Frailty, Outcomes, Recovery and Care Steps of Critically Ill Patients (FORECAST): a prospective, multi-centre, cohort study.

PURPOSE: Frailty is common in critically ill patients but the timing and optimal method of frailty ascertainment, trajectory and relationship with care processes remain uncertain. We sought to elucidate the trajectory and care processes of frailty in critically ill patients as measured by the Clinical Frailty Scale (CFS) and Frailty Index (FI). METHODS: This is a multi-centre prospective cohort study enrolling patients ≥ 50 years old receiving life support > 24 h. Frailty severity was assessed with a CFS, and a FI based on the elements of a comprehensive geriatric assessment (CGA) at intensive care unit (ICU) admission, hospital discharge and 6 months. For the primary outcome of frailty prevalence, it was a priori dichotomously defined as a CFS ≥ 5 or FI ≥ 0.2. Processes of care, adverse events were collected during ICU and ward stays while outcomes were determined for ICU, hospital, and 6 months. RESULTS: In 687 patients, whose age (mean ± standard deviation) was 68.8 ± 9.2 years, frailty prevalence was higher when measured with the FI (CFS, FI %): ICU admission (29.8, 44.8), hospital discharge (54.6, 67.9), 6 months (34.1, 42.6). Compared to ICU admission, aggregate frailty severity increased to hospital discharge but improved by 6 months; individually, CFS and FI were higher in 45.3% and 50.6% patients, respectively at 6 months. Compared to hospital discharge, 18.7% (CFS) and 20% (FI) were higher at 6 months. Mortality was higher in frail patients. Processes of care and adverse events were similar except for worse ICU/ward mobility and more frequent delirium in frail patients. CONCLUSIONS: Frailty severity was dynamic, can be measured during recovery from critical illness using the CFS and FI which were both associated with worse outcomes. Although the CFS is a global measure, a CGA FI based may have advantages of being able to measure frailty levels, identify deficits, and potential targets for intervention.

Patient-important upper gastrointestinal bleeding in the ICU: A mixed-methods study of patient and family perspectives.

INTRODUCTION: The 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. DESIGN: This 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. SETTING: Canada and the United States. PARTICIPANTS: 51 ICU survivors and family members of ICU patients. RESULTS: Participants considered gastrointestinal bleeding to be important if it resulted in death, disability, or prolonged hospitalization. The following also signaled patient-important upper gastrointestinal bleeding: blood transfusion, vasopressors, endoscopy, CT-angiography, or surgery. Whether an intervention evinced concern depended on its effectiveness, side-effects, invasiveness and accessibility; contextual influences included participant familiarity and knowledge of interventions and trust in the clinical team. CONCLUSIONS: Survivors of critical illness and family members described patient-important upper gastrointestinal bleeding differently than current definitions of clinically-important upper gastrointestinal bleeding.

An Exploratory and Qualitative Analysis of Self-Reported Evaluations for Fever.

Background: Despite the high prevalence of post-operative fever, a variety of approaches are taken as to the components of a fever evaluation, when it should be undertaken, and when empiric antibiotic agents should be started. Hypothesis: There is a lack of consensus surrounding many common components of a post-operative fever evaluation. Patients and Methods: The Surgical Infection Society membership was surveyed to determine practices surrounding evaluation of post-operative fever. Eight scenarios were posed in febrile (38.5°C), post-operative general surgery or trauma patients, with 19 possible components of work-up (physical examination, complete blood count [CBC], fungal biomarkers, lactate and procalcitonin [PCT] concentrations, cultures, imaging) and management (antibiotic agents). Each scenario was then re-considered for intensive care unit (ICU) patients (intubated/unstable hemodynamics). Agreement on a parameter (<1/4 or >3/4 of respondents) achieved consensus, positive or negative. Parameters between had equipoise; α was set at 0.05. Results: Among the examined scenarios, only CBC and physical examination received positive consensus across most scenarios. Blood/urine cultures, imaging, lactate, inflammatory biomarkers, and the empiric administration of antibiotic agents did not reach consensus; support was variable depending on the clinical scenario, illness severity, and the individual preferences of the answering clinician. The qualitative portion of the survey identified "fever threshold and duration," "clinical suspicion," and "physiologic manifestation" as the most important factors for deciding about the initiation of a fever evaluation and the potential empiric administration of antibiotic agents. Conclusions: There is consensus only for physical and examination routine laboratory work when initiating the evaluation of febrile post-operative patients. However, there are multiple components of a fever evaluation that individual respondents would select depending on the clinical scenario and severity of illness. Parameters demonstrating equipoise are potential candidates for formal guidance or pragmatic prospective trials.

