Delayed arrival of advanced life support adversely affects the neurological outcome in a multi-tier emergency response system.

AIM: Prehospital management of out-of-hospital cardiac arrest (OHCA) is based on basic life support, with the addition of advanced life support (ALS) if possible. This study aimed to investigate the effect of delayed arrival of ALS on neurological outcomes of patients with OHCA at hospital discharge. METHODS: This was a retrospective study of a registry of patients with OHCA. A multi-tier emergency response system was established in the study area. ALS was initiated when the second-arrival team arrived at the scene. A restricted cubic spline curve was used to investigate the relationship between the response time interval of the second-arrival team and neurological outcomes at hospital discharge. Multivariable logistic regression analysis was performed to assess the independent association between the response time interval of the second-arrival team and neurological outcomes of patients at hospital discharge. RESULTS: A total of 3186 adult OHCA patients who received ALS at the scene were included in the final analysis. A restricted cubic spline curve showed that a long response time interval of the second-arrival team was correlated with a high likelihood of poor neurological outcomes. Meanwhile, multivariable logistic regression analysis showed that a long response time interval of the second-arrival team was independently associated with poor neurological outcomes (odds ratio, 1.10; 95% confidence interval, 1.03-1.17). CONCLUSION: In a multi-tiered prehospital emergency response system, the delayed arrival of ALS was associated with poor neurological outcomes at hospital discharge.

Two Years of Experience and Methodology of Korean COVID-19 Living Clinical Practice Guideline Development.

BACKGROUND: In Korea, during the early phase of the coronavirus disease 2019 (COVID-19) pandemic, we responded to the uncertainty of treatments under various conditions, consistently playing catch up with the speed of evidence updates. Therefore, there was high demand for national-level evidence-based clinical practice guidelines for clinicians in a timely manner. We developed evidence-based and updated living recommendations for clinicians through a transparent development process and multidisciplinary expert collaboration. METHODS: The National Evidence-based Healthcare Collaborating Agency (NECA) and the Korean Academy of Medical Sciences (KAMS) collaborated to develop trustworthy Korean living guidelines. The NECA-supported methodological sections and 8 professional medical societies of the KAMS worked with clinical experts, and 31 clinicians were involved annually. We developed a total of 35 clinical questions, including medications, respiratory/critical care, pediatric care, emergency care, diagnostic tests, and radiological examinations. RESULTS: An evidence-based search for treatments began in March 2021 and monthly updates were performed. It was expanded to other areas, and the search interval was organized by a steering committee owing to priority changes. Evidence synthesis and recommendation review was performed by researchers, and living recommendations were updated within 3-4 months. CONCLUSION: We provided timely recommendations on living schemes and disseminated them to the public, policymakers and various stakeholders using webpages and social media. Although the output was successful, there were some limitations. The rigor of development issues, urgent timelines for public dissemination, education for new developers, and spread of several new COVID-19 variants have worked as barriers. Therefore, we must prepare systematic processes and funding for future pandemics.

Association between length of stay in the emergency department and outcomes in out-of-hospital cardiac arrest.

OBJECTIVE: Several studies have previously reported that a prolonged emergency department length of stay (EDLOS) is associated with poor outcomes in critically ill patients. This study was performed to investigate the relationship between the EDLOS and the neurologic outcome at 28 days in out-of-hospital cardiac arrest (OHCA) patients. METHODS: We conducted a retrospective analysis of prospectively collected data from OHCA patients who achieved the return of spontaneous circulation (ROSC) in the EDs of three urban tertiary teaching hospitals from December 2013 to October 2020. Patients were divided into four groups according to the EDLOS, according to the quartile distribution: EDLOS <107 min, EDLOS 107-176 min, EDLOS 176-275 min, and EDLOS ≥275 min. Comparisons of outcomes among the groups and multivariable logistic regression analysis were performed. RESULTS: A total of 807 patients were included in the analysis. The proportions of patients with a good neurologic outcome at 28 days in the groups with EDLOS <107 min, EDLOS 107-176 min, EDLOS 176-275 min, and EDLOS ≥275 min were 37.0%, 29.8%, 26.9, and 20.4%, respectively (p < 0.001). In the multivariable analysis, the odds ratios for a poor neurologic outcome at 28 days in the groups with EDLOS 107-176 min, EDLOS 176-275 min, and EDLOS ≥275 min compared with the group with EDLOS <107 min were 1.19 (95% CI, 0.67-2.13), 1.73 (95% CI, 0.95-3.21), and 1.91 (95% CI, 1.03-3.57), respectively. CONCLUSIONS: An EDLOS longer than 275 min after the ROSC was independently associated with a poor neurologic outcome at 28 days.

