Placental growth factor regulates the generation of TH17 cells to link angiogenesis with autoimmunity.

Helper T cells actively communicate with adjacent cells by secreting soluble mediators, yet crosstalk between helper T cells and endothelial cells remains poorly understood. Here we found that placental growth factor (PlGF), a homolog of the vascular endothelial growth factor that enhances an angiogenic switch in disease, was selectively secreted by the TH17 subset of helper T cells and promoted angiogenesis. Interestingly, the 'angio-lymphokine' PlGF, in turn, specifically induced the differentiation of pathogenic TH17 cells by activating the transcription factor STAT3 via binding to its receptors and replaced the activity of interleukin-6 in the production of interleukin-17, whereas it suppressed the generation of regulatory T cells. Moreover, T cell-derived PlGF was required for the progression of autoimmune diseases associated with TH17 differentiation, including experimental autoimmune encephalomyelitis and collagen-induced arthritis, in mice. Collectively, our findings provide insights into the PlGF-dictated links among angiogenesis, TH17 cell development and autoimmunity.

Effects of a Designated Ambulance Team Response on Prehospital Return of Spontaneous Circulation and Advanced Cardiac Life Support of Out-of-Hospital Cardiac Arrest: A Nationwide Natural Experimental Study.

OBJECTIVES: This study aimed to investigate the effects of adding advanced cardiac life support (ACLS) training to an existing basic life support program and the operation of a designated team response for patients with out-of-hospital cardiac arrest (OHCA) on prehospital return of spontaneous circulation (ROSC) and ACLS management. METHODS: A natural experimental study was conducted for emergency medical service (EMS)-treated adult patients with OHCA in 2020. In 2019, a quarter of the EMS clinicians were trained in a 3-day ACLS courses, and they were designated to be dispatched first in suspected OHCA. Some were dispatched only to major emergencies, such as OHCA and myocardial infarction (dedicated team), while others were dispatched to all emergencies with priority to major ones (non-dedicated team). The exposure was the ambulance response type: dedicated, non-dedicated, and basic teams (others). The primary outcome was prehospital ROSC. The secondary outcomes were prehospital ACLS (advanced airway management and intravenous access). A multivariable logistic regression analysis was conducted to investigate the effect of ambulance response type on study outcomes. RESULTS: Among 23,512 eligible patients with OHCA, 54.8% (12,874) were treated by the basic team, 36.5% (8,580) by the non-dedicated ACLS team, and 8.8% (2,058) were treated by the dedicated ACLS team. Prehospital ROSC was greater for the designated team than for the basic team (dedicated ACLS team 13.8%, non-dedicated ACLS team 11.3%, and basic team 6.7%) (p < 0.01). In the final logistic regression analysis, compared with the basic team, the designated ACLS team was associated with a higher probability of prehospital ROSC (AOR (95% CIs), 1.88 (1.68-2.09) compared to the non-dedicated ACLS team, and 2.46 (2.09-2.90) compared to the dedicated ACLS team), prehospital advanced airway management (1.72 (1.57-1.87) and 1.73 (1.48-2.03), respectively), and intravenous access (2.29 (2.16-2.43) and 2.76 (2.50-3.04), respectively). CONCLUSION: Additional ACLS training and operation of a designated OHCA team response were associated with higher rates of prehospital ROSC and prehospital ACLS provision. However, further research is needed to find the optimal operation for EMS to improve survival outcomes.

Genome-wide RNA interference screening reveals a COPI-MAP2K3 pathway required for YAP regulation.

The transcriptional regulator YAP, which plays important roles in the development, regeneration, and tumorigenesis, is activated when released from inhibition by the Hippo kinase cascade. The regulatory mechanism of YAP in Hippo-low contexts is poorly understood. Here, we performed a genome-wide RNA interference screen to identify genes whose loss of function in a Hippo-null background affects YAP activity. We discovered that the coatomer protein complex I (COPI) is required for YAP nuclear enrichment and that COPI dependency of YAP confers an intrinsic vulnerability to COPI disruption in YAP-driven cancer cells. We identified MAP2K3 as a YAP regulator involved in inhibitory YAP phosphorylation induced by COPI subunit depletion. The endoplasmic reticulum stress response pathway activated by COPI malfunction appears to connect COPI and MAP2K3. In addition, we provide evidence that YAP inhibition by COPI disruption may contribute to transcriptional up-regulation of PTGS2 and proinflammatory cytokines. Our study offers a resource for investigating Hippo-independent YAP regulation as a therapeutic target for cancers and suggests a link between YAP and COPI-associated inflammatory diseases.

