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BackgroundMechanical insufflation-exsufflation (MI-E) facilitates extubation. However, its potential to reduce the duration of ventilator use remains unclear. Therefore, the present study investigated whether the use of MI-E shortened the duration of mechanical ventilation in patients with high sputum retention.MethodsA randomized open-label trial was conducted at a single intensive care unit (ICU) in Japan between November 2017 and June 2019. Ventilated subjects requiring suctioning at least once every hour due to sputum retention were randomly assigned to the MI-E group or conventional care group. The primary endpoint was the number of ventilator-free days on day 28. Secondary endpoints were ventilator days in surviving subjects, the length of ICU stay, and mortality and tracheostomy rates among survivors.ResultsForty-eight subjects (81% males) with a median age of 72 years (interquartile range [IQR], 65-85 years) were enrolled. There were 27 subjects in the MI-E group and 21 in the control group. The median number of ventilator-free days was 21 (IQR, 13-24) and 18, respectively (IQR, 0-23) (P = .38). No significant differences were observed in the ICU length of stay (median, 10 days (IQR, 7-12) vs 12 days (IQR, 6-15); P = .31), mortality rate (19% vs 15%; odds ratio [OR], 1.36 [0.28-6.50]; P = .69), or tracheostomy rate among survivors (14% vs 28%; OR, 0.40 [0.08-1.91]; P = .25).ConclusionIn ventilated subjects in the ICU with high sputum retention, the use of MI-E did not significantly increase the number of ventilator-free days over that with conventional care.

We previously demonstrated that glycyrrhizin (GL) suppressed inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer (CC). In this study, we found an accumulation of regulatory T cells (Tregs) in the spleen and suppression by GL in model mice. ICR mice were divided into four groups: Control, GL, CC, and GL-treated CC (CC+GL), and were sacrificed 20 weeks after AOM/DSS treatment. We measured spleen weight, areas of white and red pulp, and CD8+ T cells (cytotoxic T lymphocytes, CTL), and CD11c-positive cells (dendritic cells) in splenic tissues and forkhead box protein 3 (FoxP3)-positive cells (Tregs) in colorectal and splenic tissues. In all cases, the CC group showed a significant increase compared with those in Control group, and GL administration significantly attenuated this increase. These results indicate that Tregs accumulated in the spleen may participate in inflammation-related carcinogenesis by suppressing CTL. We also suggest that GL which binds to high-mobility group box 1 (HMGB1), suppresses carcinogenesis with decreasing Tregs in the spleen. Furthermore, there was an expression of FoxP3 in cancer cells, indicating that it may be involved in the malignant transformation of cancer cells.

The real-world treatment patterns at medical facilities and their physicians' specialties treating migraine have not been fully investigated in Japan. Therefore, a retrospective cohort study aimed to describe real-world clinical practice and treatment patterns in Japanese patients with migraine according to medical facilities and physicians' specialties. Anonymized claims data of patients with migraine was obtained from JMDC Inc (January 2018-June 2023). Patient characteristics and treatment pattern according to medical facilities and physicians' specialties treating migraine were evaluated. Of 231,156 patients with migraine (mean age [SD], 38.8 [11.8] years; females, 65.3%), 81.8% had the first prescription at clinics (CPs), 42.5% underwent imaging tests, 44.4% visited general internal medicine, and 25.9% consulted neurosurgery at initial diagnosis. Imaging tests were carried out at CPs with specialists (59.4%), hospitals (HPs) with specialists (59.1%), HPs (32.9%), and CPs (26.9%) without specialists. Overall, 95.6% received acute treatment while 21.8% received preventive treatment. At facilities with specialists compared to without specialists, triptans were more frequently prescribed (67.9% vs 44.9%) whereas acetaminophen and nonsteroidal anti-inflammatory drugs were less frequently prescribed (52.4% vs 69.2%). Preventive treatment use was higher at facilities with specialists (27.4%) than without specialists (15.7%) and increased annually regardless of the type of medical institution. In Japan, only half of patients with migraine visited facilities with specialists at their first diagnosis, and specialists are more likely use migraine-specific and preventive drugs than nonspecialists. Therefore, there is a need for awareness among migraine patients that they should consult specialists and for enhancement of medical collaboration between specialists and nonspecialists. [ABSTRACT FROM AUTHOR]

