Post-operative delirium is the most common complication in older adults following surgery. Symptoms include agitation, difficulty focusing, sluggishness, hallucinations, slurred speech, restlessness, rapid mood swings, and uncooperative or aggressive behaviour. It can result in longer hospital stays, increased mortality, loss of functional independence, increased need for a higher level of care post-surgery, and an increased risk of readmission to hospital. We aimed to understand and describe the experiences of patients, families, and healthcare providers with postoperative delirium, and to identify targeted initiatives to support patient and family centered care for high-risk patients. We conducted a qualitative descriptive study using interviews and surveys with two patients with lived experience, five family caregivers, and 11 perioperative healthcare providers between June 2023 to September 2024. Interview transcripts and open-ended survey responses were analyzed deductively according to expert recommendations. Participants reported that preoperative screening for delirium risk factors was uncommon and suggested risk factors be discussed with patients and families. Participants shared that no formal anesthesia protocols were in place intraoperatively, but anesthesiologists aim to use fewer high-risk medications in at-risk patients. Healthcare providers asked basic reorientation questions after surgery, but patients did not undergo formal delirium assessments. Four main suggestions to improve care for patients at risk for postoperative delirium included standardizing protocols, sharing information about cognitive risks with patients and families, focusing on environmental and behavioural interventions, and conducting ongoing evaluation. These findings will inform the development of a patient-centered multi-hospital postoperative delirium prevention pathway to reduce delirium amongst older patients.

Importance:Delirium is common after cardiac surgery and associated with adverse outcomes. Intraoperative benzodiazepines may increase postoperative delirium but restricting intraoperative benzodiazepines has not yet been evaluated in a randomized trial. Objective:To determine whether an institutional policy of restricted intraoperative benzodiazepine administration reduced the incidence of postoperative delirium. Design, Setting, and Participants:This pragmatic, multiperiod, patient- and assessor-blinded, cluster randomized crossover trial took place at 20 North American cardiac surgical centers. All adults undergoing open cardiac surgery at participating centers during the trial period were included through a waiver of individual patient consent between November 2019 and December 2022. Intervention:Institutional policies of restrictive vs liberal intraoperative benzodiazepine administration were compared. Hospitals (clusters) were randomized to cross between the restricted and liberal benzodiazepine policies 12 to 18 times over 4-week periods. Main Outcomes and Measures:The primary outcome was the incidence of delirium within 72 hours of surgery as detected in routine clinical care, using either the Confusion Assessment Method-Intensive Care Unit or the Intensive Care Delirium Screening Checklist. Intraoperative awareness by patient report was assessed as an adverse event. Results:During the trial, 19 768 patients (mean [SD] age, 65 [12] years; 14 528 [73.5%] male) underwent cardiac surgery, 9827 during restricted benzodiazepine periods and 9941 during liberal benzodiazepine periods. During restricted periods, clinicians adhered to assigned policy in 8928 patients (90.9%), compared to 9268 patients (93.2%) during liberal periods. Delirium occurred in 1373 patients (14.0%) during restricted periods and 1485 (14.9%) during liberal periods (adjusted odds ratio [aOR], 0.92; 95% CI, 0.84-1.01; P = .07). No patient spontaneously reported intraoperative awareness. Conclusions and Relevance:In intention-to-treat analyses, restricting benzodiazepines during cardiac surgery did not reduce delirium incidence but was also not associated with an increase in the incidence of patient-reported intraoperative awareness. Given that smaller effect sizes cannot be ruled out, restriction of benzodiazepines during cardiac surgery may be considered. Research is required to determine whether restricting intraoperative benzodiazepines at the patient level can reduce the incidence of postoperative delirium. Trial Registration:ClinicalTrials.gov Identifier: NCT03928236.

