Image-based multiplex immune profiling of cancer tissues: translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer.

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Spatial analyses of immune cell infiltration in cancer: current methods and future directions: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer.

Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.

Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Post-Intensive Care Sequelae in Pediatrics-Results of an Early Rehabilitation Implementation Study.

OBJECTIVES: To compare post-PICU discharge functioning, health-related quality of life (HRQL), and parental stress before and after the implementation of an early rehabilitation bundle. DESIGN AND SETTING: Prospective cohort substudy within an early rehabilitation implementation program, conducted at the PICUs at McMaster Children's Hospital and London Health Sciences, London, Ontario, Canada. INTERVENTIONS: A bundle consisting of: 1) analgesia-first sedation; 2) delirium monitoring and prevention; and 3) early mobilization. Patients with an anticipated 48-hour PICU length of stay were approached for consent to participate. PATIENTS: Critically ill children with an anticipated 48-hour PICU length of stay were approached for consent to participate. MEASUREMENTS AND MAIN RESULTS: Patient-/proxy-reported outcome measures were assessed at baseline, PICU discharge, and 1 and 3 months post-PICU discharge using: 1) Pediatric Evaluation of Disability Inventory Computer Adaptive Test to assess physical, social, cognitive, and responsibility/caregiver domains of functioning; 2) KIDSCREEN to assess HRQL; and 3) the Pediatric Inventory for Parents to assess caregiver stress. A total of 117 participants were enrolled. Patient demographic characteristics were similar in the pre- and post-intervention groups. Following bundle implementation, 30 of 47 respondents (63.8%) experienced functional decline and 18 of 45 (40%) experienced low HRQL at PICU discharge. Eighteen of 36 (50%) at 1 month and 14 of 38 (36.8%) at 3 months experienced either persistent functional decline and/or low HRQL; 2.8% and 2.6% at 1- and 3-month follow-up, respectively, experienced both persistent functional decline and low HRQL. There were no significant differences in the rates of persistent functional decline, low HRQL, or caregiver stress scores post-bundle compared with pre-rehabilitation bundle implementation. CONCLUSIONS: We were unable to adequately determine the efficacy of a rehabilitation bundle on patient-centered outcomes as this substudy was not powered for these outcomes. Our results did reveal that persistent low functioning is common in PICU survivors, more common than low HRQL, while experiencing both functional decline and low HRQL was uncommon.

Early Rehabilitation in Critically ill Children: A Two Center Implementation Study.

OBJECTIVES: To implement an early rehabilitation bundle in two Canadian PICUs. DESIGN AND SETTING: Implementation study in the PICUs at McMaster Children's Hospital (site 1) and London Health Sciences (site 2). PATIENTS: All children under 18 years old admitted to the PICU were eligible for the intervention. INTERVENTIONS: A bundle consisting of: 1) analgesia-first sedation; 2) delirium monitoring and prevention; and 3) early mobilization. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were the duration of implementation, bundle compliance, process of care, safety, and the factors influencing implementation. Secondary endpoints were the impact of the bundle on clinical outcomes such as pain, delirium, iatrogenic withdrawal, ventilator-free days, length of stay, and mortality. Implementation occurred over 26 months (August 2018 to October 2020). Data were collected on 1,036 patients representing 4,065 patient days. Bundle compliance was optimized within 6 months of roll-out. Goal setting for mobilization and level of arousal improved significantly (p < 0.01). Benzodiazepine, opioid, and dexmedetomidine use decreased in site 1 by 23.2% (95% CI, 30.8-15.5%), 26.1% (95% CI, 34.8-17.4%), and 9.2% (95% CI, 18.2-0.2%) patient exposure days, respectively, while at site 2, only dexmedetomidine exposure decreased significantly by 10.5% patient days (95% CI, 19.8-1.1%). Patient comfort, safety, and nursing workload were not adversely affected. There was no significant impact of the bundle on the rate of delirium, ventilator-free days, length of PICU stay, or mortality. Key facilitators to implementation included institutional support, unit-wide practice guidelines, dedicated PICU educators, easily accessible resources, and family engagement. CONCLUSIONS: A rehabilitation bundle can improve processes of care and reduce patient sedative exposure without increasing patient discomfort, nursing workload, or harm. We did not observe an impact on short-term clinical outcomes. The efficacy of a PICU-rehabilitation bundle requires ongoing study. Lessons learned in this study provide evidence to inform rehabilitation implementation in the PICU setting.

