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Background Social determinants of health (SDOH) have been associated with coronavirus disease 2019 (COVID-19) outcomes. We examined patterns in COVID-19–related mortality by SDOH and compared these patterns to those for non–COVID-19 mortality. Methods Residents of Ontario, Canada, aged ≥20 years were followed from 1 March 2020 to 2 March 2021. COVID-19–related death was defined as death within 30 days following or 7 days prior to a positive COVID-19 test. Area-level SDOH from the 2016 census included median household income; proportion with diploma or higher educational attainment; proportion essential workers, racially minoritized groups, recent immigrants, apartment buildings, and high-density housing; and average household size. We examined associations between SDOH and COVID-19–related mortality, and non-COVID-19 mortality using cause-specific hazard models. Results Of 11 810 255 individuals, we observed 3880 COVID-19–related deaths and 88 107 non–COVID-19 deaths. After accounting for demographics, baseline health, and other area-level SDOH, the following were associated with increased hazards of COVID-19–related death (hazard ratio [95% confidence interval]: lower income (1.30 [1.04–1.62]), lower educational attainment (1.27 [1.07–1.52]), higher proportions essential workers (1.28 [1.05–1.57]), racially minoritized groups (1.42 [1.08–1.87]), apartment buildings (1.25 [1.07–1.46]), and large vs medium household size (1.30 [1.12–1.50]). Areas with higher proportion racially minoritized groups were associated with a lower hazard of non–COVID-19 mortality (0.88 [0.84–0.92]). Conclusions Area-level SDOH are associated with COVID-19–related mortality after accounting for demographic and clinical factors. COVID-19 has reversed patterns of lower non–COVID-19 mortality among racially minoritized groups. Pandemic responses should include strategies to address disproportionate risks and inequitable coverage of preventive interventions associated with SDOH.

Economically marginalized communities have faced disproportionately higher risks for infection and death from COVID-19 across Canada. It was anticipated that health disparities would dissipate over time and during subsequent waves. We used person-level surveillance and neighbourhood-level income data to explore, using Lorenz curves and Gini coefficients, magnitude of inequalities in COVID-19 hospitalizations and deaths over five waves of COVID-19 in Ontario, Canada (population 14 million) between February 26, 2020 and February 28, 2022. We found that despite attempts at equity-informed policies alongside fluctuating levels of public health measures, inequalities in hospitalizations and deaths by income remained at levels observed during the first wave - prior to vaccination, discussion or implementation of equity-informed policies - and despite rising levels of hybrid immunity. There was no change in the magnitude of inequalities across all waves evaluated. Our findings indicate that interventions did not sufficiently address differential exposure risks amplified at the intersections of household crowding and size, workplace exposures, and systemic barriers to prevention and care (including access to therapeutics). Equity and effectiveness of programs are inherently linked and ongoing evaluation of both is central to inform the public health response to future waves of COVID-19 and other rapidly emergent pandemics.

In March 2020, COVID-19 assessment centres were launched across the province of Ontario to facilitate COVID-19 testing outside of emergency departments. We aimed to study the degree to which assessment centres provide education and follow-up care for patients with suspected COVID-19.We conducted an online survey of Ontario COVID-19 assessment centre directors between September 15 and October 15, 2020. The primary outcomes studied were the types of educational modalities employed and information conveyed, methods and frequency of test result communication, and any follow-up care that was offered. Survey respondents were also asked to provide descriptions of barriers to patient education and test communication.A total of 56 directors (representing 73 assessment centres) completed the survey. The most frequent educational modalities employed were educational handouts (92%), direct in-person counselling (89%), and referral to website (72%). Seventy-one percent of respondents indicated patients with positive test results would be notified, and 61% of respondents indicated that follow-up care would be offered. The most frequently reported barriers to patient education were insufficient time and high volume of tests, while the most frequently reported barriers to communication of test results were difficulty accessing online health portals and high volume of tests.The ability of many assessment centres to provide patient education is limited by both individual patient and system-level factors. Assessment centres may benefit from standardization of educational materials, improved accessibility to test results for patients in marginalized groups, and virtual pathways to facilitate additional counselling and care for individuals who test positive.En mars 2020, des centres d’évaluation de la COVID-19 ont été lancés dans la province de l’Ontario afin de favoriser le dépistage de la COVID-19 hors des services d’urgence. Les chercheurs visaient à étudier dans quelle mesure ces centres transmettent de l’information et des soins de suivi aux patients chez qui on présume une COVID-19.Les chercheurs ont réalisé un sondage en ligne auprès des directeurs des centres d’évaluation de la COVID-19 de l’Ontario entre le 15 septembre et le 15 octobre 2020. Le type de modalités pédagogiques utilisé et d’information transmise, les modes et la fréquence de communication des résultats des tests et les soins de suivi offerts étaient les résultats cliniques primaires à l’étude. Les répondants au sondage ont également été invités à décrire les obstacles à la transmission d’information aux patients et à la communication des résultats.Au total, 56 directeurs (représentant 73 centres d’évaluation) ont rempli le sondage. Les principales modalités pédagogiques étaient la remise de document d’information (92 %), des conseils individuels directs (89 %) et l’orientation vers un site Web (72 %). Ainsi, 71 % des répondants ont indiqué que les patients obtenant un résultat positif en étaient avisés, et 61 %, que des soins de suivi seraient offerts. Les principaux obstacles à la transmission d’information aux patients étaient le manque de temps et le volume élevé de tests, tandis que les principaux obstacles à la transmission des résultats étaient la difficulté d’accès aux portails santé en ligne et le volume élevé de tests.La capacité de nombreux centres d’évaluation à transmettre de l’information aux patients est limitée à la fois par des facteurs liés aux patients eux-mêmes et par des facteurs systémiques. Les centres d’évaluation pourraient tirer profit de la standardisation des documents pédagogiques, d’un meilleur accès aux résultats des tests pour les patients de groupes marginalisés et de trajectoires virtuelles pour favoriser la transmission de conseils et de soins supplémentaires aux personnes dont les résultats sont positifs.

There is growing evidence of the potential for cardiac involvement in patients who have been infected with COVID-19. In this case study, we present a patient with no history of cardiovascular disease, who was hospitalized for COVID-19 pneumonia and subsequently recovered. Despite normal serum troponin levels and left ventricular structure and function, multi-parametric cardiac magnetic resonance imaging revealed a classic myocarditis-like pattern of injury approximately 6 months after his convalescence. Physicians should be aware of the possibility of late myocardial injury/inflammation in patients with recovered COVID-19, even in the absence of elevated troponin levels and/or left ventricular dysfunction.

In a multi-facility prospective cohort study, we identified 116 acute care, 26 long-term care, and 67 rehabilitation patients who received direct care from a universally masked healthcare worker while communicable with COVID-19. Among 133(64%) patients with at least 14-day follow-up, three (2.3%, 95% CI, 0.77-6.4) became positive for SARS-CoV-2. Universal masking, embedded with other infection control practices, is associated with low risk of transmission of SARS-CoV-2 from healthcare workers to patients and residents.

BACKGROUND: In pandemics, local hospitals need to anticipate a surge in health care needs. We examined the modelled surge because of the coronavirus disease 2019 (COVID-19) pandemic that was used to inform the early hospital-level response against cases as they transpired. METHODS: To estimate hospital-level surge in March and April 2020, we simulated a range of scenarios of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread in the Greater Toronto Area (GTA), Canada, using the best available data at the time. We applied outputs to hospital-specific data to estimate surge over 6 weeks at 2 hospitals (St. Michael’s Hospital and St. Joseph’s Health Centre). We examined multiple scenarios, wherein the default (R(0) = 2.4) resembled the early trajectory (to Mar. 25, 2020), and compared the default model projections with observed COVID-19 admissions in each hospital from Mar. 25 to May 6, 2020. RESULTS: For the hospitals to remain below non-ICU bed capacity, the default pessimistic scenario required a reduction in non-COVID-19 inpatient care by 38% and 28%, respectively, with St. Michael’s Hospital requiring 40 new ICU beds and St. Joseph’s Health Centre reducing its ICU beds for non-COVID-19 care by 6%. The absolute difference between default-projected and observed census of inpatients with COVID-19 at each hospital was less than 20 from Mar. 25 to Apr. 11; projected and observed cases diverged widely thereafter. Uncertainty in local epidemiological features was more influential than uncertainty in clinical severity. INTERPRETATION: Scenario-based analyses were reliable in estimating short-term cases, but would require frequent re-analyses. Distribution of the city’s surge was expected to vary across hospitals, and community-level strategies were key to mitigating each hospital’s surge.

