Neutrophil-to-Lymphocyte Ratio as a Predictor of Mortality for COVID-19-Related Acute Respiratory Distress Syndrome (ARDS) Patients Requiring Extracorporeal Membrane Oxygenation Therapy.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has been studied as an indicator of systemic inflammation and as a prognostic tool in multiple areas of medicine. Previous research has suggested that higher NLR and rapid increase to peak NLR are associated with poorer outcomes in patients with coronavirus disease 2019 (COVID-19), particularly in those experiencing acute respiratory distress syndrome (ARDS). Within vascular surgery, there is data to suggest a positive correlation between elevated pre-extracorporeal membrane oxygenation (ECMO) NLR and higher rates of mortality following major procedures. This study explores the prognostic value of peri-ECMO NLR in patients requiring veno-venous ECMO (VV-ECMO) therapy for COVID-19-related ARDS. The objective of this study was to explore the utility of pre-ECMO NLR as an easily accessible prognostic factor for patients suffering from COVID-19-associated ARDS that require VV-ECMO. METHODS: This was a retrospective cohort study within a tertiary care hospital conducted between April 2020 and January 2021. Patients requiring VV-ECMO therapy for COVID-19-associated ARDS were included. Peri-ECMO NLR values, length of stay (LOS), duration on VV-ECMO, and discharge status were recorded. Receiver operating characteristic (ROC) curve analysis and Youden's J statistics were performed to calculate a cut-off value of 11.005 for pre-ECMO NLR and 17.616 for on-ECMO NLR. Pre-ECMO and on-ECMO Kaplan-Meyer curves were generated for two groups of patients, those above and below NLR cutoff thresholds. Two-sample T-test was performed to test for significant differences in LOS and duration on VV-ECMO. RESULTS: Twenty-six patients were included in the study for final analyses. There was an overall mortality of 39% (n = 10). ROC curve analysis and Youden's J statistic revealed an optimal cut-off value of pre-ECMO NLR = 11.005 and on-ECMO NLR = 17.616. Results showed that the patient group placed on VV-ECMO with a pre-ECMO NLR less than 11.005 experienced no mortality (n = 7) and a median LOS of 28 days (IQR = 14.5-64.5 days). The patient group on VV-ECMO with a pre-ECMO NLR greater than 11.005 (n = 19) included all mortality (n = 10) and had a median LOS of 49 days (IQR = 25.5-63.5 days). The patient group with on-ECMO NLR less than 17.616 also conferred a survival advantage. There was no significant difference in LOS or duration on VV-ECMO between the two groups, pre-ECMO or on-ECMO. CONCLUSIONS:  A pre-ECMO NLR cutoff was identified and offered statistically significant prognostic value in predicting mortality. A lower on-ECMO NLR value also indicated a survival advantage. Future studies should include NLR within multivariate models to better discern the effect of NLR and elucidate how it can be factored into clinical decision-making. Importantly, this data can be expanded to assess the predictive value of NLR pertaining to the COVID-19-induced ARDS population and matched cohorts.

Three cases of acute venous thromboembolism in females after vaccination for coronavirus disease 2019.

Since December 2020, four vaccines for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) have been developed, and three have been approved for immediate use in the United States. Two are mRNA vaccines, and one uses a viral vector mechanism. Thrombotic complications have been reported after vaccine administration, which were primarily cerebral sinus thromboses after administration of the viral vector vaccines. To the best of our knowledge, we are the first to report venous thrombotic complications within days of administration of the mRNA-1273 (Moderna) vaccine. We present a series of three women who developed venous thromboembolism after RNA-1273 vaccination at a single healthcare system.

Role of FOXM1 in vascular smooth muscle cell survival and neointima formation following vascular injury.

