Central Venous Oxygen Saturation for Estimating Mixed Venous Oxygen Saturation and Cardiac Index in the ICU: A Systematic Review and Meta-Analysis.

OBJECTIVES: The objectives of our systematic review and meta-analyses were to determine the diagnostic accuracy of central venous oxygen saturation (Scvo2) in estimating mixed venous oxygen saturation (Svo2) and cardiac index in critically ill patients. DATA SOURCES: A systematic search using MEDLINE, Cochrane Central Register of Controlled Trials, and Embase was completed on May 6, 2024. STUDY SELECTION: Studies of patients in the ICU for whom Scvo2 and at least one reference standard test was performed (thermodilution and/or Svo2) were included. DATA EXTRACTION: Individual patient data were used to calculate the pooled intraclass correlation coefficient (ICC) for Svo2 and Spearman correlation for cardiac index. The Quality Assessment of Diagnostic Accuracy Studies-2 and Grading Recommendations Assessment, Development, and Evaluation tools were used for the risk of bias and certainty of evidence assessments. DATA SYNTHESIS: Of 3427 studies, a total of 18 studies with 1971 patients were identified. We meta-analyzed 16 studies (1335 patients) that used Svo2 as a reference and three studies (166 patients) that used thermodilution as reference. The ICC for reference Svo2 was 0.83 (95% CI, 0.75-0.89) with a mean difference of 2.98% toward Scvo2. The Spearman rank correlation for reference cardiac index is 0.47 (95% CI, 0.46-0.48; p < 0.0001). CONCLUSIONS: There is moderate reliability for Scvo2 in predicting Svo2 in critical care patients with variability based on sampling site and presence of sepsis. There is limited evidence on the independent use of Scvo2 in predicting cardiac index.

Resource Utilization and Costs Associated With Cardiogenic Shock Complicating Myocardial Infarction: A Population-Based Cohort Study.

Background: Cardiogenic shock due to acute myocardial infarction (AMI-CS) is associated with significant short- and long-term morbidity and mortality. Despite this, little is known about associated cost. Objectives: The purpose of this study was to evaluate the health care costs and resource use associated with AMI-CS using administrative data from the province of Ontario, Canada. Methods: This was a retrospective cohort study of adult patients with AMI-CS from April 2009 to March 2019. One-year costs following index admission were reported at an individual level. We used generalized linear models to identify factors associated with increased cost. We stratified patients by revascularization strategy to compare cost in each group and examined total cost at a patient level per individual fiscal year. Results: We included 9,789 consecutive patients with AMI-CS across 135 centers in Ontario (mean age 70.5 years; 67.7% male). Mortality in-hospital was 30.2%, and mortality at 2 years was 45.9%. The median inpatient cost per patient was $23,912 (IQR: $12,234-$41,833) with a median total 1-year cost of $37,913 (IQR: $20,113-$66,582). The median 1-year cost was $17,730 (IQR: $9,323-$38,379) for those who died in hospital, and $45,713 (IQR: $29,688-$77,683) for those surviving to discharge, with $12,719 (IQR: $4,262-$35,275) occurring after discharge. Patients who received coronary artery bypass grafting incurred the highest cost among revascularization groups. No significant differences were observed in cost per fiscal year from 2009 to 2019. Conclusions: AMI-CS is associated with significant health care costs, both during the index hospitalization and following discharge. To optimize cost-effectiveness, future therapies should aim to reduce disability in addition to improving mortality.

Urinary miRNAs: Technical Updates.

Due to its non-invasive nature and easy accessibility, urine serves as a convenient biological fluid for research purposes. Furthermore, urine samples are uncomplicated to preserve and relatively inexpensive. MicroRNAs (miRNAs), small molecules that regulate gene expression post-transcriptionally, play vital roles in numerous cellular processes, including apoptosis, cell differentiation, development, and proliferation. Their dysregulated expression in urine has been proposed as a potential biomarker for various human diseases, including bladder cancer. To draw reliable conclusions about the roles of urinary miRNAs in human diseases, it is essential to have dependable and reproducible methods for miRNA extraction and profiling. In this review, we address the technical challenges associated with studying urinary miRNAs and provide an update on the current technologies used for urinary miRNA isolation, quality control assessment, and miRNA profiling, highlighting both their advantages and limitations.

Mental health sequelae in survivors of cardiogenic shock complicating myocardial infarction. A population-based cohort study.