Annexin A5 in Patients With Severe COVID-19 Disease: A Single-Center, Randomized, Double-Blind, Placebo-Controlled Feasibility Trial.

OBJECTIVES: To evaluate the study design and feasibility of drug administration and safety in a randomized clinical trial of recombinant human annexin A5 (SY-005), a constitutively expressed protein with anti-inflammatory, antiapoptotic, and anticoagulant properties, in patients with severe coronavirus disease 2019 (COVID-19). DESIGN: Double-blind, randomized clinical trial. SETTING: Two ICUs at an academic medical center. PATIENTS/SUBJECTS: Adults admitted to the ICU with a confirmed diagnosis of COVID-19 and requiring ventilatory or vasopressor support. INTERVENTIONS: SY-005, a recombinant human annexin A5, at 50 or 100 µg/kg IV every 12 hours for 7 days. MEASUREMENTS AND MAIN RESULTS: We enrolled 18 of the 55 eligible patients (33%) between April 21, 2021, and February 3, 2022. We administered 82% (196/238) of the anticipated doses of study medication and 86% (169/196) were given within 1 hour of the scheduled time. There were no drug-related serious adverse events. We captured 100% of the data that would be required for measuring clinical outcomes in a phase 2 or 3 trial. LIMITATIONS: The small sample size was a result of decreasing admissions of patients with COVID-19, which triggered a stopping rule for the trial. CONCLUSIONS: Although enrollment was low, administration of SY-005 to critically ill patients with COVID-19 every 12 hours for up to 7 days was feasible and safe. Further clinical trials of annexin A5 for the treatment of COVID-19 are warranted. Given reduction of severe COVID-19 disease, future studies should explore the safety and effectiveness of SY-005 use in non-COVID-related sepsis.

Self-Reported Diagnosis and Management of Surgical Site Infection Highlights Lack of Objective Measures and Treatment Guidance.

Background: There is little guidance regarding empiric therapy for superficial surgical site infections (SSIs). Management of incisions with signs of SSI lacks consensus and management is variable among individual surgeons. Methods: The Surgical Infection Society was surveyed regarding management of SSIs. Cases were provided with varying wound descriptions, initial wound class (WC), post-operative day, and presence of a prosthesis. Responses were in multiple-choice format; statistics: χ2; α = 0.05. Results: Seventy-eight members responded. For appearance scenarios, respondents believed that both mild erythema (55%) and clear drainage (64%) could be observed, whereas substantial (>3 cm) erythema or purulence should be treated with complete (22% and 50%) or partial (55% and 40%) opening of the incision. Degree of erythema did not influence administration of antibiotic agents, but purulence was more likely than clear drainage to be treated with antibiotics (38% vs. 6%; p < 0.001). There were no differences based on WC, except that clean cases were more likely than higher WC scenarios to be treated with gram-positive coverage alone (WC 1 [26%] vs. 2 [10%] vs. 3 [13%] vs. 4 [4%]; p < 0.001). Post-operative day (POD) three appeared to be an inflection point for more aggressive treatment of suspected incisional SSI, with fewer (POD 0 [86%] vs. POD day 3 [54%]; p < 0.001) reporting observation. Respondents were more likely to obtain imaging, start broad-spectrum antibiotic agents, and return to the operating room for purulence in the presence of a mesh. Conclusions: Presented with escalating possibility of SSI, respondents reported lower rates of observation, increased use of antibiotic agents, and increased surgical drainage. Many scenarios lack consensus regarding appropriate therapy. The complete elimination of SSIs is unlikely to be accomplished soon, and this study provides a framework for understanding how surgeons approach SSIs, and potential areas for further research or pragmatic guidance.

Different Surgeon, Different Closure: Lack of Consensus on Appropriate Closure Technique for Various Case Scenarios.