BACKGROUND: Accelerated smooth muscle cell (SMC) proliferation is the primary cause of intimal hyperplasia (IH) following vascular interventions. Forkhead Box M1 (FOXM1) is considered a proliferation-associated transcription factor. However, the presence and role of FOXM1 in IH following vascular injury have not been determined. OBJECTIVE: We examined the expression of FOXM1 in balloon-injured rat carotid arteries and investigated the effect of FOXM1 inhibition in SMCs and on the development of IH. METHODS AND RESULTS: FOXM1 was detected by immunofluorescent staining in balloon-injured rat carotid arteries where we observed an upregulation at day 7, 14, and 28 compared to uninjured controls. Immunofluorescence staining revealed FOXM1 coincided with proliferating cell nuclear antigen (PCNA). FOXM1 was also detectable in human carotid plaque samples. Western blot showed an upregulation of FOXM1 protein in serum-stimulated SMCs. Inhibition of FOXM1 using siRNA or chemical inhibition led to the induction of apoptosis as measured by flow cytometry and western blot for cleaved caspase 3. Perturbations in survival signaling were measured by western blot following FOXM1 inhibition, which showed a decrease in phosphorylated AKT and ß-catenin. The chemical inhibitor thiostrepton was delivered by intraperitoneal injection in rats that underwent balloon injury and led to reduced intimal thickening compared to DMSO controls. CONCLUSIONS: FOXM1 is an important molecular mediator of IH that contributes to the proliferation and survival of SMCs following vascular injury.

Neonatal Intestinal Anastomosis Using a 5 mm Laparoscopic Stapler.

Recently, a 5 mm laparoscopic stapler entered the market and is currently used for a wide variety of pediatric applications. The aim of this article is to be the first report of the use of this 5 mm laparoscopic stapler for open neonatal intestinal anastomosis in humans. We used JustRight (Justright Surgical) 5 mm laparoscopic stapler® in 5 patients, with a total of six anastomoses being constructed. Enteroenterostomies after bowel resection were performed in these neonates with diagnoses of closed gastroschisis with ileal atresia, multiple intestinal atresia, ileal atresia, and jejunal atresia. Side-to-side, functional end-to-end, stapled anastomoses were performed in the standard antimesenteric manner. Using 2.5 cm long staple loads, the anastomoses approximated 1.5 cm. Minimal staple line overlap was incurred. Enteral feedings were initiated, and nutritional goals met, on postoperative days 8 and 15.2, respectively (means). Postoperative recovery was uneventful, notably without anastomotic complications of leak or stenosis. No long-term follow-up was done. The 5 mm laparoscopic stapler offers an attractive alternative in open neonatal intestinal anastomosis, particularly in both ease and time of anastomosis. Its more generalized use in neonatal intestinal reconstruction awaits further scientific investigation.

Local CXCR4 Upregulation in the Injured Arterial Wall Contributes to Intimal Hyperplasia.

CXCR4 is a stem/progenitor cell surface receptor specific for the cytokine stromal cell-derived factor-1 (SDF-1α). There is evidence that bone marrow-derived CXCR4-expressing cells contribute to intimal hyperplasia (IH) by homing to the arterial subintima which is enriched with SDF-1α. We have previously found that transforming growth factor-ß (TGFß) and its signaling protein Smad3 are both upregulated following arterial injury and that TGFß/Smad3 enhances the expression of CXCR4 in vascular smooth muscle cells (SMCs). It remains unknown, however, whether locally induced CXCR4 expression in SM22 expressing vascular SMCs plays a role in neointima formation. Here, we investigated whether elevated TGFß/Smad3 signaling leads to the induction of CXCR4 expression locally in the injured arterial wall, thereby contributing to IH. We found prominent CXCR4 upregulation (mRNA, 60-fold; protein, 4-fold) in TGFß-treated, Smad3-expressing SMCs. Chromatin immunoprecipitation assays revealed a specific association of the transcription factor Smad3 with the CXCR4 promoter. TGFß/Smad3 treatment also markedly enhanced SDF-1α-induced ERK1/2 phosphorylation as well as SMC migration in a CXCR4-dependent manner. Adenoviral expression of Smad3 in balloon-injured rat carotid arteries increased local CXCR4 levels and enhanced IH, whereas SMC-specific depletion of CXCR4 in the wire-injured mouse femoral arterial wall produced a 60% reduction in IH. Our results provide the first evidence that upregulation of TGFß/Smad3 in injured arteries induces local SMC CXCR4 expression and cell migration, and consequently IH. The Smad3/CXCR4 pathway may provide a potential target for therapeutic interventions to prevent restenosis. Stem Cells 2016;34:2744-2757.

