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Bacterial communities are highly complex, with interaction networks dictating ecosystem function. Bacterial interactions are constrained by the spatial organization of these microbial communities, yet studying the spatial organization of microbial communities at the single-cell level has been technically challenging. Here, we use the recently developed high-phylogenetic-resolution microbiota mapping by fluorescence in situ hybridization technology to image the gut microbiota at the species and single-cell level. We simultaneously image 63 different bacterial species to spatially characterize the perturbation and recovery of the gut microbiota to ampicillin and vancomycin in the cecum and distal colon of mice. To decipher the biology in this complex imaging data, we developed an analytical framework to characterize the spatial changes of the gut microbiota to a perturbation. The three-tiered analytical approach includes image-level diversity, pairwise colocalization analysis, and hypothesis-driven neighborhood analysis. Through this workflow, we identify biogeographic and antibiotic-based differences in the spatial organization of the gut microbiota. We demonstrate that the cecal microbiota has increased micrometer-scale diversity than the colon at baseline and recovers better from perturbation. Also, we identify potential foundation and keystone species that have high baseline neighborhood richness and that are associated with recovery from antibiotics. Through this workflow, we add a spatial layer to the characterization of bacterial communities and progress toward a better understanding of bacterial interactions leading to improved microbiome modulation strategies., Importance: Antibiotics have broad off-target effects on the gut microbiome. When the microbial community is unable to recover from antibiotics, it can lead to increased susceptibility to gastrointestinal infections and increased risk of immunological and metabolic diseases. In this study, we work to better understand how the gut microbiota recovers from antibiotics by employing a recent technology to image the entire bacterial community at once. Through this approach, we characterize the spatial changes in the gut microbiota after treatment with model antibiotics in both the cecum and colon of mice. We find antibiotic- and biogeographic-dependent spatial changes between bacterial species and that many of these spatial colocalizations do not recover to baseline levels even 35 days after antibiotic administration., Competing Interests: All authors that are present or former employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, may hold stocks and/or stock options in Merck & Co., Inc., Rahway, NJ. H.S. and M.P.C. are co-founders of Kanvas Biosciences; the current work does not have a conflict.

Broad-range 16S rRNA PCR and sequencing of 1,183 blood specimens from 853 unique patients yielded an interpretable sequence and bacterial identification in 29%, 16S rRNA amplification with uninterpretable sequences in 53%, and no amplification in 18%. This study highlights the potential utility of this technique in identifying fastidious gram-negative and anaerobic bacteria but the frequent recovery of environmental and contaminant organisms argues for its judicious use., Importance: The existing literature focuses on its performance compared to blood cultures in patients with sepsis, leaving a gap in the literature regarding other blood specimens in suspected infectious syndrome across the severity spectrum. We aimed to characterize its microbiological outcomes and provide insight into its potential clinical utility., Competing Interests: Unrelated to this study, Dr. Cheng reports grants from the Canadian Institutes of Health Research during the conduct of the study and is supported by the Fonds de Recherche du Québec—Santé. He reports personal fees from GEn1E Lifesciences and from nomic bio as a member of the scientific advisory board, as well as honoraria from AstraZeneca, Takeda, Merck, and Pfizer. He reports research support from Cidara Therapeutics, from Scynexis, Inc., and from Amplyx Pharmaceutics during the conduct of the study but outside the submitted work. Dr. Cheng is the co-founder of Kanvas Biosciences, Inc., and owns equity in the company. Dr. Cheng has pending patents, including (i) Methods for detecting tissue damage, graft versus host disease, and infections using cell-free DNA profiling, (ii) Methods for assessing the severity and progression of SARS-CoV-2 infections using cell-free DNA pending, and (iii) Rapid identification of antimicrobial resistance and other microbial phenotypes using highly multiplexed fluorescence in situ hybridization.

Abstract: Venetoclax is a small molecule inhibitor of BCL-2 used in the treatment of acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL). Recent postmarketing studies of ibrutinib, another small molecule inhibitor, suggested that these agents may predispose to opportunistic infections. We sought to systematically review the randomized controlled trial (RCT) evidence of venetoclax to assess whether it predisposes patients to infectious adverse events (IAEs) and neutropenia. We systematically reviewed RCTs comparing venetoclax therapy with active or placebo controls for patients with hematologic malignancies. Data on IAEs and neutropenia were pooled by Bayesian meta-analysis, and we computed the probability of any increased risk (P[risk ratio (RR) > 1]) of IAEs or neutropenic complications. Seven RCTs were included, comprising 2067 patients. In CLL (n = 1032), there was a low probability of increased risk of high-grade (P[RR > 1] = 71.2%) and fatal IAEs (P[RR > 1] = 64.5%) and high-grade neutropenia (P[RR > 1] = 63.4%). There were insufficient data to perform a meta-analysis of IAEs in AML; however, 1 trial suggested an increased risk of IAEs with venetoclax. Furthermore, in AML (n = 642), venetoclax was associated with a high probability of increased risk of high-grade neutropenia (P[RR > 1] = 94.6%) and febrile neutropenia (P[RR > 1] = 90.6%). Our results suggest that venetoclax has a low probability of increased risk of IAEs or neutropenia in CLL. By contrast, there is likely increased risk of high-grade neutropenia and febrile neutropenia in AML. Importantly, our analyses did not identify any specific IAEs that would benefit from routine antimicrobial prophylaxis or pre-emptive testing., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Rationale: Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair., Objective: To map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis., Methods: We analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC-MS/MS and DI-MS/MS analytical platforms., Results: Distinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms., Conclusion: Different metabolic phenotypes characterize ARDS associated with different viral and bacterial infections., (© 2024. The Author(s).)

Many COVID-19 survivors have post-COVID-19 conditions, and females are at a higher risk. We sought to determine (1) how protein levels change from acute to post-COVID-19 conditions, (2) whether females have a plasma protein signature different from that of males, and (3) which biological pathways are associated with COVID-19 when compared to restrictive lung disease. We measured protein levels in 74 patients on the day of admission and at 3 and 6 months after diagnosis. We determined protein concentrations by multiple reaction monitoring (MRM) using a panel of 269 heavy-labeled peptides. The predicted forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) were measured by routine pulmonary function testing. Proteins associated with six key lipid-related pathways increased from admission to 3 and 6 months; conversely, proteins related to innate immune responses and vasoconstriction-related proteins decreased. Multiple biological functions were regulated differentially between females and males. Concentrations of eight proteins were associated with FVC, %, and they together had c -statistics of 0.751 (CI:0.732-0.779); similarly, concentrations of five proteins had c -statistics of 0.707 (CI:0.676-0.737) for DLCO, %. Lipid biology may drive evolution from acute to post-COVID-19 conditions, while activation of innate immunity and vascular regulation pathways decreased over that period. (ProteomeXchange identifiers: PXD041762, PXD029437).

Background and Objectives: In this proof-of-concept study, which included blood donor samples, we aimed to demonstrate how Bayesian latent class models (BLCMs) could be used to estimate SARS-CoV-2 seroprevalence in the absence of a gold standard assay under a two-phase sampling design., Materials and Methods: To this end, 6810 plasma samples from blood donors who resided in Québec (Canada) were collected from May to July 2020 and tested for anti-SARS-CoV-2 antibodies using seven serological assays (five commercial and two non-commercial)., Results: SARS-CoV-2 seroprevalence was estimated at 0.71% (95% credible interval [CrI] = 0.53%-0.92%). The cPass assay had the lowest sensitivity estimate (88.7%; 95% CrI = 80.6%-94.7%), while the Héma-Québec assay had the highest (98.7%; 95% CrI = 97.0%-99.6%)., Conclusion: The estimated low seroprevalence (which indicates a relatively limited spread of SARS-CoV-2 in Quebec) might change rapidly-and this tool, developed using blood donors, could enable a rapid update of the prevalence estimate in the absence of a gold standard. Further, the present analysis illustrates how a two-stage BLCM sampling design, along with blood donor samples, can be used to estimate the performance of new diagnostic tests and inform public health decisions regarding a new or emerging disease for which a perfect reference standard does not exist., (© 2023 International Society of Blood Transfusion.)

Bronchoalveolar lavage is usually employed for molecular diagnosis of Pneumocystis jirovecii but requires a specialized procedure. By contrast, nasopharyngeal (NP) specimens are easily obtained. In this retrospective study of 35 patients with paired NP and bronchoscopy specimens, NP specimens had a 100% negative percent agreement (95% CI 80.5-100) but only 72.2% positive percent agreement (95% CI 46.5-90.3)., Competing Interests: The authors declare no conflict of interest.

