Pathogens in PICU before and during the SARS-CoV-2 pandemic in China: a multicenter retrospective study.

BACKGROUND: Nonpharmacological interventions for COVID-19 could reduce the incidence of children hospitalized in pediatric intensive care units (PICU) and the incidence of children with bacterial infections. This study aimed to evaluate changes in the bacterial profile of children in PICU before and during the COVID-19 pandemics. METHODS: This is a retrospective study, involving clinical data of children with positive bacterial cultures admitted to the PICU respectively in 2019 and 2021. RESULTS: In total 652 children were included in this study. The total number of hospitalized patients and the incidence of bacteria-positive children in 2021 were lower than those in 2019. There were no significant differences in the ratio of Gram-positive bacterial infection, Gram-negative bacteria infection or fungi infection between the two years. The rate of Streptococcus pneumoniae in 2021 was higher than that in 2019(p = 0.127). The incidence of Haemophilus influenzae in hospitalized patients decreased with a downward trend(p = 0.002). The distribution of previous underlying diseases in children admitted to PICU with different outcomes of bacterial infection between the two years were homogeneous (p > 0.05). CONCLUSION: After the implementation of COVID-19 isolation, prevention and control measures, the number of hospitalizations and bacterial infections in PICU decreased, which may be due to changes in population's behavior patterns. Meanwhile, the incidence of Haemophilus influenzae in hospitalized patients decreased with a downward trend.

Positive association between arterial blood lactate level before extra-corporeal membrane oxygenation and 30-day mortality in pediatric patients with severe cardiopulmonary failure.

INTRODUCTION: This study aimed to investigate the relationship between blood lactate level and mortality in pediatric patients receiving extracorporeal membrane oxygenation (ECMO) for severe cardiopulmonary failure. METHODS: A retrospective observational study was conducted on pediatric patients who received ECMO from January 2013 to December 2021 at the Seventh Medical Center of PLA General Hospital. Patient demographic characteristics, arterial blood lactate level prior to ECMO (pre-ECMO), ECMO settings, ECMO duration, and 30-days mortality were retrieved from patients' medical records. The relationships between pre-ECMO blood lactate level and mortality were interpreted using the logistic regression analysis and Kaplan-Meier survival analysis. RESULTS: A total of 160 pediatric patients who had either refractory respiratory failure (n = 89) or circulatory failure (n = 71) and received ECMO were included in this study. In both the respiratory failure and circulatory failure groups, the non-survivors showed a higher mean pre-ECMO arterial blood lactate level than the survivors. In the respiratory failure group, a pre-ECMO lactate concentration at ≥11.6 mmol/L had a sensitivity of 51% and a specificity of 82% for predicting mortality. In the circulatory failure group, a pre-ECMO lactate concentration at ≥7.2 mmol/L had a sensitivity of 90% and a specificity of 57% for predicting mortality. The Kaplan-Meier survival curves showed that respiratory failure patients with a pre-ECMO lactate level over 11.6 mmol/L or circulatory failure patients with a pre-ECMO lactate level over 7.2 mmol/L had a higher 30-days mortality rate than those with a lower lactate level. CONCLUSIONS: High pre-ECMO arterial blood lactate level serves as an independent risk factor for mortality in pediatric patients who receive ECMO for severe cardiopulmonary failure.

Risk factors and outcomes for patients with bleeding complications receiving extracorporeal membrane oxygenation: An analysis of the Chinese Extracorporeal Life Support Registry.

