Understanding, Measuring, and Ameliorating Workplace Violence in Healthcare: A Canadian Systematic Framework to Address a Global Healthcare Phenomenon (preprint)

Background: Globally, healthcare institutions have seen a marked rise in workplace violence (WPV), especially since the Covid-19 pandemic began, affecting primarily acute care and emergency departments (EDs). At the University Health Network (UHN) in Toronto, Canada, WPV incidents in EDs jumped 169% from 0.43 to 1.15 events per 1000 visits (p<.0001). In response, UHN initiated a comprehensive quality improvement (QI) project to address WPV. This study presents the project's design, implementation, results, and key takeaways, aiming to showcase effective and trauma-informed strategies for mitigating WPV in healthcare settings. Methods: Our multi-intervention QI initiative was guided by the Systems Engineering Initiative for Patient Safety (SEIPS) 3.0 framework. We also leveraged the SEIPS 101 tools to aid in crafting each QI intervention. This approach amalgamated various methodologies to approach WPV, incorporating literature reviews, a modified Delphi method, qualitative interviews, surveys, quantitative data gathering and pragmatic interventions. Results: Our complex intervention contained a total of 12 subprojects. We reviewed existing literature (n=84) pertaining to WPV in healthcare. N = 229 quality indicators utilized to measure WPV in healthcare were extracted from the literature and underwent a Delphi process which yielded 17 quality indicators for a new organizational WPV dashboard. WPV theories were critically reviewed in the context of intervention development. Educational initiatives (n=2) were implemented including ad-hoc point of care training, as well as rollout of a comprehensive trauma-informed training program for WPV prevention, verbal de-escalation and management of escalated responsive behaviour. Further changes involved establishing a Code White Governance Committee, enhancing WPV reporting and addressing underreporting. Debriefing was structured into hot and cold debriefing models. Additionally, environmental indicators promoting mutual respect were introduced, alongside security enhancements including wearable video devices for all security guards and a 100% increase in ED security guards. Outreach initiatives were implemented including qualitative interviews with ED staff (n=75) and the development of a patient partner and community outreach group. Conclusions: WPV in healthcare is a complex phenomenon that urgently requires effective solutions. We developed a 13-step framework that offers guidance for healthcare institutions seeking to develop a systemic approach in addressing WPV tailored to their organization’s needs.

Plasmacytoid dendritic cells regulate megakaryocyte and platelet homeostasis (preprint)

Platelet homeostasis is essential for vascular integrity and immune defense. While the process of platelet formation by fragmenting megakaryocytes (thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of megakaryocytes by their progenitor cells (megakaryopoiesis) remains unclear. Here we use intravital 2 photon microscopy to track individual megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as crucial bone marrow niche cells that regulate megakaryopoiesis. pDCs monitor the bone marrow for platelet-producing megakaryocytes and deliver IFN-a to the megakaryocytic niche to trigger local on-demand proliferation of megakaryocyte progenitors. This fine-tuned coordination between thrombopoiesis and megakaryopoiesis is crucial for megakaryocyte and platelet homeostasis in steady state and stress. However, uncontrolled pDC function within the megakaryocytic niche is detrimental. Accordingly, we show that pDCs activated by SARS-CoV2 drive inappropriate megakaryopoiesis associated with thrombotic complications. Together, we uncover a hitherto unknown megakaryocytic bone marrow niche maintained by the constitutive delivery of pDC-derived IFN-a.

Omicron and future public health emergencies: Sustainability and insights into support programs for healthcare providers (preprint)

Background: The mental health of healthcare workers (HCWs) has been at the forefront throughout the COVID-19 pandemic. While workplace-based support programs have been developed in hospitals globally, few systematically collected data. While critical to their success, information on these programs and the experience of mental healthcare providers (MHP) who support colleagues is limited. The objective of this study was to explore the experiences of MHP caring for HCW colleagues within a novel workplace-based mental health support program during the COVID-19 pandemic, to provide insights on facilitators, areas for improvement and barriers to program sustainability. Methods: This qualitative study used semi-structured interviews conducted by videoconference between September 2020 to October 2021.  UHN CARES (University Health Network Coping and Resilience for Employees and Staff) Program was developed during the first wave of the COVID-19 pandemic in March 2020. It supports over 21,000 staff members within the UHN, Canada’s largest academic health research institution, in Toronto, Canada. Purposive sampling was used to select 10 of the 22 MHP in the UHN CARES Program. Using a critical realism framework, key components required to sustain a successful workplace-based mental health support program for HCWs and balance the needs of MHP were determined. Results: Six psychiatrists and four psychologists with varying roles at UHN participated in 17 interviews, with repeat interviews exploring changes over time within the pandemic and program. Components which facilitated the success of the program included flexibility in scheduling, confidential health record storage, comprehensive administrative support, availability of resources and adaptive quality improvement approach. Recommendations for improvement included opportunities for peer supervision, triaging of cases, and managing HCW expectations. MHP found caring for HCWs to be meaningful and they utilized existing clinical skills during sessions. Challenges included working in a virtual setting, navigating boundaries when caring for colleagues, and managing the range of service users and their needs.Conclusions: These findings suggest how support programs can be structured for HCWs, how to provide support, and how to sustain this support, allowing health systems to balance the needs of HCWs and MHPs in preparation for future public health emergencies.