Association of the duration of on-scene advanced life support with good neurological recovery in out-of-hospital cardiac arrest.

BACKGROUND: As advanced life support (ALS) provided by emergency medical services (EMS) on scene becomes more common, the scene time interval (STI) for which EMS providers stay on scene tends to lengthen. We investigated the relationship between the STI and neurological outcome of patients at hospital discharge when ALS was provided by EMS on scene. METHODS: We conducted a retrospective analysis of prospectively collected out-of-hospital cardiac arrest (OHCA) data between August 2015 and December 2018. A restricted cubic spline curve was used to investigate the relationship between the STI and neurologic outcome, and patients were divided into two groups based on the cut-off value obtained through receiver operating characteristic (ROC) analysis. Comparisons of outcomes between the two groups were performed before and after propensity score matching. RESULTS: 4548 patients were included in the analysis. In ROC analysis, the optimal cut-off value for STI was 19 min. For the group with an STI <19 min, survival admission, survival discharge, and good neurologic outcome at hospital discharge were all higher than for the group with STI ≥19 min before and after propensity score matching. The multivariable model also showed that the STI ≥19 min was significantly associated with poor neurologic outcome at hospital discharge compared with the STI <19 min (adjusted odds ratio, 2.00; 95% CI, 1.40-2.88). CONCLUSIONS: A duration of on-scene ALS more than 19 min was associated with a poor neurologic outcome of patients at hospital discharge in OHCA.

The index of oxygenation to respiratory rate as a prognostic factor for mortality in Sepsis.

OBJECTIVES: An index combining respiratory rate and oxygenation (ROX) has been introduced, and the ROX index is defined as the ratio of oxygen saturation by pulse oximetry/fraction of inspired oxygen to respiratory rate. In sepsis, hypoxemia and tachypnea are commonly observed. We performed this study to investigate the association between the ROX index and 28-day mortality in patients with sepsis or septic shock. METHODS: This retrospective study included 2862 patients. The patients were divided into three groups according to the ROX index: Group I (ROX index >20), Group II (ROX index >10 and ≤ 20), and Group III (ROX index ≤10). RESULTS: The median ROX index was significantly lower in the nonsurvivors than in the survivors (12.8 and 18.2, respectively) (p < 0.001). The 28-day mortality rates in Groups I, II and III were 14.5%, 21.3% and 34.4%, respectively (p < 0.001). In the multivariable Cox regression analysis, Group III had an approximately 40% higher risk of death than Group I during the 28-day period (hazard ratio = 1.41, 95% confidence interval 1.13-1.76). The area under the curve of the ROX index was significantly higher than that of the quick Sequential Organ Failure Assessment score (p < 0.001). CONCLUSIONS: The ROX index was lower in nonsurvivors than in survivors, and a ROX index less than or equal to 10 was an independent prognostic factor for 28-day mortality in patients with sepsis or septic shock. Therefore, the ROX index could be used as a prognostic marker in sepsis.

External Validation of Deep Learning Algorithm for Detecting and Visualizing Femoral Neck Fracture Including Displaced and Non-displaced Fracture on Plain X-ray.