OBJECTIVE: Bleeding is a severe complication of patients supported with extracorporeal membrane oxygenation (ECMO). This study aimed to analyze the occurrence, risk factors, and clinical outcomes of patients on ECMO with bleeding complications. METHODS: ECMO cases reported to the multicenter ECMO registry database of the Chinese Society of Extracorporeal Life Support (CSECLS) from January 2017 to December 2020 were enrolled. General information, ECMO indications, application, complications, and patient outcomes were collected and analyzed. RESULTS: A total of 6541 ECMO patients from 112 centers were enrolled. Overall, 1185 patients (18.1%) presented with one of the following bleeding complications, including 82 cases (1.3%) with severe bleeding during ECMO catheterization, 462 cases (7.1%) with bleeding at the ECMO cannulation site, 200 cases (3.5%) with bleeding at the surgical site, 180 cases (2.8%) with cerebral hemorrhage, 99 cases (1.5%) with pulmonary hemorrhage, 200 cases (3.5%) with gastrointestinal hemorrhage, 82 cases (1.3%) with ECMO withdrawal, and 118 (1.8%) deaths due to severe bleeding. Extracorporeal cardiopulmonary resuscitation (ECPR) patients had the highest incidence of bleeding complications (22.4%), followed by those on circulatory support (18.7%) and respiratory support (15.4%) (p < 0.001). Multivariate analysis showed that pediatric patients (odds ratio [OR] 1.509, p < 0.001), patients receiving renal replacement therapy (OR 1.932, p < 0.001), and patients receiving central ECMO cannulation (OR 3.023, p < 0.001) were independent risk factors for all bleeding complications, while peripheral cannulation (OR 0.712, p < 0.001) was an independent protective factor. Patients with any bleeding complication had significantly higher in-hospital mortality than patients without (61.9% vs. 46.3%, p < 0.001). CONCLUSION: Up to 18.1% of ECMO patients in the CSECLS registry experienced bleeding complications, which was associated with higher in-hospital mortality, especially in patients who received ECPR, patients on circulatory support, and pediatric patients, which should arouse the attention of clinicians.

Circular RNA circFADS2 is overexpressed in sepsis and suppresses LPS-induced lung cell apoptosis by inhibiting the maturation of miR-15a-5p.

BACKGROUND: Circular RNA circFADS2 plays protective roles in LPS-induced inflammation, which promotes sepsis, suggesting its involvement in sepsis. METHODS: Expression of circFADS2, mature miR-15a-5p, and miR-15a-5p precursor in plasma samples from sepsis patients and healthy controls was determined by RT-qPCR. The circFADS2 expression vector was transfected in lung cells, followed by the measurement of the expression levels of mature miR-15a-5p and miR-15a-5p precursor to study the role of circFADS2 in miR-15a-5p maturation. Cell apoptosis was analyzed by cell apoptosis assay. RESULTS: CircFADS2 was upregulated in sepsis and inversely correlated with mature miR-15a-5p, but not miR-15a-5p precursor. In lung cells, circFADS2 overexpression decreased the level of mature miR-15a-5p, but not miR-15a-5p precursor. LPS treatment decreased miR-15a-5p expression and increased circFADS2 level. Cell apoptosis analysis showed that circFADS2 overexpression reduced miR-15a-5p overexpression-induced apoptosis of LPS-treated lung cells. CONCLUSIONS: CircFADS2 is upregulated in sepsis to suppress LPS-induced lung cell apoptosis by inhibiting miR-15a-5p maturation.

Lattice-Matched CoP/CoS2 Heterostructure Cocatalyst to Boost Photocatalytic H2 Generation.

Transition-metal phosphides and sulfides are considered as promising cocatalysts for the photocatalytic hydrogen evolution reaction (HER), and the cocatalytic effect can be improved by directed heterostructure engineering. In this study, a novel lattice-matched CoP/CoS2 heterostructure having a nanosheet morphology was developed as an HER cocatalyst and integrated in situ onto graphitic carbon nitride (g-C3N4) nanosheets via a successive phosphorization and vulcanization route. First-principles density functional theory calculations evidenced that the construction of the lattice-matched CoP/CoS2 heterostructure resulted in the redistribution of interface electrons, enhanced metallic characteristics, and improved H* adsorption. As a result of these effects, the CoP/CoS2 heterostructure cocatalyst formed a 2D/2D Schottky junction with the g-C3N4 nanosheets, thus promoting photoelectron transfer to CoP/CoS2 and realizing fast charge-carrier separation and good HER activity. As expected, the CoP/CoS2 heterostructure exhibited excellent cocatalytic activity, and the optimal loading of the cocatalyst on g-C3N4 enhanced its HER activity to 3.78 mmol g-1 h-1. This work furnishes a new perspective for the development of highly active noble-metal-free cocatalysts via heterostructure engineering for water splitting applications.