ImportanceDelirium is common after cardiac surgery and associated with adverse outcomes. Intraoperative benzodiazepines may increase postoperative delirium but restricting intraoperative benzodiazepines has not yet been evaluated in a randomized trial.ObjectiveTo determine whether an institutional policy of restricted intraoperative benzodiazepine administration reduced the incidence of postoperative delirium.Design, Setting, and ParticipantsThis pragmatic, multiperiod, patient- and assessor-blinded, cluster randomized crossover trial took place at 20 North American cardiac surgical centers. All adults undergoing open cardiac surgery at participating centers during the trial period were included through a waiver of individual patient consent between November 2019 and December 2022.InterventionInstitutional policies of restrictive vs liberal intraoperative benzodiazepine administration were compared. Hospitals (clusters) were randomized to cross between the restricted and liberal benzodiazepine policies 12 to 18 times over 4-week periods.Main Outcomes and MeasuresThe primary outcome was the incidence of delirium within 72 hours of surgery as detected in routine clinical care, using either the Confusion Assessment Method–Intensive Care Unit or the Intensive Care Delirium Screening Checklist. Intraoperative awareness by patient report was assessed as an adverse event.ResultsDuring the trial, 19 768 patients (mean [SD] age, 65 [12] years; 14 528 [73.5%] male) underwent cardiac surgery, 9827 during restricted benzodiazepine periods and 9941 during liberal benzodiazepine periods. During restricted periods, clinicians adhered to assigned policy in 8928 patients (90.9%), compared to 9268 patients (93.2%) during liberal periods. Delirium occurred in 1373 patients (14.0%) during restricted periods and 1485 (14.9%) during liberal periods (adjusted odds ratio [aOR], 0.92; 95% CI, 0.84-1.01; P = .07). No patient spontaneously reported intraoperative awareness.Conclusions and RelevanceIn intention-to-treat analyses, restricting benzodiazepines during cardiac surgery did not reduce delirium incidence but was also not associated with an increase in the incidence of patient-reported intraoperative awareness. Given that smaller effect sizes cannot be ruled out, restriction of benzodiazepines during cardiac surgery may be considered. Research is required to determine whether restricting intraoperative benzodiazepines at the patient level can reduce the incidence of postoperative delirium.Trial RegistrationClinicalTrials.gov Identifier: NCT03928236

Post-acute sequelae of COVID-19 (PASC) or the continuation of COVID-19 (Coronavirus disease 2019) symptoms past 12 weeks may affect as many as 30% of people recovering from a SARS-CoV-2 (severe acute respiratory coronavirus 2) infection. The mechanisms regulating the development of PASC are currently not known; however, hypotheses include virus reservoirs, pre-existing conditions, microblood clots, immune dysregulation, as well as poor antibody responses. Importantly, virus neutralizing antibodies are essential for COVID-19 recovery and protection from reinfection but there is currently limited information on these immune regulators and associated cytokines in PASC patients. Understanding the key drivers of general and specific symptoms associated with Long COVID and the presence of virus neutralizing antibodies in PASC will aid in the development of therapeutics, diagnostics, and vaccines which currently do not exist. We designed a cross-sectional study to investigate systemic antibody and cytokine responses during COVID-19 recovery and PASC. In total, 195 participants were recruited in one of four groups: (1) Those who never had COVID-19 (No COVID); (2) Those in acute COVID-19 recovery (Acute Recovery) (4–12 weeks post infection); (3) Those who recovered from COVID-19 (Recovered) (+ 12 weeks from infection); and (4) those who had PASC (PASC) (+ 12 weeks from infection). Participants completed a questionnaire on health history, sex, gender, demographics, experiences with COVID-19 acute and COVID-19 recovery/continuing symptoms. Serum samples collected were evaluated for antibody binding to viral proteins, virus neutralizing antibody titers, and serum cytokine levels using Ella SimplePlex Immunoassay™ panels. We found participants with PASC reported more pre-existing conditions (e.g. such as hypertension, asthma, and obesity), and PASC symptoms (e.g. fatigue, brain fog, headaches, and shortness of breath) following COVID-19 than COVID-19 Recovered individuals. Importantly, we found PASC individuals to have significantly decreased levels of neutralizing antibodies toward both SARS-CoV-2 and the Omicron BA.1 variant. Sex analysis indicated that female PASC study participants had sustained antibody levels as well as levels of the inflammatory cytokines GM-CSF and ANG-2 over time following COVID-19. Our study reports people experiencing PASC had lower levels of virus neutralizing antibodies; however, the results are limited by the collection time post-COVID-19 and post-vaccination. Moreover, we found females experiencing PASC had sustained levels of GM-CSF and ANG-2. With lower levels of virus neutralizing antibodies, this data suggests that PASC individuals not only have had a suboptimal antibody response during acute SARS-CoV-2 infection but may also have increased susceptibility to subsequent infections which may exacerbate or prolong current PASC illnesses. We also provide evidence suggesting GM-CSF and ANG-2 to play a role in the sex-bias of PASC. Taken together, our findings maybe important for understanding immune molecular drivers of PASC and PASC subgroups.