Background: Staphylococcus aureus bloodstream infection (bacteraemia) is traditionally treated with at least two weeks of IV antibiotics in adults, 3-7 days in children, and often longer for those with complicated disease. The current practice of treating S. aureus bacteraemia (SAB) with prolonged IV antibiotics (rather than oral antibiotics) is based on historical observational research and expert opinion. Prolonged IV antibiotic therapy has significant disadvantages for patients and healthcare systems, and there is growing interest in whether a switch to oral antibiotics following an initial period of IV therapy is a safe alternative for clinically stable patients., Protocol: The early oral switch (EOS) domain of the S. aureus Network Adaptive Platform (SNAP) trial will assess early switch to oral antibiotics compared with continued IV treatment in clinically stable patients with SAB. The primary endpoint is 90-day all-cause mortality. Hospitalised SAB patients are assessed at platform day 7 +/- 2 (uncomplicated SAB) and day 14 +/-2 (complicated SAB) to determine their eligibility for randomisation to EOS (intervention) or continued IV treatment (current standard of care)., Discussion: Recruitment is occurring to the EOS domain of the SNAP trial. As of August 2023, 21% of all SNAP participants had been randomised to the EOS domain, a total of 264 participants across 77 centres, with an aim to recruit at least 1000 participants. We describe challenges and facilitators to enrolment in this domain to aid those planning similar trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Omicron is the current predominant variant of concern of SARS-CoV-2. We hypothesized that vaccination alters outcomes of patients hospitalized with COVID-19 during the Omicron wave and that these patients have different characteristics and outcomes than in previous waves., Methods: This is a substudy of the Host Response Mediators in Coronavirus (COVID-19) Infection (ARBs CORONA I) trial, which included adults admitted to hospital with acute COVID-19 up to July 2022 from 9 hospitals in British Columbia, Ontario and Quebec. We excluded emergency department visits without hospital admission, readmissions and admissions for another reason. Using adjusted regression analysis, we compared mortality and organ dysfunction between vaccinated (≥ 2 doses) and unvaccinated patients during the Omicron wave, as well as between all patients in the Omicron and first 3 waves of the COVID-19 pandemic., Results: During the Omicron wave, 28-day mortality was significantly lower in vaccinated ( n = 19/237) than unvaccinated hospitalized patients ( n = 12/127) (adjusted odds ratio [OR] 0.36, 95% confidence interval [CI] 0.15-0.89); vaccinated patients had lower risk of admission to the intensive care unit, invasive ventilation and acute respiratory distress syndrome and shorter hospital length of stay. Patients hospitalized during the Omicron wave had more comorbidities than in previous waves, and lower 28-day mortality than in waves 1 and 2 (adjusted OR 0.38, 95% CI 0.24-0.59; and 0.42, 95% CI 0.26-0.65) but not wave 3 (adjusted OR 0.81, 95% CI 0.43-1.51) and had less organ dysfunction than in the first 2 waves., Interpretation: Patients who were at least double vaccinated had lower mortality than unvaccinated patients hospitalized during the Omicron wave. Patients hospitalized during the Omicron wave had more chronic disease and lower mortality than in the first 2 waves, but not wave 3. Changes in vaccination, treatments and predominant SARS-CoV-2 variant may have decreased mortality in patients hospitalized during the Omicron wave., Competing Interests: Competing interests: Keith Walley reports receiving a Canadian Institutes of Health Research (CIHR) Foundation grant, paid to the University of British Columbia. Dr. Walley has also participated on data safety monitoring boards (unpaid) for Northern Therapeutics and the Cellular Immuno-Therapy for COVID-19 Acute Respiratory Distress Syndrome (CIRCA-19) trial. Allison McGeer reports receiving grants from Sanofi, Merck and Pfizer (paid to institution), as well as payment or honoraria from AstraZeneca, Merck, Biogen and Moderna. Dr. McGeer has also received travel support from Moderna and has participated on a data safety monitoring or advisory board for Pfizer, GlaxoSmithKline, Moderna, Medicago, Janssen, AstraZeneca, Novavax and Sanofi., (© 2023 CMA Impact Inc. or its licensors.)

Objectives: There is clinical uncertainty over the optimal treatment for penicillin-susceptible Staphylococcus aureus (PSSA) infections. Furthermore, there is concern that phenotypic penicillin susceptibility testing methods are not reliably able to detect some blaZ-positive S. aureus., Methods: Nine S. aureus isolates, including six genetically diverse strains harbouring blaZ, were sent in triplicate to 34 participating laboratories from Australia (n = 14), New Zealand (n = 6), Canada (n = 12), Singapore (n = 1) and Israel (n = 1). We used blaZ PCR as the gold standard to assess susceptibility testing performance of CLSI (P10 disc) and EUCAST (P1 disc) methods. Very major errors (VMEs), major error (MEs) and categorical agreement were calculated., Results: Twenty-two laboratories reported 593 results according to CLSI methodology (P10 disc). Nineteen laboratories reported 513 results according to the EUCAST (P1 disc) method. For CLSI laboratories, the categorical agreement and calculated VME and ME rates were 85% (508/593), 21% (84/396) and 1.5% (3/198), respectively. For EUCAST laboratories, the categorical agreement and calculated VME and ME rates were 93% (475/513), 11% (84/396) and 1% (3/198), respectively. Seven laboratories reported results for both methods, with VME rates of 24% for CLSI and 12% for EUCAST., Conclusions: The EUCAST method with a P1 disc resulted in a lower VME rate compared with the CLSI methods with a P10 disc. These results should be considered in the context that among collections of PSSA isolates, as determined by automated MIC testing, less than 10% harbour blaZ. Furthermore, the clinical relevance of phenotypically susceptible, but blaZ-positive S. aureus, remains unclear., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Viral respiratory tract infections (VRTI) are extremely common. Considering the profound social and economic impact of COVID-19, it is imperative to identify novel mechanisms for early detection and prevention of VRTIs, to prevent future pandemics. Wearable biosensor technology may facilitate this. Early asymptomatic detection of VRTIs could reduce stress on the healthcare system by reducing transmission and decreasing the overall number of cases. The aim of the current study is to define a sensitive set of physiological and immunological signature patterns of VRTI through machine learning (ML) to analyze physiological data collected continuously using wearable vital signs sensors., Methods: A controlled, prospective longitudinal study with an induced low grade viral challenge, coupled with 12 days of continuous wearable biosensors monitoring surrounding viral induction. We aim to recruit and simulate a low grade VRTI in 60 healthy adults aged 18-59 years via administration of live attenuated influenza vaccine (LAIV). Continuous monitoring with wearable biosensors will include 7 days pre (baseline) and 5 days post LAIV administration, during which vital signs and activity-monitoring biosensors (embedded in a shirt, wristwatch and ring) will continuously monitor physiological and activity parameters. Novel infection detection techniques will be developed based on inflammatory biomarker mapping, PCR testing, and app-based VRTI symptom tracking. Subtle patterns of change will be assessed via ML algorithms developed to analyze large datasets and generate a predictive algorithm., Conclusion: This study presents an infrastructure to test wearables for the detection of asymptomatic VRTI using multimodal biosensors, based on immune host response signature. CliniclTrials.govregistration:NCT05290792., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Background: Coccidioidomycosis is a fungal infection with presentations ranging from asymptomatic illness to severe pneumonia and respiratory failure. The outcomes of patients with severe pulmonary coccidioidomycosis requiring mechanical ventilation (MV) are not well understood., Methods: We performed a retrospective cohort analysis utilizing the Nationwide Inpatient Sample (NIS) from 2006 to 2017. Patients >18 years of age with a diagnosis of pulmonary coccidioidomycosis were included in the cohort., Results: A total of 11,045 patients were hospitalized with a diagnosis of pulmonary coccidioidomycosis during the study period. Of these, 826 (7.5%) patients required MV during their hospitalization with a mortality rate of 33.5% compared to 1.3% ( p < 0.01) for patients not requiring MV. Results of the multivariable logistic regression model show that risk factors for MV included the history of neurological disorders and paralysis (OR 3.38[95% CI 2.70 to 4.20] p < 0.01; OR 3.13[95% CI 1.91 to 5.15] p < 0.01, respectively) and HIV (OR 1.63[95% 1.10 to 2.43] p < 0.01). Risk factors for mortality among patients requiring MV included older age (OR 1.24 per 10-year increase[95% CI 1.08 to 1.42] p < 0.01), coagulopathy (OR 1.61[95% CI 1.09 to 2.38] p = 0.01) and HIV (OR 2.83 [95% CI 1.32 to 6.10] p < 0.01)., Conclusions: Approximately 7.5% of patients admitted with coccidioidomycosis in the United States require MV, and MV is associated with high mortality (33.5%)., (© Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada), 2023.)

A new esterase gene, est6 , was discovered in an activated sludge metagenomic library. The 729-bp gene encodes a 242-amino acid protein (designated Est6) with a molecular mass of 26.1 kDa. Est6 shared only a moderate identity to a putative hydrolase with the highest BLASTP analysis score. Most of the closely related proteins are uncharacterized and are predicted from genome sequencing data of microorganisms or metagenomic DNA sequences. The phylogenetic analysis of Est6 showed that the protein was assigned to family VI esterases/lipases. The catalytic triad of Est6 was predicted to be Ser135, Asp188, and His219, with Ser135 in a typically conserved pentapeptide (GFSQG) of family VI members, which was further confirmed by site-directed mutagenesis. The est6 gene was overexpressed successfully in its soluble form in Escherichia coli and then purified to its tag-free form and homogeneity by affinity chromatography. The purified Est6 in pH 8.0 buffer was active as a monomer. The optimal conditions for Est6 activity were at a temperature of 45 °C and pH of 8.0 when using p-nitrophenyl acetate as a substrate. The enzyme was stable over wide temperature and pH ranges, and it exhibited activity in the presence of organic solvents, metal cations, or detergents. Furthermore, the enzyme showed significant regioselectivity in the spectrophotometric analysis. In conclusion, Est6 might have the potential for applications in biotechnological processes.

Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%-30%. Despite this, <3000 people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target sample size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes., Competing Interests: Potential conflicts of interest. A. M. is an employee of Berry Consultants LLC, in which capacity she is contracted as a consultant to numerous pharmaceutical and device companies on topics of statistical modeling and trial design, and reports grants and contracts unrelated to this work and consulting fees from Berry Consultants LLC. A. C. B. reports participation as a member of the CAMERA-2 data and safety monitoring board (DSMB) and as chair of the Skin Trial DSMB; a role as Vice President of the World Society of Pediatric Infectious Diseases and as Co-Chair, Australian and New Zealand Paediatric Infectious Diseases group of the Australasian Society of Infectious Diseases (ASID). D. L. P. reports grants or contracts made to institution and unrelated to this work from Shionogi, Merck, and Pfizer; consulting fees to author from Antimicrobial Resistance Action Fund and Spero Therapeutics; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events to author from Pfizer and Merck; support for attending meetings and/or travel to author from Pfizer; and an unpaid leadership or fiduciary role with ASID. J. A. R. reports contracts or grants paid to institution and unrelated to this work from the British Society of Antimicrobial Chemotherapy, bioMérieux, Pfizer, and QPEX; consulting fees paid to author from Gilead, Pfizer, Sandoz, Wolters Kluwer, Summit Pharma, and MSD; payment to author for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from MSD, Pfizer, and Cipla; an unpaid leadership or fiduciary role with Sepsis Clinical Care Standard, Australian Commission on Safety and Quality in Health Care, Consensus Guidelines on Prolonged Infusion of Beta-Lactam Antibiotics, American College of Clinical Pharmacy, Disease Modifying Treatment and Chemoprophylaxis, Australian National COVID-19 Clinical Evidence Taskforce, and Surviving Sepsis Guidelines. M. P. C. reports research support from the McGill Interdisciplinary Initiative in Infection and Immunity; research contracts from Cidara Therapeutics, Scynexis, and Amplyx; consulting fees as a scientific consultant for AstraZeneca; 3 pending patents (Methods for detecting tissue damage, graft-versus-host disease, and infections using cell-free DNA profiling; Methods for assessing the severity and progression of SARS-CoV-2 infections using cell-free DNA; and rapid identification of antimicrobial resistance and other microbial phenotypes using highly-multiplexed fluorescence in situ hybridization); stock options as a member of the scientific advisory board for GEn1E Lifesciences and Nomic Bio; and equity as co-founder of Kanvas Biosciences. R. J. L. is an employee of Berry Consultants, LLC, a statistical consulting firm that specializes in the design of adaptive and platform clinical trials. Berry Consultants received compensation for work included in the content of the submission. S. A. W. reports personal consulting fees from ClinicIQ pharma and Roche; an unpaid role as chair of Australian Clinical Trials Alliance; and stock and options with ClinicIQ. S. Y. C. T. reports a contract as a paid consultant for advice on clinical trial design, and consulting fees from Roivant Sciences as a paid consultant for advice on clinical trial design. T. C. L. reports research salary support from Fonds de Recherche Quebec–Sante, operating funds for other studies including CATCO from the CIHR; and operating funds for other studies from the McGill Interdisciplinary Institute Infection and Immunity. S. C. M. reports grants or contracts unrelated to this work from the HRC, and a nonremunerated role as the Chair of the New Zealand Microbiology Network. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Bloodstream infections in septic patients may be missed due to preceding antibiotic therapy prior to obtaining blood cultures. We leveraged the FABLED cohort study to determine if the quick Sequential Organ Failure Assessment (qSOFA) score could reliably identify patients at higher risk of bacteremia in patients who may have false negative blood cultures due to previously administered antibiotic therapy., Methods: We conducted a multi-centre diagnostic study among adult patients with severe manifestations of sepsis. Patients were enrolled in one of seven participating centres between November 2013 and September 2018. All patients from the FABLED cohort had two sets of blood cultures drawn prior to the administration of antimicrobial therapy, as well as additional blood cultures within 4 hours of treatment initiation. Participants were categorized according to qSOFA score, with a score ≥2 being considered positive., Results: Among 325 patients with severe manifestations of sepsis, a positive qSOFA score (defined as a score ≥2) on admission was 58% sensitive (95% CI 48% to 67%) and 41% specific (95% CI 34% to 48%) for predicting bacteremia. Among patients with negative post-antimicrobial blood cultures, a positive qSOFA score was 57% sensitive (95% CI 42% to 70%) and 42% specific (95% CI 35% to 49%) to detect patients who were originally bacteremic prior to the initiation of therapy., Conclusions: Our results suggest that the qSOFA score cannot be used to identify patients at risk for occult bacteremia due to the administration of antibiotics pre-blood culture., Competing Interests: The authors have nothing to disclose., (Copyright © 2022, Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada).)

As the SARS-CoV-2 pandemic evolves, vaccine evaluation needs to include consideration of both durability and cross-reactivity. This report expands on previously reported results from a Phase 1 trial of an AS03-adjuvanted, plant-based coronavirus-like particle (CoVLP) displaying the spike (S) glycoprotein of the ancestral SARS-CoV-2 virus in healthy adults (NCT04450004). Humoral and cellular responses against the ancestral strain were evaluated 6 months post-second dose (D201) as secondary outcomes. Independent of dose, all vaccinated individuals retain binding antibodies, and ~95% retain neutralizing antibodies (NAb). Interferon gamma and interleukin-4 responses remain detectable in ~94% and ~92% of vaccinees respectively. In post-hoc analyses, variant-specific (Alpha, Beta, Delta, Gamma and Omicron) NAb were assessed at D42 and D201. Using a live virus neutralization assay, broad cross-reactivity is detectable against all variants at D42. At D201, cross-reactive antibodies are detectable in almost all participants against Alpha, Gamma and Delta variants (94%) and the Beta variant (83%) and in a smaller proportion against Omicron (44%). Results are similar with the pseudovirion assay. These data suggest that two doses of 3.75 µg CoVLP+AS03 elicit a durable and cross-reactive response that persists for at least 6 months post-vaccination., (© 2022. The Author(s).)

Background: Our understanding of the global scale of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection remains incomplete: Routine surveillance data underestimate infection and cannot infer on population immunity; there is a predominance of asymptomatic infections, and uneven access to diagnostics. We meta-analyzed SARS-CoV-2 seroprevalence studies, standardized to those described in the World Health Organization's Unity protocol (WHO Unity) for general population seroepidemiological studies, to estimate the extent of population infection and seropositivity to the virus 2 years into the pandemic., Methods and Findings: We conducted a systematic review and meta-analysis, searching MEDLINE, Embase, Web of Science, preprints, and grey literature for SARS-CoV-2 seroprevalence published between January 1, 2020 and May 20, 2022. The review protocol is registered with PROSPERO (CRD42020183634). We included general population cross-sectional and cohort studies meeting an assay quality threshold (90% sensitivity, 97% specificity; exceptions for humanitarian settings). We excluded studies with an unclear or closed population sample frame. Eligible studies-those aligned with the WHO Unity protocol-were extracted and critically appraised in duplicate, with risk of bias evaluated using a modified Joanna Briggs Institute checklist. We meta-analyzed seroprevalence by country and month, pooling to estimate regional and global seroprevalence over time; compared seroprevalence from infection to confirmed cases to estimate underascertainment; meta-analyzed differences in seroprevalence between demographic subgroups such as age and sex; and identified national factors associated with seroprevalence using meta-regression. We identified 513 full texts reporting 965 distinct seroprevalence studies (41% low- and middle-income countries [LMICs]) sampling 5,346,069 participants between January 2020 and April 2022, including 459 low/moderate risk of bias studies with national/subnational scope in further analysis. By September 2021, global SARS-CoV-2 seroprevalence from infection or vaccination was 59.2%, 95% CI [56.1% to 62.2%]. Overall seroprevalence rose steeply in 2021 due to infection in some regions (e.g., 26.6% [24.6 to 28.8] to 86.7% [84.6% to 88.5%] in Africa in December 2021) and vaccination and infection in others (e.g., 9.6% [8.3% to 11.0%] in June 2020 to 95.9% [92.6% to 97.8%] in December 2021, in European high-income countries [HICs]). After the emergence of Omicron in March 2022, infection-induced seroprevalence rose to 47.9% [41.0% to 54.9%] in Europe HIC and 33.7% [31.6% to 36.0%] in Americas HIC. In 2021 Quarter Three (July to September), median seroprevalence to cumulative incidence ratios ranged from around 2:1 in the Americas and Europe HICs to over 100:1 in Africa (LMICs). Children 0 to 9 years and adults 60+ were at lower risk of seropositivity than adults 20 to 29 (p < 0.001 and p = 0.005, respectively). In a multivariable model using prevaccination data, stringent public health and social measures were associated with lower seroprevalence (p = 0.02). The main limitations of our methodology include that some estimates were driven by certain countries or populations being overrepresented., Conclusions: In this study, we observed that global seroprevalence has risen considerably over time and with regional variation; however, over one-third of the global population are seronegative to the SARS-CoV-2 virus. Our estimates of infections based on seroprevalence far exceed reported Coronavirus Disease 2019 (COVID-19) cases. Quality and standardized seroprevalence studies are essential to inform COVID-19 response, particularly in resource-limited regions., Competing Interests: I have read the journal policy and the authors of this manuscript have the following competing interests: RKA, MW, HW, ZL, XM, CC, MYL, DB, JP, MPC, ML, MS, GRD, NI, CZ, SP, HPR, TY, KCN, DK, SAA, ND, CD, NAD, EL, RKI, ASB, ELB, AS, JC and NB report grants from Canada’s COVID-19 Immunity Task Force through the Public Health Agency of Canada, and the Canadian Medical Association Joule Innovation Fund. RKA, MW, HW, ZL, CC, MYL, NB also report grants from the World Health Organisation and the Robert Koch Institute. RKA reports personal fees from the Public Health Agency of Canada and the Bill and Melinda Gates Foundation Strategic Investment Fund, as well as equity in Alethea Medical (Outside the submitted work). MPC reports grants from McGill Interdisciplinary Initiative in Infection and Immunity and Canadian Institute of Health Research, and personal fees from GEn1E Lifesciences (Outside the submitted work), nplex biosciences (Outside the submitted work), Kanvas biosciences (Outside the submitted work). JP reports grants from MedImmune (Outside the submitted work) and Sanofi-Pasteur (Outside the submitted work), grants and personal fees from Merck (Outside the submitted work) and AbbVie (Outside the submitted work), and personal fees from AstraZeneca (Outside the submitted work). DB reports grants from the World Health Organization, Canadian Institutes of Health Research, Natural Sciences and Engineering Council of Canada (Outside the submitted work), Institute national d excellence en sante et service sociaux (Outside the submitted work), and personal fees from McGill University Health Centre (Outside the submitted work) and Public Health Agency of Canada (Outside the submitted work). CC reports funding from Sanofi Pasteur (Outside of the submitted work). TY reports working for Health Canada as a part-time Senior Policy Analyst with the COVID-19 Testing and Screening Expert Panel, from Nov 2020-Jun 2021 (Outside of the submitted work). TH reports funding recieved from the United States Centers for Disease Control and Prevention for Columbia University (Outside of the submitted work). Author HCL declares receiving funding as a WHO consultant from WHO Solidarity Response Fund and the German Federal Ministry of Health COVID-19 Research and Development., (Copyright: © 2022 Bergeri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Correctional workers are at increased risk of SARS-CoV-2 infection. We examined the seroprevalence of SARS-CoV-2, determined the effects of carceral and occupational exposures on seropositivity, and explored predictors of COVID-19 vaccine uptake among correctional workers in Quebec, Canada., Methods: We conducted a cross-sectional seroprevalence study in three provincial prisons. The primary and secondary outcomes were SARS-CoV-2 antibody seropositivity (Roche Elecsys ® serology test) and self-reported COVID-19 vaccination status ("fully vaccinated" defined as two doses or prior infection plus one dose), respectively. Poisson regression models with robust standard error were used to examine the effect of occupational variables with SARS-CoV-2 seropositivity and predictors of COVID-19 vaccine uptake. Estimates are presented as crude and adjusted prevalence ratios (aPR) with 95% confidence intervals (95% CI)., Results: From 14 July to 15 November 2021, 105/600 (18%) correctional workers tested positive across three prisons (range 11-21%); 76% were fully vaccinated. Seropositivity was affected by prison occupation (aPR 1.59, 95% CI 1.11-2.27 for correctional officers vs. all other occupations) and low perceived concern of SARS-CoV-2 acquisition (aPR 1.62, 95% CI 1.11-2.38 for not/hardly worried vs. somewhat/extremely worried). Predictors of being fully vaccinated included race/ethnicity (aPR 0.86, 95% CI 0.76-0.99 for visible minority vs. White), presence of comorbidities (aPR 1.14, 95% CI 1.02-1.28 for > 2 vs. none), and prison occupation (aPR 0.82, 95% CI 0.73-0.92 for correctional officers vs. all other occupations)., Conclusions: Correctional officers were most likely to have acquired SARS-CoV-2, but least likely to be vaccinated, underscoring the importance of addressing both occupational risks and COVID-19 vaccine hesitancy to mitigate future outbreaks., Competing Interests: Author NK reports research funding from Gilead Sciences, advisory fees from Gilead Sciences, ViiV Healthcare, Merck and Abbvie, and speaker fees from Gilead Sciences, Abbvie and Merck, all outside of the submitted work. Author MM-G reports an investigator-sponsored research grant from Gilead Sciences Inc. Author MM-G reports contractual arrangements with the World Health Organization, the Institut national de santé publique du Québec, and the Institut 19 d'excellence en santé et services sociaux du Québec, all outside of the submitted work. Author MC reports grants from the McGill Interdisciplinary Initiative in Infection and Immunity and from the Canadian Institutes of Health Research. Author MC reports personal fees from GEn1E Lifesciences and form nplex biosciences, both outside the submitted work. Author MC is the co-founder of Kanvas Biosciences, Inc. and owns equity in the company. Author MC has a pending patent for Methods for detecting tissue damage, graft versus host disease, and infections using cell-free DNA profiling pending, and a pending patent for Methods for assessing the severity and progression of SARS-CoV-2 infections using cell-free DNA. Author JC has research funding from ViiV Healthcare and Gilead Sciences, and reports remuneration for advisory work (ViiV Healthcare, Gilead Sciences and Merck Canada), outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kronfli, Dussault, Maheu-Giroux, Halavrezos, Chalifoux, Park, Balso, Cheng and Cox.)

