A lipid nanoparticle platform incorporating trehalose glycolipid for exceptional mRNA vaccine safety.

The rapid development of messenger RNA (mRNA) vaccines formulated with lipid nanoparticles (LNPs) has contributed to control of the COVID-19 pandemic. However, mRNA vaccines have raised concerns about their potential toxicity and clinical safety, including side effects, such as myocarditis, anaphylaxis, and pericarditis. In this study, we investigated the potential of trehalose glycolipids-containing LNP (LNP S050L) to reduce the risks associated with ionizable lipids. Trehalose glycolipids can form hydrogen bonds with polar biomolecules, allowing the formation of a stable LNP structure by replacing half of the ionizable lipids. The efficacy and safety of LNP S050L were evaluated by encapsulating the mRNA encoding the luciferase reporter gene and measuring gene expression and organ toxicity, respectively. Furthermore, mice immunized with an LNP S050L-formulated mRNA vaccine expressing influenza hemagglutinin exhibited a significant reduction in organ toxicity, including in the heart, spleen, and liver, while sustaining gene expression and immune efficiency, compared to conventional LNPs (Con-LNPs). Our findings suggest that LNP S050L, a trehalose glycolipid-based LNP, could facilitate the development of safe mRNA vaccines with improved clinical safety.

Comparison of vancomycin area under the curve calculated based on Bayesian approach versus equation-based approach.

OBJECTIVE: Area under the curve (AUC)-based vancomycin dose adjustment is recommended to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. AUC estimation methods include Bayesian software programs and simple analytical equations. This study compared the AUC obtained using the Bayesian approach with that obtained using an equation-based approach. MATERIALS AND METHODS: Patients receiving intravenous vancomycin for MRSA infection were included. Peak and trough levels were measured for each patient on days 3, 7, and 10 post vancomycin dosing (day 1). AUC was calculated using software based on the Bayesian method (MwPharm Online) and an equation-based calculator, Stanford Health Care (SHC) calculator. RESULTS: The AUC estimated using MwPharm Online was similar to that estimated using the SHC calculator. The geometric mean ratio (GMR) and their 90% confidence intervals (90% CI) were 1.08 (1.05 - 1.11), 1.03 (0.99 - 1.07), and 0.99 (0.94 - 1.05) at days 3, 7, and 10, respectively. Furthermore, according to the software used, there were no significant differences in the proportions of patients in the categories "within" and "below or above" the AUC target range. Additionally, trough levels predicted by both software programs were lower than the observed ones. Still, there was no significant difference between the predicted and observed peak levels for both software programs on day 10. CONCLUSION: AUC calculated using the Bayesian software allows for calculation with samples at a non-steady state, can integrate covariates, and is interconvertible with that estimated using an equation-based calculator, which is simpler and relies on fewer assumptions. Therefore, either method can be used, considering each method's strengths and limitations.

DWN12088, A Prolyl-tRNA Synthetase Inhibitor, Alleviates Hepatic Injury in Nonalcoholic Steatohepatitis.

