Publications by authors named "Andrew Willmore"

10 Publications

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Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs.

Sci Immunol 2022 Jun 14:eabp8966. Epub 2022 Jun 14.

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.

Life-threatening 'breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.
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http://dx.doi.org/10.1126/sciimmunol.abp8966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9210448PMC
June 2022

Mass cytometry reveals a conserved immune trajectory of recovery in hospitalized COVID-19 patients.

Immunity 2022 07 7;55(7):1284-1298.e3. Epub 2022 Jun 7.

Department of Otolaryngology-Head and Neck Cancer, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Immunology & Immunology and Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94115, USA. Electronic address:

While studies have elucidated many pathophysiological elements of COVID-19, little is known about immunological changes during COVID-19 resolution. We analyzed immune cells and phosphorylated signaling states at single-cell resolution from longitudinal blood samples of patients hospitalized with COVID-19, pneumonia and/or sepsis, and healthy individuals by mass cytometry. COVID-19 patients showed distinct immune compositions and an early, coordinated, and elevated immune cell signaling profile associated with early hospital discharge. Intra-patient longitudinal analysis revealed changes in myeloid and T cell frequencies and a reduction in immune cell signaling across cell types that accompanied disease resolution and discharge. These changes, together with increases in regulatory T cells and reduced signaling in basophils, also accompanied recovery from respiratory failure and were associated with better outcomes at time of admission. Therefore, although patients have heterogeneous immunological baselines and highly variable disease courses, a core immunological trajectory exists that defines recovery from severe SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.immuni.2022.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170540PMC
July 2022

The Code Silver Exercise: a low-cost simulation alternative to prepare hospitals for an active shooter event.

Adv Simul (Lond) 2021 Oct 21;6(1):37. Epub 2021 Oct 21.

Department of Emergency Medicine, University of Ottawa, 1053 Carling Avenue, Ottawa, Ontario, K1Y 4E9, Canada.

Mass-shooting incidents have been increasing in recent years and Code Silver-the hospital response to a person with a weapon such as an active shooter in many Provinces or States in North America-is quickly shifting from a theoretical safety measure to a realistic scenario for which hospitals must prepare their staff. A Code Silver Exercise (CSE) involving an independent mental practice exercise with written responses to scenarios and questions, followed by a facilitated debrief with all participants, was conceptualized and trialled for feasibility and efficacy. The CSE was piloted as a quality improvement and emergency preparedness initiative in three different settings including in situ within a hospital Emergency Department or Intensive Care Unit, offsite in a large conference room workshop, and online via virtual platform. These sessions took place in 4 different cities in Canada and included 3 academic teaching hospitals. Participants of the in situ and virtual CSE completed pre- and post-simulation surveys which showed improved understanding of Code Silver protocols following participation.The CSE is a reproducible simulation alternative, designed to operationalize a Code Silver policy at a large healthcare institution in a sustainable way. This training model can be administered in multiple settings in-person (in situ or offsite), and virtually, making it versatile and easily accessible for participants. This exercise enables participants to mentally rehearse practical responses to an active shooter in their unique work environments and to discuss ethical and medical-legal implications of their responses during a facilitated debrief with fellow healthcare providers. Implementation of a CSE for training in hospitals may help staff to create a mental schema prior to an active shooter event, and thus indirectly improve the chances of survivability in the event of a real active shooter situation.
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http://dx.doi.org/10.1186/s41077-021-00190-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529569PMC
October 2021

Remember that patient you saw last week: characteristics and frequency of patients experiencing anticipated and unanticipated death following ED discharge.

CJEM 2021 11 29;23(6):767-771. Epub 2021 Sep 29.

The Ottawa Hospital Research Institute, Ottawa, ON, Canada.

Background: The emergency department (ED) is an at-risk area for medical error. We determined the characteristics of patients with unanticipated and anticipated death within 7 days of ED discharge and whether medical error contributed.

Methods: We performed a single-centre health records review of 200 consecutive cases during a 3-year period from 2014 to 2017 in two urban, academic, tertiary care EDs. We included patients evaluated by an emergency physician who were discharged and died within 7 days. Three trained and blinded reviewers determined if deaths were related to the index visit, anticipated or unanticipated, and/or due to potential medical error. Reviewers performed content analysis to identify themes.

