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Background Congenital heart disease (CHD) is a structural deformity of the heart present at birth. Pulmonary hypertension (PH) may arise from increased blood flow to the lungs, persistent pulmonary arterial pressure elevation, or the use of cardiopulmonary bypass (CPB) during surgical repair. Inhaled nitric oxide (iNO) selectively reduces high blood pressure in the pulmonary vessels without lowering systemic blood pressure, making it useful for treating children with postoperative PH due to heart disease. However, reducing or stopping iNO can exacerbate postoperative PH and hypoxemia, necessitating long-term administration and careful tapering. This study aimed to evaluate, using machine learning (ML), factors that predict the need for long-term iNO administration after open heart surgery in CHD patients in the postoperative ICU, primarily for PH management. Methods We used an ML approach to establish an algorithm to predict 'patients with long-term use of iNO' and validate its accuracy in 34 pediatric postoperative open heart surgery patients who survived and were discharged from the ICU at Kagoshima University Hospital between April 2016 and March 2019. All patients were started on iNO therapy upon ICU admission. Overall, 16 features reflecting patient and surgical characteristics were utilized to predict the patients who needed iNO for over 168 hours using ML analysis with AutoGluon. The dataset was randomly classified into training and test cohorts, comprising 80% and 20% of the data, respectively. In the training cohort, the ML model was constructed using the important features selected by the decrease in Gini impurity and a synthetic oversampling technique. In the testing cohort, the prediction performance of the ML model was evaluated by calculating the area under the receiver operating characteristics curve (AUC) and accuracy. Results Among 28 patients in the training cohort, five needed iNO for over 168 hours; among six patients in the testing cohort, one needed iNO for over 168 hours. CPB, aortic clamp time, in-out balance, and lactate were the four most important features for predicting the need for iNO for over 168 hours. In the training cohorts, the ML model achieved perfect classification with an AUC of 1.00. In the testing cohort, the ML model also achieved perfect classification with an AUC of 1.00 and an accuracy of 1.00. Conclusion The ML approach identified that four factors (CPB, in-out balance, aortic cross-clamp time, and lactate) are strongly associated with the need for long-term iNO administration after open heart surgery in CHD patients. By understanding the outcomes of this study, we can more effectively manage iNO administration in postoperative open heart surgery in CHD patients with PH, potentially preventing the recurrence of postoperative PH and hypoxemia, thereby contributing to safer patient management., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Kagoshima University's Ethics Committee for Epidemiological Research issued approval 190250epi. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Niiyama et al.)

Background/Objectives : As COVID-19 can be severe, early predictive markers of both severity and onset of secondary bacterial infections are needed. This study first examined changes over time in the levels of plasma neopterin (NP) and biopterins (BPs), among others, in patients with COVID-19 and then in those with secondary bacterial infection complications. Methods : Fifty-two patients with COVID-19 admitted to two tertiary care centers were included. They were divided into a severe group (intubated + mechanical ventilation) ( n = 10) and a moderate group (non-intubated + oxygen administration) ( n = 42), and changes over time in plasma NP, plasma BPs, IFN-γ, lymphocyte count, CRP, and IL-6 were investigated. Four of the patients in the severe group ( n = 10) developed secondary bacterial infections during treatment. Plasma NP and plasma BPs of patients with bacterial sepsis (no viral infection) ( n = 25) were also examined. Results : The plasma NP, IL-6, CRP, and SOFA levels were significantly higher in the severe group, while the IFN-γ level and lymphocyte count were significantly lower. The higher plasma NP in the severe group persisted only up to 1 week after symptom onset. The plasma BPs were higher in complications of bacterial infection. Conclusions : The timing of sample collection is important for assessing severity through plasma NP, while plasma BPs may be a useful diagnostic tool for identifying the development of secondary bacterial infection in patients with COVID-19. Further investigation is needed to clarify the mechanism by which NP and BPs, which are involved in the same biosynthetic pathway, are differentially activated depending on the type of pathogen.