Impact of COVID-19 on Out-of-Hospital Cardiac Arrest in Korea.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global public health crisis that has had a significant impact on emergency medical services (EMS). Several studies have reported an increase in the incidence of out-of-hospital cardiac arrest (OHCA) and a decreased survival due to COVID-19, which has been limited to a short period or has been reported in some regions. This study aimed to investigate the effect of COVID-19 on OHCA patients using a nationwide database. METHODS: We included adult OHCA patients treated by EMS providers from January 19, 2019 to January 20, 2021. The years before and after the first confirmed case in Korea were set as the non-COVID-19 and COVID-19 periods, respectively. The main exposure of interest was the COVID-19 period, and the primary outcome was prehospital return of spontaneous circulation (ROSC). Other OHCA variables were compared before and after the COVID-19 pandemic and analyzed. We performed a multivariable logistic regression analysis to understand the independent effect of the COVID-19 period on prehospital ROSC. RESULTS: The final analysis included 51,921 eligible patients, including 25,355 (48.8%) during the non-COVID-19 period and 26,566 (51.2%) during the COVID-19 period. Prehospital ROSC deteriorated during the COVID-19 period (10.2% vs. 11.1%, P = 0.001). In the main analysis, the adjusted odds ratios (AORs) for prehospital ROSC showed no significant differences between the COVID-19 and non-COVID-19 periods (AOR [95% confidence interval], 1.02 [0.96-1.09]). CONCLUSION: This study found that the proportion of prehospital ROSC was lower during the COVID-19 period than during the non-COVID-19 period; however, there was no statistical significance when adjusting for potential confounders. Continuous efforts are needed to restore the broken chain of survival in the prehospital phase and increase the survival rate of OHCA patients.

The Impact of the COVID-19 Outbreak on Emergency Medical Service: An Analysis of Patient Transportations and Time Intervals.

BACKGROUND: This study aimed to investigate the impact of the coronavirus disease 2019 (COVID-19) outbreak on the Emergency Medical Service (EMS) system in South Korea. The study focused on the differences in EMS time intervals following the COVID-19 outbreak, particularly for patients with fever. METHODS: A retrospective analysis of EMS patient transportation data from 2017 to 2022 was conducted using the national EMS database. RESULTS: Starting from the year 2020, coinciding with the COVID-19 outbreak, all EMS time intervals experienced an increase. For the years 2017 to 2022, the mean response time interval values were 8.6, 8.6, 8.6, 10.2, 12.8, and 11.4 minutes, and the mean scene time interval values were 7.1, 7.2, 7.4, 9.0, 9.8, and 10.9 minutes. The mean transport time interval (TTI) values were 12.1, 12.3, 12.4, 14.2, 16.9, and 16.2 minutes, and the mean turnaround time interval values were 27.6, 27.9, 28.7, 35.2, 42.0, and 43.1 minutes. Fever (≥ 37.5°C) patients experienced more pronounced prolongations in EMS time intervals compared to non-fever patients and had a higher probability of being non-transported. The mean differences in TTI between fever and non-fever patients were 0.8, 0.8, 0.8, 4.3, 4.8, and 3.2 minutes, respectively, from 2017 to 2022. Furthermore, the odds ratios for fever patients being transported to the emergency department were 2.7, 2.9, 2.8, 1.1, 0.8, and 0.7, respectively, from 2017 to 2022. CONCLUSION: The study findings highlight the significant impact of the COVID-19 outbreak on the EMS system and emphasize the importance of ongoing monitoring to evaluate the burden on the EMS system.

Type of bystander and rate of cardiopulmonary resuscitation in nursing home patients suffering out-of-hospital cardiac arrest.