Periadventitial drug delivery for the prevention of intimal hyperplasia following open surgery.

BACKGROUND: Intimal hyperplasia (IH) remains a major cause of poor patient outcomes after surgical revascularization to treat atherosclerosis. A multitude of drugs have been shown to prevent the development of IH. Moreover, endovascular drug delivery following angioplasty and stenting has been achieved with a marked diminution in the incidence of restenosis. Despite advances in endovascular drug delivery, there is currently no clinically available method of periadventitial drug delivery suitable for open vascular reconstructions. Herein we provide an overview of the recent literature regarding innovative polymer platforms for periadventitial drug delivery in preclinical models of IH as well as insights about barriers to clinical translation. METHODS: A comprehensive PubMed search confined to the past 15years was performed for studies of periadventitial drug delivery. Additional searches were performed for relevant clinical trials, patents, meeting abstracts, and awards of NIH funding. RESULTS: Most of the research involving direct periadventitial delivery without a drug carrier was published prior to 2000. Over the past 15years there have been a surge of reports utilizing periadventitial drug-releasing polymer platforms, most commonly bioresorbable hydrogels and wraps. These methods proved to be effective for the inhibition of IH in various animal models (e.g. balloon angioplasty, wire injury, and vein graft), but very few have advanced to clinical trials. There are a number of barriers that may account for this lack of translation. Promising new approaches including the use of nanoparticles will be described. CONCLUSIONS: No periadventitial drug delivery system has reached clinical application. For periadventitial delivery, polymer hydrogels, wraps, and nanoparticles exhibit overlapping and complementary properties. The ideal periadventitial delivery platform would allow for sustained drug release yet exert minimal mechanical and inflammatory stresses to the vessel wall. A clinically applicable strategy for periadventitial drug delivery would benefit thousands of patients undergoing open vascular reconstruction each year.

A crosstalk between TGF-ß/Smad3 and Wnt/ß-catenin pathways promotes vascular smooth muscle cell proliferation.

RATIONALE: Endovascular interventions performed for atherosclerotic lesions trigger excessive vascular smooth muscle cell (SMC) proliferation leading to intimal hyperplasia. Our previous studies show that following endovascular injury, elevated TGF-ß/Smad3 promotes SMC proliferation and intimal hyperplasia. Furthermore in cultured SMCs, elevated TGF-ß/Smad3 increases the expression of several Wnt genes. Here we investigate a crosstalk between TGF-ß/Smad3 and Wnt/ß-catenin signaling and its role in SMC proliferation. METHODS AND RESULTS: To mimic TGF-ß/Smad3 up-regulation in vivo, rat aortic SMCs were treated with Smad3-expressing adenovirus (AdSmad3) or AdGFP control followed by stimulation with TGF-ß1 (or solvent). AdSmad3/TGF-ß treatment up-regulated Wnt2b, Wnt4, Wnt5a, Wnt9a, and Wnt11 (confirmed by qRT-PCR and ELISA), and also increased ß-catenin protein as detected by Western blotting. Blocking Wnt signaling using a Frizzled receptor inhibitor (Niclosamide) abolished TGF-ß/Smad3-induced ß-catenin stabilization. Increasing ß-catenin through degradation inhibition (using SKL2001) or by adenoviral expression enhanced SMC proliferation. Furthermore, application of recombinant Wnt2b, Wnt4, Wnt5a, or Wnt9a, but not Wnt11, stabilized ß-catenin and stimulated SMC proliferation as well. In addition, increased ß-catenin was found in the neointima of injured rat carotid artery where TGF-ß and Smad3 are known to be up-regulated. CONCLUSIONS: These results suggest a novel mechanism whereby elevated TGF-ß/Smad3 stimulates the secretion of canonical Wnts which in turn enhances SMC proliferation through ß-catenin stabilization. This crosstalk between TGF-ß/Smad3 and Wnt/ß-catenin canonical pathways provides new insights into the pathophysiology of vascular SMCs linked to intimal hyperplasia.