Impact of the COVID-19 Pandemic on Hepatitis C Treatment Initiation in British Columbia, Canada: An Interrupted Time Series Study.

We investigated the impacts of the COVID-19 pandemic on hepatitis C (HCV) treatment initiation, including by birth cohort and injection drug use status, in British Columbia (BC), Canada. Using population data from the BC COVID-19 Cohort, we conducted interrupted time series analyses, estimating changes in HCV treatment initiation following the introduction of pandemic-related policies in March 2020. The study included a pre-policy period (April 2018 to March 2020) and three follow-up periods (April to December 2020, January to December 2021, and January to December 2022). The level of HCV treatment initiation decreased by 26% in April 2020 (rate ratio 0.74, 95% confidence interval [CI] 0.60 to 0.91). Overall, no statistically significant difference in HCV treatment initiation occurred over the 2020 and 2021 post-policy periods, and an increase of 34.4% (95% CI 0.6 to 75.8) occurred in 2022 (equating to 321 additional people initiating treatment), relative to expectation. Decreases in HCV treatment initiation occurred in 2020 for people born between 1965 and 1974 (25.5%) and people who inject drugs (24.5%), relative to expectation. In summary, the pandemic was associated with short-term disruptions in HCV treatment initiation in BC, which were greater for people born 1965 to 1974 and people who inject drugs.

Subnational Projections of Lymphatic Filariasis Elimination Targets in Ethiopia to Support National Level Policy.

BACKGROUND: Lymphatic filariasis (LF) is a debilitating, poverty-promoting, neglected tropical disease (NTD) targeted for worldwide elimination as a public health problem (EPHP) by 2030. Evaluating progress towards this target for national programmes is challenging, due to differences in disease transmission and interventions at the subnational level. Mathematical models can help address these challenges by capturing spatial heterogeneities and evaluating progress towards LF elimination and how different interventions could be leveraged to achieve elimination by 2030. METHODS: Here we used a novel approach to combine historical geo-spatial disease prevalence maps of LF in Ethiopia with 3 contemporary disease transmission models to project trends in infection under different intervention scenarios at subnational level. RESULTS: Our findings show that local context, particularly the coverage of interventions, is an important determinant for the success of control and elimination programmes. Furthermore, although current strategies seem sufficient to achieve LF elimination by 2030, some areas may benefit from the implementation of alternative strategies, such as using enhanced coverage or increased frequency, to accelerate progress towards the 2030 targets. CONCLUSIONS: The combination of geospatial disease prevalence maps of LF with transmission models and intervention histories enables the projection of trends in infection at the subnational level under different control scenarios in Ethiopia. This approach, which adapts transmission models to local settings, may be useful to inform the design of optimal interventions at the subnational level in other LF endemic regions.

Nasopharyngeal angiotensin converting enzyme 2 (ACE2) expression as a risk-factor for SARS-CoV-2 transmission in concurrent hospital associated outbreaks.

BACKGROUND: Widespread human-to-human transmission of the severe acute respiratory syndrome coronavirus two (SARS-CoV-2) stems from a strong affinity for the cellular receptor angiotensin converting enzyme two (ACE2). We investigate the relationship between a patient's nasopharyngeal ACE2 transcription and secondary transmission within a series of concurrent hospital associated SARS-CoV-2 outbreaks in British Columbia, Canada. METHODS: Epidemiological case data from the outbreak investigations was merged with public health laboratory records and viral lineage calls, from whole genome sequencing, to reconstruct the concurrent outbreaks using infection tracing transmission network analysis. ACE2 transcription and RNA viral load were measured by quantitative real-time polymerase chain reaction. The transmission network was resolved to calculate the number of potential secondary cases. Bivariate and multivariable analyses using Poisson and Negative Binomial regression models was performed to estimate the association between ACE2 transcription the number of SARS-CoV-2 secondary cases. RESULTS: The infection tracing transmission network provided n = 76 potential transmission events across n = 103 cases. Bivariate comparisons found that on average ACE2 transcription did not differ between patients and healthcare workers (P = 0.86). High ACE2 transcription was observed in 98.6% of transmission events, either the primary or secondary case had above average ACE2. Multivariable analysis found that the association between ACE2 transcription (log2 fold-change) and the number of secondary transmission events differs between patients and healthcare workers. In health care workers Negative Binomial regression estimated that a one-unit change in ACE2 transcription decreases the number of secondary cases (ß = -0.132 (95%CI: -0.255 to -0.0181) adjusting for RNA viral load. Conversely, in patients a one-unit change in ACE2 transcription increases the number of secondary cases (ß = 0.187 (95% CI: 0.0101 to 0.370) adjusting for RNA viral load. Sensitivity analysis found no significant relationship between ACE2 and secondary transmission in health care workers and confirmed the positive association among patients. CONCLUSION: Our study suggests that ACE2 transcription has a positive association with SARS-CoV-2 secondary transmission in admitted inpatients, but not health care workers in concurrent hospital associated outbreaks, and it should be further investigated as a risk-factor for viral transmission.