A general-purpose method of emphasizing abnormal lesions in chest radiographs, named EGGPALE (Extrapolative, Generative and General-Purpose Abnormal Lesion Emphasizer), is presented. The proposed EGGPALE method is composed of a flow-based generative model and L-infinity-distance-based extrapolation in a latent space. The flow-based model is trained using only normal chest radiographs, and an invertible mapping function from the image space to the latent space is determined. In the latent space, a given unseen image is extrapolated so that the image point moves away from the normal chest X-ray hyperplane. Finally, the moved point is mapped back to the image space and the corresponding emphasized image is created. The proposed method was evaluated by an image interpretation experiment with nine radiologists and 1,000 chest radiographs, of which positive suspected lung cancer cases and negative cases were validated by computed tomography examinations. The sensitivity of EGGPALE-processed images showed +0.0559 average improvement compared with that of the original images, with -0.0192 deterioration of average specificity. The area under the receiver operating characteristic curve of the ensemble of nine radiologists showed a statistically significant improvement. From these results, the feasibility of EGGPALE for enhancing abnormal lesions was validated. Our code is available at https://github.com/utrad-ical/Eggpale. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 pandemic alerted the potential for significant harm due to future cross-species transmission of various animal coronaviruses to human. There is a significant need of antibody-based drugs to treat patients infected with previously unseen coronaviruses. In this study, we generated CV804, an antibody that binds to the S2 domain of SARS-CoV-2 spike protein, which is highly conserved across the coronavirus family and less susceptible to mutations. CV804 demonstrated broad cross-reactivities not only disease-associated human beta coronaviruses including SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-HKU1 and with existing mutant strains of SARS-CoV-2 and but also with 20 representative animal-origin coronaviruses. CV804 exhibits strong antibody-dependent cellular cytotoxicity (ADCC) to SARS-CoV-2 spike protein expressed on cells in vitro, while completely lacks virus-neutralization activity. In animal models, CV804 suppressed disease progression caused by SARS-CoV-2 infection. Structural studies using HDX-MS combined with reactivity analysis with point mutants of recombinant spike proteins revealed that CV804 binds to a unique conformational epitope within the S2 domain of the spike proteins that is highly conserved among various coronaviruses. Overall, obtained data suggest that the non-neutralizing CV804 antibody recognizes the conformational structure of the spike protein displayed on the surface of infected cells and weakens the viral virulence by supporting the host immune cells' attack through ADCC activity in vivo. The CV804 epitope information revealed in this study is useful for designing pan-corona antibody therapeutics and universal coronavirus vaccines for preparing potential future pandemics. [ABSTRACT FROM AUTHOR]

Objective: Assessing the histology-specific prognosis of epithelial ovarian cancer (OvCa) is clinically challenging, especially in a patient population with a favorable prognosis. This study investigated the histology-specific long-term oncologic outcomes in OvCa patients who underwent complete tumor resection using a large-scale patient cohort form multiple institutions under a central pathological review system. Methods: A regional multi-institutional study was conducted from 1986 to 2019. Of the 4,898 patients with ovarian tumors enrolled, 1,175 patients who underwent complete tumor resection were classified into three classes based on clinically important prognostic factors: stage, cytology, ascites volume. For each class category, the effect of histology types on recurrence-free survival, the site of recurrence, and post-recurrence survival was evaluated. Results: Recurrence-free survival varied significantly across different histologies (P < 0.001). The risk of recurrence was higher in serous carcinoma compare to other histologies (P < 0.001). The site of tumor recurrence varied by the histology type. Multinominal logistic regression analysis revealed that mucinous histology had a significantly higher likelihood of developing recurrent tumors at distant sites from the peritoneum compared to other histologies (P = 0.002). Conversely, serous histology was associated with better post-recurrence survival (Log-rank P < 0.001). Conclusions: Long-term oncologic outcomes significantly differ by histology type in OvCa patients who have undergone complete tumor resection at the initial surgery. A careful evaluation of the clinical background is necessary for these patients, and further clinical research into individualized treatment approaches is essential. [ABSTRACT FROM AUTHOR]

