Comparative Evaluation of Recombinant and Acellular Pertussis Vaccines in a Murine Model.

Since the 2000s, sporadic outbreaks of whooping cough have been reported in advanced countries, where the acellular pertussis vaccination rate is relatively high, and in developing countries. Small-scale whooping cough has also continued in many countries, due in part to the waning of immune protection after childhood vaccination, necessitating the development of an improved pertussis vaccine and vaccination program. Currently, two different production platforms are being actively pursued in Korea; one is based on the aP (acellular pertussis) vaccine purified from B. pertussis containing pertussis toxoid (PT), filamentous hemagglutin (FHA) and pertactin (PRN), and the other is based on the recombinant aP (raP), containing genetically detoxified pertussis toxin ADP-ribosyltransferase subunit 1 (PtxS1), FHA, and PRN domain, expressed and purified from recombinant E. coli. aP components were further combined with diphtheria and tetanus vaccine components as a prototype DTaP vaccine by GC Pharma (GC DTaP vaccine). We evaluated and compared the immunogenicity and the protective efficacy of aP and raP vaccines in an experimental murine challenge model: humoral immunity in serum, IgA secretion in nasal lavage, bacterial clearance after challenge, PTx (pertussis toxin) CHO cell neutralization titer, cytokine secretion in spleen single cell, and tissue resident memory CD4+ T cell (CD4+ TRM cell) in lung tissues. In humoral immunogenicity, GC DTaP vaccines showed high titers for PT and PRN and showed similar patterns in nasal lavage and IL-5 cytokine secretions. The GC DTaP vaccine and the control vaccine showed equivalent results in bacterial clearance after challenge, PTx CHO cell neutralization assay, and CD4+ TRM cell. In contrast, the recombinant raP vaccine exhibited strong antibody responses for FHA and PRN, albeit with low antibody level of PT and low titer in PTx CHO neutralization assay, as compared to control and GC DTaP vaccines. The raP vaccine provided a sterile lung bacterial clearance comparable to a commercial control vaccine after the experimental challenge in murine model. Moreover, raP exhibited a strong cytokine response and CD4+ TRM cell in lung tissue, comparable or superior to the experimental and commercial DTaP vaccinated groups. Contingent on improving the biophysical stability and humoral response to PT, the raP vaccine warrants further development as an effective alternative to aP vaccines for the control of a pertussis outbreak.

Scientific Publication Speed of Korean Medical Journals during the COVID-19 Era.

OBJECTIVES: This study compared the scientific publication speeds of Korean medical journals before and during the coronavirus disease 2019 (COVID-19) era. METHODS: We analyzed 2,064 papers from 43 international Korean medical journals, selecting 12 papers annually from 2019 to 2022. We assessed publication speed indicators, including the time from submission to revision and from submission to publication. Additionally, we examined variations in publication speed based on journal and paper characteristics, including whether the studies were related to COVID-19. RESULTS: Among the 43 journals analyzed, 39.5% disclosed the peer review duration from submission to the first decision, and 11.6% reported their acceptance rates. The average time from submission to acceptance was 127.0 days in 2019, 126.1 days in 2020, 124.6 days in 2021, and 126.4 days in 2022. For COVID-19-related studies, the average time from submission to revision was 61.4 days, compared to 105.1 days for non-COVID-19 studies; from submission to acceptance, it was 87.4 days for COVID-19-related studies and 127.1 days for non-COVID-19 studies. All indicators for COVID-19-related studies showed shorter durations than those for non-COVID-19 studies, and the proportion of studies accepted within 30 or 60 days was significantly higher for COVID-19-related studies. CONCLUSIONS: This study investigated the publication speed of Korean international medical journals before and during the COVID-19 pandemic. The pandemic influenced journals' review and publication processes, potentially impacting the quality of academic papers. These findings provide insights into publication speeds during the COVID-19 era, suggesting that journals should focus on maintaining the integrity of their publication and review processes.

The experiences of students with intellectual and developmental disabilities, parents, and teachers regarding health self-advocacy program with school-home connection: a qualitative study.