Outpatient parenteral antimicrobial therapy (OPAT) is a safe and effective alternative to hospitalization for many patients with infectious disease. The objective of this study was to describe the experience with a newly established formal OPAT program at a Canadian academic centre.We conducted a retrospective cohort study including all patients referred to the OPAT clinic between July 2016 and June 2017 and a contemporary cohort of patients who received home parenteral therapy without clinic referral. A quasi-experimental design was used to assess the impact of the clinic on patient outcomes compared with a pre-intervention cohort of patients from 2012 to 2013.Between July 2016 and June 2017, 334 patients were referred to the OPAT clinic; 33% of the patients visited the emergency department (ED), and 21% required readmission within 60 days. Compared with the clinic patients, urinary tract infection diagnoses were more common among the 39 contemporary patients who were treated with home parenteral antibiotics without OPAT clinic referral (51% versus 4%, respectively;The OPAT clinic served a high volume of patients in its first year of operation and may be helpful in reducing unfavourable patient outcomes.L’antibiothérapie parentérale ambulatoire (APA) remplace l’hospitalisation de manière sécuritaire et efficace pour bien des patients atteints d’une maladie infectieuse. La présente étude visait à décrire l’expérience d’un nouveau programme officiel d’APA dans un centre universitaire canadien.Les auteurs ont procédé à une étude de cohorte rétrospective incluant tous les patients orientés vers une clinique d’APA entre juillet 2016 et juin 2017 et une cohorte de patients qui, pendant la même période, ont reçu un traitement parentéral à domicile sans être orientés en clinique. Ils ont utilisé une méthodologie quasi-expérimentale pour évaluer les répercussions du suivi en clinique sur les patients par rapport à une cohorte de patients avant l’intervention, entre 2012 et 2013.Entre juillet 2016 et juin 2017, 334 patients ont été orientés vers la clinique d’APA; 33 % ont consulté à l’urgence et 21 % ont dû être réhospitalisés dans les 60 jours. Les diagnostics d’infection urinaire étaient plus courants chez les 39 patients recevant une antibiothérapie parentérale à domicile sans être dirigés vers une clinique d’APA que dans la cohorte suivie en clinique (51 % par rapport à 4 %, respectivement;La clinique d’APA a accueilli un fort volume de patients pendant sa première année de fonctionnement et peut contribuer à réduire les résultats cliniques défavorables chez les patients.

Social determinants of health (SDOH) have been associated with COVID-19 outcomes. We examined differential patterns in COVID-19-related mortality by SDOH accounting for confounders and compared these patterns to those for non-COVID-19 mortality.Residents of Ontario, Canada aged ≥20 years were followed from March-01-2020 to March-02-2021. COVID-19-related death was defined as death within [-7,30] days of a positive COVID-19 test. Area-level SDOH from 2016 Census included: median household income; proportion with diploma or higher educational-attainment; proportion essential workers, racially-minoritised groups, recent immigrants, apartment buildings, and high-density housing; and average household size. We examined associations between SDOH and COVID-19-related mortality using cause-specific hazard models, treating non-COVID-19 mortality as competing risks, and vice-versa.Of 11,810,255 individuals, we observed 3,880(0.03%) COVID-19-related deaths and 88,107(0.75%) non-COVID-19 deaths. After accounting for individual-level demographics, baseline health, and other area-level SDOH, the following area-level SDOH were associated with increased hazards of COVID-19-related death (hazard ratios[95% confidence intervals]: lower income (1.30[1.04-1.62]), lower educational-attainment (1.27[1.07-1.52]), higher proportions essential workers (1.28[1.05-1.57]), racially-minoritised groups (1.42[1.08-1.87]), apartment buildings (1.25[1.07-1.46]), and large vs. medium household size (1.30[1.12-1.50]). In comparison, areas with higher proportion racially-minoritised groups were associated with a lower hazard of non-COVID-19 mortality (0.88[0.84-0.92]).Area-level SDOH are associated with COVID-19-related mortality after accounting for demographic and clinical factors. COVID-19 has reversed patterns of lower non-COVID-19 mortality among racially-minoritised groups vs. their counterparts. Pandemic responses should include strategies (e.g., 'hotspot' and risk-group tailored vaccination) to address disproportionate risks and inequitable reach of, and access to, preventive interventions associated with SDOH.

ImportanceSocial determinants of health (SDOH) play an important role in COVID-19 outcomes. More research is needed to quantify this relationship and understand the underlying mechanisms.ObjectivesTo examine differential patterns in COVID-19-related mortality by area-level SDOH accounting for confounders; and to compare these patterns to those for non-COVID-19 mortality, and COVID-19 case fatality (COVID-19-related death among those diagnosed).Design, setting, and participantsPopulation-based retrospective cohort study including all community living individuals aged 20 years or older residing in Ontario, Canada, as of March 1, 2020 who were followed through to March 2, 2021.ExposureSDOH variables derived from the 2016 Canada Census at the dissemination area-level including: median household income; educational attainment; proportion of essential workers, racialized groups, recent immigrants, apartment buildings, and high-density housing; and average household size.Main outcomes and measuresCOVID-19-related death was defined as death within 30 days following, or 7 days prior to a positive SARS-CoV-2 test. Cause-specific hazard models were employed to examine the associations between SDOH and COVID-19-related mortality, treating non-COVID-19 mortality as a competing risk.ResultsOf 11,810,255 individuals included, 3,880 (0.03%) died related to COVID-19 and 88,107 (0.75%) died without a positive test. After accounting for demographics, baseline health, and other SDOH, the following SDOH were associated with increased hazard of COVID-19-related death (hazard ratios [95% confidence intervals]) comparing the most to least vulnerable group): lower income (1.30[1.09-1.54]), lower educational attainment (1.27[1.10-1.47]), higher proportion essential workers (1.28[1.10-1.50]), higher proportion racialized groups (1.42[1.16-1.73]), higher proportion apartment buildings (1.25[1.11-1.41]), and larger vs. medium household size (1.30[1.13-1.48]). In comparison, areas with higher proportion racialized groups were associated with a lower hazard of non-COVID-19 mortality (0.88[0.85-0.92]). With the exception of income, SDOH were not independently associated with COVID-19 case fatality.Conclusions and relevanceArea-level social and structural inequalities determine COVID-19-related mortality after accounting for individual demographic and clinical factors. COVID-19 has reversed the pattern of lower non-COVID-19 mortality by racialized groups. Pandemic responses should include prioritized and community-tailored intervention strategies to address SDOH that mechanistically underpin disproportionate acquisition and transmission risks and shape barriers to the reach of, and access to prevention interventions.Key pointsQuestionAre area-level social determinants of health factors independently associated with coronavirus disease 2019 (COVID-19)-related mortality after accounting for demographics and clinical factors?FindingsIn this population-based cohort study including 11.8 million adults residing in Ontario, Canada and 3,880 COVID-19-related death occurred between Mar 1, 2020 and Mar 2, 2021, we found that areas characterized by lower SES (including lower income, lower educational attainment, and higher proportion essential workers), greater ethnic diversity, more apartment buildings, and larger vs. medium household size were associated with increased hazard of COVID-19-related mortality compared to their counterparts, even after accounting for individual-level demographics, baseline health, and other area-level SDOH.MeaningPandemic responses should include prioritized and community-tailored intervention strategies to address SDOH that mechanistically underpin inequalities in acquisition and transmission risks, and in the reach of, and access to prevention interventions.