Systematic review and meta-analysis of disease clustering in multimorbidity: a study protocol.

INTRODUCTION: Multimorbidity is defined as the presence of two or more chronic diseases. Co-occurring diseases can have synergistic negative effects, and are associated with significant impacts on individual health outcomes and healthcare systems. However, the specific effects of diseases in combination will vary between different diseases. Identifying which diseases are most likely to co-occur in multimorbidity is an important step towards population health assessment and development of policies to prevent and manage multimorbidity more effectively and efficiently. The goal of this project is to conduct a systematic review and meta-analysis of studies of disease clustering in multimorbidity, in order to identify multimorbid disease clusters and test their stability. METHODS AND ANALYSIS: We will review data from studies of multimorbidity that have used data clustering methodologies to reveal patterns of disease co-occurrence. We propose a network-based meta-analytic approach to perform meta-clustering on a select list of chronic diseases that are identified as priorities for multimorbidity research. We will assess the stability of obtained disease clusters across the research literature to date, in order to evaluate the strength of evidence for specific disease patterns in multimorbidity. ETHICS AND DISSEMINATION: This study does not require ethics approval as the work is based on published research studies. The study findings will be published in a peer-reviewed journal and disseminated through conference presentations and meetings with knowledge users in health systems and public health spheres. PROSPERO REGISTRATION NUMBER: CRD42023411249.

A cost benefit analysis of a virtual overdose monitoring service/mobile overdose response service: the national overdose response service.

BACKGROUND: The overdose crisis continues across Canada which calls for novel harm reduction strategies. Previous research indicates that a majority of eHealth solutions are cost-effective however current literature on the cost-benefit of eHealth for harm reduction is sparse. The National Overdose Response Service (NORS) is a Canada-wide telephone-based harm reduction service. Service users can call the phone number and connect to a peer who can virtually monitor the substance use session and dispatch appropriate interventions in the case of overdose. OBJECTIVES OF THE RESEARCH/PROJECT: We aim to assess the cost-benefit of NORS by comparing the estimated cost-savings from prevented overdose mortality to the operating costs of the program, alongside healthcare costs associated with its operation. METHODS: Data around systems costs and operational costs were gathered for our calculations. Our primary outcome was cost-benefit ratios, derived from estimates and models of mortality rates in current literature and value of life lost. We presented our main results across a range of values for costs and the probability of death following an unwitnessed overdose. These values were utilized to calculate cost-benefit ratios and value per dollar spent on service provision by NORS over the length of the program's operation (December 2020-2022). RESULTS: Over the total funded lifespan of the program, and using a Monte Carlo estimate, the benefit-to-cost ratio of the NORS program was 8.59 (1.53-15.28) per dollar spent, depending on estimated mortality rates following unwitnessed overdose and program operation costs. Further, we conservatively estimate that early community-based naloxone intervention results in healthcare system savings of $4470.82 per overdose response. CONCLUSIONS: We found the NORS program to have a positive benefit-to-cost ratio when the probability of death following an unwitnessed overdose was greater than 5%. NORS and potentially other virtual overdose monitoring services have the potential to be cost-effective solutions for managing the drug poisoning crisis.

SARS-CoV-2 cross-sectional seroprevalence study among public school staff in Metro Vancouver after the first Omicron wave in British Columbia, Canada.