Continuous Blood purification on Influenza-Associated Neurological Disease in children: a retrospective cohort study.

BACKGROUND: Due to lack of proven therapies, we evaluated the effect of CBP on Influenza-Associated Neurological Disease in children. METHODS: A single-center, retrospective, cohort study was conducted in Luoyang, Henan province, China from January 2018 to January 2020. Children (<18 years) with influenza-associated neurological disease were enrolled in the study. Children with indications for CBP and parental consent received CBP (Continuous Blood purification), while others received maximal intensive care treatment because of the absence of parental consent. The outcomes of the CBP and non-CBP groups were compared. Categorical variables were presented as percentage and compared by Chi-square test. Continuous variables were expressed as median (interquartile ranges) and compared with non-parametric independent sample test. Statistical analyses were carried out by SPSS (version 26.0) and p < 0.05 (2 tailed) was considered to be statistically significant. RESULTS: 30 children with influenza-associated neurological disease were recruited to the study. 18 received CBP and the other 12 received maximal intensive care. There were no differences between CBP and non-CBP children in age, sex, body weight, type of influenza virus, neurological complications, Glasgow score, PIM-2 score and PCIS at admission (p > 0.05). The inflammatory factors (CRP, PCT and IL-6) of 30 cases were tested at admission and after 3 days of admission. In the CBP group, there was a significant decrease in IL-6 levels at 3 days of admission (p = 0.003) and a decrease in CRP and PCT levels, but no significant difference (p > 0.05). In the non-CBP group, there were no significant difference on levels of CRP, PCT and IL-6 at admission and 3-day of admission (p > 0.05). The 28-day mortality was significantly lower in the CBP group compared with the non-CBP group (11.11% vs. 50%, p = 0.034). CONCLUSIONS: CBP definitely reduces IL-6 levels significantly. We did find that the survival rate of patients in the CBP group was improved. But we don't know if there is a relationship between the reduction of IL-6 levels and the survival rate. TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx (ChiCTR2000031754).

Extracorporeal membrane oxygenation (ECMO) for critically ill patients with coronavirus disease 2019 (COVID-19): A retrospective cohort study.

PURPOSE: The role of extracorporeal membrane oxygenatio (ECMO) for rescue therapy of respiratory failure in critically ill coronavirus disease 2019 (COVID-19) patients remains controversial. We aimed to evaluate the clinical outcomes of ECMO in the treatment of COVID-19 compared with conventional ventilation support. METHODS: In this retrospective cohort study, data were collected on extremely critical patients with COVID-19 from January 2020 to March 2020 in intensive care unit of a hospital in charge by national rescue team in Wuhan, China, the epicenter of pandemic. Patients were classified into the ECMO group and the conventional ventilation non-ECMO group. Clinical characteristics, technical characteristics, laboratory results, mortality, and complications of the two groups were analyzed. RESULTS: 88 patients with extremely critical COVID-19 were screened; 34 received ECMO support and 31 received conventional ventilation support. Both groups had comparable characteristics at baseline in terms of age, gender, and comorbidities. Before ECMO or conventional therapy, patients in the two groups had sever acute respiratory distress syndrome with a mean partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2 /FiO2 ) ratio of 69.6 and 75.4, respectively. At the time of reporting, patients in the ECMO had significantly lower in-hospital mortality compared with the control group (58.8 vs. 93.5%, p = .001). CONCLUSION: ECMO is shown to decrease the mortality of extremely critical ill COVID-19 patients compared with the conventional treatment. Although complications occurred frequently, ECMO could still be a rescue therapy for the treatment of COVID-19 during the pandemic.

Corticosteroid therapy in critically ill patients with COVID-19: a multicenter, retrospective study.

