Spon1+ inflammatory monocytes promote collagen remodeling and lung cancer metastasis through lipoprotein receptor 8 signaling.

Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung cancer (NSCLC) is the most common subset. We previously found that infiltration of tumor inflammatory monocytes (TIMs) into lung squamous carcinoma (LUSC) tumors is associated with increased metastases and poor survival. To further understand how TIMs promote metastases, we compared RNA-Seq profiles of TIMs from several LUSC metastatic models with inflammatory monocytes (IMs) of non-tumor-bearing controls. We identified Spon1 as upregulated in TIMs and found that Spon1 expression in LUSC tumors corresponded with poor survival and enrichment of collagen extracellular matrix signatures. We observed SPON1+ TIMs mediate their effects directly through LRP8 on NSCLC cells, which resulted in TGF-ß1 activation and robust production of fibrillar collagens. Using several orthogonal approaches, we demonstrated that SPON1+ TIMs were sufficient to promote NSCLC metastases. Additionally, we found that Spon1 loss in the host, or Lrp8 loss in cancer cells, resulted in a significant decrease of both high-density collagen matrices and metastases. Finally, we confirmed the relevance of the SPON1/LRP8/TGF-ß1 axis with collagen production and survival in patients with NSCLC. Taken together, our study describes how SPON1+ TIMs promote collagen remodeling and NSCLC metastases through an LRP8/TGF-ß1 signaling axis.

Delivery Timing and Associated Outcomes in Pregnancies With Maternal Congenital Heart Disease at Term.

Background Current recommendations for delivery timing of pregnant persons with congenital heart disease (CHD) are based on expert opinion. Justification for early-term birth is based on the theoretical concern of increased cardiovascular stress. The objective was to evaluate whether early-term birth with maternal CHD is associated with lower adverse maternal or neonatal outcomes. Methods and Results This is a retrospective cohort study of pregnant persons with CHD who delivered a singleton after 37 0/7 weeks gestation at a quaternary care center with a multidisciplinary cardio-obstetrics care team between 2013 and 2021. Patients were categorized as early-term (37 0/7 to 38 6/7 weeks) or full-term (≥39 0/7) births and compared. Multivariable logistic regression was conducted to calculate the adjusted odds ratio for the primary outcomes. The primary outcomes were composite adverse cardiovascular, maternal obstetric, and adverse neonatal outcome. Of 110 pregnancies delivering at term, 55 delivered early-term and 55 delivered full-term. Development of adverse cardiovascular and maternal obstetric outcome was not significantly different by delivery timing. The rate of composite adverse neonatal outcomes was significantly higher in early-term births (36% versus 5%, P<0.01). After adjusting for confounding variables, early-term birth remained associated with a significantly increased risk of adverse neonatal outcomes (adjusted odds ratio 11.55 [95% CI, 2.59-51.58]). Conclusions Early-term birth for pregnancies with maternal CHD was associated with an increased risk of adverse neonatal outcomes, without an accompanying decreased rate in adverse cardiovascular or obstetric outcomes. In the absence of maternal or fetal indications for early birth, induction of labor before 39 weeks for pregnancies with maternal CHD should be reserved for routine obstetrical indications.

Landscape and selection of vaccine epitopes in SARS-CoV-2.

BACKGROUND: Early in the pandemic, we designed a SARS-CoV-2 peptide vaccine containing epitope regions optimized for concurrent B cell, CD4+ T cell, and CD8+ T cell stimulation. The rationale for this design was to drive both humoral and cellular immunity with high specificity while avoiding undesired effects such as antibody-dependent enhancement (ADE). METHODS: We explored the set of computationally predicted SARS-CoV-2 HLA-I and HLA-II ligands, examining protein source, concurrent human/murine coverage, and population coverage. Beyond MHC affinity, T cell vaccine candidates were further refined by predicted immunogenicity, sequence conservation, source protein abundance, and coverage of high frequency HLA alleles. B cell epitope regions were chosen from linear epitope mapping studies of convalescent patient serum, followed by filtering for surface accessibility, sequence conservation, spatial localization near functional domains of the spike glycoprotein, and avoidance of glycosylation sites. RESULTS: From 58 initial candidates, three B cell epitope regions were identified. From 3730 (MHC-I) and 5045 (MHC-II) candidate ligands, 292 CD8+ and 284 CD4+ T cell epitopes were identified. By combining these B cell and T cell analyses, as well as a manufacturability heuristic, we proposed a set of 22 SARS-CoV-2 vaccine peptides for use in subsequent murine studies. We curated a dataset of ~ 1000 observed T cell epitopes from convalescent COVID-19 patients across eight studies, showing 8/15 recurrent epitope regions to overlap with at least one of our candidate peptides. Of the 22 candidate vaccine peptides, 16 (n = 10 T cell epitope optimized; n = 6 B cell epitope optimized) were manually selected to decrease their degree of sequence overlap and then synthesized. The immunogenicity of the synthesized vaccine peptides was validated using ELISpot and ELISA following murine vaccination. Strong T cell responses were observed in 7/10 T cell epitope optimized peptides following vaccination. Humoral responses were deficient, likely due to the unrestricted conformational space inhabited by linear vaccine peptides. CONCLUSIONS: Overall, we find our selection process and vaccine formulation to be appropriate for identifying T cell epitopes and eliciting T cell responses against those epitopes. Further studies are needed to optimize prediction and induction of B cell responses, as well as study the protective capacity of predicted T and B cell epitopes.