BACKGROUND Disproportionate risks of COVID-19 in congregate settings including long-term care homes, retirement homes, and shelters both affect and are affected by SARS-CoV-2 infections among facility-staff. In cities across Canada, there has been a consistent trend of geographic clustering of COVID-19 cases. However, there remain limited data on how COVID-19 among facility-staff reflect urban neighbourhood disparities, particularly stratified by the social and structural determinants of community-level transmission. OBJECTIVE To compare the concentration of cumulative cases by geography and social/structural determinants across three mutually exclusive subgroups in the Greater Toronto Area (population 7.1 million): community, facility-staff, and healthcare workers (HCW) in other settings. METHODS We conducted a retrospective, observational study using surveillance data on laboratory-confirmed COVID-19 cases (January 23 to December 13, 2020; prior to vaccination roll-out). We derived neighbourhood-level social/structural determinants from census data, and generated Lorenz curves and Gini coefficients to visualize and quantify inequalities in cases. RESULTS The hardest-hit neighbourhoods (comprising 20% of the population) accounted for 53.4% of community cases, 48.6% of facility-staff cases, and 42.3% of other HCW cases. Compared with other HCW, cases in facility-staff more closely reflected the distribution of community cases. Cases in facility-staff reflected greater social and structural inequalities (larger Gini coefficients) than other HCW across all determinants. Facility-staff cases were also more likely than community cases to be concentrated in lower income neighbourhoods (Gini 0.24[0.15-0.38] vs 0.14[0.08-0.21] with lower household density (Gini 0.23[0.17-0.29] vs 0.17[0.12-0.22]) and with a greater proportion working in other essential services (Gini 0.29 [0.21-0.40], 0.22[0.17-0.28]). CONCLUSIONS COVID-19 cases among facility-staff largely reflects neighbourhood-level heterogeneity and disparities; even more so than cases in other HCW. Findings signal the importance of interventions prioritized and tailored to home geographies of facility-staff in addition to workplace measures, including prioritization and reach of vaccination at home (neighbourhood-level) and at work.

The role of inhaled corticosteroids for outpatient COVID-19 is evolving. We meta-analyzed reported clinical trials and estimated probability of any effect and number needed to treat of 50 or 20 for symptom resolution by day 14 [100%, 99.8%, 93.1%] and hospitalization [89.3%, 72.9%, 26.7%] respectively.

POINTS CLES La reponse initiale du Canada a la maladie a coronavirus 2019 (COVID-19) a principalement repose sur des strategies universelles telles que le confinement et l’isolement des personnes infectees par le coronavirus du syndrome respiratoire aigu severe 2 (SRAS-CoV-2) ou y ayant

Despite being highly vulnerable to acquiring HIV, no effective evidence-based interventions (EBI) exist for street-connected young people (SCY) in low- and middle-income countries (LMICs). Therefore, this paper describes the research process of adapting an existing EBI in Eldoret, Kenya using a modified ADAPT-ITT model with a young key population. From May to August 2018 we adapted the combined Stepping Stones and Creating Futures interventions. We used community-based participatory methods, focus group discussions, and working groups with four Peer Facilitators and 24 SCY aged 16-24 years. At the inception of this project, a matched-savings programme was integrated into the intervention to further address structural drivers of HIV. Numerous adaptations came forth through the participatory process. Engaging SCY in the adaptation process ensured the programme was responsive to their needs, relevant to the street context, and respected their right to participate in the research process.

Background Disproportionate risks of COVID-19 in congregate care facilities including long-term care homes, retirement homes, and shelters both affect and are affected by SARS-CoV-2 infections among facility staff. In cities across Canada, there has been a consistent trend of geographic clustering of COVID-19 cases. However, there is limited information on how COVID-19 among facility staff reflects urban neighborhood disparities, particularly when stratified by the social and structural determinants of community-level transmission. Objective This study aimed to compare the concentration of cumulative cases by geography and social and structural determinants across 3 mutually exclusive subgroups in the Greater Toronto Area (population: 7.1 million): community, facility staff, and health care workers (HCWs) in other settings. Methods We conducted a retrospective, observational study using surveillance data on laboratory-confirmed COVID-19 cases (January 23 to December 13, 2020; prior to vaccination rollout). We derived neighborhood-level social and structural determinants from census data and generated Lorenz curves, Gini coefficients, and the Hoover index to visualize and quantify inequalities in cases. Results The hardest-hit neighborhoods (comprising 20% of the population) accounted for 53.87% (44,937/83,419) of community cases, 48.59% (2356/4849) of facility staff cases, and 42.34% (1669/3942) of other HCW cases. Compared with other HCWs, cases among facility staff reflected the distribution of community cases more closely. Cases among facility staff reflected greater social and structural inequalities (larger Gini coefficients) than those of other HCWs across all determinants. Facility staff cases were also more likely than community cases to be concentrated in lower-income neighborhoods (Gini 0.24, 95% CI 0.15-0.38 vs 0.14, 95% CI 0.08-0.21) with a higher household density (Gini 0.23, 95% CI 0.17-0.29 vs 0.17, 95% CI 0.12-0.22) and with a greater proportion working in other essential services (Gini 0.29, 95% CI 0.21-0.40 vs 0.22, 95% CI 0.17-0.28). Conclusions COVID-19 cases among facility staff largely reflect neighborhood-level heterogeneity and disparities, even more so than cases among other HCWs. The findings signal the importance of interventions prioritized and tailored to the home geographies of facility staff in addition to workplace measures, including prioritization and reach of vaccination at home (neighborhood level) and at work.

ObjectivesThe majority of patients with mild-to-moderate COVID-19 can be managed using virtual care. Dyspnoea is challenging to assess remotely, and the accuracy of subjective dyspnoea measures in capturing hypoxaemia have not been formally evaluated for COVID-19. We explored the accuracy of subjective dyspnoea in diagnosing hypoxaemia in COVID-19 patients.MethodsThis is a retrospective cohort study of consecutive outpatients with COVID-19 who met criteria for home oxygen saturation monitoring at a university-affiliated acute care hospital in Toronto, Canada from 3 April 2020 to 13 September 2020. Dyspnoea measures were treated as diagnostic tests, and we determined their sensitivity (SN), specificity (SP), negative/positive predictive value (NPV/PPV) and positive/negative likelihood ratios (+LR/−LR) for detecting hypoxaemia. In the primary analysis, hypoxaemia was defined by oxygen saturation ResultsDuring the study period, 89/501 (17.8%) of patients met criteria for home oxygen saturation monitoring, and of these 17/89 (19.1%) were diagnosed with hypoxaemia. The presence/absence of dyspnoea had limited accuracy for diagnosing hypoxaemia, with SN 47% (95% CI 24% to 72%), SP 80% (95% CI 68% to 88%), NPV 86% (95% CI 75% to 93%), PPV 36% (95% CI 18% to 59%), +LR 2.4 (95% CI 1.2 to 4.7) and −LR 0.7 (95% CI 0.4 to 1.1). The SN of dyspnoea was 50% (95% CI 19% to 81%) when a cut-off of <92% was used to define hypoxaemia. A modified Medical Research Council dyspnoea score >1 (SP 98%, 95% CI 88% to 100%), Roth maximal count ConclusionsSubjective dyspnoea measures have inadequate accuracy for ruling out hypoxaemia in high-risk patients with COVID-19. Safe home management of patients with COVID-19 should incorporate home oxygenation saturation monitoring.

BACKGROUND: Optimizing the public health response to reduce the burden of COVID-19 necessitates characterizing population-level heterogeneity of risks for the disease. However, heterogeneity in SARS-CoV-2 testing may introduce biased estimates depending on analytic design. We aimed to explore the potential for collider bias in a large study of disease determinants, and evaluate individual, environmental and social determinants associated with SARS-CoV-2 testing and diagnosis among residents of Ontario, Canada. METHODS: We explored the potential for collider bias and characterized individual, environmental and social determinants of being tested and testing positive for SARS-CoV-2 infection using cross-sectional analyses among 14.7 million community-dwelling people in Ontario, Canada. Among those with a diagnosis, we used separate analytic designs to compare predictors of people testing positive versus negative; symptomatic people testing positive versus testing negative; and people testing positive versus people not testing positive (i.e., testing negative or not being tested). Our analyses included tests conducted between Mar. 1 and June 20, 2020. RESULTS: Of 14 695 579 people, we found that 758 691 were tested for SARS-CoV-2, of whom 25 030 (3.3%) had a positive test result. The further the odds of testing from the null, the more variability we generally observed in the odds of diagnosis across analytic design, particularly among individual factors. We found that there was less variability in testing by social determinants across analytic designs. Residing in areas with the highest household density (adjusted odds ratio [OR] 1.86, 95% confidence interval [CI] 1.75-1.98), highest proportion of essential workers (adjusted OR 1.58, 95% CI 1.48-1.69), lowest educational attainment (adjusted OR 1.33, 95% CI 1.26-1.41) and highest proportion of recent immigrants (adjusted OR 1.10, 95% CI 1.05-1.15) were consistently related to increased odds of SARS-CoV-2 diagnosis regardless of analytic design. INTERPRETATION: Where testing is limited, our results suggest that risk factors may be better estimated using population comparators rather than test-negative comparators. Optimizing COVID-19 responses necessitates investment in and sufficient coverage of structural interventions tailored to heterogeneity in social determinants of risk, including household crowding, occupation and structural racism.

