Intravenous immunoglobulin resistance in Kawasaki disease patients: prediction using clinical data.

BACKGROUND: About 10-20% of Kawasaki disease (KD) patients are resistant to the initial infusion of intravenous immunoglobin (IVIG). The aim of this study was to assess whether IVIG resistance in KD patients could be predicted using standard clinical and laboratory features. METHODS: Data were from two cohorts: a Korean cohort of 7101 KD patients from 2015 to 2017 and a cohort of 649 KD patients from San Diego enrolled from 1998 to 2021. Features included laboratory values, the worst Z-score from the initial echocardiogram or during hospitalization, and the five clinical KD signs at presentation. RESULTS: Five machine learning models achieved a maximum median AUC of 0.711 [IQR: 0.706-0.72] in the Korean cohort and 0.696 [IQR: 0.609-0.722] in the San Diego cohort during stratified 10-fold cross-validation using significant laboratory features identified from univariate analysis. Adding the Z-score, KD clinical signs, or both did not considerably improve the median AUC in either cohort. CONCLUSIONS: Using commonly measured clinical laboratory data alone or in conjunction with echocardiographic findings and clinical features is not sufficient to predict IVIG resistance. Further attempts to predict IVIG resistance will need to incorporate additional data such as transcriptomics, proteomics, and genetics to achieve meaningful predictive utility. IMPACT: We demonstrated that laboratory, echocardiographic, and clinical findings cannot predict intravenous immunoglobin (IVIG) resistance to a clinically meaningful extent using machine learning in a homogenous Asian or ethnically diverse population of patients with Kawasaki disease (KD). Visualizing these features using uniform manifold approximation and projection (UMAP) is an important step to evaluate predictive utility in a qualitative manner. Further attempts to predict IVIG resistance in KD patients will need to incorporate novel biomarkers or other specialized features such as genetic differences or transcriptomics to be clinically useful.

Genetically Stable and Scalable Nanoengineering of Human Primary T Cells via Cell Mechanoporation.

Effective tumor regression has been observed with chimeric antigen receptor (CAR) T cells; however, the development of an affordable, safe, and effective CAR-T cell treatment remains a challenge. One of the major obstacles is that the suboptimal genetic modification of T cells reduces their yield and antitumor activity, necessitating the development of a next-generation T cell engineering approach. In this study, we developed a nonviral T cell nanoengineering system that allows highly efficient delivery of diverse functional nanomaterials into primary human T cells in a genetically stable and scalable manner. Our platform leverages the unique cell deformation and restoration process induced by the intrinsic inertial flow in a microchannel to create nanopores in the cellular membrane for macromolecule internalization, leading to effective transfection with high scalability and viability. The proposed approach demonstrates considerable potential as a practical alternative technique for improving the current CAR-T cell manufacturing process.

The effects of ammonia acclimation on biogas recovery and the microbial population in continuous anaerobic digestion of swine manure.

This study investigated the ammonia toxicity and the acclimation of anaerobic microbiome in continuous anaerobic digestion of swine manure using unacclimated inoculum. When the total ammonia nitrogen concentration (TAN) reached 2.5 g N/L, the methane yield decreased from 254.1 ± 9.6 to 154.6 ± 9.9 mL/g COD. The free ammonia nitrogen concentration of the inhibited condition was 190 mg N/L. The methane yield was eventually recovered as 269.6 ± 3.6 mL/g COD with a further operation. Anaerobic toxicity assay (ATA) showed that mixed liquor from the recovered phase possessed enhanced tolerance to ammonia, not only within the exposed level in continuous operation (<2.5 g NH3/L) but also over the range (>2.5 g NH3/L). Microbial analysis revealed that continuous operation under ammonia stress resulted in the change of both bacterial and archaeal populations. The ammonia adaptation was concurrent with the archaeal population shift from Methanosaeta to Methanosarcina and Methanobacterium. The dominancy of Clostridia in bacterial population was found in the recovered phase. It is highly recommended to use an inoculum acclimated to a target ammonia level which can be pre-checked by ATA and to secure a start-up period for ammonia adaptation in the field application of anaerobic digestion for swine manure.