PURPOSE: Cardiogenic shock secondary to acute myocardial infarction (AMI-CS) is associated with substantial short- and long-term morbidity and mortality. However, there are limited data on mental health sequelae that survivors experience following discharge. METHODS: We conducted a retrospective, population-based cohort study in Ontario, Canada of critically ill adult (≥ 18 years) survivors of AMI-CS, admitted to hospital between April 1, 2009 and March 31, 2019. We compared these patients to AMI survivors without shock. We captured outcome data using linked health administrative databases. The primary outcome was a new mental health diagnosis (a composite of mood, anxiety, or related disorders; schizophrenia/psychotic disorders; and other mental health disorders) following hospital discharge. We secondarily evaluated incidence of deliberate self-harm and death by suicide. We compared patients using overlap propensity score-weighted, cause-specific proportional hazard models. RESULTS: We included 7812 consecutive survivors of AMI-CS, from 135 centers. Mean age was 68.4 (standard deviation (SD) 12.2) years, and 70.3% were male. Median follow-up time was 767 days (interquartile range (IQR) 225-1682). Incidence of new mental health diagnosis among AMI-CS survivors was 109.6 per 1,000 person-years (95% confidence interval (CI) 105.4-113.9), compared with 103.8 per 1000 person-years (95% CI 102.5-105.2) among AMI survivors without shock. After propensity score adjustment, there was no difference in the risk of new mental health diagnoses following discharge [hazard ratio (HR) 0.99 (95% CI 0.94-1.03)]. Factors associated with new mental health diagnoses following AMI-CS included female sex, pre-existing mental health diagnoses, and discharge to a long-term hospital or rehabilitation institute. CONCLUSION: Survivors of AMI-CS experience substantial mental health morbidity following discharge. Risk of new mental health diagnoses was comparable between survivors of AMI with and without shock. Future research on interventions to mitigate psychiatric sequelae after AMI-CS is warranted.

Canadian Cardiovascular Society/Canadian Cardiovascular Critical Care Society/Canadian Association of Interventional Cardiology Clinical Practice Update on Optimal Post Cardiac Arrest and Refractory Cardiac Arrest Patient Care.

Survival to hospital discharge among patients with out-of-hospital cardiac arrest (OHCA) is low and important regional differences in treatment practices and survival have been described. Since the 2017 publication of the Canadian Cardiovascular Society's position statement on OHCA care, multiple randomized controlled trials have helped to better define optimal post cardiac arrest care. This working group provides updated guidance on the timing of cardiac catheterization in patients with ST-elevation and without ST-segment elevation, on a revised temperature control strategy targeting normothermia instead of hypothermia, blood pressure, oxygenation, and ventilation parameters, and on the treatment of rhythmic and periodic electroencephalography patterns in patients with a resuscitated OHCA. In addition, prehospital trials have helped craft new expert opinions on antiarrhythmic strategies (amiodarone or lidocaine) and outline the potential role for double sequential defibrillation in patients with refractory cardiac arrest when equipment and training is available. Finally, we advocate for regionalized OHCA care systems with admissions to a hospital capable of integrating their post OHCA care with comprehensive on-site cardiovascular services and provide guidance on the potential role of extracorporeal cardiopulmonary resuscitation in patients with refractory cardiac arrest. We believe that knowledge translation through national harmonization and adoption of contemporary best practices has the potential to improve survival and functional outcomes in the OHCA population.

Sphingolipids in Childhood Asthma and Obesity (SOAP Study): A Protocol of a Cross-Sectional Study.

Asthma and obesity are two of the most common chronic conditions in children and adolescents. There is increasing evidence that sphingolipid metabolism is altered in childhood asthma and is linked to airway hyperreactivity. Dysregulated sphingolipid metabolism is also reported in obesity. However, the functional link between sphingolipid metabolism, asthma, and obesity is not completely understood. This paper describes the protocol of an ongoing study on sphingolipids that aims to examine the pathophysiology of sphingolipids in childhood asthma and obesity. In addition, this study aims to explore the novel biomarkers through a comprehensive multi-omics approach including genomics, genome-wide DNA methylation, RNA-Seq, microRNA (miRNA) profiling, lipidomics, metabolomics, and cytokine profiling. This is a cross-sectional study aiming to recruit 440 children from different groups: children with asthma and normal weight (n = 100), asthma with overweight or obesity (n = 100), overweight or obesity (n = 100), normal weight (n = 70), and siblings of asthmatic children with normal weight, overweight, or obesity (n = 70). These participants will be recruited from the pediatric pulmonology, pediatric endocrinology, and general pediatric outpatient clinics at Sidra Medicine, Doha, Qatar. Information will be obtained from self-reported questionnaires on asthma, quality of life, food frequency (FFQ), and a 3-day food diary that are completed by the children and their parents. Clinical measurements will include anthropometry, blood pressure, biochemistry, bioelectrical impedance, and pulmonary function tests. Blood samples will be obtained for sphingolipid analysis, serine palmitoyltransferase (SPT) assay, whole-genome sequencing (WGS), genome-wide DNA methylation study, RNA-Seq, miRNA profiling, metabolomics, lipidomics, and cytokine analysis. Group comparisons of continuous outcome variables will be carried out by a one-way analysis of variance or the Kruskal-Wallis test using an appropriate pairwise multiple comparison test. The chi-squared test or a Fisher's exact test will be used to test the associations between categorical variables. Finally, multivariate analysis will be carried out to integrate the clinical data with multi-omics data. This study will help us to understand the role of dysregulated sphingolipid metabolism in obesity and asthma. In addition, the multi-omics data from the study will help to identify novel genetic and epigenetic signatures, inflammatory markers, and mechanistic pathways that link asthma and obesity in children. Furthermore, the integration of clinical and multi-omics data will help us to uncover the potential interactions between these diseases and to offer a new paradigm for the treatment of pediatric obesity-associated asthma.