BackgroundInequities in the burden of COVID-19 observed across Canada suggest heterogeneity within community transmission.ObjectivesTo quantify the magnitude of heterogeneity in the wider community (outside of long-term care homes) in Toronto, Canada and assess how the magnitude in concentration evolved over time (January 21 to November 21, 2020).DesignRetrospective, population-based observational study using surveillance data from Ontario’s Case and Contact Management system.SettingToronto, Canada.ParticipantsLaboratory-confirmed cases of COVID-19 (N=33,992).MeasurementsWe generated epidemic curves by SDOH and crude Lorenz curves by neighbourhoods to visualize inequities in the distribution of COVID-19 cases by social determinants of health (SDOH) and estimated the crude Gini coefficient. We examined the correlation between SDOH using Pearson correlation coefficients.ResultsThe Gini coefficient of cumulative cases by population size was 0.41 (95% CI: 0.36-0.47) and were 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); multi-generational households (0.19, 95%CI: 0.15-0.23); and essential workers (0.28, 95% CI: 0.23-0.34). Most SDOH were highly correlated.Locally acquired cases were concentrated in higher income neighbourhoods in the early phase of the epidemic, and then concentrated in lower income neighbourhoods. Mirroring the trajectory of epidemic curves by income, the Lorenz curve shifted over time from below to above the line of equality with a similar pattern across SDOH.LimitationsStudy relied on area-based measures of the SDOH and individual case counts of COVID-19. We cannot infer concentration of cases by specific occupational exposures given limitation to broad occupational categories.ConclusionCOVID-19 is increasingly concentrated by SDOH given socioeconomic inequities and structural racism.Primary Funding SourceCanadian Institutes of Health Research.

Background With the global shortage of skilled health workers estimated at 7.2 million, outpatient tuberculosis (TB) care is commonly task-shifted to lay health workers (LHWs) in many low- and middle-income countries where the shortages are greatest. While shown to improve access to care and some health outcomes including TB treatment outcomes, lack of training and supervision limit the effectiveness of LHW programs. Our objective was to refine and evaluate an intervention designed to address common causes of non-adherence to TB treatment and LHW knowledge and skills training needs. Methods We employed a pragmatic cluster randomized controlled trial. Participants included 103 health centres (HCs) providing TB care in four districts in Malawi, randomized 1:1 stratified by district and HC funding (Ministry of Health, non-Ministry funded). At intervention HCs, a TB treatment adherence intervention was implemented using educational outreach, a point-of-care reminder tool, and a peer support network. Clusters in the control arm provided usual care. The primary outcome was the proportion of patients with successful TB treatment (i.e., cure or treatment completion). We used a generalized linear mixed model, with district as a fixed effect and HC as a random effect, to compare proportions of patients with treatment success, among the trial arms, with adjustment for baseline differences. Results We randomized 51 HCs to the intervention group and 52 HCs to the control group. Four intervention and six control HCs accrued no eligible patients, and 371 of 1169 patients had missing outcome, HC, or demographic data, which left 74 HCs and 798 patients for analysis. Randomization group was not related to missing outcome, however, district, age, and TB type were significantly related and included in the primary analysis model. Among the 1153 patients with HC and demographic data, 297/605 (49%) and 348/548 (64%) in the intervention and control arms, respectively, had treatment success. The intervention had no significant effect on treatment success (adjusted odds ratio 1.35 [95% confidence interval 0.93–1.98]). Conclusion We found no significant effect of the intervention on TB treatment outcomes with high variability in implementation quality, highlighting important challenges to both scale-up and sustainability. Trial registration ClinicalTrials.gov NCT02533089. Registered August 20, 2015.

Importance Optimizing the public health response to reduce coronavirus disease 2019 (COVID-19) burden necessitates characterizing population-level heterogeneity of COVID-19 risks. However, heterogeneity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing may introduce biased estimates depending on analytic design. Objective Characterizing individual, environmental, and social determinants of SARS-CoV-2 testing and COVID-19 diagnosis. Design We conducted cross-sectional analyses among 14.7 million people comparing individual, environmental, and social determinants among individuals who were tested versus not yet tested. Among those diagnosed, we used three analytic designs to compare predictors of: 1) individuals testing positive versus negative; 2) symptomatic individuals testing positive versus negative; and 3) individuals testing positive versus individuals not testing positive (i.e. testing negative or not being tested). Analyses included tests conducted between March 1 and June 20, 2020. Setting Ontario, Canada. Participants All individuals with ≥1 healthcare system contact since March 2012, excluding individuals deceased before, or born after, March 1, 2020, or residing in a long-term care facility. Exposures Individual-level characteristics (age, sex, underlying health conditions, prior healthcare use), area-based environmental (air pollution) exposures, and area-based social determinants of health (income, education, housing, marital status, race/ethnicity, and recent immigration). Main Outcomes and Measures Odds of SARS-CoV-2 test, and of COVID-19 diagnosis. Results Of a total of 14,695,579 individuals, 758,691 had been tested, of whom 25,030 (3.3%) tested positive. The further the odds of testing from the null, the more variability observed in the odds of diagnosis across analytic design, particularly among individual factors. There was less variability in testing by social determinants across analytic design. Residing in areas with highest household density (adjusted odds ratio: 2.08; 95%CI: 1.95-1.21), lowest educational attainment (adjusted odds ratio: 1.52; 95%CI: 1.44-1.60), and highest proportion of recent immigrants (adjusted odds ratio: 1.12; 95%CI: 1.07-1.16) were consistently related to increased odds of COVID-19 across analytic designs. Conclusions and Relevance Where testing is limited, risk factors may be better estimated using population comparators rather than test-negative comparators. Optimizing COVID-19 responses necessitates investment and sufficient coverage of structural interventions tailored to heterogeneity in social determinants of risk, including household crowding and systemic racism. Key Points Question What are the social determinants of health that contextualize individual-level risks for coronavirus disease 2019 (COVID-19), and how do selection biases affect our understanding of these risks? Findings In this province-wide observational study of 14.7 million Canadians, social determinants related to housing, education, and recent immigration were associated with increased COVID-19 risks, with little evidence of selection bias. Individual factors, such as underlying health conditions, were more prone to selection bias using certain analytic approaches. Meaning Social determinants of health appear to drive COVID-19 incidence in Ontario, Canada. Interventions aiming to prevent COVID-19 transmission should address these empiric structural risks.