BACKGROUND: Corticoid therapy has been recommended in the treatment of critically ill patients with COVID-19, yet its efficacy is currently still under evaluation. We investigated the effect of corticosteroid treatment on 90-day mortality and SARS-CoV-2 RNA clearance in severe patients with COVID-19. METHODS: 294 critically ill patients with COVID-19 were recruited between December 30, 2019 and February 19, 2020. Logistic regression, Cox proportional-hazards model and marginal structural modeling (MSM) were applied to evaluate the associations between corticosteroid use and corresponding outcome variables. RESULTS: Out of the 294 critically ill patients affected by COVID-19, 183 (62.2%) received corticosteroids, with methylprednisolone as the most frequently administered corticosteroid (175 accounting for 96%). Of those treated with corticosteroids, 69.4% received corticosteroid prior to ICU admission. When adjustments and subgroup analysis were not performed, no significant associations between corticosteroids use and 90-day mortality or SARS-CoV-2 RNA clearance were found. However, when stratified analysis based on corticosteroid initiation time was performed, there was a significant correlation between corticosteroid use (≤ 3 day after ICU admission) and 90-day mortality (logistic regression adjusted for baseline: OR 4.49, 95% CI 1.17-17.25, p = 0.025; Cox adjusted for baseline and time varying variables: HR 3.89, 95% CI 1.94-7.82, p < 0.001; MSM adjusted for baseline and time-dependent variants: OR 2.32, 95% CI 1.16-4.65, p = 0.017). No association was found between corticosteroid use and SARS-CoV-2 RNA clearance even after stratification by initiation time of corticosteroids and adjustments for confounding factors (corticosteroids use ≤ 3 days initiation vs no corticosteroids use) using MSM were performed. CONCLUSIONS: Early initiation of corticosteroid use (≤ 3 days after ICU admission) was associated with an increased 90-day mortality. Early use of methylprednisolone in the ICU is therefore not recommended in patients with severe COVID-19.

Mesenchymal stem cells-based therapies for severe ARDS with ECMO: a review.

Acute respiratory distress syndrome (ARDS) is the primary cause of respiratory failure in critically ill patients. Despite remarkable therapeutic advances in recent years, ARDS remains a life-threatening clinical complication with high morbidity and mortality, especially during the global spread of the coronavirus disease 2019 (COVID-19) pandemic. Previous studies have demonstrated that mesenchymal stem cell (MSC)-based therapy is a potential alternative strategy for the treatment of refractory respiratory diseases including ARDS, while extracorporeal membrane oxygenation (ECMO) as the last resort treatment to sustain life can help improve the survival of ARDS patients. In recent years, several studies have explored the effects of ECMO combined with MSC-based therapies in the treatment of ARDS, and some of them have demonstrated that this combination can provide better therapeutic effects, while others have argued that some critical issues need to be solved before it can be applied to clinical practice. This review presents an overview of the current status, clinical challenges and future prospects of ECMO combined with MSCs in the treatment of ARDS.

Veno-arterial extracorporeal membrane oxygenation for respiratory and cardiac support in neonates: a single center experience.

Objective: Extracorporeal membrane oxygenation (ECMO) is an advanced life support that has been utilized in the neonate for refractory respiratory and circulatory failure. Striving for the best outcomes and understanding optimal surgical techniques continue to be at the forefront of discussion and research. This study presents a single-center experience of cervically cannulated neonatal patients on V-A ECMO, a description of our cannulation/decannulation techniques and our patient outcomes. Methods: Single center retrospective review of neonates who received neck V-A ECMO support from January 2012 to December 2022. The data and outcomes of the patients were retrospectively analyzed. Results: A total of 78 neonates received V-A ECMO support. There were 66 patients that received ECMO for respiratory support, the other 12 patients that received ECMO for cardiac support. The median duration of ECMO support was 109 (32-293) hours for all patients. During ECMO support, 20 patients died and 5 patients discontinued treatment due to poor outcome or the cost. A total of 53 (68%) patients were successfully weaned from ECMO, but 3 of them died in the subsequent treatment. Overall 50 (64%) patients survived to hospital discharge. In this study, 48 patients were cannulated using the vessel sparing technique, the other 30 patients were cannulated using the ligation technique. We found no significant difference in the rates of normal cranial MRI at discharge between survivors with and without common carotid artery ligation. Conclusion: We achieved satisfactory outcomes of neonatal ECMO in 11-year experience. This study found no significant difference in early neuroimaging between survivors with and without common carotid artery ligation. The long-term neurological function of ECMO survivors warranted further follow-up and study.