Optimal ligament balance is crucial for successful total knee arthroplasty (TKA), which is a standard procedure for managing end-stage knee osteoarthritis. However, the reported values of ligament balance vary due to different methodologies and population differences, which requires further studies. This study aimed to investigate the varus-valgus ligament balance in healthy knees of Japanese individuals and its relationship with lower limb alignment. The studyanalyzed64 knees from 33 healthy young adults using stress radiographs to measure varus-valgus laxity. The mechanical hip-knee-ankle angle, medial proximal tibial angle, and lateral distal femoral angles were determined using digital long-leg radiographs. Varus and valgus laxities were compared, and the relationship between ligament balance and alignment parameters was analyzed. Mean varus laxity (3.6°± 1.3°) was significantly greater than mean valgus laxity(2.9°± 1.0°) (p<0.0001). No significant association was observed between ligament balance and alignment parameters. Healthy knees of Japanese individuals exhibited slightly greater varus laxity (0.7°) than valgus laxity, with no correlation observed between ligament balance and lower limb alignment. The finding underscores the importance of recognizing alignment diversity while noting that alignment does not influence ligament balance; this is particularly relevant in modern TKA techniques focusing on patient-specific joint and ligament reconstructions. The study's findings could help formulate strategies benefiting knee osteoarthritis management. [ABSTRACT FROM AUTHOR]

Cold atmospheric plasma (CAP) has been studied and clinically applied to treat chronic wounds, cancer, periodontitis, and other diseases. CAP exerts cytotoxic, bactericidal, cell-proliferative, and anti-inflammatory effects on living tissues by generating reactive species. Therefore, CAP holds promise as a treatment for diseases involving chronic inflammation and bacterial infections. However, the cellular mechanisms underlying these anti-inflammatory effects of CAP are still unclear. Thus, this study aimed to elucidate the anti-inflammatory mechanisms of CAP in vitro. The human acute monocytic leukemia cell line, THP-1, was stimulated with lipopolysaccharide and irradiated with CAP, and the cytotoxic effects of CAP were evaluated. Time-course differentiation of gene expression was analyzed, and key transcription factors were identified via transcriptome analysis. Additionally, the nuclear localization of the CAP-induced transcription factor was examined using western blotting. The results indicated that CAP showed no cytotoxic effects after less than 70 s of irradiation and significantly inhibited interleukin 6 (IL6) expression after more than 40 s of irradiation. Transcriptome analysis revealed many differentially expressed genes (DEGs) following CAP irradiation at all time points. Cluster analysis classified the DEGs into four distinct groups, each with time-dependent characteristics. Gene ontology and gene set enrichment analyses revealed CAP-induced suppression of IL6 production, other inflammatory responses, and the expression of genes related to major histocompatibility complex (MHC) class II. Transcription factor analysis suggested that nuclear factor erythroid 2-related factor 2 (NRF2), which suppresses intracellular oxidative stress, is the most activated transcription factor. Contrarily, regulatory factor X5, which regulates MHC class II expression, is the most suppressed transcription factor. Western blotting revealed the nuclear localization of NRF2 following CAP irradiation. These data suggest that CAP suppresses the inflammatory response, possibly by promoting NRF2 nuclear translocation.

