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Abstract One of the most common causes of peritoneal dialysis withdrawal is ultrafiltration failure which is characterized by peritoneal membrane thickening and fibrosis. Although previous studies have demonstrated the inhibitory effect of p38 MAPK inhibitors on peritoneal fibrosis in mice, it was unclear which specific cells contribute to peritoneal fibrosis. To investigate the role of p38 MAPK in peritoneal fibrosis more precisely, we examined the expression of p38 MAPK in human peritoneum and generated systemic inducible p38 MAPK knockout mice and macrophage-specific p38 MAPK knockout mice. Furthermore, the response to lipopolysaccharide (LPS) was assessed in p38 MAPK-knocked down RAW 264.7 cells to further explore the role of p38 MAPK in macrophages. We found that phosphorylated p38 MAPK levels were increased in the thickened peritoneum of both human and mice. Both chlorhexidine gluconate (CG)-treated systemic inducible and macrophage-specific p38 MAPK knockout mice ameliorated peritoneal thickening, mRNA expression related to inflammation and fibrosis, and the number of αSMA- and MAC-2-positive cells in the peritoneum compared to CG control mice. Reduction of p38 MAPK in RAW 264.7 cells suppressed inflammatory mRNA expression induced by LPS. These findings suggest that p38 MAPK in macrophages plays a critical role in peritoneal inflammation and thickening.

Metal–tetrapyrrole cofactors are involved in multiple cellular functions, and chelatases are key enzymes for the biosynthesis of these cofactors. CfbA is an ancestral, homodimeric‐type class II chelatase which is able to use not only Ni2+ as a physiological metal substrate, but also Co2+ as a nonphysiological substrate with higher activity than for Ni2+. The Ni/Co‐chelatase function found in CfbA is also observed in SirB, a descendant, monomeric‐type class II chelatase. This is despite the distinct active site structure of CfbA and SirB; specifically, CfbA shows a unique four His residue arrangement, unlike other monomeric class II chelatases such as SirB. Herein, we studied the Ni‐chelatase activity of SirB variants R134H, L200H, and R134H/L200H, the latter of which mimics the His alignment of CfbA. Our results showed that the SirB R134H variant exhibited the highest Ni‐chelatase activity among the SirB enzymes, which in turn suggests that the position of His134 could be more important for the Ni‐chelatase activity than that of His200. The SirB R134H/L200H variant showed lower activity than R134H, despite the four His residues found in SirB R134H/L200H. CD spectroscopy showed secondary structure denaturation and a slight difficulty in Ni‐binding of SirB R134H/L200H, which may be related to its lower activity. Finally, a docking simulation suggested that the His134 of the SirB R134H variant could function as a base catalyst for the Ni‐chelatase reaction in a class II chelatase architecture.

We successfully treated a 4-year-old girl with short bowel syndrome and eosinophilic enterocolitis with teduglutide, a glucagon-like peptide-2 analog. Her eosinophilic enterocolitis was cured without relapse, and we were able to increase enteral nutrition. We found that teduglutide had an anti-inflammatory effect in this patient with eosinophilic gastrointestinal disease associated with short bowel syndrome. This report is the first to describe use of teduglutide in the treatment of eosinophilic gastrointestinal disease.

Background: Acute gastroenteritis is one of the major causes of morbidity and mortality in young children worldwide. Among these, rotavirus, norovirus, and adenovirus have been reported as the primary viral pathogens associated with the disease. Rapid diagnosis of viral pathogens is crucial when diarrhea outbreaks occur to ensure the timely administration of appropriate treatment and control measures. Methods: We evaluated three immunochromatographic test kits designed for the detection of norovirus, rotavirus, and adenovirus in 71 stool specimens collected from children with diarrhea who visited clinics in Japan. The first kit is a triplex immunochromatographic test kit designed for simultaneous detections of norovirus, rotavirus, and adenovirus on a single strip (this kit was referred to as IC-A). The other two immunochromatographic test kits are a dual detection kit for rotavirus and adenovirus, and a single detection kit for norovirus (IC-B). The RT-PCR/PCR was used as the gold standard method. Results: The results revealed that both IC-A and IC-B kits exhibited the same level of sensitivity of detection for rotavirus (72.7%) and adenovirus (22.7%), although the detection rate was lower than that of the RT-PCR/PCR method. However, there was a slight difference in the sensitivity of detection for norovirus between IC-A and IC-B, at 86.7% and 93.3%, respectively. The sensitivity of detection for adenovirus of both kits was relatively lower than those of RT-PCR method. This could be due to low viral load of adenovirus in clinical specimens below the detection limit of IC-A and IC-B kits. However, both immunochromatographic test kits (IC-A and IC-B) exhibited 100% specificity for norovirus, rotavirus, and adenovirus. Conclusions: The triplex immunochromatographic test kit (IC-A) designed for simultaneous detection of norovirus, rotavirus, and adenovirus has been proved to be more practical and convenient than the use of single or dual detection kits with more or less the same sensitivity and specificity of detections.

Ovarian mature teratomas are benign, but malignant transformation can occur infrequently, especially in women of advanced age. The tissue that undergoes malignant change is mostly squamous cell carcinoma, although adenocarcinoma has been reported in a small number of cases. The immunostaining results of adenocarcinoma usually show a cytokeratin (CK)7−/CK20+ expression profile, corresponding to lower gastrointestinal tract origin. In this report, we describe a case of mucinous carcinoma arising from an ovarian mature teratoma showing a CK7+/CK20+ profile and discuss its imaging features. A 40-year-old woman presented to her primary care physician with abdominal distension and poor oral intake, and she was referred to our hospital. She had been diagnosed with an ovarian mature teratoma at our institution 3 years earlier. At the current presentation, pelvic magnetic resonance imaging showed a large multilocular cystic mass with adipose tissue extending into the upper abdomen. Densely packed cysts were observed inside the mass, which showed weak contrast enhancement on contrast-enhanced imaging and a mildly high signal on diffusion-weighted imaging. A portion of the cysts also showed abnormal 18F-fluorodeoxyglucose uptake (maximum standardized uptake value, 13.2) on positron emission tomography/computed tomography. The patient was subsequently diagnosed with mucinous carcinoma showing a CK7+/CK20+ profile arising from a mature teratoma by pathologic examination. This mucinous carcinoma arising from a mature teratoma showed a CK7+/CK20+ profile and took the form of densely packed multilocular cysts. In this respect, it was similar to primary ovarian epithelial mucinous carcinoma on both magnetic resonance imaging and pathologic examination despite showing a much higher maximum standardized uptake value than that of primary ovarian mucinous carcinoma. When a large ovarian teratoma contains a large multilocular cyst, the presence of densely packed multilocular cysts should not be missed even in a mass without solid components. Clinicians should consider the possibility of mucinous carcinoma showing a CK7+/CK20+ profile arising from a mature teratoma in such cases.

Background: Human norovirus is a predominant etiological agent responsible for acute gastroenteritis across all age groups. Recently, norovirus recombinant strains have been reported as the cause of norovirus outbreaks in several settings and the strains that cause outbreaks mostly belong to the norovirus GII. However, yet, the norovirus GI recombinant strains have never been reported previously in Thailand. The aims of this study were to investigate the genetic recombination and genotype diversity of norovirus GI strains in children hospitalized with acute gastroenteritis in Chiang Mai, Thailand during a period of seven years from 2015 to 2021. Methods: A total of 2829 stool specimens were screened for norovirus GI by real-time PCR, and the polymerase and capsid genes were sequenced and analyzed. Results: Of 2829 specimens tested, 12 (0.4%) were positive for norovirus GI. Of these, 7 out of 12 (58.3%) strains were identified as norovirus GI recombinant strains. Among 7 norovirus GI recombinant strains, 3, 3, and 1 were identified as GI.3[P13], GI.5[P4], and GI.6[P11], respectively. The remaining five strains were identified as non-recombinant strains of the GI.4[P4], GI.5[P5], and GI.6[P6] genotypes. Conclusions: The findings highlight the genetic diversity and multiple intergenotype recombinant strains of norovirus GI circulating in children with acute gastroenteritis in Chiang Mai, Thailand from 2015 to 2021. The detection of multiple intergenotype norovirus GI recombinant strains further underscore the complexity of norovirus GI strains circulating in this region.