AIM: We investigated bystander cardiopulmonary resuscitation (CPR) provision rate and survival outcomes of out-of-hospital cardiac arrest (OHCA) patients in nursing homes by bystander type. METHODS: A population-based observational study was conducted for nursing home OHCAs during 2013-2018. The exposure was the bystander type: medical staff, non-medical staff, or family. The primary outcome was bystander CPR provision rate; the secondary outcomes were prehospital return of spontaneous circulation (ROSC) and survival to discharge. Multivariable logistic regression analysis which corrected for various demographic and clinical characteristics evaluated bystander type impact on study outcomes. Bystander CPR rate trend was investigated by bystander type. RESULTS: Of 8281 eligible OHCA patients, 26.0%, 70.8%, and 3.2% cases were detected by medical staff, non-medical staff, and family, respectively. Provision rate of bystander CPR was 69.9% and rate of bystander defibrillation was 0.4% in total. Bystander CPR was provided by medical staff, non-medical staff, and families in 74.8%, 68.9%, and 52.1% respectively. Total survival rate was 2.2%, out of which, 3.3% was for medical staff, 3.2% for non-medical staff, and 0.6% for family. Compared to the results of detection by medical staff, the adjusted odds ratios (95% CIs) for provision of bystander CPR were 0.56 (0.49-0.63) for detection by non-medical staff and 0.33 (0.25-0.44) for detection by family. The bystander CPR rates of all three groups increased over time, and among them, the medical staff group increased the most. For prehospital ROSC and survival to discharge, no significant differences were observed according to bystander type. CONCLUSION: Although OHCA was detected more often by non-medical staff, they provided bystander CPR less frequently than the medical staff did. To improve survival outcome of nursing home OHCA, bundle interventions including increasing the usage of automated external defibrillators and expanding CPR training for non-medical staff in nursing home are needed.

T lymphocytes negatively regulate lymph node lymphatic vessel formation.

Lymph node lymphatic vessels (LNLVs) serve as a conduit to drain antigens from peripheral tissues to within the lymph nodes. LNLV density is known to be positively regulated by vascular endothelial growth factors secreted by B cells, macrophages, and dendritic cells (DCs). Here, we show that LNLV formation was negatively regulated by T cells. In both steady and inflammatory states, the density of LNLVs was increased in the absence of T cells but decreased when T cells were restored. Interferon-γ secretion by T cells suppressed lymphatic-specific genes in lymphatic endothelial cells and consequently caused marked reduction in LNLV formation. When T cells were depleted, recruitment of antigen-carrying DCs to LNs was augmented, reflecting a compensatory mechanism for antigen presentation to T cells through increased LNLVs. Thus, T cells maintain the homeostatic balance of LNLV density through a negative paracrine action of interferon-γ.

Endothelial Sox17 promotes allergic airway inflammation.

BACKGROUND: IL-33, levels of which are known to be increased in patients with eosinophilic asthma and which is suggested as a therapeutic target for it, activates endothelial cells in which Sry-related high-mobility-group box (Sox) 17, an endothelium-specific transcription factor, was upregulated. OBJECTIVE: We investigated the relationship between Sox17 and IL-33 and the possible role of Sox17 in the pathogenesis of asthma using a mouse model of airway inflammation. METHODS: We used ovalbumin (OVA) to induce airway inflammation in endothelium-specific Sox17 null mutant mice and used IL-33 neutralizing antibody to evaluate the interplay between IL-33 and Sox17. We evaluated airway inflammation and measured levels of various cytokines, chemokines, and adhesion molecules. We also carried out loss- or gain-of-function experiments for Sox17 in human endothelial cells. RESULTS: Levels of IL-33 and Sox17 were significantly increased in the lungs of OVA-challenged mice. Anti-IL-33 neutralizing antibody treatment attenuated not only OVA-induced airway inflammation but also Sox17 expression in pulmonary endothelial cells. Importantly, endothelium-specific deletion of Sox17 resulted in significant alleviation of various clinical features of asthma, including airway inflammation, immune cell infiltration, cytokine/chemokine production, and airway hyperresponsiveness. Sox17 deletion also resulted in decreased densities of Ly6chigh monocytes and inflammatory dendritic cells in the lungs. In IL-33-stimulated human endothelial cells, Sox17 showed positive correlation with CCL2 and intercellular adhesion molecule 1 levels. Lastly, Sox17 promoted monocyte adhesion to endothelial cells and upregulated the extracellular signal-regulated kinase-signal transducer and activator of transcription 3 pathway. CONCLUSION: Sox17 was regulated by IL-33, and its genetic ablation in endothelial cells resulted in alleviation of asthma-related pathophysiologic features. Sox17 might be a potential target for asthma management.