SummaryBackgroundThere are currently no effective treatments for outpatients with coronavirus disease 2019 (COVID-19). Interferon-lambda-1 is a Type III interferon involved in the innate antiviral response with activity against respiratory pathogens.MethodsIn this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomized to a single subcutaneous injection of peginterferon-lambda 180μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. The primary endpoint was proportion negative for SARS-CoV-2 RNA on Day 7 post-injection.FindingsThere were 30 patients per arm, with median baseline SARS-CoV-2 viral load of 6.71 (IQR 1.3-8.0) log copies/mL. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon-lambda than placebo (p=0.04). On Day 7, 24 participants (80%) in the peginterferon-lambda group had an undetectable viral load compared to 19 (63%) in the placebo arm (p=0.15). After controlling for baseline viral load, peginterferon lambda treatment resulted in a 4.12-fold (95CI 1.15-16.7, p=0.029) higher likelihood of viral clearance by Day 7. Of those with baseline viral load above 10E6 copies/mL, 15/19 (79%) in the peginterferon-lambda group were undetectable on Day 7 compared to 6/16 (38%) in the placebo group (p=0.012). Adverse events were similar between groups with only mild reversible transaminase elevations more frequently observed in the peginterferon-lambda group.InterpretationPeginterferon-lambda accelerated viral decline in outpatients with COVID-19 resulting in a greater proportion with viral clearance by Day 7, particularly in those with high baseline viral load. Peginterferon-lambda may have potential to prevent clinical deterioration and shorten duration of viral shedding.(NCT04354259)FundingThis study was supported by the Toronto COVID-19 Action Initiative, University of Toronto and the Ontario First COVID-19 Rapid Research Fund. Medication was supplied by Eiger BioPharma.Research in ContextTreatment trials for COVID-19 have largely focused on hospitalized patients and no treatments are approved for people with mild to moderate disease in the outpatient setting. A number of studies in ambulatory populations have been registered but no controlled studies in the outpatient setting have been reported to date (Pubmed Search October 20, 2020, COVID-19 treatment; controlled trials). Uncontrolled case series of hydroxychloroquine with or without azithromycin have been reported with mixed results but no clear signal of efficacy and some concerns raised about cardiac toxicity. Treamtent in the outpatient setting has potential to prevent infected individuals from deteriorating and perhaps more importantly, may shorten the duration of viral shedding, reducing the risk of transmission and the duration required for self-isolation, with significant public health and societal impact.Added value of this studyThis is the first study to show an antiviral effect in outpatients with COVID-19. After controlling for baseline viral load, those treated with peginterferon-lambda had a 4.12-fold (95%CI 1.15-16.7, p=0.029) higher odds of viral clearance by Day 7 compared to those who received placebo. The viral load decline was faster with pegterferon-lambda and the effect was most pronounced in those with high viral loads. In individuals with a baseline viral load of 10E6 copies/mL or higher, 15/19 (79%) in the peginterferon-lambda arm cleared by Day 7 compared to 6/16 (38%) (p=0.012) in the placebo arm (OR 6.25, 95%CI 1.49-31.1, p=0.012), translating to a median time to viral clearance of 7 days (95%CI 6.2-7.8 days) with peginterferon-lambda compared to 10 days (95%CI 7.8-12.2 days) with placebo (p=0.038). Those with low viral loads (Implications of all available evidenceThere is no currently approved therapy for outpatients with COVID-19. This study showed that peginterferon-lambda accelerated viral clearance, particularly in those with high baseline viral loads, highlighting the importance of quantitative viral load testing in the evaluation of antiviral agents for COVID-19. Treatment early in the course of disease may prevent clinical deterioration and shorenting of the duration of viral shedding may have important public health impact by limiting transmission and reducing the duration required for self-isolation. Additional trials of peginterferon-lambda and other antiviral strategies in the outpatient setting are required.

Introduction - Worldwide, nursing home residents have experienced disproportionately high COVID-19 mortality due to the intersection of congregate living, multimorbidity, and advanced age. Among 12 OECD countries, Canada has had the highest proportion of COVID-19 deaths in nursing home residents (78%), raising concerns about a skewed pandemic response that averted much transmission and mortality in community-dwelling residents, but did not adequately protect those in nursing homes. To investigate this, we measured temporal variations in hospitalizations among community and nursing home-dwelling decedents with COVID-19 during the first and second waves of the pandemic.Methods - We conducted a population-based cohort study of residents of Ontario, Canada with COVID-19 who died between March 11, 2020 (first COVID-19 death in Ontario) and October 28, 2020. We examined hospitalization prior to death as a function of 4 factors: community (defined as all non-nursing home residents) vs. nursing home residence, age in years (Results - A total of 3,114 people with confirmed COVID-19 died in Ontario from March to October, 2020 (Table 1), of whom 1,354 (43.5%) were hospitalized prior to death (median: 9 days before death, interquartile range: 4-19). Among nursing home decedents (N=2000), 22.4% were admitted to hospital prior to death, but this varied substantially from a low of 15.5% in March-April (peak of wave 1) to a high of 41.2% in June-July (nadir of wave 1). Among community-dwelling decedents (N=1,114), admission to acute care was higher (81.4%) and remained relatively stable throughout the first and second waves. Similar temporal trends for nursing home versus community decedents were apparent in age-stratified analyses (Figure 1). Women who died were less likely to have been hospitalized compared to men in both community (80% women vs 84% men) and nursing home (21% women vs 24% men) settings.Discussion - Only a minority of Ontario nursing home residents who died of COVID-19 were hospitalized prior to death, and that there were substantial temporal variations, with hospitalizations reaching their lowest point when overall COVID-19 incidence peaked in mid-April, 2020. While many nursing home residents had pre-pandemic advance directives precluding hospitalization, the low admission rate observed in March-April 2020 (15.5%) was inconsistent with both higher admission rates in subsequent months (>30%), and comparatively stable rates among community-dwelling adults. Our findings substantiate reports suggesting that hospitalizations for nursing home residents with COVID-19 were low during the peak of the pandemic’s first wave in Canada, which may have contributed to the particularly high concentration of COVID-19 mortality in Ontario’s nursing homes.

Summary Background To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19. Methods In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Participants were randomly assigned (1:1) using a computer-generated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ2 test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259. Findings Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2·42 log copies per mL at day 7 (p=0·0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0·15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4·12 [95% CI 1·15–16·73; p=0·029). Of those with baseline viral load above 106 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6·25 [95% CI 1·49–31·06]; p=0·012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported. Interpretation Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding. Funding The Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

BACKGROUND: Congregate settings have been disproportionately affected by coronavirus disease 2019 (COVID-19). Our objective was to compare testing for, diagnosis of and death after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across 3 settings (residents of long-term care homes, people living in shelters and the rest of the population). METHODS: We conducted a population-based prospective cohort study involving individuals tested for SARS-CoV-2 in the Greater Toronto Area between Jan. 23, 2020, and May 20, 2020. We sourced person-level data from COVID-19 surveillance and reporting systems in Ontario. We calculated cumulatively diagnosed cases per capita, proportion tested, proportion tested positive and case-fatality proportion for each setting. We estimated the age- and sex-adjusted rate ratios associated with setting for test positivity and case fatality using quasi-Poisson regression. RESULTS: Over the study period, a total of 173 092 individuals were tested for and 16 490 individuals were diagnosed with SARS-CoV-2 infection. We observed a shift in the proportion of cumulative cases from all cases being related to travel to cases in residents of long-term care homes (20.4% [3368/16 490]), shelters (2.3% [372/16 490]), other congregate settings (20.9% [3446/16 490]) and community settings (35.4% [5834/16 490]), with cumulative travel-related cases at 4.1% (674/16490). Cumulatively, compared with the rest of the population, the diagnosed cases per capita was 64-fold and 19-fold higher among long-term care home and shelter residents, respectively. By May 20, 2020, 76.3% (21 617/28 316) of long-term care home residents and 2.2% (150 077/6 808 890) of the rest of the population had been tested. After adjusting for age and sex, residents of long-term care homes were 2.4 (95% confidence interval [CI] 2.2-2.7) times more likely to test positive, and those who received a diagnosis of COVID-19 were 1.4-fold (95% CI 1.1-1.8) more likely to die than the rest of the population. INTERPRETATION: Long-term care homes and shelters had disproportionate diagnosed cases per capita, and residents of long-term care homes diagnosed with COVID-19 had higher case fatality than the rest of the population. Heterogeneity across micro-epidemics among specific populations and settings may reflect underlying heterogeneity in transmission risks, necessitating setting-specific COVID-19 prevention and mitigation strategies.

There is a pressing need for an in-depth understanding of immunity to SARS-CoV-2. Here we investigated T cell recall responses to fully glycosylated Spike trimer, recombinant N protein as well as to S, N, M and E peptide pools in the early convalescent phase. All subjects showed SARS-CoV-2-specific T cell responses to at least one antigen. SARS-CoV-2-specific CD4+ T cells were primarily of the central memory phenotype and exhibited a lower IFN-γ to TNF-α ratio compared to influenza-specific responses of the same donors, independent of disease severity. SARS-CoV-2-specific T cells were less multifunctional than influenza-specific T cells, particularly in severe cases, potentially suggesting exhaustion. High IL-10 production was noted in response to N protein, possibly contributing to immunosuppression, with potential implications for vaccine design. We observed granzyme B+/IFN-γg+ CD4+ and CD8+ proliferative responses to peptide pools in most individuals, with CD4+ responses predominating over CD8+ responses. Peripheral T follicular helper responses to S or N strongly correlated with serum neutralization assays as well as RBD-specific IgA. Overall, T cell responses to SARS-CoV-2 are robust, however, CD4+ Th1 responses predominate over CD8+ responses and are more inflammatory with a weaker Tfh response than influenza-specific CD4+ responses, potentially contributing to COVID-19 disease.

