Cough Response to High-Dose Inhaled Corticosteroids in Patients with Chronic Cough and Fractional Exhaled Nitric Oxide Levels ≥ 25 ppb: A Prospective Study.

This study aimed to investigate the effects of high-dose inhaled corticosteroids (ICS) on chronic cough patients with elevated fractional exhaled nitric oxide (FeNO) levels. In a prospective study, adults with chronic cough and FeNO ≥ 25 ppb, without any other apparent etiology, received fluticasone furoate (200 mcg) for three weeks. Outcomes were evaluated using FeNO levels, cough severity, and Leicester Cough Questionnaire (LCQ) before and after treatment. Of the fifty participants (average age: 58.4 years; 58% female), the treatment responder rate (≥ 1.3-point increase in LCQ) was 68%, with a significant improvement in cough and LCQ scores and FeNO levels post-treatment. However, improvements in cough did not significantly correlate with changes in FeNO levels. These findings support the guideline recommendations for a short-term ICS trial in adults with chronic cough and elevated FeNO levels, but the lack of correlations between FeNO levels and cough raises questions about their direct mechanistic link.

Functional brain network analysis using electroencephalography in late-onset Lennox-Gastaut syndrome.

OBJECTIVE: We aimed to explore the clinical characteristics and functional network properties of patients with late-onset Lennox-Gastaut syndrome (LGS). METHODS: Late-onset LGS was defined by the appearance of LGS features after 8 years of age. We reviewed the medical charts of 9 patients with late-onset LGS, and performed electroencephalography connectivity analysis using graph theory. We assessed the clustering coefficient (CC) and characteristic path length (CPL), which are common basic measures of functional networks that represent local segregation and global integration. The characteristics and brain parameters of late-onset LGS were compared with a typical age-onset LGS group. RESULTS: Late onset LGS subjects were older than typical age onset LGS at the time of testing, but otherwise there were no significant differences in clinical characteristics. The late-onset group showed higher median CC values in the alpha (p = 0.045) and beta (p < 0.001) bands over brain regions implicated in cognitive processing. There were no significant differences in CPL between the LGS groups. CONCLUSIONS: Higher clustering coefficient values, in alpha/beta bands over brain regions implicated in cognitive processing, are consistent with increased cognitive network segregation in late onset LGS compared to typical age-onset LGS. Given network segregation is a normal aspect of brain maturation, these results imply that this process is less disturbed when the LGS process begins later in childhood.

Weight loss impacts risky decisions in obesity.

BACKGROUND & AIMS: Risky decision making is shaped by individual psychological and metabolic state. Individuals with obesity show not only altered risk behavior, but also metabolic and psychological abnormalities. The aim of the present study was to investigate whether a substantial weight loss in individuals with severe obesity will 1) normalize their metabolic and psychological state and 2) will change their pattern of decision guidance. METHODS: We assessed the effect of glycated hemoglobin (HbA1c) and mood on risk behavior in individuals with obesity (n = 62, 41 women; BMI, 46.5 ± 4.8 kg/m2; age, 44.9 ± 14.7 years) before and after 10-weeks weight loss intervention. RESULTS: Results showed that this intervention reduced participants' risk behavior, which was significantly predicted by their changes in BMI. Before intervention, mood, but not HbA1c significantly predicted decisions. After the weight loss, mood no longer, but HbA1c significantly predicted decisions. CONCLUSION: Our findings shed light on the psychological and metabolic mechanisms underlying altered risky decision making in severe obesity and can inform the development of strategies in the context of weight loss interventions.

Inhibitory regulation of FoxO1 in PPARδ expression drives mitochondria dysfunction and insulin resistance.