Background: Altruistic cooperation (AC) is essential in human social interactions. Previous studies have investigated AC-related behavior in children with autism spectrum disorder (ASD), revealing that there is considerable individual variability in the behavior. However, this issue is still largely unexplored especially in the adult population. Aims: To investigate individual differences in AC-related behavior, we conducted the resource allocation task (RAT) and modified version of the ultimatum game (mUG) among adults with and without ASD. Methods and procedures: The study employed a cross-sectional design, involving 27 adults with ASD (mean age 29.1 ± 4.3 years; three females) and 27 adults with typical development (TD) (mean age 25.8 ± 6.7 years; two females), who completed the RAT and mUG tasks. Beyond clinical characteristics, we assessed three primary psychological metrics: the interpersonal reactivity index (IRI), Barratt impulsiveness scale, and the behavioral inhibition and activation systems. Outcomes and results: No significant differences were observed in the proportions of participants with high AC when assessed by RAT (p = 0.15) and mUG (p = 0.59) between the TD and ASD groups. Participants with high AC from the RAT demonstrated higher perspective-taking scores on the IRI than those with low AC within both the TD (p = 0.04) and ASD groups (p = 0.03). In the TD group, high AC individuals also scored higher on the IRI's fantasy subscale as per the mUG (p = 0.03); however, this trend was not present in the ASD group. Conclusions and implications: The present findings indicate that empathy plays an important role in individual differences in AC-related behavior among adults with and without ASD, although the role could be different depending on the types of AC-related behavior between TD and ASD populations.

ABSTRACT During surveillance of Staphylococcus aureus in lesions from patients with atopic dermatitis (AD), we isolated Staphylococcus argenteus, a species registered in 2011 as a new member of the genus Staphylococcus and previously considered a lineage of S. aureus. Genome sequence comparisons between S. argenteus isolates and representative S. aureus clinical isolates from various origins revealed that the S. argenteus genome from AD patients closely resembles that of S. aureus causing skin infections. We previously reported that 17%–22% of S. aureus isolated from skin infections produce staphylococcal enterotoxin Y (SEY), which predominantly induces T-cell proliferation via the T-cell receptor (TCR) Vα pathway. Complete genome sequencing of S. argenteus isolates revealed a gene encoding a protein similar to superantigen SEY, designated as SargEY, on its chromosome. Population structure analysis of S. argenteus revealed that these isolates are ST2250 lineage, which was the only lineage positive for the SEY-like gene among S. argenteus. Recombinant SargEY demonstrated immunological cross-reactivity with anti-SEY serum. SargEY could induce proliferation of human CD4+ and CD8+ T cells, as well as production of TNF-α and IFN-γ. SargEY showed emetic activity in a marmoset monkey model. SargEY and SET (a phylogenetically close but uncharacterized SE) revealed their dependency on TCR Vα in inducing human T-cell proliferation. Additionally, TCR sequencing revealed other previously undescribed Vα repertoires induced by SEH. SargEY and SEY may play roles in exacerbating the respective toxin-producing strains in AD.IMPORTANCEStaphylococcus aureus is frequently isolated from active lesions of atopic dermatitis (AD) patients. We reported that 17%–22% of S. aureus isolated from AD patients produced a novel superantigen staphylococcal enterotoxin Y (SEY). Unlike many S. aureus superantigens that activate T cells via T-cell receptor (TCR) Vß, SEY activates T cells via TCR Vα and stimulates cytokine secretion. Staphylococcus argenteus was isolated from AD patients during the surveillance for S. aureus. Phylogenetic comparison of the genome indicated that the isolate was very similar to S. aureus causing skin infections. The isolate encoded a SEY-like protein, designated SargEY, which, like SEY, activated T cells via the TCR Vα. ST2250 is the only lineage positive for SargEY gene. ST2250 S. argenteus harboring a superantigen SargEY gene may be a novel staphylococcal clone that infects human skin and is involved in the exacerbation of AD.

Background: People worldwide are routinely exposed to tellurium mainly via dietary ingestion. There has been no study to clarify the contribution of tellurium to blood pressure in humans or animals. Methods: In this cross-sectional study conducted in a general population of 2592 residents in Japan, the associations of urinary tellurium levels with blood pressure and prevalence of hypertension were investigated. The potential sources of tellurium were also investigated. An interventional study in mice confirmed the effect of tellurium exposure on blood pressure. Results: Linear and logistic regression analyses with consideration of confounders including urinary sodium–potassium ratio showed significant positive associations of urinary tellurium level with prevalence of hypertension and blood pressure. Cereals/beans and vegetables/fruits were determined to be potential dietary sources of tellurium exposure. Intermediary analysis suggested that increased intake of cereals/beans, but not that of vegetables/fruits, is positively associated with the tellurium-mediated risk of hypertension. Correspondingly, the mouse study showed that exposure to a putative human-equivalent dose of tellurium via drinking water increased blood pressure with an elevated level of urinary tellurium. The temporally increased blood pressure was decreased to the normal level by a break of tellurium exposure with a reduced level of urinary tellurium. Conclusions: The interdisciplinary approach provided the first evidence that tellurium exposure is a potential risk for increase of blood pressure. Since the human urinary tellurium level in this study is comparable with the levels in general populations in other Asian and European countries in previous studies, exposure to tellurium may be a latent universal risk for hypertension.

Background: Human astrovirus (HAstV) infection is one of the leading causes of acute gastroenteritis in young children. The present study reports the outbreak of HAstV in children with acute gastroenteritis in Kyoto, Japan, during the COVID-19 pandemic, 2021. Methods: A total of 61 stool samples were collected from children with acute gastroenteritis who visited a pediatric outpatient clinic in Maizuru city, Kyoto, Japan from July to October, 2021. HAstV was screened by RT-PCR, and the genotypes were identified by nucleotide sequence analysis. Results: Of 61 cases of acute gastroenteritis, 20 were mono-infected with HAstV alone. In addition, mixed infection of HAstV and NoV, and HAstV and RVA were also detected in 15 and 1 cases, respectively. Of 36 HAstV strains detected in this outbreak, 29 and 7 were HAstV1 and MLB2 genotypes, respectively. All HAstV1 strains were closely related to the HAstV1 reported from Thailand and Japan in 2021 and all of them belonged to subgenotype HAstV1a. Among MLB2, they were most closely related to the MLB2 strains reported from China in 2016 and 2018. Conclusions: After the kindergartens and schools were re-opened at the middle of 2021 in Japan, an outbreak of HAstV was reported. Control measures against the COVID-19 pandemics might affect the spread of diarrheal virus infection. Here we report the outbreak of HAstV1 and MLB2 in Kyoto, Japan, during COVID-19 pandemic in 2021.

Background: Active molecular surveillance and rapid diagnosis method to track an outbreak of norovirus in Bangladesh is lacking. This study aims to determine the genotypic diversity, molecular epidemiology and evaluate a rapid diagnosis method. Methods: A total of 404 fecal specimens were collected from children aged below 60 months from January 2018 to December 2021. All samples were analyzed by reverse transcriptase polymerase chain reaction molecular sequencing of partial VP1 nucleotide. Immunochromatography kit (IC, IP Rota/Noro) was evaluated against reference test method. Results: We found norovirus in 6.7 % (27 of 404) fecal specimens. A wide diversity of norovirus genotype including GII.3, GII.4, GII.5, GII.6, GII.7, and GII.9 were detected. Norovirus strain GII.4 Sydney-2012 was the most predominant (74 %, 20 of 27) followed by GII.7 (7.4 %), GII.9 (7.4 %), GII.3 (3.7 %), GII.5 (3.7 %) and GII.6 (3.7 %), respectively. Co-infection of rotavirus and norovirus (19 [4.7 %] of 404) was the most prevalent. We found higher odds of prolonged health impact [OR 1.93 (95 % CI 0.87–3.12) (p = .001)] among patients with co-infection. The incidence of norovirus was significant among the children below 24 months (p = 0.001). Significant relation of temperature with the cases of norovirus was detected (p = 0.001). The IC kit provided high specificity (99.3 %) and sensitivity (100 %) for the detection of norovirus. Conclusions: This study will provide an integrated insight on the genotypic diversity and rapid identification method of norovirus in Bangladesh.