The rapid spread of SARS-CoV-2 continues to impact humanity on a global scale with rising total morbidity and mortality. Despite the development of several effective vaccines, new products are needed to supply ongoing demand and to fight variants. We report herein a pre-specified interim analysis of the phase 2 portion of a Phase 2/3, randomized, placebo-controlled trial of a coronavirus virus-like particle (CoVLP) vaccine candidate, produced in plants that displays the SARS-CoV-2 spike glycoprotein, adjuvanted with AS03 (NCT04636697). A total of 753 participants were recruited between 25th November 2020 and 24th March 2021 into three groups: Healthy Adults (18-64 years: N = 306), Older Adults (≥65 years: N = 282) and Adults with Comorbidities (≥18 years: N = 165) and randomized 5:1 to receive two intramuscular doses of either vaccine (3.75 µg CoVLP/dose+AS03) or placebo, 21 days apart. This report presents safety, tolerability and immunogenicity data up to 6 months post-vaccination. The immune outcomes presented include neutralizing antibody (NAb) titres as measured by pseudovirion assay at days 21 and 42 as well as neutralizing antibody cross-reactivity to several variants of concern (VOCs): Alpha, Beta, Gamma, Delta, and Omicron (BA.1), up to 201 days post-immunization. Cellular (IFN-γ and IL-4 ELISpot) response data in day 21 and 42 peripheral blood are also presented. In this study, CoVLP+AS03 was well-tolerated and adverse events (AE) after each dose were generally mild to moderate and transient. Solicited AEs in Older Adults and Adults with Comorbidities were generally less frequent than in Healthy Adults and the reactogenicity was higher after the second dose. CoVLP+AS03 induced seroconversion in &gt;35% of participants in each group after the first dose and in ~98% of participants, 21 days after the second dose. In all cohorts, 21-days after the second dose, NAb levels in sera against the vaccine strain were ~10-times those in a panel of convalescent sera. Cross-reactivity to Alpha, Beta and Delta variants was generally retained to day 201 (&gt;80%) while cross-reactivity to the Gamma variant was reduced but still substantial at day 201 (73%). Cross-reactivity to the Omicron variant fell from 72% at day 42 to 20% at day 201. Almost all participants in all groups (&gt;88%) had detectable cellular responses (IFN-γ, IL-4 or both) at 21 days after the second dose. A Th1-biased response was most evident after the first dose and was still present after the second dose. These data demonstrated that CoVLP+AS03 is well-tolerated and highly immunogenic, generating a durable (at least 6 months) immune response against different VOCs, in adults ≥18 years of age, with and without comorbidities., (© 2022. The Author(s).)

Public health vaccination recommendations for COVID-19 primary series and boosters in previously infected individuals differ worldwide. As infection with SARS-CoV-2 is often asymptomatic, it remains to be determined if vaccine immunogenicity is comparable in all previously infected subjects. This study presents detailed immunological evidence to clarify the requirements for one- or two-dose primary vaccination series for naturally primed individuals. The main objective was to evaluate the immune response to COVID-19 mRNA vaccination to establish the most appropriate vaccination regimen to induce robust immune responses in individuals with prior SARS-CoV-2 infection. The main outcome measure was a functional immunity score (zero to three) before and after vaccination, based on anti-RBD IgG levels, serum capacity to neutralize live virus and IFN-γ secretion capacity in response to SARS-CoV-2 peptide pools. One point was attributed for each of these three functional assays with response above the positivity threshold. The immunity score was compared based on subjects' symptoms at diagnosis and/or serostatus prior to vaccination. None of the naïve participants (n=14) showed a maximal immunity score of three following one dose of vaccine compared to 84% of the previously infected participants (n=55). All recovered individuals who did not have an immunity score of three were seronegative prior to vaccination, and 67% had not reported symptoms resulting from their initial infection. Following one dose of vaccine, their immune responses were comparable to naïve individuals, with significantly weaker responses than individuals who were symptomatic during infection. These results indicate that the absence of symptoms during initial infection and negative serostatus prior to vaccination predict the strength of immune responses to COVID-19 mRNA vaccine. Altogether, these findings highlight the importance of administering the complete two-dose primary regimen and following boosters of mRNA vaccines to individuals who experienced asymptomatic SARS-CoV-2 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nantel, Bourdin, Adams, Carbonneau, Rabezanahary, Hamelin, McCormack, Savard, Longtin, Cheng, De Serres, Corbeil, Gilca, Baz, Boivin, Quach and Decaluwe.)

