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Background: Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, remarkable advances have been made in vaccine development to reduce mortality. However, therapeutic interventions for COVID-19 are comparatively limited despite these intensive efforts. Furthermore, the rapid mutation capability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a characteristic of its RNA structure, has led to the emergence of multiple variants, necessitating a shift from a predominantly vaccine-centric approach to one that encompasses therapeutic strategies. 6'-Hydroxy justicidin B (6'-HJB), an arylnaphthalene lignan isolated from Justicia procumbens, a traditional Chinese medicine, is known for its antiviral properties., Hypothesis/purpose: The aim of the present study was to assess the effectiveness and safety of 6'-HJB against SARS-CoV-2 in order to determine its potential as a therapeutic agent against COVID-19., Methods: The efficacy of 6'-HJB was evaluated both in vitro using Vero and Calu-3 cell lines and in vivo using ferrets. The safety assessment included toxicokinetics, safety pharmacology, and Good Laboratory Practice (GLP)-compliant toxicity evaluations following single- and repeated-dose toxicity studies in dogs., Results: The anti-SARS-CoV-2 efficacy of 6'-HJB was evaluated through dose-response curve (DRC) analysis using immunofluorescence; 6'-HJB demonstrated superior inhibition of SARS-CoV-2 growth and lower cytotoxicity than remdesivir. In SARS-CoV-2-infected ferret, 6'-HJB showed efficacy comparable to that of the positive control, Truvada. Further GLP toxicity studies corroborated the safety profile of 6'-HJB. Single-dose and 4-week repeated oral toxicity studies in Beagle dogs demonstrated minimal harmful effects at the highest dosages. The lethal dose of 6'-HJB exceeded 2,000 mg kg -1 in Beagle dogs. Toxicokinetic and GLP safety pharmacology studies demonstrated no adverse effects of 6'-HJB on metabolic processes, respiratory or central nervous systems, or cardiac functions., Conclusion: This research highlights both the antiviral efficacy and safety profile of 6'-HJB, underscoring its potential as a novel COVID-19 treatment option. The potential of 6'-HJB was demonstrated using modern scientific methodologies and standards., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Patients with respiratory disease often need oxygen supplements through a High-flow nasal cannula (HFNC), both hypoxia and hyperoxia can be harmful. Proper oxygen therapy requires careful monitoring of oxygen levels and adjustments to oxygen levels. A new automated system called Targeted SpO2 Feedback (TSF) improved the oxygen delivery system compared to manual adjustments. [Correction added on 25 October 2024, after first online publication: Background subsection in Abstract has been added on this version.] AIM: To test whether targeted SpO2 feedback (TSF), an automatic control system for fraction of inspired oxygen (FiO2), achieves more time in the optimal SpO2 range and/or reduces the frequency of manual adjustments to administered FiO2 compared with conventional manual titration in patients with hypoxia on high-flow nasal cannula (HFNC) therapy., Study Design: Twenty-two patients were recruited from two hospitals. For each, two sessions of manual mode and two sessions of TSF were applied in a random order, each session lasting 2 h. The target SpO2 on TSF was 95%. Oxygen monitoring levels were classified into four SpO2 ranges: hypoxia (≤ 89%), borderline (90%-93%), optimal (94%-96%) and hyperoxia (≥ 97%). The two modes were compared based on the proportion of time spent in each SpO2 range and the number of manual FiO2 adjustments., Results: The proportion of time in the optimal SpO2 range was 20.5% under manual titration mode and 65.4% under TSF (p < .01). The proportions of time in the hypoxia range were 1.1% and 0.4%, respectively (p = .31), in the borderline range 4.7% and 3.5%, respectively (p = .54), and in the hyperoxia range 73.7% and 30.7%, respectively (p < .01). There were statistical differences only in the optimal and hyperoxia SpO2 ranges. During the 8 h, the frequency of manual FiO2 adjustment was 0.7 times for the manual mode and 0.2 times for TSF, showing no statistically significant difference (p = 0.076)., Conclusion: Compared with manual titration, TSF achieved greater time of the optimal SpO2 and less time of hyperoxia during HFNC. The frequency of manual adjustments on TSF tended to be less than on manual titration mode., Relevance to Clinical Practice: Automatic closed-loop algorithm FiO2 monitoring systems can achieve better oxygen treatments than conventional monitoring and may reduce nurse workloads. In the era of pandemic respiratory diseases, this system can also facilitate contactless SpO2 monitoring during HFNC therapy., (© 2024 British Association of Critical Care Nurses.)

Objectives: To identify preoperative breast MR imaging and clinicopathological variables related to recurrence and develop a risk prediction model for recurrence in young women with breast cancer treated with upfront surgery., Methods: This retrospective study analyzed 438 consecutive women with breast cancer aged 35 years or younger between January 2007 and December 2016. Breast MR images before surgery were independently reviewed by breast radiologists blinded to patient outcomes. The clinicopathological data including patient demographics, clinical features, and tumor characteristics were reviewed. Univariate and multivariate logistic regression analyses were used to identify the independent factors associated with recurrence. The risk prediction model for recurrence was developed, and the discrimination and calibration abilities were assessed., Results: Of 438 patients, 95 (21.7%) developed recurrence after a median follow-up of 65 months. Tumor size at MR imaging (HR = 1.158, p = 0.006), multifocal or multicentric disease (HR = 1.676, p = 0.017), and peritumoral edema on T2WI (HR = 2.166, p = 0.001) were identified as independent predictors of recurrence, while adjuvant endocrine therapy (HR = 0.624, p = 0.035) was inversely associated with recurrence. The prediction model showed good discrimination ability in predicting 5-year recurrence (C index, 0.707 in the development cohort; 0.686 in the validation cohort) and overall recurrence (C index, 0.699 in the development cohort; 0.678 in the validation cohort). The calibration plot demonstrated an excellent correlation (concordance correlation coefficient, 0.903)., Conclusion: A prediction model based on breast MR imaging and clinicopathological features showed good discrimination to predict recurrence in young women with breast cancer treated with upfront surgery, which could contribute to individualized risk stratification., Clinical Relevance Statement: Our prediction model, incorporating preoperative breast MR imaging and clinicopathological features, predicts recurrence in young women with breast cancer undergoing upfront surgery, facilitating personalized risk stratification and informing tailored management strategies., Key Points: Younger women with breast cancer have worse outcomes than those diagnosed at more typical ages. The described prediction model showed good discrimination performance in predicting 5-year and overall recurrence. Incorporating better risk stratification tools in this population may help improve outcomes., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Background: The effects of age at HBsAg seroclearance on clinical outcomes and survival in chronic hepatitis B (CHB) have not been adequately assessed. We evaluated the impact of age at HBsAg seroclearance on long-term outcomes, along with how coexisting factors modified risks and life expectancy in CHB patients., Methods: We used multi-state modeling approach to examine transitions through the CHB continuum in a longitudinal cohort study of male civil servants recruited in 1989-1992. Hepatic outcomes and deaths were identified by clinical evaluation and linkage with national health databases. Four sets of risk factors (CHB-related, metabolic, lifestyle, and genetic factors) were assessed., Results: Of 2551 HBsAg carriers, with follow-up until 2021 or death, 695 achieved HBsAg seroclearance, 490 developed cirrhosis (88 decompensated), 252 developed hepatocellular carcinoma (HCC), and 652 died. The cumulative rates for HCC were 1.1% and 1.5% at 10 years after HBsAg seroclearance, respectively, for patients achieving seroclearance at age 50 and 60; correspondingly, the rates for cirrhosis were 2.3% and 3.0%. Developing HBsAg seroclearance was associated with a reduced risk of cirrhosis (HR = 0.37, 95% CI 0.15-0.92) but not HCC. Patients experiencing HBsAg seroclearance lived longer years free of major liver diseases than HBsAg-persistent patients, and achieving seroclearance at age 50 (vs 60) led to a greater increase in the disease-free life expectancy. However, obesity and smoking were associated with adverse hepatic outcomes and loss of the disease-free life expectancy following HBsAg seroclearance., Conclusions: Our findings highlight the benefit of earlier HBsAg seroclearance for gains in disease-free life expectancy and the impact of obesity and smoking on loss of the life years free of major liver diseases following HBsAg seroclearance., (© 2024. Japanese Society of Gastroenterology.)

