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To identify factors associated with prehospital intravenous access (IVA) in non-minor emergencies and compare the outcomes of emergency medical service (EMS)-witnessed out-of-hospital cardiac arrest (OHCA) occurring before and after IVA was established. IVA performance varied significantly among prefectures; high performance was associated with a high sensitivity of IVA for subsequent EMS-witnessed OHCA. Cases with a high likelihood of IVA before OHCA included lethal cases, those transported to tertiary emergency hospitals, and medical emergency cases. Among EMS-witnessed OHCA cases, the proportion of hospital transports outside the jurisdiction, physician presence in ambulances, and shockable initial rhythms were higher in patients who received IVA before OHCA than in those who received it afterward. Conversely, incidences of advanced airway management and adrenaline administration were lower. In a multivariate logistic regression model with an interaction test, the neurologically favourable 1-month survival rate was higher in patients who received IVA before OHCA than in those who received it afterward. The impact of IVA before OHCA was more pronounced in OHCA with presumed cardiac aetiology and was negated in cases where prehospital adrenaline was administered. Compared with IVA administered after EMS-witnessed OHCA, IVA performed before OHCA is likely associated with better outcomes.

Background Suicide is a leading cause of death in children. The COVID-19 pandemic might change the characteristics, causes (medical, suicidal, accidental, and other non-medical), and outcomes of pediatric OHCA. This study aimed to investigate the impact of pediatric OHCA in age, location, and quarantine-related movement restriction subgroups. Methods Combining the nationwide OHCA registry with the emergency medical service transportation database, we created a database with detailed information on 7657 non-neonatal, pediatric OHCA cases. Results The pandemic period did not significantly alter neurologically favorable 1-month survival compared to pre-pandemic 4 years (95% confidence interval 0.73-1.00). However, the survival rate significantly decreased in the following subgroups of OHCA: school-age (0.62–0.96), outside of school or home (0.52–0.96), and cases where no quarantine-related movement restrictions were applied (0.68–0.97). There was a prominent increase in the proportion of suicide-related OHCA in these subgroups: from 30.3 to 38.1% (1.22–1.64), from 10.2 to 15.9% (1.21–2.28), and from 12.5 to 17.8% (1.30–1.77), respectively. Conclusion The COVID-19 pandemic did not significantly alter neurologically favorable 1-month survival. However, it led to worsened survival in subgroups with higher suicide attempt rates. Prevention of suicide is likely essential in the assurance of children’s lives during the pandemic. Impact This cohort study found that during the 2020/2021 pandemic, neurologically favorable survival decreased in school-age out-of-hospital cardiac arrest (OHCA) cases, those not subject to quarantine-related movement restrictions, and those in locations outside of school or home. Within these three subgroups, there was a notable rise in OHCA cases related to suicide, historically known to be more challenging to manage successfully. However, survival rates for overall OHCA and medically related OHCA cases remained unchanged throughout the pandemic. Preventive measures for suicide attempts may be necessary to improve the overall survival of pediatric OHCA during the pandemic.

Before meiosis II, centromeric sister chromatid cohesion is protected by shugoshin and protein phosphatase 2A, but the identity of the antagonising kinase has remained unclear. Casein kinase 1 is found to phosphorylate cohesin to promote its cleavage during fission yeast meiosis. During meiosis, the cohesin complexes that maintain sister chromatid cohesion are lost in a stepwise manner 1 , 2 . At meiosis I the cohesin subunit Rec8 is cleaved only along the chromosome arms; until meiosis II it is protected at centromeres by the action of shugoshin (Sgo1)–protein phosphatase 2A (PP2A) 3 , 4 , 5 . Although this regulation hypothetically involves phosphorylation that is antagonized by Sgo1–PP2A, the kinase and substrate that are responsible are as yet unknown 6 , 7 . Using a genetic screen for 'anti-shugoshin', we identify Hhp2, an orthologue of casein kinase 1δ/ɛ (CK1), as a factor required for Rec8 cleavage in fission yeast. We show that CK1, rather than a Polo-like kinase that is widely believed to do so, acts as the cohesin kinase to promote this cleavage during meiosis. Crucially, forced localization of excess Hhp2 at the pericentromeric region abrogates the ability of Sgo1–PP2A to protect centromeric Rec8. Thus, our studies prove the key notion that the balance between Rec8 phosphorylation and its dephosphorylation by Sgo1–PP2A regulates the step-wise loss of chromosomal cohesion in meiosis.

