John C Marshall

Sepsis is common, global, and deadly. Although most of its victims live in low-and middle-income countries (LMICs)(1), clinical trials of treatment approaches are disproportionately conducted in high-income countries (HICs)(2). This disparity in access to research is an important and modifiable contributor to the inequitable distribution of the global burden of sepsis.Multiple factors—host, pathogen, and healthcare system factors—can impact the effectiveness of specific sepsis treatments; these differ around the world and are only rarely incorporated into trial design (Figure 1). Malnutrition and the human immunodeficiency virus may be more prevalent in LMICs. In HICs, sepsis is primarily driven by bacterial infection, whereas in LMICs parasitic and mycobacterial infections are more common (3). Antimicrobial resistance causes excess mortality worldwide, but its impact is most notable in Sub-Saharan Africa (4 …

RationaleAcute 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.ObjectiveTo map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis.MethodsWe 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 …

Sepsis is a common and deadly condition. The current framing of dysregulated host immune responses within the sepsis immunobiology model into pro-inflammatory and immunosuppressive responses for testing novel treatments, have not resulted in successful immunomodulatory therapies.

IntroductionThe objective of this study was to create a definition of patient-important upper gastrointestinal bleeding during critical illness as an outcome for a randomized trial.DesignThis was a sequential mixed-methods qualitative-dominant multi-center study with an instrument-building aim. In semi-structured individual interviews or focus groups we elicited views from survivors of critical illness and family members of patients in the intensive care unit (ICU) regarding which features indicate important gastrointestinal bleeding. Quantitative demographic characteristics were collected. We analyzed qualitative data using inductive content analysis to develop a definition for patient-important upper gastrointestinal bleeding.SettingCanada and the United States.Participants51 ICU survivors and family members of ICU patients.ResultsParticipants considered gastrointestinal bleeding to be important if it resulted in death …

Sepsis is a common and deadly condition. Within the current model of sepsis immunobiology, the framing of dysregulated host immune responses into proinflammatory and immunosuppressive responses for the testing of novel treatments has not resulted in successful immunomodulatory therapies. Thus, the recent focus has been to parse observable heterogeneity into subtypes of sepsis to enable personalised immunomodulation. In this Personal View, we highlight that many fundamental immunological concepts such as resistance, disease tolerance, resilience, resolution, and repair are not incorporated into the current sepsis immunobiology model. The focus for addressing heterogeneity in sepsis should be broadened beyond subtyping to encompass the identification of deterministic molecular networks or dominant mechanisms. We explicitly reframe the dysregulated host immune responses in sepsis as …

Critical care uses syndromic definitions to describe patient groups for clinical practice and research. There is growing recognition that a “precision medicine” approach is required and that integrated biologic and physiologic data identify reproducible subpopulations that may respond differently to treatment. This article reviews the current state of the field and considers how to successfully transition to a precision medicine approach. In order to impact clinical care, identified subpopulations must do more than differentiate prognosis. They must differentiate response to treatment, ideally by defining subgroups with distinct functional or pathobiological mechanisms (endotypes). There are now multiple examples of reproducible subpopulations of sepsis, acute respiratory distress syndrome, and acute kidney or brain injury described using clinical, physiological, and/or biological data. Many of these subpopulations have …

Background Community acquired pneumonia (CAP) is a common cause of morbidity and mortality globally. Poor outcomes are driven by maladaptive inflammatory and thrombotic host responses. Effective therapies that modulate host responses are lacking. Anti-platelet medications modulate thrombotic and inflammatory pathways and improve long term outcomes in COVID-19 pneumonia, however, the role of anti-platelets in other etiologies of CAP remains uncertain. Methods We will conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies including adult patients hospitalized for non-COVID-19 community acquired pneumonia (CAP) investigating the effect of anti-platelets (ASA or P2Y12 inhibitors) vs. control on all-cause mortality. We will search electronic databases including MEDLINE (Epub Ahead of Print and In-Process, In-Data-Review & Other Non-Indexed Citations), Embase, Cochrane Central Register of Controlled Trials (CENTRAL), clinical trial registries (clinicaltrials.gov, International Clinical Trials Registry Platform) and conference abstracts from inception to August 2023. Two blinded reviewers will extract data in parallel from included studies after title and abstract screening and application of eligibility criteria. We will use the Cochrane Risk of Bias tool and Newcastle Ottawa Scale to assess risk of bias and study quality from included studies. The primary meta-analysis will be conducted separately for RCTs and observational studies using Random effect inverse variance model. For observational studies, adjusted mortality estimates will be presented as hazard ratios (HR) or …

Background In preclinical studies, mesenchymal stromal cells (MSCs), including umbilical cord-derived MSCs (UC-MSCs), demonstrate the ability to modulate numerous pathophysiological processes related to sepsis; however, a systematic synthesis of the literature is needed to assess the efficacy of UC-MSCs for treating sepsis. Objective To examine the effects of UC-MSCs on overall mortality (primary outcome) as well as on organ dysfunction, coagulopathy, endothelial permeability, pathogen clearance, and systemic inflammation (secondary outcomes) at prespecified time intervals in preclinical models of sepsis. Methods A systematic search was conducted on Embase, Ovid MEDLINE, and Web of Science up to June 20, 2023. Preclinical controlled studies using in vivo sepsis models with systemic UC-MSC administration were included. Meta-analyses …