Background: The optimal duration of dual antiplatelet therapy (DAPT) in patients with chronic kidney disease undergoing percutaneous coronary intervention (PCI), especially with third-generation drug-eluting stents (DES), remains unknown., Methods and Results: We conducted a prespecified post hoc analysis of the HOST-IDEA trial, randomizing patients undergoing PCI with third-generation DES to 3- to 6-month or 12-month DAPT. In all, 1,997 patients were grouped by their estimated glomerular filtration rate (eGFR): high (>90 mL/min/1.73 m 2 ), intermediate (60-90 mL/min/1.73 m 2 ), and low (<60 mL/min/1.73 m 2 ). The primary outcome was net adverse clinical events (NACE), a composite of cardiac death, target vessel myocardial infarction, clinically driven target lesion revascularization, stent thrombosis, or major bleeding (Bleeding Academic Research Consortium Type 3 or 5) at 12 months. Secondary outcomes were target lesion failure (TLF) and major bleeding. The low eGFR group had the highest rates of NACE, TLF, and major bleeding compared with the other 2 groups (P<0.001). Rates of NACE were similar in the 3- to 6-month and 12-month DAPT in the high (2.9% vs. 3.2%; P=0.84), intermediate (2.1% vs. 2.8%, P=0.51), and low (8.9% vs. 9.1%; hazard ratio 0.99; P=0.97; P interaction =0.88) eGFR groups. TLF and major bleeding events showed similar trends., Conclusions: In patients undergoing PCI with third-generation DES, 3- to 6-month DAPT was comparable to 12-month DAPT for clinical outcomes regardless of renal function.

Purpose: To evaluate the diagnostic value of 16α- 18 F-fluoro-17β-fluoroestradiol ( 18 F-FES) PET/CT for distant metastasis or recurrence in patients with estrogen receptor (ER)-positive breast cancer., Methods: Patients with ER-positive breast cancer and suspected of de novo metastasis or recurrence were retrospectively identified from a prospective cohort enrolled for a postmarketing surveillance study of 18 F-FES at our institution. Per-patient diagnostic accuracy was assessed using pathology or 2 or more standard-of-care imaging procedures with a minimum of 6 months of follow-up as the reference standard. The per-region detection rate of 18 F-FES PET/CT was evaluated and compared with that of standard-of-care imaging., Results: Of the 162 included patients, 104 and 58 were suspected to have recurrence or de novo metastasis, respectively. The overall sensitivity and specificity of 18 F-FES PET/CT were 95% (95% confidence interval [CI], 89%-98%) and 89% (95% CI, 76%-96%), respectively. When stratified according to clinical settings, the sensitivity and specificity were 95% (95% CI, 88%-99%) and 96% (95% CI, 78%-100%), respectively, for detecting recurrence, and 94% (95% CI, 81%-99%) and 82% (95% CI, 60%-95%) for detecting distant metastasis. In region-based analysis, the overall detection rate of 18 F-FES PET/CT was significantly higher than that of standard-of-care imaging (92% [95% CI, 89%-94%] vs 83% [95% CI, 79%-87%], P < 0.001)., Conclusions: 18 F-FES PET/CT showed excellent diagnostic performance in patients with ER-positive breast cancer suspected of de novo metastasis or recurrence., Competing Interests: Conflicts of interest and sources of funding: none declared. This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HR18C0016), and by a fund from the research program of the Korea Medical Institute., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Chronic cough is a common symptom encountered by healthcare practitioners. The global prevalence of chronic cough is 9.6%, with a female predominance. The aim of our study is to reveal the sex differences in prevalence and severity of chronic cough in South Korea, stratified by age and etiology., Methods: This study included adult patients with chronic cough who were recruited from 19 respiratory centers in South Korea. Patients completed the cough numeric rating scale (NRS) and COugh Assessment Test (COAT) questionnaire to assess the severity and multidimensional impact of cough., Results: Among the 625 patients, 419 (67.0%) were females, with a male-to-female ratio of 1:2.03. The mean age was 49.4 years, and the median duration of cough was 12 weeks. The mean NRS and COAT scores were 5.5 ± 1.8 and 9.5 ± 3.6, respectively. Female patients were older (45.3 ± 15.4 vs. 51.6 ± 15.2, P < 0.001) and more likely to have asthma/cough variant asthma (CVA) (26.7% vs. 40.8%, P = 0.001) than male patients. There was no difference in the duration or severity of cough between sexes, regardless of the cause. The male-to-female ratio was lower for upper airway cough syndrome (UACS), asthma/CVA, and gastro-esophageal reflux disease (GERD), but not for eosinophilic bronchitis (EB) or unexplained cough. The mean age of female patients was higher in UACS and asthma/CVA, but not in EB, GERD, or unexplained cough. The majority (24.2%) fell within the age category of 50s. The proportion of females with cough increased with age, with a significant rise in the 50s, 60s, and 70-89 age groups. The severity of cough decreased in the 50s, 60s, and 70-89 age groups, with no significant sex differences within the same age group., Conclusion: The sex disparities in prevalence and severity of cough varied significantly depending on the age category and etiology. Understanding the specific sex-based difference could enhance comprehension of cough-related pathophysiology and treatment strategies., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

In this study, a mixture of Platycodon grandiflorum , Pyrus serotina , Chaenomeles sinensis , and Raphanus sativus (PPCRE) was investigated for their immuno-enhancing effects, as well as the molecular mechanism of PPCRE in RAW264.7 cells. PPCRE dramatically increased nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) generation depending on the concentration while exhibiting no cytotoxicity. PPCRE markedly upregulated the mRNA and protein expression of immune-related cytotoxic factors such as cyclooxygenase (COX)-1, COX-2, and inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α), as well as the mRNA level of IL-4 . PPCRE increased the mitogen-activated protein kinase (MAPK) signaling pathway by upregulating the phosphorylation of extracellular signal-regulated kinase (ERK), stress-activated protein kinase/Jun N-terminal-kinase (SAPK/JNK), and p38. Furthermore, PPCRE considerably activated the nuclear factor kappa B (NF-κB) signaling pathway by increasing phosphorylation of NF-κB-p65. PPCRE-stimulated RAW264.7 cells increased macrophage phagocytic capacity. In conclusion, our study found that PPCRE improved immune function by modulating inflammatory mediators and regulating the MAPK and NF-κB pathway of signaling in macrophages.

Background: Cough severity represents an important endpoint to assess the impact of therapies for patients with refractory chronic cough (RCC)., Objective: To develop a new patient-reported outcome measure addressing cough severity in patients with RCC., Methods: Phase 1 (item generation): A systematic survey, focus groups, and expert consultation generated 51 items. Phase 2 (item reduction): From a list of 51 items, 100 patients identified those they had experienced in the previous year and rated their importance on a 5-point scale. The MCSQ included items reported to occur most frequently and that had the highest importance scores. Patient feedback on the MCSQ led to elimination of redundant items. Another 100 patients completed the MCSQ, from which we performed an exploratory factor analysis and a Rasch analysis to further refine items on the MCSQ., Results: Phase 2 led to selection of 15 items from the initial 51. Patient feedback on the 15 items led to elimination of 5 redundant items. An exploratory factor analysis of the 10-item MCSQ led to selection of two domains, elimination of one item that demonstrated cross-loading, and another that had high inter-item correlations. A Rasch analysis of the 8-item MCSQ confirmed that the response options functioned in a logically progressive manner and that no items exhibited differential item functioning. The final 8-item MCSQ has a one-week recall period and includes two domains (intensity and frequency). The 8-item MCSQ had high internal consistency (Cronbach's alpha, 0.89), proved able to distinguish different levels of cough severity (Pearson separation index, 0.89), and demonstrated high cross-sectional convergent validity (Pearson's correlation, 0.76 [95% CI 0.66 to 0.83]) with the 100-mm cough severity visual analogue scale., Conclusion: Initial evidence supports the validity of the MCSQ, an 8-item instrument measuring cough severity in patients with RCC. Future studies should evaluate its properties in measuring change over time., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Effective antihypertensive therapy is essential for achieving optimal blood pressure (BP) control and reducing cardiovascular events. This double-blind, multicenter, randomized trial aimed to compare the antihypertensive efficacy and safety of a combination of amlodipine (AML) and candesartan cilexetil (CC) versus AML monotherapy in patients with essential hypertension (HTN). After a 4-week run-in period with AML 5 mg, patients whose HTN remained uncontrolled (diastolic BP [DBP]) ≥ 90 mmHg and < 120 mmHg) were randomized to receive either AML + CC or AML alone for 8 weeks. Efficacy was assessed by measuring changes in DBP and systolic BP (SBP). The primary safety measure was the incidence of adverse events (AEs). A total of 174 participants were included in the efficacy analysis. After 8 weeks, DBP decreased by -9.92 ± 0.86 mmHg in the AML + CC arm and - 2.08 ± 0.86 mmHg in the AML arm (p < 0.0001). SBP decreased by -14.27 ± 1.39 mmHg in the AML + CC arm versus - 2.77 ± 1.39 mmHg in the AML arm (p < 0.0001). AEs occurred in 11.24% of the AML + CC group and 5.62% of the AML group (p = 0.1773). AML + CC combination therapy demonstrated superior efficacy with good tolerance, making it a promising option for patients with inadequately controlled hypertension on amlodipine alone., (© 2024. The Author(s).)