COVID-19 plasma proteome reveals novel temporal and cell-specific signatures for disease severity and high-precision disease management.

Coronavirus disease 2019 (COVID-19) is a systemic inflammatory condition with high mortality that may benefit from personalized medicine and high-precision approaches. COVID-19 patient plasma was analysed with targeted proteomics of 1161 proteins. Patients were monitored from Days 1 to 10 of their intensive care unit (ICU) stay. Age- and gender-matched COVID-19-negative sepsis ICU patients and healthy subjects were examined as controls. Proteomic data were resolved using both cell-specific annotation and deep-analysis for functional enrichment. COVID-19 caused extensive remodelling of the plasma microenvironment associated with a relative immunosuppressive milieu between ICU Days 3-7, and characterized by extensive organ damage. COVID-19 resulted in (1) reduced antigen presentation and B/T-cell function, (2) increased repurposed neutrophils and M1-type macrophages, (3) relatively immature or disrupted endothelia and fibroblasts with a defined secretome, and (4) reactive myeloid lines. Extracellular matrix changes identified in COVID-19 plasma could represent impaired immune cell homing and programmed cell death. The major functional modules disrupted in COVID-19 were exaggerated in patients with fatal outcome. Taken together, these findings provide systems-level insight into the mechanisms of COVID-19 inflammation and identify potential prognostic biomarkers. Therapeutic strategies could be tailored to the immune response of severely ill patients.

Risk Factors for Major Cardiovascular Events in Adult Sepsis Survivors: A Population-Based Cohort Study.

OBJECTIVES: To describe risk factors for major cardiovascular events in adults following hospital discharge after sepsis. DESIGN: Population-based cohort study. SETTING: Ontario, Canada (2008-2017). PATIENTS: Adult patients (age 18 yr or older) who survived a first sepsis hospitalization without preexisting cardiovascular disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary composite outcome was myocardial infarction, stroke, or cardiovascular death up to 5 years following hospital discharge. We used cause-specific Cox proportional hazards models that accounted for the competing risk of noncardiovascular death to describe factors associated with major cardiovascular events. We identified 268,259 adult patients without cardiovascular disease (median age, 72 yr), of whom 10.4% experienced a major cardiovascular event during a median follow-up of 3 years. After multivariable adjustment, age (hazard ratio [HR], 1.53 for every 10 yr; 95% CI, 1.51-1.54), male sex (HR, 1.23; 95% CI, 1.20-1.26), diabetes mellitus (HR, 1.24; 95% CI, 1.21-1.27), hypertension (HR, 1.34; 95% CI, 1.30-1.38), prevalent atrial fibrillation (HR, 1.46; 95% CI, 1.40-1.52), and chronic kidney disease (HR, 1.11; 95% CI, 1.06-1.16) were associated with major cardiovascular events during long-term follow-up. Sepsis characteristics such as site of infection (pneumonia vs other: HR, 1.09; 95% CI, 1.05-1.12), septic shock (HR, 1.08; 95% CI, 1.05-1.11), and renal replacement therapy (HR, 1.51; 95% CI, 1.38-1.64) were also associated with subsequent cardiovascular events. In an analysis restricting to patients with troponin values measured during the hospitalization (26,400 patients), an elevated troponin was also associated with subsequent cardiovascular events (HR, 1.23; 95% CI, 1.13-1.33). CONCLUSIONS: Classic cardiovascular risk factors, comorbid conditions, and characteristics of the sepsis episode were associated with a higher hazard of major cardiovascular events in adult sepsis survivors. These findings may inform enrichment strategies for future studies.

Safety Outcomes of Direct Discharge Home From ICUs: An Updated Systematic Review and Meta-Analysis (Direct From ICU Sent Home Study).