Background: Despite the importance of health as a significant indicator of quality of life, individuals with intellectual and developmental disabilities (IDD) often face low expectations, stigma, and insufficient opportunities in health care and education. In response, we developed a health self-advocacy program with a school-home connection for students with IDD to promote self-directed health care and verified its effectiveness by implementing the program for students with IDD. Objective: This study aimed to explore participants' program experiences and support needs to reduce the stigma surrounding individuals with IDD and provide implications for enhancing health self-advocacy skills. Methods: Individual and focus group interviews were conducted with 14 students, six parents, and four teachers who participated in the program. The collected data were analyzed using the constant comparative method. Results: The following five main themes emerged: (a) the gap between perception and practice in health care; (b) advantages and influencing factors of the program; (c) challenges in program implementation; (d) outcomes of program implementation; and (e) support needs for promoting health self-advocacy. Conclusion: Based on these findings, implications are provided and discussed to reduce the stigma surrounding individuals with IDD and enhance health self-advocacy.

Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation.

Hemodynamic shear force has been implicated as modulating Notch signaling-mediated cardiac trabeculation. Whether the spatiotemporal variations in wall shear stress (WSS) coordinate the initiation of trabeculation to influence ventricular contractile function remains unknown. Using light-sheet fluorescent microscopy, we reconstructed the 4D moving domain and applied computational fluid dynamics to quantify 4D WSS along the trabecular ridges and in the groves. In WT zebrafish, pulsatile shear stress developed along the trabecular ridges, with prominent endocardial Notch activity at 3 days after fertilization (dpf), and oscillatory shear stress developed in the trabecular grooves, with epicardial Notch activity at 4 dpf. Genetic manipulations were performed to reduce hematopoiesis and inhibit atrial contraction to lower WSS in synchrony with attenuation of oscillatory shear index (OSI) during ventricular development. γ-Secretase inhibitor of Notch intracellular domain (NICD) abrogated endocardial and epicardial Notch activity. Rescue with NICD mRNA restored Notch activity sequentially from the endocardium to trabecular grooves, which was corroborated by observed Notch-mediated cardiomyocyte proliferations on WT zebrafish trabeculae. We also demonstrated in vitro that a high OSI value correlated with upregulated endothelial Notch-related mRNA expression. In silico computation of energy dissipation further supports the role of trabeculation to preserve ventricular structure and contractile function. Thus, spatiotemporal variations in WSS coordinate trabecular organization for ventricular contractile function.

A Rapid Capillary-Pressure Driven Micro-Channel to Demonstrate Newtonian Fluid Behavior of Zebrafish Blood at High Shear Rates.

Blood viscosity provides the rheological basis to elucidate shear stress underlying developmental cardiac mechanics and physiology. Zebrafish is a high throughput model for developmental biology, forward-genetics, and drug discovery. The micro-scale posed an experimental challenge to measure blood viscosity. To address this challenge, a microfluidic viscometer driven by surface tension was developed to reduce the sample volume required (3µL) for rapid (<2 min) and continuous viscosity measurement. By fitting the power-law fluid model to the travel distance of blood through the micro-channel as a function of time and channel configuration, the experimentally acquired blood viscosity was compared with a vacuum-driven capillary viscometer at high shear rates (>500 s-1), at which the power law exponent (n) of zebrafish blood was nearly 1 behaving as a Newtonian fluid. The measured values of whole blood from the micro-channel (4.17cP) and the vacuum method (4.22cP) at 500 s-1 were closely correlated at 27 °C. A calibration curve was established for viscosity as a function of hematocrits to predict a rise and fall in viscosity during embryonic development. Thus, our rapid capillary pressure-driven micro-channel revealed the Newtonian fluid behavior of zebrafish blood at high shear rates and the dynamic viscosity during development.

Ambient Ultrafine Particle Ingestion Alters Gut Microbiota in Association with Increased Atherogenic Lipid Metabolites.