A child with spontaneous recovery of normal sinus rhythm from idiopathic complete atrioventricular block.

Atrioventricular block in children is not common but is a life-threatening disease. As no spontaneous regression of conductive disruption was reported, those sustaining idiopathic atrioventricular blocks are difficult to manage and often require pacemaker implantation. In this study, we presented the first case of a child who surprisingly recovered from idiopathic complete atrioventricular block without intervention 4 years after initial presentation.

Changes of hospitalization trend in the pediatric cardiology division of a single center by increasing adult with congenital heart disease.

BACKGROUND: As a result of advances in pediatric care and diagnostic testing, there is a growing population of adults with congenital heart disease (ACHD). The purpose of this study was to better define the epidemiology and changes in the trend of hospitalizations for ACHD in Korean society. METHODS: We reviewed outpatient and inpatient data from 2005 to 2017 to identify patient ≥18 years of age admitted for acute care with a congenital heart disease (CHD) diagnosis in the pediatric cardiology division. We tried to analyze changes of hospitalization trend for ACHD. RESULTS: The ratio of outpatients with ACHD increased 286.5%, from 11.1% (1748/15,682) in 2005 to 31.8% (7795/24,532) in 2017. The number of ACHD hospitalizations increased 360.7%, from 8.9% (37/414) in 2005 to 32.1% (226/705) in 2017. The average patient age increased from 24.3 years in 2005 to 27.4 in 2017. The main diagnosis for admission of ACHD is heart failure, arrhythmia and Fontan-related complications. The annual ICU admission percentage was around 5% and mean length of intensive care unit (ICU) stay was 8.4 ± 14.6 days. Mean personal hospital charges by admission of ACHD increased to around two times from 2005 to 2017. (from $2578.1 to $3697.0). Total annual hospital charges by ACHD markedly increased ten times (from $95,389.7 to $831,834.2). CONCLUSIONS: The number of hospital cares for ACHD dramatically increased more than five times from 2005 to 2017. We need preparations for efficient healthcare for adults with CHD such as a multi-dimensional approach, effective communication, and professional training.

Relation Between Exercise Capacity and Extracardiac Conduit Size in Patients with Fontan Circulation.

Because Fontan circulation does not have a subpulmonary ventricle, the preload is limited. In Fontan circulation with extracardiac conduit, the size of conduit could be an important factor in determining the preload. We compared exercise capacity with each conduit size and tried to search for optimal conduit size in Fontan circulation. We reviewed the medical record of 677 patients with Fontan circulation. Patients who had other type Fontan circulation (Kawashima, atriopulmonary, lateral tunnel), SpO2 < 85%, protein losing enteropathy, results of inappropriate exercise test were excluded. As a result, 150 patients were enrolled and classified according to conduit size. We compared with their exercise capacity and analyzed correlation between exercise capacity and conduit size per body surface area (BSA). 97 Males were included and mean age was 17.5 ± 5.1 years old. In cardiac catheterization, central venous pressure (CVP) was 12.4 ± 2.5 mmHg and pulmonary vascular resistance was 1.2 ± 0.5 wu m2. In cardiopulmonary exercise test, predictive peak VO2 was 59.1 ± 9.7% and VE/VCO2 was 36.2 ± 6.9. In analysis using quadratic model, impacts of gender, age at Fontan operation, ventricular morphology, isomerism, and fenestration on exercise capacity were excluded and conduit size per BSA had a significant curved correlation with predictive peak VO2 and VE/VCO2. Our results showed that patients with about 12.5 mm/m2 conduit per BSA have the best exercise capacity. Patients with larger than smaller-sized conduit were found to be more attenuated in their ability to exercise.

Making the Brightest Ones Dim: Maximizing the Photothermal Conversion Efficiency of BODIPY-Based Photothermal Agents.

The successful implementation of photothermal therapy (PTT) in cancer treatment hinges on the development of highly effective photothermal agents (PTAs). Boron dipyrromethene (BODIPY) dyes, being well known for their high brightness and quantum efficiencies, are the antithesis of PTAs. Nonetheless, a systematic exploration of the photophysics and photothermal characteristics of a series of π-extended BODIPY dyes with high absorptivity in the near-infrared (NIR) region has achieved superior photothermal conversion efficiencies (>90%), in both monomeric state and nanoparticles after encapsulation in a biocompatible polyethyleneglycol 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-(polyethylene glycol)-2000]. Optimal PTA candidates combine strong NIR absorption provided by extended donor-acceptor conjugation and an optimization of the electronic and steric effects of meso-substituents to maximize photothermal conversion performance. The PTT-optimized meso-CF3-BODIPY, TCF3PEn exhibits exceptional efficacy in inducing cancer cell apoptosis and in vivo tumor ablation using low-power NIR laser irradiation (0.3 W cm-2, 808 nm) as well as excellent biological safety, underscoring its potential for advancing light-induced cancer therapies.

Microstructural Evolution, Hardness and Wear Resistance of WC-Co-Ni Composite Coatings Fabricated by Laser Cladding.

This study investigated how process parameters of laser cladding affect the microstructure and mechanical properties of WC-12Co composite coating for use as a protective layer of continuous caster rolls. WC-Co powders, WC-Ni powders, and Ni-Cr alloy powder with various wear resistance characteristics were evaluated in order to determine their applicability for use as cladding materials for continuous caster roll coating. The cladding process was conducted with various parameters, including laser powers, cladding speeds, and powder feeding rates, then the phases, microstructure, and micro-hardness of the cladding layer were analyzed in each specimen. Results indicate that, to increase the hardness of the cladding layer in WC-Co composite coating, the dilution of the cladding layer by dissolution of Fe from the substrate should be minimized, and the formation of the Fe-Co alloy phase should be prevented. The mechanical properties and wear resistance of each powder with the same process parameters were compared and analyzed. The microstructure and mechanical properties of the laser cladding layer depend not only on the process parameters, but also on the powder characteristics, such as WC particle size and the type of binder material. Additionally, depending on the degree of thermal decomposition of WC particles and evolution of W distribution within the cladding layer, the hardness of each powder can differ significantly, and the wear mechanism can change.

Long QT syndrome: a Korean single center study.

The long QT syndrome (LQTS) is a rare hereditary disorder in which affected individuals have a possibility of ventricular tachyarrhythmia and sudden cardiac death. We investigated 62 LQTS (QTc ≥ 0.47 sec) and 19 family members whose genetic study revealed mutation of LQT gene. In the proband group, the modes of presentation were ECG abnormality (38.7%), aborted cardiac arrest (24.2%), and syncope or seizure (19.4%). Median age of initial symptom development was 10.5 yr. Genetic studies were performed in 61; and mutations were found in 40 cases (KCNQ1 in 19, KCNH2 in 10, SCN5A in 7, KCNJ2 in 3, and CACNA1C in 1). In the family group, the penetrance of LQT gene mutation was 57.9%. QTc was longer as patients had the history of syncope (P = 0.001), ventricular tachycardia (P = 0.017) and aborted arrest (P = 0.010). QTc longer than 0.508 sec could be a cut-off value for major cardiac events (sensitivity 0.806, specificity 0.600). Beta-blocker was frequently applied for treatment and had significant effects on reducing QTc (P = 0.007). Implantable cardioverter defibrillators were applied in 6 patients. Congenital LQTS is a potentially lethal disease. It shows various genetic mutations with low penetrance in Korean patients.

Volumetric and functional assessment using cardiac magnetic resonance imaging in young children exposed to acute pulmonary regurgitation: is pulmonary regurgitation just a long-term matter?