Tissue-resident macrophages exacerbate lung injury after remote sterile damage.

Remote organ injury, which is a common secondary complication of sterile tissue damage, is a major cause of poor prognosis and is difficult to manage. Here, we report the critical role of tissue-resident macrophages in lung injury after trauma or stroke through the inflammatory response. We found that depleting tissue-resident macrophages rather than disrupting the recruitment of monocyte-derived macrophages attenuated lung injury after trauma or stroke. Our findings revealed that the release of circulating alarmins from sites of distant sterile tissue damage triggered an inflammatory response in lung-resident macrophages by binding to receptor for advanced glycation end products (RAGE) on the membrane, which activated epidermal growth factor receptor (EGFR). Mechanistically, ligand-activated RAGE triggered EGFR activation through an interaction, leading to Rab5-mediated RAGE internalization and EGFR phosphorylation, which subsequently recruited and activated P38; this, in turn, promoted RAGE translation and trafficking to the plasma membrane to increase the cellular response to RAGE ligands, consequently exacerbating inflammation. Our study also showed that the loss of RAGE or EGFR expression by adoptive transfer of macrophages, blocking the function of RAGE with a neutralizing antibody, or pharmacological inhibition of EGFR activation in macrophages could protect against trauma- or stroke-induced remote lung injury. Therefore, our study revealed that targeting the RAGE-EGFR signaling pathway in tissue-resident macrophages is a potential therapeutic approach for treating secondary complications of sterile damage.

Microbial-derived Urolithin A Targets GLS1 to Inhibit Glutaminolysis and Attenuate Cirrhotic Portal Hypertension.

BACKGROUND & AIMS: Cirrhotic portal hypertension (CPH) is the leading cause of mortality in patients with cirrhosis. Over 50% of patients with CPH treated with current clinical pharmacotherapy still present variceal bleeding or sometimes death owing to insufficient reduction in portal pressure. Elevated intrahepatic vascular resistance (IHVR) plays a fundamental role in increasing portal pressure. Because of its potent effect in reducing portal pressure and maintaining normal portal inflow to preserve liver function, lowering the IHVR is acknowledged as an optimal anti-CPH strategy but without clinical drugs. We aimed to investigate the protective effect of microbial-derived Urolithin A (UroA) in IHVR and CPH. METHODS: Carbon tetrachloride or bile duct ligation surgery was administered to mice to induce liver fibrosis and CPH. 16S rRNA gene sequencing was used for microbial analysis. Transcriptomics and metabolomics analyses were employed to study the host and cell responses. RESULTS: UroA was remarkably deficient in patients with CPH and was negatively correlated with disease severity. UroA deficiency was also confirmed in CPH mice and was associated with a reduced abundance of UroA-producing bacterial strain (Lactobacillus murinus, L. murinus). Glutaminolysis of hepatic stellate cells (HSCs) was identified as a previously unrecognized target of UroA. UroA inhibited the activity of glutaminase1 to suppress glutaminolysis, which counteracted fibrogenesis and contraction of HSCs and ameliorated CPH by relieving IHVR. Supplementation with UroA or L. murinus effectively ameliorated CPH in mice. CONCLUSIONS: We for the first time identify the deficiency of gut microbial metabolite UroA as an important cause of CPH. We demonstrate that UroA exerts an excellent anti-CPH effect by suppressing HSC glutaminolysis to lower the IHVR, which highlighted its great potential as a novel therapeutic agent for CPH.

The numerical value of fluid balance to predict survival in neonates requiring extracorporeal membrane oxygenation.