In Staphylococcus aureus bacteremia, mortality rates in randomized controlled trials (RCTs) are consistently lower than observational studies. Stringent eligibility criteria and omission of early deaths in RCTs contribute to this mortality gap. Clinicians should acknowledge the possibility of a lower treatment effect when applying RCT results to bedside care., Competing Interests: Potential conflicts of interest. M. P. C. reports grants from McGill Interdisciplinary Initiative in Infection and Immunity and grants from Canadian Institutes of Health Research during the conduct of the study; personal fees from GEn1E Lifesciences (as a member of the scientific advisory board) and personal fees from nplex biosciences (as a member of the scientific advisory board) and consulting fees from Astra Zaneca outside the submitted work. He is the co-founder of Kanvas Biosciences and owns equity in the company. In addition, M. P. C. has a patent Methods for detecting tissue damage, graft versus host disease, and infections using cell-free DNA profiling pending (Cornell Reference number 9401-01-US), and a patent Methods for assessing the severity and progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections using cell-free DNA pending (Cornell Reference number 9561-01-US) and rapid identification of antimicrobial resistance and other microbial phenotypes using highly multiplexed fluorescence in situ hybridization (Cooley Reference: BEEB-001/00US 342794-2002). T. C. L. and E. G. M. receive research salary support from the Fonds de recherche du Québec – Santé. M. L. reports having served on advisory boards for Sanofi, Pfizer, Medicago, Merck, Seqirus, Paladin Labs; Pan Data Safety, and Monitoring Committees for Medicago, CanSino biologics, National Institutes of Health (NIH), the World Health Organization (WHO) EML Antibiotic Working Group. E. G. M. reports being co-investigator on the SNAP staph aureus platform trial CIHR outside of the submitted work. T. C. L. reports operating funds for other studies from Canadian Institutes of Health Research and McGill Interdisciplinary Institute Infection and Immunity. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The role of remdesivir in the treatment of hospitalized patients with COVID-19 remains ill-defined. We conducted a cost-effectiveness analysis alongside the Canadian Treatments for COVID-19 (CATCO) open-label, randomized clinical trial evaluating remdesivir., Methods: Patients with COVID-19 in Canadian hospitals from Aug. 14, 2020, to Apr. 1, 2021, were randomly assigned to receive remdesivir plus usual care versus usual care alone. Taking a public health care payer's perspective, we collected in-hospital outcomes and health care resource utilization alongside estimated unit costs in 2020 Canadian dollars over a time horizon from randomization to hospital discharge or death. Data from 1281 adults admitted to 52 hospitals in 6 Canadian provinces were analyzed., Results: The total mean cost per patient was $37 918 (standard deviation [SD] $42 413; 95% confidence interval [CI] $34 617 to $41 220) for patients randomly assigned to the remdesivir group and $38 026 (SD $46 021; 95% CI $34 480 to $41 573) for patients receiving usual care (incremental cost -$108 [95% CI -$4953 to $4737], p > 0.9). The difference in proportions of in-hospital deaths between remdesivir and usual care groups was -3.9% (18.7% v. 22.6%, 95% CI -8.3% to 1.0%, p = 0.09). The difference in proportions of incident invasive mechanical ventilation events between groups was -7.0% (8.0% v. 15.0%, 95% CI -10.6% to -3.4%, p = 0.006), whereas the difference in proportions of total mechanical ventilation events between groups was -5.7% (16.4% v. 22.1%, 95% CI -10.0% to -1.4%, p = 0.01). Remdesivir was the dominant intervention (but only marginally less costly, with mildly lower mortality) with an incalculable incremental cost effectiveness ratio; we report results of incremental costs and incremental effects separately. For willingness-to-pay thresholds of $0, $20 000, $50 000 and $100 000 per death averted, a strategy using remdesivir was cost-effective in 60%, 67%, 74% and 79% of simulations, respectively. The remdesivir costs were the fifth highest cost driver, offset by shorter lengths of stay and less mechanical ventilation., Interpretation: From a health care payer perspective, treating patients hospitalized with COVID-19 with remdesivir and usual care appears to be preferrable to treating with usual care alone, albeit with marginal incremental cost and small clinical effects. The added cost of remdesivir was offset by shorter lengths of stay in the intensive care unit and less need for ventilation., Study Registration: ClinicalTrials. gov, no. NCT04330690., Competing Interests: Competing interests: Robert Fowler is the H. Barrie Fairley Professor of Critical Care Medicine at the University Health Network and the University of Toronto Interdepartmental Division of Critical Care Medicine. Robert Fowler declares a Canadian Institutes of Health Research (CIHR) operating grant. John Conly declares grants from the CIHR, Pfizer and the World Health Organization (WHO). He declares a peer-reviewed research grant on acute and primary care preparedness for COVID-19 in Alberta, Canada; he was a primary local investigator for the STRIVE Staphylococcus aureus vaccine randomized controlled trial in vertebral spinal surgery with instrumentation for which all funding was provided only to the University of Calgary; he was a co-investigator on a WHO-funded study using integrated human factors and ethnography approaches to identify and scale innovative infection prevention and control (IPC) guidance implementation supports in primary care with a focus on low-resource settings and using drone aerial systems to deliver medical supplies and personal protective equipment to remote First Nations communities during the COVID-19 pandemic. John Conly also reports receiving accommodations and airfare from the Centers for Disease Control and Prevention to attend a meeting in 2019. He is a member and chair of the WHO Infection Prevention and Control Research and Development Expert Group for COVID-19 and a member of the WHO Health Emergencies Programme Ad-hoc COVID-19 IPC Guidance Development Group, both of which provide multidisciplinary advice to the WHO, for which no funding is received and from which no funding recommendations are made for any WHO contracts or grants. He is also a member of the Cochrane Acute Respiratory Infections Group. Darrell Tan is supported by a Tier 2 Canada Research Chair in HIV Prevention and STI Research. Ryan Zarychanski reports grants from the CIHR, the Peter Munk Cardiac Centre, the Thistledown Foundation and the National Institutes of Health. He is a WHO thrombostasis technical advisory member. Ryan Zarychanski is the recipient of the Lyonel G. Israels Research Chair in Hematology at the University of Manitoba. Todd Lee reports a CATCO operating grant from the CIHR as a co–principal investigator and a co-investigator. He reports various operating grants from the CIHR, a technical development grant from the Centre for Aging + Brain Health Innovation and research salary support from the Fonds de recherche du Québec — Santé. He is the co-owner of a company that is bringing Med-Safer to market. Srinivas Murthy is the Innovative Medicines Canada and Health Research Foundation Chair in Pandemic Preparedness Research. Srinivas Murthy reports a grants from the CIHR and Health Research Foundation and Innovative Medicines Canada., (© 2022 CMA Impact Inc. or its licensors.)

