who also reported feelings of depression. Consistent with what has been found in previous studies, participants responded to their HIV diagnosis with shock, disbelief, and often anger. Prior depression, drug and alcohol use, multiple losses, stigma, and social isolation also shaped how participants experienced their diagnosis. We consider how the history of colonization of Aboriginal communities in Canada relates to the experience of HIV diagnosis, and end with a discussion of the service implications of our findings.

Fluorescent ratiometric indicators based on Cu(II)-induced changes in poly(NIPAM) microparticle volume.

Microparticles consisting of the thermal responsive polymer N-isopropyl acrylamide (polyNIPAM), a metal ion-binding ligand and a fluorophore pair that undergoes fluorescence resonance energy transfer (FRET) have been prepared and characterized. Upon the addition of Cu(II), the microparticles swell or contract depending on whether charge is introduced or neutralized on the polymer backbone. The variation in microparticle morphology is translated into changes in emission of each fluorophore in the FRET pair. By measuring the emission intensity ratio between the FRET pair upon Cu(II) addition, the concentration of metal ion in solution can be quantified. This ratiometric fluorescent indicator is the newest technique in an ongoing effort to use emission spectroscopy to monitor Cu(II) thermodynamic activity in environmental water samples.

Intermolecular approach to metal ion indicators based on polymer phase transitions coupled to fluorescence resonance energy transfer.

An approach to ratiometric fluorescence detection of quenching metal ions was devised by copolymerizing N-isopropylacrylamide with small percentages of bipyridine and amine monomers. The copolymer was divided into two portions. The amine group on one portion was functionalized with AlexaFluor555 (donor fluorophore) and the other with AlexaFluor647 (acceptor fluorophore). The indicator consists of a mixture of these two portions. Aggregation above the lower critical solution temperature (LCST) of this copolymer brings about a large increase in fluorescence resonance energy transfer (FRET). Addition of Cu(II) and other complexing metal ions to the aggregated copolymer introduces charge onto the backbone, causing the copolymer to redissolve with a resulting decrease in FRET. The ratio of acceptor to donor fluorescence varies with Cu(II) concentration. A plot of intensity ratio vs. pCu is sigmoidal with a log K(f) of 6.1 for the Cu(II)-bipyridine complex. The data are consistent with the formation of a 1 : 1 complex. The copolymer responds to higher concentrations of other transition metal ions. The selectivity for Cu(II) is consistent with the literature values for 1 : 1 formation constants for bipyridine with metal ions.