This study aimed to develop a method for detection of femoral neck fracture (FNF) including displaced and non-displaced fractures using convolutional neural network (CNN) with plain X-ray and to validate its use across hospitals through internal and external validation sets. This is a retrospective study using hip and pelvic anteroposterior films for training and detecting femoral neck fracture through residual neural network (ResNet) 18 with convolutional block attention module (CBAM) + + . The study was performed at two tertiary hospitals between February and May 2020 and used data from January 2005 to December 2018. Our primary outcome was favorable performance for diagnosis of femoral neck fracture from negative studies in our dataset. We described the outcomes as area under the receiver operating characteristic curve (AUC), accuracy, Youden index, sensitivity, and specificity. A total of 4,189 images that contained 1,109 positive images (332 non-displaced and 777 displaced) and 3,080 negative images were collected from two hospitals. The test values after training with one hospital dataset were 0.999 AUC, 0.986 accuracy, 0.960 Youden index, and 0.966 sensitivity, and 0.993 specificity. Values of external validation with the other hospital dataset were 0.977, 0.971, 0.920, 0.939, and 0.982, respectively. Values of merged hospital datasets were 0.987, 0.983, 0.960, 0.973, and 0.987, respectively. A CNN algorithm for FNF detection in both displaced and non-displaced fractures using plain X-rays could be used in other hospitals to screen for FNF after training with images from the hospital of interest.

Developing neural network models for early detection of cardiac arrest in emergency department.

BACKGROUND: Automated surveillance for cardiac arrests would be useful in overcrowded emergency departments. The purpose of this study is to develop and test artificial neural network (ANN) classifiers for early detection of patients at risk of cardiac arrest in emergency departments. METHODS: This is a single-center electronic health record (EHR)-based study. The primary outcome was the development of cardiac arrest within 24 h after prediction. Three ANN models were trained: multilayer perceptron (MLP), long-short-term memory (LSTM), and hybrid. These were compared to other classifiers including the modified early warning score (MEWS), logistic regression, and random forest. We used AUROC, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the comparison. RESULTS: During the study period, there were a total of 374,605 ED visits and 2,910,321 patient status updates. The ANN models (MLP, LSTM, and hybrid) achieved higher AUROC (AUROC: 0.929, 0.933, and 0.936; 95% confidential interval: 0.926-0.932, 0.930-0.936, and 0.933-0.939, respectively) compared to the non-ANN models, and the hybrid model exhibited the best performance. The ANN classifiers displayed higher performance in most of the test characteristics when the threshold levels of the classifiers were fixed to display the same positive result as those at the three MEWS thresholds (score ≥ 3, ≥4, and ≥5), and when compared with each other. CONCLUSIONS: The ANN improves upon MEWS and conventional machine learning algorithms for the prediction of cardiac arrests in emergency departments. The hybrid ANN model utilizing both baseline and sequence information achieved the best performance.

Moderate to severe hyperphosphataemia as an independent prognostic factor for 28-day mortality in adult patients with sepsis.

BACKGROUND: Ischaemic tissue injury caused by tissue hypoperfusion is one of the major consequences of sepsis. Phosphate concentrations are elevated in ischaemic tissue injury. This study was performed to investigate the association of phosphate concentrations with mortality in patients with sepsis. METHODS: This was a retrospective cohort study of patients with sepsis conducted at an urban, tertiary care emergency department (ED) in Korea. Patients with sepsis arriving between March 2010 and April 2017 were stratified into four groups according to the initial phosphate concentration at presentation to the ED: group I (hypophosphataemia, phosphate <2 mg/dL), group II (normophosphataemia, phosphate 2-4 mg/dL), group III (mild hyperphosphataemia, phosphate 4-6 mg/dL), group IV (moderate to severe hyperphosphataemia, phosphate ≥6 mg/dL). Multivariable Cox proportional hazard regression analyses were performed to evaluate the independent association of initial phosphate concentration with 28-day mortality. RESULTS: Of the 3034 participants in the study, the overall mortality rate was 21.9%. The 28-day mortality rates were group I (hypophosphataemia) 14.6%, group II 17.4% (normophosphataemia), group III (mild hyperphosphataemia) 29.2% and group IV (moderate to severe hyperphosphataemia) 51.4%, respectively (p<0.001). In the multivariable analyses, patients with severe hyperphosphataemia had a significantly higher risk of death than those with normal phosphate levels (HR 1.59; 95% CI 1.23 to 2.05). Mortality in the other groups was not significantly different from mortality in patients with normophosphataemia. CONCLUSIONS: Moderate to severe hyperphosphataemia was associated with 28-day mortality in patients with sepsis. Phosphate level could be used as a prognostic indicator in sepsis.