BACKGROUND: The aim of this study was to understand numerical variation of fluid balance in neonates requiring extracorporeal membrane oxygenation (ECMO) and to assess the relationship between hourly fluid balance and mortality. METHODS: This is a prospective cohort study. All neonates supported by ECMO were enrolled from October 2011 to September 2017. All of the enrolled neonates were divided into survival group and non- survival group. The numerical value of fluid balance of the enrolled neonates were recorded at 6 hours, 12 hours, 24 hours, 36 hours and 48 hours after initiation of ECMO respectively. The differences between the two groups were compared. The numerical value of fluid balance predict survival by the receiver operating characteristic (ROC) curve. RESULTS: Forty-eight neonates were enrolled, in which 35 cases were survival and the survival rate was 72.9%. The numerical value of fluid balance in the survival group were lower than that in the non-survival group at 6 hours, 12 hours, 24 hours, 36 hours and 48 hours after ECMO(all P<0.05). The area under ROC curve at 6h, 12h, 24h, 36h and 48h after initiation of ECMO was 0.835, 0.900, 0.839, 0.909 and 0.974 respectively. There were statistically significant in the numerical value of fluid balance predicting survival (all P<0.05) and a high sensitivity, specificity and positive predictive value at the each time point. CONCLUSIONS: The negative hourly fluid balance were associated with decreased mortality, and the lower the numerical value of fluid balance in neonates requiring ECMO, the higher the survival rate.

EGFR-TNFR1 pathway in endothelial cell facilitates acute lung injury by NF-κB/MAPK-mediated inflammation and RIP3-dependent necroptosis.

Tumor necrosis factor-α (TNFα) has emerged as a pivotal effector critically correlated with disease severity in acute lung injury (ALI). Because both the excessive activation of epidermal growth factor receptor (EGFR) and tumor necrosis factor receptor 1 (TNFR1) in sepsis-induced vasculitis are markedly diminished through EGFR tyrosine kinase inhibitor, a specific mechanism must exist to modulate TNFR1 cellular fates regulated by EGFR. Here, we demonstrated that EGFR, a specific binding partner of TNFR1, exhibited an increased NF-κB/MAPK-mediated inflammation that was governed by enhanced recruitment of TNFR-associated factor 2 (TRAF2) to TNFR1 complex I in endothelial cell (EC). Moreover, EGFR activation triggered a remarkable increase in the phosphorylation of receptor-interacting protein 1 (RIP1) and its binding with receptor-interacting protein 3 (RIP3) which led to enhanced frequency of necroptosis in complex IIb. Inhibiting the kinase of EGFR disrupted the formation of complex I and complex IIb and prevents EC from NF-κB/MAPK-mediated inflammation and RIP3-dependent necroptosis. Consistently, pharmacological inhibition of EGFR can limit the destructive effects of neutrophils activation and the hyperpermeability of lung vascular in hyperinflammation period. Collectively, we have identified EC-EGFR as a modulator of TNFR1-mediated inflammation and RIP3-dependent necroptosis, providing a possible explanation for the immunological basis of anti-EGFR therapy in sepsis-induced ALI.

Perioperative extracorporeal membrane oxygenation in pediatric congenital heart disease: Chinese expert consensus.

BACKGROUND: Congenital heart disease (CHD) is one of the main supportive diseases of extracorporeal membrane oxygenation in children. The management of extracorporeal membrane oxygenation (ECMO) for pediatric CHD faces more severe challenges due to the complex anatomical structure of the heart, special pathophysiology, perioperative complications and various concomitant malformations. The survival rate of ECMO for CHD was significantly lower than other classifications of diseases according to the Extracorporeal Life Support Organization database. This expert consensus aims to improve the survival rate and reduce the morbidity of this patient population by standardizing the clinical strategy. METHODS: The editing group of this consensus gathered 11 well-known experts in pediatric cardiac surgery and ECMO field in China to develop clinical recommendations formulated on the basis of existing evidences and expert opinions. RESULTS: The primary concern of ECMO management in the perioperative period of CHD are patient selection, cannulation strategy, pump flow/ventilator parameters/vasoactive drug dosage setting, anticoagulation management, residual lesion screening, fluid and wound management and weaning or transition strategy. Prevention and treatment of complications of bleeding, thromboembolism and brain injury are emphatically discussed here. Special conditions of ECMO management related to the cardiovascular anatomy, haemodynamics and the surgical procedures of common complex CHD should be considered. CONCLUSIONS: The consensus could provide a reference for patient selection, management and risk identification of perioperative ECMO in children with CHD. Video abstract (MP4 104726 kb).