The Long Life Family Study (LLFS) enrolled 4953 participants in 539 pedigrees displaying exceptional longevity. To identify genetic mechanisms that affect cardiovascular risks in the LLFS population, we developed a multi-omics integration pipeline and applied it to 11 traits associated with cardiovascular risks. Using our pipeline, we aggregated gene-level statistics from rare-variant analysis, GWAS, and gene expression-trait association by Correlated Meta-Analysis (CMA). Across all traits, CMA identified 64 significant genes after Bonferroni correction (p ≤ 2.8 × 10 -7 ), 29 of which replicated in the Framingham Heart Study (FHS) cohort. Notably, 20 of the 29 replicated genes do not have a previously known trait-associated variant in the GWAS Catalog within 50 kb. Thirteen modules in Protein-Protein Interaction (PPI) networks are significantly enriched in genes with low meta-analysis p-values for at least one trait, three of which are replicated in the FHS cohort. The functional annotation of genes in these modules showed a significant over-representation of trait-related biological processes including sterol transport, protein-lipid complex remodeling, and immune response regulation. Among major findings, our results suggest a role of triglyceride-associated and mast-cell functional genes FCER1A, MS4A2, GATA2, HDC, and HRH4 in atherosclerosis risks. Our findings also suggest that lower expression of ATG2A, a gene we found to be associated with BMI, may be both a cause and consequence of obesity. Finally, our results suggest that ENPP3 may play an intermediary role in triglyceride-induced inflammation. Our pipeline is freely available and implemented in the Nextflow workflow language, making it easily runnable on any compute platform ( https://nf-co.re/omicsgenetraitassociation )., (© 2024. The Author(s).)

Objective: Patients with symptomatic lower extremity arterial disease (LEAD) are recommended to receive antiplatelet therapy, while direct oral anticoagulants (DOACs) are standard for stroke prevention in patients with atrial fibrillation (AF). For patients with concomitant LEAD and AF, data comparing dual antithrombotic therapy (an antiplatelet agent used in conjunction with a DOAC) vs. DOAC monotherapy are scarce. This retrospective cohort study, based on data from the Taiwan National Health Insurance Research Database, aimed to compare the efficacy and safety of these antithrombotic strategies., Methods: Patients with AF who underwent revascularisation for LEAD between 2012 - 2020 and received any DOAC within 30 days of discharge were included. Patients were grouped by antiplatelet agent exposure into the dual antithrombotic therapy and DOAC monotherapy groups. Inverse probability of treatment weighting was used to mitigate selection bias. Major adverse limb events (MALEs), ischaemic stroke or systemic embolism, and bleeding outcomes were compared. Patients were followed until the occurrence of any study outcome, death, or up to two years., Results: A total of 1 470 patients were identified, with 736 in the dual antithrombotic therapy group and 734 in the DOAC monotherapy group. Among them, 1 346 patients received endovascular therapy as the index revascularisation procedure and 124 underwent bypass surgery. At two years, dual antithrombotic therapy was associated with a higher risk of MALEs than DOAC monotherapy (subdistribution hazard ratio [SHR] 1.34, 95% confidence interval [CI] 1.15 - 1.56), primarily driven by increased repeat revascularisation. Dual antithrombotic therapy was also associated with a higher risk of major bleeding (SHR 1.43, 95% CI 1.05 - 1.94) and gastrointestinal bleeding (SHR 2.17, 95% CI 1.42 - 3.33) than DOAC monotherapy., Conclusion: In patients with concomitant LEAD and AF who underwent peripheral revascularisation, DOAC monotherapy was associated with a lower risk of MALEs and bleeding events than dual antithrombotic therapy., (Copyright © 2024 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Objectives: To evaluate the use of a commercial artificial intelligence (AI)-based mammography analysis software for improving the interpretations of breast ultrasound (US)-detected lesions., Methods: A retrospective analysis was performed on 1109 breasts that underwent both mammography and US-guided breast biopsy. The AI software processed mammograms and provided an AI score ranging from 0 to 100 for each breast, indicating the likelihood of malignancy. The performance of the AI score in differentiating mammograms with benign outcomes from those revealing cancers following US-guided breast biopsy was evaluated. In addition, prediction models for benign outcomes were constructed based on clinical and imaging characteristics with and without AI scores, using logistic regression analysis., Results: The AI software had an area under the receiver operating characteristics curve (AUROC) of 0.79 (95% CI, 0.79-0.82) in differentiating between benign and cancer cases. The prediction models that did not include AI scores (non-AI model), only used AI scores (AI-only model), and included AI scores (integrated model) had AUROCs of 0.79 (95% CI, 0.75-0.83), 0.78 (95% CI, 0.74-0.82), and 0.85 (95% CI, 0.81-0.88) in the development cohort, and 0.75 (95% CI, 0.68-0.81), 0.82 (95% CI, 0.76-0.88), and 0.84 (95% CI, 0.79-0.90) in the validation cohort, respectively. The integrated model outperformed the non-AI model in the development and validation cohorts (p < 0.001 for both)., Conclusion: The commercial AI-based mammography analysis software could be a valuable adjunct to clinical decision-making for managing US-detected breast lesions., Clinical Relevance Statement: The commercial AI-based mammography analysis software could potentially reduce unnecessary biopsies and improve patient outcomes., Key Points: • Breast US has high rates of false-positive interpretations. • A commercial AI-based mammography analysis software could distinguish mammograms having benign outcomes from those revealing cancers after US-guided breast biopsy. • A commercial AI-based mammography analysis software may improve interpretations for breast US-detected lesions., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may have neuroprotective effects in patients with type 2 diabetes (T2D). However, their comparative effectiveness in preventing dementia remains uncertain., Objective: To compare the risk for dementia between SGLT2 inhibitors and dulaglutide (a GLP-1 RA)., Design: Target trial emulation study., Setting: Nationwide health care data of South Korea obtained from the National Health Insurance Service between 2010 and 2022., Patients: Patients aged 60 years or older who have T2D and are initiating treatment with SGLT2 inhibitors or dulaglutide., Measurements: The primary outcome was the presumed clinical onset of dementia. The date of onset was defined as the year before the date of dementia diagnosis, assuming that the time between the onset of dementia and diagnosis was 1 year. The 5-year risk ratios and risk differences comparing SGLT2 inhibitors with dulaglutide were estimated in a 1:2 propensity score-matched cohort adjusted for confounders., Results: Overall, 12 489 patients initiating SGLT2 inhibitor treatment (51.9% dapagliflozin and 48.1% empagliflozin) and 1075 patients initiating dulaglutide treatment were included. In the matched cohort, over a median follow-up of 4.4 years, the primary outcome event occurred in 69 participants in the SGLT2 inhibitor group and 43 in the dulaglutide group. The estimated risk difference was -0.91 percentage point (95% CI, -2.45 to 0.63 percentage point), and the estimated risk ratio was 0.81 (CI, 0.56 to 1.16)., Limitation: Residual confounding is possible; there was no adjustment for hemoglobin A 1c levels or duration of diabetes; the study is not representative of newer drugs, including more effective GLP-1 RAs; and the onset of dementia was not measured directly., Conclusion: Under conventional statistical criteria, a risk for dementia between 2.5 percentage points lower and 0.6 percentage point greater for SGLT2 inhibitors than for dulaglutide was estimated to be highly compatible with the data from this study. However, whether these findings generalize to newer GLP-1 RAs is uncertain. Thus, further studies incorporating newer drugs within these drug classes and better addressing residual confounding are required., Primary Funding Source: Ministry of Food and Drug Safety of South Korea., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-3220.

Purpose: We determined the cough counts and their variability in subjects with persistent cough for 30 days., Methods: The Hyfe cough tracker app uses the mobile phone microphone to monitor sounds and recognizes cough with artificial intelligence-enabled algorithms. We analyzed the daily cough counts including the daily predictability rates of 97 individuals who monitored their coughs over 30 days and had a daily cough rate of at least 5 coughs per hour., Results: The mean (median) daily cough rates varied from 6.5 to 182 (6.2 to 160) coughs per hour, with standard deviations (interquartile ranges) varying from 0.99 to 124 (1.30 to 207) coughs per hour among all subjects. There was a positive association between cough rate and variability, as subjects with higher mean cough rates (OLS) have larger standard deviations. The accuracy of any given day for predicting all 30 days is the One Day Predictability for that day, defined as the percentage of days when cough frequencies fall within that day's 95% confidence interval. Overall Predictability was the mean of the 30-One Day Predictability percentages and ranged from 95% (best predictability) to 30% (least predictability)., Conclusion: There is substantial within-day and day-to-day variability for each subject with persistent cough recorded over 30 days. If confirmed in future studies, the clinical significance and the impact on the use of cough counts as a primary end-point of cough interventions of this variability need to be assessed., (© 2024. The Author(s).)