BACKGRUOUND: Nonalcoholic steatohepatitis (NASH) is a liver disease caused by obesity that leads to hepatic lipoapoptosis, resulting in fibrosis and cirrhosis. However, the mechanism underlying NASH is largely unknown, and there is currently no effective therapeutic agent against it. DWN12088, an agent used for treating idiopathic pulmonary fibrosis, is a selective prolyl-tRNA synthetase (PRS) inhibitor that suppresses the synthesis of collagen. However, the mechanism underlying the hepatoprotective effect of DWN12088 is not clear. Therefore, we investigated the role of DWN12088 in NASH progression. METHODS: Mice were fed a chow diet or methionine-choline deficient (MCD)-diet, which was administered with DWN12088 or saline by oral gavage for 6 weeks. The effects of DWN12088 on NASH were evaluated by pathophysiological examinations, such as real-time quantitative reverse transcription polymerase chain reaction, immunoblotting, biochemical analysis, and immunohistochemistry. Molecular and cellular mechanisms of hepatic injury were assessed by in vitro cell culture. RESULTS: DWN12088 attenuated palmitic acid (PA)-induced lipid accumulation and lipoapoptosis by downregulating the Rho-kinase (ROCK)/AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein-1c (SREBP-1c) and protein kinase R-like endoplasmic reticulum kinase (PERK)/α subunit of eukaryotic initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) signaling cascades. PA increased but DWN12088 inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 (Ser536, Ser276) and the expression of proinflammatory genes. Moreover, the DWN12088 inhibited transforming growth factor ß (TGFß)-induced pro-fibrotic gene expression by suppressing TGFß receptor 1 (TGFßR1)/Smad2/3 and TGFßR1/glutamyl-prolyl-tRNA synthetase (EPRS)/signal transducer and activator of transcription 6 (STAT6) axis signaling. In the case of MCD-diet-induced NASH, DWN12088 reduced hepatic steatosis, inflammation, and lipoapoptosis and prevented the progression of fibrosis. CONCLUSION: Our findings provide new insights about DWN12088, namely that it plays an important role in the overall improvement of NASH. Hence, DWN12088 shows great potential to be developed as a new integrated therapeutic agent for NASH.

Effect of dietary inclusion of Bacillus-based probiotics on performance, egg quality, and the faecal microbiota of laying hen.

OBJECTIVE: Our study examined the impact of propriety blends of Bacillus strain probiotics on the performance, egg quality, and faecal microflora of laying hens. METHODS: A total of 183 Institut de selection Animale (ISA) brown laying hens aged 23 weeks with an average body weight of 1,894±72 g were randomly allocated into 3 groups as control (corn-soybean meal based diet, CON), 0.5 g/kg Enterosure probiotics (ET1, 3×108 colony-forming unit [CFU]/kg feed), and 5 g/kg Enterosure probiotics (ET2, 3×109 CFU/kg feed) administered in mashed form. At the completion of each phase hen day egg production (HDEP), average egg weight (AEW), feed intake, and faecal microbiota were evaluated. RESULTS: HDEP and AEW were higher (p<0.05) in the ET2-supplemented diet in phase 3 (week 9 to 12) compared with CON. Egg mass (EM) was higher (p<0.05) in phase 2 at ET2, and also higher (p<0.05) in phase 3 at the ET1 and ET2-supplemented diets compared with CON. Feed conversion ratio was lower (p<0.05) in phase 3 at the ET1 and ET2-supplemented diets, with ET2 being the lowest compared with ET1 and CON. Yolk colour was higher (p<0.05) in the ET-supplemented diets at phase 3 compared with CON. Bifidobacterium spp. was higher (p<0.05) in the ET2- supplemented diet compared with CON in phase 2, while in In phase 3, Lactobacillus spp. and Bifidobacterium spp. were higher (p<0.05) in the ET-supplemented diets compared with CON. Coliforms were lower (p<0.05) in the ETsupplemented diets compared with CON in phase 3. CONCLUSION: The propriety blends of Bacillus strain probiotics supplements at 0.5 g/kg and 5 g/kg could improve the production and quality of eggs with more significance at 5 g/kg for HDEP, AEW and EM, which was achieved via the increase of beneficial microbiomes such as Lactobacillus spp., Bifidobacterium spp., and the decrease of pathogenic microbiomes like Escherichia coli and Coliforms which was speculated to improve gut barrier function and the reproductive hormone.

Effects of uric acid on ischemic diseases, stratified by lipid levels: a drug-target, nonlinear Mendelian randomization study.