Objectives Primary Objective: To determine if pre-exposure prophylaxis (PrEP) with 400mg hydroxychloroquine (HCQ), taken orally once daily reduces microbiologically confirmed COVID-19 among front line health care workers at high risk for SARS-CoV-2 exposure. Secondary Objectives: To compare the following between study arms: adverse events; symptomatic COVID-19; duration of symptomatic COVID-19; days hospitalized attributed to COVID-19; respiratory failure attributable to COVID-19 requiring i) non-invasive ventilation or ii) intubation/mechanical ventilation; mortality attributed to COVID-19, number of days unable to work attributed to COVID-19, seroconversion (COVID-19 negative to COVID-19 positive over the study period); ability of participant plasma to neutralize SARS-CoV-2 virus in vitro; To describe short-term psychological distress associated with risk of COVID-19 exposure at 1, 60, 120 days of the study. To explore laboratory markers within participants with confirmed COVID-19: including circulating markers of host immune and endothelial activation in participant plasma and their correlation with disease severity and outcome Trial design The HEROS study is a two-arm, parallel-group, individually randomized (1:1 allocation ratio), placebo controlled, participant and investigator-blinded, multi-site superiority trial of oral HCQ 400 mg taken once daily for 90 days as PrEP to prevent COVID-19 in health care workers at high risk of SARS-CoV-2 exposure. At 90 days, there is an open label extension wherein all participants are offered a one-month course of HCQ 400mg once daily for PrEP of COVID-19. Participants Frontline HCWs aged 18 years of age or older, at high risk of SARS-CoV-2 exposure (including staff of emergency departments, intensive care units, intubation teams, COVID-wards, and staff deployed to Long Term Care facilities) of five academic hospitals in downtown Toronto, Canada. Exclusion criteria include: currently pregnant, planning to become pregnant during the study period, and/or breast feeding; known hypersensitivity/allergy to hydroxychloroquine or to 4-aminoquinoline compounds; current use of hydroxychloroquine; known prolonged QT syndrome and/or baseline resting ECG with QTc>450 ms and/or concomitant medications which simultaneously may prolong the QTc that cannot be temporarily suspended/replaced; known pre-existing retinopathy, G6PD deficiency, porphyria, liver disease including cirrhosis, encephalopathy, hepatitis or alcoholism, diabetes on oral hypoglycemics or insulin, or renal insufficiency/failure; disclosure of self-administered use of hydroxychloroquine or chloroquine within 12 weeks prior to study; confirmed symptomatic COVID-19 at time of enrollment. Intervention and comparator Intervention: hydroxychloroquine, 400mg (2 tablets) orally per day. Comparator: placebo, two tablets visually identical to the intervention, orally per day Main outcomes The primary outcome is microbiologically confirmed COVID-19 (i.e. SARS-CoV-2 infection). This is a composite endpoint which includes positive results from any validated SARS-CoV-2 diagnostic assay including detection of viral RNA, and/or seroconversion. Participants will be assessed at baseline, and then undergo monthly follow-up at day 30, 60, and 90, 120. At each visit, participants will provide an oropharyngeal sample, blood sample, and will undergo electrocardiogram monitoring of the QTc interval. Secondary outcome measures include: adverse events; symptom duration of COVID-19; days of hospitalization attributed to COVID-19; respiratory failure requiring ventilator support attributed to COVID-19; mortality attributed to COVID-19; total days off work attributed to COVID-19; seropositivity (reactive serology by day 120); and short term psychological impact of exposure to SARS-CoV-2 at day 1, 60, 120 days using the K10, a validated measure of non-specific psychological distress. Randomisation Within each site, participants will be individually randomized to either the intervention arm with HCQ or the placebo arm using a fixed 1:1 allocation ratio using an interactive web-based response system to ensure concealment of allocation. Randomization schedules will be computer-generated and blocked using variable block sizes. Blinding (masking) All participants, research coordinators, technicians, clinicians and investigators will be blinded to the participant allocation group. Numbers to be randomised (sample size) N=988, randomised into two groups of 494 patients. Trial Status This summary describes protocol version No. 1.6, May 15, 2020. Recruitment is ongoing - started April 20, 2020 and anticipated end date is July 30, 2021 Trial registration ISRCTN.com Identifier: ISRCTN14326006, registered April 14, 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

KEY POINTS Canada’s early response to coronavirus disease 2019 (COVID-19) largely comprised universal strategies of confinement alongside efforts to isolate people infected with or exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to increase testing. Underscoring early

BACKGROUND: In patients who are discharged home to self-isolate while coronavirus disease 2019 (COVID-19) test results are pending, there is no formal method for physician assessments or counselling to occur if the result returns positive. Our aim was to develop and test the feasibility of a virtual care program for self-isolating outpatients diagnosed with COVID-19. METHODS: In preparation for this gap in health care, the COVID-19 Expansion to Outpatients (COVIDEO) program was developed at the Sunnybrook Health Sciences Centre, Toronto, Ontario, to provide ongoing care for outpatients diagnosed with COVID-19. As part of a feasibility study, we describe our experiences with the first 50 patients managed using this program from its inception (Mar. 1, 2020) until Mar. 27, 2020. RESULTS: All 50 people who tested positive for COVID-19 at the Sunnybrook Health Sciences Centre and were discharged home to self-isolation during the study period were assessed through the COVIDEO program. Thirty-two patients (64%) were assessed via the Ontario Telemedicine Network virtual care platform, and the remainder by telephone. The median time from viral swab collection to first COVIDEO program assessment was 2 (interquartile range [IQR] 1–2) days. Among the 26 patients for whom further follow-up care through the COVIDEO program was discontinued by the end of March 2020, the median duration of virtual care was 12.5 (IQR 8.75–16) days. During the study period, 6 patients required transfer to hospital for assessment, of whom 4 required admission. INTERPRETATION: We have shown that a virtual care program can be used in the management of outpatients diagnosed with COVID-19. Further studies evaluating its sustainability and impact on health outcomes are underway.

BackgroundA hospital-level pandemic response involves anticipating local surge in healthcare needs.MethodsWe developed a mechanistic transmission model to simulate a range of scenarios of COVID-19 spread in the Greater Toronto Area. We estimated healthcare needs against 2019 daily admissions using healthcare administrative data, and applied outputs to hospital-specific data on catchment, capacity, and baseline non-COVID admissions to estimate potential surge by day 90 at two hospitals (St. Michael’s Hospital [SMH] and St. Joseph’s Health Centre [SJHC]). We examined fast/large, default, and slow/small epidemics, wherein the default scenario (R0 2.4) resembled the early trajectory in the GTA.ResultsWithout further interventions, even a slow/small epidemic exceeded the city’s daily ICU capacity for patients without COVID-19. In a pessimistic default scenario, for SMH and SJHC to remain below their non-ICU bed capacity, they would need to reduce non-COVID inpatient care by 70% and 58% respectively. SMH would need to create 86 new ICU beds, while SJHC would need to reduce its ICU beds for non-COVID care by 72%. Uncertainty in local epidemiological features was more influential than uncertainty in clinical severity. If physical distancing reduces contacts by 20%, maximizing the diagnostic capacity or syndromic diagnoses at the community-level could avoid a surge at each hospital.InterpretationAs distribution of the city’s surge varies across hospitals over time, efforts are needed to plan and redistribute ICU care to where demand is expected. Hospital-level surge is based on community-level transmission, with community-level strategies key to mitigating each hospital’s surge.

This case reports cryptococcal meningitis in an HIV positive woman on antiretroviral therapy, presenting with left middle cerebral artery stroke at 30 weeks gestation. The patient had well-controlled HIV (CD4 count over 200 cells/mL). The immunosuppressive effects of the pregnancy likely contributed to the development of cryptococcal disease. The patient was successfully treated with two weeks of amphotericin B followed by fluconazole, delivered a healthy baby, but remained with a permanent severe neurological deficit.