Microscopic cell detection is a challenging task due to significant inter-cell occlusions in dense clusters and diverse cell morphologies. This paper introduces a novel framework designed to enhance automated cell detection. The proposed approach integrates a deep learning model that produces an inverse distance transform-based detection map from the given image, accompanied by a secondary network designed to regress a cell density map from the same input. The inverse distance transform-based map effectively highlights each cell instance in the densely populated areas, while the density map accurately estimates the total cell count in the image. Then, a custom counting-aided cell center extraction strategy leverages the cell count obtained by integrating over the density map to refine the detection process, significantly reducing false responses and thereby boosting overall accuracy. The proposed framework demonstrated superior performance with F-scores of 96.93%, 91.21%, and 92.00% on the VGG, MBM, and ADI datasets, respectively, surpassing existing state-of-the-art methods. It also achieved the lowest distance error, further validating the effectiveness of the proposed approach. These results demonstrate significant potential for automated cell analysis in biomedical applications.

Soft actuators have assumed vital roles in a diverse number of research and application fields, driving innovation and transformative advancements. Using 3D molding of smart materials and combining these materials through structural design strategies, a single soft actuator can achieve multiple functions. However, it is still challenging to realize soft actuators that possess high environmental adaptability while capable of different tasks. Here, the response threshold of a soft actuator is modulated by precisely tuning the ratio of stimulus-responsive groups in hydrogels. By combining a heterogeneous bilayer membrane structure and in situ multimaterial printing, the obtained soft actuator deformed in response to changes in the surrounding medium. The response medium is suitable for both biotic and abiotic environments, and the response rate is fast. By changing the surrounding medium, the precise capture, manipulation, and release of micron-sized particles of different diameters in 3D are realized. In addition, static capture of a single red blood cell is realized using biologically responsive medium changes. Finally, the experimental results are well predicted using finite element analysis. It is believed that with further optimization of the structure size and autonomous navigation platform, the proposed soft microactuator has significant potential to function as an easy-to-manipulate multifunctional robot., (© 2024 The Authors. Small published by Wiley‐VCH GmbH.)

Objective: Downregulation of N-myc downstream-regulated gene 2 (NDRG2), a tumor suppressor gene, has been associated with poor clinical outcomes in various cancers. However, the prognostic significance of NDRG2 in oral squamous cell carcinoma (OSCC) remains unknown. This study aimed to evaluate the prognostic value of NDRG2 downregulation in OSCC and to elucidate the mechanism by which NDRG2 is downregulated and the biological role of NDRG2 in tumor progression., Methods: Immunohistochemical and in silico analyses of NDRG2 expression were performed, and the correlation between NDRG2 expression and clinicopathological data was analyzed. The effect of NDRG2 knockdown on the biological behavior of OSCC cells was investigated and the effect of 5-aza-2'-deoxycytidine (5-aza-dC) on NDRG2 expression was determined., Results: NDRG2 expression was significantly downregulated and DNA hypermethylation of NDRG2 was frequently found in head and neck SCC, including OSCC. Low NDRG2 expression was significantly correlated with adverse clinicopathological features and worse survival in OSCC. NDRG2 knockdown could enhance the oncogenic properties of OSCC cells. NDRG2 mRNA levels in OSCC cells could be restored by 5-aza-dC., Conclusion: Downregulation of NDRG2 promotes tumor progression and predicts poor prognosis in OSCC. Therefore, restoration of NDRG2 expression may be a potential therapeutic strategy in OSCC., (© 2024 Wiley Periodicals LLC.)

Purpose: Although diffusion-weighted imaging (DWI) with ultra-high b-values is reported to be advantageous in the detection of some tumors, its applicability is not yet known in biliary malignancy. Therefore, this study aimed to evaluate the impact of measured b = 1400 s/mm 2 (M1400) and calculated b = 1400 s/mm 2 (C1400) DWI on image quality and quality of lesion discernibility using a modern 3T MR system compared to conventional b = 800 s/mm 2 DWI (M800)., Methods: We evaluated 56 patients who had pathologically proven biliary malignancy. All the patients underwent preoperative or baseline 3T MRI using DWI (b = 50, 400, 800, and 1400 s/mm 2 ). The calculated DWI was obtained using a conventional DWI set (b = 50, 400, and 800). The tumor-to-bile contrast ratio (CR) and tumor SNR were compared between the different DWI images. Likert scores were given on a 5-point scale to assess the overall image quality, overall artifacts, ghost artifacts, misregistration artifacts, margin sharpness, and lesion discernibility. Repeated-measures analysis of variance with post hoc analyses was used for statistical evaluations., Results: The CR of the tumor-to-bile was significantly higher in both M1400 and C1400 than in M800 (P a < 0.01). SNRs were significantly higher in M800, followed by C1400 and M1400 (P a < 0.01). Lesion discernibility was significantly improved for M1400, followed by C1400 and M800 for both readers (P a < 0.01)., Conclusion: Using a 3T MRI, both measured and calculated DWI with an ultra-high b-value offer superior lesion discernibility for biliary malignancy compared to the conventional DWI.

Background: Limited data are available on the prescription patterns and efficacy of antitussives and expectorants for patients with acute and chronic cough. This study examined the use and efficacy of these medications in a nationally representative sample of Korean patients., Methods: We examined 4,206,016 individuals from the National Health Insurance Service (NHIS)-National Health Information Database (NHID) between 2015 and 2017. Among them, a sample of 10% (n=420,602) was retrieved for the diagnosis of respiratory diseases using the International Classification of Diseases, 10 th edition (ICD-10; J00-J99), or the prescription of antitussives and expectorants for cough (ICD-10; R05). The acute cough group included those who were prescribed medications within 4 weeks of initial diagnosis (prescription within 14 days), whereas the chronic cough group included patients who were prescribed medications within 16 weeks of initial diagnosis (prescription within 56 days). If the prescription was discontinued or not changed to an alternative drug after the initial prescription, these cases were considered to have achieved symptom relief., Results: This study included 288,460 patients (971,065 cases) with acute cough and 5,888 patients (15,399 cases) with chronic cough. 'Expectorants, excluding combinations with cough suppressants' had the highest prescription rates in both groups (acute cough, 63.8%; chronic cough, 61.7%), and showed the highest symptom relief regardless of the number of medications prescribed (acute cough, 84.3%; chronic cough, 70.4%)., Conclusions: 'Expectorants, excluding combinations with cough suppressants' were the most prescribed and effective medications for relieving cough symptoms in Korea patients. Further studies are needed to determine the optimal duration for using antitussives and expectorants in cough management., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1744/coif). The series “Cough Section” was commissioned by the editorial office without any funding or sponsorship. W.J.S. served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Journal of Thoracic Disease. The authors have no other conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Background: Disease control in chronic diseases is an overarching concept that reflects the degree to which the goals of therapy are met. However, to date, there is no consensus on the definition of disease control in chronic cough. This study aimed to provide a conceptual exploration of patient-reported cough control in chronic cough., Methods: This research is comprised of two subanalyses. First, patients with chronic cough receiving care at referral clinics were evaluated. Correlation analyses were performed between patient-reported cough control (a 5-point Likert scale), cough-specific patient-reported outcomes (PROs) and generic health PRO scores. Second, a survey was conducted among patients with refractory chronic cough and physicians to identify factors pertinent to cough control., Results: The analysis of 341 patients (mean age: 55.5±15.1 years; female: 66.6%) revealed that cough control rating was moderately correlated with cough severity visual analogue scale and Leicester Cough Questionnaire scores, while demonstrating weaker correlations with cough-associated throat symptoms, cough-related complications or general health-related quality of life (QoL). In the survey of patients and physicians, both groups considered certain factors, such as cough frequency, severity and impact on QoL, to be relevant to the concept of cough control. However, patients rated "need for cough rescue drug" notably higher than physicians., Conclusion: Patient-reported cough control was associated with cough severity or impact on QoL; however, cough control may not be fully captured by conventional cough PRO measurement tools. Further studies are warranted to define the consensus and tools to measure disease control in chronic cough., Competing Interests: Conflict of interest: S.S. Birring declares grants from Merck Sharp & Dohme Corp., and consulting fees from Merck, Shionogi, Bayer, Nerre, Genentech/Roche and Bellus. Conflict of interest: W-J. Song declares grants from Merck Sharp & Dohme Corp. and AstraZeneca, consulting fees from Merck, Bellus, AstraZeneca, Shionogi and GSK, and lecture fees from Merck, AstraZeneca, GSK, Sanofi and Novartis; and is chief editor of this journal. Conflict of interest: Other authors declare that they have no competing interests., (Copyright ©The authors 2024.)