Although uric acid-lowering agents such as xanthine oxidase inhibitors have potential cardioprotective effects, studies on their use in preventing cardiovascular diseases are lacking. We investigated the genetically proxied effects of reducing uric acid on ischemic cardiovascular diseases in a lipid-level-stratified population. We performed drug-target Mendelian randomization (MR) analyses using UK Biobank data to select genetic instruments within a uric acid-lowering gene, xanthine dehydrogenase (XDH), and construct genetic scores. For nonlinear MR analyses, individuals were stratified by lipid level. Outcomes included acute myocardial infarction (AMI), ischemic heart disease, cerebral infarction, transient cerebral ischemic attack, overall ischemic disease, and gout. We included 474,983 non-gout individuals with XDH-associated single-nucleotide polymorphisms. The XDH-variant-induced uric acid reduction was associated with reduced risk of gout (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.78-0.93; P < 0.001), cerebral infarction (OR, 0.86; 95% CI, 0.75-0.98; P = 0.023), AMI (OR, 0.79; 95% CI, 0.66-0.94; P = 0.010) in individuals with triglycerides ≥ 188.00 mg/dL, and cerebral infarction in individuals with low-density lipoprotein cholesterol (LDL-C) ≤ 112.30 mg/dL (OR, 0.76; 95% CI, 0.61-0.96; P = 0.020) or LDL-C of 136.90-157.40 mg/dL (OR, 0.67; 95% CI, 0.49-0.92; P = 0.012). XDH-variant-induced uric acid reduction lowers the risk of gout, AMI for individuals with high triglycerides, and cerebral infarction except for individuals with high LDL-C, highlighting the potential heterogeneity in the protective effects of xanthine oxidase inhibitors for treating AMI and cerebral infarction depending on the lipid profiles.

Intranasal immunization with the recombinant measles virus encoding the spike protein of SARS-CoV-2 confers protective immunity against COVID-19 in hamsters.

BACKGROUND: As the nasal mucosa is the initial site of infection for COVID-19, intranasal vaccines are more favorable than conventional vaccines. In recent clinical studies, intranasal immunization has been shown to generate higher neutralizing antibodies; however, there is a lack of evidence on sterilizing immunity in the upper airway. Previously, we developed a recombinant measles virus encoding the spike protein of SARS-CoV-2 (rMeV-S), eliciting humoral and cellular immune responses against SARS-CoV-2. OBJECTIVES: In this study, we aim to provide an experiment on nasal vaccines focusing on a measles virus platform as well as injection routes. STUDY DESIGN: Recombinant measles viruses expressing rMeV-S were prepared, and 5 × 105 PFUs of rMeV-S were administered to Syrian golden hamsters via intramuscular or intranasal injection. Subsequently, the hamsters were challenged with inoculations of 1 × 105 PFUs of SARS-CoV-2 and euthanized 4 days post-infection. Neutralizing antibodies and RBD-specific IgG in the serum and RBD-specific IgA in the bronchoalveolar lavage fluid (BALF) were measured, and SARS-CoV-2 clearance capacity was determined via quantitative reverse-transcription PCR (qRT-PCR) analysis and viral titer measurement in the upper respiratory tract and lungs. Immunohistochemistry and histopathological examinations of lung samples from experimental hamsters were conducted. RESULTS: The intranasal immunization of rMeV-S elicits protective immune responses and alleviates virus-induced pathophysiology, such as body weight reduction and lung weight increase in hamsters. Furthermore, lung immunohistochemistry demonstrated that intranasal rMeV-S immunization induces effective SARS-CoV-2 clearance that correlates with viral RNA content, as determined by qRT-PCR, in the lung and nasal wash samples, SARS-CoV-2 viral titers in lung, nasal wash, BALF samples, serum RBD-specific IgG concentration, and RBD-specific IgA concentration in the BALF. CONCLUSION: An intranasal vaccine based on the measles virus platform is a promising strategy owing to the typical route of infection of the virus, the ease of administration of the vaccine, and the strong immune response it elicits.

mRNA-HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV-mediated cancers via subcutaneous immunization.