Excessive gameplay can have negative effects on both mental and physical health, especially among young people. Nowadays, social media platforms are bombarding users with gaming-related content daily. Understanding the effect of this content on people’s behavior is essential to gain insight into problematic gaming habits. However, this issue is yet to be studied extensively. In this study, we examined how gaming-related content on social media affects young adults explicitly and implicitly. We studied 25 healthy young adults (average age 21.5 ± 2.2) who played online games casually and asked them to report their gaming desire. We also conducted an implicit association test (IAT) to measure their implicit attitudes toward gaming-related content. We also investigated the relationship between these measures and various psychological factors, such as personality traits, self-efficacy, impulsiveness, and cognitive flexibility. The results revealed that participants had a higher explicit gaming desire when exposed to gaming-related cues on social media than neutral cues. They also had a robust positive implicit attitude toward gaming-related content on social media. Explicit gaming desire was positively correlated with neuroticism levels. Furthermore, the IAT effect was negatively correlated with self-efficacy and cognitive flexibility levels. However, there were no significant correlations between explicit gaming desire/IAT effect and impulsiveness levels. These findings suggest that gaming-related content on social media can affect young adults’ behavior both explicitly and implicitly, highlighting the need for further research to prevent gaming addiction in vulnerable individuals.

Introduction: H-type anorectal malformation (ARM) is a rare type defined as a congenital ano-recto-urogenital communication with an external anal opening in a normal or ectopic position. The management of male H-type ARM is controversial because of its rarity and diverse phenotypes. Excision or ligation of the fistula using the anterior perineal approach has mostly been selected for treatment in previous reports, but recurrence of the fistula is not uncommon. Case presentation: An 18-day-old boy presented to our hospital with abdominal bloating and bilious emesis. Anal stenosis was detected on examination. Dilatations by bougienage and enemas were initiated. He experienced urinary infections twice at within the following month. At seven months of age, his mother noticed gas and fecal discharge from his urethral opening. Retrograde cystourethrography and contrast enema revealed a rectourethral fistula, leading to the diagnosis of an H-type ARM. We did a rectal pull-through using the posterior sagittal anorectoplasty (PSARP) approach, with a sigmoid colostomy to minimize the risk of recurrence. The postoperative course was uneventful and there were no complications. The patient had good urinary function and defecation without fistula recurrence. Conclusion: Rectal pull-through with a PSARP seems to be an effective procedure for the management of male H-type ARM.

Abstract Background There is no unified view of the necessity of prophylactic antimicrobial agents in trabeculectomy. Preoperative prophylactic antimicrobial agent injection and cefazolin sodium (CEZ) for trabeculectomy were discontinued at the Hiroshima University Hospital. In this study, we evaluated whether discontinuation of preoperative administration of CEZ in ophthalmology affects the incidence of postoperative infections. Methods We retrospectively investigated patient background, concomitant medications, subconjunctival dexamethasone sodium phosphate (DEX) injection at the end of the surgery, and the incidence of infective endophthalmitis within 6 weeks after surgery in the CEZ and non-CEZ groups. We also performed propensity score matching for background matching. Statistical analysis was performed using the Mann-Whitney U-test and Fisher’s exact test. Results The incidence of postoperative endophthalmitis was not significantly different between 629 and 751 patients in the CEZ and no-CEZ groups, respectively (0 in the CEZ group and 2 in the no-CEZ group, P = 0.504). More patients in the CEZ group were taking diabetes drugs preoperatively (P = 0.028) and fewer patients were receiving subconjunctival DEX at the end of surgery (P

Abstract Background Abnormal cardiotocogram (CTG) tracing may appear after induction of neuraxial labor analgesia. Non-reassuring fetal status (NRFS) indicated by severely abnormal tracings, such as prolonged deceleration (PD) or bradycardia, can necessitate immediate operative delivery. Combined spinal epidural analgesia (CSEA) is known to result in more frequent abnormal tracings than epidural analgesia (EA); however, the corresponding data related to dural puncture epidural (DPE) are unclear. We aimed to evaluate the rates of incidence of severe abnormal CTG after induction of DPE and CSEA. Methods In this study of nulliparous women with full-term pregnancy, data for the DPE intervention group were prospectively collected, while those for the CSEA control group were obtained from medical records. Neuraxial analgesia was performed with cervical dilation ≤ 5 cm, administering initial epidural dosing of 15 mL of 0.125% levobupivacaine with fentanyl 2.5µg/mL for DPE, and intrathecal 0.5% bupivacaine 2.5 mg (0.5ml), fentanyl 10 µg (0.2ml), and 1.3 mL of saline for CSEA. The primary outcome was the incidence of PD, defined as a fetal heart rate reduction ≥ 15 bpm below the baseline and with a lowest value

Abstract Background Segmental dilatation of the colon (SDC) is a rare disease that is characterized by an abrupt segment of dilated colon between regions of normal-sized colon. We herein report a case of SDC associated with Hirschsprung’s disease (HD). Case presentation The patient developed abdominal distension soon after birth, and enema examination showed localized intestinal dilatation from the descending colon to the sigmoid colon with significant caliber changes on both the oral and anal sides of the dilated colon. The findings of the rectal mucosal biopsy were consistent with HD. We considered this case to be a combination of HD and SDC and performed laparoscopic-assisted Soave pull-through with resection of the dilated colon when the patient was 7 months old. Resected specimens showed steep caliber changes on the oral and anal sides of the dilated colon. In the pathological examination, no ganglion cells were found in the submucosa on the anal side of the dilated colon. Based on the above findings, we finally made the diagnosis of HD with SDC. Conclusion In HD with a characteristic dilated colon, the possibility of SDC should be considered.

The Wada test is the gold standard for determining language-dominant hemisphere. However, the precise determination of language areas in each patient requires more invasive methods, such as electrocortical stimulation. Some studies have reported the use of anesthetic injection into selective cerebral arteries to predict postoperative function. To assess the function of the anterior and posterior language areas separately, we developed an advanced test named the “super-selective Wada test” (ssWada). The ssWada procedure is as follows: an endovascular neurosurgeon identifies the arterial branches of the middle cerebral artery (MCA) perfusing the anterior language area of the inferior frontal gyrus and the posterior language area of the posterior part of the superior temporal gyrus using angiography. Behavioral neurologists assess language symptoms before and after propofol administration using a microcatheter tip in the selected arterial branch. From 30 serial patients with epilepsy who underwent ssWada test at Tohoku University Hospital, we retrospectively reviewed patients in whom multiple areas in the bilateral MCA region was examined. Eight cases were identified in this study. All eight cases had been considered for resection of the area overlapping the classical language area. Three of the eight cases were left-dominant, and the within-hemisphere distribution was also considered typical. One case was determined to be left-dominant but atypical in the intra-hemispheric functional distribution. Two cases were right-dominant, and the intra-hemispheric functional distribution was considered a mirror image of the typical pattern. The remaining two cases were considered atypical, not only in terms of bilateral language function, but also in terms of anterior-posterior functional distribution. This case series demonstrates the potential utility of ssWada in revealing separate function of the anterior and posterior language areas. The ssWada allows simulation of local surgical brain resection and detailed investigation of language function, which potentially contributes to planning the resection area. Although indications for ssWada are quite limited, it could play a complementary role to noninvasive testing because it provides information related to resection using a different approach.