Forkhead box protein O1 (FoxO1) regulates muscle growth, but the metabolic role of FoxO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FoxO1 in skeletal muscle, we generated skeletal muscle-specific FoxO1 inducible knockout (mFoxO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFoxO1 iKO mice, and assessed the correlation between FoxO1 and mitochondrial-related protein in the skeletal muscle of diabetic patients. Obese mFoxO1 iKO mice exhibited improved mitochondrial respiratory capacity, which was followed by attenuated insulin resistance, enhanced fatty acid oxidation, and improved skeletal muscle exercise capacity. Transcriptional inhibition of FoxO1 in peroxisome proliferator-activated receptor δ (PPARδ) expression was confirmed in skeletal muscle and deletion of PPARδ abolished the beneficial effects of FoxO1 deficiency. FoxO1 protein levels were higher in the skeletal muscle of diabetic patients and negatively correlated with PPARδ and electron transport chain protein levels. These findings highlight FoxO1 as a new repressor in PPARδ gene expression in skeletal muscle and suggest that FoxO1 links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ.

Fear of Sexual Victimization in Metaverse: A Comparison of Adolescent and Adult Female Users.

Metaverse platforms have gained worldwide popularity in recent years. This increase in popularity has also heightened safety concerns, as virtual sexual assault against children and the youth is on the rise. The issue of sexual abuse in the metaverse is becoming increasingly controversial due to the gaps in the current regulatory framework that result from the uncertain consequences of such virtual crimes. Drawing on an online survey of female users of Zepeto (n = 343), a metaverse social network platform where users interact with others while creating personalized avatars and virtual spaces, this study aims to explore how female users interpret the risk of sexual harassment in Zepeto, examining the triggers of emotional distress and behavioral change that result from such risk assessments by users. It investigates how these interpretations and responses vary depending on their sense of presence and engagement in the virtual environment and identification with their avatars and how all these processes differ between adolescent and adult female users. Overall, this study provides insights into the complex dynamics of virtual victimization. The findings could inform the development of regulatory frameworks that protect users from virtual sexual assault and create a safer environment for all users, especially the youngest generations.

HLA-DRB1 is associated with cefaclor-induced immediate hypersensitivity.

Background: Drug-induced hypersensitivity such as anaphylaxis is an important cause of drug-related morbidity and mortality. Cefaclor is a leading cause of drug induced type I hypersensitivity in Korea, but little is yet known about genetic biomarkers to predict this hypersensitivity reaction. We aimed to evaluate the possible involvement of genes in cefaclor induced type I hypersensitivity. Methods: Whole exome sequencing (WES) and HLA genotyping were performed in 43 patients with cefaclor induced type I hypersensitivity. In addition, homology modeling was performed to identify the binding forms of cefaclor to HLA site. Results: Anaphylaxis was the most common phenotype of cefaclor hypersensitivity (90.69%). WES results show that rs62242177 and rs62242178 located in LIMD1 region were genome-wide significant at the 5 × 10-8 significance level. Cefaclor induced type I hypersensitivity was significantly associated with HLA-DRB1∗04:03 (OR 4.61 [95% CI 1.51-14.09], P < 0.002) and HLA-DRB1∗14:54 (OR 3.86 [95% CI 1.09-13.67], P < 0.002). Conclusion: LIMD1, HLA-DRB1∗04:03 and HLA-DRB1∗14:54 may affect susceptibility to cefaclor induced type I hypersensitivity. Further confirmative studies with a larger patient population should be performed to ascertain the role of HLA-DRB1 and LIMD1 in the development of cefaclor induced hypersensitivity.

Lactobacillus plantarum isolated from kimchi regulates inflammation by increasing interleukin-10 secretion by antigen-presenting cells, leading to diminishing of STAT5 phosphorylation in Th2 cells.