OBJECTIVE: To determine the SARS-CoV-2 seroprevalence among school workers within the Greater Vancouver area, British Columbia, Canada, after the first Omicron wave. DESIGN: Cross-sectional study by online questionnaire, with blood serology testing. SETTING: Three main school districts (Vancouver, Richmond and Delta) in the Vancouver metropolitan area. PARTICIPANTS: Active school staff enrolled from January to April 2022, with serology testing between 27 January and 8 April 2022. Seroprevalence estimates were compared with data obtained from Canadian blood donors weighted over the same sampling period, age, sex and postal code distribution. PRIMARY AND SECONDARY OUTCOMES: SARS-CoV-2 nucleocapsid antibody testing results adjusted for test sensitivity and specificity, and regional variation across school districts using Bayesian models. RESULTS: Of 1850 school staff enrolled, 65.8% (1214/1845) reported close contact with a COVID-19 case outside the household. Of those close contacts, 51.5% (625/1214) were a student and 54.9% (666/1214) were a coworker. Cumulative incidence of COVID-19 positive testing by self-reported nucleic acid or rapid antigen testing since the beginning of the pandemic was 15.8% (291/1845). In a representative sample of 1620 school staff who completed serology testing (87.6%), the adjusted seroprevalence was 26.5% (95% CrI 23.9% to 29.3%), compared with 32.4% (95% CrI 30.6% to 34.5%) among 7164 blood donors. CONCLUSION: Despite frequent COVID-19 exposures reported, SARS-CoV-2 seroprevalence among school staff in this setting remained no greater than the community reference group. Results are consistent with the premise that many infections were acquired outside the school setting, even with Omicron.

Associations between maternal depressive symptoms and selective serotonin reuptake inhibitor antidepressant treatment on internalising and anxiety behaviours in children: 12-year longitudinal study.

BACKGROUND: Prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure is associated with increased internalising and anxious behaviours in young children; whether this continues into early adolescence is unknown. Also, it is not well established whether it is the in utero exposure to SSRIs or the underlying maternal mood that contributes more to these associations. AIMS: To examine associations between maternal depressive symptoms, prenatal SSRI antidepressant treatment and internalising and anxiety behaviours from childhood into pre-adolescence. METHOD: From a prospective longitudinal cohort, measures of maternal depressive symptoms and SSRI use and child outcomes (n = 191 births) were obtained from the second trimester to 12 years. Maternal reports of internalising and anxiety behaviours in children were obtained at 3, 6 and 12 years. RESULTS: Multilevel mixed-effects models revealed that maternal depressed mood at the third trimester assessment, not prenatal SSRI exposure, was associated with longitudinal patterns of higher levels of internalising and anxiety behaviours across childhood from 3 to 12 years of age. At each age, hierarchical regressions showed that maternal mood at the third trimester, compared with current maternal depression or prenatal SSRI exposure, explained a greater proportion of the variance in internalising and anxiety behaviours. CONCLUSIONS: Even with prenatal SSRI treatment, maternal depressed mood during the third trimester still had an enduring effect as it was associated with increased levels of internalising and anxiety behaviours across childhood and into early adolescence. Importantly, we found no evidence of a 'main effect' association between prenatal SSRI exposure and internalising and anxiety behaviours in children.

Impact of Time to Diagnosis on Morbidity and Survival in Children With Malignant Central Nervous System Tumors.

OBJECTIVE: The aim was to determine the impact of time to diagnosis (TTD) on morbidity and mortality and to identify factors associated with overall survival (OS) in pediatric patients with malignant central nervous system (CNS) tumors. METHODS: This is a retrospective review of all malignant CNS tumors presenting to 2 tertiary care pediatric hospitals from 2000 to 2019. Cox proportional hazard model analysis outcomes included TTD and OS as well as morbidity; stratified by tumor category, age, relapse, and presence of metastatic disease. RESULTS: There were 197 children with malignant CNS tumors (mean age 8.7 y, 61% male). Tumors included medulloblastoma (N=58, 29.4%), ependymoma (N=27, 13.7%), high-grade glioma (N=42, 21.3%), germ cell tumors (N=47, 23.9%), and other embryonal tumors (N=23, 11.7%). Median TTD from symptom onset was 62 (interquartile range: 26.5 to 237.5 d) and 28% had metastatic disease. Three-year progression free survival was 55% and 3-year OS was 73.1%. Increased OS was associated with increased TTD (parameter estimate 0.12; confidence interval [CI]: 0.019-7.06; P =0.019), high-grade glioma (hazard ratio [HR]: 2.46; CI [1.03-5.86]; P =0.042), other embryonal tumor (HR: 2.84; CI [1.06-7.56]; P =0.037), relapse (HR: 10.14; CI: 4.52-22.70; P <0.001) and metastatic disease (HR: 3.25; CI: 1.51-6.96; P =0.002). Vision change (HR: 0.58; CI: 0.313-1.06; P =0.078), hearing loss (HR: 0.71; CI: 0.35-1.42; P =0.355), and cognitive impairment (HR: 0.73; CI: 0.45-1.19; P =0.205) were not associated with TTD in this model. CONCLUSIONS: Increased median TTD is associated with higher OS in pediatric patients treated for malignant CNS tumors. Tumor biology and treatment modality are more important factors than TTD for predicting morbidity and long-term outcomes in pediatric patients with CNS tumors.