Aim: To evaluate whether the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors which have shown potential neuroprotective effects, is associated with lower risk of dementia in patients with type 2 diabetes (T2D) and comorbid mental disorders, who are considerably more susceptible to dementia., Methods: Using the nationwide healthcare data of South Korea between 2010 and 2022, we conducted a retrospective cohort study among patients with T2D and comorbid mental disorders initiating SGLT2 inhibitors versus active comparator (Dipeptidyl Peptidase IV (DPP4) inhibitors). Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years of incident dementia were estimated after weighting by propensity score fine stratification method., Results: Over a 4.8-year median follow-up, SGLT2 inhibitors were associated with a 12 % lower risk of dementia compared with DPP4 inhibitors (11.31 vs. 12.86 events per 1000 person years; HR 0.88, 95 % CI 0.84 to 0.92; RD -1.55, -2.13 to -0.97). The results were consistent when stratified by age, sex, individual component, severe mental disorders, presence of insulin, history of cardiovascular disease, or history of hypertension., Conclusions: SGLT2 inhibitors versus DPP4 inhibitors were associated with a lower risk of incident dementia in patients with T2D and comorbid mental disorders. Further randomized controlled trials are required to confirm our findings., Competing Interests: Declaration of competing interest All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: this study was funded by the Ministry of Food and Drug Safety, South Korea. JYS received grants from the Ministry of Food and Drug Safety, Ministry of Health and Welfare, National Research Foundation of Korea, and Government-wide R&D Fund for Infectious Disease Research and Pharmaceutical Companies, including Pfizer, LG Chemical, and Union Chimique Belge. BH was supported by China Scholarship Council (Grant no. #202,308,260,057). YMC received research grants from Daewoong Pharmaceuticals and Sanofi, and consultation fees from Hanmi and LG Chemical. The other authors report no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Artificial intelligence and human-computer interaction advances demand bioinspired sensing modalities capable of comprehending human affective states and speech. However, endowing skin-like interfaces with such intricate perception abilities remains challenging. Here, we have developed a flexible piezoresistive artificial ear (AE) sensor based on gold nanoparticles, which can convert sound signals into electrical signals through changes in resistance. By testing the sensor's performance at both frequency and sound pressure level (SPL), the AE has a frequency response range of 20 Hz to 12 kHz and can sense sound signals from up to 5 m away at a frequency of 1 kHz and an SPL of 126 dB. Furthermore, through deep learning, the device achieves up to 96.9% and 95.0% accuracy in classification and recognition applications for seven emotional and eight urban environmental noises, respectively. Hence, on one hand, our device can monitor the patient's emotional state by their speech, such as sudden yelling and screaming, which can help healthcare workers understand patients' condition in time. On the other hand, the device could also be used for real-time monitoring of noise levels in aircraft, ships, factories, and other high-decibel equipment and environments.

Background: Effective interventions for overall healthy subjects with mild cognitive impairment are currently limited. Choline alphoscerate (alpha glyceryl phosphorylcholine, αGPC) is a choline-containing phospholipid used to treat cognitive function impairments in specific neurological conditions. This study aimed to investigate the efficacy and safety of αGPC in individuals diagnosed with mild cognitive impairment., Methods: In this multicenter, randomized, placebo-controlled trial, 100 study subjects with mild cognitive impairment underwent a double-blind SHCog™ soft capsule (600 mg αGPC) or placebo treatment for 12 weeks. The primary efficacy outcome included changes from baseline on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). Safety assessments included regular monitoring of adverse events, and clinical laboratory tests were conducted at baseline and the end of the trial., Results: After 12 weeks of αGPC treatment, the ADAS-cog score decreased by 2.34 points, which was significantly greater than the change observed in the placebo group. No serious AEs were reported, and no study subjects discontinued the intervention because of AEs. There was no significant difference in incidence rate of AEs between the αGPC group and the placebo group., Conclusion: This study suggests that αGPC is a safe and effective intervention for improving cognitive function in study subjects with mild cognitive impairment., Trial Registration: Clinical Research Information Service; Osong (Chungcheongbuk-do): Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea); KCT0008797; A 12-week, multicenter, randomized, double-blind, placebo-controlled human application study to evaluate the efficacy and safety of SH&#95;CAPK08 on cognitive function improvement in mild cognitive decline., (© 2024. The Author(s).)

A 6-year-old castrated male mixed dog presented with a rapidly growing mass at the right chest wall two weeks after initial detection. A mesenchymal origin of the malignancy was suspected based on fine-needle aspiration. Computed tomography (CT) revealed that the mass originated from the right chest wall and protruded externally (6.74 × 5.51 × 4.13 cm 3 ) and internally (1.82 × 1.69 × 1.50 cm 3 ). The patient revisited the hospital because of breathing difficulties. Radiography confirmed pleural effusion, and ultrasonography-guided thoracocentesis was performed. The effusion was hemorrhagic, and microscopic evaluation showed no malignant cells. Before surgery, CT without anesthesia was performed to evaluate the status of the patient. The 7-10th ribs were en bloc resected at a 3-cm margin dorsally and ventrally, and two ribs cranially and caudally from the mass. After recovering the collapsed right middle lobe of the lung due to compression from the internal mass with positive-pressure ventilation, a 3D-printed bone model contoured titanium mesh was tied to each covering rib and surrounding muscles using 2-0 blue nylon and closed routinely. The thoracic cavity was successfully reconstructed, and no flail chest was observed. The patient was histo-pathologically diagnosed with extraskeletal osteosarcoma. A CT scan performed 8 months after surgery showed no evident recurrence, metastasis, or implant failure. This is the first case report of chest wall reconstruction using titanium mesh in a dog. The use of a titanium mesh allows for the reconstruction of extensive chest wall defects, regardless of location, without major postoperative complications.

Background and Objective: Heart failure (HF) is associated with high mortality and hospitalization rates, and its prevalence increases with age. As congestion is the most common cause of hospitalization for HF, diuretics are the most prescribed drugs. However, these agents have side effects due to electrolyte imbalance. In Asian countries, Oryeongsan (ORS) and its variants are used to manage fluid imbalances, including HF congestion. Therefore, ORS is considered a complementary treatment to overcome the limitations of diuretics. This review aimed to elucidate the safety and effectiveness of ORS combined with conventional Western medicine (CWM) for HF., Materials and Methods: A literature search was conducted using the PubMed, Embase, CENTRAL, Scopus, CiNii, CNKI, and ScienceON databases to retrieve relevant studies published up to July 2024. Two independent investigators were involved in the data collection and analysis. Randomized controlled trials (RCTs) that evaluated the effects of ORS and its variants in combination with CWM as treatments for HF were selected. The outcome measures included left ventricular ejection fraction (LVEF), total effective rate (TER), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), 6-min Walk Test (6MWT), Minnesota Living with Heart Failure Questionnaire (MLHF-Q), serum brain natriuretic peptide (BNP) level, serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level, 24-h urine volume, Lee's score, and New York Heart Association (NYHA) grade I ratio for effectiveness; and incidence of adverse events (AEs) for safety. The methodological quality of the included RCTs was assessed using the Cochrane's Risk of Bias tool., Results: Fifty-nine RCTs that comprised 5069 participants and compared CWM combined with ORS and its variants (treatment group) to CWM alone or CWM plus placebo (control group) were included. Based on the meta-analysis, LVEF was found to significantly improve (mean difference: 6.36, 95 % confidence interval: 5.11 to 7.61, P < 0.00001) in the treatment group. TER, LVEDD, LVESD, 6MWT, MLHF-Q, serum BNP and NT-proBNP levels, 24-h urine volume, Lee's score, and NYHA grade I ratio were also significantly improved in the treatment group compared with the control group with CWM alone. LVEF and TER were improved without significance in the treatment group compared with the control group with CWM plus placebo. The incidence of AEs did not significantly differ between the two groups., Conclusions: Combining CWM with ORS or its variants was more effective than CWM alone in managing HF and could serve as a relatively safe treatment for HF. Further studies are required to validate the findings of the present study., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Seungwon Kwon reports financial support was provided by 10.13039/501100003710Korea Health Industry Development Institute. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Background/objectives: Anemia is a global health issue affecting diverse populations, particularly older adults, and conventional treatments often show limited efficacy. This study aimed to evaluate the utilization and effectiveness of Sipjeondaebotang (SDT), a prescription drug used in traditional East Asian medicine, in treating various types of anemia., Methods: A scoping review was conducted following Arksey and O'Malley's framework and PRISMA-ScR guidelines. Six electronic databases were searched for clinical studies on SDT, while focusing on human participants and excluding animal and cellular studies. Sixteen studies, including nine randomized controlled trials, two controlled clinical trials, two case series, and three case reports, involving 863 participants, were analyzed. These studies were primarily conducted in China, Korea, and Japan., Results: According to the analysis, SDT improved hemoglobin levels across all types of anemia studied, with all controlled studies showing significant improvements compared with the control groups. Additionally, SDT reduced blood loss, improved recovery times, and decreased transfusion requirements in patients with post-operative anemia, with lower adverse event rates than those in the control groups. These findings suggest that SDT may enhance hematological parameters and improve overall patient outcomes., Conclusions: In conclusion, SDT may be an effective treatment for anemia that improves hemoglobin levels and patient outcomes. However, further high-quality, large-scale studies are necessary to standardize SDT prescriptions, confirm the optimal treatment duration, and validate its efficacy and safety across different anemia types.