OBJECTIVE: To evaluate the impact of direct discharge home (DDH) from ICUs compared with ward transfer on safety outcomes of readmissions, emergency department (ED) visits, and mortality. DATA SOURCES: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature from inception until March 28, 2022. STUDY SELECTION: Randomized and nonrandomized studies of DDH patients compared with ward transfer were eligible. DATA EXTRACTION: We screened and extracted studies independently and in duplicate. We assessed risk of bias using the Newcastle-Ottawa Scale for observational studies. A random-effects meta-analysis model and heterogeneity assessment was performed using pooled data (inverse variance) for propensity-matched and unadjusted cohorts. We assessed the overall certainty of evidence for each outcome using the Grading Recommendations Assessment, Development and Evaluation approach. DATA SYNTHESIS: Of 10,228 citations identified, we included six studies. Of these, three high-quality studies, which enrolled 49,376 patients in propensity-matched cohorts, could be pooled using meta-analysis. For DDH from ICU, compared with ward transfers, there was no difference in the risk of ED visits at 30-day (22.4% vs 22.7%; relative risk [RR], 0.99; 95% CI, 0.95-1.02; p = 0.39; low certainty); hospital readmissions at 30-day (9.8% vs 9.6%; RR, 1.02; 95% CI, 0.91-1.15; p = 0.71; very low-to-low certainty); or 90-day mortality (2.8% vs 2.6%; RR, 1.06; 95% CI, 0.95-1.18; p = 0.29; very low-to-low certainty). There were no important differences in the unmatched cohorts or across subgroup analyses. CONCLUSIONS: Very low-to-low certainty evidence from observational studies suggests that DDH from ICU may have no difference in safety outcomes compared with ward transfer of selected ICU patients. In the future, this research question could be further examined by randomized control trials to provide higher certainty data.

Prevalent diabetes and long-term cardiovascular outcomes in adult sepsis survivors: a population-based cohort study.

BACKGROUND: Sepsis survivors are at elevated risk for cardiovascular disease during long-term follow-up. Whether diabetes influences cardiovascular risk after sepsis survival remains unknown. We sought to describe the association of diabetes with long-term cardiovascular outcomes in adult sepsis survivors. METHODS: Population-based cohort study in the province of Ontario, Canada (2008-2017). Adult survivors of a first sepsis-associated hospitalization, without pre-existing cardiovascular disease, were included. Main exposure was pre-existing diabetes (any type). The primary outcome was the composite of myocardial infarction, stroke, and cardiovascular death. Patients were followed up to 5 years from discharge date until outcome occurrence or end of study period (March 2018). We used propensity score matching (i.e., 1:1 to patients with sepsis but no pre-existing diabetes) to adjust for measured confounding at baseline. Cause-specific Cox proportional hazards models with robust standard errors were used to estimate hazard ratios (HR) alongside 95% confidence intervals (CI). A main secondary analysis evaluated the modification of the association between sepsis and cardiovascular disease by pre-existing diabetes. RESULTS: 78,638 patients with pre-existing diabetes who had a sepsis-associated hospitalization were matched to patients hospitalized for sepsis but without diabetes. Mean age of patients was 71 years, and 55% were female. Median duration from diabetes diagnosis was 9.8 years; mean HbA1c was 7.1%. Adult sepsis survivors with pre-existing diabetes experienced a higher hazard of major cardiovascular disease (HR 1.25; 95% CI 1.22-1.29)-including myocardial infarction (HR 1.40; 95% CI 1.34-1.47) and stroke (HR 1.24; 95% CI 1.18-1.29)-during long-term follow-up compared to sepsis survivors without diabetes. Pre-existing diabetes modified the association between sepsis and cardiovascular disease (risk difference: 2.3%; 95% CI 2.0-2.6 and risk difference: 1.8%; 95% CI 1.6-2.0 for the effect of sepsis-compared to no sepsis-among patients with and without diabetes, respectively). CONCLUSIONS: Sepsis survivors with pre-existing diabetes experience a higher long-term hazard of major cardiovascular events when compared to sepsis survivors without diabetes. Compared to patients without sepsis, the absolute risk increase of cardiovascular events after sepsis is higher in patients with diabetes (i.e., diabetes intensified the higher cardiovascular risk induced by sepsis).

A real-world study of second or later-line osimertinib in patients with EGFR T790M-positive NSCLC: the final ASTRIS data.