Neutrophils disturb pulmonary microcirculation in sepsis-induced acute lung injury.

The lung is highly vulnerable during sepsis, yet its functional deterioration accompanied by disturbances in the pulmonary microcirculation is poorly understood. This study aimed to investigate how the pulmonary microcirculation is distorted in sepsis-induced acute lung injury (ALI) and reveal the underlying cellular pathophysiologic mechanism.Using a custom-made intravital lung microscopic imaging system in a murine model of sepsis-induced ALI, we achieved direct real-time visualisation of the pulmonary microcirculation and circulating cells in vivo We derived the functional capillary ratio (FCR) as a quantitative parameter for assessing the fraction of functional microvasculature in the pulmonary microcirculation and dead space.We identified that the FCR rapidly decreases in the early stage of sepsis-induced ALI. The intravital imaging revealed that this decrease resulted from the generation of dead space, which was induced by prolonged neutrophil entrapment within the capillaries. We further showed that the neutrophils had an extended sequestration time and an arrest-like dynamic behaviour, both of which triggered neutrophil aggregates inside the capillaries and arterioles. Finally, we found that Mac-1 (CD11b/CD18) was upregulated in the sequestered neutrophils and that a Mac-1 inhibitor restored the FCR and improved hypoxaemia.Using the intravital lung imaging system, we observed that Mac-1-upregulated neutrophil aggregates led to the generation of dead space in the pulmonary microcirculation that was recovered by a Mac-1 inhibitor in sepsis-induced ALI.

Effects of 18ß-Glycyrrhetinic Acid on Fungal Protease-Induced Airway Inflammatory Responses.

Airway epithelial cells secrete diverse inflammatory mediators in response to various stimuli. Thus, early regulation of immune responses in the airway epithelium is likely critical for the control of chronic inflammatory diseases. The purpose of the present study was to evaluate the effects of 18ß-glycyrrhetinic acid (GA) on inflammatory responses generated in response to a fungal protease allergen that induces epithelial damage. To understand the underlying mechanisms, we also investigated the inhibitory effects of GA on the production of mitochondrial reactive oxygen species (ROS) in the human bronchial epithelial cell line BEAS2B. In this study, GA treatment reduced cytokine production and the human neutrophil cell line HL60 migration through decreased mitochondrial ROS production. In addition, GA significantly reduced inflammatory cell infiltration and cytokine levels in the bronchoalveolar lavage (BAL) fluid of fungal allergen-administered mice. Inhibitory effects of GA are dependent on the mitochondrial ROS/MAPK axis. Moreover, the effect of GA on the regulation of mitochondrial ROS depends on the expression of uncoupling protein-2 (UCP-2). Taken together, GA might represent a potential therapeutic agent for blocking inflammatory responses in airways.

Non-transcriptional regulation of NLRP3 inflammasome signaling by IL-4.

Th2 cytokine IL-4 has been previously shown to suppress the production of proinflammatory cytokines in monocytes. However, the underlying molecular mechanism by which IL-4 signaling antagonizes proinflammatory responses is poorly characterized. In particular, whether IL-4 can modulate inflammasome signaling remains unknown. Here, we provide evidence that IL-4 suppresses NLRP3-dependent caspase-1 activation and the subsequent IL-1ß secretion but does not inhibit absent in melanoma 2 (AIM2)- or NLRC4 (NOD-like receptor family, CARD domain-containing 4)-dependent caspase-1 activation in THP-1 and mouse bone marrow-derived macrophages. Upon lipopolysaccharide (LPS) or LPS/ATP stimulation, IL-4 markedly inhibited the assembly of NLRP3 inflammasome, including NLRP3-dependent ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) oligomerization, NLRP3-ASC interaction and NLRP3 speck-like oligomeric structure formation. The negative regulation of NLRP3 inflammasome by IL-4 was not due to the impaired mRNA or protein production of NLRP3 and proinflammatory cytokines. Supporting this observation, IL-4 attenuated NLRP3 inflammasome activation even in reconstituted NLRP3-expressing macrophages in which NLRP3 expression is not transcriptionally regulated by TLR-NF-κB signaling. Furthermore, the IL-4-mediated suppression of NLRP3 inflammasome was independent of STAT6-dependent transcription and mitochondrial reactive oxygen species (ROS). Instead, IL-4 inhibited subcellular redistribution of NLRP3 into mitochondria and microtubule polymerization upon NLRP3-activating stimulation. Our results collectively suggest that IL-4 could suppress NLRP3 inflammasome activation in a transcription-independent manner, thus providing an endogenous regulatory machinery to prevent excessive inflammasome activation.