The relationship between allergic inflammation and gut microbiota has been elucidated, and the effect of probiotics on immune disorders has been studied as well. Identifying the role of probiotics in individual diseases and immune responses and selecting and applying specific microorganisms based on these findings can be an effective strategy for using probiotics. Herein, lactobacilli isolated from kimchi were investigated in depth, focusing on their immune regulatory effects and the mechanisms involved. Lactic acid bacteria (LAB) effectively diminished the increased secretion of T helper 2 cytokines, such as IL-4, IL-5, and IL-13, from ovalbumin (OVA)-sensitized mouse splenocytes. The gene expression of GATA3, IL-4, IL-5, IL-9, and IL-13 was confirmed to be regulated by LAB. LAB also suppressed IL-2 production and STAT5 phosphorylation. An IL-10-neutralizing antibody attenuated these effects, indicating that LAB-induced upregulation of IL-10 in antigen-presenting cells was responsible at least partially for the increased IL-2 production and STAT5 phosphorylation in CD4+ T cells. In conclusion, the current study identified one immunomodulatory mechanism that allows LAB to regulate allergic immune reactions and the potential of LAB from kimchi to modulate various immune reactions.

Flip the switch: the role of FleQ in modulating the transition between the free-living and sessile mode of growth in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a Gram-negative, opportunistic pathogen causing chronic infections that are associated with the sessile/biofilm mode of growth rather than the free-living/planktonic mode of growth. The transcriptional regulator FleQ contributes to both modes of growth by functioning both as an activator and repressor and inversely regulating flagella genes associated with the planktonic mode of growth and genes contributing to the biofilm mode of growth. Here, we review findings that enhance our understanding of the molecular mechanism by which FleQ enables the transition between the two modes of growth. We also explore recent advances in the mechanism of action of FleQ to both activate and repress gene expression from a single promoter. Emphasis will be on the role of sigma factors, cyclic di-GMP, and the transcriptional regulator AmrZ in inversely regulating flagella and biofilm-associated genes and converting FleQ from a repressor to an activator.

Morphometric Comparison and Prognostic Analysis of Permanent Maxillary Central Incisors with Eruption Disturbances-A Cross-Sectional Study.

AIMS: The aim of this study was to retrospectively compare the morphometrics of permanent maxillary central incisors with and without eruption disturbances, while simultaneously evaluating prognosis based on different factors. MATERIALS AND METHODS: Seventy patients with unilateral permanent maxillary central incisor eruption disturbances were included. Within a group of 70 subjects, measurements were taken for both normally erupted central incisors and central incisors with eruption disturbances to determine the length of the roots and the volume of the teeth. Various factors, such as angulation of impaction, and vertical height of impaction, were assessed to investigate their correlation with surgical intervention. RESULTS: Both the root length and tooth volume were significantly smaller in the eruption disturbance incisors than in the normally erupted incisors (p ≤ 0.001). Moreover, there was a statistically significant increase in surgical intervention among cases with no clear physical barrier (primary retention) (p < 0.05) or when adjacent normally erupted central incisors exhibited more than 2/3 of root development (p < 0.05). CONCLUSIONS: The results of this study numerically demonstrated the delayed tooth development of the permanent maxillary central incisors with unilateral eruption disturbances compared to appropriately erupted incisors by measuring root length and tooth volume. The absence of obstacles and the degree of root development in adjacent erupted incisors might serve as factors for clinicians to determine the necessity and timing of surgical intervention.

Tailored polyhydroxyalkanoate production from renewable non-fatty acid carbon sources using engineered Cupriavidus necator H16.

As thermoplastic, nontoxic, and biocompatible polyesters, polyhydroxyalkanoates (PHAs) are considered promising biodegradable plastic candidates for diverse applications. Short-chain-length/medium-chain-length (SCL/MCL) PHA copolymers are flexible and versatile PHAs that are typically produced from fatty acids, which are expensive and toxic. Therefore, to achieve the sustainable biosynthesis of SCL/MCL-PHAs from renewable non-fatty acid carbon sources (e.g., sugar or CO2), we used the lithoautotrophic bacterium Cupriavidus necator H16 as a microbial platform. Specifically, we synthesized tailored PHA copolymers with varying MCL-3-hydroxyalkanoate (3HA) compositions (10-70 mol%) from fructose by rewiring the MCL-3HA biosynthetic pathways, including (i) the thioesterase-mediated free fatty acid biosynthetic pathway coupled with the beta-oxidation cycle and (ii) the hydroxyacyl transferase-mediated fatty acid de novo biosynthetic pathway. In addition to sugar-based feedstocks, engineered strains are also promising platforms for the lithoautotrophic production of SCL/MCL-PHAs from CO2. The set of engineered C. necator strains developed in this study provides greater opportunities to produce customized polymers with controllable monomer compositions from renewable resources.