BACKGROUND: The early effect of pulmonary regurgitation (PR) on both ventricular volume and function has not been well established in children. We evaluated the early effect of PR on both ventricular volume and function in young children. METHODS: Among patients who underwent total repair of pulmonary atresia with ventricular septal defect between January 2007 and December 2008, cardiac magnetic resonance imaging (CMRI) was performed in 12 patients at a median interval of 15.6 months (6-22 months). Valveless right ventricular outflow tract (RVOT) reconstruction was performed in five patients (valveless group) and RVOT reconstruction using valved conduit in seven patients (valve group). Age and weight at operation, and the interval between the operation and CMRI were not different between the groups. RESULTS: We observed a higher pulmonary regurgitant fraction (p = 0.003), a higher right ventricular end-diastolic volume index (RVEDVI) (p = 0.003), a higher right ventricular end-systolic volume index (p = 0.003), a higher left ventricular end-diastolic volume index (p = 0.010), a higher left ventricular end-systolic volume index (p = 0.018), and a lower left ventricular ejection fraction (LVEF; p = 0.048) in the valveless group. Right ventricular ejection fraction (RVEF) was not different between two groups. The RVEDVI was negatively correlated with RVEF (rho = -0.601, p = 0.039) and LVEF (rho = -0.580, p = 0.048). CONCLUSIONS: Both ventricular volumes increased and left ventricular function was compromised, but right ventricular function was preserved early after the exposure to PR in children. Right ventricular volume was associated with both ventricular functions.

Anaerobic digestion of sewage sludge using anaerobic dynamic membrane bioreactor under various sludge composition and organic loading rates.

This study investigates the effects of sludge compositions and organic loading rates (OLRs) on stable biogas production during sludge digestion. Batch digestion experiments evaluate the effects of alkaline-thermal pretreatment and waste activated sludge (WAS) fractions on the biochemical methane potential (BMP) of sludge. A lab-scale anaerobic dynamic membrane bioreactor (AnDMBR) is fed with a mixture of primary sludge and pretreated WAS. Monitoring of volatile fatty acid to total alkalinity (FOS/TAC) helps maintain operational stability. The highest average methane production rate of 0.7 L/L·d is achieved when the OLR, hydraulic retention time, WAS volume fraction, and FOS/TAC ratio are 5.0 g COD/L·d, 12 days, 0.75, and 0.32, respectively. This study finds functional redundancy in two pathways: hydrogenotrophic and acetolactic. An increase in OLR promotes bacterial and archaeal abundance and specific methanogenic activity. These results can be applied to the design and operation of sludge digestion for stable, high-rate biogas recovery.

Trend of fetal echocardiography use and comparison of medical costs for congenital heart disease treatment based on fetal echocardiography use in a Korean single center.

Background: The rate of the prenatal diagnosis of congenital heart disease is increasing along with advances in fetal echocardiography techniques. Here, we aimed to investigate the trend of the use of fetal echocardiography over time and to compare the medical costs of congenital heart disease treatment according to whether fetal echocardiography was performed. Methods: We reviewed our hospital's database, and patients who underwent the first surgery for congenital heart disease within 30 days of birth during 2005-2007, 2011-2013, and 2017-2019 were included. The severity of congenital heart disease diagnosed in each case was evaluated according to The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Mortality Scores (STS-EACTS Mortality Scores) and Mortality Categories (STAT Mortality Categories). Results: In total, 375 patients were analyzed, and fetal echocardiography use increased significantly after the 2010s compared with in 2005-2007 (19.1% vs. 39%, p = 0.032 in Mortality Category 1-3; 15.5% vs. 69.5%, p = 0.000 in Mortality Category 4-5). Additionally, the mean STS-EACTS Mortality Score was higher in prenatally diagnosed patients than in postnatally diagnosed patients (2.287 vs. 1.787, p = 0.001). In the recent period, there was no significant difference in hospitalization durations and medical costs according to whether or not fetal echocardiography was performed. Conclusions: This single center study showed the use of fetal echocardiography is increasing. Further, prenatal diagnosis with fetal echocardiography causing no differences in medical costs in recent years. Therefore, we suggest that fetal echocardiography can be applied more widely without increasing the economic burden.

Carbamate JNK3 Inhibitors Show Promise as Effective Treatments for Alzheimer's Disease: In Vivo Studies on Mouse Models.