To determine the acceptability of the ClearSight™ system (Edwards Lifesciences Corp., Irvine, CA, USA) for continuous blood pressure monitoring during elective cardiac surgery compared with arterial catheterization. We enrolled 30 patients undergoing elective cardiac surgery in a prospective observational study. Blood pressure measurements were recorded every 10 sec intraoperatively. We determined agreement based on the Association for the Advancement of Medical Instrumentation (AAMI) recommendations. Statistical analysis included fixed bias (difference of measurements between methods), percentage error (accuracy between ClearSight measurement and expected measurement from arterial line), and interchangeability (ability to substitute ClearSight monitor without effecting overall outcome of analysis). We used a paired samples t test to compare the time required for placing each monitor. We found fixed bias in the differences between the ClearSight monitor and invasive arterial blood pressure measurement in systolic blood pressure (SBP; mean difference, 8.7; P < 0.001) and diastolic blood pressure (DBP; mean difference, −2.2; P < 0.001), but not in mean arterial pressure (MAP; mean difference, −0.5; P < 0.001). Bland–Altman plots showed that the means of the limits of agreement were greater than 5 mm Hg for SBP, DBP, and MAP. The percentage errors for SBP, DBP, and MAP were lower than the cutoff we calculated from the invasive arterial blood pressure measurements. Average interchangeability rates were 38 NCT05825937 ); first submitted 11 April 2023.

Post-acute sequelae of COVID-19 (PASC) or the continuation of COVID-19 (Coronavirus disease 2019) symptoms past 12 weeks may affect as many as 30% of people recovering from a SARS-CoV-2 (severe acute respiratory coronavirus 2) infection. The mechanisms regulating the development of PASC are currently not known; however, hypotheses including poor antibody responses have been suggested. Due to the importance of virus neutralizing antibodies during COVID-19 recovery and protection from reinfection, we designed a cross-sectional study to investigate systemic antibody and cytokine responses during COVID-19 recovery and PASC. In total, 195 participants were recruited in one of five groups: 1.) those who had PASC (PASC); 2.) those who recovered from COVID-19 (Recovered); 3.) those in acute recovery (Acute Recovery); 4.) those experiencing acute COVID-19 (Acute COVID-19); and 5.) those who never had COVID-19 (No COVID). Participants completed a questionnaire detailing their demographics, as well as COVID-19 experiences. Serum samples were evaluated for virus binding and neutralizing antibodies as well as serum cytokine levels. We found that participants with PASC reported more pre-existing conditions (such as hypertension), and PASC symptoms (ie., shortness of breath) following COVID-19 than Recovered individuals. PASC individuals also had significantly decreased levels of neutralizing antibodies toward both SARS-CoV-2 and the Omicron BA.1 variant. Sex analysis indicated that female PASC study participants had sustained antibody levels as well as inflammatory cytokines (GM-CSF) over time following COVID-19 while males had decreasing concentrations. Our study reports for the first time that people experiencing PASC have lower levels of virus neutralizing antibodies and females experiencing PASC have sustained levels of antibodies and inflammatory markers. With lower levels of virus neutralizing antibodies, this data suggests that PASC individuals not only have had a suboptimal antibody response during acute SARS-CoV-2 infection but may also have increased susceptibility to subsequent infections which may exacerbate or prolong current PASC illnesses. The work may be applied directly to developing PASC diagnostic screening tools, treatments, as well as public health policies.

Delirium is common after cardiac surgery and is associated with adverse outcomes. Administration of benzodiazepines before and after cardiac surgery is associated with delirium; guidelines recommend minimizing their use. Benzodiazepine administration during cardiac surgery remains common because of its recognized benefits. The Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free) trial is a randomized cluster crossover trial evaluating whether an institutional policy of restricting intraoperative benzodiazepine administration (ie, ≥ 90% of patients do not receive benzodiazepines during cardiac surgery), as compared with a policy of liberal intraoperative benzodiazepine administration (ie, ≥ 90% of patients receive ≥ 0.03 mg/kg midazolam equivalent), reduces delirium. Hospitals performing ≥ 250 cardiac surgeries a year are included if their cardiac anesthesia group agrees to apply both benzodiazepine policies per their randomization, and patients are assessed for postoperative delirium every 12 hours in routine clinical care. Hospitals apply the restricted or liberal benzodiazepine policy during 12 to 18 crossover periods of 4 weeks each. Randomization for all periods takes place in advance of site startup; sites are notified of their allocated policy during the last week of each crossover period. Policies are applied to all patients undergoing cardiac surgery during the trial period. The primary outcome is the incidence of delirium at up to 72 hours after surgery. The B-Free trial will enroll ≥ 18,000 patients undergoing cardiac surgery at 20 hospitals across North America. Delirium is common after cardiac surgery, and benzodiazepines are associated with the occurrence of delirium. The B-Free trial will determine whether an institutional policy restricting the administration of benzodiazepines during cardiac surgery reduces the incidence of delirium after cardiac surgery. Clinicaltrials.gov registration number: NCT03928236 (First registered April 26, 2019).