Abstract Japanese asteroid explorer Hayabusa2 arrived at C-type asteroid 162,173 Ryugu in June 2018. The laser altimeter (LIDAR) onboard Hayabusa2 measured its own transmitted laser and returned pulse intensities from a Ryugu surface until November 2019. Because the Ryugu surface is extremely rough, topography dominates over the material properties in the conventional derivation of normal albedo. Thus, we developed a method to retrieve the normal albedo from the rough surface of a C-type asteroid at a LIDAR laser wavelength of 1.064 μm. The albedo map covering an equatorial band between – 40° and + 20° in latitude was created with 3˚-by-3˚ resolution using the intensity data obtained before the conjunction of the spacecraft with the Sun. The average of the normal albedo is 0.0405 $$\pm$$ ± 0.0027, whereas approximately half of the 3°-by-3° grids are between 0.04 and 0.045. The low and uniform normal albedo feature is common to other remote-sensing observations of Ryugu by visible and near-infrared cameras onboard Hayabusa2. Graphical Abstract

ABSTRACT Atopic dermatitis (AD) shows frequent recurrence. Staphylococcus aureus is the primary microbial component in AD and is associated with disease activity. However, traditional typing methods have failed to characterize virulent AD isolates at the clone level. We conducted a comprehensive genomic characterization of S. aureus strains isolated from the skin of AD patients and healthy donors, comparing the whole-genome sequences of the 261 isolates with anatomical and lesional (AD-A)/nonlesional (AD-NL)/healthy sites, eruption types, clinical scores, virulence, and antimicrobial resistance gene repertoires in Japan. Sequence type (ST) diversity was lost with worsening disease activity; ST188 was the most frequently detected ST in AD-A and had the strongest correlation with AD according to the culture rate and proportion with worsening disease activity. ST188 and ST20 isolates inhabited all skin conditions, with significantly higher proportions in AD skin than in healthy skin. ST8, ST15, and ST5 proportions were equivalent for all skin conditions; ST30 was detected only in healthy skin; and ST12 was detected only in AD skin. ST97 detected in AD-A and healthy skin was clearly branched into two subclades, designated ST97A and ST97H. A comparison of two genomes led to the discovery that only ST97A possessed the complete trp operon, enabling bacterial survival without exogenous tryptophan (Trp) on AD skin, where the Trp level was significantly reduced. Primary STs showing an AD skin inhabitation trend (ST188, ST97A, ST20, and ST12) were all trp operon positive. The predominant clones (ST188 and ST97) possessed almost no enterotoxin genes, no mecA gene, and few other antimicrobial resistance genes, different from the trend observed in Europe/North America. IMPORTANCE While Staphylococcus aureus is a member of the normal human skin flora, its strong association with the onset of atopic dermatitis (AD) has been suggested. However, previous studies failed to assign specific clones relevant to disease activities. Enterotoxins produced by S. aureus have been suggested to aggravate and exacerbate the inflammation of AD skin, but their role remains ambiguous. We conducted a nuanced comprehensive characterization of isolates from AD patients and healthy donors, comparing the whole-genome sequences of the isolates with anatomical and lesional/nonlesional/healthy sites, eruption types, clinical scores, virulence, and antimicrobial resistance gene repertoires in Japan. We demonstrate that specific clones are associated with disease severity and clinical manifestations, and the dominant clones are devoid of enterotoxin genes and antimicrobial resistance genes. These findings undermine the established notion of the pathophysiological function of S. aureus associated with AD and introduce a new concept of S. aureus colonization in AD.

ABSTRACT Human astroviruses (HAstVs) are important causative pathogens of acute gastroenteritis (AGE) in children worldwide. MLB and VA HAstVs, which are genetically distinct from the previously known classic HAstVs, have been detected since 2008. To investigate the role of HAstVs in AGE, we conducted molecular detection and characterization of HAstVs circulating in children with AGE in Japan from 2014 to 2021. Out of 2,841 stool samples, HAstVs were detected in 130 (4.6%). MLB1 was the predominant genotype detected (45.4%), followed by HAstV1 (39.2%), MLB2 (7.4%), VA2 (3.1%), HAstV3 (2.3%), HAstV4, HAstV5, and MLB3 (0.8% each). The results demonstrated that HAstV infection in pediatric patients in Japan was dominated by the two major genotypes MLB1 and HAstV1, with a small proportion of other genotypes. The overall infection rates of MLB and VA HAstVs were higher than those of classic HAstVs. The HAstV1 strains detected in this study belonged solely to lineage 1a. The rare MLB3 genotype was detected for the first time in Japan. All three HAstV3 strains belonged to lineage 3c based on the ORF2 nucleotide sequence and were shown to be recombinant strains. IMPORTANCE HAstVs are one of the pathogens of viral AGE and are considered the third most common viral agents of AGE after rotavirus and norovirus. HAstVs are also suspected to be the causative agents of encephalitis or meningitis in immunocompromised patients and elderly persons. However, little is known about the epidemiology of HAstVs in Japan, especially that of MLBs and VA HAstVs. This study demonstrated epidemiological features and molecular characterization of human astroviruses encompassing a 7-year study period in Japan. This study highlights the genetic diversity of HAstV circulating in pediatric patients with acute AGE in Japan.

The “meal first” strategy is traditionally recommended for athletes' conditioning. However, the importance of the “meal first” principle has not been detailly well documented in athletes' lives. Supplement use has recently become a common part of athletes' diets, but unmonitored supplement use can cause negative consequences, such as anti-doping violations and health issues. Therefore, this review summarizes how the “meal first” strategy and planned supplement use are important for enhancing athletes’ health and performance. We believe that the “meal first” strategy is beneficial in terms of the following aspects: (1) consumption of multi-nutrients and other functional components simultaneously; (2) positive effects on psychological well-being; (3) contribution to athletes' health by way of mastication; and (4) less risk for anti-doping violations. Before supplement use, we recommend that athletes first verify their basic factors (e.g., diet, training, and sleep), given that the benefits of supplements are examined and demonstrated with the control of those factors. Otherwise, athletes cannot obtain maximal benefits from the supplements. In contrast, there are situations in which supplements in athletes' lives can be advantageous, such as (1) nutrient deficiency due to ongoing dietary characteristics; (2) interruption of meals due to disease; (3) inaccessibility of quality food during athletic travel; (4) difficulty preparing food due to societal restrictions associated with disasters or infection outbreaks; (5) having a meal before, during, or after exercise is difficult; and (6) achieving targeted intake of performance-enhancing ingredients is not practical. In summary, we emphasize that the “meal first” strategy is recommended for athletes' conditioning, but there are several contexts when supplement use can be more useful in athletes' lives.

Background: Rotavirus A (RVA) is a major cause of severe acute gastroenteritis (AGE) in infants and children worldwide. In Japan, two kinds of rotavirus vaccines have been introduced as voluntary vaccines in 2011 and 2012, respectively, and launched into the national vaccine program in October 2020. Methods: In this study, we investigated prevalence of RVA and their molecular characterization in the stool samples collected from infants and children with AGE who visited one outpatient clinic in Japan, from July 2014 to June 2020, during voluntary vaccination with two kinds of rotavirus vaccines. Results: The RVA detection rates decreased from 44.7 % in 2014–2015 to 35.4 % in 2018–2019, whereas in 2019–2020 the numbers of samples collected were dramatically decreased and none of RVA was detected. During this study period, rotavirus vaccination rates in this area increased from 32.4 % to 62.2 %. Distribution of RVA VP7 (G), VP4 (P), and VP6 (I) genotypes in this area had changed year by year; the major genotype combinations were G1P[8]I1 and G1P[8]I2 in 2014–2015, G2P[4]I2 and G9P[8]I1 in 2015-2016, G1P[8]I1 and G8P[8]I2 in 2017–2018, and G8P[8]I2 in 2018–2019. Phylogenetic analysis demonstrated that VP7 nucleotide sequences of G1 were genetically diverse compared with those of other G genotypes in this study. Meanwhile, predominance of unusual G2P[8]I1, G2P[8]I2 and mixed P genotypes were observed only in 2016–2017, but did not carry on in 2017–2019. The equine-like G3 was detected only in 2016–2017. Conclusions: The results revealed diversity of RVA genotypes and the genotype combinations have changed year by year in Japan, during the study period of 2016–2020.

Level 3 automated driving requires a driver to operate a vehicle in response to a takeover request according to the Society of Automotive Engineers; therefore, the driver should maintain a state of wakefulness. The study aimed to evaluate and verify whether the presented stimuli, i.e., saccade-inducing stimuli (SaS) as visual stimuli, scent stimuli (ScS) as olfactory stimuli, and a combination of saccade-inducing and scent stimuli (CoS), can maintain the wakeful state of a driver. A driving simulator (DS) that can reproduce the actual movement of a motor vehicle using a turn table and six-axis motion device is used to simulate driving under four different conditions: no stimulation, SaS, ScS, and CoS. The percentage of eye closure (PERCLOS) and the electroencephalogram (EEG) analysis were used for the quantitative evaluation, while the participants were subjected to subjective evaluation. The results showed that the average increase in arousal time for each condition was 30.2, 53.7, and 82.3% for the SaS, ScS, and CoS cases, respectively. The average reduction rate in the EEG readings was 39.9, 41.0, and 71.4% for the SaS, ScS, and CoS cases, respectively. All participants indicated that the CoS had the highest effect of arousal as a driver stimulation tool.