Protective Immune Trajectories in Early Viral Containment of Non-Pneumonic SARS-CoV-2 Infection (preprint)

The immune system of most SARS-CoV-2 infected individuals limits viral spread to the upper airways without pulmonary involvement. This prevents the development of pneumonic COVID-19. However, the protective immunological responses causative of successful viral containment in the upper airways remain unclear. Here, we combine longitudinal single-cell RNA sequencing, proteomic profiling, multidimensional flow cytometry, RNA-Seq of FACS-sorted leukocyte subsets and multiplex plasma interferon profiling to uncover temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients.We compare host responses in a high-risk patient population infected with SARS-CoV-2 but without pulmonary involvement to patients with COVID-19 pneumonia. Our data reveal a distinct immunological signature of successful viral containment, characterized by an early prominent interferon stimulated gene (ISG) upregulation across immune cell subsets. In addition, reduced cytotoxic potential of Natural Killer (NK) and T cells, as well as a monocyte phenotype with immune-modulatory potential are hallmarks of protective immunity. Temporal resolution across disease trajectories highlights ISG upregulation as particularly prominent early in the disease and confirms increased expression also in comparison to healthy controls.We validate this distinct temporal ISG signature by in-depth RNA-seq of FACS-sorted leukocyte subsets in a large prospective ambulatory SARS-CoV-2 infected cohort confirming early and robust ISG upregulation particularly in monocytes and T cells. In vitro experiments show that Stimulator of Interferon Genes (STING) agonist treatment of PBMCs recapitulates the identified protective immunological signature and might therefore offer a novel therapeutic approach in early disease, without being affected by previously described anti-interferon antibodies. In conclusion, our data demonstrate a protective ISG phenotype in patients with successful containment of SARS-CoV-2 infection without progression to COVID-19. This early protective interferon response might be exploited as a therapeutic approach and for disease course prediction.Funding: This study was supported by the Deutsche Herzstiftung e.V., Frankfurt a.M. [LN],Deutsche Forschungsgemeinschaft (DFG) SFB 914 (S.M. [B02 and Z01], K.S. [B02]), the DFG SFB 1123 (S.M. [B06], K.S. [A07]), M.J and R.Z [Z02]), the DFG FOR 2033 (S.M.), the DGF SFB1243 (W.E., L.E.W. [A14], the DGF EN 1093/2-1 (W.E., A.J.), the German Centre for Cardiovascular Research (DZHK) (Clinician Scientist Programme [L.N.], MHA 1.4VD [S.M.]), DZIF MD student programme (TI 07.003_Deák [F.D.]), FP7 program (project 260309, PRESTIGE [S.M.]), FöFoLe project 1015/1009 (L.N.), and the DFG Clinician Scientist Programme PRIME (413635475, K.P., R.K.). The work was also supported by the European Research Council (ERC 2018-ADG “IMMUNOTHROMBOSIS” [S.M.] and ERC- “T-MEMORE” [K.S.])The CORKUM cohort study was supported by LMUexcellent, funded by the Federal Ministry of Education and Research (BMBF) and the Free State of Bavaria under the Excellence Strategy of the Federal Government and the Länder.The Koco19-Immu Study is funded by Bavarian State Ministry of Science and the Arts, University Hospital, LMU Munich, Helmholtz Centre Munich, University of Bonn, University of Bielefeld, German Ministry for Education and Research (Project No.: 01KI20271).Conflict of Interest: The authors declare no conflict of interest.Ethical Approval: In accordance with the Declaration of Helsinki, and with the approval of the Ethics Committee of Ludwig-Maximilian University Munich, informed consent of the patients or their guardians was obtained. COVID-19 patients are part of the COVID-19 Registry of the LMU University Hospital Munich (CORKUM, WHO trial ID DRKS00021225). Pseudonymizeddata was used for analysis, the CORKUM and KocoImmu studies were approved by the ethics committee of LMUMunich (No: 20-245 & No: 20-371 respectively).

Protective immune trajectories in early viral containment of non-pneumonic SARS-CoV-2 infection (preprint)

The immune system of most SARS-CoV-2 infected individuals limits viral spread to the upper airways without pulmonary involvement. This prevents the development of pneumonic COVID-19. However, the protective immunological responses causative of successful viral containment in the upper airways remain unclear. Here, we combine longitudinal single-cell RNA sequencing, proteomic profiling, multidimensional flow cytometry, RNA-Seq of FACS-sorted leukocyte subsets and multiplex plasma interferon profiling to uncover temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients. We compare host responses in a high-risk patient population infected with SARS-CoV-2 but without pulmonary involvement to patients with COVID-19 pneumonia. Our data reveal a distinct immunological signature of successful viral containment, characterized by an early prominent interferon stimulated gene (ISG) upregulation across immune cell subsets. In addition, reduced cytotoxic potential of Natural Killer (NK) and T cells, as well as a monocyte phenotype with immune-modulatory potential are hallmarks of protective immunity. Temporal resolution across disease trajectories highlights ISG upregulation as particularly prominent early in the disease and confirms increased expression also in comparison to healthy controls. We validate this distinct temporal ISG signature by in-depth RNA-seq of FACS-sorted leukocyte subsets in a large prospective ambulatory SARS-CoV-2 infected cohort confirming early and robust ISG upregulation particularly in monocytes and T cells. In conclusion, our data demonstrate a protective ISG phenotype in patients with successful containment of SARS-CoV-2 infection without progression to COVID-19. This early protective interferon response might be exploited as a therapeutic approach and for disease course prediction.

Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease (preprint)

Here we present the crystal structure of SARS-CoV-2 main protease (Mpro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of Mpro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of Mpro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by Mpro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by Mpro, followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors.