Nimodipine Protects Vascular and Cognitive Function in an Animal Model of Cerebral Small Vessel Disease.

BACKGROUND: Cerebral small vessel disease is a common cause of vascular cognitive impairment and dementia. There is an urgent need for preventative treatments for vascular cognitive impairment and dementia, and reducing vascular dysfunction may provide a therapeutic route. Here, we investigate whether the chronic administration of nimodipine, a central nervous system-selective dihydropyridine calcium channel blocking agent, protects vascular, metabolic, and cognitive function in an animal model of cerebral small vessel disease, the spontaneously hypertensive stroke-prone rat. METHODS: Male spontaneously hypertensive stroke-prone rats were randomly allocated to receive either a placebo (n=24) or nimodipine (n=24) diet between 3 and 6 months of age. Animals were examined daily for any neurological deficits, and vascular function was assessed in terms of neurovascular and neurometabolic coupling at 3 and 6 months of age, and cerebrovascular reactivity at 6 months of age. Cognitive function was evaluated using the novel object recognition test at 6 months of age. RESULTS: Six untreated control animals were terminated prematurely due to strokes, including one due to seizure, but no treated animals experienced strokes and so had a higher survival (P=0.0088). Vascular function was significantly impaired with disease progression, but nimodipine treatment partially preserved neurovascular coupling and neurometabolic coupling, indicated by larger (P<0.001) and more prompt responses (P<0.01), and less habituation upon repeated stimulation (P<0.01). Also, animals treated with nimodipine showed greater cerebrovascular reactivity, indicated by larger dilation of arterioles (P=0.015) and an increase in blood flow velocity (P=0.001). This protection of vascular and metabolic function achieved by nimodipine treatment was associated with better cognitive function (P<0.001) in the treated animals. CONCLUSIONS: Chronic treatment with nimodipine protects from strokes, and vascular and cognitive deficits in spontaneously hypertensive stroke-prone rat. Nimodipine may provide an effective preventive treatment for stroke and cognitive decline in cerebral small vessel disease.

Exploring the dynamics of the 2022 mpox outbreak in Canada.

The 2022 mpox outbreak predominantly impacted gay, bisexual, and other men who have sex with men (gbMSM). Two models were developed to support situational awareness and management decisions in Canada. A compartmental model characterized epidemic drivers at national/provincial levels, while an agent-based model (ABM) assessed municipal-level impacts of vaccination. The models were parameterized and calibrated using empirical case and vaccination data between 2022 and 2023. The compartmental model explored: (1) the epidemic trajectory through community transmission, (2) the potential for transmission among non-gbMSM, and (3) impacts of vaccination and the proportion of gbMSM contributing to disease transmission. The ABM incorporated sexual-contact data and modeled: (1) effects of vaccine uptake on disease dynamics, and (2) impacts of case importation on outbreak resurgence. The calibrated, compartmental model followed the trajectory of the epidemic, which peaked in July 2022, and died out in December 2022. Most cases occurred among gbMSM, and epidemic trajectories were not consistent with sustained transmission among non-gbMSM. The ABM suggested that unprioritized vaccination strategies could increase the outbreak size by 47%, and that consistent importation (≥5 cases per 10 000) is necessary for outbreak resurgence. These models can inform time-sensitive situational awareness and policy decisions for similar future outbreaks.

Geographic concentration of SARS-CoV-2 cases by social determinants of health in metropolitan areas in Canada: a cross-sectional study.