Intermittent fasting promotes rejuvenation of immunosenescent phenotypes in aged adipose tissue.

The aging of white adipose tissue (WAT) involves senescence of adipose stem and progenitor cells (ASPCs) and dysregulation of immune cell populations, serving as a major driver of age-associated adipose dysfunction and metabolic diseases. Conversely, the elimination of senescent ASPCs is associated with improvements in overall health. Intermittent fasting (IF), a dietary intervention that incorporates periodic cycles of fasting and refeeding, has been reported to promote weight loss and fat mass reduction and improve glucose and insulin homeostasis in both murine and human studies. While previous studies have assessed the effects of IF on obesity-associated metabolic dysfunction, few studies have examined the aging-specific changes to ASPCs and immune cell populations in WAT. Here, we show that IF in 18-20-month-old mice reduced senescent phenotypes of ASPCs and restored their adipogenic potential. Intriguingly, IF-treated mice exhibited an increase in adipose eosinophils, which has been reported to be associated with improved WAT homeostasis and immunological fitness in aged mice. The observed cellular and metabolic changes suggest that IF may be a feasible lifestyle regimen to reduce cellular senescence which could result in attenuation of downstream aging-induced WAT dysfunction and metabolic diseases.

Characterization of Codeine Treatment Responders Among Patients with Refractory or Unexplained Chronic Cough: A Prospective Real-World Cohort Study.

PURPOSE: Codeine is a narcotic antitussive often considered for managing patients with refractory or unexplained chronic cough. This study aimed to evaluate the proportion and characteristics of patients who responded to codeine treatment in real-world practice. METHODS: Data from the Korean Chronic Cough Registry, a multicenter prospective cohort study, were analyzed. Physicians assessed the response to codeine based on the timing and degree of improvement after treatment initiation. Follow-up assessments included the Leicester Cough Questionnaire and cough severity visual analog scale at six months. In a subset of subjects, objective cough frequency was evaluated following the initiation of codeine treatment. RESULTS: Of 305 patients, 124 (40.7%) responded to treatments based on anatomic diagnostic protocols, while 181 (59.3%) remained unexplained or refractory to etiological treatments. Fifty-one subjects (16.7%) were classified as codeine treatment responders (those showing a rapid and clear response), 57 (18.7%) as partial responders, and 62 (20.3%) as non-responders. Codeine responders showed rapid improvement in objective cough frequency and severity scores within a week of the treatment. At 6 months, responders showed significantly improved scores in cough scores, compared to non-responders. Several baseline parameters were associated with a more favorable treatment response, including older age, non-productive cough, and the absence of heartburn. CONCLUSIONS: Approximately 60% of chronic cough patients in specialist clinics may require antitussive drugs. While codeine benefits some, only a limited proportion (about 20%) of patients may experience rapid and significant improvement. This underscores the urgent need for new antitussive drugs to address these unmet clinical needs.

Consumer acceptability and texture analysis of frozen dumplings using different cooking methods.

Four frozen dumplings were prepared using air-frying, microwaving, pan-frying, and steaming for consumer acceptability and texture perception measure. Cluster analysis was performed and two groups resulted. Neutral consumers who generally rated 'like slightly' and 'neither like nor dislike' were influenced by the combinations of dumpling and cooking methods. Dumpling likers who rated higher than 'like moderately' were influenced by cooking methods. When divided into clusters, each effect was significant. For dumplings, consumers preferred three products over one. Regarding cooking methods, neutral consumers preferred pan-frying and air-frying. However, dumpling likers preferred pan-frying. Chewy, soft, crisp, and sticky characteristics positively influenced on acceptability. In addition, dumpling shells and fillings were analyzed to measure crispness and firmness, respectively, using a texture analyzer. Cooking methods influenced skin crispness but dumplings influenced filling firmness. Although correlation was very low between consumer texture perception and analytical measure, using both would be beneficial in further understanding. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01389-9.