Tumor-intrinsic metabolic reprogramming and how it drives resistance to anti-PD-1/PD-L1 treatment.

The development of immune checkpoint blockade (ICB) therapies has been instrumental in advancing the field of immunotherapy. Despite the prominence of these treatments, many patients exhibit primary or acquired resistance, rendering them ineffective. For example, anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed cell death ligand 1 (anti-PD-L1) treatments are widely utilized across a range of cancer indications, but the response rate is only 10%-30%. As such, it is necessary for researchers to identify targets and develop drugs that can be used in combination with existing ICB therapies to overcome resistance. The intersection of cancer, metabolism, and the immune system has gained considerable traction in recent years as a way to comprehensively study the mechanisms that drive oncogenesis, immune evasion, and immunotherapy resistance. As a result, new research is continuously emerging in support of targeting metabolic pathways as an adjuvant to ICB to boost patient response and overcome resistance. Due to the plethora of studies in recent years highlighting this notion, this review will integrate the relevant articles that demonstrate how tumor-derived alterations in energy, amino acid, and lipid metabolism dysregulate anti-tumor immune responses and drive resistance to anti-PD-1/PD-L1 therapy.

Age and associated outcomes among patients receiving venoarterial extracorporeal membrane oxygenation-analysis of the Extracorporeal Life Support Organization registry.

PURPOSE: Venoarterial extracorporeal membrane oxygenation (V-A ECMO) can be used to support severely ill patients with cardiogenic shock. While age is commonly used in patient selection, little is known regarding its association with outcomes in this population. We sought to evaluate the association between increasing age and outcomes following V-A ECMO. METHODS: We used individual-level patient data from 440 centers in the international Extracorporeal Life Support Organization registry. We included all adult patients receiving V-A ECMO from 2017 to 2019. The primary outcome was hospital mortality. Secondary outcomes included a composite of complications following initiation of V-A ECMO. We conducted Bayesian analyses of the relationship between increasing age and outcomes of interest. RESULTS: We included 15,172 patients receiving V-A ECMO. Of these, 8172 (53.9%) died in hospital. For the analysis conducted using weakly informed priors, and as compared to the reference category of age 18-29, the age bracket of 30-39 (odds ratio [OR] 0.94, 95% credible interval [CrI] 0.79-1.10) was not associated with hospital mortality, but age brackets 40-49 (odds ratio [OR] 1.26, 95% CrI: 1.08-1.47), 50-59 (OR 1.78, 95% CrI: 1.55-2.06), 60-69 (OR 2.24, 95% CrI: 1.94-2.59), 70-79 (OR 2.90, 95% CrI: 2.49-3.39) and ≥ 80 (OR 4.02, 95% CrI: 3.13-5.20) were independently associated with increasing hospital mortality. Similar results were found in the analysis conducted with an informative prior, as well as between increasing age and post-ECMO complications. CONCLUSIONS: Among patients receiving V-A ECMO for cardiogenic shock, increasing age is strongly associated with increasing odds of death and complications, and this association emerges as early as 40 years of age.

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity.

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance1,2. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity3-6. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8+ T cell function by enhancing JAK-STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.

Long-Term Outcomes of Cardiogenic Shock Complicating Myocardial Infarction.