Asia has a disproportionately large share of the world's hepatocellular carcinoma (HCC), mainly because of the endemic status of chronic hepatitis B and C viruses, which leads to liver cirrhosis and an increased risk of HCC. This etiological factor presents important opportunities for prevention, early detection, diagnosis, and treatment of HCC. This consensus statement reviews the available medical evidence for management of HCC in Asia, and gives treatment recommendations that are adapted to resource availability in this diverse region with disparate health-care delivery systems.

Cutibacterium acnes is a major commensal human skin bacteria. It is a producer of propionic acids that maintain skin acidic pH to inhibit the growth of pathogens. On the other hand, it is also associated with diseases such as acne vulgaris and sarcoidosis. C. acnes strains have been classified into six phylotypes using DNA-based approaches. Because several characteristic features of C. acnes vary according to the phylotype, the development of a practical method to identify these phylotypes is needed. For rapid identification of phylotypes for C. acnes strains, a matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) fingerprinting technique has been applied; however, some phylotypes have not been discriminated. We developed a high-throughput protein purification method to detect biomarker proteins by ultrafiltration. MALDI-MS proteotyping using profiling of identified biomarker peaks was applied for the classification of 24 strains of C. acnes, and these were successfully classified into the correct phylotypes. This is a promising method that allows the discrimination of C. acnes phylotypes independent of a DNA-based approach.

Amyloid-β (Aβ) deposition in the brain parenchyma is one of the pathological hallmarks of Alzheimer disease (AD). We have previously identified amyloid precursor protein (APP)669-711 (a.k.a. Aβ(-3)-40) in human plasma using immunoprecipitation combined with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (IP-MALDI-MS). Furthermore, we found that the level of a composite biomarker, i.e., a combination of APP669-711/Aβ1-42 ratio and Aβ1-40/Aβ1-42 ratio in human plasma, correlates with the amyloid PET status of AD patients. However, the production mechanism of APP669-711 has remained unclear. Using in vitro and in vivo assays, we identified A Disintegrin and Metalloproteinase with a Thrombospondin type 1 motif, type 4 (ADAMTS4) as a responsible enzyme for APP669-711 production. ADAMTS4 cleaves APP directly to generate the C-terminal stub c102, which is subsequently proteolyzed by γ-secretase to release APP669-711. Genetic knockout of ADAMTS4 reduced the production of endogenous APP669-711 by 30% to 40% in cultured cells as well as mouse plasma, irrespectively of Aβ levels. Finally, we found that the endogenous murine APP669-711/Aβ1-42 ratio was increased in aged AD model mice, which shows Aβ deposition as observed in human patients. These data suggest that ADAMTS4 is involved in the production of APP669-711, and a plasma biomarker determined by IP-MALDI-MS can be used to estimate the level of Aβ deposition in the brain of mouse models.

