Inhibition of cyclo-oxygenase 2 reduces tumor metastasis and inflammatory signaling during blockade of vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) blockade is an effective therapy for human cancer, yet virtually all neoplasms resume primary tumor growth or metastasize during therapy. Mechanisms of progression have been proposed to include genes that control vascular remodeling and are elicited by hypoperfusion, such as the inducible enzyme cyclooxygenase-2 (COX-2). We have previously shown that COX-2 inhibition by the celecoxib analog SC236 attenuates perivascular stromal cell recruitment and tumor growth. We therefore examined the effect of combined SC236 and VEGF blockade, using the metastasizing orthotopic SKNEP1 model of pediatric cancer. Combined treatment perturbed tumor vessel remodeling and macrophage recruitment, but did not further limit primary tumor growth as compared to VEGF blockade alone. However, combining SC236 and VEGF inhibition significantly reduced the incidence of lung metastasis, suggesting a distinct effect on prometastatic mechanisms. We found that SC236 limited tumor cell viability and migration in vitro, with effects enhanced by hypoxia, but did not change tumor proliferation or matrix metalloproteinase expression in vivo. Gene set expression analysis (GSEA) indicated that the addition of SC236 to VEGF inhibition significantly reduced expression of gene sets linked to macrophage mobilization. Perivascular recruitment of macrophages induced by VEGF blockade was disrupted in tumors treated with combined VEGF- and COX-2-inhibition. Collectively, these findings suggest that during VEGF blockade COX-2 may restrict metastasis by limiting both prometastatic behaviors in individual tumor cells and mobilization of macrophages to the tumor vasculature

Veno-Venous Extracorporeal Membrane Oxygenation for Continuous Renal Replacement in a Neonate with Propionic Acidemia

The usual indications for extra corporeal membrane oxygenation (ECMO) are for respiratory or cardiac failure. Although continuous renal replacement therapy (CRRT) is frequently used when patients are on ECMO, the need for CRRT as the primary indication for ECMO is rare. A case of a neonate placed onto veno-venous ECMO for the use of CRRT to treat hyperammonemia from propionic acidemia is presented

Postoperative Respiratory Complications in SARS-CoV-2 Positive Pediatric Patients Across 20 United States Hospitals: A Cohort Study

IntroductionData examining rates of postoperative complications among SARS-CoV-2 positive children are limited. The purpose of this study was to evaluate the impact of symptomatic and asymptomatic SARS-CoV-2 positive status on postoperative respiratory outcomes for children.MethodsThis retrospective cohort study included SARS-CoV-2 positive pediatric patients across 20 hospitals who underwent general anesthesia from March to October 2020. The primary outcome was frequency of postoperative respiratory complications, including: high-flow nasal cannula/non invasive ventilation, reintubation, pneumonia, Extracorporeal Membrane Oxygenation (ECMO), and 30-day respiratory-related readmissions or emergency department (ED) visits. Univariate analyses were used to evaluate associations between patient and procedure characteristics and stratified analyses by symptoms were performed examining incidence of complications.ResultsOf 266 SARS-CoV-2 positive patients, 163 (61.7%) were male, and the median age was 10 years (interquartile range 4-14). The majority of procedures were emergent or urgent (n = 214, 80.5%). The most common procedures were appendectomies (n = 78, 29.3%) and fracture repairs (n = 40,15.0%). 13 patients (4.9%) had preoperative symptoms including cough or dyspnea. 26 patients (9.8%) had postoperative respiratory complications, including 15 requiring high-flow oxygen, 8 with pneumonia, 4 requiring non invasive ventilation, 3 respiratory ED visits, and 2 respiratory readmissions. Respiratory complications were more common among symptomatic patients than asymptomatic patients (30.8% vs. 8.7%, p = 0.01). Higher ASA class and comorbidities were also associated with postoperative respiratory complications.ConclusionsPostoperative respiratory complications are less common in asymptomatic versus symptomatic SARS-COV-2 positive children. Relaxation of COVID-19-related restrictions for time-sensitive, non urgent procedures in selected asymptomatic patients may be reasonably considered. Additionally, further research is needed to evaluate the costs and benefits of routine testing for asymptomatic patients.Level of evidenceIii, Respiratory complications

Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection.

IMPORTANCE: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. OBJECTIVE: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. EXPOSURE: SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES: PASC and 44 participant-reported symptoms (with severity thresholds). RESULTS: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. CONCLUSIONS AND RELEVANCE: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC

Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. METHODS: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. DISCUSSION: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options. REGISTRATION: NCT05172024