Objective To determine if inhaled and intranasal ciclesonide are superior to placebo at decreasing respiratory symptoms in adult outpatients with covid-19. Design Randomised, double blind, placebo controlled trial. Setting Three Canadian provinces (Quebec, Ontario, and British Columbia). Participants 203 adults aged 18 years and older with polymerase chain reaction confirmed covid-19, presenting with fever, cough, or dyspnoea. Intervention Participants were randomised to receive either inhaled ciclesonide (600 μg twice daily) and intranasal ciclesonide (200 μg daily) or metered dose inhaler and nasal saline placebos for 14 days. Main outcome measures The primary outcome was symptom resolution at day 7. Analyses were conducted on the modified intention-to-treat population (participants who took at least one dose of study drug and completed one follow-up survey) and adjusted for stratified randomisation by sex. Results The modified intention-to-treat population included 203 participants: 105 were randomly assigned to ciclesonide (excluding two dropouts and one loss to follow-up) and 98 to placebo (excluding three dropouts and six losses to follow-up). The median age was 35 years (interquartile range 27-47 years) and 54% were women. The proportion of participants with resolution of symptoms by day 7 did not differ significantly between the intervention group (42/105, 40%) and control group (34/98, 35%); absolute adjusted risk difference 5.5% (95% confidence interval −7.8% to 18.8%). Results might be limited to the population studied, which mainly included younger adults without comorbidities. The trial was stopped early, therefore could have been underpowered. Conclusion Compared with placebo, the combination of inhaled and intranasal ciclesonide did not show a statistically significant increase in resolution of symptoms among healthier young adults with covid-19 presenting with prominent respiratory symptoms. As evidence is insufficient to determine the benefit of inhaled and intranasal corticosteroids in the treatment of covid-19, further research is needed. Trial registration ClinicalTrials.gov NCT04435795 .

Setting: All community health workers (CHWs) in rural Kenema District, Sierra Leone. Objective: CHW programmes provide basic health services to fill gaps in human health resources. We compared trends in the reporting and management of childhood malaria, diarrhoea and pneumonia by CHWs before, during and after the Ebola outbreak (2014-2016). Design: Retrospective cross-sectional study using programme data. Results: CHW reporting increased from 59% pre-outbreak to 95% during the outbreak (P < 0.001), and was sustained at 98% post-outbreak. CHWs stopped using rapid diagnostic tests for malaria mid-outbreak, and their use had not resumed post-outbreak. The average monthly number of presumptive treatments for malaria increased from 2931 pre-outbreak to 5013 during and 5331 post-outbreak (P < 0.001). The average number of monthly treatments for diarrhoea and pneumonia decreased from respectively 1063 and 511 pre-outbreak to 547 and 352 during the outbreak (P = 0.01 and P = 0.04). Post-outbreak pneumonia treatments increased (mean 1126 compared to pre-outbreak, P = 0.003), and treatments for diarrhoea returned to pre-outbreak levels (P = 0.2). Conclusion: The CHW programme demonstrated vulnerability, but also resilience, during and in the early period after the Ebola outbreak. Investment in CHWs is required to strengthen the health care system, as they can cover pre-existing gaps in facility-based health care and those created by outbreaks.

Setting: All health facility and community malnutrition screening programmes in Tonkolili, a rural Ebola-affected district in Sierra Leone. Objectives: Before the Ebola disease outbreak, Sierra Leone had set a goal to reduce the prevalence of severe acute malnutrition (SAM) in children aged

Setting: All 100 health facilities providing maternal services in Moyamba, Sierra Leone, a rural district that experienced a smaller Ebola outbreak than other areas. Objective: To compare trends in antenatal care (the first and fourth visit [ANC1 and ANC4]), delivery, and postnatal care (PNC1) service utilisation before, during and after the Ebola outbreak (2014–2016). Design: Cross-sectional study using secondary programme data. Results: A total of 211 Ebola cases occurred in Moyamba District. The mean number of monthly ANC visits remained stable over time, except for the subset of care provided via outreach visits where, compared with before the outbreak (n = 390), ANC1 visits declined during (n = 331, P = 0.002) and after the outbreak (n = 342, P = 0.03). Most (>97%) deliveries occurred in health facilities, assisted by maternal and child health aides (>80%). During the outbreak, the mean number of community-based deliveries per month declined from 31 to 21 (P = 0.03), and the mean number of deliveries performed by midwives increased from 49 to 78 (P < 0.001) compared with before the outbreak. Before, during and after Ebola, there was no significant change in the mean number of live births (respectively n = 1134, n = 1110, n = 1162), maternal PNC1 (respectively n = 1110, n = 1105, n = 1165) or neonatal PNC1 (respectively n = 1028, n = 1050, n = 1085). Conclusion: In a rural district less affected by Ebola transmission than other areas, utilisation of maternal primary care remained robust, despite the outbreak.

Background: There are currently no effective treatments for outpatients with coronavirus disease. 2019 (COVID-19). Interferon-lambda-1 is a Type III interferon involved in the innate antiviral response with activity against respiratory pathogens. Methods: In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomized to a single subcutaneous injection of peginterferon-lambda 180μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. The primary endpoint was proportion negative for SARS-CoV-2 RNA on Day 7 post-injection. Results: There were 30 patients per arm, with median baseline SARS-CoV-2 viral load of 6.71 (IQR 1.3-8.0) log copies/mL. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon-lambda than placebo (p=0.04). On Day 7, 24 participants (80%) in the peginterferon-lambda group had an undetectable viral load compared to 19 (63%) in the placebo arm (p=0.15). After controlling for baseline viral load, peginterferon-lambda treatment resulted in a 4.12-fold (95CI 1.15-16.7, p=0.029) higher likelihood of viral clearance by Day 7. Of those with baseline viral load above 10E6 copies/mL, 15/19 (79%) in the peginterferon-lambda group were undetectable on Day 7 compared to 6/16 (38%) in the placebo group (p=0.012). Adverse events were similar between groups with only mild reversible transaminase elevations more frequently observed in the peginterferon-lambda group. Conclusion: Peginterferon-lambda accelerated viral decline in outpatients with COVID-19 resulting in a greater proportion with viral clearance by Day 7, particularly in those with high baseline viral load. Peginterferon-lambda may have potential to prevent clinical deterioration and shorten duration of viral shedding. Trial Registration: NCT04354259 Funding Statement: This study was supported by the Toronto COVID-19 Action Initiative, University of Toronto and the Ontario First COVID-19 Rapid Research Fund. Medication was supplied by Eiger BioPharma. Declaration of Interests: JJF reports research support unrelated to this work from Eiger BioPharmaceuticals. BC has received research support unrelated to this work from Nubiyota LLC and Sanofi. IC and CH are employees of Eiger BioPharmaceuticals. JSG is a board member and founder of Eiger BioPharmaceuticals, Inc., in which he has an equity interest, and is an inventor on a patent application for the use of interferon lambda to treat coronavirus infections. All other authors have nothing to declare. Ethics Approval Statement: The Research Ethics Boards of all participating institutions approved the study, which was conducted under a Clinical Trial Application approved by Health Canada.

Background Management of Ebola virus disease (EVD) has historically focused on infection prevention, case detection and supportive care. Several specific anti-Ebola therapies have been investigated, including during the 2014–2016 West African outbreak. Our objective was to conduct a systematic review of the effect of anti-Ebola virus therapies on clinical outcomes to guide their potential use and future evaluation. Methods We searched PubMed, EMBASE, Global Health, Cochrane Library, African Index Medicus, WHOLIS (inception-9 April 2018), and trial registries for observational studies or clinical trials, in any language, that enrolled patients with confirmed EVD who received therapy targeting Ebola virus and reported on mortality, symptom duration, or adverse effects. Results From 11,257 citations and registered trials, we reviewed 55 full-text citations, of which 35 met eligibility criteria (1 randomized clinical trial (RCT), 8 non-randomized comparative studies, 9 case series and 17 case reports) and collectively examined 21 anti-Ebola virus agents. The 31 studies performed during the West African outbreak reported on 4.8% (1377/28616) of all patients with Ebola. The only RCT enrolled 72 patients (0.25% of all patients with Ebola) and compared the monoclonal antibody ZMapp vs. standard care (mortality, 22% vs. 37%; 95% confidence interval for risk difference, − 36 to 7%). Studies of convalescent plasma, interferon-β-1a, favipiravir, brincidofovir, artesunate-amodiaquine and TKM-130803 were associated with at least moderate risk of bias. Conclusions Research evaluating anti-Ebola virus agents has reached very few patients with EVD, and inferences are limited by non-randomized study designs. ZMapp has the most promising treatment signal. Electronic supplementary material The online version of this article (10.1186/s12879-019-3980-9) contains supplementary material, which is available to authorized users.