T cell-mediated targeted delivery of tadalafil regulates immunosuppression and polyamine metabolism to overcome immune checkpoint blockade resistance in hepatocellular carcinoma.

BACKGROUND: Immune checkpoint blockade (ICB) monotherapy provides poor survival benefit in hepatocellular carcinoma (HCC) due to ICB resistance caused by immunosuppressive tumor microenvironment (TME) and drug discontinuation resulting from immune-related side effects. Thus, novel strategies that can simultaneously reshape immunosuppressive TME and ameliorate side effects are urgently needed. METHODS: Both in vitro and orthotopic HCC models were used to explore and demonstrate the new role of a conventional, clinically used drug, tadalafil (TA), in conquering immunosuppressive TME. In detail, the effect of TA on M2 polarization and polyamine metabolism in tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) was identified. After making clear the aforementioned immune regulatory effect of TA, we introduced a nanomedicine-based strategy of tumor-targeted drug delivery to make better use of TA to reverse immunosuppressive TME and overcome ICB resistance for HCC immunotherapy. A dual pH-sensitive nanodrug simultaneously carrying both TA and programmed cell death receptor 1 antibody (aPD-1) was developed, and its ability for tumor-targeted drug delivery and TME-responsive drug release was evaluated in an orthotopic HCC model. Finally, the immune regulatory effect, antitumor therapeutic effect, as well as side effects of our nanodrug combining both TA and aPD-1 were analyzed. RESULTS: TA exerted a new role in conquering immunosuppressive TME by inhibiting M2 polarization and polyamine metabolism in TAMs and MDSCs. A dual pH-sensitive nanodrug was successfully synthesized to simultaneously carry both TA and aPD-1. On one hand, the nanodrug realized tumor-targeted drug delivery by binding to circulating programmed cell death receptor 1-positive T cells and following their infiltration into tumor. On the other hand, the nanodrug facilitated efficient intratumoral drug release in acidic TME, releasing aPD-1 for ICB and leaving TA-encapsulated nanodrug to dually regulate TAMs and MDSCs. By virtue of the combined application of TA and aPD-1, as well as the efficient tumor-targeted drug delivery, our nanodrug effectively inhibited M2 polarization and polyamine metabolism in TAMs and MDSCs to conquer immunosuppressive TME, which contributed to remarkable ICB therapeutic efficacy with minimal side effects in HCC. CONCLUSIONS: Our novel tumor-targeted nanodrug expands the application of TA in tumor therapy and holds great potential to break the logjam of ICB-based HCC immunotherapy.

Dual plasmonic Au and TiN cocatalysts to boost photocatalytic hydrogen evolution.

Employing a suitable cocatalyst is very important to improve photocatalytic H2 evolution activity. Herein, two plasmonic cocatalysts, Au nanoparticles and TiN nanoparticles were in-situ coupled over the g-C3N4 nanotube to form a ternary 0D/0D/1D Au/TiN/g-C3N4 composite via a successive thermal polycondensation and chemical reduction method. The g-C3N4 nanotube acted as a support for the growth of Au and TiN nanoparticles, leading to intimate contact between g-C3N4 nanotube with Au nanoparticles and TiN nanoparticles. As a result, multiple interfaces and dual-junctions of Au/g-C3N4 Schottky-junction and TiN/g-C3N4 ohmic-junction were constructed, which helped to promote the charged carriers' separation and enhanced the photocatalytic performance. Furthermore, loading plasmonic cocatalysts of Au nanoparticles and TiN nanoparticles can enhance the light absorption capacity. Consequently, the Au/TiN/g-C3N4 composite exhibited significantly enhanced photocatalytic H2 evolution activity (596 µmol g-1 h-1) compared to g-C3N4 or binary composites of Au/g-C3N4 and TiN/g-C3N4. This work highlights the significant role of cocatalysts in photocatalysis.