NF-κB-responsive miRNA-31-5p elicits endothelial dysfunction associated with preeclampsia via down-regulation of endothelial nitric-oxide synthase.

Inflammatory cytokines, including tumor necrosis factor-α (TNFα), were elevated in patients with cardiovascular diseases and are also considered as crucial factors in the pathogenesis of preeclampsia; however, the underlying pathogenic mechanism has not been clearly elucidated. This study provides novel evidence that TNFα leads to endothelial dysfunction associated with hypertension and vascular remodeling in preeclampsia through down-regulation of endothelial nitric-oxide synthase (eNOS) by NF-κB-dependent biogenesis of microRNA (miR)-31-5p, which targets eNOS mRNA. In this study, we found that miR-31-5p was up-regulated in sera from patients with preeclampsia and in human endothelial cells treated with TNFα. TNFα-mediated induction of miR-31-5p was blocked by an NF-κB inhibitor and NF-κB p65 knockdown but not by mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase inhibitors, indicating that NF-κB is essential for biogenesis of miR-31-5p. The treatment of human endothelial cells with TNFα or miR-31-5p mimics decreased endothelial nitric-oxide synthase (eNOS) mRNA stability without affecting eNOS promoter activity, resulting in inhibition of eNOS expression and NO/cGMP production through blocking of the functional activity of the eNOS mRNA 3'-UTR. Moreover, TNFα and miR-31-5p mimic evoked endothelial dysfunction associated with defects in angiogenesis, trophoblastic invasion, and vasorelaxation in an ex vivo cultured model of human placental arterial vessels, which are typical features of preeclampsia. These results suggest that NF-κB-responsive miR-31-5p elicits endothelial dysfunction, hypertension, and vascular remodeling via post-transcriptional down-regulation of eNOS and is a molecular risk factor in the pathogenesis and development of preeclampsia.

TNF-α elicits phenotypic and functional alterations of vascular smooth muscle cells by miR-155-5p-dependent down-regulation of cGMP-dependent kinase 1.

cGMP-dependent protein kinase 1 (PKG1) plays an important role in nitric oxide (NO)/cGMP-mediated maintenance of vascular smooth muscle cell (VSMC) phenotype and vasorelaxation. Inflammatory cytokines, including tumor necrosis factor-α (TNFα), have long been understood to mediate several inflammatory vascular diseases. However, the underlying mechanism of TNFα-dependent inflammatory vascular disease is unclear. Here, we found that TNFα treatment decreased PKG1 expression in cultured VSMCs, which correlated with NF-κB-dependent biogenesis of miR-155-5p that targeted the 3'-UTR of PKG1 mRNA. TNFα induced VSMC phenotypic switching from a contractile to a synthetic state through the down-regulation of VSMC marker genes, suppression of actin polymerization, alteration of cell morphology, and elevation of cell proliferation and migration. All of these events were blocked by treatment with an inhibitor of miR-155-5p or PKG1, whereas transfection with miR-155-5p mimic or PKG1 siRNA promoted phenotypic modulation, similar to the response to TNFα. In addition, TNFα-induced miR-155-5p inhibited the vasorelaxant response of de-endothelialized mouse aortic vessels to 8-Br-cGMP by suppressing phosphorylation of myosin phosphatase and myosin light chain, both of which are downstream signal modulators of PKG1. Moreover, TNFα-induced VSMC phenotypic alteration and vasodilatory dysfunction were blocked by NF-κB inhibition. These results suggest that TNFα impairs NO/cGMP-mediated maintenance of the VSMC contractile phenotype and vascular relaxation by down-regulating PKG1 through NF-κB-dependent biogenesis of miR-155-5p. Thus, the NF-κB/miR-155-5p/PKG1 axis may be crucial in the pathogenesis of inflammatory vascular diseases, such as atherosclerotic intimal hyperplasia and preeclamptic hypertension.

REDD-1 aggravates endotoxin-induced inflammation via atypical NF-κB activation.