Tetrahydrobiopterin (BH4) is an essential cofactor for dopamine and serotonin synthesis in monoaminergic neurons, phenylalanine metabolism in hepatocytes, and nitric oxide synthesis in endothelial and immune cells. BH4 is consumed as a cofactor or is readily oxidized by autooxidation. Quinonoid dihydropteridine reductase (QDPR) is an enzyme that reduces quinonoid dihydrobiopterin (qBH2) back to BH4, and we have previously demonstrated the significance of QDPR in maintaining BH4 in vivo using Qdpr-KO mice. In addition to the levels of BH4 in the cells, the ratios of oxidized to reduced forms of BH4 are supposed to be important for regulating nitric oxide synthase (NOS) via the so-called uncoupling of NOS. However, previous studies were limited due to the absence of specific and high-affinity inhibitors against QDPR. Here, we performed a high-throughput screening for a QDPR inhibitor and identified Compound 9b with an IC 50 of 0.72 μM. To understand the inhibition mechanism, we performed kinetic analyses and molecular dynamics simulations. Treatment with 9b combined with methotrexate (MTX), an inhibitor of another BH4-reducing enzyme, dihydrofolate reductase (DHFR), significantly oxidized intracellular redox states in HepG2, Jurkat, SH-SY5Y, and PC12D cells. Collectively, these findings suggest that 9b may enhance the anticancer and anti-autoimmune effects of MTX., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: To assess the performance of pediatric extracorporeal membrane oxygenation (ECMO) centers, outcomes were compared between metropolitan and other areas., Methods: A retrospective cohort study was conducted at three regional centers on Kyushu Island and the largest center in the Tokyo metropolitan area of Japan. The clinical outcomes of patients of ≤15 years of age who received ECMO during 2010-2019 were investigated, targeting the survival and performance at discharge from intensive care units (ICUs), using medical charts., Results: One hundred and fifty-five patients were analyzed (regional, n = 70; metropolitan, n = 85). Survival rates at ICU discharge were similar between the two areas (64%). In regional centers, deterioration of Pediatric Cerebral Performance Category (PCPC) scores were more frequent (65.7% vs. 49.4%; p = 0.042), but survival rates and ΔPCPC scores (PCPC at ICU discharge-PCPC before admission) improved in the second half of the study period (p = 0.005 and p = 0.046, respectively). Veno-arterial ECMO (odds ratio [OR], 3.00; p < 0.03), extracorporeal cardiopulmonary resuscitation (OR, 8.98; p < 0.01), and absence of myocarditis (OR, 5.47; p < 0.01) were independent risk factors for deterioration of the PCPC score. A sub-analysis of patients with acute myocarditis (n = 51), the main indicator for ECMO, revealed a significantly higher proportion of cases with deteriorated PCPC scores in regional centers (51.9% vs. 25.0%; p = 0.049)., Conclusions: The survival rates of pediatric patients supported by ECMO in regional centers were similar to those in a metropolitan center. However, neurological outcomes must be improved, particularly in patients with acute myocarditis., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Central venous pressure is an estimate of right atrial pressure and is often used to assess hemodynamic status. However, since it is measured invasively, non-invasive alternatives would be of great utility. The aim of this preliminary study was a) to investigate whether photoplethysmography (PPG) can be used to characterize venous system fluid motion and b) to find the model for venous blood volume modulations. For this purpose, we monitored the internal jugular veins using contact (cPPG) and video PPG during clinically validated physiological tests: abdominojugular test (AJT) and breath holding (BH). Video PPG and cPPG signals were captured simultaneously on the left and right sides of the neck, respectively. ECG was also captured using the same clinical monitor as cPPG. Two volunteers underwent AJT and BH with head up/down, each with: baseline (15s), experiment (15s), and recovery (15s). Video PPG was split into remote PPG (rPPG) and micromotion detection. All signal modalities were significantly affected by physiological testing. Moreover, cPPG and micromotion waveforms exhibited primary features of jugular vein waveforms and, therefore, have great potential for venous blood flow monitoring. Specifically, remote patient monitoring applications may be enabled by this methodology, facilitating physical collection without a specially trained care provider., Competing Interests: The authors declare no conflict of interest., (© 2024 Optica Publishing Group.)