CD11a polymorphisms regulate TH2 cell homing and TH2-related disease.

BACKGROUND: TH2-dependent diseases vary in severity according to genotype, but relevant gene polymorphisms remain largely unknown. The integrin CD11a is a critical determinant of allergic responses, and allelic variants of this gene might influence allergic phenotypes. OBJECTIVE: We sought to determine major CD11a allelic variants in mice and human subjects and their importance to allergic disease expression. METHODS: We sequenced mouse CD11a alleles from C57BL/6 and BALB/c strains to identify major polymorphisms; human CD11a single nucleotide polymorphisms were compared with allergic disease phenotypes as part of the international HapMap project. Mice on a BALB/c or C57BL/6 background and congenic for the other strain's CD11a allele were created to determine the importance of mouse CD11a polymorphisms in vivo and in vitro. RESULTS: Compared with the C57BL/6 allele, the BALB/c CD11a allele contained a nonsynonymous change from asparagine to aspartic acid within the metal ion binding domain. In general, the BALB/c CD11a allele enhanced and the C57BL/6 CD11a allele suppressed TH2 cell-dependent disease caused by the parasite Leishmania major and allergic lung disease caused by the fungus Aspergillus niger. Relative to the C57BL/6 CD11a allele, the BALB/c CD11a allele conferred both greater T-cell adhesion to CD54 in vitro and enhanced TH2 cell homing to lungs in vivo. We further identified a human CD11a polymorphism that significantly associated with atopic disease and relevant allergic indices. CONCLUSIONS: Polymorphisms in CD11a critically influence TH2 cell homing and diverse TH2-dependent immunopathologic states in mice and potentially influence the expression of human allergic disease.

CD53, a suppressor of inflammatory cytokine production, is associated with population asthma risk via the functional promoter polymorphism -1560 C>T.

BACKGROUND: In this study, the association of asthma with CD53, a member of the tetraspanin family, was assessed for the first time in a mechanism-based study. METHODS: Genetic polymorphisms of CD53 were analyzed in 591 subjects and confirmed in a replication study of 1001 subjects. CD53 mRNA and protein levels were measured in peripheral blood leukocytes, and the effects of the promoter polymorphisms on nuclear factor binding were examined by electrophoretic mobility shift assay. Cellular functional studies were conducted by siRNA transfections. RESULTS: Among tagging SNPs of CD53, the -1560 C>T in the promoter region was significantly associated with asthma risk. Compared with the CC genotype, the CT and TT genotypes were associated with a higher asthma risk, with odd ratios of 1.74 (P=0.009) and 2.03 (P=0.004), respectively. These findings were confirmed in the replication study with odd ratios of 1.355 (P=0.047) and 1.495 (P=0.039), respectively. The -1560 C>T promoter SNP had functional effects on nuclear protein binding as well as mRNA and protein expression levels in peripheral blood leukocytes. When CD53 was knocked down by siRNA in THP-1 human monocytic cells stimulated with house dust mite, the production of inflammatory cytokines as well as NFκB activity was significantly over-activated, suggesting that CD53 suppresses over-activation of inflammatory responses. CONCLUSIONS: The -1560 C>T SNP is a functional promoter polymorphism that is significantly associated with population asthma risk, and is thought to act by directly modulating nuclear protein binding, thereby altering the expression of CD53, a suppressor of inflammatory cytokine production.

Antielastin autoimmunity in tobacco smoking-induced emphysema.