Objective Routinely collected health administrative data can be used to efficiently assess disease burden in large populations, but it is important to evaluate the validity of these data. The objective of this study was to develop and validate International Classification of Disease 10th revision (ICD -10) algorithms that identify laboratory-confirmed influenza or laboratory-confirmed respiratory syncytial virus (RSV) hospitalizations using population-based health administrative data from Ontario, Canada. Study design and setting Influenza and RSV laboratory data from the 2014–15, 2015–16, 2016–17 and 2017–18 respiratory virus seasons were obtained from the Ontario Laboratories Information System (OLIS) and were linked to hospital discharge abstract data to generate influenza and RSV reference cohorts. These reference cohorts were used to assess the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the ICD-10 algorithms. To minimize misclassification in future studies, we prioritized specificity and PPV in selecting top-performing algorithms. Results 83,638 and 61,117 hospitalized patients were included in the influenza and RSV reference cohorts, respectively. The best influenza algorithm had a sensitivity of 73% (95% CI 72% to 74%), specificity of 99% (95% CI 99% to 99%), PPV of 94% (95% CI 94% to 95%), and NPV of 94% (95% CI 94% to 95%). The best RSV algorithm had a sensitivity of 69% (95% CI 68% to 70%), specificity of 99% (95% CI 99% to 99%), PPV of 91% (95% CI 90% to 91%) and NPV of 97% (95% CI 97% to 97%). Conclusion We identified two highly specific algorithms that best ascertain patients hospitalized with influenza or RSV. These algorithms may be applied to hospitalized patients if data on laboratory tests are not available, and will thereby improve the power of future epidemiologic studies of influenza, RSV, and potentially other severe acute respiratory infections.

C. neoformansvar.grubii(C. neoformans) is an environmentally acquired pathogen causing 181 000 HIV-associated deaths each year. We used whole genome sequencing (WGS) to characterise 699 isolates, primarilyC. neoformansfrom HIV-infected patients, from 5 countries in Asia and Africa. We found that 91% of our clinical isolates belonged to one of three highly clonal sub-clades of VNIa, which we have termed VNIa-4, VNIa-5 and VNIa-93. Parsimony analysis revealed frequent, long distance transmissions ofC. neoformans; international transmissions took place on 13% of VNIa-4 branches, and intercontinental transmissions on 7% of VNIa-93 branches. The median length of within sub-clade internal branches was 3-6 SNPs, while terminal branches were 44.5-77.5 SNPs. The short median internal branches were partly driven by the large number (12-15% of internal branches) of polytomies in the within-sub-clade trees. To simultaneously explain our observation of no apparent molecular clock, short internal branches and frequent polytomies we hypothesise thatC. neoformansVNIa spends much of its time in the environment in a quiescent state, while, when it is sampled, it has almost always undergone an extended period of growth. Infections with VNIa-93 were associated with a significantly reduced risk of death by 10 weeks compared with infections with VNIa-4 (Hazard Ratio = 0.45, p = 0.003). We detected a recombination in the mitochondrial sequence of VNIa-5, suggesting that mitochondria could be involved in the propensity of this sub-clade to infect HIV-uninfected patients. These data highlight the insight into the biology and epidemiology of pathogenic fungi which can be gained from WGS data.

To determine whether C-reactive protein (CRP) is an inflammatory biomarker that may identify patients at risk of infections or death. Mortality among HIV-infected persons commencing antiretroviral therapy (ART) is often attributed to tuberculosis (TB) or bloodstream infections (BSI). In two district hospitals in southern Malawi we recruited HIV-infected adults with one or more unexplained symptoms present for at least one month (weight loss, fever, or diarrhea), and negative expectorated sputum microscopy for TB. CRP determination for 452/469 (96%) participants at study enrolment was analyzed for associations with TB, BSI or death to 120 days post-enrolment. Baseline CRP was significantly elevated among patients with confirmed and probable TB (52), BSI (50) or death (60) compared to those with no identified infection who survived at least 120 days (269). A CRP value of >10 mg/L was associated with confirmed and probable TB (adjusted odds ratio 5.7; 95% CI 2.6, 14.3; 87% sensitivity) or death by 30 days (adjusted odds ratio 9.2; 95% CI 2.2, 55.1; 88% sensitivity). CRP was independently associated with TB, BSI or Death but prediction of these endpoints was enhanced by including hemoglobin (all outcomes), CD4 count (BSI, death), and whether ART was started (death) in logistic regression models. High CRP at the time of ART initiation is associated with TB, BSI and early mortality, and so has potential utility for stratifying patients for intensified clinical and laboratory investigation and follow-up. They may also be considered for empirical treatment of opportunistic infections including TB. This article is protected by copyright. All rights reserved.

Background Despite availability of effective treatment, tuberculosis (TB) remains an important cause of morbidity and mortality globally, with low- and middle-income countries most affected. In many such settings, including Malawi, the high burden of disease and severe shortage of skilled healthcare workers has led to task-shifting of outpatient TB care to lay health workers (LHWs). LHWs improve access to healthcare and some outcomes, including TB completion rates, but lack of training and supervision limit their impact. The goals of this study are to improve TB care provided by LHWs in Malawi by refining, implementing, and evaluating a knowledge translation strategy designed to address a recognized gap in LHWs’ TB and job-specific knowledge and, through this, to improve patient outcomes. Methods/design We are employing a mixed-methods design that includes a pragmatic cluster randomized controlled trial and a process evaluation using qualitative methods. Trial participants will include all health centers providing TB care in four districts in the South East Zone of Malawi. The intervention employs educational outreach, a point-of-care reminder tool, and a peer support network. The primary outcome is proportion of treatment successes, defined as the total of TB patients cured or completing treatment, with outcomes taken from Ministry of Health treatment records. With an alpha of 0.05, power of 0.80, a baseline treatment success of 0.80, intraclass correlation coefficient of 0.1 based on our pilot study, and an estimated 100 clusters (health centers providing TB care), a minimum of 6 patients per cluster is required to detect a clinically significant 0.10 increase in the proportion of treatment successes. Our process evaluation will include interviews with LHWs and patients, and a document analysis of LHW training logs, quarterly peer trainer meetings, and mentorship meeting notes. An estimated 10–15 LHWs and 10–15 patients will be required to reach saturation in each of 2 planned interview periods, for a total of 40–60 interview participants. Discussion This study will directly inform the efforts of knowledge users within TB care and, through extension of the approach, other areas of care provided by LHWs in Malawi and other low- and middle-income countries. Trial registration ClinicalTrials.gov NCT02533089. Registered 20 August 2015. Protocol Date/Version 29 May 2016/Version 2. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1563-2) contains supplementary material, which is available to authorized users.

Background Malawi adopted the PMTCT strategy ‘Option B+’ in 2011, providing life-long ART for all HIV-infected pregnant and breastfeeding women. We explored differences in characteristics and outcomes of women initiating ART during pregnancy versus breastfeeding. Methods We conducted a retrospective cohort analysis of women in Zomba District, southern Malawi, from January 2012- September 2013. Data were extracted from the Zomba District Observational Cohort Study, a surveillance project collecting data from standardized Ministry of Health ART monitoring tools. Results 1986 (67.2 %) women initiated ART during pregnancy and 969 (32.8 %) during breastfeeding. Women initiating ART in breastfeeding were more likely to be > 30 years (aOR = 1.33, 95 % CI1.11–1.59, p = 0.003) and have WHO Stage 3/4 (aOR = 2.74, 95 % CI1.94–3.87, p