BACKGROUND: Understanding inequalities in SARS-CoV-2 transmission associated with the social determinants of health could help the development of effective mitigation strategies that are responsive to local transmission dynamics. This study aims to quantify social determinants of geographic concentration of SARS-CoV-2 cases across 16 census metropolitan areas (hereafter, cities) in 4 Canadian provinces, British Columbia, Manitoba, Ontario and Quebec. METHODS: We used surveillance data on confirmed SARS-CoV-2 cases and census data for social determinants at the level of the dissemination area (DA). We calculated Gini coefficients to determine the overall geographic heterogeneity of confirmed cases of SARS-CoV-2 in each city, and calculated Gini covariance coefficients to determine each city's heterogeneity by each social determinant (income, education, housing density and proportions of visible minorities, recent immigrants and essential workers). We visualized heterogeneity using Lorenz (concentration) curves. RESULTS: We observed geographic concentration of SARS-CoV-2 cases in cities, as half of the cumulative cases were concentrated in DAs containing 21%-35% of their population, with the greatest geographic heterogeneity in Ontario cities (Gini coefficients 0.32-0.47), followed by British Columbia (0.23-0.36), Manitoba (0.32) and Quebec (0.28-0.37). Cases were disproportionately concentrated in areas with lower income and educational attainment, and in areas with a higher proportion of visible minorities, recent immigrants, high-density housing and essential workers. Although a consistent feature across cities was concentration by the proportion of visible minorities, the magnitude of concentration by social determinant varied across cities. INTERPRETATION: Geographic concentration of SARS-CoV-2 cases was observed in all of the included cities, but the pattern by social determinants varied. Geographically prioritized allocation of resources and services should be tailored to the local drivers of inequalities in transmission in response to the resurgence of SARS-CoV-2.

Past dynamics of HIV transmission among men who have sex with men in Montréal, Canada: a mathematical modeling study.

BACKGROUND: Gay, bisexual, and other men who have sex with men (gbMSM) experience disproportionate risks of HIV acquisition and transmission. In 2017, Montréal became the first Canadian Fast-Track City, setting the 2030 goal of zero new HIV infections. To inform local elimination efforts, we estimate the evolving role of prevention and sexual behaviours on HIV transmission dynamics among gbMSM in Montréal between 1975 and 2019. METHODS: Data from local bio-behavioural surveys were analyzed to develop, parameterize, and calibrate an agent-based model of sexual HIV transmission. Partnership dynamics, HIV's natural history, and treatment and prevention strategies were considered. The model simulations were analyzed to estimate the fraction of HIV acquisitions and transmissions attributable to specific groups, with a focus on age, sexual partnering level, and gaps in the HIV care-continuum. RESULTS: The model-estimated HIV incidence peaked in 1985 (2.3 per 100 person years (PY); 90% CrI: 1.4-2.9 per 100 PY) and decreased to 0.1 per 100 PY (90% CrI: 0.04-0.3 per 100 PY) in 2019. Between 2000-2017, the majority of HIV acquisitions and transmissions occurred among men aged 25-44 years, and men aged 35-44 thereafter. The unmet prevention needs of men with > 10 annual anal sex partners contributed 90-93% of transmissions and 67-73% of acquisitions annually. The primary stage of HIV played an increasing role over time, contributing to 11-22% of annual transmissions over 2000-2019. In 2019, approximately 70% of transmission events occurred from men who had discontinued, or never initiated antiretroviral therapy. CONCLUSIONS: The evolving HIV landscape has contributed to the declining HIV incidence among gbMSM in Montréal. The shifting dynamics identified in this study highlight the need for continued population-level surveillance to identify gaps in the HIV care continuum and core groups on which to prioritize elimination efforts.

Dual-target one-step nested PCR for sensitive detection of SARS-CoV-2 nucleic acids.

The Corona Virus Disease reported in 2019 (COVID-19) poses a significant threat to human and public health. Its early and accurate detection can reduce the spread and recurrence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Real-time reverse transcription fluorescent quantitative polymerase chain reaction (RT-qPCR) is the "gold standard" for detecting the nucleic acid of SARS-CoV-2. This study developed and tested a dual-target (ORF1ab and N gene) one-step nested RT-qPCR (DTO-N-PCR) to detect SARS-CoV-2. Ten-fold serial dilutions of mixed synthetic DNA from SARS-CoV-2 ORF1ab and N gene were used as templates to test the sensitivity of DTO-N-PCR. Its specificity was subsequently tested using throat swab specimens from 10 COVID-19 patients and 35 healthy participants. DTO-N-PCR was more sensitive and specific than conventional RT-qPCR. It has unique features, including a dual-target (ORF1ab and N gene), rapid one-step operation of reverse transcription and PCR, four pairs of inner and outer primers, and specific probes. These features aid in its rapid, accurate, and efficient detection of SARS-CoV-2 RNA.

Rheological characterization of complex dynamics in Na-Zn metaphosphate glass-forming liquids.

The viscoelastic behavior and shear relaxation in supercooled [NaPO3]x[Zn(PO3)2]1-x metaphosphate liquids with 0.2 ≤ x ≤ 1.0 are investigated using a combination of small amplitude oscillatory and steady shear parallel plate rheometry, resonant ultrasound spectroscopy, and differential scanning calorimetry. The results demonstrate that these liquids are thermorheologically complex with the coexistence of a fast and a slow relaxation process, which could be attributed to the segmental motion of the phosphate chains and the Zn-O bond scission/renewal dynamics, respectively. The segmental motion of the phosphate chains is found to be the dominant process associated with the shear relaxation for all metaphosphate liquids. The compositional evolution of the calorimetric fragility of these liquids is shown to be related to the conformational entropy of the constituent phosphate chains, which is manifested by the width of the relaxation time distribution for the segmental chain motion. This entropy decreases and the temporal coupling between the chain dynamics and Zn-O bond scission-renewal increases with the increasing Zn content as the higher field strength Zn modifier ions provide more effective cross-linking between the phosphate chains.

Observation of polymer-like flow mechanism in a short-chain phosphate glass-forming liquid.

The dynamics of the phosphate chains and the attendant shear relaxation in a short-chain silver phosphate glass-forming liquid with the composition 51.5%Ag2O-48.5% P2O5 are studied using a combination of high-temperature 31P NMR spectroscopy and parallel plate rheometry. The temperature-dependent evolution of the 31P NMR spectral line shapes indicates that the constituent PO4 tetrahedral chains in this liquid undergo rapid rotational reorientation. The time scale of this dynamics is in complete agreement with that of shear relaxation and, thus, must be responsible for the viscous flow of this liquid. These results demonstrate for the first time that, although the shear relaxation of the network oxide glass-forming liquids is typically controlled by the scission and renewal of bonds between the network-forming cations and oxygen atoms, such a scenario may not always be tenable for liquids with low-dimensional structures consisting of chains.

Nature of the floppy-to-rigid transition in chalcogenide glass-forming liquids.

The viscoelastic properties of supercooled AsxSe100-x and GexSe100-x (0 ≤ x ≤ 30) liquids are studied using oscillatory parallel plate rheometry. The liquids with average selenium chain segment length L longer than ∼3 to 5 atoms or average coordination number ⟨r⟩ less than ∼2.2 are characterized by the coexistence of a low-frequency bond scission/renewal based relaxation process as well as high-frequency segmental chain dynamics. The latter process disappears for liquids with higher connectivity, thus implying a dynamical rigidity transition. The temporal decoupling of the high-frequency chain mode from that of the bond scission/renewal process and the shear modulus Gs associated with the low-frequency mode are shown to be unique functions of L or ⟨r⟩ and display strong similarity with the corresponding variation in the fragility m and the conformational entropy of the chain segments. When taken together, these results provide direct experimental support to the entropic rigidity argument originally proposed by Phillips but suggest a floppy-to-rigid transition of the structural network at ⟨r⟩ ∼ 2.2, instead of the conventional rigidity percolation threshold value of 2.4.

Electrodeposition of High Density Silver Nanosheets with Controllable Morphologies Served as Effective and Reproducible SERS Substrates.

Silver nanosheets with a nanogap smaller than 10 nm and high reproducibility were constructed through simple and environmentally friendly electrodeposition method on copper plate. The sizes of the nanogaps can be varied from around 7 to 150 nm by adjusting the deposition time and current density. The nanosheets with different nanogaps exhibited varied surface-enhanced Raman scattering (SERS) properties due to electromagnetic mechanism (EM). The optimized high density silver nanosheets with a nanogap smaller than 10 nm showed effective SERS ability with an enhanced factor as high as 2.0 × 10(5). Furthermore, the formation mechanism of the nanosheets during the electrodeposition process has been investigated by discussing the influence of boric acid and current density. This method has proved to be applicable on different metal substrates, which exhibits the potential to be widely used in different fields.