Aim: Report the final analysis from ASTRIS, the largest real-world study of second-/later-line osimertinib in advanced/metastatic EGFR T790M non-small-cell lung cancer (NSCLC). Methods: Patients with advanced/metastatic EGFR T790M NSCLC and prior EGFR-TKI treatment, received once-daily osimertinib 80 mg. Primary end point: overall survival (OS); secondary end points: progression-free survival (PFS), time-to-treatment discontinuation (TTD) and response rate. Safety was also recorded. Results: In 3014 patients, median OS: 22.8 months (21.6-23.8), median PFS: 11.1 months (11.0-12.0), median TTD: 13.5 months (12.6-13.9), and response rate: 57.3% (55.5-59.2). All end points reported with 95% CIs. Numerically longer median OS was observed in patients with baseline WHO performance status <2 versus 2 (24.0 vs 11.1 months) and those without versus with brain/leptomeningeal metastases (25.4 vs 18.0 months). No new safety signals were identified. Conclusion: Second-/later-line osimertinib demonstrated real-world clinical benefit and safety in advanced/metastatic EGFR T790M NSCLC. Clinical Trial Registration: NCT02474355 (ClinicalTrials.gov).

Osimertinib is a drug that blocks the activity of a protein called EGFR on cancer cells, reducing their growth and spread. ASTRIS is the largest real-world study that evaluated the outcomes with osimertinib treatment for patients with advanced non-small-cell lung cancer (NSCLC), and the EGFR T790M mutation, who had received previous treatment for their cancer. There were 3014 patients included in this study. The main aim of this study was to measure the time at which half of the patients were still alive after starting osimertinib treatment, this was 22.8 months. The study also measured the time at which half of the patients had experienced worsening (progression) of their cancer (11.1 months) and the time when half of the patients had stopped receiving osimertinib treatment (13.5 months). None of the patients experienced any unexpected side effects of the treatment. These data are consistent with those observed in comparable clinical trials with osimertinib, supporting the use of osimertinib treatment for patients with advanced NSCLC and the EGFR T790M mutation after their initial cancer treatment has stopped working.

Effect of inhaled anaesthetics on cognitive and psychiatric outcomes in critically ill adults: a systematic review and meta-analysis.

BACKGROUND: Sedation of critically ill patients with inhaled anaesthetics may reduce lung inflammation, time to extubation, and ICU length of stay compared with intravenous (i.v.) sedatives. However, the impact of inhaled anaesthetics on cognitive and psychiatric outcomes in this population is unclear. In this systematic review, we aimed to summarise the effect of inhaled anaesthetics on cognitive and psychiatric outcomes in critically ill adults. METHODS: We searched MEDLINE, EMBASE, and PsycINFO for case series, retrospective, and prospective studies in critically ill adults sedated with inhaled anaesthetics. Outcomes included delirium, psychomotor and neurological recovery, long-term cognitive dysfunction, ICU memories, anxiety, depression, post-traumatic stress disorder (PTSD), and instruments used for assessment. RESULTS: Thirteen studies were included in distinct populations of post-cardiac arrest survivors (n=4), postoperative noncardiac patients (n=3), postoperative cardiac patients (n=2), and mixed medical-surgical patients (n=4). Eight studies reported delirium incidence, two neurological recovery, and two ICU memories. One study reported on psychomotor recovery, long-term cognitive dysfunction, anxiety, depression, and PTSD. A meta-analysis of five trials found no difference in delirium incidence between inhaled and i.v. sedatives (relative risk 0.95 [95% confidence interval: 0.59-1.54]). Compared with i.v. sedatives, inhaled anaesthetics were associated with fewer hallucinations and faster psychomotor recovery but no differences in other outcomes. There was heterogeneity in the instruments used and timing of these assessments. CONCLUSIONS: Based on the limited evidence available, there is no difference in cognitive and psychiatric outcomes between adults exposed to volatile sedation or intravenous sedation in the ICU. Future studies should incorporate outcome assessment with validated tools during and after hospital stay. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42021236455.

Diagnostic accuracy of ancillary tests for death by neurologic criteria: a systematic review and meta-analysis.