Regulated in development and DNA damage responses 1 (REDD-1), an inhibitor of mammalian target of rapamycin (mTOR), is induced by various cell stressors, including LPS, a major player in the pathogenesis of endotoxemic shock. However, the pathologic role of REDD-1 in endotoxemia is largely unknown. We found that LPS increased REDD-1 expression, nuclear transcription factor-κB (NF-κB) activation, and inflammation and that these responses were suppressed by REDD-1 knockdown and in REDD-1+/- macrophages. REDD-1 overexpression stimulated NF-κB-dependent inflammation without additional LPS stimulation. REDD-1-induced NF-κB activation was independent of 2 classic IKK-dependent NF-κB pathways and the mTOR signaling pathway; however, REDD-1, particularly its C-terminal region (178-229), interacted with and sequestered IκBα, to elicit atypical NF-κB activation during the delayed and persistent phases of inflammation after stimulation. Moreover, REDD-1 knockdown mitigated vascular inflammation and permeability in endotoxemic mice, resulting in decreases in immune cell infiltration, systemic inflammation, caspase-3 activation, apoptosis, and consequent mortality. We further confirmed the inflammatory and cytotoxic effects of REDD-1 in endotoxemic REDD-1+/- mice. Our data support the likelihood that REDD-1 exacerbates endotoxemic inflammation via atypical NF-κB activation by sequestering IκBα.-Lee, D.-K., Kim, J.-H., Kim, J., Choi, S., Park, M., Park, W., Kim, S., Lee, K.-S., Kim, T., Jung, J., Choi, Y. K., Ha, K.-S., Won, M.-H., Billiar, T. R., Kwon, Y.-G., Kim, Y.-M. REDD-1 aggravates endotoxin-induced inflammation via atypical NF-κB activation.

Effect of Automated Simultaneous Sternothoracic Cardiopulmonary Resuscitation Device on Hemodynamics in Out-of-Hospital Cardiac Arrest Patients.

BACKGROUND: An automatic simultaneous sternothoracic cardiopulmonary resuscitation (SST-CPR) device is an apparatus that performs CPR by providing simultaneous cyclic compressions of the thorax with a thoracic strap and compression of the sternum with a piston. OBJECTIVE: This study was conducted to compare the hemodynamic effects of CPR with an automatic SST-CPR device to those with standard CPR (STD-CPR) in cardiac arrest patients. METHODS: A randomized trial was performed on victims of out-of-hospital cardiac arrest resistant to initial 20 min of CPR after emergency department (ED) arrival. Patients were instrumented with femoral arterial and internal jugular venous lines before enrollment. Informed consent was waived per protocol. Patients were randomized to SST-CPR or STD-CPR based on the day of the month. The primary outcome was a comparison of the mean estimated coronary perfusion pressure (CPP) between SST-CPR and STD-CPR. The secondary outcome was a comparison of compression arterial systolic pressure, compression arterial diastolic pressure, right atrial systolic pressure, right atrial diastolic pressure, return of spontaneous circulation rate, survival to hospital admission, survival at 30 days, favorable neurologic outcomes at 30 days, and adverse events between two groups. RESULTS: Of 62 patients with non-traumatic, adult, out-of-hospital cardiac arrest who presented to the ED, 24 received CPR with an automatic SST-CPR device (SST-CPR group), and 38 received standard CPR (STD-CPR group). Acquisition and analysis of hemodynamic data were completed in 11 (46%) patients in the SST-CPR group and 14 (37%) patients in the STD-CPR group. Compression arterial systolic pressure, right atrial systolic/diastolic pressures, and end-tidal carbon dioxide tension were not different between the two groups. Median compression arterial diastolic pressure (femoral arterial pressure during relaxation) was 20 mm Hg (mean 22 mm Hg; 95% confidence interval [CI] 5 to 38 mm Hg) and 0 mm Hg (mean -2 mm Hg; 95% CI -21 to 18 mm Hg) in the SST-CPR group and the STD-CPR group (p = 0.002), respectively. Median estimated CPP was 10 mm Hg (mean 16 mmHg; 95% CI 1 to 31 mm Hg) and 2 mm Hg (mean 4 mm Hg; 95% CI -4 to 12 mm Hg) in the SST-CPR group and the STD-CPR group (p = 0.017), respectively. CONCLUSIONS: CPR with an automatic SST-CPR device results in higher estimated CPP compared to standard CPR in patients with non-traumatic, out-of-hospital cardiac arrest.