Regulators of phagocytosis as pharmacologic targets for stroke treatment.

Stroke, including ischemic and hemorrhagic stroke, causes massive cell death in the brain, which is followed by secondary inflammatory injury initiated by disease-associated molecular patterns released from dead cells. Phagocytosis, a cellular process of engulfment and digestion of dead cells, promotes the resolution of inflammation and repair following stroke. However, professional or non-professional phagocytes also phagocytose stressed but viable cells in the brain or excessively phagocytose myelin sheaths or prune synapses, consequently exacerbating brain injury and impairing repair following stroke. Phagocytosis includes the smell, eating and digestion phases. Notably, efficient phagocytosis critically depends on phagocyte capacity to take up dead cells continually due to the limited number of phagocytes vs. dead cells after injury. Moreover, phenotypic polarization of phagocytes occurring after phagocytosis is also essential to the proresolving and prorepair properties of phagocytosis. Much has been learned about the molecular signals and regulatory mechanisms governing the sense and recognition of dead cells by phagocytes during the smell and eating phase following stroke. However, some key areas remain extremely understudied, including the mechanisms involved in digestion regulation, continual phagocytosis and phagocytosis-induced phenotypic switching following stroke. Here, we summarize new discoveries related to the molecular mechanisms and multifaceted effects of phagocytosis on brain injury and repair following stroke and highlight the knowledge gaps in poststroke phagocytosis. We suggest that advancing the understanding of poststroke phagocytosis will help identify more biological targets for stroke treatment.

Rapid diagnostic testing for syphilis in Arctic communities (the STAR study): a multisite prospective field diagnostic accuracy study in an intended-use setting.

OBJECTIVES: We evaluated the field diagnostic accuracy of a syphilis rapid test (RDT), using serum and whole blood by non-laboratorians in two Canadian Arctic communities. METHODS: We implemented a multisite prospective field evaluation wherein patients were screened by an RDT containing treponemal and non-treponemal components (Chembio DPP® Syphilis Screen & Confirm) between January 2020 and December 2021. Venous whole blood and serum were collected for rapid testing and compared with laboratory-based serology reference testing using a reverse sequence algorithm of treponemal and rapid plasma reagin (RPR) testing. RESULTS: Overall, 135 whole blood and 139 serum specimens were collected from 161 participants during clinical encounters. Treponemal-RDT sensitivity against a treponemal-reference standard (38/161 confirmed cases) was similar for serum (78% [95% CI: 61-90%]) and whole blood (81% [95% CI: 63-93%]). In those with RPR titres ≥1:8 (i.e. suggestive of recent/active infection), sensitivity increased to 93% (95% CI: 77-99%) for serum and 92% (95% CI: 73-99%) for whole blood. Treponemal-RDT specificity was excellent (99% [95% CI: 95-100%]) for both specimen types. Non-treponemal-RDT sensitivity against RPR was 94% (95% CI: 80-99%) for serum and 79% (95% CI: 60-92%) for whole blood. Sensitivity increased to 100% (95% CI: 88-100%) for serum and 92% (95% CI: 73-99%) for whole blood when RPR titres ≥1:8. RDT performance with whole blood was similar to that with serum. DISCUSSION: Non-laboratorians using the RDT accurately identified individuals with infectious syphilis under real-world conditions in an intended-use setting at the point of care. Implementing the RDT can eliminate treatment delays and may enhance disease control.

Population-level impact of expanding PrEP coverage by offering long-acting injectable PrEP to MSM in three high-resource settings: a model comparison analysis.

INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) demonstrated superiority to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis (PrEP) in the HPTN 083/084 trials. We compared the potential impact of expanding PrEP coverage by offering CAB-LA to men who have sex with men (MSM) in Atlanta (US), Montreal (Canada) and the Netherlands, settings with different HIV epidemics. METHODS: Three risk-stratified HIV transmission models were independently parameterized and calibrated to local data. In Atlanta, Montreal and the Netherlands, the models, respectively, estimated mean TDF/FTC coverage starting at 29%, 7% and 4% in 2022, and projected HIV incidence per 100 person-years (PY), respectively, decreasing from 2.06 to 1.62, 0.08 to 0.03 and 0.07 to 0.001 by 2042. Expansion of PrEP coverage was simulated by recruiting new CAB-LA users and by switching different proportions of TDF/FTC users to CAB-LA. Population effectiveness and efficiency of PrEP expansions were evaluated over 20 years in comparison to baseline scenarios with TDF/FTC only. RESULTS: Increasing PrEP coverage by 11 percentage points (pp) from 29% to 40% by 2032 was expected to avert a median 36% of new HIV acquisitions in Atlanta. Substantially larger increases (by 33 or 26 pp) in PrEP coverage (to 40% or 30%) were needed to achieve comparable reductions in Montreal and the Netherlands, respectively. A median 17 additional PYs on PrEP were needed to prevent one acquisition in Atlanta with 40% PrEP coverage, compared to 1000+ in Montreal and 4000+ in the Netherlands. Reaching 50% PrEP coverage by 2032 by recruiting CAB-LA users among PrEP-eligible MSM could avert >45% of new HIV acquisitions in all settings. Achieving targeted coverage 5 years earlier increased the impact by 5-10 pp. In the Atlanta model, PrEP expansions achieving 40% and 50% coverage reduced differences in PrEP access between PrEP-indicated White and Black MSM from 23 to 9 pp and 4 pp, respectively. CONCLUSIONS: Achieving high PrEP coverage by offering CAB-LA can impact the HIV epidemic substantially if rolled out without delays. These PrEP expansions may be efficient in settings with high HIV incidence (like Atlanta) but not in settings with low HIV incidence (like Montreal and the Netherlands).

Population-level effectiveness of pre-exposure prophylaxis for HIV prevention among men who have sex with men in Montréal (Canada): a modelling study of surveillance and survey data.

INTRODUCTION: HIV pre-exposure prophylaxis (PrEP) has been recommended and partly subsidized in Québec, Canada, since 2013. We evaluated the population-level impact of PrEP on HIV transmission among men who have sex with men (MSM) in Montréal, Québec's largest city, over 2013-2021. METHODS: We used an agent-based mathematical model of sexual HIV transmission to estimate the fraction of HIV acquisitions averted by PrEP compared to a counterfactual scenario without PrEP. The model was calibrated to local MSM survey, surveillance, and cohort data and accounted for COVID-19 pandemic impacts on sexual activity, HIV prevention, and care. PrEP was modelled from 2013 onwards, assuming 86% individual-level effectiveness. The PrEP eligibility criteria were: any anal sex unprotected by condoms (past 6 months) and either multiple partnerships (past 6 months) or multiple uses of post-exposure prophylaxis (lifetime). To assess potential optimization strategies, we modelled hypothetical scenarios prioritizing PrEP to MSM with high sexual activity (≥11 anal sex partners annually) or aged ⩽45 years, increasing coverage to levels achieved in Vancouver, Canada (where PrEP is free-of-charge), and improving retention. RESULTS: Over 2013-2021, the estimated annual HIV incidence decreased from 0.4 (90% credible interval [CrI]: 0.3-0.6) to 0.2 (90% CrI: 0.1-0.2) per 100 person-years. PrEP coverage among HIV-negative MSM remained low until 2015 (<1%). Afterwards, coverage increased to a maximum of 10% of all HIV-negative MSM, or about 16% of the 62% PrEP-eligible HIV-negative MSM in 2020. Over 2015-2021, PrEP averted an estimated 20% (90% CrI: 11%-30%) of cumulative HIV acquisitions. The hypothetical scenarios modelled showed that, at the same coverage level, prioritizing PrEP to high sexual activity MSM could have averted 30% (90% CrI: 19%-42%) of HIV acquisitions from 2015-2021. Even larger impacts could have resulted from higher coverage. Under the provincial eligibility criteria, reaching 10% coverage among HIV-negative MSM in 2015 and 30% in 2019, like attained in Vancouver, could have averted up to 63% (90% CrI: 54%-70%) of HIV acquisitions from 2015 to 2021. CONCLUSIONS: PrEP reduced population-level HIV transmission among Montréal MSM. However, our study suggests missed prevention opportunities and adds support for public policies that reduce PrEP barriers, financial or otherwise, to MSM at risk of HIV acquisition.