In in-source decay (ISD) in matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry (MS), 1,5-diaminonaphthalene (1,5-DAN) is a most frequently used matrix probably due to the highly sensitive detection of fragment ions. 1,5-DAN is a reducing matrix generating c - and z -series ions by N–Cα bond cleavage. However, it is difficult for reducing matrices to distinguish leucine and isoleucine, and generate c (n-1) -series ions owing to proline (Pro) at residues n . Oxidizing matrices providing a - and x -series ions accompanied by d -series ions by Cα–C bond cleavage solve the problem, but their sensitivity of the ISD fragment ions has been lower than reducing matrices such as 1,5-DAN. Recently, 3-hydroxy-4-nitrobenzoic acid (3H4NBA) had been reported as an oxidizing matrix generating a -series ions with higher intensity compared with conventional oxidizing matrices such as 5-nitrosalicylic acid, but a little lower intensity compared with 1,5-DAN (Anal Chem 88, 8058–8063, 2016). In this study, 3H4NBA isomers (2H3NBA, 2H4NBA, 2H5NBA, 2H6NBA, 3H2NBA, 3H5NBA, 4H2NBA, 4H3NBA, 5H2NBA, and 3H4NBA) were evaluated. All the isomers generated a -series ions accompanied by d -series ions, wherein 3H2NBA, 3H5NBA, 4H2NBA, 4H3NBA, and 5H2NBA were first confirmed as oxidizing matrices for ISD. Among the isomers, 3H2NBA and 4H3NBA generated a -series ions with higher peak intensity compared with 3H4NBA for several peptides. Especially, 3H2NBA generated a -series ions with almost the same or higher intensity, and clearly higher peak resolution compared with c -series ions using 1,5-DAN in several cases. 3H2NBA was expected to contribute to ISD analyses in MALDI-MS as one of the most effective oxidizing matrices. Graphical Abstract ᅟ

Mycobacteroides ( Mycobacterium ) abscessus , which causes a variety of infectious diseases in humans, is becoming detected more frequently in clinical specimens as cases are spreading worldwide. Taxonomically, M. abscessus is composed of three subspecies of M. abscessus subsp. abscessus , M. abscessus subsp. bolletii , and M. abscessus subsp. massiliense, with different susceptibilities to macrolides. In order to identify rapidly these three subspecies, we determined useful biomarker proteins, including ribosomal protein L29, L30, and hemophore-related protein, for distinguishing the subspecies of M. abscessus using the matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) profiles. Thirty-three clinical strains of M. abscessus were correctly identified at the subspecies-level by the three biomarker protein peaks. This study ultimately demonstrates the potential of routine MALDI-MS-based laboratory methods for early identification and treatment for M. abscessus infections.

Mesenchymal stem cells are multipotent cells that can differentiate into cardiomyocytes and vascular endothelial cells. Here we show, using cell sheet technology, that monolayered mesenchymal stem cells have multipotent and self-propagating properties after transplantation into infarcted rat hearts. We cultured adipose tissue–derived mesenchymal stem cells characterized by flow cytometry using temperature-responsive culture dishes. Four weeks after coronary ligation, we transplanted the monolayered mesenchymal stem cells onto the scarred myocardium. After transplantation, the engrafted sheet gradually grew to form a thick stratum that included newly formed vessels, undifferentiated cells and few cardiomyocytes. The mesenchymal stem cell sheet also acted through paracrine pathways to trigger angiogenesis. Unlike a fibroblast cell sheet, the monolayered mesenchymal stem cells reversed wall thinning in the scar area and improved cardiac function in rats with myocardial infarction. Thus, transplantation of monolayered mesenchymal stem cells may be a new therapeutic strategy for cardiac tissue regeneration.

High‐resolution matrix‐assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is an emerging application for lipid research that provides a comprehensive and detailed spatial distribution of ionized molecules. Recent lipidomic approach has identified several phospholipids and phosphatidylinositols (PIs) are accumulated in breast cancer tissues and are therefore novel biomarker candidates. Because their distribution and significance remain unclear, we investigated the precise spatial distribution of PIs in human breast cancer tissues using high‐resolution MALDI IMS. We evaluated tissues from nine human breast cancers and one normal mammary gland by negative ion MALDI IMS at a resolution of 10 μm. We detected 10 PIs with different fatty acid compositions, and their proportions were remarkably variable in the malignant epithelial regions. High‐resolution imaging enabled us to discriminate cancer cell clusters from the adjacent stromal tissue within epithelial regions; moreover, this technique revealed that several PIs were specifically localized to cancer cell clusters. These PIs were heterogeneously distributed within cancer cell clusters, allowing us to identify two different populations of cancer cells that predominantly expressed either PI(18:0/18:1) or PI(18:0/20:3). Tracing the expression level of PIs during cancer cell progression suggested that the latter population is associated with the invasion. Our study documents a novel model for phospholipid analysis of breast cancer tissues by using high‐resolution MALDI IMS and identifies candidate PIs that can describe a specific phenotype of cancer cells.