The E6 and E7 proteins of specific subtypes of human papillomavirus (HPV), including HPV 16 and 18, are highly associated with cervical cancer as they modulate cell cycle regulation. The aim of this study was to investigate the potential antitumor effects of a messenger RNA-HPV therapeutic vaccine (mHTV) containing nononcogenic E6 and E7 proteins. To achieve this, C57BL/6j mice were injected with the vaccine via both intramuscular and subcutaneous routes, and the resulting effects were evaluated. mHTV immunization markedly induced robust T cell-mediated immune responses and significantly suppressed tumor growth in both subcutaneous and orthotopic tumor-implanted mouse model, with a significant infiltration of immune cells into tumor tissues. Tumor retransplantation at day 62 postprimary vaccination completely halted progression in all mHTV-treated mice. Furthermore, tumor expansion was significantly reduced upon TC-1 transplantation 160 days after the last immunization. Immunization of rhesus monkeys with mHTV elicited promising immune responses. The immunogenicity of mHTV in nonhuman primates provides strong evidence for clinical application against HPV-related cancers in humans. All data suggest that mHTV can be used as both a therapeutic and prophylactic vaccine.

mRNA vaccine encoding Gn provides protection against severe fever with thrombocytopenia syndrome virus in mice.

We developed a promising mRNA vaccine against severe fever with thrombocytopenia syndrome (SFTS), an infectious disease caused by the SFTS virus that is primarily transmitted through tick bites. Administration of lipid nanoparticle-encapsulated mRNA-Gn successfully induced neutralizing antibodies and T-cell responses in mice. The vaccinated mice were protected against a lethal SFTS virus challenge, suggesting that this mRNA vaccine may be an effective and successful SFTS vaccine candidate.

Exogenous protease influences protein digestibility, growth performance, and gut microflora in weanling pigs on a limited protein diet.

The study was conducted to evaluate the impact of dietary level of crude protein (CP) and protease supplementation on growth performance, digestibility of nutrients, intestinal morphology, and gut microbiota in weaning pigs. Three hundred cross-bred piglets (Duroc × Landrace × Yorkshire) were allotted to five dietary treatments on the basis of initial body weight (BW) and sex. Pigs were group-housed in pens with each treatment with 10 replicate pens with six pigs per pen. The treatments included a standard diet (STD), STD with 0.6% lower protein (STD0.6), STD with 0.6% lower protein and protease supplementation (Pro0.6), STD with 1.0% lower protein (STD1.0), STD with 1.0% lower protein and protease supplementation (Pro1.0). Results indicated a higher BW (p < 0.05) of piglets in the Pro0.6 group at days 0-42 compared to the STD0.6 and STD1.0 groups. The average daily gain was higher (p < 0.05) in the Pro0.6 treatments at days 0-42 compared to the STD0.6 and STD1.0. The gain to feed ratio was higher (p < 0.05) in the STD, and Pro0.6 groups compared to the STD0.6, Pro1.0 and the STD1.0 groups at days 0-42. Dry matter digestibility was lower (p < 0.05) in the STD1.0 group than the Pro0.6 and Pro1.0 groups. The crude protein digestibility was higher (p < 0.05) in the Pro0.6 group compared to the STD, STD0.6 and STD1.0 treatment groups while crude fat digestibility was higher (p < 0.05) in the STD and Pro0.6 compared with the STD0.6 and STD1.0 groups. Digestibility was higher for histidine (p < 0.05), leucine (p < 0.05) in the protease Pro0.6 and Pro1.0 groups than in the STD0.6 and STD1.0 groups. The digestibility of non-essential AA was higher for alanine (p < 0.05) in the Pro0.6 than the STD1.0 group. For faecal microbial population, Faecalibacterium abundance was higher (p < 0.05) in the Pro0.6 compared to all the other groups while the population of Actinobacteria was greater (p < 0.05) in the STD group and lowest in the Pro1.0 treatment. In the ileum, villus height was greater (p < 0.05) in the protease Pro0.6, and Pro1.0 groups compared to the STD0.6, and STD1.0 groups while the villus height to crypts depth ratio was lower (p < 0.05) in the STD 1.0 group compared to the STD, Pro0.6, and Pro1.0 groups. Based on these results, dietary protease supplementation improved nutrient digestibility and gut histo-morphology translating to improved utilisation of nutrients thus positively impacting growth performance in weaned pigs. Further, reducing the CP content in the diets increased the abundance of Muribaculaceae while protease supplementation increased the population of Faecalibacterium in the gut of the weanling piglets on the STD0.6 diet.