Brain network reconstruction of abnormal functional connectivity in Lennox-Gastaut syndrome according to drug responsiveness: A retrospective study.

OBJECTIVE: Functional network effects of resective or palliative epilepsy surgery in Lennox-Gastaut syndrome (LGS) patients are different according to the seizure outcome. This study aimed to clarify whether the response to antiseizure medications (ASM) can affect to alteration of brain network connectivity. METHODS: In this retrospective study, 37 patients with LGS who underwent 1st electroencephalography (EEG) and 40 healthy controls were enrolled. Among them, 24 LGS patients had follow-up EEG data and were classified as drug responders and non-responders according to the ASM response. Graphical theoretical analysis was used to assess functional connectivity using resting-state EEG. RESULTS: The 1st EEG showed a decreased radius in patients with LGS compared with that in healthy controls (3.987 vs. 4.279, P = 0.003). Follow-up EEG data of patients with LGS revealed significant differences in functional connectivity depending on the ASM response. On follow-up EEG, non-responders (n = 11) demonstrated significant increases in global network parameters, whereas responders (n = 13) showed no significant difference in functional connectivity compared with healthy controls. CONCLUSIONS: The functional connectivity patterns in patients with LGS differed from those in healthy controls. Functional connectivity in drug-responsive patients with LGS tended to preserve the network of brain connections in a pattern similar to that in healthy controls, whereas non-responders showed more disrupted functional connectivity.

Predictors of Early and Late Lung Function Improvement in Severe Eosinophilic Asthma on Type2-Biologics in the PRISM Study.

BACKGROUND: The determinants linked to the short- and long-term improvement in lung function in patients with severe eosinophilic asthma (SEA) on biological treatment (BioT) remain elusive. OBJECTIVE: We sought to identify the predictors of early and late lung function improvement in patients with SEA after BioT. METHODS: 140 adult patients with SEA who received mepolizumab, dupilumab, or reslizumab were followed up for 6 months to evaluate improvement in forced expiratory volume in one second (FEV1). Logistic regression was used to determine the association between potential prognostic factors and improved lung function at 1 and 6 months of treatment. RESULTS: More than a third of patients with SEA using BioT showed early and sustained improvements in FEV1 after 1 month. A significant association was found between low baseline FEV1 and high blood eosinophil count and sustained FEV1 improvement after 1 month (0.54 [0.37-0.79] and 1.88 [1.28-2.97] odds ratios and 95% confidence interval, respectively). Meanwhile, among patients who did not experience FEV1 improvement after 1 month, 39% exhibited improvement at 6 months follow-up. A high ACT score measured at this visit was the most reliable predictor of late response after 6 months of treatment (OR and 95% CI 1.75 [1.09-2.98]). CONCLUSION: Factors predicting the efficacy of biological agents that improve lung function in SEA vary according to the stage of response.

SIRT1-dependent PGC-1α deacetylation by SRT1720 rescues progression of atherosclerosis by enhancing mitochondrial function.