Contact sites between lipid droplets and other organelles are essential for cellular lipid and energy homeostasis upon metabolic demands. Detection of these contact sites at the nanometer scale over time in living cells is challenging. We developed a tool kit for detecting contact sites based on fluorogen-activated bimolecular complementation at CONtact sites, FABCON, using a reversible, low-affinity split fluorescent protein, splitFAST. FABCON labels contact sites with minimal perturbation to organelle interaction. Via FABCON, we quantitatively demonstrated that endoplasmic reticulum (ER)- and mitochondria (mito)-lipid droplet contact sites are dynamic foci in distinct metabolic conditions, such as during lipid droplet biogenesis and consumption. An automated analysis pipeline further classified individual contact sites into distinct subgroups based on size, likely reflecting differential regulation and function. Moreover, FABCON is generalizable to visualize a repertoire of organelle contact sites including ER-mito. Altogether, FABCON reveals insights into the dynamic regulation of lipid droplet-organelle contact sites and generates new hypotheses for further mechanistical interrogation during metabolic regulation., (© 2024 Li et al.)

The dense mechanoreceptors in human fingertips enable texture discrimination. Recent advances in flexible electronics have created tactile sensors that effectively replicate slowly adapting (SA) and rapidly adapting (RA) mechanoreceptors. However, the influence of dermatoglyphic structures on tactile signal transmission, such as the effect of fingerprint ridge filtering on friction-induced vibration frequencies, remains unexplored. A novel multi-layer flexible sensor with an artificially synthesized skin surface capable of replicating arbitrary fingerprints is developed. This sensor simultaneously detects pressure (SA response) and vibration (RA response), enabling texture recognition. Fingerprint ridge patterns from notable historical figures - Rosa Parks, Richard Nixon, Martin Luther King Jr., and Ronald Reagan - are fabricated on the sensor surface. Vibration frequency responses to assorted fabric textures are measured and compared between fingerprint replicas. Results demonstrate that fingerprint topography substantially impacts skin-surface vibrational transmission. Specifically, Parks' fingerprint structure conveyed higher frequencies more clearly than those of Nixon, King, or Reagan. This work suggests individual fingerprint ridge morphological variation influences tactile perception and can confer adaptive advantages for fine texture discrimination. The flexible bioinspired sensor provides new insights into human vibrotactile processing by modeling fingerprint-filtered mechanical signals at the finger-object interface., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Previous research has indicated a negative correlation between exclusive breastfeeding and the incidence of Kawasaki disease (KD). However, the validation of this discovery through meta-analytical studies has been lacking. Furthermore, uncertainties persist regarding whether breastfeeding reduces the risk of coronary artery lesions (CAL) or resistance to intravenous immunoglobulin (IVIG)., Methods: A systematic exploration of the MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, and ClinicalTrials.gov databases was conducted to identify longitudinal or randomized controlled trials investigating the efficacy of breastfeeding in preventing KD. The primary focus was on the incidence of KD, with secondary emphasis placed on the incidence of CAL and IVIG resistance. Data were pooled using a frequentist-restricted maximum-likelihood random-effects model., Results: Of the 179 potentially eligible studies identified, five (n = 1,982,634) were included. The analysis revealed a significantly lower risk of KD (expressed as odds ratio, with 95% confidence intervals and p-values) in comparisons between exclusive breastfeeding and formula feeding (0.62, 0.43-0.91, p = 0.014), exclusive breastfeeding/partial breastfeeding and formula feeding (0.66, 0.46- 0.96, p = 0.03), and exclusive breastfeeding and partial breastfeeding/formula feeding (0.81, 0.74- 0.90, p < 0.01). However, no significant difference was observed in the risk of developing KD when comparing partial breastfeeding to formula feeding exclusively. Regarding secondary outcomes, no statistically significant difference was found in the risk of CAL or IVIG resistance across any comparison formats., Conclusions: Our study suggests that breastfeeding correlated with a reduced risk of KD but not with a reduced risk of CAL or IVIG resistance. These findings advocate for the implementation of breastfeeding policies in clinical practice., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Vitamin D is known to influence the risk of cardiovascular disease, which is a recognized risk factor for sudden cardiac arrest (SCA). However, the relationship between vitamin D and SCA is not well understood. Therefore, this study aims to investigate the association between vitamin D and SCA in out-of-hospital cardiac arrest (OHCA) patients compared to healthy controls., Methods and Results: Using the Phase II Cardiac Arrest Pursuit Trial with Unique Registration and Epidemiologic Surveillance (CAPTURES II) registry, a 1:1 propensity score-matched case-control study was conducted between 2017 and 2020. Serum 25-hydroxyvitamin D (vitamin D) levels in patients with OHCA (454 cases) and healthy controls (454 cases) were compared after matching for age, sex, cardiovascular risk factors, and lifestyle behaviors. The mean vitamin D levels were 14.5 ± 7.6 and 21.3 ± 8.3 ng/mL among SCA cases and controls, respectively. Logistic regression analysis was used adjusting for cardiovascular risk factors, lifestyle behaviors, corrected serum calcium levels, and estimated glomerular filtration rate (eGRF). The adjusted odds ratio (aOR) for vitamin D was 0.89 (95% confidence interval [CI] 0.87-0.91). The dose-response relationship demonstrated that vitamin D deficiency was associated with SCA incidence (severe deficiency, aOR 10.87, 95% CI 4.82-24.54; moderate deficiency, aOR 2.24, 95% CI 1.20-4.20)., Conclusion: Vitamin D deficiency was independently and strongly associated with an increased risk of SCA, irrespective of cardiovascular and lifestyle factors, corrected calcium levels, and eGFR., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objectives: This study aimed to predict blood pressure during CPR using chest compression waveform information obtained from a CPR feedback device., Methods: Quantitative data including chest compression waveforms from a CPR feedback device and the blood pressure measured by arterial cannulation in patients with cardiac arrest during CPR were used. Forty-one features to predict blood pressure were selected from chest compression waveform and demographic characteristics with neighborhood component analysis algorithm. Optimized Gaussian process regression was used as a machine learning algorithm., Results: A total of 14,619 datasets from 19 patients with cardiac arrest (mean age: 66 ± 13 years, 14 men) were used in the analysis. The model could predict blood pressure with high precision and low bias for almost the whole range of systolic (SBP), diastolic (DBP), and mean arterial blood pressure (MAP). The correlation coefficients (r) between the predicted and actual values were 0.954 (95% confidence interval: 0.951-0.957, p < 0.001) for SBP, 0.926 (95% confidence interval: 0.921-0.931, p < 0.001) for DBP, and 0.958 (95% confidence interval: 0.955-0.961, p < 0.001) for MBP, which all indicated a very good agreement., Conclusions: Blood pressure generated by chest compressions can be predicted with high accuracy by a machine learning method using chest compression waveform information obtained from a CPR feedback device and the patient's demographic characteristics. Real-time provision of the predicted blood pressure can be used to monitor the quality and efficacy of CPR., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sung Oh Hwang, Jiho Han, Young Ro Yoon, Kyoung-chul Cha have patent CPR DEVICE PROVIDING ESTIMATED BLOOD PRESSURES OF THE PATIENT AND THE METHOD THEREOF pending to Yonsei University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Heavy metal contamination of aquatic environments adversely affects the health of aquatic organisms and consumption of fish contaminated with heavy metals poses serious health risks to humans. Among various strategies, probiotics (living microorganisms known to have beneficial effects on the host), which have been extensively applied in the aquaculture industry, could be helpful for heavy metal detoxification and remediation. Several probiotics, including Lactobacillus strains, exhibit heavy metal binding, high heavy metal tolerance, and other beneficial characteristics for the host. Notably, numerous probiotics have been reported to bind heavy metals and excrete them from the host. Various probiotic strains (Lactobacillus, Bacillus, Lactococcus, etc.) show beneficial effects in alleviating heavy metal toxicity in cultured fish species. Certain probiotic bacteria reduce the absorption and bioavailability of heavy metals by enhancing heavy metal detoxification and sequestration while preserving gut barrier function. This review summarises the toxic effects of selected heavy metals on the health of farmed fish and discusses the role of probiotic strains in remediating the consequential exposure-induced immune toxicity and oxidative stress. Moreover, we discussed the protective strategies of probiotics against heavy metal accumulation in various tissues and gut dysbiosis in fish to alleviate heavy metal toxicity in fish farming, thereby promoting a sustainable blue economy worldwide., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Se Chang Park reports article publishing charge was provided by Companion Animal Research of the Rural Development Administration, Republic of Korea., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A Rh(III)-catalyzed C-H activation/cyclization cascade was developed for the first divergent synthesis of pyrazolo[1,5- a ]quinazolines through a [5 + 1] annulation reaction exclusively. The one-pot procedure is recognized for its broad substrate scope, functional group tolerance, and high atom economy. Mechanistic studies reveal the reaction pathway, addressing current limitations. Notably, this catalytic transition metal-assisted tandem annulation smoothly proceeds through the reaction of substituted phenyl-1 H -pyrazol-5-amine with an alkyne ester or amide, where a one ring carbon is provided by the alkynoate building block. This transformation highlights the potential of transition metal-catalyzed methods for synthesizing diverse pyrazolo[1,5- a ]quinazoline frameworks.