Background: Upon cellular injury, damage-associated molecular patterns (DAMPs) are released into the extracellular space and evoke proinflammatory and prothrombotic responses in animal models of sterile inflammation. However, in clinical settings, the dynamics of DAMP levels after trauma and links between DAMPs and trauma-associated coagulopathy remain largely undetermined., Methods: Thirty-one patients with severe trauma, who were transferred to Kagoshima City Hospital between June 2018 and December 2019, were consecutively enrolled in this study. Blood samples were taken at the time of delivery, and 6 and 12 h after the injury, and once daily thereafter. The time-dependent changes of coagulation/fibrinolysis markers, including thrombin-antithrombin complex, α2-plasmin inhibitor (α2-PI), plasmin-α2-PI complex, and plasminogen activator inhibitor-1 (PAI-1), and DAMPs, including high mobility group box 1 and histone H3, were analyzed. The relationship between coagulation/fibrinolysis markers, DAMPs, Injury Severity Score, in-hospital death, and amount of blood transfusion were analyzed., Results: The activation of coagulation/fibrinolysis pathways was evident at the time of delivery. In contrast, PAI-1 levels remained low at the time of delivery, and then were elevated at 6-12 h after traumatic injury. Histone H3 and high mobility group box 1 levels were elevated at admission, and gradually subsided over time. PAI-1 levels at 6 h were associated with serum histone H3 levels at admission. Increased histone H3 levels and plasmin-α2-PI complex levels were associated with in-hospital mortality. α2-PI levels at admission showed the strongest negative correlation with the amount of blood transfusion., Conclusion: The elevation of histone H3 levels and fibrinolysis perturbation are associated with fatal outcomes in patients with traumatic injury. Patients with low α2-PI levels at admission tend to require blood transfusion., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Early prediction of outcomes after cardiopulmonary arrest (CPA) is important for considering the best support. Our purpose was to evaluate predictors of the 30-day mortality in patients with CPA after return of spontaneous circulation (ROSC) and to assess an equation for calculating the 30-day mortality using clinical parameters., Methods: We retrospectively analyzed the data of 194 consecutive patients with CPA and ROSC in a derivation study (2015-2022). We compared clinical parameters between the survived (n = 78) and dead (n = 116) patients. We derived an equation for estimated probability of death based on clinical parameters, using multivariate logistic regression analysis. The reliability of the equation was validated in 80 additional patients with CPA., Results: The 30-day mortality was associated with sex, witnessed cardiac arrest, bystander cardiopulmonary resuscitation (CPR), CPA due to acute myocardial infarction, pupil diameter, Glasgow Coma Scale score (GCS), presence of light reflex, arterial or venous pH, lactate levels, initial ventricular fibrillation (VF), CPA time, and age. The derived logistic regression equation was as follows: Estimated probability of death = 1 / (1 + e -x ), x = (0.25 × bystander CPR) + (0.44 × pupil diameter) - (0.14 × GCS) + (0.09 × lactate) - (1.87 × initial VF) + (0.07 × CPA time) + (0.05 × age) - 7.03. The cut-off value for estimated probability of death calculated by this equation was 54.5 %, yielding a sensitivity, specificity, and accuracy of 86.2 %, 80.8 %, and 84.5 %, respectively. In the validation model, these values were 81.8 %, 85.7 %, and 82.5 %, respectively., Conclusions: The 30-day mortality may be calculated after ROSC in patients with CPA using simple clinical parameters. This equation may facilitate further best support for patients with CPA., Competing Interests: Disclosures The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Hereditary hemorrhagic telangiectasia (HHT) is a vascular disease caused by the defects of ALK1/ACVRL1 receptor signaling. In this study, we evaluated 25 recently identified ACVRL1 missense variants using multiple computational pathogenicity classifiers and experimentally characterized their signal transduction capacity. Three extracellular residue variants showed no detectable cell surface expression and impairment of bone morphogenetic protein 9 (BMP9) responsiveness of SMAD-dependent transcription in luciferase assays. Four variants with amino acid replacement in the motifs essential for the intracellular kinase function lost SMAD-dependent signaling. Most of other variations in the kinase domain also caused marked downregulation of signaling; however, two variants behaved as the wild-type ACVRL1 did, while computational classifiers predicted their functional abnormalities. Three-dimensional structure prediction using the ColabFold program supported the significance of the L45 loop and NANDOR domain of ACVRL1 for its association with SMAD1 and BMPR2, respectively, and the variations in these motifs resulted in the reduction of SMAD signaling. On the other hand, two of the GS domain variants maintained high signal transduction capacity, which did not accord with their computational pathogenicity prediction. These results affirm the requirement of a combinatory approach using computational and experimental analyses to accurately predict the pathogenicity of ACVRL1 missense variants in the HHT patients.