Association between close interpersonal contact and vaccine hesitancy: Findings from a population-based survey in Canada.

Background: Vaccine hesitancy threatens efforts to bring the coronavirus disease 2019 (COVID-19) pandemic to an end. Given that social or interpersonal contact is an important driver for COVID-19 transmission, understanding the relationship between contact rates and vaccine hesitancy may help identify appropriate targets for strategic intervention. The purpose of this study was to assess the association between interpersonal contact and COVID-19 vaccine hesitancy among a sample of unvaccinated adults in the Canadian province of British Columbia (BC). Methods: Unvaccinated individuals participating in the BC COVID-19 Population Mixing Patterns Survey (BC-Mix) were asked to indicate their level of agreement to the statement, "I plan to get the COVID-19 vaccine." Multivariable multinomial logistic regression was used to assess the association between self-reported interpersonal contact and vaccine hesitancy, adjusting for age, sex, ethnicity, educational attainment, occupation, household size and region of residence. All analyses incorporated survey sampling weights based on age, sex, geography, and ethnicity. Results: Results were based on survey responses collected between March 8, 2021 and December 6, 2021, by a total of 4,515 adults aged 18 years and older. Overall, 56.7% of respondents reported that they were willing to get the COVID-19 vaccine, 27.0% were unwilling and 16.3% were undecided. We found a dose-response association between interpersonal contact and vaccine hesitancy. Compared to individuals in the lowest quartile (least contact), those in the fourth quartile (highest contact), third quartile and second quartile groups were more likely to be vaccine hesitant, with adjusted odd ratios (aORs) of 2.85 (95% CI: 2.02, 4.00), 1.91(95% CI: 1.38, 2.64), 1.78 (95% CI: 1.13, 2.82), respectively. Conclusion: Study findings show that among unvaccinated people in BC, vaccine hesitancy is greater among those who have high contact rates, and hence potentially at higher risk of acquiring and transmitting infection. This may also impact future uptake of booster doses.

Optimized Infliximab Induction Predicts Better Long-Term Clinical and Biomarker Outcomes Compared to Standard Induction Dosing.

OBJECTIVES: To evaluate the efficacy of standard and optimized infliximab induction dosing in attaining corticosteroid (CS) free clinical remission at week 52 and the effect that post-induction trough levels have on long-term outcome. METHODS: Inflammatory bowel disease (IBD) patients ≤18 years commenced on infliximab between August 1, 2016, and August 1, 2018, from Vancouver, Canada, and Glasgow, Scotland, were included. The Glasgow cohort followed standard induction while the Vancouver cohort undertook induction optimization based on clinical, biomarker, and proactive infliximab trough levels. Baseline characteristics and laboratory values were documented. RESULTS: In total, 140 children were included [median age 14.1 years (interquartile range (IQR) 12.0-16.0)]; 54% male. CS-free clinical remission at week 52 was higher in the optimized group compared to the standard cohort [65/78 (83%) vs. 32/62 (52%), P < 0.001]. Combined CS-free clinical and biomarker remission (CRP < 5 mg/L) was also higher in the optimized compared to the standard cohort [65/78 (83%) vs 25/62 (40%), P < 0.001]. The median post-induction trough level was higher in children who were in CS-free clinical remission at week 52 [3.6 mg/L (1.5-7.1)] vs. those who were not [2.0 mg/L (0.8-4.1), P = 0.04]. The odds of attaining a therapeutic post-induction trough level were almost 4-fold higher in the optimized group than the standard cohort (OR 3.97, 95% CI: 1.89-8.68, P < 0.001). CONCLUSIONS: Standard infliximab induction resulted in less favorable long-term outcomes for pediatric IBD patients. Optimizing induction using clinical, biomarker, and proactive trough levels resulted in higher post-induction trough levels and a greater odds of attaining long-term clinical remission.

Cohort profile: the British Columbia COVID-19 Population Mixing Patterns Survey (BC-Mix).