Background: Many techniques for closure of surgical incisions are available to the surgeon, but there is minimal guidance regarding which technique(s) should be utilized at the conclusion of surgery and under what circumstances. Hypothesis: Management of incisions at the conclusion of surgery lacks consensus and varies among individual surgeons. Methods: The Surgical Infection Society membership was surveyed on the management of incisions at the conclusion of surgery. Several case scenarios were provided to test the influences of operation type, intra-operative contamination, and hemodynamic stability on incision management (e.g., close fascia or skin, use of incision/wound vacuum-assisted closure [VAC] device). Responses by two-thirds of participants were required to achieve consensus. Data analysis by χ2 test and logistic regression, a = 0.05. Response heterogeneity was quantified by the Shannon index (SI). Results: Among 78 respondents, consensus was achieved for elective splenectomy (91% close skin/dry dressing). Open appendectomy and left colectomy/end-colostomy had the greatest heterogeneity (SI, 1.68 and 1.63, respectively). During trauma laparotomy, the majority used damage control for hemodynamic instability (53%-67%) but not for hemodynamically stable patients (0%-1.3%; p < 0.001). Additional consensus was achieved for close skin/dry dressing for hemodynamically stable trauma splenectomy patients (87%) and fascia open/wound VAC for hemodynamically unstable colon resection/anastomosis (67%). Fecal diversion for rectal injury and colon resection/anastomosis (both when hemodynamically stable) had high heterogeneity (SI, 1.56 and 1.48, respectively). In penetrating trauma, sentiment was for more use of wet-to-dry dressings and incision/wound VAC with increased contamination in hemodynamically stable patients. Conclusions: Damage control was favored in hemodynamically unstable trauma patients, with use of wet-to-dry dressings and incision/wound VAC with spillage after penetrating trauma. However, most scenarios did not achieve consensus. High variability of practices regarding incision management at the conclusion of surgery was confirmed. Prospective studies and evidence-based guidance are needed to guide decision making at end-operation.

What counts as patient-important upper gastrointestinal bleeding in the ICU? A mixed-methods study protocol of patient and family perspectives.

INTRODUCTION: Clinically important upper gastrointestinal bleeding is conventionally defined as bleeding accompanied by haemodynamic changes, requiring red blood cell transfusions or other invasive interventions. However, it is unclear if this clinical definition reflects patient values and preferences. This protocol describes a study to elicit views from patients and families regarding features, tests, and treatments for upper gastrointestinal bleeding that are important to them. METHODS AND ANALYSIS: This is a sequential mixed-methods qualitative-dominant multi-centre study with an instrument-building aim. We developed orientation tools and educational materials in partnership with patients and family members, including a slide deck and executive summary. We will invite intensive care unit (ICU) survivors and family members of former ICU patients to participate. Following a virtual interactive presentation, participants will share their perspectives in an interview or focus group. Qualitative data will be analysed using inductive qualitative content analysis, wherein codes will be derived directly from the data rather than using preconceived categories. Concurrent data collection and analysis will occur. Quantitative data will include self-reported demographic characteristics. This study will synthesise the values and perspectives of patients and family members to create a new trial outcome for a randomised trial of stress ulcer prophylaxis. This study is planned for May 2022 to August 2023. The pilot work was completed in Spring 2021. ETHICS AND DISSEMINATION: This study has ethics approval from McMaster University and the University of Calgary. Findings will be disseminated via manuscript and through incorporation as a secondary trial outcome on stress ulcer prophylaxis. TRIAL REGISTRATION NUMBER: NCT05506150.

Longitudinal analysis of mucosa-associated invariant T cells in sepsis reveals their early numerical decline with prognostic implications and a progressive loss of antimicrobial functions.