Analysis of the immunostimulatory effects of cytokine-expressing internal ribosome entry site-based RNA adjuvants and their applications.

Developing new adjuvants that can effectively induce both humoral and cellular immune responses while broadening the immune response is of great value. In this study, we aimed to develop GM-CSF- or IL-18-expressing single-stranded RNA (ssRNA) adjuvants based on the encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES) and tested their efficacy in combination with ovalbumin (OVA) or inactivated influenza vaccines. Notably, cytokine-expressing RNA adjuvants increased the expression of antigen-presenting cell activation markers. Specifically, GM-CSF-expressing RNA adjuvants increased CD4+T cell responses, while IL-18-expressing RNA adjuvants increased CD8+T cell responses in mice when combined with OVA. In addition, cytokine-expressing RNA adjuvants increased the frequency of polyclonal T cells in combination with the influenza vaccine and reduced the clinical illness scores and weight loss of mice after viral challenge. Collectively, our results suggest that cytokine-expressing RNA adjuvants can be applied to protein-based or inactivated vaccines to increase their efficacy.

Analyzing immune responses to varied mRNA and protein vaccine sequences.

In response to the COVID-19 pandemic, different types of vaccines, such as inactive, live-attenuated, messenger RNA (mRNA), and protein subunit, have been developed against SARS-CoV-2. This has unintentionally created a unique scenario where heterologous prime-boost vaccination against a single virus has been administered to a large human population. Here, we aimed to analyze whether the immunization order of vaccine types influences the efficacy of heterologous prime-boost vaccination, especially mRNA and protein-based vaccines. We developed a new mRNA vaccine encoding the hemagglutinin (HA) glycoprotein of the influenza virus using the 3'-UTR and 5'-UTR of muscle cells (mRNA-HA) and tested its efficacy by heterologous immunization with an HA protein vaccine (protein-HA). The results demonstrated higher IgG2a levels and hemagglutination inhibition titers in the mRNA-HA priming/protein-HA boosting (R-P) regimen than those induced by reverse immunization (protein-HA priming/mRNA-HA boosting, P-R). After the viral challenge, the R-P group showed lower virus loads and less inflammation in the lungs than the P-R group did. Transcriptome analysis revealed that the heterologous prime-boost groups had differentially activated immune response pathways, according to the order of immunization. In summary, our results demonstrate that the sequence of vaccination is critical to direct desired immune responses. This study demonstrates the potential of a heterologous vaccination strategy using mRNA and protein vaccine platforms against viral infection.

Heterologous vaccination utilizing viral vector and protein platforms confers complete protection against SFTSV.

Severe fever with thrombocytopenia syndrome virus was first discovered in 2009 as the causative agent of severe fever with thrombocytopenia syndrome. Despite its potential threat to public health, no prophylactic vaccine is yet available. This study developed a heterologous prime-boost strategy comprising priming with recombinant replication-deficient human adenovirus type 5 (rAd5) expressing the surface glycoprotein, Gn, and boosting with Gn protein. This vaccination regimen induced balanced Th1/Th2 immune responses and resulted in potent humoral and T cell-mediated responses in mice. It elicited high neutralizing antibody titers in both mice and non-human primates. Transcriptome analysis revealed that rAd5 and Gn proteins induced adaptive and innate immune pathways, respectively. This study provides immunological and mechanistic insight into this heterologous regimen and paves the way for future strategies against emerging infectious diseases.

Measurement of craving among gamers with internet gaming disorder using repeated presentations of game videos: a resting-state electroencephalography study.