Maternal Central Blood Pressure Is Associated with Fetal Middle Cerebral Artery Dopplers.

Cardiovascular adaptations to pregnancy involve physiological mechanisms that increase cardiac output, decrease total vascular resistance, and decrease both systolic and diastolic blood pressure (BP). These maternal hemodynamic changes modulate uteroplacental blood flow and fetal-placental Doppler indices. Our objective was to create maternal cardiac profiles of pregnant women using non-invasive measurements of central BP to identify changes in maternal-fetal hemodynamics as a surrogate to fetal status. This was a prospective cohort study of all singleton pregnancies in a perinatal referral center between January and April 2018. Central BP was measured non-invasively using the BP+ device. The BP+ device is a supra-systolic oscillometric central BP device, which measures BP waveforms peripherally and calculates central BP. We compared various BP+ values for peripheral BP with central BP and stratified by gestational age. We investigated the correlations between peripheral BP, central BP, estimated fetal weight (EFW), and the pulsatility indices (PI) of Doppler velocimetry and demonstrate that both central systolic and diastolic BP correlated to peripheral systolic and diastolic BP. Linear regression analysis confirmed that central BP predicts the middle cerebral artery (MCA) PI. The MCA PI correlated with EFW, specifically higher central systolic BP is associated with a lower MCA PI, implying a possible etiology of fetal brain shunting with poor placental perfusion. Future studies using predictors and markers of fetal outcomes from maternal cardiac parameters should consider maternal cardiovascular measurements to peripheral arterial BP.

Central hemodynamics are associated with fetal outcomes in pregnancies of advanced maternal age.

OBJECTIVES: Age is a known risk factor for both maternal cardiovascular disease and adverse outcomes in pregnancy. We aimed to characterize the hemodynamic profiles in pregnancies of advanced maternal age (AMA) and correlate these with fetal outcomes. STUDY DESIGN: This was a prospective observational study of pregnancies undergoing antenatal testing. Maternal hemodynamics were measured non-invasively using an imaging probe at the descending aorta and the Uscom BP + arm cuff utilizing pulse pressure wave analysis. The Wilcoxon rank-sum test, Fisher's exact test, and Spearman rank correlation test were used for statistical analysis in R. MAIN OUTCOME MEASURES: Hemodynamic measurements, neonatal birthweight. RESULTS: Twenty-one AMA and twenty-four control patients were enrolled. Mean age ± SD was 39 ± 3.22 in the AMA cohort and 28 ± 4.32 in the control cohort (p < 0.001). AMA patients were evaluated at a later gestational age (36 4/7 weeks) compared to control (34 1/7 weeks, p = 0.02). Between groups, there was no difference in BMI, race, hypertensive disease, diabetes, asthma, drug use, or indication for antenatal testing. 38% (AMA) and 37% (control) had hypertensive disorders of pregnancy. In AMA patients but not control patients, cardiac output (r = 0.52, p = 0.01), systemic vascular resistance (r = -0.53, p = 0.01), and systemic vascular resistance index (r = -0.62, p = 0.002) were significantly correlated with neonatal birthweight percentile. CONCLUSIONS: Hemodynamic alterations consistent with a low output, high resistance cardiovascular circuit were associated with lower birthweight in AMA, but not in control pregnancies.

An Innovative Approach to Improving the Accuracy of Delirium Assessments Using the Confusion Assessment Method for the Intensive Care Unit.

BACKGROUND: Delirium occurs in up to 80% of intensive care unit (ICU) patients. Despite its prevalence in this population, there continues to be inaccuracies in delirium assessments. In the absence of accurate delirium assessments, delirium in critically ill ICU patients will remain unrecognized and will lead to negative clinical and organizational outcomes. OBJECTIVES: The goal of this quality improvement project was to facilitate sustained improvement in the accuracy of delirium assessments among all ICU patients including those who were sedate or agitated. METHODS: A pretest-posttest design was used to evaluate the effectiveness of a program to improve the accuracy of delirium screenings among patients admitted to a medical ICU or coronary care unit. RESULTS: Two hundred thirty-six delirium assessment audits were completed during the baseline period and 535 during the postintervention period. Compliance with performing at least 1 delirium assessment every shift was 85% at baseline and improved to 99% during the postintervention period. Baseline assessment accuracy was 70.31% among all patients and 53.49% among sedate and agitated patients. Postintervention assessment accuracy improved to 95.51% for all patients and 89.23% among sedate and agitated patients. CONCLUSION: The results from this project suggest the effectiveness of the program in improving assessment accuracy among difficult-to-assess patients. Further research is needed to demonstrate the effectiveness of this model across other critical care units, patient populations, and organizations.