PURPOSE: Ancillary tests are frequently used in death determination by neurologic criteria (DNC), particularly when the clinical neurologic examination is unreliable. Nevertheless, their diagnostic accuracy has not been extensively studied. Our objective was to synthesize the sensitivity and specificity of commonly used ancillary tests for DNC. SOURCE: We performed a systematic review and meta-analysis by searching MEDLINE, EMBASE, Cochrane databases, and CINAHL Ebsco from their inception to 4 February 2022. We selected cohort and case-control studies including patients with 1) clinically diagnosed death by neurologic criteria or 2) clinically suspected death by neurologic criteria who underwent ancillary testing for DNC. We excluded studies without a priori diagnostic criteria and studies conducted solely on pediatric patients. Accepted reference standards were clinical examination, four-vessel conventional angiography, and radionuclide imaging. Data were directly extracted from published reports. We assessed the methodological quality of studies with the QUADAS-2 tool and estimated ancillary test sensitivities and specificities using hierarchical Bayesian models with diffuse priors. PRINCIPAL FINDINGS: Overall, 137 records met the selection criteria. One study (0.7%) had a low risk of bias in all QUADAS-2 domains. Among clinically diagnosed death by neurologic criteria patients (n = 8,891), ancillary tests had similar pooled sensitivities (range, 0.82-0.93). Sensitivity heterogeneity was greater within (σ = 0.10-0.15) than between (σ = 0.04) ancillary test types. Among clinically suspected death by neurologic criteria patients (n = 2,732), pooled ancillary test sensitivities ranged between 0.81 and 1.00 and specificities between 0.87 and 1.00. Most estimates had high statistical uncertainty. CONCLUSION: Studies assessing ancillary test diagnostic accuracy have an unclear or high risk of bias. High-quality studies are required to thoroughly validate ancillary tests for DNC. STUDY REGISTRATION: PROSPERO (CRD42013005907); registered 7 October 2013.

RéSUMé: OBJECTIF: Les examens auxiliaires sont fréquemment utilisés dans la détermination du décès selon des critères neurologiques (DCN), en particulier lorsque l'examen neurologique clinique n'est pas fiable. Néanmoins, leur précision diagnostique n'a pas été étudiée de manière approfondie. Notre objectif était de synthétiser la sensibilité et la spécificité des examens auxiliaires couramment utilisés pour la DCN. SOURCES: Nous avons réalisé une revue systématique et une méta-analyse en effectuant des recherches dans les bases de données MEDLINE, EMBASE, Cochrane et CINAHL Ebsco de leur création jusqu'au 4 février 2022. Nous avons sélectionné des études de cohorte et cas témoins incluant des patients présentant 1) un décès selon des critères neurologiques diagnostiqué cliniquement ou 2) un décès selon des critères neurologiques soupçonné cliniquement qui ont été soumis à des examens auxiliaires pour un DCN. Nous avons exclu les études sans critères diagnostiques a priori et les études menées uniquement auprès de patients pédiatriques. Les normes de référence acceptées étaient l'examen clinique, l'angiographie conventionnelle à quatre vaisseaux et l'imagerie nucléaire. Les données ont été directement extraites de comptes rendus publiés. Nous avons évalué la qualité méthodologique des études avec l'outil QUADAS-2 et estimé les sensibilités et les spécificités des examens auxiliaires à l'aide de modèles hiérarchiques bayésiens avec des distributions préalables diffuses. CONSTATATIONS PRINCIPALES: Au total, 137 études répondaient aux critères de sélection. Une étude (0,7 %) présentait un faible risque de biais dans tous les domaines de QUADAS-2. Parmi les patients ayant reçu un diagnostic clinique de décès selon des critères neurologiques (n = 8891), les examens auxiliaires présentaient des sensibilités combinées similaires (intervalle de 0,82 à 0,93). L'hétérogénéité de sensibilité était plus grande au sein (σ = 0,10-0,15) plutôt qu'entre (σ = 0,04) les types d'examens auxiliaires. Parmi les patients cliniquement soupçonnés de décès selon des critères neurologiques (n = 2732), les sensibilités combinées des examens auxiliaires variaient entre 0,81 et 1,00 et les spécificités entre 0,87 et 1,00. La plupart des estimations comportaient une grande incertitude statistique. CONCLUSION: Les études évaluant la précision diagnostique des examens auxiliaires présentent un risque de biais incertain ou élevé. Des études de haute qualité sont nécessaires pour valider en profondeur les examens auxiliaires pour la DCN. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42013005907); enregistrée le 7 octobre 2013.

Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism.