ObjectivesThe effectiveness of early childhood education and care (ECEC) programs for children's development in various domains is well documented. Adding to existing meta-analyses on associations between the quality of ECEC services and children's developmental outcomes, the present meta-analysis synthesizes the global literature on structural characteristics and indicators of process quality to test direct and moderated effects of ECEC quality on children's outcomes across a range of domains.DesignA systematic review of the literature published over a 10-year period, between January 2010 and June 2020 was conducted, using the databases PsychInfo, Eric, EbscoHost, and Pubmed. In addition, a call for unpublished research or research published in the grey literature was sent out through the authors' professional network. The search yielded 8,932 articles. After removing duplicates, 4,880 unique articles were identified. To select articles for inclusion, it was determined whether studies met eligibility criteria: (1) study assessed indicators of quality in center-based ECEC programs catering to children ages 0-6 years; and (2) study assessed child outcomes. Inclusion criteria were: (1) a copy of the full article was available in English; (2) article reported effect size measure of at least one quality indicator-child outcome association; and (3) measures of ECEC quality and child outcomes were collected within the same school year. A total of 1,044 effect sizes reported from 185 articles were included.ResultsThe averaged effects, pooled within each of the child outcomes suggest that higher levels of ECEC quality were significantly related to higher levels of academic outcomes (literacy, n = 99: 0.08, 95% C.I. 0.02, 0.13; math, n = 56: 0.07, 95% C.I. 0.03, 0.10), behavioral skills (n = 64: 0.12, 95% C.I. 0.07, 0.17), social competence (n = 58: 0.13, 95% C.I. 0.07, 0.19), and motor skills (n = 2: 0.09, 95% C.I. 0.04, 0.13), and lower levels of behavioral (n = 60: -0.12, 95% C.I. -0.19, -0.05) and social-emotional problems (n = 26: -0.09, 95% C.I. -0.15, -0.03). When a global assessment of child outcomes was reported, the association with ECEC quality was not significant (n = 13: 0.02, 95% C.I. -0.07, 0.11). Overall, effect sizes were small. When structural and process quality indicators were tested separately, structural characteristics alone did not significantly relate to child outcomes whereas associations between process quality indicators and most child outcomes were significant, albeit small. A comparison of the indicators, however, did not yield significant differences in effect sizes for most child outcomes. Results did not provide evidence for moderated associations. We also did not find evidence that ECEC quality-child outcome associations differed by ethnic minority or socioeconomic family background.ConclusionsDespite the attempt to provide a synthesis of the global literature on ECEC quality-child outcome associations, the majority of studies included samples from the U.S. In addition, studies with large samples were also predominately from the U.S. Together, the results might have been biased towards patterns prevalent in the U.S. that might not apply to other, non-U.S. ECEC contexts. The findings align with previous meta-analyses, suggesting that ECEC quality plays an important role for children's development during the early childhood years. Implications for research and ECEC policy are discussed.

[This corrects the article DOI: 10.1371/journal.pone.0285985.].

We previously demonstrated that glycyrrhizin (GL) suppressed inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer (CC). In this study, we found an accumulation of regulatory T cells (Tregs) in the spleen and suppression by GL in model mice. ICR mice were divided into four groups: Control, GL, CC, and GL-treated CC (CC+GL), and were sacrificed 20 weeks after AOM/DSS treatment. We measured spleen weight, areas of white and red pulp, and CD8+ T cells (cytotoxic T lymphocytes, CTL), and CD11c-positive cells (dendritic cells) in splenic tissues and forkhead box protein 3 (FoxP3)-positive cells (Tregs) in colorectal and splenic tissues. In all cases, the CC group showed a significant increase compared with those in Control group, and GL administration significantly attenuated this increase. These results indicate that Tregs accumulated in the spleen may participate in inflammation-related carcinogenesis by suppressing CTL. We also suggest that GL which binds to high-mobility group box 1 (HMGB1), suppresses carcinogenesis with decreasing Tregs in the spleen. Furthermore, there was an expression of FoxP3 in cancer cells, indicating that it may be involved in the malignant transformation of cancer cells. [ABSTRACT FROM AUTHOR]