Abstract Background Endocytoscopy (ECS) enables microscopic observation in vivo for the gastrointestinal mucosa; however, there has been no prospective study in which the diagnostic accuracy of ECS for lesions that have not yet undergone histological diagnosis was evaluated. We conducted a surveillance study for patients in a high-risk group of esophageal squamous cell carcinoma (ESCC) and evaluated the in vivo histological diagnostic accuracy of ECS. Methods This study was a multicenter prospective study. We enrolled 197 patients in the study between September 1, 2019 and November 30, 2020. The patients first underwent white light imaging and narrow band imaging, and ultra-high magnifying observation was performed if there was a lesion suspected to be an esophageal tumor. Endoscopic submucosal dissection (ESD) was later performed for lesions that were diagnosed to be ESCC by ECS without biopsy. We evaluated the diagnostic accuracy of ECS for esophageal tumorous lesions. Results ESD was performed for 37 patients (41 lesions) who were diagnosed as having ESCC by ECS, and all of them were histopathologically diagnosed as having ESCC. The sensitivity [95% confidence interval (CI)] was 97.6% (87.7–99.7%), specificity (95% CI) was 100% (92.7–100%), diagnostic accuracy (95% CI) was 98.9% (94.0–99.8%), positive predictive value (PPV) (95% CI) was 100% (91.4–100%) and negative predictive value (NPV) (95% CI) was 98.0% (89.5–99.7%). Conclusions ECS has a high diagnostic accuracy and there were no false positives in cases diagnosed and resected as ESCC. Optical biopsy by using ECS for esophageal lesions that are suspected to be tumorous is considered to be sufficient in clinical practice.

Background: Human sapovirus (SaV) is an important etiologic agent of childhood diarrhea. This study aims to investigate the burden of SaV infection in childhood diarrhea in Japan from 2009–2019, to understand the changes in SaV infection after the introduction of rotavirus (RV) vaccination in Japan in 2011. Methods: Stool samples were collected from children aged ≤ 12 years old with acute gastroenteritis (AGE) who visited outpatient clinics of six prefectures in Japan. The viral RNA was detected by RT-PCR and genogroups and genotypes were determined through sequence-based analysis. Results: Among 5697 stool samples, 318 (5.6%) samples remained SaV-positives showing the highest prevalence in June and 12–24 month aged children. The most predominant genotype was GI.1 (56.8%), followed by GI.2 (19.2%), GII.1 (10.8%), GIV.1 (9.4%), GI.3 (1.7%), GII.2 (1.4%), GII.3 and GII.5 (0.3%). Importantly, an increasing trend (P = 0.016) of SaV infection was observed during this period. In particular, SaV-detection rate was increased significantly (P = 0.033) from 4.3% in pre-rotavirus (RV)-vaccination era to 6.1% in post-RV-vaccination era. We provided evidence that this increase in SaV infection was mainly attributed by coinfections. Conclusions: The upward trend of SaV infection, particularly after the introduction of RV-vaccination, is an emerging concern. Attention should be paid to control this upward trend of SaV infection to ensure maximum benefits of implementation of RV vaccines towards reducing overall childhood diarrhea worldwide.

Abstract Most patients with ovarian cancer experience recurrence and develop resistance to platinum-based agents. The diagnosis of platinum resistance based on the platinum-free interval is not always accurate and timely in clinical settings. Herein, we used laser ablation inductively coupled plasma mass spectrometry to visualize the platinum distribution in the ovarian cancer tissues at the time of interval debulking surgery after neoadjuvant chemotherapy in 27patients with advanced high-grade serous ovarian cancer. Two distinct patterns of platinum distribution were observed. Type A (n = 16): platinum accumulation at the adjacent stroma but little in the tumor; type B (n = 11): even distribution of platinum throughout the tumor and adjacent stroma. The type A patients treated post-surgery with platinum-based adjuvant chemotherapy showed significantly shorter periods of recurrence after the last platinum-based chemotherapy session (p = 0.020) and were diagnosed with “platinum-resistant recurrence”. Moreover, type A was significantly correlated with worse prognosis (p = 0.031). Post-surgery treatment with non-platinum-based chemotherapy could be effective for the patients classified as type A. Our findings indicate that the platinum resistance can be predicted prior to recurrence, based on the platinum distribution; this could contribute to the selection of more appropriate adjuvant chemotherapy, which may lead to improves prognoses.

Sapoviruses, like noroviruses, are single-stranded positive-sense RNA viruses classified in the family Caliciviridae and are recognized as a causative pathogen of diarrhea in infants and the elderly. Like human norovirus, human sapovirus (HuSaV) has long been difficult to replicate in vitro. Recently, it has been reported that HuSaV can be replicated in vitro by using intestinal epithelial cells (IECs) derived from human tissues and cell lines derived from testicular and duodenal cancers. In this study, we report that multiple genotypes of HuSaV can sufficiently infect and replicate in human-induced pluripotent stem cell-derived IECs. We also show that this HuSaV replication system can be used to investigate the conditions for inactivation of HuSaV by heat and alcohol, and the effects of virus neutralization of antisera obtained by immunization with vaccine antigens, under conditions closer to the living environment. The results of this study confirm that HuSaV can also infect and replicate in human normal IECs regardless of their origin and are expected to contribute to future virological studies.

In plant genomes, both mCG and H3K9me2/mCH are important for silencing transposable elements (TEs). Here, the authors show that establishment of mCH is abolished in both TE and active genes when mCG is lost and targeting efficiency of mCH depends on relative levels of mCG within the genome.

Aberrant glycosylation is a prominent feature of cancer, that can be used as targets to improve the existing cancer biomarkers, and help to assess metastasis risks, and therapeutic effects. We developed a targeted O-glycoproteomics method using serum specimens, and evaluated its utility in identifying advanced colorectal cancer (CRC) markers. To this end, we combined consecutive lectin affinity purification using Maclura pomifera lectin (MPL), jacalin, and Sambucus nigra lectin, which have affinities for the following O-glycans, that have received attention as cancer-related antigens, Tn (GalNAc-Ser/Thr), Sialyl Tn (Siaα2-6GalNAc-Ser/Thr), T (Galβ1-3GalNAc-Ser/Thr), Sialyl T (Siaα2-3Galβ1-GalNAc-Ser/Thr), and di-Sialyl T (Siaα2-3Galβ1-3[Siaα2-6] GalNAc-Ser/Thr), with a unique O-glycoproteomics approach. A total of 2,068 O-glycoforms derived from 265 proteins were identified in healthy individuals and patients with advanced CRC, of which 44 CRC-specific O-glycoforms were extracted. Particularly, five glycoproteins with T, Sialyl T, and di-Sialyl T antigens in specific peptide regions were evaluated quantitatively and statistically. We found that fibulin-2 (FBLN2) (aa330-349)/T antigen (area under the curve [AUC] = 0.92); macrophage colony-stimulating factor 1 (CSF1) (aa370-395)/(T + di-Sialyl T) (AUC = 0.94); macrophage mannose receptor 1 (MRC1) (aa1083-1101 and aa1215-1229)/T (AUC = 0.96 and 0.99); fibrinogen alpha chain (FGA) (aa354-367, aa511-527 and aa559-573)/Sialyl T (AUC = 0.98, 0.90 and 0.94); and complement component C7 (C7) (aa692-701)/di-Sialyl T (AUC = 1.00), can have high diagnostic efficacy to strategically predict advanced CRC groups. Hence, they could be promising markers for detection of advanced CRC, and provide new clinical test indicators along with lectins, such as MPL and jacalin. Our O-glycoproteomics platform provides a novel tool and resource, for researchers and clinicians seeking to better understand and treat advanced CRC.