Sepsis-elicited immunosuppression elevates the risk of secondary infections. We used a clinically relevant mouse model and serial peripheral blood samples from patients to assess the antimicrobial activities of mucosa-associated invariant T (MAIT) cells in sepsis. Hepatic and splenic MAIT cells from B6-MAITCAST mice displayed increased CD69 expression and a robust interferon-γ (IFNγ) production capacity shortly after sublethal cecal ligation and puncture, but not at a late timepoint. Peripheral blood MAIT cell frequencies were reduced in septic patients at the time of intensive care unit (ICU) admission, and more dramatically so among nonsurvivors, suggesting the predictive usefulness of early MAIT cell enumeration. In addition, at ICU admission, MAIT cells from sepsis survivors launched stronger IFNγ responses to several bacterial species compared with those from patients who subsequently died of sepsis. Of note, while low human leukocyte antigen (HLA)-DR+ monocyte frequencies, widely regarded as a surrogate indicator of sepsis-induced immunosuppression, were gradually corrected, the numerical insufficiency of MAIT cells was not resolved over time, and their CD69 expression continued to decline. MAIT cell responses to bacterial pathogens, a major histocompatibility complex-related protein 1 (MR1) ligand, and interleukin (IL)-12 and IL-18 were also progressively lost during sepsis and did not recover by the time of ICU/hospital discharge. We propose that MAIT cell dysfunctions contribute to post-sepsis immunosuppression.

Clinical characteristics, multiorgan dysfunction and outcomes of patients with COVID-19: a prospective case series.

BACKGROUND: Characterizing the multiorgan manifestations and outcomes of patients hospitalized with COVID-19 will inform resource requirements to address the long-term burden of this disease. We conducted a descriptive analysis using prospectively collected data to describe the clinical characteristics and spectrum of organ dysfunction, and in-hospital and longer-term clinical outcomes of patients hospitalized with COVID-19 during the first wave of the pandemic at a Canadian centre. METHODS: We conducted a prospective case series involving adult patients (aged ≥ 18 yr) with COVID-19 admitted to 1 of 2 hospitals in London, Ontario, from Mar. 17 to June 18, 2020, during the first wave of the pandemic. We recorded patients' baseline characteristics, physiologic parameters, measures of organ function and therapies administered during hospitalization among patients in the intensive care unit (ICU) and in non-ICU settings, and compared the characteristics of hospital survivors and nonsurvivors. Finally, we recorded follow-up thoracic computed tomography (CT) and echocardiographic findings after hospital discharge. RESULTS: We enrolled 100 consecutive patients (47 women) hospitalized with COVID-19, including 32 patients who received ICU care and 68 who received treatment in non-ICU settings. Respiratory sequelae were common: 23.0% received high-flow oxygen by nasal cannula, 9.0% received noninvasive ventilation, 24.0% received invasive mechanical ventilation and 2.0% received venovenous extracorporeal membrane oxygenation. Overall, 9.0% of patients had cerebrovascular events (3.0% ischemic stroke, 6.0% intracranial hemorrhage), and 6.0% had pulmonary embolism. After discharge, 11 of 19 patients had persistent abnormalities on CT thorax, and 6 of 15 had persistent cardiac dysfunction on echocardiography. INTERPRETATION: This study provides further evidence that COVID-19 is a multisystem disease involving neurologic, cardiac and thrombotic dysfunction, without evidence of hepatic dysfunction. Patients have persistent organ dysfunction after hospital discharge, underscoring the need for research on long-term outcomes of COVID-19 survivors.

Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit.

BACKGROUND: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

Lessening Organ Dysfunction With Vitamin C (LOVIT) Trial: Statistical Analysis Plan.

BACKGROUND: The LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor. OBJECTIVE: We aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database. METHODS: The SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses. RESULTS: The SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status. CONCLUSIONS: We have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36261.

Different Surgeon, Different Duration: Lack of Consensus on the Appropriate Duration of Antimicrobial Prophylaxis and Therapy in Surgical Practice.