Purpose Airway evaluation is a fundamental component of the preanesthetic examination. Virtual care has increased during the COVID-19 pandemic. We aimed to assess the reliability of a virtual preanesthetic airway evaluation compared with a traditional in-person airway evaluation. Methods This prospective observational study compared the inter-rater agreement of an in-person airway evaluation performed by a consultant anesthesiologist with a virtual airway evaluation (VAE) performed by consultant anesthesiologists and medical students. The airway evaluation was completed using a comprehensive airway evaluation and scoring tool. The primary outcome was the inter-rater agreement of total scores between in-person anesthesiologist airway evaluations and the VAEs of both the anesthesiologists and medical students, assessed using Cohen's Kappa (CK). Secondary outcomes included the inter-rater agreement for each airway evaluation component between the in-person anesthesiologists and both the anesthesiologist and medical student VAEs, assessed using prevalence-adjusted and bias-adjusted Kappa. Results One hundred out of 111 participants completed all three evaluations. The in-person anesthesiologist airway evaluations had fair and good levels of agreement of total scores with the VAEs of the anesthesiologists (CK, 0.21; 97.5% confidence interval [CI], 0.07 to 0.34) and the medical students (CK, 0.74; 97.5% CI, 0.62 to 0.86), respectively. One participant was reported to have a difficult intubation. Conclusion Virtual airway evaluations performed by anesthesiologists and medical students had fair and good inter-rater agreement, respectively, with in-person anesthesiologist airway evaluations. Further study with a focus on patients with difficult airways is required to define the predictive value of VAEs regarding difficult intubations.

IntroductionOlder patients undergoing cardiac surgery carry the highest risk for developing major postoperative neurocognitive disorder (postoperative NCD or P-NCD) with up to 25% incidence 3 months after surgery. P-NCD is associated with significant morbidity, mortality, loss of independence, premature retirement and increased healthcare costs. This multicentre randomised trial is investigating the efficacy of postoperative dexmedetomidine sedation in reducing the incidence of major P-NCD after cardiac surgery compared with standard protocols. CODEX will be the largest interventional trial with major P-NCD as the primary outcome.Methods and analysisCODEX is recruiting patients ≥60 years old, undergoing elective cardiac surgery and without pre-existing major cognitive dysfunction or dementia. Eligible participants are randomised to receive postoperative dexmedetomidine or standard institutional sedation protocols in the intensive care unit. Baseline preoperative cognitive function is assessed with the computer-based Cogstate Brief Battery. The primary outcome, major P-NCD, 3 months after surgery is defined as a decrease in cognitive function ≥1.96 SD below age-matched, non-operative controls. Secondary outcomes include delirium, major P-NCD at 6/12 months, depressive symptoms, mild P-NCD and quality of surgical recovery at 3/6/12 months. The specific diagnostic criteria used in this protocol are consistent with the recommendations for clinical assessment and management of NCD from the Nomenclature Consensus Working Group on perioperative cognitive changes. Intention-to-treat analysis will compare major P-NCD at 3 months between study groups.Ethics and disseminationCODEX was approved by Sunnybrook Health Sciences Centre Research Ethics Board (REB) (Project ID 1743). This will be the first multicentre, randomised controlled trial to assess the efficacy of a pharmacological intervention to reduce the incidence of major P-NCD after cardiac surgery in patients ≥60 years old. Dissemination of the study results will include briefings of key findings and interpretation, conference presentations and peer-reviewed publications.Trial registration numberNCT04289142.