Objectives: Staphylococcus aureus bacteremia (SAB) is a common infection worldwide. We compared SAB mortality in low- and middle-income countries (LMIC) versus high-income countries (HIC) in a meta-analysis., Methods: We searched MEDLINE, Embase, and Cochrane Database of Systematic Reviews from 1991-2021 and included observational, single-country studies on patients with positive blood cultures for S. aureus. The main outcome was the proportion of patients with SAB who died in the hospital. A generalized linear mixed random-effects model was used to pool estimates, and a meta-regression was used to adjust for study-level characteristics., Results: A total of 332 studies involving 517,671 patients in 39 countries were included. No study was conducted in a low-income country. Only 33 (10%) studies were performed in middle-income countries (MIC), which described 6,216 patients. The pooled in-hospital mortality was 32.4% (95% confidence interval [CI] 27.2%-38.2%, T 2  = 0.3063) in MIC and 22.3% (95% CI 20.1%-24.6%, T 2  = 0.3257) in HIC. In a meta-regression model, MIC had higher in-hospital mortality (adjusted odds ratio 1.37, 95% CI 1.11-1.71; P = 0.0042) than HIC., Conclusion: In SAB studies, LMIC are poorly represented. In-hospital mortality was significantly higher in MIC than in HIC. Research should be conducted in LMIC to characterize differences in care processes driving the mortality gap., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To determine whether angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors are associated with improved outcomes in hospitalized patients with COVID-19 according to sex and to report sex-related differences in renin-angiotensin system (RAS) components., Design: Prospective observational cohort study comparing the effects of ARB or ACE inhibitors versus no ARBs or ACE inhibitors in males versus females. Severe acute respiratory syndrome coronavirus 2 downregulates ACE-2, potentially increasing angiotensin II (a pro-inflammatory vasoconstrictor). Sex-based differences in RAS dysregulation may explain sex-based differences in responses to ARBs because the ACE2 gene is on the X chromosome. We recorded baseline characteristics, comorbidities, prehospital ARBs or ACE inhibitor treatment, use of organ support and mortality, and measured RAS components at admission and days 2, 4, 7, and 14 in a subgroup ( n = 46), recorded d -dimer ( n = 967), comparing males with females., Setting: ARBs CORONA I is a multicenter Canadian observational cohort of patients hospitalized with acute COVID-19. This analysis includes patients admitted to 10 large urban hospitals across the four most populated provinces., Patients: One-thousand six-hundred eighty-six patients with polymerase chain reaction-confirmed COVID-19 (February 2020 to March 2021) for acute COVID-19 illness were included., Interventions: None., Measurements and Main Results: Males on ARBs before admission had decreased use of ventilation (adjusted odds ratio [aOR] = 0.52; p = 0.007) and vasopressors (aOR = 0.55; p = 0.011) compared with males not on ARBs or ACE inhibitors. No significant effects were observed in females for these outcomes. The test for interaction was significant for use of ventilation ( p = 0.006) and vasopressors ( p = 0.044) indicating significantly different responses to ARBs according to sex. Males had significantly higher plasma ACE-1 at baseline and angiotensin II at day 7 and 14 than females., Conclusions: ARBs use was associated with less ventilation and vasopressors in males but not females. Sex-based differences in RAS dysregulation may contribute to sex-based differences in outcomes and responses to ARBs in COVID-19., Competing Interests: Drs. Rocheleau’s, Cheng’s, Lee’s, Haljan’s, Vinh’s, Mann’s, Donohoe’s, and Russell’s institutions received funding from the Canadian Institutes for Health Research. Dr. Mohammed’s institution received funding from Genome Canada and Genome British Colombia. Dr. Goodlett disclosed that he is the founder of Pataigin LLC and Deurion LLC and that the University of Victoria Genome British Columbia Proteome Centre (for which he is a director) received funding from Genome Canada and Genome British Colombia. Dr. Burns disclosed that he is a consultant to JN Nova Pharma. Dr. Cheng’s institution received funding from McGill Interdisciplinary Initiative in Infection and Immunity; he received funding from GEn1E Lifesciences and NPlex Biosciences; he disclosed that he is the cofounder of Kanvas Biosciences and owns equity in the company; and he disclosed that he is a named coinventor on a pending patent entitled “Methods for assessing the severity and progression of SARS-CoV2 infections using cell-free DNA.” Dr. Slutsky received funding from Apeiron, GlaxoSmithKline, Baxter, Cellenkos, Diffusion, Edesa, Exvastat, Faron, and Novalung. Dr. Lee received funding from the Fonds de recherche du Quebec santé (FRQS). Dr. Haljan’s institution received funding from Michael Smith Foundation for Health Research and Surrey Hospital Foundation. Dr. Vinh’s institution received funding from the Jeffrey Modell Foundation and FRQS; he received funding from CSL Behring, Astra Zeneca, Moderna, Takeda, QU Biologics, Merck Canada, Novartis Canada, and the COVID Immunity Task Force (Public Health Agency of Canada); he disclosed he has patent applications pending (Encrypting File System Identification [EFS ID] 40101099; EFS ID 44321620). Dr. Russell reports patents owned by the University of British Columbia (UBC) that are related to the use of proprotein convertase subtilisin/kexin type 9 inhibitor(s) in sepsis and related to the use of vasopressin in septic shock and a patent owned by Ferring for use of selepressin in septic shock; he is an inventor on these patents; he was a founder, director, and shareholder in Cyon Therapeutics and is a shareholder in Molecular You Corp; he reports receiving consulting fees in the last 3 years from: Asahi Kesai Pharmaceuticals of America (was developing recombinant thrombomodulin in sepsis), SIB Therapeutics LLC (developing a sepsis drug), and Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin); he is no longer actively consulting for the following: La Jolla Pharmaceuticals (developing angiotensin II; Dr. Russell chaired the Data Safety Monitoring Board of a trial of angiotensin II from 2015 to 2017), PAR Pharma (sells prepared bags of vasopressin); and he reports having received an investigator-initiated grant from Grifols (entitled “Is HBP a mechanism of albumin’s efficacy in human septic shock?”) that was provided to and administered by UBC. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Background: Understanding the immune response to natural infection by SARS-CoV-2 is key to pandemic management, especially in the current context of emerging variants. Uncertainty remains regarding the efficacy and duration of natural immunity against reinfection., Methods: We conducted an observational prospective cohort study in Canadian healthcare workers (HCWs) with a history of PCR-confirmed SARS-CoV-2 infection to (i) measure the average incidence rate of reinfection and (ii) describe the serological immune response to the primary infection., Results: Our cohort comprised 569 HCWs; median duration of individual follow-up was 371 days. We detected six cases of reinfection in absence of vaccination between August 21, 2020, and March 1, 2022, for a reinfection incidence rate of 4.0 per 100 person-years. Median duration of seropositivity was 415 days in symptomatics at primary infection compared with 213 days in asymptomatics (p < 0.0001). Other characteristics associated with prolonged seropositivity for IgG against the spike protein included age over 55 years, obesity, and non-Caucasian ethnicity., Conclusions: Among unvaccinated healthcare workers, reinfection with SARS-CoV-2 following a primary infection remained rare., (© 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: People in prison are at increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We examined the seroprevalence of SARS-CoV-2 and associated carceral risk factors among incarcerated adult men in Quebec, Canada., Methods: We conducted a cross-sectional seroprevalence study in 2021 across 3 provincial prisons, representing 45% of Quebec's incarcerated male provincial population. The primary outcome was SARS-CoV-2 antibody seropositivity (Roche Elecsys serology test). Participants completed self-administered questionnaires on sociodemographic, clinical, and carceral characteristics. The association of carceral variables with SARS-CoV-2 seropositivity was examined using Poisson regression models with robust standard errors. Crude and adjusted prevalence ratios (aPR) with 95% confidence intervals (95% CIs) were calculated., Results: Between 19 January 2021 and 15 September 2021, 246 of 1100 (22%) recruited individuals tested positive across 3 prisons (range, 15%-27%). Seropositivity increased with time spent in prison since March 2020 (aPR, 2.17; 95% CI, 1.53-3.07 for "all" vs "little time"), employment during incarceration (aPR, 1.64; 95% CI, 1.28-2.11 vs not), shared meal consumption during incarceration ("with cellmates": aPR, 1.46; 95% CI, 1.08-1.97 vs "alone"; "with sector": aPR, 1.34; 95% CI, 1.03-1.74 vs "alone"), and incarceration post-prison outbreak (aPR, 2.32; 95% CI, 1.69-3.18 vs "pre-outbreak")., Conclusions: The seroprevalence of SARS-CoV-2 among incarcerated individuals was high and varied among prisons. Several carceral factors were associated with seropositivity, underscoring the importance of decarceration and occupational safety measures, individual meal consumption, and enhanced infection prevention and control measures including vaccination during incarceration., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Precise estimates of mortality in Staphylococcus aureus bacteraemia (SAB) are important to convey prognosis and guide the design of interventional studies., Objectives: We performed a systematic review and meta-analysis to estimate all-cause mortality in SAB and explore mortality change over time., Data Sources: The MEDLINE and Embase databases, as well as the Cochrane Database of Systematic Reviews, were searched from January 1, 1991 to May 7, 2021., Study Eligibility Criteria: Human observational studies on patients with S. aureus bloodstream infection were included., Participants: The study analyzed data of patients with a positive blood culture for S. aureus., Methods: Two independent reviewers extracted study data and assessed risk of bias using the Newcastle-Ottawa Scale. A generalized, linear, mixed random effects model was used to pool estimates., Results: A total of 341 studies were included, describing a total of 536,791 patients. From 2011 onward, the estimated mortality was 10.4% (95% CI, 9.0%-12.1%) at 7 days, 13.3% (95% CI, 11.1%-15.8%) at 2 weeks, 18.1% (95% CI, 16.3%-20.0%) at 1 month, 27.0% (95% CI, 21.5%-33.3%) at 3 months, and 30.2% (95% CI, 22.4%-39.3%) at 1 year. In a meta-regression model of 1-month mortality, methicillin-resistant S. aureus had a higher mortality rate (adjusted OR (aOR): 1.04; 95% CI, 1.02-1.06 per 10% increase in methicillin-resistant S. aureus proportion). Compared with prior to 2001, more recent time periods had a lower mortality rate (aOR: 0.88; 95% CI, 0.75-1.03 for 2001-2010; aOR: 0.82; 95% CI, 0.69-0.97 for 2011 onward)., Conclusions: SAB mortality has decreased over the last 3 decades. However, more than one in four patients will die within 3 months, and continuous improvement in care remains necessary., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection of immunocompromised hosts with significant morbidity and mortality. The current standard of care, trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of 15-20 mg/kg/day, is associated with serious adverse drug events (ADE) in 20%-60% of patients. ADEs include hypersensitivity reactions, drug-induced liver injury, cytopenias and renal failure, all of which can be treatment limiting. In a recent meta-analysis of observational studies, reduced dose TMP-SMX for the treatment of PJP was associated with fewer ADEs, without increased mortality., Methods and Analysis: A phase III randomised, placebo-controlled, trial to directly compare the efficacy and safety of low-dose TMP-SMX (10 mg/kg/day of TMP) with the standard of care (15 mg/kg/day of TMP) among patients with PJP, for a composite primary outcome of change of treatment, new mechanical ventilation, or death. The trial will be undertaken at 16 Canadian hospitals. Data will be analysed as intention to treat. Primary and secondary outcomes will be compared using logistic regression adjusting for stratification and presented with 95% CI., Ethics and Dissemination: This study has been conditionally approved by the McGill University Health Centre; Ethics approval will be obtained from all participating centres. Results will be submitted for publication in a peer-reviewed journal., Trial Registration Number: NCT04851015., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite the availability of highly efficacious vaccines, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lacks effective drug treatment, which results in a high rate of mortality. To address this therapeutic shortcoming, we applied a systems biology approach to the study of patients hospitalized with severe COVID. We show that, at the time of hospital admission, patients who were equivalent on the clinical ordinal scale displayed significant differential monocyte epigenetic and transcriptomic attributes between those who would survive and those who would succumb to COVID-19. We identified messenger RNA metabolism, RNA splicing, and interferon signaling pathways as key host responses overactivated by patients who would not survive. Those pathways are prime drug targets to reduce mortality of critically ill patients with COVID-19, leading us to identify tacrolimus, zotatifin, and nintedanib as three strong candidates for treatment of severely ill patients at the time of hospital admission.

Background: Few reports exist on the characteristics and outcomes of persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in immunocompromised hosts., Methods: A 49-year-old patient with granulomatosis with polyangiitis (GPA) and a renal transplant experienced multiple hospitalizations for coronavirus disease 2019 (COVID-19) pneumonia and relapses between October 2020 and February 2021. Careful chart review of medical history, hospitalizations, and microbiological testing including SARS-CoV-2 cycle threshold values, therapies, and imaging was undertaken. SARS-CoV-2 genome sequencing was performed in five viral samples to distinguish persistent infection from re-infection with a different strain., Results: Sequencing confirmed that all samples tested were from the same viral lineage, indicating a long-term, persistent infection rather than re-infection with a new strain. The patient ultimately stabilized after two courses of remdesivir plus dexamethasone, replacement intravenous immunoglobulin, and bamlanivimab. Rituximab maintenance therapy for vasculitis remains on hold., Conclusions: SARS-CoV-2 may persist for several months in immunocompromised hosts and may go unrecognized as an ongoing active infection. More studies are needed to determine how to optimize COVID-19 treatment in this vulnerable population., Competing Interests: TC Lee reports funds from Fonds de Recherche Quebec-Santé and Canadian Institutes of Health Research during the conduct of the study. MP Cheng reports grants from the McGill Interdisciplinary Initiative in Infection and Immunity and Canadian Institutes of Health Research during the conduct of the study and personal fees from GEn1E Lifesciences (as a member of the scientific advisory board) and nplex biosciences (as a member of the scientific advisory board), both outside the submitted work. He is the co-founder of Kanvas Biosciences and owns equity in the company. In addition, MP Cheng has a pending patent for ‘Methods for detecting tissue damage, graft versus host disease, and infections using cell-free DNA profiling’ and a pending patent for ‘Methods for assessing the severity and progression of SARS-CoV-2 infections using cell-free DNA.’ The other authors have nothing to disclose., (Copyright © 2022, Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada).)