Chronic obstructive pulmonary disease and emphysema are common destructive inflammatory diseases that are leading causes of death worldwide. Here we show that emphysema is an autoimmune disease characterized by the presence of antielastin antibody and T-helper type 1 (T(H)1) responses, which correlate with emphysema severity. These findings link emphysema to adaptive immunity against a specific lung antigen and suggest the potential for autoimmune pathology of other elastin-rich tissues such as the arteries and skin of smokers.

Innate type 2 immunity is associated with eosinophilic pleural effusion in primary spontaneous pneumothorax.

RATIONALE: Eosinophilic pleural effusion (EPE) is characterized by greater than 10% eosinophilia and is frequently associated with air and/or blood in the pleural cavity. Primary spontaneous pneumothorax (PSP), defined as the spontaneous presence of air in the pleural space, is one of the most common causes of EPE. Recent studies have shown that type 2 immune responses play important roles in eosinophilic airway inflammation resulting in pleural pathology. OBJECTIVES: To determine the predominant immune responses associated with PSP in humans, and to examine whether IL-33, thymic stromal lymphopoietin (TSLP), or type 2 innate lymphoid cell (ILC2)-mediated immune responses are associated factors. METHODS: Eosinophil-associated cytokines were measured in the pleural fluid of patients with PSP and control subjects. Th2 cell and ILC2 responses in the pleural cavity and peripheral blood were also evaluated by in vitro restimulation and intracellular cytokine staining of T cells and ILC2s in patients with PSP (n = 62) and control subjects (n = 33). IL-33-mediated IL-5 production by ILC2s was also evaluated. MEASUREMENTS AND MAIN RESULTS: Significantly higher concentrations of IL-5 and eotaxin-3 were detected in the pleural fluid of patients with PSP, in addition to significantly higher concentrations of IL-33 and TSLP. Although IL-5 production was induced by IL-33 treatment of ILC2s, other Th2 cell-mediated immune responses were not detected. CONCLUSIONS: Our results indicate that innate immune responses characterized by the production of IL-33, TSLP, and IL-5 are associated with the development of EPE in PSP by an ILC2-dependent and Th2-independent mechanism.

Cytokines, Vascular Endothelial Growth Factors, and PlGF in Autoimmunity: Insights From Rheumatoid Arthritis to Multiple Sclerosis.

In this review, we will explore the intricate roles of cytokines and vascular endothelial growth factors in autoimmune diseases (ADs), with a particular focus on rheumatoid arthritis (RA) and multiple sclerosis (MS). AD is characterized by self-destructive immune responses due to auto-reactive T lymphocytes and Abs. Among various types of ADs, RA and MS possess inflammation as a central role but in different sites of the patients. Other common aspects among these two ADs are their chronicity and relapsing-remitting symptoms requiring continuous management. First factor inducing these ADs are cytokines, such as IL-6, TNF-α, and IL-17, which play significant roles in the pathogenesis by contributing to inflammation, immune cell activation, and tissue damage. Secondly, vascular endothelial growth factors, including VEGF and angiopoietins, are crucial in promoting angiogenesis and inflammation in these two ADs. Finally, placental growth factor (PlGF), an emerging factor with bi-directional roles in angiogenesis and T cell differentiation, as we introduce as an "angio-lymphokine" is another key factor in ADs. Thus, while angiogenesis recruits more inflammatory cells into the peripheral sites, cytokines secreted by effector cells play critical roles in the pathogenesis of ADs. Various therapeutic interventions targeting these soluble molecules have shown promise in managing autoimmune pathogenic conditions. However, delicate interplay between cytokines, angiogenic factors, and PlGF has more to be studied when considering their complementary role in actual pathogenic conditions. Understanding the complex interactions among these factors provides valuable insights for the development of innovative therapies for RA and MS, offering hope for improved patient outcomes.

Smartphone AI vs. Medical Experts: A Comparative Study in Prehospital STEMI Diagnosis.