Ambient particulate matter (PM) exposure is associated with atherosclerosis and inflammatory bowel disease. Ultrafine particles (UFP, dp < 0.1-0.2 µm) are redox active components of PM. We hypothesized that orally ingested UFP promoted atherogenic lipid metabolites in both the intestine and plasma via altered gut microbiota composition. Low density lipoprotein receptor-null (Ldlr-/-) mice on a high-fat diet were orally administered with vehicle control or UFP (40 µg/mouse/day) for 3 days a week. After 10 weeks, UFP ingested mice developed macrophage and neutrophil infiltration in the intestinal villi, accompanied by elevated cholesterol but reduced coprostanol levels in the cecum, as well as elevated atherogenic lysophosphatidylcholine (LPC 18:1) and lysophosphatidic acids (LPAs) in the intestine and plasma. At the phylum level, Principle Component Analysis revealed significant segregation of microbiota compositions which was validated by Beta diversity analysis. UFP-exposed mice developed increased abundance in Verrocomicrobia but decreased Actinobacteria, Cyanobacteria, and Firmicutes as well as a reduced diversity in microbiome. Spearman's analysis negatively correlated Actinobacteria with cecal cholesterol, intestinal and plasma LPC18:1, and Firmicutes and Cyanobacteria with plasma LPC 18:1. Thus, ultrafine particles ingestion alters gut microbiota composition, accompanied by increased atherogenic lipid metabolites. These findings implicate the gut-vascular axis in a atherosclerosis model.

4-Dimensional light-sheet microscopy to elucidate shear stress modulation of cardiac trabeculation.

Hemodynamic shear forces are intimately linked with cardiac development, during which trabeculae form a network of branching outgrowths from the myocardium. Mutations that alter Notch signaling also result in trabeculation defects. Here, we assessed whether shear stress modulates trabeculation to influence contractile function. Specifically, we acquired 4D (3D + time) images with light sheets by selective plane illumination microscopy (SPIM) for rapid scanning and deep axial penetration during zebrafish morphogenesis. Reduction of blood viscosity via gata1a morpholino oligonucleotides (MO) reduced shear stress, resulting in downregulation of Notch signaling and attenuation of trabeculation. Arrest of cardiomyocyte contraction either by troponin T type 2a (tnnt2a) MO or in weak atriumm58 (wea) mutants resulted in reduced shear stress and downregulation of Notch signaling and trabeculation. Integrating 4D SPIM imaging with synchronization algorithm demonstrated that coinjection of neuregulin1 mRNA with gata1 MO rescued trabeculation to restore contractile function in association with upregulation of Notch-related genes. Crossbreeding of Tg(flk:mCherry) fish, which allows visualization of the vascular system with the Tg(tp1:gfp) Notch reporter line, revealed that shear stress-mediated Notch activation localizes to the endocardium. Deleting endocardium via the clochesk4 mutants downregulated Notch signaling, resulting in nontrabeculated ventricle. Subjecting endothelial cells to pulsatile flow in the presence of the ADAM10 inhibitor corroborated shear stress-activated Notch signaling to modulate trabeculation.

Cardiac Light-Sheet Fluorescent Microscopy for Multi-Scale and Rapid Imaging of Architecture and Function.

Light Sheet Fluorescence Microscopy (LSFM) enables multi-dimensional and multi-scale imaging via illuminating specimens with a separate thin sheet of laser. It allows rapid plane illumination for reduced photo-damage and superior axial resolution and contrast. We hereby demonstrate cardiac LSFM (c-LSFM) imaging to assess the functional architecture of zebrafish embryos with a retrospective cardiac synchronization algorithm for four-dimensional reconstruction (3-D space + time). By combining our approach with tissue clearing techniques, we reveal the entire cardiac structures and hypertrabeculation of adult zebrafish hearts in response to doxorubicin treatment. By integrating the resolution enhancement technique with c-LSFM to increase the resolving power under a large field-of-view, we demonstrate the use of low power objective to resolve the entire architecture of large-scale neonatal mouse hearts, revealing the helical orientation of individual myocardial fibers. Therefore, our c-LSFM imaging approach provides multi-scale visualization of architecture and function to drive cardiovascular research with translational implication in congenital heart diseases.