Results: Of 200 cases, 129 had sufficient information for analysis, translating to 44 deaths per 100,000 ED discharges (200/458,634). 13 cases per 100,000 ED discharges (58/458,634) were related and unanticipated deaths. 4 cases per 100,000 were due to potential medical errors (18/458,634). Over half (52.7%) of 129 patients displayed abnormal vital signs at discharge. Pneumonia (27.1%) was the most common cause of death. Patient themes were: difficult historian, multiple complaints, multiple comorbidities, acute progression of chronic disease, and recurrent falls. Provider themes were: failure to consider infectious etiology, failure to admit high-risk elderly patient, and missed diagnosis. System themes were: multiple ED visits or recent admission, and no repeat vital signs recorded.

Conclusion: Though the frequency of related and unanticipated deaths and those due to medical error was low, clinicians should carefully consider the highlighted common patient, provider, and system themes to facilitate safe discharge from the ED.
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http://dx.doi.org/10.1007/s43678-021-00190-zDOI Listing
November 2021

Tracheal aspirate RNA sequencing identifies distinct immunological features of COVID-19 ARDS.

Nat Commun 2021 08 26;12(1):5152. Epub 2021 Aug 26.

Department of Pathology, University of California, San Francisco, CA, USA.

The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a "cytokine storm," we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS is characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity. In silico analysis of gene expression identifies several candidate drugs that may modulate gene expression in COVID-19 ARDS, including dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 is characterized by impaired interferon-stimulated gene (ISG) expression. The relationship between SARS-CoV-2 viral load and expression of ISGs is decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients reveals distinct immunological features of COVID-19 ARDS.
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http://dx.doi.org/10.1038/s41467-021-25040-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390461PMC
August 2021

Ten (+1) lessons from conducting a mass casualty in situ simulation exercise in a Canadian academic hospital setting.

J Emerg Manag 2021 May-Jun;19(3):253-265

Department of Emergency Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario.

Providing care in a twenty-first century urban emergency department (ED) and trauma center is a complex high-pressure practice environment. The pressure is intensified during patient surge scenarios commonly seen during mass casualty incidents, such that response must be practiced regularly. Beyond clinical mastery of individual patient trauma care, a coordinated system-level response is essential to optimize patient care during these relatively infrequent events. This paper highlights the need to perform exercises in hospitals while providing practical advice on how to utilize in situ simulation for mass casualty testing. Eleven lessons are presented to assist other emergency management professionals, hospital administrators, or clinical staff to achieve success with in situ simulation. Based upon our experience designing and executing an in situ mass casualty simulation within an ED, we offer lessons applicable to any type of disaster exercise. Simulation offers a powerful tool for the conduct of disaster preparedness exercises for staff across multiple hospital departments and professions.
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http://dx.doi.org/10.5055/jem.0581DOI Listing
July 2021

Integration of In Situ Simulation Into an Emergency Department Code Orange Exercise in a Tertiary Care Trauma Referral Center.

AEM Educ Train 2021 Apr 17;5(2):e10485. Epub 2020 Jun 17.

and the Department of Obstetrics & Gynecology Department of Innovation in Medical Education University of Ottawa Ottawa Ontario Canada.

Objectives: Disaster-preparedness and response are a commonly overlooked aspect of hospital policy and can frequently be outdated and undertested. Simulation-based education has become a core education modality within Canadian medical training programs. We hypothesized that integrating in situ simulation (ISS) into a hospital-wide, mass-casualty response exercise would enhance realism and our ability to identify latent safety threats (LSTs).

Methods: Using ISS we created a simulated mass shooting scenario with 20 patients, played by actors in full moulage, presenting to a large tertiary care hospital over a 50-minute period.

Results: Integrating ISS into our exercise created a realistic experience for the participants involved and improved participant education, while imparting enough systemic stress to expose LSTs associated within patient care and hospital policy.

Conclusion: Overall, ISS was successfully used and enhanced a large-scale test of our hospital's mass-casualty response plan.
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http://dx.doi.org/10.1002/aet2.10485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019225PMC
April 2021

Large Differences in Urinary Benzene Metabolite S-Phenylmercapturic Acid Quantitation: A Comparison of Five LC-MS-MS Methods.