BACKGROUND: Cardiogenic shock secondary to acute myocardial infarction (AMI-CS) is associated with substantial short-term mortality; however, there are limited data on long-term outcomes and trends. OBJECTIVES: This study sought to examine long-term outcomes of AMI-CS patients. METHODS: This was a population-based, retrospective cohort study in Ontario, Canada of critically ill adult patients with AMI-CS who were admitted to hospitals between April 1, 2009 and March 31, 2019. Outcome data were captured using linked health administrative databases. RESULTS: A total of 9,789 consecutive patients with AMI-CS from 135 centers were included. The mean age was 70.5 ± 12.3 years, and 67.7% were male. The incidence of AMI-CS was 8.2 per 100,000 person-years, and it increased over the study period. Critical care interventions were common, with 5,422 (55.4%) undergoing invasive mechanical ventilation, 1,425 (14.6%) undergoing renal replacement therapy, and 1,484 (15.2%) receiving mechanical circulatory support. A total of 2,961 patients (30.2%) died in the hospital, and 4,004 (40.9%) died by 1 year. Mortality at 5 years was 58.9%. Small improvements in short- and long-term mortality were seen over the study period. Among survivors to discharge, 2,870 (42.0%) required increased support in care from their preadmission baseline, 3,244 (47.5%) were readmitted to the hospital within 1 year, and 1,047 (15.3%) died within 1 year. The mean number of days at home in the year following discharge was 307.9 ± 109.6. CONCLUSIONS: Short- and long-term mortality among patients with AMI-CS is high, with minimal improvement over time. AMI-CS survivors experience significant morbidity, with high risks of readmission and death. Future studies should evaluate interventions to minimize postdischarge morbidity and mortality among AMI-CS survivors.

Efficacy of Milrinone and Dobutamine in Cardiogenic Shock: An Updated Systematic Review and Meta-Analysis.

OBJECTIVES: Inotropic support is commonly used in patients with cardiogenic shock (CS). High-quality data guiding the use of dobutamine or milrinone among this patient population is limited. We compared the efficacy and safety of these two inotropes among patients with low cardiac output states (LCOS) or CS. DATA SOURCES: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched up to February 1, 2023, using key terms and index headings related to LCOS or CS and inotropes. DATA EXTRACTION: Two independent reviewers included studies that compared dobutamine to milrinone on all-cause in-hospital mortality, length of ICU stay, length of hospital stay, and significant arrhythmias in hospitalized patients. DATA SYNTHESIS: A total of eleven studies with 21,084 patients were included in the meta-analysis. Only two randomized controlled trials were identified. The primary outcome, all-cause mortality, favored milrinone in observational studies only (odds ratio [OR] 1.19 (95% CI, 1.02-1.39; p = 0.02). In-hospital length of stay (LOS) was reduced with dobutamine in observational studies only (mean difference -1.85 d; 95% CI -3.62 to -0.09; p = 0.04). There was no difference in the prevalence of significant arrhythmias or in ICU LOS. CONCLUSIONS: Only limited data exists supporting the use of one inotropic agent over another exists. Dobutamine may be associated with a shorter hospital LOS; however, there is also a potential for increased all-cause mortality. Larger randomized studies sufficiently powered to detect a difference in these outcomes are required to confirm these findings.

Inotrope versus placebo therapy in cardiogenic shock: Rationale and study design of the CAPITAL DOREMI2 trial.

BACKGROUND: Cardiogenic shock (CS) is a state of end-organ hypoperfusion related to cardiac dysfunction. Current guidelines recommend consideration of inotrope therapy in patients with CS, however no robust data support their use. The purpose of the CAPITAL DOREMI2 trial is to examine the efficacy and safety of inotrope therapy against placebo in the initial resuscitation of patients with CS. METHODS AND DESIGN: This is a multi-center, double-blind, randomized, placebo-controlled trial comparing single-agent inotrope therapy to placebo in patients with CS. A total of 346 participants with Society for Cardiovascular Angiography and Interventions class C or D CS will be randomized in a 1:1 fashion to inotrope or placebo therapy, which will be administered over a 12-hour period. After this period, participants will continue open-label therapies at the discretion of the treating team. The primary outcome is a composite of all-cause in-hospital death, and, as measured during the 12-hour intervention period, any of: sustained hypotension or high dose vasopressor requirements, lactate greater than 3.5 mmol/L at 6 hours or thereafter, need for mechanical circulatory support, arrhythmia leading to emergent electrical cardioversion, and resuscitated cardiac arrest. All participants will be followed for the duration of their hospitalization, and secondary outcomes will be assessed at the time of discharge. IMPLICATION: This trial will be the first to establish the safety and efficacy of inotrope therapy against placebo in a population of patients with CS and has the potential to alter the standard care provided to this group of patients.