Background: The principles of antimicrobial stewardship promote the appropriate prescribing of agents with respect to efficacy, safety, duration, and cost. Antibiotic resistance often results from inappropriate use (e.g., indication, selection, duration). We evaluated practice variability in duration of antimicrobials in surgical infection treatment (Rx) or prophylaxis (Px). Hypothesis: There is lack of consensus regarding the duration of antibiotic Px and Rx for many common indications. Methods: A survey was distributed to the Surgical Infection Society (SIS) regarding the use of antimicrobial agents for a variety of scenarios. Standard descriptive statistics were used to compare survey responses. Heterogeneity among question responses were compared using the Shannon Index, expressed as natural units (nats). Results: Sixty-three SIS members responded, most of whom (67%) have held a leadership position within the SIS or contributed as an annual meeting moderator or discussant; 76% have been in practice for more than five years. Regarding peri-operative Px, more than 80% agreed that a single dose is adequate for most indications, with the exceptions of gangrenous cholecystitis (40% single dose, 38% pre-operative +24 hours) and inguinal hernia repair requiring a bowel resection (70% single dose). There was more variability regarding the use of antibiotic Px for various bedside procedures with respondents split between none needed (range, 27%-66%) versus a single dose (range, 31%-67%). Opinions regarding the duration of antimicrobial Rx for hospitalized patients who have undergone a source control operation or procedure varied widely based on indication. Only two of 20 indications achieved more than 60% consensus despite available class 1 evidence: seven days for ventilator-associated pneumonia (77%), and four plus one days for perforated appendicitis (62%). Conclusions: Except for peri-operative antibiotic Px, there is little consensus regarding antibiotic duration among surgical infection experts, despite class 1 evidence and several available guidelines. This highlights the need for further high-level research and better dissemination of guidelines.

Surgical Infections and the Future of Research: Re-Defining the Research Agenda for the Surgical Infection Society.

Background: Infections represent a major component of surgical practice. Risk mitigation, seeking eradication and optimal patient outcomes, require a concerted, multifocal effort to understand disease and microbiology, prevent infections, and treat them. The present study was undertaken to re-define the Surgical Infection Society (SIS) research agenda for the next decade. Hypothesis: We utilized the expertise of the SIS membership to identify research questions regarding surgical infections, hypothesizing that consensus among participants could be used to re-define the future research agenda. Methods: Members of the SIS were surveyed using a modified Delphi. The three rounds of the survey were targeted at: question generation; question ranking; and reaching consensus. Each of the 15 questions to emerge was evaluated according to level of consensus, feasibility, and data availability. Results: One hundred twenty-four participants contributed. Initially, 226 questions were generated that were condensed to 35 unique questions for consideration in the subsequent two rounds. The 35 questions encompassed several research themes, with antibiotic prophylaxis (n = 8), prevention of surgical site infections (SSIs; n = 6), and improved diagnostics (n = 5) being most common. Standard deviation of importance scores was inversely proportional to the question rank, indicating greater consensus among higher ranking questions. All 15 questions had a feasibility score of greater than three (five-point Likert scale), and the majority (12/15) had a mean data availability score of less than three. In the final round of the survey, the top three topics for further research surrounded non-antimicrobial treatments, optimal treatment duration for bacteremia, and treatment duration for necrotizing soft tissue infections. Conclusions: Using a modified Delphi process, 15 research questions addressing surgical infections were identified. Such questions can assist the SIS and the SIS Foundation for Research and Education in prioritizing and enabling research efforts, and development of a strategic research plan for the next decade.

Scoring Sepsis Severity in Mice.

A reliable scoring system that predicts the development of sepsis, septic shock, and death enables comparison of disease severity and treatment outcomes in animal models of sepsis. Mice are used in the majority of preclinical sepsis studies. We describe a murine sepsis score that evaluates seven clinical variables in an experimental mouse model of polymicrobial sepsis.

Knowledge translation tools to guide care of non-intubated patients with acute respiratory illness during the COVID-19 Pandemic.

Providing optimal care to patients with acute respiratory illness while preventing hospital transmission of COVID-19 is of paramount importance during the pandemic; the challenge lies in achieving both goals simultaneously. Controversy exists regarding the role of early intubation versus use of non-invasive respiratory support measures to avoid intubation. This review summarizes available evidence and provides a clinical decision algorithm with risk mitigation techniques to guide clinicians in care of the hypoxemic, non-intubated, patient during the COVID-19 pandemic. Although aerosolization of droplets may occur with aerosol-generating medical procedures (AGMP), including high flow nasal oxygen and non-invasive ventilation, the risk of using these AGMP is outweighed by the benefit in carefully selected patients, particularly if care is taken to mitigate risk of viral transmission. Non-invasive support measures should not be denied for conditions where previously proven effective and may be used even while there is suspicion of COVID-19 infection. Patients with de novo acute respiratory illness with suspected/confirmed COVID-19 may also benefit. These techniques may improve oxygenation sufficiently to allow some patients to avoid intubation; however, patients must be carefully monitored for signs of increased work of breathing. Patients showing signs of clinical deterioration or high work of breathing not alleviated by non-invasive support should proceed promptly to intubation and invasive lung protective ventilation strategy. With adherence to these principles, risk of viral spread can be minimized.

Gender Disparities in Medical Student Surgical Skills Education.

OBJECTIVE: Female medical students and surgical trainees are more likely to lack confidence in their clinical abilities than their male peers despite equal or superior performance. This study aims to examine the role of gender in medical student experience and confidence performing technical skills in surgical clerkship. DESIGN: This was a single-center survey study conducted over 2 academic years (2016-2018). Students were surveyed on their experience and confidence performing a set of 9 technical skills during surgical clerkship and to identify skill-specific barriers to learning. SETTING: This study was performed at Western University, London, Ontario, Canada. PARTICIPANTS: All third-year medical students were invited to participate. RESULTS: A total of 253 students participated yielding a survey response rate of 74.0%. Both male and female students reported similar levels of preclerkship interest in a surgical career, enjoyment in performing technical skills, confidence in ability to learn surgical skills and pursuit of available learning opportunities. At the conclusion of their surgical rotations, female students reported less experience and confidence performing technical skills compared to their male colleagues. Female students were more likely to cite an insufficient number of learning opportunities from consultant and resident teachers, time constraints, and lack of confidence as barriers to the achievement of technical proficiency. CONCLUSIONS: Female gender was associated with less procedural experience and inferior confidence performing procedural skills. It is important for educators to be aware of this gender disparity and to actively promote equitable learning opportunities for female trainees.

Harnessing the Versatility of Invariant NKT Cells in a Stepwise Approach to Sepsis Immunotherapy.

Sepsis results from a heavy-handed response to infection that may culminate in organ failure and death. Many patients who survive acute sepsis become immunosuppressed and succumb to opportunistic infections. Therefore, to be successful, sepsis immunotherapies must target both the initial and the protracted phase of the syndrome to relieve early immunopathology and late immunosuppression, respectively. Invariant NKT (iNKT) cells are attractive therapeutic targets in sepsis. However, repeated treatments with α-galactosylceramide, the prototypic glycolipid ligand of iNKT cells, result in anergy. We designed a double-hit treatment that allows iNKT cells to escape anergy and exert beneficial effects in biphasic sepsis. We tested the efficacy of this approach in the sublethal cecal ligation and puncture mouse model, which mirrors polymicrobial sepsis with progression to an immunosuppressed state. Septic mice were treated with [(C2S, 3S, 4R)-1-O-(α-d-galactopyranosyl)-N-tetracosanoyl-2-amino-1,3,4-nonanetriol] (OCH), a TH2-polarizing iNKT cell agonist, before they received α-galactosylceramide. This regimen reduced the morbidity and mortality of cecal ligation and puncture, induced a transient but robust IFN-γ burst within a proinflammatory cytokine/chemokine landscape, transactivated NK cells, increased MHC class II expression on macrophages, and restored delayed-type hypersensitivity to a model hapten, consistent with recovery of immunocompetence in protracted sepsis. Structurally distinct TH2-polarizing agonists varied in their ability to replace OCH as the initial hit, with their lipid chain length being a determinant of efficacy. The proposed approach effectively exploits iNKT cells' versatility in biphasic sepsis and may have translational potentials in the development of new therapies.

Surgical Infection Society Research Priorities: A Narrative Review of Fourteen Years of Progress.