BACKGROUND: Long-COVID is characterized by prolonged, diffuse symptoms months after acute COVID-19. Accurate diagnosis and targeted therapies for Long-COVID are lacking. We investigated vascular transformation biomarkers in Long-COVID patients. METHODS: A case-control study utilizing Long-COVID patients, one to six months (median 98.5 days) post-infection, with multiplex immunoassay measurement of sixteen blood biomarkers of vascular transformation, including ANG-1, P-SEL, MMP-1, VE-Cad, Syn-1, Endoglin, PECAM-1, VEGF-A, ICAM-1, VLA-4, E-SEL, thrombomodulin, VEGF-R2, VEGF-R3, VCAM-1 and VEGF-D. RESULTS: Fourteen vasculature transformation blood biomarkers were significantly elevated in Long-COVID outpatients, versus acutely ill COVID-19 inpatients and healthy controls subjects (P < 0.05). A unique two biomarker profile consisting of ANG-1/P-SEL was developed with machine learning, providing a classification accuracy for Long-COVID status of 96%. Individually, ANG-1 and P-SEL had excellent sensitivity and specificity for Long-COVID status (AUC = 1.00, P < 0.0001; validated in a secondary cohort). Specific to Long-COVID, ANG-1 levels were associated with female sex and a lack of disease interventions at follow-up (P < 0.05). CONCLUSIONS: Long-COVID patients suffer prolonged, diffuse symptoms and poorer health. Vascular transformation blood biomarkers were significantly elevated in Long-COVID, with angiogenesis markers (ANG-1/P-SEL) providing classification accuracy of 96%. Vascular transformation blood biomarkers hold potential for diagnostics, and modulators of angiogenesis may have therapeutic efficacy.

Outcomes After Direct Discharge Home From Critical Care Units: A Population-Based Cohort Analysis.

OBJECTIVES: To compare health service use and clinical outcomes for patients with and without direct discharge to home (DDH) from ICUs in Ontario. DESIGN: Population-based, observational, cohort study using propensity scoring to match patients who were DDH to those not DDH and a preference-based instrumental variable (IV) analysis using ICU-level DDH rate as the IV. SETTING: ICUs in Ontario. PATIENTS: Patients discharged home from a hospitalization either directly or within 48 hours of care in an ICU between April 1, 2015, and March 31, 2017. INTERVENTION: DDH from ICU. MEASUREMENTS AND MAIN RESULTS: Among 76,737 patients in our cohort, 46,859 (61%) were DDH from the ICU. In the propensity matched cohort, the odds for our primary outcome of hospital readmission or emergency department (ED) visit within 30 days were not significantly different for patients DDH (odds ratio [OR], 1.00; 95% CI, 0.96-1.04), and there was no difference in mortality at 90 days for patients DDH (OR, 1.08; 95% CI, 0.97-1.21). The effect on hospital readmission or ED visits was similar in the subgroup of patients discharged from level 2 (OR, 0.98; 95% CI, 0.92-1.04) and level 3 ICUs (OR, 1.02; 95% CI, 0.96-1.09) and in the subgroups with cardiac conditions (OR, 1.03; 95% CI, 0.96-1.12) and noncardiac conditions (OR, 0.98; 95% CI, 0.94-1.03). Similar results were obtained in the IV analysis (coefficient for hospital readmission or ED visit within 30 d = -0.03 ± 0.03 ( se ); p = 0.3). CONCLUSIONS: There was no difference in outcomes for patients DDH compared with ward transfer prior to discharge when two approaches were used to minimize confounding within a large health systemwide observational cohort. We did not evaluate how patients are selected for DDH. Our results suggest that with careful patient selection, this practice might be feasible for routine implementation to ensure efficient and safe use of limited healthcare resources.

Wellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey.

OBJECTIVES: Few surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic. DESIGN: Cross-sectional survey using four validated instruments. SETTING: Sixty-two sites in Canada and the United States. SUBJECTS: Attending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures. CONCLUSIONS: Despite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness.

Novel plasma protein biomarkers from critically ill sepsis patients.