In recent years, automatic driving and advanced driving support systems have become more widespread; however, control systems do not consider the driving characteristics of each driver. This study constructed a personalized driver model for following forward vehicles on highways using LSTM (Long Short-Term Memory). In particular, the setting parameters for training with LSTM was focused upon and consequently, the relationship between the setting parameters and model accuracy was evaluated. The LSTM parameters considered were the number of hidden units, learning rate, number of epochs, and number of LSTM layers. Further, the driving data were measured using a driving simulator. Moreover, the model was evaluated in terms of accuracy using the coefficient of determination, and 125 combinations of parameters were compared using the mean value of the coefficient of determination and its significant difference. The order of parameter comparisons was performed considering the accuracy and learning time of the model. Consequently, the parameter set that is likely to allow efficient building of a highly accurate driver model was determined. Applying the parameter evaluation in this study contributes to the development of personalized driver models with high accuracy.

IntroductionCurrently, little is known about Chinese-speaking primary progressive aphasia (PPA) patients compared to patients who speak Indo-European languages. We examined the demographics and clinical manifestations, particularly reading and writing characteristics, of Chinese patients with PPA over the last two decades to establish a comprehensive profile and improve diagnosis and care.MethodsWe reviewed the demographic features, clinical manifestations, and radiological features of Chinese-speaking PPA patients from 56 articles published since 1994. We then summarized the specific reading and writing errors of Chinese-speaking patients.ResultsThe average age of onset for Chinese-speaking patients was in their early 60's, and there were slightly more male patients than female patients. The core symptoms and images of Chinese-speaking patients were similar to those of patients who speak Indo-European languages. Reading and writing error patterns differed due to Chinese's distinct tone and orthography. The types of reading errors reported in Chinese-speaking patients with PPA included tonal errors, regularization errors, visually related errors, semantic errors, phonological errors, unrelated errors, and non-response. Among these errors, regularization errors were the most common in semantic variant PPA, and tonal errors were specific to Chinese. Writing errors mainly consisted of non-character errors (stroke, radical/component, visual, pictograph, dyskinetic errors, and spatial errors), phonologically plausible errors, orthographically similar errors, semantic errors, compound word errors, sequence errors, unrelated errors, and non-response.ConclusionThis paper provides the latest comprehensive demographic information and unique presentations on the reading and writing of Chinese-speaking patients with PPA. More detailed studies are needed to address the frequency of errors in reading and writing and their anatomical substrates.

Abstract Natriuretic peptides exert multiple effects by binding to natriuretic peptide receptors (NPRs). Osteocrin (OSTN) binds with high affinity to NPR-C, a clearance receptor for natriuretic peptides, and inhibits degradation of natriuretic peptides and consequently enhances guanylyl cyclase-A (GC-A/NPR1) signaling. However, the roles of OSTN in the kidney have not been well clarified. Adriamycin (ADR) nephropathy in wild-type mice showed albuminuria, glomerular basement membrane changes, increased podocyte injuries, infiltration of macrophages, and p38 mitogen-activated protein kinase (MAPK) activation. All these phenotypes were improved in OSTN- transgenic (Tg) mice and NPR3 knockout (KO) mice, with no further improvement in OSTN-Tg/NPR3 KO double mutant mice, indicating that OSTN works through NPR3. On the contrary, OSTN KO mice increased urinary albumin levels, and pharmacological blockade of p38 MAPK in OSTN KO mice ameliorated ADR nephropathy. In vitro, combination treatment with ANP and OSTN, or FR167653, p38 MAPK inhibitor, reduced Ccl2 and Des mRNA expression in murine podocytes (MPC5). OSTN increased intracellular cyclic guanosine monophosphate (cGMP) in MPC5 through GC-A. We have elucidated that circulating OSTN improves ADR nephropathy by enhancing GC-A signaling and consequently suppressing p38 MAPK activation. These results suggest that OSTN could be a promising therapeutic agent for podocyte injury.

Abstract Background Therapy for eradication of Helicobacter pylori (H. pylori) improves symptoms of H. pylori-associated dyspepsia (HPD), but the effects of eradication in elderly patients are unclear. The aim of our study was to investigate dyspepsia symptoms and long-term effects of eradication in elderly patients. Methods This retrospective study included 496 patients who received H. pylori eradication therapy. The patients were divided into a group of elderly patients (group E: ≧ 65 years old) and a group of non-elderly patients (group N:

Although two live oral rotavirus (RV) vaccines, Rotarix and RotaTeq, play a critical role toward reducing disease severity, hospitalization, and death rate in RV infections, regular monitoring of vaccine effectiveness (VE) is yet necessary because the segmented genome structure and reassortment capability of RVs pose considerable threats toward waning VE. In this study, we examined the VE by a test-negative study design against G9P[8]I2 strain during a seasonal outbreak in February–May, 2018, in an outpatient clinic in Kyoto Prefecture, Japan. It remains important because G9P[8]I2 strain remains partially heterotypic to these vaccines and predominating in post-vaccination era. During year-long surveillance, RV infections were detected only from February to May. During this outbreak, 33 (42.3%) children out of 78 with acute gastroenteritis (AGE) remained RV-positive, of which 29 (87.8%) children were infected with G9P[8]I2. Two immunochromatographic (IC) assay kits exhibited 100% sensitivity and specificity to detect G9P[8]I2 strain. Only 23.2% children were found to be vaccinated. Yet, significant VE 69.7% (95% CI: 2.5%-90.6%) was recognized against all RV strains that increased with disease severity. Similar significant VE 71.8% (95% CI: 1%-92%) was determined against G9P[8]I2 strain. The severity score remained substantially low in vaccinated children. Our data reveal that vaccine-preventable G9P[8]I2 strain yet may cause outbreak where vaccination coverage remains low. Thus, this study emphasizes the necessity of global introduction of RV-vaccines in national immunization programs of every country.

Abstract Background Basal cell carcinoma (BCC) is the most commonly occurring neoplasm in patients with Gorlin syndrome. It is widely accepted that multiple basal cell carcinomas simultaneously develop in middle-aged patients with this syndrome. However, the presence of driver genes other than the PTCH1 in Gorlin syndrome has not been explored. This study aimed to identify common gene mutations other than PTCH1 in simultaneously occurring basal cell carcinomas in patients with Gorlin syndrome via exome sequencing analysis. Methods Next-generation sequencing analysis was performed using four basal cell carcinoma samples, one dental keratinocyte sample, and two epidermoid cyst samples, which were surgically resected from one patient with Gorlin syndrome on the same day. Results Overall, 282 somatic mutations were identified in the neoplasms. No additional somatic mutations in PTCH1, PTCH2, TP53, and SMO were identified. However, enrichment analysis showed that multiple genes, such as IFT172 and KIFAP3, could regulate ciliary functions important for Hedgehog signaling. Conclusion The development of BCCs in patients with Gorlin syndrome may be triggered by mutations that cause substantial dysfunction of cilia.

Abstract Background and Aim The mechanism underlying carcinogenesis and the genomic features of superficial non‐ampullary duodenal epithelial tumors (SNADETs) have not been elucidated in detail. In this study, we examined the genomic features of incipient SNADETs, such as small lesions resected via endoscopic treatment, using next‐generation sequencing (NGS). Methods Twenty consecutive patients who underwent endoscopic treatment for SNADETs of less than 20 mm between January and December 2017 were enrolled. Targeted genomic sequencing was performed through NGS using a panel of 160 cancer‐related genes. Furthermore, the alteration/mutation frequencies in SNADETs were examined. Results The maximum size of the SNADETs examined in this study was 12 mm in diameter. Five SNADETs were classified as low‐grade dysplasia (LGD) tumors, while 14 SNADETs were classified as high‐grade dysplasia tumors. Only one carcinoma in situ was detected. NGS data for 16 samples were obtained. APC alterations were detected in 81% of samples (13/16). KRAS, BRAF, and TP53 alterations were detected in 25% (4/16), 18.8% (3/16), and 6.3% (1/16) of cases, respectively. Conclusion We detected APC alterations in most small SNADETs resected via endoscopic treatment, from LGD to carcinoma samples. Even in SNADETs classified as small LGD exhibited KRAS and BRAF alterations.