Specific activation of insulin-like growth factor-1 receptor by ginsenoside Rg5 promotes angiogenesis and vasorelaxation.

Ginsenoside Rg5 is a compound newly synthesized during the steaming process of ginseng; however, its biological activity has not been elucidated with regard to endothelial function. We found that Rg5 stimulated in vitro angiogenesis of human endothelial cells, consistent with increased neovascularization and blood perfusion in a mouse hind limb ischemia model. Rg5 also evoked vasorelaxation in aortic rings isolated from wild type and high cholesterol-fed ApoE(-/-) mice but not from endothelial nitric-oxide synthase (eNOS) knock-out mice. Angiogenic activity of Rg5 was highly associated with a specific increase in insulin-like growth factor-1 receptor (IGF-1R) phosphorylation and subsequent activation of multiple angiogenic signals, including ERK, FAK, Akt/eNOS/NO, and Gi-mediated phospholipase C/Ca(2+)/eNOS dimerization pathways. The vasodilative activity of Rg5 was mediated by the eNOS/NO/cGMP axis. IGF-1R knockdown suppressed Rg5-induced angiogenesis and vasorelaxation by inhibiting key angiogenic signaling and NO/cGMP pathways. In silico docking analysis showed that Rg5 bound with high affinity to IGF-1R at the same binding site of IGF. Rg5 blocked binding of IGF-1 to its receptor with an IC50 of ∼90 nmol/liter. However, Rg5 did not induce vascular inflammation and permeability. These data suggest that Rg5 plays a novel role as an IGF-1R agonist, promoting therapeutic angiogenesis and improving hypertension without adverse effects in the vasculature.

Nickel oxide nanoparticles can recruit eosinophils in the lungs of rats by the direct release of intracellular eotaxin.

BACKGROUND: Instillation of highly soluble nanoparticles (NPs) into the lungs of rodents can cause acute eosinophilia without any previous sensitizations by the role of dissolved ions. However, whether gradually dissolving NPs can cause the same type of eosinophilia remains to be elucidated. We selected nickel oxide (NiO) as a gradually dissolving NP and evaluated the time course pulmonary inflammation pattern as well as its mechanisms. METHODS: NiO NPs were intratracheally instilled into female Wistar rats at various concentrations (50, 100, and 200 cm(2)/rat) and the lung inflammation was evaluated at various time-points (1, 2, 3, and 4 days). As positive controls, NiCl2 and the ovalbumin-induced allergic airway inflammation model was applied. NiCl2 was instilled at 171.1 µg Ni/rat, which is equivalent nickel concentration of 200 cm(2)/rat of NiO NPs. Cytological analysis and biochemical analysis including lactate dehydrogenase (LDH), total protein, and pro-inflammatory cytokines were measured in bronchoalveolar lavage fluid (BALF). The levels of total immunoglobulin E (IgE) and anaphylatoxins (C3a and C5a) were measured in BALF and serum. The levels of eotaxin were measured in the alveolar macrophages and normal lung tissue before and after addition of cell lysis buffer to evaluate whether the direct lysis of cells can release intracellular eotaxin. RESULTS: NiO NPs produced acute neutrophilic inflammation throughout the study. However, eosinophils were recruited at 3 and 4 days post-instillation of NiO NPs and the magnitude and pattern of inflammation was similar with NiCl2 at 24 h post-instillation. The eosinophil recruitment by NiO NPs was not related with either the levels of total IgE or anaphylatoxins. The lysis of alveolar macrophages and normal lung tissue showed high levels of intracellular eotaxin and the levels of LDH showed positive correlation with the levels of eotaxin. CONCLUSIONS: Instillation of NiO NPs produced neutrophilia at 1 and 2 days after instillation, while the mixed type of neutrophilic and eosinophilic inflammation was produced at 3 and 4 days post-instillation, which was consistent with NiCl2. The mechanism of the eosinophilia involves the direct release of intracellular eotaxin due to the rupture of cells by the accumulated solubilized nickel ions in the phagolysosome.

The tetrapeptide Arg-Leu-Tyr-Glu inhibits VEGF-induced angiogenesis.