Introduction: Noninvasive stool DNA-based methylation testing has emerged as an effective strategy for the early colorectal cancer (CRC) detection. Syndecan-2 (SDC2) methylation frequently occurs in all stages of CRC; therefore, the aim of this study was to evaluate the clinical performance of a stool DNA-based SDC2 methylation test for detecting CRC in asymptomatic or high-risk CRC populations., Methods: This multicenter prospective study was conducted to determine the clinical performance of the SDC2 methylation test on stool DNA using real-time polymerase chain reaction. Stool samples were collected from asymptomatic individuals before colonoscopy, and the test results were independently analyzed through comparison with colonoscopic findings and pathological outcomes as reference standards., Results: Of the 1,124 evaluable participants, 20 had CRC, 73 had advanced adenomatous polyps (≥1.0 cm), 469 had nonadvanced adenomatous polyps (<1.0 cm), 178 had non-neoplastic polyps, and 384 had negative colonoscopy results. The stool SDC2 methylation test had a sensitivity and specificity of 95.0% and 81.5%, respectively, for detecting CRC, while the sensitivity for detecting advanced adenomatous polyps and CRC was 58.1%. The rate of adenoma detection increased with polyp size (P < 0.01), and sensitivity was not associated with CRC stage (P = 0.864)., Discussion: The stool DNA-based SDC2 methylation test attained a high sensitivity for CRC detection in an asymptomatic high-risk population. Further large-scale clinical studies are required to validate the clinical utility of this test as a population-based CRC screening tool., (Copyright © 2024 by The American College of Gastroenterology.)

Background: Anti-type 2 (T2) biologic therapies (biologics) improve exacerbation rates, lung function, and asthma-related quality of life (QoL) in patients with severe T2 asthma. However, studies comparing different biologics are lacking. We evaluated the QoL in patients with severe asthma comprehensively and compare the efficacy of different T2-directed biologics using QoL questionnaires., Methods: We compared the QoL between severe and mild-to-moderate asthma and between severe asthma with and without biologics treatment. Data of mild-to-moderate were extracted from the Cohort for Reality and Evolution of Adult Asthma in Korea, and data of severe asthma were collected from the Precision Medicine Intervention in Severe Asthma. We included 183 patients with severe asthma treated with T2 biologics or conventional therapy between April 2020 and May 2021 and assessed QoL of them using the Questionnaire for Adult Korean Asthmatics (QLQAKA), Severe Asthma Questionnaire (SAQ), and EuroQoL-5Dimensions (EQ-5D) at baseline and 6 months., Results: The EQ-5D index (0.803) of severe asthma was lower than that of other chronic diseases representing a worse QoL. The scores for all questions of QLQAKA, except "cough," were lower (less control) in the severe asthma group than in the mild-to-moderate asthma group at baseline and 6 months ( P  < 0.05). The total scores and subscores of all domains of the QLQAKA, SAQ, and EQ-5D improved significantly 6 months after biologic therapy but not after conventional therapy. The total QLQAKA, SAQ, and EQ-5D scores improved after 6 months in the anti-IL-5 ( P  < 0.05) and anti-IL-4/IL-13 ( P  < 0.05) treatment groups with no significant difference between groups ( P  > 0.05)., Conclusion: QoL was worse in severe asthma than in mild-to-moderate asthma and other chronic diseases. T2 biologics equally improved QoL in patients with severe asthma., Competing Interests: The authors declare that they have no relevant conflicts of interest., (© 2024 The Authors.)

Our research focused on extracting polysaccharides from Suaeda maritima (SMP) to obtain crude polysaccharides (SMP-C), which were subsequently purified into SMP-F1 and SMP-F2. SMPs were evaluated for anti-inflammatory effects and SMP-F1 showed the highest inhibitory effects on nitric oxide (NO) production. The monosaccharide composition analysis of SMP-F1 (molecular weight of 112.2 × 10 3 g/mol) revealed predominant levels of glucose (45.4 %), arabinose (20.5 %), mannose (14.2 %), and galactose (12.7 %). The primary backbone of SMP-F1 consisted of (1 → 4)-D-glucopyranoside, (1 → 4,6)-D-glucopyranoside, (1 → 3)-D-mannopyranoside, (1 → 3,6)-D-mannopyranoside, and (1 → 5)-L-arabifuranoside. In addition, we hydrolysed SMP-F1 to SMP-H1, SMP-H2, and SMP-H3 and investigated their anti-inflammatory effects on RAW264.7 macrophages. Following SMP-F1 hydrolysis, SMP-H3 (molecular weight of 25.8 × 10 3 g/mol) exhibited superior anti-inflammatory properties compared to SMP-H1 and SMP-H2, demonstrating a significant decrease in NO production. SMP-H3 also demonstrated a remarkable reduction in the secretion of inflammatory mediators including NO, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines including tumour necrosis factor-alpha (TNF-α), interleukin (IL-1β and IL-6), while increasing IL-10 expression. Furthermore, SMP-H3 significantly inhibited LPS-stimulated cluster of differentiation (CD) 11b and CD40 expression. Our subsequent investigation unveiled the involvement of SMP-H3-activated macrophages in the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Additionally, SMP-H3 exhibited antioxidant activity by scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH), superoxide, and 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) free radicals. These findings suggest the potential of SMP-H3 as an ingredient in the development of alternative drugs or functional foods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Iron and myelin are primary susceptibility sources in the human brain. These substances are essential for a healthy brain, and their abnormalities are often related to various neurological disorders. Recently, an advanced susceptibility mapping technique, which is referred to as χ-separation (pronounced as "chi"-separation), has been proposed, successfully disentangling paramagnetic iron from diamagnetic myelin. This method provided a new opportunity for generating high-resolution iron and myelin maps of the brain. Utilizing this technique, this study constructs a normative χ-separation atlas from 106 healthy human brains. The resulting atlas provides detailed anatomical structures associated with the distributions of iron and myelin, clearly delineating subcortical nuclei, thalamic nuclei, and white matter fiber bundles. Additionally, susceptibility values in a number of regions of interest are reported along with age-dependent changes. This atlas may have direct applications such as localization of subcortical structures for deep brain stimulation or high-intensity focused ultrasound and also serve as a valuable resource for future research., (© 2024 The Author(s). NMR in Biomedicine published by John Wiley & Sons Ltd.)