Vascular smooth muscle cell (VSMC) senescence promotes atherosclerosis via lipid-mediated mitochondrial dysfunction and oxidative stress. However, the mechanisms of mitochondrial dysfunction and VSMC senescence in atherosclerosis have not been established. Here, we investigated the mechanisms whereby signaling pathways regulated by SRT1720 enhance or regulate mitochondrial functions in atherosclerotic VSMCs to suppress atherosclerosis. Initially, we examined the effect of SRT1720 on oleic acid (OA)-induced atherosclerosis. Atherosclerotic VSMCs exhibited elevated expressions of BODIPY and ADRP (adipose differentiation-related protein) and associated intracellular lipid droplet markers. In addition, the expression of collagen I was upregulated by OA, while the expressions of elastin and α-SMA were downregulated. mtDNA copy numbers, an ATP detection assay, transmission electron microscopy (TEM) imaging of mitochondria, mitochondria membrane potentials (assessed using JC-1 probe), and levels of mitochondrial oxidative phosphorylation (OXPHOS) were used to examine the effects of SRT1720 on OA-induced mitochondrial dysfunction. SRT1720 reduced mtDNA damage and accelerated mitochondria repair in VSMCs with OA-induced mitochondria dysfunction. In addition, mitochondrial reactive oxygen species (mtROS) levels were downregulated by SRT1720 in OA-treated VSMCs. Importantly, SRT1720 significantly increased SIRT1 and PGC-1α expression levels, but VSMCs senescence, inflammatory response, and atherosclerosis phenotypes were not recovered by treating cells with EX527 and SR-18292 before SRT1720. Mechanistically, the upregulations of SIRT1 and PGC-1α deacetylation by SRT1720 restored mitochondrial function, and consequently suppressed VSMC senescence and atherosclerosis-associated proteins and phenotypes. Collectively, this study indicates that SRT1720 can attenuate OA-induced atherosclerosis associated with VSMC senescence and mitochondrial dysfunction via SIRT1-mediated deacetylation of the PGC-1α pathway.

The KAAACI Guidelines for Sublingual Immunotherapy.

Allergen immunotherapy is regarded as the only disease-modifying treatment option for various allergic conditions, including allergic rhinitis and asthma. Among the routes of administration of allergens, sublingual immunotherapy (SLIT) has gained clinical interest recently, and the prescription of SLIT is increasing among patients with allergies. After 30 years of SLIT use, numerous pieces of evidence supporting its efficacy, safety, and mechanism allows SLIT to be considered as an alternative option to subcutaneous immunotherapy. Based on the progressive development of SLIT, the current guideline from the Korean Academy of Asthma, Allergy, and Clinical Immunology aims to provide an expert opinion by allergy, pediatrics, and otorhinolaryngology specialists with an extensive literature review. This guideline addresses the use of SLIT, including 1) mechanisms of action, 2) appropriate patient selection for SLIT, 3) the currently available SLIT products in Korea, and 4) updated information on its efficacy and safety. This guideline will facilitate a better understanding of practical considerations for SLIT.

Evaluation of the Drug-Induced Liver Injury Potential of Saxagliptin through Reactive Metabolite Identification in Rats.

A liver injury was recently reported for saxagliptin, which is a dipeptidyl peptidase-4 (DPP-4) inhibitor. However, the underlying mechanisms of saxagliptin-induced liver injury remain unknown. This study aimed to evaluate whether saxagliptin, a potent and selective DPP-4 inhibitor that is globally used for treating type 2 diabetes mellitus, binds to the nucleophiles in vitro. Four DPP-4 inhibitors, including vildagliptin, were evaluated for comparison. Only saxagliptin and vildagliptin, which both contain a cyanopyrrolidine group, quickly reacted with L-cysteine to enzyme-independently produce thiazolinic acid metabolites. This saxagliptin-cysteine adduct was also found in saxagliptin-administered male Sprague-Dawley rats. In addition, this study newly identified cysteinyl glycine conjugates of saxagliptin and 5-hydroxysaxagliptin. The observed metabolic pathways were hydroxylation and conjugation with cysteine, glutathione, sulfate, and glucuronide. In summary, we determined four new thiazoline-containing thiol metabolites (cysteine and cysteinylglycine conjugates of saxagliptin and 5-hydroxysaxagliptin) in saxagliptin-administered male rats. Our results reveal that saxagliptin can covalently bind to the thiol groups of cysteine residues of endogenous proteins in vivo, indicating the potential for saxagliptin to cause drug-induced liver injury.