MicroRNA-375-3p in endothelial progenitor cells-derived extracellular vesicles relieves myocardial injury in septic rats via BRD4-mediated PI3K/AKT signaling pathway.

OBJECTIVE: Sepsis can induce myocardial dysfunctions and endothelial progenitor cells (EPCs)-derived extracellular vesicles (EVs) can attenuate sepsis. Concerning to that, this article is intended to decode whether microRNA (miR)-375-3p in EPCs-EVs could affect myocardial injury in sepsis. METHODS: Rat bone marrow-derived EPCs and EPCs-EVs were harvested. A rat model of sepsis was established by cecal ligation and puncture. Septic rats were injected with EPCs-EVs that interfered with miR-375-3p, after which cardiac function, inflammatory response, pathological damage, oxidative stress and apoptosis were detected in myocardial tissues. miR-375-3p, bromodomain 4 (BRD4), phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) expression in myocardial tissues, and their reciprocals were identified. RESULTS: Septic rats expressed reduced miR-375-3p and elevated BRD4 in myocardial tissues. EPCs-EVs improved cardiac function, suppressed inflammation, oxidative stress and apoptosis, as well as attenuated the pathological damage of myocardial tissues in septic rats. Up-regulated/down-regulated miR-375-3p in EPCs-EVs relieved/deteriorated myocardial injury in septic rats. miR-375-3p targeted BRD4 to activate PI3K/AKT pathway, thereafter to ameliorate myocardial injury in septic rats. CONCLUSION: It is illustrated that miR-375-3p in EPCs-EVs activates BRD4-mediated PI3K/AKT signaling pathway to ameliorate myocardial injury in septic rats, which provides a therapeutic target for myocardial injury in sepsis.

The safety and efficacy of high-speed train transport for critical children: a retrospective propensity score matching cohort study.

It is widely acknowledged that efficiency of pediatric critical care transport plays a vital role in treatment of critically-ill children. In developing countries, most critically-ill children were transported by ambulance, and a few by air, such as a helicopter or fixed airplane. High-speed train (HST) transport may be a potential choice for critically-ill children to a tertiary medical center for further therapy. This is a single-center, retrospective cohort study from June 01, 2016 to June 30, 2019. All the patients transported to the Pediatric Intensive Care Unit (PICU) of PLA general hospital were divided into two groups, HST group and ambulance group. The propensity score matching method was performed for the comparison between the two groups. Finally, a 2:1 patient matching was performed using the nearest-neighbor matching method without replacement. The primary outcome was hospital mortality. Secondary outcomes included duration of transport, transport cost, hospital stay, and hospitalization cost. A total of 509 critically-ill children were transported and admitted. Of them, 40 patients were transported by HST, and 469 by ambulance. The hospital mortality showed no difference between the two groups (p > 0.05). The transport distance in the HST group was longer than that in the ambulance group (1894.5 ± 907.09 vs. 902.66 ± 735.74, p < 0.001). However, compared to the HST group, the duration of transport time by ambulance was significantly longer (p < 0.001). No difference in vital signs, blood gas analysis, and critical illness score between groups at admission was noted (p > 0.05). There was no death during the transport. There was no difference between groups regarding the transport cost, hospital stays, and hospitalization cost (p > 0.05). High-quality tertiary medical centers are usually located in megacities. HST transport network for critically-ill children could be established to cover most regions of the country. Without increasing financial burden, HST medical transport can be a potentially promising option to improve the outcomes of critically-ill children in developing countries with developed HST network.Clinical Trial Registration: This study was registered at http://www.chictr.org.cn/index.aspx (chiCTR.gov; Identifier: ChiCTR2000032306).