Aim: To examine the dynamic change in hepatic steatosis status during repeated assessments over time, and its potential impact on the risk of developing cardiovascular disease (CVD)., Methods: We assessed trajectories of hepatic steatosis and other metabolic disorders in 3134 middle-aged adults undergoing longitudinal assessment of ultrasonography during a pre-baseline period (1993-2009) in a population-based cohort study of liver health. Subsequently, we determined the association of hepatic steatosis trajectories with the incidence of CVD among 2185 CVD-free individuals, followed until 2021. Metabolic risk factors and cardiovascular events (including coronary heart disease and stroke) were determined through medical examination and linkage with nationwide health databases., Results: We identified three discrete trajectories of hepatic steatosis according to changing pattern over time through group-based trajectory modeling: "stable, non-steatosis" (n = 1298), "intermittent" (n = 921), and "persistent steatosis" (n = 915). During the pre-baseline period, hepatic steatosis trajectories were associated with trajectories of developing diabetes and hypertension, and persistent steatosis (vs. other trajectories) was associated with higher risks and rapidly progressive disease patterns. At a median 13.6 years of follow-up, 629 CVD events occurred. A persistent (vs. non-steatosis: HR 1.44, 95% CI 1.17-1.76), but not intermittent, steatosis pattern predicted the future risk of CVD, after adjustment for age, sex, smoking, and obesity. This association was independent of genetic background, and remained after accounting for pre-baseline body-mass index, other cardiometabolic risk factors, Framingham risk score, medications, and hepatic fibrosis score., Conclusions: The persistence of hepatic steatosis is associated with trajectories of metabolic disorder development and increased risk of CVD. These data have important implications for practice and further research., (© 2024 Japan Society of Hepatology.)

Microbial agents such as the Bacillus species are recognized for their role as biocontrol agents against various phytopathogens through the production of diverse bioactive compounds. This study evaluates the effectiveness of Bacillus subtilis PE7 in inhibiting the growth of Didymella bryoniae , the pathogen responsible for gummy stem blight (GSB) in cucurbits. Dual culture assays demonstrate significant antifungal activity of strain PE7 against D. bryoniae . Volatile organic compounds (VOCs) produced by strain PE7 effectively impede mycelial formation in D. bryoniae , resulting in a high inhibition rate. Light microscopy revealed that D. bryoniae hyphae exposed to VOCs exhibited abnormal morphology, including swelling and excessive branching. Supplementing a potato dextrose agar (PDA) medium with a 30% B. subtilis PE7 culture filtrate significantly decreased mycelial growth. Moreover, combining a 30% culture filtrate with half the recommended concentration of a chemical fungicide yielded a more potent antifungal effect than using the full fungicide concentration alone, inducing dense mycelial formation and irregular hyphal morphology in D. bryoniae . Strain PE7 was highly resilient and was able to survive in fungicide solutions. Additionally, B. subtilis PE7 enhanced the nutrient content, growth, and development of melon plants while mitigating the severity of GSB compared to fungicide and fertilizer treatments. These findings highlight B. subtilis PE7 as a promising biocontrol candidate for integrated disease management in crop production.

Aims: FKBP5 encodes FKBP51, which has been implicated in stress-related psychiatric disorders, and its expression is often increased under chronic stress, contributing to mental dysfunctions. However, the precise role of FKBP51 in brain inflammation remains unclear. This study aimed to investigate the role of FKBP51 in microglia-mediated inflammatory responses in the central nervous system., Main Methods: We employed a peripheral lipopolysaccharide (LPS) administration model to compare microglial activation and cytokine gene expression between Fkbp5 knockout (Fkbp5-KO) and wild-type (WT) male mice. Additionally, we used both BV2 and primary microglia in vitro to examine how Fkbp5 deletion influenced inflammation-related pathways and microglial functions., Key Findings: This study revealed that systemic LPS-induced microglial activation was significantly attenuated in Fkbp5-KO mice compared with WT mice. In Fkbp5-KO mice following the LPS challenge, there was a notable decrease in the expression of pro-inflammatory genes, coupled with an increase in the anti-inflammatory gene Arg1. Furthermore, Fkbp5 knockdown in BV2 microglial cells led to reduced expression of LPS-induced inflammatory markers, and targeted inhibition of NF-κB activation, while Akt signaling remained unaffected. Similar results were observed in Fkbp5-KO primary microglia, which exhibited not only decreased microglial activation but also a significant reduction in phagocytic activity in response to LPS stimulation., Significance: This study highlights the critical role of FKBP51 in LPS-induced microglial activation and neuroinflammation. It shows that reducing FKBP51 levels attenuates inflammation through NF-κB signaling in microglia. This suggests that FKBP51 is a potential target for alleviating neuroinflammation-induced stress responses., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study was conducted to evaluate the potential anti-inflammatory and immune-enhancement properties of lipids derived from Aptocyclus ventricosus eggs on RAW264.7 cells. Firstly, we determined the fatty acid compositions of A. ventricosus lipids by performing gas chromatography analysis. The results showed that A. ventricosus lipids contained saturated fatty acids (24.37%), monounsaturated fatty acids (20.90%), and polyunsaturated fatty acids (54.73%). They also contained notably high levels of DHA (25.91%) and EPA (22.05%) among the total fatty acids. Our results for the immune-associated biomarkers showed that A. ventricosus lipids had immune-enhancing effects on RAW264.7 cells. At the maximum dose of 300 µg/mL, A. ventricosus lipids generated NO (119.53%) and showed greater phagocytosis (63.69%) ability as compared with untreated cells. A. ventricosus lipids also upregulated the expression of iNOS , IL-1β , IL-6 , and TNF-α genes and effectively upregulated the phosphorylation of MAPK (JNK, p38, and ERK) and NF-κB p65, indicating that these lipids could activate the MAPK and NF-κB pathways to stimulate macrophages in the immune system. Besides their immune-enhancing abilities, A. ventricosus lipids significantly inhibited LPS-induced RAW264.7 inflammatory responses via the NF-κB and MAPK pathways. The results indicated that these lipids significantly reduced LPS-induced NO production, showing a decrease from 86.95% to 38.89%. Additionally, these lipids downregulated the expression of genes associated with the immune response and strongly suppressed the CD86 molecule on the cell surface, which reduced from 39.25% to 33.80%. Collectively, these findings imply that lipids extracted from A. ventricosus eggs might have biological immunoregulatory effects. Thus, they might be considered promising immunomodulatory drugs and functional foods.

Background: This study aimed to analyze the current status of brain death/death by neurologic criteria (BD/DNC) determination in Korea over a decade, identifying key areas for improvement in the process., Methods: We conducted a retrospective analysis of data from the Korea Organ Donation Agency spanning 2011 to 2021, focusing on donors whose donations were not completed. The study reviewed demographics, medical settings, diagnoses, and outcomes, with particular emphasis on cases classified as nonbrain death and those resulting in death by cardiac arrest during the BD/DNC assessment., Results: Of the 5047 patients evaluated for potential brain death from 2011 to 2021, 361 were identified as noncompleted donors. The primary reasons for noncompletion included nonbrain death (n = 68, 18.8%), cardiac arrests during the BD/DNC assessment process (n = 80, 22.2%), organ ineligibility (n = 151, 41.8%), and logistical and legal challenges (n = 62, 17.2%). Notably, 25 (36.8%) of them failed to meet the minimum clinical criteria, and 7 of them were potential cases of disagreement between the two clinical examinations. Additionally, most cardiac arrests (n = 44, 55.0%) occurred between the first and second examinations, indicating management challenges in critically ill patients during the assessment period., Conclusions: Our study highlights significant challenges in the BD/DNC determination process, including the need for improved consistency in neurologic examinations and the management of critically ill patients. The study underscores the importance of refining protocols and training to enhance the accuracy and reliability of brain death assessments, while also ensuring streamlined and effective organ donation practices., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Gene expression can provide distinct information compared to clinical biomarkers in the context of longitudinal clinical outcomes in asthma patients., Objective: This study examined the association between the gene expression levels of upstream (IL-25, IL-33, and TSLP) and downstream cytokines (IL-5, IL-4, and IL-13) in the T2 inflammatory pathway with a 12-month follow-up of exacerbation, lung function, and steroid use., Methods: Transcriptomic sequencing analysis was performed on peripheral blood mononuclear cells from 279 adult asthmatics. Survival analysis and linear mixed-effect models were used to investigate potential differences between the high-level and low-level gene expression groups and the clinical outcomes. Analysis was performed separately for the upstream, downstream, and all 6 cytokines., Results: In general, T2 inflammatory cytokine gene expression showed a weak correlation with blood eosinophil counts (all r < 0.1) and clinical outcomes. Among moderate-to-severe eosinophilic asthma (MSEA) patients, individuals with elevated levels of downstream cytokines were at increased risk of time-to-first exacerbation (p = 0.044) and a greater increase of inhaled corticosteroid use over time (p = 0.002) compared to those with lower gene expression. There was no association between baseline T2 inflammatory cytokine gene expression and the longitudinal changes in lung function over time among MSEA patients., Conclusion: These findings suggest that, among MSEA patients, the gene expression levels of downstream cytokines in the T2 inflammatory pathway may serve as indicators for endotyping asthma., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)