We have been developing new inhibitors for c-Jun N-terminal kinase 3 (JNK3) as a potential treatment for Alzheimer's disease (AD). We identified potential JNK3 inhibitors through pharmacodynamic optimization studies, including benzimidazole compounds 2 and 3, but their unreliable pharmacokinetic properties led us to develop carbamate inhibitors 2h and 3h. In vitro studies validated carbamate inhibitors 2h and 3h as potent and highly selective JNK3 inhibitors with favorable pharmacokinetic profiles. Oral administration of 2h and 3h to both APP/PS1 and 3xTg AD mouse models improved cognitive function, indicating their potential as effective treatments for Alzheimer's disease. Carbamate JNK3 inhibitor 3h, in particular, restored cognitive function to near-normal levels in the 3xTg mice model of AD and led to pTau reduction in the hippocampal tissues of 3xTg-AD mice during in vivo behavioral evaluations. We intend to further develop these carbamate JNK3 inhibitors in preclinical studies as a potential first-in-class treatment for AD.

Proteogenomic landscape of human pancreatic ductal adenocarcinoma in an Asian population reveals tumor cell-enriched and immune-rich subtypes.

We report a proteogenomic analysis of pancreatic ductal adenocarcinoma (PDAC). Mutation-phosphorylation correlations identified signaling pathways associated with somatic mutations in significantly mutated genes. Messenger RNA-protein abundance correlations revealed potential prognostic biomarkers correlated with patient survival. Integrated clustering of mRNA, protein and phosphorylation data identified six PDAC subtypes. Cellular pathways represented by mRNA and protein signatures, defining the subtypes and compositions of cell types in the subtypes, characterized them as classical progenitor (TS1), squamous (TS2-4), immunogenic progenitor (IS1) and exocrine-like (IS2) subtypes. Compared with the mRNA data, protein and phosphorylation data further classified the squamous subtypes into activated stroma-enriched (TS2), invasive (TS3) and invasive-proliferative (TS4) squamous subtypes. Orthotopic mouse PDAC models revealed a higher number of pro-tumorigenic immune cells in TS4, inhibiting T cell proliferation. Our proteogenomic analysis provides significantly mutated genes/biomarkers, cellular pathways and cell types as potential therapeutic targets to improve stratification of patients with PDAC.

Chronic total occlusion by stent fracture in Kawasaki disease: is recanalisation possible?

Despite various medications for Kawasaki disease, a small number of children have been undergoing interventions for severe coronary artery complications. Transcatheter intervention is a feasible alternative to coronary artery bypass grafting in a patient with chronic totally occluded lesion after Kawasaki disease, even by stent fracture.

Biohydrogen and biomethane production from food waste using a two-stage dynamic membrane bioreactor (DMBR) system.

This study examined a two-stage dynamic membrane bioreactor (DMBR) system for biohydrogen and biomethane production from food waste (FW) in mesophilic condition. The two-stage DMBR system enabled high-rate H2 and CH4 production from particulate feedstock by enhanced microorganism retention. Chemical energy in FW was recovered up to 79% as renewable energy. The highest average hydrogen production rate of 7.09 ± 0.42 L/L-d was observed at a hydraulic retention time (HRT) of 8 h in the H2-DMBR, while the highest CH4 average production rate of 0.99 ± 0.02 L/L-d was observed at an HRT of 6 d in the CH4-DMBR. The high specific methanogenic activity of 71.7 mL CH4/g VSS-d was maintained at the short HRT, which also contributed to the high MPR. The genus Clostridium was dominant in the H2-DMBR, while bacterial and archaeal populations in the CH4-DMBR were dominated by the class Clostridia and genera Methanobacterium and Methanosaeta, respectively.

Sludge disintegration and anaerobic digestion enhancement by alkaline-thermal pretreatment: Economic evaluation and microbial population analysis.