PURPOSE: Several non-pharmaceutical interventions, such as physical distancing, handwashing, self-isolation, and school and business closures, were implemented in British Columbia (BC) following the first laboratory-confirmed case of COVID-19 on 26 January 2020, to minimise in-person contacts that could spread infections. The BC COVID-19 Population Mixing Patterns Survey (BC-Mix) was established as a surveillance system to measure behaviour and contact patterns in BC over time to inform the timing of the easing/re-imposition of control measures. In this paper, we describe the BC-Mix survey design and the demographic characteristics of respondents. PARTICIPANTS: The ongoing repeated online survey was launched in September 2020. Participants are mainly recruited through social media platforms (including Instagram, Facebook, YouTube, WhatsApp). A follow-up survey is sent to participants 2-4 weeks after completing the baseline survey. Survey responses are weighted to BC's population by age, sex, geography and ethnicity to obtain generalisable estimates. Additional indices such as the Material and Social Deprivation Index, residential instability, economic dependency, and others are generated using census and location data. FINDINGS TO DATE: As of 26 July 2021, over 61 000 baseline survey responses were received of which 41 375 were eligible for analysis. Of the eligible participants, about 60% consented to follow-up and about 27% provided their personal health numbers for linkage with healthcare databases. Approximately 83.5% of respondents were female, 58.7% were 55 years or older, 87.5% identified as white and 45.9% had at least a university degree. After weighting, approximately 50% were female, 39% were 55 years or older, 65% identified as white and 50% had at least a university degree. FUTURE PLANS: Multiple papers describing contact patterns, physical distancing measures, regular handwashing and facemask wearing, modelling looking at impact of physical distancing measures and vaccine acceptance, hesitancy and uptake are either in progress or have been published.

Safety of COVID-19 vaccines in pregnancy: a Canadian National Vaccine Safety (CANVAS) network cohort study.

BACKGROUND: Pregnant individuals have been receiving COVID-19 vaccines following pre-authorisation clinical trials in non-pregnant people. This study aimed to determine the frequency and nature of significant health events among pregnant females after COVID-19 vaccination, compared with unvaccinated pregnant controls and vaccinated non-pregnant individuals. METHODS: We did an observational cohort study, set in seven Canadian provinces and territories including Ontario, Quebec, British Columbia, Alberta, Nova Scotia, Yukon, and Prince Edward Island. Eligibility criteria for vaccinated individuals were a first dose of a COVID-19 vaccine within the previous 7 days; an active email address and telephone number; ability to communicate in English or French; and residence in the aforementioned provinces or territories. Study participants were pregnant and non-pregnant females aged 15-49 years. Individuals were able to participate as controls if they were unvaccinated and fulfilled the other criteria. Data were collected primarily by self-reported survey after both vaccine doses, with telephone follow-up for those reporting any medically attended event. Participants reported significant health events (new or worsening of a health event sufficient to cause work or school absenteeism, medical consultation, or prevent daily activities) occurring within 7 days of vaccination or within the past 7 days for unvaccinated individuals. We employed multivariable logistic regression to examine significant health events associated with mRNA vaccines, adjusting for age group, previous SARS-CoV-2 infection, and trimester, as appropriate. FINDINGS: As of Nov 4, 2021, 191 360 women aged 15-49 years with known pregnancy status had completed the first vaccine dose survey and 94 937 had completed the second dose survey. 180 388 received one dose and 94 262 received a second dose of an mRNA vaccine, with 5597 pregnant participants receiving dose one and 3108 receiving dose two, and 174 765 non-pregnant participants receiving dose one and 91 131 receiving dose two. Of 6179 included unvaccinated control participants, 339 were pregnant and 5840 were not pregnant. Overall, 226 (4·0%) of 5597 vaccinated pregnant females reported a significant health event after dose one of an mRNA vaccine, and 227 (7·3%) of 3108 after dose two, compared with 11 (3·2%) of 339 pregnant unvaccinated females. Pregnant vaccinated females had an increased odds of a significant health event within 7 days of the vaccine after dose two of mRNA-1273 (adjusted odds ratio [aOR] 4·4 [95% CI 2·4-8·3]) compared with pregnant unvaccinated controls within the past 7 days, but not after dose one of mRNA-1273 or any dose of BNT162b2. Pregnant vaccinated females had decreased odds of a significant health event compared with non-pregnant vaccinated females after both dose one (aOR 0·63 [95% CI 0·55-0·72]) and dose two (aOR 0·62 [0·54-0·71]) of any mRNA vaccination. There were no significant differences in any analyses when restricted to events which led to medical attention. INTERPRETATION: COVID-19 mRNA vaccines have a good safety profile in pregnancy. These data can be used to appropriately inform pregnant people regarding reactogenicity of COVID-19 vaccines during pregnancy, and should be considered alongside effectiveness and immunogenicity data to make appropriate recommendations about best use of COVID-19 vaccines in pregnancy. FUNDING: Canadian Institutes of Health Research, Public Health Agency of Canada.

Glomerular Filtration Rate Abnormalities in Children With Type 1 Diabetes.