The chytrid fungus Batrachochytrium salamandrivorans [Bsal] is causing declines in the amphibian populations. After a decade of mapping the pathogen in Europe, where it is causing dramatic outbreaks, and North America, where its arrival would affect to the salamander's biodiversity hotspot, little is known about its current status in Asia, from presumably is native. Japan has several species considered as potential carriers, but no regulation is implemented against Bsal spreading. Previous Bsal known presence detected various cases on the Okinawa Island, southwestern Japan. Previous studies on its sister species, B. dendrobatidis presented a high genomic variation in this area and particularly on Cynops ensicauda. Here, we have done the largest monitoring to date in Japan on the Cynops genus, focusing on Okinawa Island and updating its distribution and providing more information to unravel the still unknown origin of Bsal. Interestingly, we have provided revealing facts about different detectability depending on the used molecular techniques and changes in its Japanese distribution. All in all, the Bsal presence in Japan, together with its low variability in the sequenced amplicons, and the lack of apparent mortalities, may indicate that this part of Asia has a high diversity of chytrids. [ABSTRACT FROM AUTHOR]

Background: Mechanical insufflation-exsufflation (MI-E) facilitates extubation. However, its potential to reduce the duration of ventilator use remains unclear. Therefore, the present study investigated whether the use of MI-E shortened the duration of mechanical ventilation in patients with high sputum retention. Methods: A randomized open-label trial was conducted at a single intensive care unit (ICU) in Japan between November 2017 and June 2019. Ventilated subjects requiring suctioning at least once every hour due to sputum retention were randomly assigned to the MI-E group or conventional care group. The primary endpoint was the number of ventilator-free days on day 28. Secondary endpoints were ventilator days in surviving subjects, the length of ICU stay, and mortality and tracheostomy rates among survivors. Results: Forty-eight subjects (81% males) with a median age of 72 years (interquartile range [IQR], 65–85 years) were enrolled. There were 27 subjects in the MI-E group and 21 in the control group. The median number of ventilator-free days was 21 (IQR, 13–24) and 18, respectively (IQR, 0–23) (P =.38). No significant differences were observed in the ICU length of stay (median, 10 days (IQR, 7–12) vs 12 days (IQR, 6–15); P =.31), mortality rate (19% vs 15%; odds ratio [OR], 1.36 [0.28–6.50]; P =.69), or tracheostomy rate among survivors (14% vs 28%; OR, 0.40 [0.08–1.91]; P =.25). Conclusion: In ventilated subjects in the ICU with high sputum retention, the use of MI-E did not significantly increase the number of ventilator-free days over that with conventional care. [ABSTRACT FROM AUTHOR]

Backgrounds: The prognostic implication of weight loss after discharge from acute heart failure (AHF) remains unclear. We sought to investigate the association of weight loss between discharge and 6-month visit with subsequent clinical outcomes in patients with AHF. Methods: We analyzed 686 patients with AHF in the prospective longitudinal follow-up study derived from the Kyoto Congestive Heart Failure registry, and divided them into 2 groups based on the weight loss at 6-month index visit. We defined the weight loss as ≥ 5% decrease in body weight from discharge to 6-month index visit. Results: There were 90 patients (13.1%) with a weight loss at 6-month visit. Patients in the weight loss group compared with those in the no weight loss group had higher body weight at discharge and lower body weight at 6-mont visit. Patients in the weight loss group had a lower systolic blood pressure, higher brain-type natriuretic peptide, lower serum albumin, lower hemoglobin, higher prevalence of heart failure with reduced ejection fraction at 6-month visit, and a lower prescription rate of inhibitors of renin-angiotensin system than those in the no weight loss group. The cumulative 6-month incidence of all-cause death was significantly higher in the weight loss group than in the no weight loss group (14.2% and 4.3%, log-rank P<0.001). The excess adjusted risk of the weight loss group relative to the no weight loss group remained significant for all-cause death (HR 2.39, 95%CI 1.01–5.65, P = 0.048). Conclusion: Body weight loss of ≥5% at 6-month visit after discharge was associated with subsequent all-cause death in patients with AHF. [ABSTRACT FROM AUTHOR]