BACKGROUND: Despite the high morbidity and mortality associated with sepsis, the relationship between the plasma proteome and clinical outcome is poorly understood. In this study, we used targeted plasma proteomics to identify novel biomarkers of sepsis in critically ill patients. METHODS: Blood was obtained from 15 critically ill patients with suspected/confirmed sepsis (Sepsis-3.0 criteria) on intensive care unit (ICU) Day-1 and Day-3, as well as age- and sex-matched 15 healthy control subjects. A total of 1161 plasma proteins were measured with proximal extension assays. Promising sepsis biomarkers were narrowed with machine learning and then correlated with relevant clinical and laboratory variables. RESULTS: The median age for critically ill sepsis patients was 56 (IQR 51-61) years. The median MODS and SOFA values were 7 (IQR 5.0-8.0) and 7 (IQR 5.0-9.0) on ICU Day-1, and 4 (IQR 3.5-7.0) and 6 (IQR 3.5-7.0) on ICU Day-3, respectively. Targeted proteomics, together with feature selection, identified the leading proteins that distinguished sepsis patients from healthy control subjects with ≥ 90% classification accuracy; 25 proteins on ICU Day-1 and 26 proteins on ICU Day-3 (6 proteins overlapped both ICU days; PRTN3, UPAR, GDF8, NTRK3, WFDC2 and CXCL13). Only 7 of the leading proteins changed significantly between ICU Day-1 and Day-3 (IL10, CCL23, TGFα1, ST2, VSIG4, CNTN5, and ITGAV; P < 0.01). Significant correlations were observed between a variety of patient clinical/laboratory variables and the expression of 15 proteins on ICU Day-1 and 14 proteins on ICU Day-3 (P < 0.05). CONCLUSIONS: Targeted proteomics with feature selection identified proteins altered in critically ill sepsis patients relative to healthy control subjects. Correlations between protein expression and clinical/laboratory variables were identified, each providing pathophysiological insight. Our exploratory data provide a rationale for further hypothesis-driven sepsis research.

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial.

BACKGROUND: First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit. METHODS: This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov, number NCT03215706. FINDINGS: Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4-12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI 13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50 [14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related. INTERPRETATION: Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC. FUNDING: Bristol Myers Squibb.

The Role of a Cachexia Grading System in Patients with Non-Small Cell Lung Cancer Treated with Immunotherapy: Implications for Survival.

OBJECTIVE: The association between cancer-induced weight-loss (CIWL) and poor clinical outcomes in patients treated with immunotherapy is scarcely understood. We evaluated the use of a cachexia-grading system in IO-treated non-small cell lung cancer (NSCLC) patients in order to predict clinical outcomes. MATERIALS: 300 patients with NSCLC, who received immunotherapy during any line of therapy, were included. All patients were graded according to a previously validated cachexia scale, which takes into consideration body mass index (BMI) and weight loss, stratifying patients into five risk categories (0 [pre-cachexia] - 4 [refractory cachexia]). Primary endpoint was overall survival (OS). RESULTS: Ninety-one (30.3%) patients were classified in the low risk category, 176 (58.6%) were classified in the intermediate risk category and 33 (11%) were in the high risk category. Patients classified as low-risk had a significantly longer OS compared with those with intermediate or high risk (22.4 mo, [95%CI: 16.6-NR] vs. 17.1 [95%CI: 13.5-22.4] vs. 8.0 [3.9-18.4]; p < 0.001). In the multivariate analysis, after adjusting for age, hemoglobin and ORR, hazard of death increased as per the cachexia risk scale (Hazard ratio: 1.62 [1.22-2.16]; p = 0.001). CONCLUSION: Cachexia is independently associated with worse OS in NSCLC patients who receive immunotherapy, highlighting the role for nutritional assessment.

Novel severe traumatic brain injury blood outcome biomarkers identified with proximity extension assay.

OBJECTIVES: Severe traumatic brain injury (sTBI) patients suffer high mortality. Accurate prognostic biomarkers have not been identified. In this exploratory study, we performed targeted proteomics on plasma obtained from sTBI patients to identify potential outcome biomarkers. METHODS: Blood sample was collected from patients admitted to the ICU suffering a sTBI, using standardized clinical and computerized tomography (CT) imaging criteria. Age- and sex-matched healthy control subjects and sTBI patients were enrolled. Targeted proteomics was performed on plasma with proximity extension assays (1,161 proteins). RESULTS: Cohorts were well-balanced for age and sex. The majority of sTBI patients were injured in motor vehicle collisions and the most frequent head CT finding was subarachnoid hemorrhage. Mortality rate for sTBI patients was 40%. Feature selection identified the top performing 15 proteins for identifying sTBI patients from healthy control subjects with a classification accuracy of 100%. The sTBI proteome was dominated by markers of vascular pathology, immunity/inflammation, cell survival and macrophage/microglia activation. Receiver operating characteristic (ROC) curve analyses demonstrated areas-under-the-curves (AUC) for identifying sTBI that ranged from 0.870-1.000 (p≤0.005). When mortality was used as outcome, ROC curve analyses identified the top 3 proteins as Willebrand factor (vWF), Wnt inhibitory factor-1 (WIF-1), and colony stimulating factor-1 (CSF-1). Combining vWF with either WIF-1 or CSF-1 resulted in excellent mortality prediction with AUC of 1.000 for both combinations (p=0.011). CONCLUSIONS: Targeted proteomics with feature classification and selection distinguished sTBI patients from matched healthy control subjects. Two protein combinations were identified that accurately predicted sTBI patient mortality. Our exploratory findings require confirmation in larger sTBI patient populations.