Background: In 2006, the Surgical Infection Society (SIS) utilized a modified Delphi approach to define 15 specific priority research questions that remained unanswered in the field of surgical infections. The aim of the current study was to evaluate the scientific progress achieved during the ensuing period in answering each of the 15 research questions and to determine if additional research in these fields is warranted. Methods: For each of the questions, a literature search using the National Center for Biotechnology Information (NCBI) was performed by the Scientific Studies Committee of the SIS to identify studies that attempted to address each of the defined questions. This literature was analyzed and summarized. The data on each question were evaluated by a surgical infections expert to determine if the question was answered definitively or remains unanswered. Results: All 15 priority research questions were studied in the last 14 years; six questions (40%) were definitively answered and 9 questions (60%) remain unanswered in whole or in part, mainly because of the low quality of the studies available on this topic. Several of the 9 unanswered questions were deemed to remain research priorities in 2020 and warrant further investigation. These included, for example, the role of empiric antimicrobial agents in nosocomial infections, the use of inotropes/vasopressors versus volume loading to raise the mean arterial pressure, and the role of increased antimicrobial dosing and frequency in the obese patient. Conclusions: Several surgical infection-related research questions prioritized in 2006 remain unanswered. Further high-quality research is required to provide a definitive answer to many of these priority knowledge gaps. An updated research agenda by the SIS is warranted at this time to define research priorities for the future.

Circular RNA Foxo3 in cardiac ischemia-reperfusion injury in heart transplantation: A new regulator and target.

Ischemia-reperfusion (I/R) injury occurring in heart transplantation (HT) remains as a leading cause of transplant heart graft failure. Circular RNAs (circRNAs) play important roles in gene regulation and diseases. However, the impact of circRNAs on I/R injury during HT remains unknown. This study aims to investigate the role of circular RNA Foxo3 (circFoxo3) in I/R injury in HT. Using an in vivo mouse HT model and an in vitro cardiomyocyte culture model, we demonstrated that circFoxo3 is significantly upregulated in I/R-injured hearts and hypoxia/reoxygenation (H/R)-damaged cardiomyocytes. Knockdown of circFoxo3 using siRNA not only reduces cell apoptosis and death, mitochondrial damage, and expression of apoptosis/death-related genes in vitro, but also protects heart grafts from prolonged cold I/R injury in HT. We also show that circFoxo3 interacts with Foxo3 proteins and inhibits the phosphorylation of Foxo3 and that it indirectly affects the expression of miR-433 and miR-136. In conclusion, circRNA is involved in I/R injury in HT and knockdown of circFoxo3 with siRNA can reduce I/R injury and improve heart graft function through interaction with Foxo3. This study highlights that circRNA is a new type of molecular regulator and a potential target for preventing I/R injury in HT.

Improving gender equity in critical care medicine: a protocol to establish priorities and strategies for implementation.

INTRODUCTION: While the number of women entering medical school now equals or surpasses the number of men, gender equity in medicine has not been achieved. Women continue to be under-represented in leadership roles (eg, deans, medical chairs) and senior faculty positions. In addition, women do not enter medical specialties as often as men, which can have important implications for work environment, reimbursement and the delivery of patient care. Compared with other medical specialties (eg, anaesthesiology, dermatology, etc), critical care medicine is a medical specialty with some of the lowest representation of women. While strategies to improve gender equity in critical care medicine exist in the published literature, efforts to comprehensively synthesise, prioritise and implement solutions have been limited.The objective of this programme of work is to establish priorities for the development and implementation of key strategies to improve the outcomes, well-being and experiences of women in critical care in Canada. METHODS AND ANALYSIS: Three phases encompass this programme of work. In phase I, we will catalogue published strategies focused on improving gender inequity across medical specialties through a scoping review. In phase II, we will conduct a modified Delphi consensus process with decision-makers, physicians and researchers to identify key strategies (identified in phase I and proposed by participants in phase II) for improving gender inequity in the specialty of critical care medicine. Finally, in phase III, we will conduct a 1-day stakeholder meeting that engages participants from phase II to build capacity for the development and implementation of top ranked strategies. Data analyses from this programme of work will be both quantitative and qualitative. ETHICS AND DISSEMINATION: The proposed programme of work is a foundational step towards establishing targeted strategies to improve gender inequity in the medical specialty of critical care medicine. Strategies will be prioritised by stakeholders, mapped to preidentified drivers of gender equity in the specialty and be scalable to institutional needs. A final report of our results including the list of top prioritised strategies and implementation objectives will be disseminated to panel participants, critical care leadership teams and major critical care societies who are partners in this work, around the country to facilitate uptake at the local level.The University of Calgary Conjoint Health Research Ethics Board has approved this study (REB16-0890).