Reverse electrodialysis (RED) power generation using seawater (SW) and river water is expected to be a promising environmentally friendly power generation system. Experiments with large RED stacks are needed for the practical application of RED power generation, but only a few experimental results exist because of the need for large facilities and a large area of ion-exchange membranes (IEMs). In this study, to predict the power output of a large RED stack, the power generation performances of a lab-scale RED stack (40 membrane pairs and 7040 cm 2 total effective membrane area) with several IEMs were evaluated. The results were converted to the power output of a pilot-scale RED stack (299 membrane pairs and 179.4 m 2 total effective membrane area) via the reference IEMs. The use of low-area-resistance IEMs resulted in lower internal resistance and higher power density. The power density was 2.3 times higher than that of the reference IEMs when natural SW was used. The net power output was expected to be approximately 230 W with a pilot-scale RED stack using low-area-resistance IEMs and natural SW. This value is one of the indicators of the output of a large RED stack and is a target to be exceeded with further improvements in the RED system.

Oxidation of BH 4 , a cofactor of nitric oxide synthase (NOS), produces reactive oxygen species (ROS) through uncoupling of NOS and affects vascular endothelial dysfunction. Ascorbic acid (AsA) inhibits the oxidation of BH 4 and reduces ROS. However, the kinetic changes of BH 4 in sepsis and its effect on the kinetic changes in AsA administration therapy, as well as the appropriate timing of AsA administration for AsA therapy to be effective, are unclear. Mice with sepsis, induced by cecal ligation and puncture (CLP), were examined for the effect of AsA administration (200 mg/kg) on vascular endothelial cell dysfunction at two administration timings: early group (AsA administered immediately after CLP) and late group (AsA administered 12 h after CLP). Survival rates were compared between the early and late administration groups, and vascular endothelial cell damage, indicated by the dihydrobiopterin/tetrahydrobiopterin ratio, serum syndecan-1, and endothelial nitric oxide synthase, as well as liver damage, were examined. The early group showed significantly improved survival compared to the non-treatment group ( p < 0.05), while the late group showed no improved survival compared to the non-treatment group. Compared to the non-treated group, the early AsA group showed less oxidation of BH 4 in sepsis. Syndecan1, a marker of vascular endothelial cell damage, was less elevated and organ damage was reduced in the early AsA-treated group. In septic mice, early AsA administration immediately after CLP may protect vascular endothelial cells by inhibiting BH 4 oxidation, thereby reducing organ dysfunction and improving survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Madokoro, Kamikokuryo, Niiyama, Ito, Hara, Ichinose and Kakihana.)

Background: Neopterin (NP) is a biomarker for activated cellular immunity and is elevated in diseases including viral and bacterial infections, autoimmune diseases, and cancer. However, the clinical assessment of neopterin has not been used for these disorders because the physiological significance of measuring NP is obscure. It would be important to compare the NP profiles with those of other inflammation markers especially in relatively early phase of patients to reveal the significance of NP measurements in pathological states., Methods: Plasma NP, biopterin, CRP, and IL-6 levels were measured in 46 patients with Coronavirus Disease 2019 (COVID-19) and 23 patients with non-COVID-19 disorders. The correlations between these markers were analyzed in the COVID-19 and non-COVID-19 patients independently., Results: The NP levels were significantly higher in the COVID-19 patients than in the non-COVID-19 patients, while biopterin, CRP and IL-6 were not changed significantly. The NP levels were found to show a weak negative correlation against the days after onset in the COVID-19 patients ( rs = -0.348, p = 0.0192), suggesting that the elevation of NP would be an early event of viral infection. Correlations between NP and CRP, or between NP and IL-6 in COVID-19 patients were weaker than that between CRP and IL-6., Conclusions: The elevation of NP levels was supposed to be distinct from those of CRP and IL-6 in relatively early and mild COVID-19 patients. Our data suggest that NP is produced at the early phase of infection by different signaling pathways and/or cells from those of CRP and IL-6. Further study on the signaling pathway to induce NP is expected., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Although