J Anal Toxicol 2021 Aug;45(7):657-665

Tobacco and Volatiles Branch, Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, 30341, USA.

Benzene is a known genotoxic carcinogen linked to many hematological abnormalities. S-phenylmercapturic acid (PHMA, N-acetyl-S-(phenyl)-L-cysteine, CAS# 4775-80-8) is a urinary metabolite of benzene and is used as a biomarker to assess benzene exposure. Pre-S-phenylmercapturic acid (pre-PHMA) is a PHMA precursor that dehydrates to PHMA at acidic pH. Published analytical methods that measure urinary PHMA adjust urine samples to a wide range of pH values using several types of acid, potentially leading to highly variable results depending on the concentration of pre-PHMA in a sample. Information is lacking on the variation in sample preparation among laboratories regularly measuring PHMA and the effect of those differences on PHMA quantitation in human urine samples. To investigate the differences in PHMA quantitation, we conducted an inter-laboratory comparison that included the analysis of 50 anonymous human urine samples (25 self-identified smokers and 25 self-identified non-smokers), quality control samples and commercially available reference samples in five laboratories using different analytical methods. Observed urinary PHMA concentrations were proportionally higher at lower pH, and results for anonymous urine samples varied widely among the methods. The method with the neutral preparation pH yielded results about 60% lower than the method using the most acidic conditions. Samples spiked with PHMA showed little variation, suggesting that the variability in results in human urine samples across methods is driven by the acid-mediated conversion of pre-PHMA to PHMA.
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http://dx.doi.org/10.1093/jat/bkaa137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363762PMC
August 2021

Effectiveness and safety of a prehospital program of continuous positive airway pressure (CPAP) in an urban setting.

CJEM 2015 Nov 24;17(6):609-16. Epub 2015 Mar 24.

*Department of Emergency Medicine,University of Ottawa,Ottawa,ON.

Background: Continuous positive airway pressure (CPAP) is commonly used in the treatment of acute cardiogenic pulmonary edema (ACPE) and acute exacerbations of chronic obstructive pulmonary disease (AECOPD). In-hospital evidence is robust: CPAP has been shown to improve respiratory status and to reduce intubation rates. There is less evidence on prehospital CPAP, although the emergency medical services (EMS) adoption of this modality is increasing. The objectives of this study were to 1) measure the effectiveness of prehospital CPAP on morbidity, mortality, and transport times; and 2) audit the selection of patients by medics for appropriateness and safety.

Methods: We conducted a before-and-after study from August 1 to October 31 in 2010 and 2011, before and after the implementation of prehospital CPAP in a city of one million people with large rural areas. Medics were trained to apply CPAP to patients with respiratory distress and a presumed diagnosis of ACPE or AECOPD. Charts were selected using the search criteria of the chief complaint of shortness of breath, emergent transport to hospital, and any patients receiving CPAP in the field. Data extracted from ambulance call reports and hospital records were analysed with appropriate univariate statistics.

Results: A total of 373 patients enrolled (186 pre-non-invasive ventilation [NIV] and 187 post-NIV), mean age 71.5 years, female 51.4%, and final diagnoses of ACPE 18.9%, AECOPD 21.9%. In the post group of 84 patients meeting NIV criteria, 41.6% received NIV; and of 102 patients not meeting the criteria, 5.2% received NIV. There were 12 minor adverse events in 36 applications (33.3%) as per protocol. Comparing post versus pre, there were higher rates of emergency department (ED) NIV (20.0% v. 13.4%, p<0.0001) and higher overall mortality (18.8% v. 14.9%, p<0.0001). There were no differences in ED intubation (2.1% v. 2.3%, p<0.001) and length of stay (6.8 v. 8.7 days, p=0.24).

Conclusion: Despite the robust in-hospital data supporting its use, we could not find benefit from CPAP in our prehospital setting with respect to morbidity, mortality, and length of stay. EMS must exercise caution in making the decision to invest in the equipment and training required to implement prehospital CPAP.
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http://dx.doi.org/10.1017/cem.2014.60DOI Listing
November 2015
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