BACKGROUND: Internet gaming disorder (IGD) is receiving increasing attention owing to its effects on daily living and psychological function. METHODS: In this study, electroencephalography was used to compare neural activity triggered by repeated presentation of a stimulus in healthy controls (HCs) and those with IGD. A total of 42 adult men were categorized into two groups (IGD, n = 21) based on Y-IAT-K scores. Participants were required to watch repeated presentations of video games while wearing a head-mounted display, and the delta (D), theta (T), alpha (A), beta (B), and gamma (G) activities in the prefrontal (PF), central (C), and parieto-occipital (PO) regions were analyzed. RESULTS: The IGD group exhibited higher absolute powers of DC, DPO, TC, TPO, BC, and BPO than HCs. Among the IGD classification models, a neural network achieves the highest average accuracy of 93% (5-fold cross validation) and 84% (test). CONCLUSIONS: These findings may significantly contribute to a more comprehensive understanding of the neurological features associated with IGD and provide potential neurological markers that can be used to distinguish between individuals with IGD and HCs.

Improving Performance of Motor Imagery-based Brain-computer Interface in Poorly Performing Subjects Using a Hybrid-imagery Method utilizing Combined Motor and Somatosensory Activity.

The phenomena of brain-computer interface-inefficiency in transfer rates and reliability can hinder development and use of brain-computer interface technology. This study aimed to enhance the classification performance of motor imagery-based brain-computer interface (three-class: left hand, right hand, and right foot) of poor performers using a hybrid-imagery approach that combined motor and somatosensory activity. Twenty healthy subjects participated in these experiments involving the following three paradigms: (1) Control-condition: motor imagery only, (2) Hybrid-condition I: combined motor and somatosensory stimuli (same stimulus: rough ball), and (3) Hybrid-condition II: combined motor and somatosensory stimuli (different stimulus: hard and rough, soft and smooth, and hard and rough ball). The three paradigms for all participants, achieved an average accuracy of 63.60±21.62%, 71.25±19.53%, and 84.09±12.79% using the filter bank common spatial pattern algorithm (5-fold cross-validation), respectively. In the poor performance group, the Hybrid-condition II paradigm achieved an accuracy of 81.82%, showing a significant increase of 38.86% and 21.04% in accuracy compared to the control-condition (42.96%) and Hybrid-condition I (60.78%), respectively. Conversely, the good performance group showed a pattern of increasing accuracy, with no significant difference between the three paradigms. The Hybrid-condition II paradigm provided high concentration and discrimination to poor performers in the motor imagery-based brain-computer interface and generated the enhanced event-related desynchronization pattern in three modalities corresponding to different types of somatosensory stimuli in motor and somatosensory regions compared to the Control-condition and Hybrid-condition I. The hybrid-imagery approach can help improve motor imagery-based brain-computer interface performance, especially for poorly performing users, thus contributing to the practical use and uptake of brain-computer interface.

Recombinant measles virus encoding the spike protein of SARS-CoV-2 efficiently induces Th1 responses and neutralizing antibodies that block SARS-CoV-2 variants.

Owing to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, the development of effective and safe vaccines has become a priority. The measles virus (MeV) vaccine is an attractive vaccine platform as it has been administered to children for more than 40 years in over 100 countries. In this study, we developed a recombinant MeV expressing the full-length SARS-CoV-2 spike protein (rMeV-S) and tested its efficacy using mouse and hamster models. In hCD46Tg mice, two-dose rMeV-S vaccination induced higher Th1 secretion and humoral responses than one-dose vaccination. Interestingly, neutralizing antibodies induced by one-dose and two-dose rMeV-S immunization effectively blocked the entry of the α, ß, γ, and δ variants of SARS-CoV-2. Furthermore, two-dose rMeV-S immunization provided complete protection against SARS-CoV-2 in the hamster model. These results suggest the potential of rMeV-S as a vaccine candidate for targeting SARS-CoV-2 and its variants.

Modeling Approach with Therapeutic Drug Monitoring Data to Describe Time Course of Clozapine Exposure and Positive and Negative Syndrome Scale Scores.