Rubella virus (RuV) infections in pregnant women, especially first-trimester infections, can lead to congenital rubella syndrome (CRS). However, the mechanisms of fetal RuV infection are not completely understood, and it is not observed in every pregnant woman infected with RuV. As gestational diabetes mellitus is a risk factor for congenital viral infections, we investigated the possible roles of hypoglycemia-related endoplasmic reticulum (ER) stress as a key factor for vertical RuV infection using immortalized human first-trimester trophoblasts. Low-glucose stress was induced prior to RuV infection by culturing HTR-8/SVneo and Swan.71 cells in low-glucose (LG) medium for 24 h or high-glucose medium for 6 h and then LG medium for an additional 18 h. Clinically isolated RuV was inoculated at a multiplicity of infection of 5 to 10. The intracellular localization of the RuV capsid protein was investigated 24 to 48 h post-infection (pi) with flow cytometry (FCM) analysis and fluorescence microscopy. Viral progeny production was monitored by FCM analysis. Increases in RuV infection in LG-induced ER-stressed trophoblasts were observed. No significant increase in apoptosis of RuV-infected cells was noted at days 2 and 5 pi, and substantial viral progeny production was observed until day 5 pi. An approximate fivefold increase in viral binding was noted for the LG-stressed cells. Although the detailed mechanisms underlying viral entry into LG-stressed cells are not known and require further investigation, these findings suggest that a certain degree of LG stress in early pregnancy may facilitate infection and cause CRS.

ABSTRACT Human norovirus is a major virus that causes acute gastroenteritis in all age groups. Recently, norovirus recombinant strains have been reported as the cause of norovirus outbreaks. This study has investigated the distribution of norovirus genotypes and recombinant strains circulating in children hospitalized with diarrhea in Chiang Mai, Thailand from 2017 to 2018. A total of 882 stool specimens were tested for the presence of norovirus GI and GII by reverse transcription-PCR (RT-PCR) assay. Genotypes of the viruses were assessed by partial VP1 nucleotide sequencing and the representative strains were further characterized for norovirus recombinant strains by amplification of ORF1 (RdRp)/ORF2 (VP1 capsid) junction region. From a total of 882 stool samples, 131 (14.9%) were positive for norovirus, of which the majority of norovirus genogroups were norovirus GII, and only one was identified as norovirus GI. A wide variety of norovirus genotypes were detected in this study, including GI.5, GII.2, GII.3, GII.4, GII.6, GII.7, GII.13, GII.14, and GII.17 with the predominance of GII.2 (62.5%) in 2017 and GII.4 (57.0%) in 2018. Nevertheless, it should be noted that GII.4 remained the most predominant genotype (50.4%) in overall prevalence. Analysis of norovirus recombination revealed that several norovirus recombinant strains (GII.2[P16], GII.3[P16], GII.4[P16], GII.4[P31], GII.6[P7], GII.13[P16], and GII.14[P7]) had been identified with the predominance of GII.2[P16] in 2017 and changed to GII.4[P16] and GII.4[P31] in 2018. In conclusion, this study reported the detection of a wide variety of norovirus genotypes and several norovirus recombinant strains in Chiang Mai, Thailand from 2017 to 2018. IMPORTANCE In the present study, the prevalence of norovirus infection in children with acute gastroenteritis in Chiang Mai, Thailand between 2017 and 2018 was 14.9%. A variety of norovirus genotypes were detected, including GI.5, GII.2, GII.3, GII.4, GII.6, GII.7, GII.13, GII.14, and GII.17 with the predominance of GII.4 genotype. In addition, several norovirus recombinant strains (GII.2[P16], GII.3[P16], GII.4[P16], GII.4[P31], GII.6[P7], GII.13[P16], and GII.14[P7]) had been identified. Our results revealed that GII.2[P16] was a predominant strain till the end of 2017 and then was replaced by GII.4[P16] and GII.4[P31] in 2018. The findings imply that norovirus recombinant strains emerged in Chiang Mai, Thailand and that circulating strains changes over time.

Abstract Background Fibrinogen concentration is an important indicator of the treatment for obstetric disseminated intravascular coagulation (DIC). We present how using the fibrinogen measuring device could solve problems in the treatment of postpartum hemorrhage with complicated DIC. Case presentation A 32-year-old woman with monochorionic diamniotic twins at 22 weeks of pregnancy was diagnosed with placental abruption and underwent emergent cesarean section. The estimated blood loss was 8375 g. She was transferred to our hospital for further treatment. Compressive uterine sutures and balloon tamponade were performed. We transfused fibrinogen and fresh frozen plasma actively during the operation to maintain plasma fibrinogen above 200 mg/dL by using a point-of-care fibrinogen measuring device. In spite of massive hemorrhage exceeding 10 L, she was extubated at the end of the operation and discharged on the 7th day after the operation. Conclusion The portable fibrinogen measuring device was useful for point-of-care assessment of obstetric DIC.

Pedestrian deaths account for the highest percentage of fatality caused by traffic accidents in Japan. Increasing pedestrian safety is a key objective for reducing such deaths. For pedestrian fatality caused by vehicles at low speed, turning the vehicle toward the right was the most common behavior under left-hand traffic. Autonomous emergency braking (AEB) systems for pedestrian safety have great potential to mitigate pedestrian injuries and fatalities in traffic accidents. However, pedestrian-AEB systems, especially for vehicles turning right, are still under development. This study identified the characteristics of dangerous traffic scenarios between vehicles turning right and pedestrians, focusing on two directions of pedestrian crossing: from the left to the right side (Left-Pedestrian) and from the right to the left side (Right-Pedestrian). The ego vehicle recorded near-miss incidents using a drive recorder. The results revealed that the Left-Pedestrian and Right-Pedestrian scenarios had different features for both the width of roads going to and through the intersection and the average of the travel speeds of the ego vehicles. They had similar characteristics in terms of the presence of other vehicle categories, but differences in the relationship of numbers and/or travel directions of other vehicles. The findings of this study will contribute to the development and evaluation of safety systems for preventing collisions between right-turning vehicles and pedestrians at intersections.

Abstract In this study, we determined the alignment of the laser altimeter aboard Hayabusa2 with respect to the spacecraft using in-flight data. Since the laser altimeter data were used to estimate the trajectory of the Hayabusa2 spacecraft, the pointing direction of the altimeter needed to be accurately determined. The boresight direction of the receiving telescope was estimated by comparing elevations of the laser altimeter data and camera images, and was confirmed by identifying prominent terrains of other datasets. The estimated boresight direction obtained by the laser link experiment in the winter of 2015, during the Earth’s gravity assist operation period, differed from the direction estimated in this study, which fell on another part of the candidate direction; this was not selected in a previous study. Assuming that the uncertainty of alignment determination of the laser altimeter boresight was 4.6 pixels in the camera image, the trajectory error of the spacecraft in the cross- and/or along-track directions was determined to be 0.4, 2.1, or 8.6 m for altitudes of 1, 5, or 20 km, respectively.

Background: Enteric caliciviruses, including noroviruses (NoVs) and sapoviruses (SaVs) are the most significant pathogens associated with waterborne and foodborne outbreaks of nonbacterial acute gastroenteritis in humans worldwide. Methods: In this study, 126 environmental water samples collected from 6 different sources in Chiang Mai, Thailand from November 2016 to July 2018 were examined for the presence of genogroups I, II, IV (GI, GII, GIV) NoVs and SaVs by using RT-nested PCR assays, genome sequencing, and phylogenetic analysis, Results: Forty out of 126 (31.7%) water samples were positive for one or more caliciviruses throughout the years of study with high prevalence in winter. Among 126 tested specimens, 34 (27.0%), 30 (23.8%), 3 (2.4%), and 2 (1.6%) were positive for NoV GI, GII, GIV, and SaV, respectively. For NoV GI, 6 different genotypes were identified with the most predominant of GI.1 genotype (17 strains). In addition, 6 different genotypes of GII were detected with high prevalence of GII.17 (12 strains) and GII.2 (11 strains). It was interesting to note that our study reported the detection of NoV GIV for the first time in water samples in Thailand, and all were GIV.1 genotype. For SaV detection, only 2 water samples were positive for SaV GI. Conclusions: The data revealed heterogeneity and highly dynamic distribution of NoV GI, GII, GIV, and SaV in environmental water in Chiang Mai, Thailand, during the study period of 2016–2018.