Impact of a vaccine passport on first-dose SARS-CoV-2 vaccine coverage by age and area-level social determinants of health in the Canadian provinces of Quebec and Ontario: an interrupted time series analysis.

BACKGROUND: In Canada, all provinces implemented vaccine passports in 2021 to reduce SARS-CoV-2 transmission in non-essential indoor spaces and increase vaccine uptake (policies active September 2021-March 2022 in Quebec and Ontario). We sought to evaluate the impact of vaccine passport policies on first-dose SARS-CoV-2 vaccination coverage by age, and area-level income and proportion of racialized residents. METHODS: We performed interrupted time series analyses using data from Quebec's and Ontario's vaccine registries linked to census information (population of 20.5 million people aged ≥ 12 yr; unit of analysis: dissemination area). We fit negative binomial regressions to first-dose vaccinations, using natural splines adjusting for baseline vaccination coverage (start: July 2021; end: October 2021 for Quebec, November 2021 for Ontario). We obtained counterfactual vaccination rates and coverage, and estimated the absolute and relative impacts of vaccine passports. RESULTS: In both provinces, first-dose vaccination coverage before the announcement of vaccine passports was 82% (age ≥ 12 yr). The announcement resulted in estimated increases in coverage of 0.9 percentage points (95% confidence interval [CI] 0.4-1.2) in Quebec and 0.7 percentage points (95% CI 0.5-0.8) in Ontario. This corresponds to 23% (95% CI 10%-36%) and 19% (95% CI 15%-22%) more vaccinations over 11 weeks. The impact was larger among people aged 12-39 years. Despite lower coverage in lower-income and more-racialized areas, there was little variability in the absolute impact by area-level income or proportion racialized in either province. INTERPRETATION: In the context of high vaccine coverage across 2 provinces, the announcement of vaccine passports had a small impact on first-dose coverage, with little impact on reducing economic and racial inequities in vaccine coverage. Findings suggest that other policies are needed to improve vaccination coverage among lower-income and racialized neighbourhoods and communities.

Mortality trends and length of stays among hospitalized patients with COVID-19 in Ontario and Québec (Canada): a population-based cohort study of the first three epidemic waves.

BACKGROUND: Epidemics of COVID-19 strained hospital resources. We describe temporal trends in mortality risk and length of stays in hospital and intensive care units (ICUs) among patients with COVID-19 hospitalized through the first three epidemic waves in Canada. METHODS: We used population-based provincial hospitalization data from the epicenters of Canada's epidemics (Ontario and Québec). Adjusted estimates were obtained using marginal standardization of logistic regression models, accounting for patient-level and hospital-level determinants. RESULTS: Using all hospitalizations from Ontario (N = 26,538) and Québec (N = 23,857), we found that unadjusted in-hospital mortality risks peaked at 31% in the first wave and was lowest at the end of the third wave at 6-7%. This general trend remained after adjustments. The odds of in-hospital mortality in the highest patient load quintile were 1.2-fold (95% CI: 1.0-1.4; Ontario) and 1.6-fold (95% CI: 1.3-1.9; Québec) that of the lowest quintile. Mean hospital and ICU length of stays decreased over time but ICU stays were consistently higher in Ontario than Québec. CONCLUSIONS: In-hospital mortality risks and length of ICU stays declined over time despite changing patient demographics. Continuous population-based monitoring of patient outcomes in an evolving epidemic is necessary for health system preparedness and response.