OBJECTIVES: Type 1 diabetes (T1D) increases the risk of chronic kidney disease (CKD) development. The primary objective of this study was to assess the prevalence of abnormalities in estimated glomerular filtration rate (eGFR) in children with T1D. As a secondary objective, we sought to explore the relationship between clinical characteristics and abnormalities in eGFR. METHODS: This cross-sectional study involved children ≤18 years of age with T1D followed in the diabetes clinic at a pediatric tertiary care centre. Data were collected from health records between 2016 and 2020. Using the Bedside Schwartz, Chronic Kidney Disease in Children Under 25 (CKiD U25) and European Kidney Function Consortium (EKFC) equations, eGFR was categorized as CKD (<60 mL/min/1.73 m2), mildly decreased (60 to <90 mL/min/1.73 m2), normal (90 to <158 mL/min/1.73 m2) and hyperfiltration (≥158 mL/min/1.73 m2). Linear regression analysis was used to describe the relationship between eGFR and clinical characteristics. RESULTS: Of the 420 participants, 225 were male (54%); the median age at diagnosis and duration of T1D were 6.1 and 4.8 years, respectively. The proportion of participants with mildly decreased eGFR was similar regardless of eGFR equation, with 11% to 14% of participants with an eGFR <90 mL/min/1.73 m2. When analyzed as a function of duration of T1D, eGFR was 1.4 mL/min/1.73 m2 lower per year duration of T1D. CONCLUSIONS: A notable proportion of children with T1D demonstrates eGFR abnormalities early in their T1D course. This finding along with evidence of lower eGFR in adolescence is concerning for long-term risk of CKD and warrants systematic serum creatinine monitoring at diagnosis and regular intervals thereafter in children with T1D.

Social Contacts and Transmission of COVID-19 in British Columbia, Canada.

Background: Close-contact rates are thought to be a driving force behind the transmission of many infectious respiratory diseases. Yet, contact rates and their relation to transmission and the impact of control measures, are seldom quantified. We quantify the response of contact rates, reported cases and transmission of COVID-19, to public health contact-restriction orders, and examine the associations among these three variables in the province of British Columbia, Canada. Methods: We derived time series data for contact rates, daily cases and transmission of COVID-19 from a social contacts survey, reported case counts and by fitting a transmission model to reported cases, respectively. We used segmented regression to investigate impacts of public health orders; Pearson correlation to determine associations between contact rates and transmission; and vector autoregressive modeling to quantify lagged associations between contacts rates, daily cases, and transmission. Results: Declines in contact rates and transmission occurred concurrently with the announcement of public health orders, whereas declines in cases showed a reporting delay of about 2 weeks. Contact rates were a significant driver of COVID-19 and explained roughly 19 and 20% of the variation in new cases and transmission, respectively. Interestingly, increases in COVID-19 transmission and cases were followed by reduced contact rates: overall, daily cases explained about 10% of the variation in subsequent contact rates. Conclusion: We showed that close-contact rates were a significant time-series driver of transmission and ultimately of reported cases of COVID-19 in British Columbia, Canada and that they varied in response to public health orders. Our results also suggest possible behavioral feedback, by which increased reported cases lead to reduced subsequent contact rates. Our findings help to explain and validate the commonly assumed, but rarely measured, response of close contact rates to public health guidelines and their impact on the dynamics of infectious diseases.

Age-Associated Seroprevalence of Coronavirus Antibodies: Population-Based Serosurveys in 2013 and 2020, British Columbia, Canada.