OBJECTIVE: The Positive and Negative Syndrome Scale (PANSS) is commonly used to assess the severity of the clinical symptoms of schizophrenia (SCZ). This study aimed to develop a pharmacokinetic (PK)/pharmacodynamic (PD) model based on therapeutic drug monitoring (TDM) data to characterize the relationship between clozapine exposure and the PANSS scores in patients with SCZ. METHODS: TDM data for clozapine and PANSS scores from 45 patients with SCZ were included in this modeling analysis using NONMEM. Based on published data, intensive PK sampling data collected up to 12 hours postdose from 23 patients was incorporated into the PK data set to improve the fitting of absorption and disposition. For PD model development, the PANSS score was assessed at baseline, followed by 8 and 18 weeks after the initiation of clozapine dosing. Visual predictive check plots, the precision of parameter estimates, and decreases in the minimum objective function values were used for the model evaluation. RESULTS: A 2-compartment model with an absorption lag and a combined error model adequately described the PK of clozapine. The implementation of disease progression with placebo and drug effects improved the model's ability to describe the time course of the PANSS scores. In the final PK/PD model, Weibull and maximum effect (E max ) models were selected as disease progression models for the placebo and drug effect models, respectively. The model evaluation results supported the adequacy of the final model. CONCLUSIONS: A clozapine PK/PD model based on clinical settings adequately described the PANSS time course in patients with SCZ. These findings may aid the development of treatment strategies for patients with SCZ.

Effects of Temporary Respiration Exercise with Individual Harmonic Frequency on Blood Pressure and Autonomic Balance.

This study investigated the effects of modulated respiration on blood pressure and autonomic balance to develop a healthcare application system for stabilizing autonomic balance. Thirty-two participants were asked to perform self-regulated tasks with 18 different respiration sequences, and their electrocardiograms (ECG) and blood pressure were measured. Changes in cardiovascular system functions and blood pressure were compared between free-breathing and various respiration conditions. Systolic and diastolic blood pressures stabilized after individual harmonic breathing. Autonomic balance, characterized by heart rate variability, was also stabilized with brief respiration training according to harmonic frequency. Five machine-learning algorithms were used to classify the two opposing factors between the free and modulated breathing conditions. The random forest models outperformed the other classifiers in the training data of systolic blood pressure and heart rate variability. The mean areas under the curves (AUCs) were 0.82 for systolic blood pressure and 0.98 for heart rate variability. Our findings lend support that blood pressure and autonomic balance were improved by temporary harmonic frequency respiration. This study provides a self-regulated respiration system that can control and help stabilize blood pressure and autonomic balance, which would help reduce mental stress and enhance human task performance in various fields.

Incorporation of real-world data to a clinical trial: use of external controls.

As real-world data (RWD) becomes more available and the methodology for handling RWD evolves, the use of RWD in drug development and drug approval is drawing interest. One of the ways RWD can be applied to a clinical trial is using an external control, a cohort of patients established separately serving as a control group for the clinical trial's treatment group. Although external controls have the possibility of bias as a result of differences in baseline characteristics between the external control and experimental groups, selecting an appropriate data source and ensuring comparability through proper handling of the data can increase the utility of external controls, raising the efficiency of drug development. This article discusses several topics relevant to using external controls in clinical trials, including the definition of external control, the selection of data sources, the strategy ensuring comparability, current regulatory circumstances, and future directions.

Knowledge-Based Design Algorithm for Support Reduction in Material Extrusion Additive Manufacturing.

Although additive manufacturing (AM) enables designers to develop products with a high degree of design freedom, the manufacturing constraints of AM restrict design freedom. One of the key manufacturing constraints is the use of support structures for overhang features, which are indispensable in AM processes, but increase material consumption, manufacturing costs, and build time. Therefore, controlling support structure generation is a significant issue in fabricating functional products directly using AM. The goal of this paper is to propose a knowledge-based design algorithm for reducing support structures whilst considering printability and as-printed quality. The proposed method consists of three steps: (1) AM ontology development, for characterizing a target AM process, (2) Surrogate model construction, for quantifying the impact of the AM parameters on as-printed quality, (3) Design and process modification, for reducing support structures and optimizing the AM parameters. The significance of the proposed method is to not only optimize process parameters, but to also control local geometric features for a better surface roughness and build time reduction. To validate the proposed algorithm, case studies with curve-based (1D), surface-based (2D), and volume (3D) models were carried out to prove the reduction of support generation and build time while maintaining surface quality.