Stopping syphilis transmission in Arctic communities through rapid diagnostic testing: The STAR study protocol.

BACKGROUND: Intense transmission of syphilis has emerged in some Canadian Arctic communities despite screening and prevention efforts. The remoteness of most communities and limited diagnostic infrastructure yield long delays (≥14 days) between screening and treatment of cases. These hamper syphilis control efforts and may contribute to sustained transmission. Syphilis rapid diagnostic tests (RDTs) have been developed to make screening more accessible and to inform clinical decision-making within the same clinical encounter. These RDTs have been successfully deployed in several countries, but not yet in Canada. METHODS AND DESIGN: We describe the methodology of the "Stopping Syphilis Transmission in Arctic Communities Through Rapid Diagnostic Testing" (STAR) study, wherein the clinical and epidemiological impact of deploying a dual syphilis RDT in the context of ongoing transmission in Nunavut and Nunavik will be evaluated. In this prospective multisite field evaluation, sexually active individuals aged ≥14 years at risk for syphilis will be offered screening by an RDT at the point-of-care by non-laboratory trained registered nurses. Whole blood and serum specimens will be concurrently collected, when feasible, for rapid testing with an RDT containing both treponemal and non-treponemal components (Chembio DPP® Syphilis Screen & Confirm) and compared to laboratory-based reference testing according to a reverse sequence algorithm. The diagnostic accuracy of the RDT, using both whole blood and centrifuged serum specimens, will be validated under real-world conditions in remote Northern settings, outside of specialized laboratories. Additionally, screening-to-treatment time, case detection rates, and the number of infectious contacts averted by using the RDT relative to reference testing will be estimated. The impact of both diagnostic approaches on syphilis transmission dynamics will also be modeled. DISCUSSION: This study will provide much needed evidence for strengthening rapid responses to emerging syphilis outbreaks in remote Arctic regions, by supplementing traditional diagnostic strategies with an RDT to rapidly triage patients likely in need of treatment. These results will also inform the development and tailoring of future diagnostic strategies and public health responses to emerging outbreaks in the North.

Endogenous H2S targets mitochondria to promote continual phagocytosis of erythrocytes by microglia after intracerebral hemorrhage.

Hematoma clearance, which is achieved largely by phagocytosis of erythrocytes in the hemorrhagic brain, limits injury and facilitates recovery following intracerebral hemorrhage (ICH). Efficient phagocytosis critically depends on the capacity of a single phagocyte to phagocytize dead cells continually. However, the mechanism underlying continual phagocytosis following ICH remains unclear. We aimed to investigate the mechanism in this study. By using ICH models, we found that the gasotransmitter hydrogen sulfide (H2S) is an endogenous modulator of continual phagocytosis following ICH. The expression of the H2S synthase cystathionine ß-synthase (CBS) and CBS-derived H2S were elevated in brain-resident phagocytic microglia following ICH, which consequently promoted continual phagocytosis of erythrocytes by microglia. Microglia-specific deletion of CBS delayed spontaneous hematoma clearance via an H2S-mediated mechanism following ICH. Mechanistically, oxidation of CBS-derived endogenous H2S by sulfide-quinone oxidoreductase initiated reverse electron transfer at mitochondrial complex I, leading to superoxide production. Complex I-derived superoxide, in turn, activated uncoupling protein 2 (UCP2) to promote microglial phagocytosis of erythrocytes. Functionally, complex I and UCP2 were required for spontaneous hematoma clearance following ICH. Moreover, hyperhomocysteinemia, an established risk factor for stroke, impaired ICH-enhanced CBS expression and delayed hematoma resolution, while supplementing exogenous H2S accelerated hematoma clearance in mice with hyperhomocysteinemia. The results suggest that the microglial CBS-H2S-complex I axis is critical to continual phagocytosis following ICH and can be targeted to treat ICH.

Increasing concentration of COVID-19 by socioeconomic determinants and geography in Toronto, Canada: an observational study.