Background: Older adults have been disproportionately affected during the SARS-CoV-2 pandemic, including higher risk of severe disease and long-COVID. Prior exposure to endemic human coronaviruses (HCoV) may modulate the response to SARS-CoV-2 infection and contribute to age-related observations. We hypothesized that cross-reactive antibodies to SARS-CoV-2 are associated with antibodies to HCoV and that both increase with age. Methods: To assess SARS-CoV-2 unexposed individuals, we drew upon archived anonymized residual sero-surveys conducted in British Columbia (BC), Canada, including before SARS-CoV-2 emergence (May, 2013) and before widespread community circulation in BC (May, 2020). Fifty sera, sex-balanced per ten-year age band, were sought among individuals ≤10 to ≥80 years old, supplemented as indicated by sera from March and September 2020. Sera were tested on the Meso Scale Diagnostics (MSD) electrochemiluminescent multiplex immunoassay to quantify IgG antibody against the Spike proteins of HCoV, including alpha (HCoV-229E, HCoV-NL63) and beta (HCoV-HKU1, HCoV-OC43) viruses, and the 2003 epidemic beta coronavirus, SARS-CoV-1. Cross-reactive antibodies to Spike, Nucleocapsid, and the Receptor Binding Domain (RBD) of SARS-CoV-2 were similarly measured, with SARS-CoV-2 sero-positivity overall defined by positivity on ≥2 targets. Results: Samples included 407 sera from 2013, of which 17 were children ≤10 years. The 2020 samples included 488 sera, of which 88 were children ≤10 years. Anti-Spike antibodies to all four endemic HCoV were acquired by 10 years of age. There were 20/407 (5%) sera in 2013 and 8/488 (2%) in 2020 that were considered sero-positive for SARS-CoV-2 based on MSD testing. Of note, antibody to the single SARS-CoV-2 RBD target was detected in 329/407 (81%) of 2013 sera and 91/488 (19%) of 2020 sera. Among the SARS-CoV-2 overall sero-negative population, age was correlated with anti-HCoV antibody levels and these, notably 229E and HKU1, were correlated with cross-reactive anti-SARS-CoV-2 RBD titres. SARS-CoV-2 overall sero-positive individuals showed higher titres to HCoV more generally. Conclusion: Most people have an HCoV priming exposure by 10 years of age and IgG levels are stable thereafter. Anti-HCoV antibodies can cross-react with SARS-CoV-2 epitopes. These immunological interactions warrant further investigation with respect to their implications for COVID-19 clinical outcomes.

Clinical characteristics, risk factors and outcomes in patients with severe COVID-19 registered in the International Severe Acute Respiratory and Emerging Infection Consortium WHO clinical characterisation protocol: a prospective, multinational, multicentre, observational study.

Due to the large number of patients with severe coronavirus disease 2019 (COVID-19), many were treated outside the traditional walls of the intensive care unit (ICU), and in many cases, by personnel who were not trained in critical care. The clinical characteristics and the relative impact of caring for severe COVID-19 patients outside the ICU is unknown. This was a multinational, multicentre, prospective cohort study embedded in the International Severe Acute Respiratory and Emerging Infection Consortium World Health Organization COVID-19 platform. Severe COVID-19 patients were identified as those admitted to an ICU and/or those treated with one of the following treatments: invasive or noninvasive mechanical ventilation, high-flow nasal cannula, inotropes or vasopressors. A logistic generalised additive model was used to compare clinical outcomes among patients admitted or not to the ICU. A total of 40 440 patients from 43 countries and six continents were included in this analysis. Severe COVID-19 patients were frequently male (62.9%), older adults (median (interquartile range (IQR), 67 (55-78) years), and with at least one comorbidity (63.2%). The overall median (IQR) length of hospital stay was 10 (5-19) days and was longer in patients admitted to an ICU than in those who were cared for outside the ICU (12 (6-23) days versus 8 (4-15) days, p<0.0001). The 28-day fatality ratio was lower in ICU-admitted patients (30.7% (5797 out of 18 831) versus 39.0% (7532 out of 19 295), p<0.0001). Patients admitted to an ICU had a significantly lower probability of death than those who were not (adjusted OR 0.70, 95% CI 0.65-0.75; p<0.0001). Patients with severe COVID-19 admitted to an ICU had significantly lower 28-day fatality ratio than those cared for outside an ICU.

A majority of uninfected adults show preexisting antibody reactivity against SARS-CoV-2.

Preexisting cross-reactivity to SARS-CoV-2 occurs in the absence of prior viral exposure. However, this has been difficult to quantify at the population level due to a lack of reliably defined seroreactivity thresholds. Using an orthogonal antibody testing approach, we estimated that about 0.6% of nontriaged adults from the greater Vancouver, Canada, area between May 17 and June 19, 2020, showed clear evidence of a prior SARS-CoV-2 infection, after adjusting for false-positive and false-negative test results. Using a highly sensitive multiplex assay and positive/negative thresholds established in infants in whom maternal antibodies have waned, we determined that more than 90% of uninfected adults showed antibody reactivity against the spike protein, receptor-binding domain (RBD), N-terminal domain (NTD), or the nucleocapsid (N) protein from SARS-CoV-2. This seroreactivity was evenly distributed across age and sex, correlated with circulating coronaviruses' reactivity, and was partially outcompeted by soluble circulating coronaviruses' spike. Using a custom SARS-CoV-2 peptide mapping array, we found that this antibody reactivity broadly mapped to spike and to conserved nonstructural viral proteins. We conclude that most adults display preexisting antibody cross-reactivity against SARS-CoV-2, which further supports investigation of how this may impact the clinical severity of COVID-19 or SARS-CoV-2 vaccine responses.