the treatment of municipal wastewater using microbial fuel cells (MFCs) has been extensively studied, scaling the systems up for practical use remains challenging. In this study, a 226 L sewage treatment reactor was equipped with 27 MFC units, and its chemical oxygen demand (COD) removal and electricity production were evaluated. The MFC units were tubular air cores with a diameter of 5 cm and length of 100 cm, which were wrapped with a carbon-based cathode, anion exchange membrane (AEM), and nonwoven graphite fabric. The air-cathode-AEM MFC generated 0.12-0.30 A/m 2 , 0.072-0.51 W/m 3 , and 1.7-4.6 Wh/m 3 in a chemostat reactor with a COD of 140-36 mg/L and hydraulic retention time (HRT) of 9-42 h throughout a year. The decrease in the COD was represented as the first-order rate constant of 0.038. The rate constant was comparable to that of other air-cathode MFCs with cation exchange membranes, indicating the necessity of a posttreatment to meet the discharge standard. It has been estimated that the MFC operation for 24 h before post-aeration can reduce the energy required to meet the discharge standard by 70%, suggesting the potential applicability of MFC in long HRT-treatments such as oxidation ditch. The resistances of the anode, cathode, and AEM were 15, 7.0, and 0.51 mΩ m 2 , respectively, and surface dirt rather than deterioration primarily increased the AEM resistance. A current exceeding 0.2 A/m 2 significantly increases the anode potential, indicating that the current was limited by low COD. Increasing the anode-specific surface area can improve air-AEM MFCs used for practical applications., (Copyright © 2021. Published by Elsevier Inc.)

Background: Administration of recombinant human soluble thrombomodulin (rTM) is often used in Japan to treat septic disseminated intravascular coagulation (DIC). Thrombin-activatable fibrinolysis inhibitor (TAFI) is a fibrinolysis inhibitor activated by the thrombin-thrombomodulin complex, however, it is unknown whether circulating activated TAFI is increased after rTM administration in patients with DIC. Furthermore, the relationship between TAFI activation and the prognosis of septic DIC is not defined yet., Case Presentation: We report a series of 8 patient's TAFI activation with septic DIC treated by rTM. We sought to investigate the effect of rTM on TAFI activation and the association of plasma activated TAFI (TAFIa/ai) levels with the prognosis of septic DIC. Using plasma samples from clinical studies conducted from May 2016-March 2017 on eight patients with septic DIC at Kagoshima University Hospital, we measured plasma levels of total TAFI, TAFIa/ai, thrombin-antithrombin complex (TAT), prothrombin fragment 1 + 2 (F1 + 2), soluble fibrin (SF), antithrombin (AT), protein C (PC), protein S (PS), and plasminogen activator inhibitor-1 (PAI-1) before and after intravenous rTM administration. Then, we evaluated the relationship of these marker levels to prognosis. The thrombin-rTM complex activated TAFI in vitro in plasma from a healthy volunteer. However, TAFIa/ai levels did not significantly increase over baseline in the septic DIC patients after intravenous rTM administration. Baseline TAFIa/ai levels in non-survivors were significantly higher than those in survivors., Conclusions: Plasma TAFIa/ai did not increase with rTM administration. Elevated baseline TAFIa/ai concentration may be a negative prognostic indicator in septic DIC. Larger studies are needed to confirm the in vivo effect of rTM on TAFI activation., (© 2022. The Author(s).)

This study compared the performance of two microbial fuel cells (MFCs) equipped with separators of anion or cation exchange membranes (AEMs or CEMs) for sewage wastewater treatment. Under chemostat feeding of sewage wastewater (hydraulic retention time of approximately 7 h and polarization via an external resistance of 1 Ω), the MFCs with AEM (MFC AEM ) generated a maximum current that was 4-5 times greater than that generated by the MFC with CEM (MFC CEM ). The high current in the MFC AEM was attributed to the approximately neutral pH of its cathode, in contrast to the extremely high pH of the MFC CEM cathode. Due to the elimination of the pH imbalance, the cathode resistance for the MFC AEM (13-19 Ω·m 2 ) was lower than that for the MFC CEM (41-44 Ω·m 2 ). The membrane resistance measured as the Cl - mobility of AEMs for the MFC AEM operated for 35, 583, and 768 days showed an increase with operation time and depth, and this increase contributed minimally to the cathode resistance of the MFC AEM . These results indicate the advantage of the AEM over the CEM for air-cathode MFCs. The membrane resistance may increase when the AEM is applied in large-scale MFCs on a meter scale for extended periods.