BACKGROUND: Inequities in the burden of COVID-19 were observed early in Canada and around the world, suggesting economically marginalized communities faced disproportionate risks. However, there has been limited systematic assessment of how heterogeneity in risks has evolved in large urban centers over time. PURPOSE: To address this gap, we quantified the magnitude of risk heterogeneity in Toronto, Ontario from January to November 2020 using a retrospective, population-based observational study using surveillance data. METHODS: We generated epidemic curves by social determinants of health (SDOH) and crude Lorenz curves by neighbourhoods to visualize inequities in the distribution of COVID-19 and estimated Gini coefficients. We examined the correlation between SDOH using Pearson-correlation coefficients. RESULTS: Gini coefficient of cumulative cases by population size was 0.41 (95% confidence interval [CI]:0.36-0.47) and estimated for: household income (0.20, 95%CI: 0.14-0.28); visible minority (0.21, 95%CI:0.16-0.28); recent immigration (0.12, 95%CI:0.09-0.16); suitable housing (0.21, 95%CI:0.14-0.30); multigenerational households (0.19, 95%CI:0.15-0.23); and essential workers (0.28, 95%CI:0.23-0.34). CONCLUSIONS: There was rapid epidemiologic transition from higher- to lower-income neighborhoods with Lorenz curve transitioning from below to above the line of equality across SDOH. Moving forward necessitates integrating programs and policies addressing socioeconomic inequities and structural racism into COVID-19 prevention and vaccination programs.

Kinetic and Calorimetric Fragility of Chalcogenide Glass-Forming Liquids: Role of Shear vs Enthalpy Relaxation.

The kinetic and calorimetric fragility indices m of binary As-Se and Se-Te chalcogenide liquids with a wide range of fragility are determined using a combination of parallel plate rheometry, beam bending viscometry, and conventional differential scanning calorimetry (DSC). It is shown that both sets of measurements lead to consistent m values only if the validity of the assumptions often implicit in the methodology for the estimation of m are considered. These assumptions are (i) the glass transition temperature Tg corresponds to a viscosity of ∼1012 Pa s and (ii) enthalpy and shear relaxation time scales τen and τshear are comparable near Tg. Both assumptions are shown to be untenable for highly fragile liquids, for which modulated DSC studies demonstrate that τen ≫ τshear near Tg. In these cases, the above-mentioned assumptions are shown to lead to consistently higher values for the kinetic fragility compared to its calorimetric counterpart.

Accuracy of self-reported HIV-testing history and awareness of HIV-positive status in four sub-Saharan African countries.

BACKGROUND: In many countries in sub-Saharan Africa, self-reported HIV testing history and awareness of HIV-positive status from household surveys are used to estimate the percentage of people living with HIV (PLHIV) who know their HIV status. Despite widespread use, there is limited empirical information on the sensitivity of those self-reports, which can be affected by nondisclosure. METHODS: Bayesian latent class models were used to estimate the sensitivity of self-reported HIV-testing history and awareness of HIV-positive status in four Population-based HIV Impact Assessment surveys in Eswatini, Malawi, Tanzania, and Zambia. Antiretroviral (ARV) metabolite biomarkers were used to identify persons on treatment who did not accurately report their status. For those without ARV biomarkers, we used a pooled estimate of nondisclosure among untreated persons that was 1.48 higher than those on treatment. RESULTS: Among PLHIV, the model-estimated sensitivity of self-reported HIV-testing history ranged from 96% to 99% across surveys. The model-estimated sensitivity of self-reported awareness of HIV status varied from 91% to 97%. Nondisclosure was generally higher among men and those aged 15-24 years. Adjustments for imperfect sensitivity did not substantially influence estimates of PLHIV ever tested (difference <4%) but the proportion of PLHIV aware of their HIV-positive status was higher than the unadjusted proportion (difference <8%). CONCLUSION: Self-reported HIV-testing histories in four Eastern and Southern African countries are generally robust although adjustment for nondisclosure increases estimated awareness of status. These findings can contribute to further refinements in methods for monitoring progress along the HIV testing and treatment cascade.