Importance: Longitudinal mass testing using rapid antigen detection tests (RADT) for serial screening of asymptomatic persons has been proposed for preventing SARS-CoV-2 community transmission. The feasibility of this strategy relies on accurate self-testing., Objective: To quantify the adequacy of serial self-performed SARS-CoV-2 RADT testing in the workplace, in terms of the frequency of correct execution of procedural steps and accurate interpretation of the range of possible RADT results., Design, Setting, and Participants: This prospective repeated cross-sectional study was performed from July to October 2021 at businesses with at least 2 active cases of SARS-CoV-2 infection in Montreal, Canada. Participants included untrained persons in their workplace, not meeting Public Health quarantine criteria (ie, required quarantine for 10 days after a moderate-risk contact with someone infected with SARS-CoV-2). Interpretation and performance were compared between participants who received instructions provided by the manufacturer vs those who received modified instructions that were informed by the most frequent or most critical errors we observed. Data were analyzed from October to November 2021., Exposures: RADT testing using a modified quick reference guide compared with the original manufacturer's instructions., Main Outcomes and Measures: The main outcome was the difference in correctly interpreted RADT results. Secondary outcomes included difference in proportions of correctly performed procedural steps. Additional analyses, assessed among participants with 2 self-testing visits, compared the second self-test visit with the first self-test visit using the same measures., Results: Overall, 1892 tests were performed among 647 participants, of whom 278 participants (median [IQR] age, 43 [31-55] years; 156 [56.1%] men) had at least 1 self-testing visit. For self-test visit 1, significantly better accuracy in test interpretation was observed among participants using the modified quick reference guide than those using the manufacturer's instructions for reading results that were weak positive (64 of 115 participants [55.6%] vs 20 of 163 participants [12.3%]; difference, 43.3 [95% CI, 33.0-53.8] percentage points), positive (103 of 115 participants [89.6%] vs 84 of 163 participants [51.5%]; difference, 38.1 [95% CI, 28.5-47.5] percentage points), strong positive (219 of 229 participants [95.6%] vs 274 of 326 participants [84.0%]; difference, 11.6 [95% CI, 6.8-16.3] percentage points), and invalid (200 of 229 participants [87.3%] vs 252 of 326 participants [77.3%]; difference, 10.0 [95% CI, 3.8-16.3] percentage points). Use of the modified guide was associated with improvements on self-test visit 2 for results that were weak positive (difference, 15.4 [95% CI, 0.7-30.1] percentage points), positive (difference, 19.0 [95% CI, 7.2-30.9] percentage points), and invalid (difference, 8.0 [95% CI, 0.8-15.4] percentage points). For procedural steps identified as critical for test validity, adherence to procedural testing steps did not differ meaningfully according to instructions provided or reader experience., Conclusions and Relevance: In this cross-sectional study of self-performed SARS-CoV-2 RADT in an intended-use setting, a modified quick reference guide was associated with significantly improved accuracy in RADT interpretations.

Background: Renin-angiotensin aldosterone system inhibitors (RAASi) are commonly used among patients hospitalized with a severe acute respiratory syndrome coronavirus 2 infection coronavirus disease 2019 (COVID-19). We evaluated whether continuation versus discontinuation of RAASi were associated with short term clinical or biochemical outcomes., Methods: The RAAS-COVID-19 trial was a randomized, open label study in adult patients previously treated with RAASi who are hospitalized with COVID-19 (NCT04508985). Participants were randomized 1:1 to discontinue or continue RAASi. The primary outcome was a global rank score calculated from baseline to day 7 (or discharge) incorporating clinical events and biomarker changes. Global rank scores were compared between groups using the Wilcoxon test statistic and the negative binomial test (using incident rate ratio [IRR]) and the intention-to-treat principle., Results: Overall, 46 participants were enrolled; 21 participants were randomized to discontinue RAASi and 25 to continue. Patients' mean age was 71.5 years and 43.5% were female. Discontinuation of RAASi, versus continuation, resulted in a non-statistically different mean global rank score (discontinuation 6 [standard deviation [SD] 6.3] vs continuation 3.8 (SD 2.5); P = .60). The negative binomial analysis identified that discontinuation increased the risk of adverse outcomes (IRR 1.67 [95% CI 1.06-2.62]; P = .027); RAASi discontinuation increased brain natriuretic peptide levels (% change from baseline: +16.7% vs -27.5%; P = .024) and the incidence of acute heart failure (33% vs 4.2%, P = .016)., Conclusion: RAASi continuation in participants hospitalized with COVID-19 appears safe; discontinuation increased brain natriuretic peptide levels and may increase risk of acute heart failure; where possible, RAASi should be continued., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We performed retrospective chart reviews and described the clinical characteristics, exposure risks, and disease severity of people living with HIV (PLWH) attending the Chronic Viral Illness Service (CVIS) in Montreal, Canada, who developed coronavirus disease 2019 (COVID-19) during September 2020-August 2021, coinciding with the second and third waves of the pandemic. A total of 61 PLWH with a positive COVID-19 polymerase chain reaction were identified, giving a COVID-19 prevalence of 5%. The most common exposure risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during waves two and three was having a family member/close contact with COVID-19 (36%). Similar to what we observed during the first wave, PLWH who acquired COVID-19 during waves two and three of the pandemic often worked or lived in long-term care residences or health care settings, putting them at risk. Five people (8%) were asymptomatic. Nearly all persons had mild disease on initial presentation and most had a full recovery. Two individuals were admitted to hospital with COVID-19, whereas three individuals acquired COVID-19 nosocomially. No individuals died due to COVID-19. Two individuals developed symptoms associated with long COVID-19 syndrome. Findings highlight the ongoing impact of the social determinants of health during the second and third waves of the pandemic in PLWH.

Background: There have been multiple waves in the COVID-19 pandemic in many countries. We sought to compare mortality and respiratory, cardiovascular and renal dysfunction between waves in 3 Canadian provinces., Methods: We conducted a substudy of the ARBs CORONA I study, a multicentre Canadian pragmatic observational cohort study that examined the association of pre-existing use of angiotensin receptor blockers with outcomes in adults admitted to hospital with acute COVID-19 up to April 2021 from 9 community and teaching hospitals in 3 Canadian provinces (British Columbia, Ontario and Quebec). We excluded emergency department admissions without hospital admission, readmissions and admissions for another reason. We used logistic and 0-1-inflated β regression models to compare 28-day and in-hospital mortality, and the use of invasive mechanical ventilation, vasopressors and renal replacement therapy (RRT) between the first 3 waves of the COVID-19 pandemic in these provinces., Results: A total of 520, 572 and 245 patients in waves 1, 2 and 3, respectively, were included. Patients in wave 3 were on average younger and had fewer comorbidities than those in waves 1 and 2. The unadjusted 28-day mortality rate was significantly lower in wave 3 (7.8%) than in wave 1 (18.3%) (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.24-0.78) and wave 2 (16.3%) (OR 0.46, 95% CI 0.27-0.79). After adjustment for differences in baseline characteristics, the difference in 28-day mortality remained significant (adjusted OR wave 3 v. wave 1: 0.46, 95% CI 0.26-0.81; wave 3 v. wave 2: 0.52, 95% CI 0.29-0.91). In-hospital mortality findings were similar. Use of invasive mechanical ventilation or vasopressors was less common in waves 2 and 3 than in wave 1, and use of RRT was less common in wave 3 than in wave 1., Interpretation: Severity of illness decreased (lower mortality and less use of organ support) across waves among patients admitted to hospital with acute COVID-19, possibly owing to changes in patient demographic characteristics and management, such as increased use of dexamethasone. Continued application of proven therapies may further improve outcomes., Study Registration: ClinicalTrials.gov, no. NCT04510623., Competing Interests: Competing interests: James Russell reports an investigator-initiated grant from Grifols that was provided to and administered by the University of British Columbia (UBC). He reports patents owned by UBC that are related to the use of PCSK9 inhibitor(s) in sepsis and the use of vasopressin in septic shock, and a patent owned by Ferring Pharmaceuticals for use of selepressin in septic shock. He is an inventor on these patents. He was a founder, director and shareholder in Cyon Therapeutics and is a shareholder in Molecular You. He reports consulting fees from SIB Therapeutics (developing a sepsis drug) and Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin). He is no longer actively consulting for any industry. He was a nonfunded science advisor and member of the Government of Canada COVID-19 Therapeutics Task Force (June 2020–December 2021) and a nonfunded member of the data and safety monitoring board of a trial of plasma in COVID-19 (PassITON) (2020–2021) sponsored by the National Institutes of Health. No other competing interests were declared., (© 2022 CMA Impact Inc. or its licensors.)