Evaluation of telephone and virtual visits for routine pediatric diabetes care during the COVID-19 pandemic.

AIMS: To evaluate pediatric type 1 diabetes telehealth visits during the COVID-19 pandemic, with a focus on assessing the usability of these visits and gathering patient perspectives. METHODS: An online survey, which included a validated telehealth usability questionnaire, was offered via email to families with a telephone or virtual visit since the COVID-19-related cancellation of routine in-person care. Survey data was linked with the British Columbia (BC) Clinical Diabetes Registry. Outcomes between groups were assessed using Welch's t-test. Associations with type of visit as well as with desire to return to in-person care were assessed with logistic regression models. RESULTS: The response rate was 47%. Of 141 survey respondents, 87 had clinical data available in the BC Clinical Diabetes Registry, and thus were included in our analysis. Overall, telephone and virtual visits were rated highly for usability. Telephone visits were easier to learn to use, and simpler to understand; however, telephone and virtual visits were similar across multiple areas. No factors associated with choosing one type of visit over the other, or with desire to return to in-person care, could be identified. 72% of participants want future telehealth care; however, some would like all future care to be in-person. CONCLUSIONS: Telephone and virtual visits had impressive usability. Many families want telehealth to play a significant part in their future care.

Opioid agonist treatment and risk of mortality during opioid overdose public health emergency: population based retrospective cohort study.

OBJECTIVE: To compare the risk of mortality among people with opioid use disorder on and off opioid agonist treatment (OAT) in a setting with a high prevalence of illicitly manufactured fentanyl and other potent synthetic opioids in the illicit drug supply. DESIGN: Population based retrospective cohort study. SETTING: Individual level linkage of five health administrative datasets capturing drug dispensations, hospital admissions, physician billing records, ambulatory care reports, and deaths in British Columbia, Canada. PARTICIPANTS: 55 347 people with opioid use disorder who received OAT between 1 January 1996 and 30 September 2018. MAIN OUTCOME MEASURES: All cause and cause specific crude mortality rates (per 1000 person years) to determine absolute risk of mortality and all cause age and sex standardised mortality ratios to determine relative risk of mortality compared with the general population. Mortality risk was calculated according to treatment status (on OAT, off OAT), time since starting and stopping treatment (1, 2, 3-4, 5-12, >12 weeks), and medication type (methadone, buprenorphine/naloxone). Adjusted risk ratios compared the relative risk of mortality on and off OAT over time as fentanyl became more prevalent in the illicit drug supply. RESULTS: 7030 (12.7%) of 55 347 OAT recipients died during follow-up. The all cause standardised mortality ratio was substantially lower on OAT (4.6, 95% confidence interval 4.4 to 4.8) than off OAT (9.7, 9.5 to 10.0). In a period of increasing prevalence of fentanyl, the relative risk of mortality off OAT was 2.1 (95% confidence interval 1.8 to 2.4) times higher than on OAT before the introduction of fentanyl, increasing to 3.4 (2.8 to 4.3) at the end of the study period (65% increase in relative risk). CONCLUSIONS: Retention on OAT is associated with substantial reductions in the risk of mortality for people with opioid use disorder. The protective effect of OAT on mortality increased as fentanyl and other synthetic opioids became common in the illicit drug supply, whereas the risk of mortality remained high off OAT. As fentanyl becomes more widespread globally, these findings highlight the importance of interventions that improve retention on opioid agonist treatment and prevent recipients from stopping treatment.

Whole blood genome-wide transcriptome profiling and metagenomics next-generation sequencing in young infants with suspected sepsis in a low-and middle-income country: A study protocol.

Conducting collaborative and comprehensive epidemiological research on neonatal sepsis in low- and middle-income countries (LMICs) is challenging due to a lack of diagnostic tests. This prospective study protocol aims to obtain epidemiological data on bacterial sepsis in newborns and young infants at Kamuzu Central Hospital in Lilongwe, Malawi. The main goal is to determine if the use of whole blood transcriptome host immune response signatures can help in the identification of infants who have sepsis of bacterial causes. The protocol includes a detailed clinical assessment with vital sign measurements, strict aseptic blood culture protocol with state-of-the-art microbial analyses and RNA-sequencing and metagenomics evaluations of host responses and pathogens, respectively. We also discuss the directions of a brief analysis plan for RNA sequencing data. This study will provide robust epidemiological data for sepsis in neonates and young infants in a setting where sepsis confers an inordinate burden of disease.