Alkaline-thermal pretreatment was examined for waste activated sludge (WAS) disintegration and subsequent anaerobic digestion (AD). Pretreatment at 60 °C was estimated to provide better economic benefits than higher temperature conditions. The maximum methane yield of 215.6 mL/g COD was achieved when WAS was pretreated at 60 °C and pH 10 for 24 h, which was 46.6% higher than untreated WAS. The pretreatment condition also provided the maximum net savings. The degree of sludge disintegration, considering both loosely bound-extracellular polymeric substance and soluble COD, would be a better indicator to predict anaerobic digestibility than the solubilization rate that considers soluble COD alone. Microbial analysis implied that pretreatment facilitated the growth of hydrolytic bacteria, phyla Bacteroidetes and Firmicutes. In addition, sludge pretreatment enhanced the growth of both acetoclastic and hydrogenotrophic methanogens, genera Methanosaeta and Methanobacterium. The mild AT-PT would be useful to enhance the digestion performance and economic benefit of WAS digestion.

Biofilm formation as a method of improved treatment during anaerobic digestion of organic matter for biogas recovery.

The efficiency of anaerobic digestion could be increased by promoting microbial retention through biofilm development. The inclusion of certain types of biofilm carriers has differentiated existing AD biofilm reactors through their respective mode of biofilm growth. Bacteria and archaea engaged in methanogenesis during anaerobic processes potentially build biofilms by adhering or attaching to biofilm carriers. Meta-analyzed results depicted varying degrees of biogas enhancement within AD biofilm reactors. Furthermore, different carrier materials highly induced the dynamicity of the dominant microbial population in each system. It is suggested that the promotion of surface contact and improvement of interspecies electron transport have greatly impacted the treatment results. Modern spectroscopy techniques have been and will continue to give essential information regarding biofilm's composition and structural organization which can be useful in elucidating the added function of this special layer of microbial cells.

Enhanced anaerobic digestion of waste-activated sludge via bioaugmentation strategy-Phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt2) analysis through hydrolytic enzymes and possible linkage to system performance.

In this study, anaerobic digestion of waste-activated sludge was bioaugmented with hydrolytic bacteria, Bacteroidetes uniformis (Bacteroidetes, B) and Clostridium sp. (Firmicutes, F) at various dosages. Bioaugmentation resulted in enhanced methane conversion of waste-activated sludge. The highest methane yield of 298.1 mL CH4/g-COD, 85.2% COD conversion efficiency was obtained when Bacteroidetes uniformis and Clostridium sp. were augmented at 100 and 900 CFU/mL, respectively. The microbial community analysis demonstrated that bioaugmentation increased the proportion of Bacteroidetes, Firmicutes, and Proteobacteria. Furthermore, at the highest methane yield, the principal methanogenic pathway was altered from acetoclastic to a mixture of hydrogenotrophic and acetoclastic; the major species shifted from Methanosaeta concilii to Methanobacterium subterraneum. Predicted gene analysis revealed that increased expression of hydrolases resulted in enhanced methane conversion through bioaugmentation.

Highly Efficient Transfection of Human Primary T Lymphocytes Using Droplet-Enabled Mechanoporation.

Whole-cell-based therapy has been extensively used as an effective disease treatment approach, and it has rapidly changed the therapeutic paradigm. To fully accommodate this shift, advances in genome modification and cell reprogramming methodologies are critical. Traditionally, molecular tools such as viral and polymer nanocarriers and electroporation have been the norm for internalizing external biomolecules into cells for cellular engineering. However, these approaches are not fully satisfactory considering their cytotoxicity, high cost, low scalability, and/or inconsistent and ineffective delivery and transfection. To address these challenges, we present an approach that leverages droplet microfluidics with cell mechanoporation, bringing intracellular delivery to the next level. In our approach, cells and external cargos such as mRNAs and plasmid DNAs are coencapsulated into droplets, and as they pass through a series of narrow constrictions, the cell membrane is mechanically permeabilized where the cargos in the vicinity are internalized via convective solution exchange enhanced by recirculation flows developed in the droplets. Using this principle, we demonstrated a high level of functional macromolecule delivery into various immune cells, including human primary T cells. By utilizing droplets, the cargo consumption was drastically reduced, and near-zero clogging was realized. Furthermore, high scalability without sacrificing cell viability and superior delivery over state-of-the-art methods and benchtop techniques were demonstrated. Notably, the droplet-based intracellular delivery strategy presented here can be further applied to other mechanoporation microfluidic techniques, highlighting its potential for cellular engineering and cell-based therapies.