Kringle 5, derived from plasminogen, is highly capable of inhibiting angiogenesis. Here, we have designed and synthesized 10 tetrapeptides, based on the amino acid properties of the core tetrapeptide Lys-Leu-Tyr-Asp (KLYD) originating from anti-angiogenic kringle 5 of human plasminogen. Of these, Arg-Leu-Tyr-Glu (RLYE) effectively inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration and tube formation, with an IC50 of 0.06-0.08 nM, which was about ten-fold lower than that of the control peptide KLYD (0.79 nM), as well as suppressed developmental angiogenesis in a zebrafish model. Furthermore, this peptide effectively inhibited the cellular events that precede angiogenesis, such as ERK and eNOS phosphorylation and nitric oxide production, in endothelial cells stimulated with VEGF. Collectively, these data demonstrate that RLYE is a potent anti-angiogenic peptide that targets the VEGF signaling pathway.

Functional role of NF-κB in expression of human endothelial nitric oxide synthase.

The transcription factor NF-κB has an essential role in inflammation in endothelial cells. Endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) prevents vascular inflammation. However, the molecular mechanism underlying NF-κB-mediated regulation of eNOS expression has not been clearly elucidated. We here found that NF-κB-activating stimuli, such as lipopolysaccharide, tumor necrosis factor-α (TNF-α), and interleukin-1ß, suppressed eNOS mRNA and protein levels by decreasing mRNA stability, without affecting promoter activity. TNF-α-mediated suppression of eNOS expression, mRNA stability, and 3'-untranslated region (3'UTR) activity were inhibited by NF-κB inhibitors and Dicer knockdown, but not by p38 MAPK and MEK inhibitors, suggesting the involvement of NF-κB-responsive miRNAs in eNOS expression. Moreover, TNF-α increased MIR155HG expression and promoter activity as well as miR-155 biogenesis, and these increases were blocked by NF-κB inhibitors. Transfection with antagomiR-155 blocked TNF-α-mediated suppression of eNOS 3'UTR activity, eNOS mRNA and protein levels, and NO and cGMP production. These data provide evidence that NF-κB is a negative regulator of eNOS expression via upregulation of miR-155 under inflammatory conditions. These results suggest that NF-κB is a potential therapeutic target for preventing vascular inflammation and endothelial dysfunction induced by suppression of miR-155-mediated eNOS expression.

The Magnitude of Change in Serum Phosphate Concentration Is Associated with Mortality in Patients with Severe Trauma.

PURPOSE: Previous studies have suggested that serum phosphate concentration is a prognostic factor in critically ill patients. However, the association between changes in serum phosphate levels and prognosis of patients with trauma remains unclear. MATERIALS AND METHODS: This study included patients with severe trauma who were treated at the emergency department. Delta phosphate (Δ phosphate) was defined as the difference between serum phosphate concentrations measured at baseline and after 24 hours from the initial measurement. Patients were divided into five groups according to their Δ phosphate levels: group I (Δ phosphate <-2 mg/dL), group II (Δ phosphate -2 to -0.5 mg/dL), group III (Δ phosphate -0.5 to 0.5 mg/dL), group IV (Δ phosphate 0.5 to 2 mg/dL), and group V (Δ phosphate ≥2 mg/dL). RESULTS: Overall, 1905 patients with severe trauma were included in the analysis. The 30-day mortality was the lowest in group III and tended to increase in groups with a larger Δ phosphate in both the positive and negative directions (group I: 13.7%, group II: 6.8%, group III: 4.6%, group IV: 6.6%, and group V: 26.8%). In multivariable analysis with group III as the reference group, the odds ratios (ORs) of mortality were statistically significant in group IV [OR, 1.92; 95% confidence interval (CI), 1.05-3.56] and group V (OR, 5.28; 95% CI, 2.47-11.24). CONCLUSION: An increase in serum phosphate concentrations 24 hours after the initial measurement could be considered as an independent prognostic factor in patients with severe trauma.

DWN12088, A Prolyl-tRNA Synthetase Inhibitor, Alleviates Hepatic Injury in Nonalcoholic Steatohepatitis.