PURPOSE: Prehospital telecardiology facilitates early ST-elevation myocardial infarction (STEMI) detection, yet its widespread implementation remains challenging. Extracting digital STEMI biomarkers from printed electrocardiograms (ECGs) using phone cameras could offer an affordable and scalable solution. This study assessed the feasibility of this approach with real-world prehospital ECGs. MATERIALS AND METHODS: Patients suspected of having STEMI by emergency medical technicians (EMTs) were identified from a policy research dataset. A deep learning-based ECG analyzer (QCG™ analyzer) extracted a STEMI biomarker (qSTEMI) from prehospital ECGs. The biomarker was compared to a group of human experts, including five emergency medical service directors (board-certified emergency physicians) and three interventional cardiologists based on their consensus score (number of participants answering "yes" for STEMI). Non-inferiority of the biomarker was tested using a 0.100 margin of difference in sensitivity and specificity. RESULTS: Among 53 analyzed patients (24 STEMI, 45.3%), the area under the receiver operating characteristic curve of qSTEMI and consensus score were 0.815 (0.691-0.938) and 0.736 (0.594-0.879), respectively (p=0.081). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of qSTEMI were 0.750 (0.583-0.917), 0.862 (0.690-0.966), 0.826 (0.679-0.955), and 0.813 (0.714-0.929), respectively. For the consensus score, sensitivity, specificity, PPV, and NPV were 0.708 (0.500-0.875), 0.793 (0.655-0.966), 0.750 (0.600-0.941), and 0.760 (0.655-0.880), respectively. The 95% confidence interval of sensitivity and specificity differences between qSTEMI and consensus score were 0.042 (-0.099-0.182) and 0.103 (-0.043-0.250), respectively, confirming qSTEMI's non-inferiority. CONCLUSION: The digital STEMI biomarker, derived from printed prehospital ECGs, demonstrated non-inferiority to expert consensus, indicating a promising approach for enhancing prehospital telecardiology.

Dual-dispatch protocols and return of spontaneous circulation in patients with out-of-hospital cardiac arrest: a nationwide observational study.

OBJECTIVE: The Korean National Fire Agency conducted a pilot project examining Advanced Life Support (ALS) protocols, including epinephrine administration, to improve survival among patients suffering out-of-hospital cardiac arrest (OHCA). In this study, we aimed to evaluate the effects of the Korean National Fire Agency ALS protocol on prehospital return of spontaneous circulation (ROSC) in patients with OHCA. METHODS: This study included patients with adult-presumed cardiac arrest between January and December 2020. The main factor of interest was ambulance type according to ALS protocol, which was divided into dedicated ALS ambulance (DA), smartphone-based ALS ambulance (SALS), and non-DA, and the main analysis factor was prehospital ROSC. Multivariate logistic regression analysis was performed. RESULTS: During the study period, a total of 18,031 adult patients with OHCA was treated by the emergency medical services, including 7,520 DAs (41.71%), 2,622 SALSs (14.54%), and 7,889 non-DAs (43.75%). The prehospital ROSC ratio was 13.19% for DA, 11.17% for SALS, and 7.91% for non-DA (P<0.01). Compared with that of the DA group, the odds ratios (95% confidence interval) for prehospital ROSC ratio were 0.97 (0.82-1.15) in the SALS group and 0.57 (0.50-0.65) in the non-DA group. The prehospital ROSC ratio of the DA group was higher than those of the non-DA group and the SALS group. CONCLUSION: ALS protocol intervention was associated with prehospital ROSC rates. Therefore, continuous efforts to promote systemic implementation of the ALS protocol to improve OHCA outcomes are necessary.

Dual protective mechanisms of matrix metalloproteinases 2 and 9 in immune defense against Streptococcus pneumoniae.

A localized and effective innate immune response to pathogenic bacterial invasion is central to host survival. Identification of the critical local innate mediators of lung defense against such pathogens is essential for a complete understanding of the mechanism(s) underlying effective host defense. In an acute model of Streptococcus pneumoniae lung infection, deficiency in matrix metalloproteinase (MMP)2 and MMP9 (Mmp2/9(-/-)) conferred a survival disadvantage relative to wild-type mice treated under the same conditions. S. pneumoniae-infected Mmp2/9(-/-) mice recruited more polymorphonuclear leukocytes to the lung but had higher bacterial burdens. Mmp2/9(-/-) mice showed significantly higher levels of IL-17A, IP-10, and RANTES in the lung. Although MMP2-dependent cleavage partially inactivated IL-17A, MMP9 was critical for effective bacterial phagocytosis and reactive oxygen species generation in polymorphonuclear neutrophils. These data demonstrate critical nonredundant and protective roles for MMP2 and MMP9 in the early host immune response against S. pneumoniae infection.