Background: Deaths following Staphylococcus aureus bacteremia (SAB) may be related or unrelated to the infection. In SAB therapeutics research, the length of follow-up should be optimized to capture most attributable deaths and minimize nonattributable deaths. We performed a secondary analysis of a systematic review to describe attributable mortality in SAB over time., Methods: We systematically searched Medline, Embase, and Cochrane Database of Systematic Reviews from 1 January 1991 to 7 May 2021 for human observational studies of SAB. To be included in this secondary analysis, the study must have reported attributable mortality. Two reviewers extracted study data and assessed risk of bias independently. Pooling of study estimates was not performed due to heterogeneity in the definition of attributable deaths., Results: Twenty-four observational cohort studies were included. The median proportion of all-cause deaths that were attributable to SAB was 77% (interquartile range [IQR], 72%-89%) at 1 month and 62% (IQR, 58%-75%) at 3 months. At 1 year, this proportion was 57% in 1 study. In 2 studies that described the rate of increase in mortality over time, 2-week follow-up captured 68 of 79 (86%) and 48 of 57 (84%) attributable deaths that occurred by 3 months. By comparison, 1-month follow-up captured 54 of 57 (95%) and 56 of 60 (93%) attributable deaths that occurred by 3 months in 2 studies., Conclusions: The proportion of deaths that are attributable to SAB decreases as follow-up lengthens. Follow-up duration between 1 and 3 months seems optimal if evaluating processes of care that impact SAB mortality., Clinical Trials Registration: PROSPERO CRD42021253891., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The host response to COVID-19 pathophysiology over the first few days of infection remains largely unclear, especially the mechanisms in the blood compartment. We report on a longitudinal proteomic analysis of acute-phase COVID-19 patients, for which we used blood plasma, multiple reaction monitoring with internal standards, and data-independent acquisition. We measured samples on admission for 49 patients, of which 21 had additional samples on days 2, 4, 7, and 14 after admission. We also measured 30 externally obtained samples from healthy individuals for comparison at baseline. The 31 proteins differentiated in abundance between acute COVID-19 patients and healthy controls belonged to acute inflammatory response, complement activation, regulation of inflammatory response, and regulation of protein activation cascade. The longitudinal analysis showed distinct profiles revealing increased levels of multiple lipid-associated functions, a rapid decrease followed by recovery for complement activation, humoral immune response, and acute inflammatory response-related proteins, and level fluctuation in the regulation of smooth muscle cell proliferation, secretory mechanisms, and platelet degranulation. Three proteins were differentiated between survivors and nonsurvivors. Finally, increased levels of fructose-bisphosphate aldolase B were determined in patients with exposure to angiotensin receptor blockers versus decreased levels in those exposed to angiotensin-converting enzyme inhibitors. Data are available via ProteomeXchange PXD029437.

Superelastic NiTi alloy and 304 stainless steel (304 SS) were joined with a Cu interlayer by ultrasonic spot welding (USW) using different welding energy inputs. The surface morphology, interfacial microstructure, mechanical properties, and fracture mechanisms of the dissimilar NiTi/304 SS USWed joints were studied. The results showed that the surface oxidation intensified with increasing ultrasonic welding energy due to mutual rubbing between tools and sheets. The weld interface microstructure exhibited voids or unbonded zones at low energy inputs, while an intimate contact was established at the joining interface when applying a higher energy input of 750 J. With increasing energy input to 750 J, the weld interface shows two interfaces due to the behavior of plastic flow of Cu interlayer. The lap-shear load of the joints first increased, achieving a maximum value of ∼690 N at an energy input of 750 J, and then decreased with further increase in welding energy. Interfacial failure was observed at NiTi/Cu interface at all energy inputs, and no intermetallic compounds were found on the fracture surfaces of both the NiTi/Cu and Cu/304 SS interfaces., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems., Methods: We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation., Results: Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir ( n = 634) or standard of care ( n = 648). Of these, 15 withdrew consent or were still in hospital, for a total sample of 1267 patients. Among patients assigned to receive remdesivir, in-hospital mortality was 18.7%, compared with 22.6% in the standard-of-care arm (relative risk [RR] 0.83 (95% confidence interval [CI] 0.67 to 1.03), and 60-day mortality was 24.8% and 28.2%, respectively (95% CI 0.72 to 1.07). For patients not mechanically ventilated at baseline, the need for mechanical ventilation was 8.0% in those assigned remdesivir, and 15.0% in those receiving standard of care (RR 0.53, 95% CI 0.38 to 0.75). Mean oxygen-free and ventilator-free days at day 28 were 15.9 (± standard deviation [SD] 10.5) and 21.4 (± SD 11.3) in those receiving remdesivir and 14.2 (± SD 11) and 19.5 (± SD 12.3) in those receiving standard of care ( p = 0.006 and 0.007, respectively). There was no difference in safety events of new dialysis, change in creatinine, or new hepatic dysfunction between the 2 groups., Interpretation: Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation. Trial registration : ClinicalTrials.gov, no. NCT04330690., Competing Interests: Competing interests: Alexandra Binnie reports receiving research grants from the Canadian Institutes of Health Research (CIHR) and the Physicians Services Incorporated Foundation. Sergio Borgia reports receiving honoraria from Gilead Sciences and GSK. Yiorgos Alexandros Cavayas reports receiving a grant from CIHR. Matthew Cheng reports receiving grants from the McGill Interdisciplinary Initiative in Infection and Immunity and from CIHR, during the conduct of the study (payments made to the institution). Dr. Cheng also reports receiving personal fees from AstraZeneca, outside the submitted work; and from Nplex Biosciences and GEn1E lifesciences (in the form of stock options for being a member of the scientific advisory board) outside the submitted work. Dr. Cheng co-founded Kanvas Biosicences and owns equity in the company, and reports 3 patents pending. John Conly reports receiving grants from CIHR, Pfizer, the World Health Organization (WHO), Sunnybrook Research Institute, University of Calgary, and the Calgary Health Foundation. Dr. Conly also reports receiving support to attend the Think Tank Meeting 2019. Dr. Conly is a member and Chair of the WHO Infection Prevention and Control Research and Development Expert Group for COVID-19, a member of the WHO Health Emergencies Programme (WHE) Ad-hoc COVID-19 IPC Guidance Development Group, and a member of the Cochrane Acute Respiratory Infections Group. Madeleine Durand reports receiving grants from CIHR and the Fonds Recherche du Québec–Santé (FRQS). Rob Fowler reports receiving a grant from CIHR for the CATCO trial and is the H. Barrie Fairley Professor of Critical Care at the University Health Network. Michael Fralick reports receiving multiple grants from CIHR and support from grants from the Canadian military for clinical trials to identify treatments for COVID-19 (payments made to institution). Dr. Fralick is a paid consultant for a start-up company called Proof DiagnosticsDx, which has created a point-of-care testing device using CRISPR for COVID-19. Holly Hoang reports receiving payment from CATCO Sunnybrook to fund research assistant (payment made to institution) and a research grant from Covenant Health Research Centre. Marina Klein reports receiving grants from Gilead, ViiV Healthcare, Merck and AbbVie for investigator-initiated studies, and consulting fees from Gilead, ViiV Healthcare, Merck and AbbVie, all outside the submitted work. Todd Lee reports receiving operating grants from CIHR and McGill Interdisciplinary Initiative in Infection and Immunity (MI4), and research salary support from FRQS. Alexandra Lostun reports receiving per-case funding to cover the costs of enrolling patients (paid to institution, North York General Hospital). François Carrier reports receiving grants from the Instituts de recherche en santé du Canada and the Canadian Donation and Transplantation Research Program, and a grant and salary support from FRQS. Marlee McGuinty reports receiving speaking fees from Merck. Srinivas Murthy reports receiving a grant from CIHR, during the conduct of the study, and is the Health Research Foundation and Innovative Medicines Canada Chair in Pandemic Preparedness Research. Conar O’Neil reports receiving conference sponsorship from Gilead Sciences, and is a member of a Gilead Sciences advisory board. Jesse Papenburg reports receiving a grant from CIHR, during the conduct of the study, as well as research grants and contracts from AbbVie and research contracts (site investigator for clinical trial) from MedImmune, Merck and Sanofi Pasteur. Dr. Papenburg has received consulting fees from Merck for an ad hoc advisory board meeting, and honoraria for presentations from Seegene, AbbVie and AstraZeneca. Dr. Papenburg is also a voting member of the National Advisory Committee on Immunization. Ken Kuljit S. Parhar reports receiving a CIHR project grant, Alberta Innovates grant and Alberta Health Innovation Implementation and Spread grant (all paid to institution). Seema Nair Parvathy reports receiving funding from St. Joseph’s Health Care Foundation and London Health Sciences Foundation. Moira Rushton-Marovac reports receiving advisory board honoraria from Gilead. Marina Salvadori reports being an employee of the Public Health Agency of Canada. Makeda Semret reports receiving support from the McGill MI4 for the clinical research platform through which CATCO was supported at the McGill University Health Centre. Ameeta Singh reports receiving consulting fees from Gilead for membership of an advisory board. Ranjani Somayaji reports receiving contract research funding from Sunnybrook Research Institute, University of Calgary and Calgary Health Foundation, and clinical research funding from CIHR and the Cystic Fibrosis Foundation. Dr. Somayaji also reports participation on an oncovir data monitoring safety board. Darrell Tan reports receiving grants from AbbVie (in-kind drug only) and Gilead (in-kind drug and grants to institution), and a contract between GSK and the institution for clinical trials. Alain Tremblay reports receiving contract research funding from the Sunnybrook Research Institute, and grants for COVID-19 clinical trials from the University of Calgary and Calgary Health Foundation. Alexis Turgeon reports receiving a grant from CIHR. Jason Weatherald reports receiving grants (paid to institution) and consulting fees (paid to Dr. Weatherald) from Janssen and Actelion, as well as honoraria and travel support from Janssen. Dr. Weatherald has served on advisory boards for Janssen and Acceleron (paid) and on a Data Safety Monitoring Board for Université Laval (unpaid). Dr. Weatherald also reports membership of the Medical Advisory Committee of the Pulmonary Hypertension Association of Canada, and is a shareholder of Precision Lung Consultants and Diagnostics. Cedric Yansouni reports receiving grants from FRQS and consulting fees from Medicago Inc. Dr. Yansouni also reports participation in a Medicago Inc. Independent Data Monitoring Committee and held the role of scientific advisor for the COVID-19 Immunity Task Force. No other competing interests were declared., (© 2022 CMA Impact Inc. or its licensors.)