BACKGRUOUND: Nonalcoholic steatohepatitis (NASH) is a liver disease caused by obesity that leads to hepatic lipoapoptosis, resulting in fibrosis and cirrhosis. However, the mechanism underlying NASH is largely unknown, and there is currently no effective therapeutic agent against it. DWN12088, an agent used for treating idiopathic pulmonary fibrosis, is a selective prolyl-tRNA synthetase (PRS) inhibitor that suppresses the synthesis of collagen. However, the mechanism underlying the hepatoprotective effect of DWN12088 is not clear. Therefore, we investigated the role of DWN12088 in NASH progression. METHODS: Mice were fed a chow diet or methionine-choline deficient (MCD)-diet, which was administered with DWN12088 or saline by oral gavage for 6 weeks. The effects of DWN12088 on NASH were evaluated by pathophysiological examinations, such as real-time quantitative reverse transcription polymerase chain reaction, immunoblotting, biochemical analysis, and immunohistochemistry. Molecular and cellular mechanisms of hepatic injury were assessed by in vitro cell culture. RESULTS: DWN12088 attenuated palmitic acid (PA)-induced lipid accumulation and lipoapoptosis by downregulating the Rho-kinase (ROCK)/AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein-1c (SREBP-1c) and protein kinase R-like endoplasmic reticulum kinase (PERK)/α subunit of eukaryotic initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) signaling cascades. PA increased but DWN12088 inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 (Ser536, Ser276) and the expression of proinflammatory genes. Moreover, the DWN12088 inhibited transforming growth factor ß (TGFß)-induced pro-fibrotic gene expression by suppressing TGFß receptor 1 (TGFßR1)/Smad2/3 and TGFßR1/glutamyl-prolyl-tRNA synthetase (EPRS)/signal transducer and activator of transcription 6 (STAT6) axis signaling. In the case of MCD-diet-induced NASH, DWN12088 reduced hepatic steatosis, inflammation, and lipoapoptosis and prevented the progression of fibrosis. CONCLUSION: Our findings provide new insights about DWN12088, namely that it plays an important role in the overall improvement of NASH. Hence, DWN12088 shows great potential to be developed as a new integrated therapeutic agent for NASH.

Effect of resuscitative endovascular balloon occlusion of the aorta in nontraumatic out-of-hospital cardiac arrest: a multinational, multicenter, randomized, controlled trial.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a significant public health issue worldwide and is associated with low survival rates and poor neurological outcomes. The generation of optimal coronary perfusion pressure (CPP) via high-quality chest compressions is a key factor in enhancing survival rates. However, it is often challenging to provide adequate CPP in real-world cardiopulmonary resuscitation (CPR) scenarios. Based on animal studies and human trials on improving CPP in patients with nontraumatic OHCA, resuscitative endovascular balloon occlusion of the aorta (REBOA) is a promising technique in these cases. This study aims to investigate the benefits of REBOA adjunct to CPR compared with conventional CPR for the clinical management of nontraumatic OHCA. METHODS: This is a parallel-group, randomized, controlled, multinational trial that will be conducted at two urban academic tertiary hospitals in Korea and Taiwan. Patients aged 20-80 years presenting with witnessed OHCA will be enrolled in this study. Eligible participants must fulfill the inclusion criteria, and written informed consent should be collected from their legal representatives. Patients will be randomly assigned to the intervention (REBOA-CPR) or control (conventional CPR) group. The intervention group will receive REBOA and standard advanced cardiovascular life support (ACLS). Meanwhile, the control group will receive ACLS based on the 2020 American Heart Association guidelines. The primary outcome is the return of spontaneous circulation (ROSC). The secondary outcomes include sustained ROSC, survival to admission, survival to discharge, neurological outcome, and hemodynamic changes. DISCUSSION: Our upcoming trial can provide essential evidence regarding the efficacy of REBOA, a mechanical method for enhancing CPP, in OHCA resuscitation. Our study aims to determine whether REBOA can improve treatment strategies for patients with nontraumatic OHCA based on clinical outcomes, thereby potentially providing valuable insights and guiding further advancements in this critical public health area. TRIAL REGISTRATION: ClinicalTrials.gov NCT06031623. Registered on September 9, 2023.