Prions are a novel form of infectivity based on the misfolding of a self-protein (PrP(C)) into a pathological, infectious isomer (PrP(Sc)). The current uncontrolled spread of chronic wasting disease in cervids, coupled with the demonstrated zoonotic nature of select livestock prion diseases, highlights the urgent need for disease management tools. While there is proof-of-principle evidence for a prion vaccine, these efforts are complicated by the challenges and risks associated with induction of immune responses to a self-protein. Our priority is to develop a PrP(Sc)-specific prion vaccine based on epitopes that are uniquely exposed upon misfolding. These disease specific epitopes (DSEs) have the potential to enable specific targeting of the pathological species through immunotherapy. Here we review outcomes of the translation of a prion DSE into a PrP(Sc)-specific vaccine based on the criteria of immunogenicity, safety and specificity.

Transmissible spongiform encephalopathies (TSEs), or prion diseases, represent a unique form of infectious disease based on misfolding of a self-protein (PrP(C)) into a pathological, infectious conformation (PrP(Sc)). Prion diseases of food animals gained notoriety during the bovine spongiform encephalopathy (BSE) outbreak of the 1980s. In particular, disease transmission to humans, to the generation of a fatal, untreatable disease, elevated the perspective on livestock prion diseases from food production to food safety. While the immediate threat posed by BSE has been successfully addressed through surveillance and improved management practices, another prion disease is rapidly spreading. Chronic wasting disease (CWD), a prion disease of cervids, has been confirmed in wild and captive populations with devastating impact on the farmed cervid industries. Furthermore, the unabated spread of this disease through wild populations threatens a natural resource that is a source of considerable economic benefit and national pride. In a worst-case scenario, CWD may represent a zoonotic threat either through direct transmission via consumption of infected cervids or through a secondary food animal, such as cattle. This has energized efforts to understand prion diseases as well as to develop tools for disease detection, prevention, and management. Progress in each of these areas is discussed.

Transmissible spongiform encephalopathies (TSEs) depend on misfolding of a normal cellular protein (PrPC) to an infectious conformation (PrPSc). Targeting PrPSc may represent an effective strategy for immunotherapy while avoiding consequences associated with immune responses to self-proteins. A weakly immunogenic epitope of PrPC (YYR), which induces PrPSc-specific antibodies, is used as a starting point for vaccine development. Through optimization of epitope, as well as formulation/delivery, we enhance immunogenicity while retaining PrPSc specificity. In particular, QVYYRPVDQYSNQN, presented by a leukotoxin carrier protein, emerges as a strong vaccine candidate. A vaccine representing this construct induces consistent and sustained serum PrPSc-specific IgG antibody responses following two vaccinations. Antigen specific antibodies are also present within cerebral spinal fluid and mucosal secretions. These characteristics provide a foundation for development of a TSE vaccine.

PURPOSE:Haemophilus influenzae is a known ocular pathogen, particularly in the pediatric population. The purpose of this study was to determine the minimal inhibitory concentration (MIC) and mutant prevention concentration (MPC) values of third-generation (i.e., ciprofloxacin and ofloxacin) and fourth-generation (i.e., gatifloxacin and moxifloxacin) fluoroquinolone antibiotics against clinical ocular isolates of H. influenzae.METHODS:Twenty-six clinical isolates of H. influenzae were evaluated. For MIC testing, approximately 10(5) colony-forming units/mL of test organism was added to an H. influenzae test medium containing twofold dilution increments of each fluoroquinolone. Cultures were incubated for 18 to 24 hours at 35 degrees C to 37 degrees C in 5% CO2. The lowest drug concentration that prevented growth was recorded as the MIC. The lowest drug concentration that inhibited 90% of strains tested was recorded as the MIC90. To determine MPC values, more than 10(10) bacteria were inoculated to agar plates containing varying drug concentrations and incubated for 24 to 48 hours at 35 degrees C to 37 degrees C in 5% CO2. To confirm MPC values, bacteria isolated from drug-containing plates were subcultured to drug-free agar, incubated, and then subcultured to a plate with the same drug concentration. The lowest drug concentration that allowed no growth was recorded as the MPC.RESULTS:All tested fluoroquinolones were highly active against H. influenzae. The MIC90 values were 0.016 microg/mL for gatifloxacin and ciprofloxacin and 0.031 microg/mL for moxifloxacin and ofloxacin. The MPC90 values were 0.125 microg/mL for gatifloxacin and 0.5 microg/mL for moxifloxacin, ofloxacin, and ciprofloxacin.CONCLUSIONS:All evaluated fluoroquinolones were effective against H. influenzae. The MIC90 and MPC90 values for gatifloxacin were consistently lower than those for moxifloxacin.