A retrospective observational study of daytime and nighttime transfers from the intensive care unit: through the lens of critical care response teams.

PURPOSE: To evaluate the impact of nighttime compared with daytime transfers from the intensive care unit (ICU) on mortality in a hospital with a critical care response team (CCRT). METHODS: We performed a retrospective observational study of ICU patients transferred between January 2011 and July 2013 who received CCRT follow-up. The transferred patients were divided into cohorts of daytime and nighttime transfers. A multivariable logistic regression model was used to identify independent predictors of mortality after ICU transfer. RESULTS: There were 1,857 patients included in the study. With the exception of Multiple Organ Dysfunction Score on admission, transfers to a step-down unit, and lower urine output, there were no differences in the baseline characteristics, clinical events identified by CCRTs, and the number of CCRT interventions performed between daytime and nighttime transfers. Patients transferred at night were at higher risk of death in the univariate analysis but not in the multivariate analysis. Independent predictors of mortality included older age (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.002 to 1.04), transfer to a medical service (OR, 1.96; 95% CI, 1.11 to 3.43), CCRT identification of hypoxemic respiratory failure (OR, 5.86; 95% CI, 3.11 to 11.04), decreased level of consciousness (OR, 3.14; 95% CI, 1.23 to 8.02), hypotension (OR, 3.69; 95% CI, 1.36 to 10.01), and longer CCRT duration of follow-up (OR, 1.02; 95% CI, 1.004 to 1.03). CONCLUSIONS: Nighttime transfer from the ICU was not an independent predictor of mortality. We identified unique predictors of mortality, including clinical events that CCRTs identified in patients immediately after ICU transfer. Future studies are required to validate these predictors of mortality in transferred ICU patients.

RéSUMé: OBJECTIF: Évaluer l'impact sur la mortalité des transferts de nuit par rapport aux transferts de jour de l'unité de soins intensifs (USI) dans un hôpital disposant d'une équipe d'intervention en soins intensifs (EISI). MéTHODE: Nous avons réalisé une étude observationnelle rétrospective des patients de l'USI transférés entre janvier 2011 et juillet 2013 suivis par l'EISI. Les patients transférés ont été divisés en cohortes de transferts de jour et de nuit. Un modèle de régression logistique multivariée a été utilisé pour identifier les prédicteurs indépendants de mortalité après un transfert de l'USI. RéSULTATS: L'étude a inclus 1857 patients. À l'exception du Score de défaillance multiviscérale, des transferts à une unité de soins intermédiaires et de la réduction du débit d'urine, aucune différence n'a été notée dans les caractéristiques de base, les événements cliniques identifiés par l'EISI et le nombre d'interventions de l'EISI effectuées entre les transferts de jour et de nuit. Les patients transférés la nuit étaient plus à risque de décès dans l'analyse univariée, mais pas dans l'analyse multivariée. Les prédicteurs indépendants de mortalité comprenaient un âge avancé (rapport de cotes [RC], 1,02; intervalle de confiance [IC] 95 %, 1,002 à 1,04), le transfert à un service médical (RC, 1,96; IC 95 %, 1,11 à 3,43), l'identification par l'EISI d'une insuffisance respiratoire hypoxémique (RC, 5,86; IC 95 %, 3,11 à 11,04), la diminution du niveau de conscience (RC, 3,14; IC 95%, 1,23 à 8,02), l'hypotension (RC, 3,69; IC 95%, 1,36 à 10,01), et une durée plus longue de suivi par l'EISI (RC, 1,02; IC 95 %, 1,004 à 1,03). CONCLUSION: Le transfert nocturne de l'USI n'est pas un prédicteur indépendant de mortalité. Nous avons identifié des prédicteurs particuliers de mortalité, notamment les événements cliniques identifiés par l'EISI chez les patients immédiatement après leur transfert de l'USI. Des études futures sont nécessaires pour valider ces prédicteurs de mortalité chez les patients transférés des soins intensifs.