Abstract Backgrouund For patients with any kind of atypical squamous intraepithelial lesion of the uterine cervix or vagina, colposcopy and punch biopsy are common procedures for histological determination following cytology. However, colposcopy-guided biopsy does not provide a high level of diagnostic accuracy. The aim of this study was to determine the usefulness of optical biopsy in vivo using endocytoscopy compared with conventional procedures using colposcopy. Methods Between May 2018 and March 2019, patients who were scheduled for cervical conization or mapping biopsies of the vagina were prospectively enrolled. Endocytoscopy was performed by senior endoscopists prior to scheduled procedures, and endocytoscopic images and biopsy samples were taken from the most prominent site and surrounding area of the cervical or vaginal lesions. The collection process of images was randomized and anonymous, and three doctors separately evaluated the images according to the ECA classification. ECA 4 and 5 are indicative of endoscopic malignancy. The primary endpoint was diagnostic accuracy (benign or malignant: cervical intraepithelial neoplasia (CIN) 3 or vaginal intraepithelial neoplasia (VAIN) 3 or worse) of cell images at the most prominent site in each patient. Results A total of 28 consecutive patients were enrolled. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of endocytoscopic images were 95.0% (84.8–98.6%), 87.5% (61.9–96.5%), 95.0% (84.8–98.6%), 87.5% (61.9–96.5%) and 92.9% (78.2–98.0%), respectively. Inter-observer agreement among three reviewers was 0.78 (0.08–9.88, P

Abstract The precise orbit of the Hayabusa2 spacecraft with respect to asteroid Ryugu is dynamically determined using the data sets collected by the spacecraft’s onboard laser altimeter (LIght Detection And Ranging, LIDAR) and automated image tracking (AIT). The LIDAR range data and the AIT angular data play complementary roles because LIDAR is sensitive to the line-of-sight direction from Hayabusa2 to Ryugu, while the AIT is sensitive to the directions perpendicular to it. Using LIDAR and AIT, all six components of the initial state vector can be derived stably, which is difficult to achieve using only LIDAR or AIT. The coefficient of solar radiation pressure (SRP) of the Hayabusa2 spacecraft and standard gravitational parameter (GM) of Ryugu can also be estimated in the orbit determination process, by combining multiple orbit arcs at various altitudes. In the process of orbit determination, the Ryugu-fixed coordinate of the center of the LIDAR spot is determined by fitting the range data geometrically to the topography of Ryugu using the Markov Chain Monte Carlo method. Such an approach is effective for realizing the rapid convergence of the solution. The root mean squares of the residuals of the observed minus computed values of the range and brightness-centroid direction of the image are 1.36 m and 0.0270°, respectively. The estimated values of the GM of Ryugu and a correction factor to our initial SRP model are 29.8 ± 0.3 m3/s2 and 1.13 ± 0.16, respectively.

Clinically relevant human induced pluripotent stem cell (hiPSC) derivatives require efficient protocols to differentiate hiPSCs into specific lineages. Here we developed a fully defined xeno-free strategy to direct hiPSCs toward osteoblasts within 21 days. The strategy successfully achieved the osteogenic induction of four independently derived hiPSC lines by a sequential use of combinations of small-molecule inducers. The induction first generated mesodermal cells, which subsequently recapitulated the developmental expression pattern of major osteoblast genes and proteins. Importantly, Col2.3-Cherry hiPSCs subjected to this strategy strongly expressed the cherry fluorescence that has been observed in bone-forming osteoblasts in vivo. Moreover, the protocol combined with a three-dimensional (3D) scaffold was suitable for the generation of a xeno-free 3D osteogenic system. Thus, our strategy offers a platform with significant advantages for bone biology studies and it will also contribute to clinical applications of hiPSCs to skeletal regenerative medicine.

Abstract Well water could be a stable source of drinking water. Recently, the use of well water as drinking water has been encouraged in developing countries. However, many kinds of disorders caused by toxic elements in well drinking water have been reported. It is our urgent task to resolve the global issue of element-originating diseases. In this review article, our multidisciplinary approaches focusing on oncogenic toxicities and disturbances of sensory organs (skin and ear) induced by arsenic and barium are introduced. First, our environmental monitoring in developing countries in Asia showed elevated concentrations of arsenic and barium in well drinking water. Then our experimental studies in mice and our epidemiological studies in humans showed arsenic-mediated increased risks of hyperpigmented skin and hearing loss with partial elucidation of their mechanisms. Our experimental studies using cultured cells with focus on the expression and activity levels of intracellular signal transduction molecules such as c-SRC, c-RET, and oncogenic RET showed risks for malignant transformation and/or progression arose from arsenic and barium. Finally, our original hydrotalcite-like compound was proposed as a novel remediation system to effectively remove arsenic and barium from well drinking water. Hopefully, comprehensive studies consisting of (1) environmental monitoring, (2) health risk assessments, and (3) remediation will be expanded in the field of environmental health to prevent various disorders caused by environmental factors including toxic elements in drinking water.

Basic helix-loop-helix (BHLH) transcription factors differentiated embryonic chondrocyte gene 1 (DEC1) and gene 2 (DEC2) regulate circadian rhythms, apoptosis, epithelial mesenchymal transition (EMT), invasions and metastases in various kinds of cancer. The stem cell markers SOX2 and c-MYC are involved in the regulation of apoptosis and poor prognosis. In cervical cancer, however, their roles are not well elucidated yet. To determine the function of these genes in human cervical cancer, we examined the expression of DEC1, DEC2, SOX2 and c-MYC in human cervical cancer tissues. In immunohistochemistry, they were strongly expressed in cancer cells compared with in non-cancerous cells. Notably, the strong rate of DEC1 and SOX2 expressions were over 80% among 20 cases. We further examined the roles of DEC1 and DEC2 in apoptosis. Human cervical cancer HeLa and SiHa cells were treated with cisplatin—HeLa cells were sensitive to apoptosis, but SiHa cells were resistant. DEC1 expression decreased in the cisplatin-treated HeLa cells, but had little effect on SiHa cells. Combination treatment of DEC1 overexpression and cisplatin inhibited apoptosis and affected SOX2 and c-MYC expressions in HeLa cells. Meanwhile, DEC2 overexpression had little effect on apoptosis and on SOX2 and c-MYC expressions. We conclude that DEC1 has anti-apoptotic effects and regulates SOX2 and c-MYC expressions on apoptosis.

Abstract Stem cell-based regeneration therapy offers new therapeutic options for patients with bone defects because of significant advances in stem cell research. Although bone marrow mesenchymal stem cells are the ideal material for bone regeneration therapy using stem cell, they are difficult to obtain. Induced pluripotent stem cells (iPSCs) are now considered an attractive tool in bone tissue engineering. Recently, the efficiency of establishing iPSCs has been improved by the use of the Sendai virus vector, and it has become easier to establish iPSCs from several type of somatic cells. In our previous study, we reported a method to purify osteogenic cells from iPSCs. Objective: This study aimed to evaluate the osteogenic ability of iPSCs derived from peripheral blood cells. Methodology: Mononuclear cells (MNCs) were obtained from human peripheral blood. Subsequently, T cells were selectively obtained from these MNCs and iPSCs were established using Sendai virus vectors. Established iPSCs were evaluated by the expression of undifferentiated markers and teratoma formation assays. Osteoblasts were induced from these iPSCs and evaluated by the expression of osteoblast markers. Additionally, the induced osteoblasts were transplanted into rat critical size calvaria bone defect models with collagen sponge scaffolds. Samples were evaluated by radiographical and histological assessments. Results: Induced osteoblasts expressed several osteoblast-specific markers. The results of radiographical and histological assessments revealed that the cell transplant group had bone formations superior to those of the control group. Conclusions: This study suggests that peripheral blood MNCs have the potential to differentiate into osteoblasts. Although there are some hurdles in iPSC transplantation, osteoblasts obtained from MNC-iPSCs could be applied to bone regeneration therapy in the future.

Background and study aims Linked color imaging (LCI) is a new image-enhancing technique that facilitates the differentiation of slight differences in mucosal color tone. We performed an exploratory analysis to evaluate the diagnostic capability of LCI in ultraslim endoscopy, using data from patients examined in the LCI-Further Improving Neoplasm Detection in upper gastrointestinal (LCI-FIND) trial, a large-scale, multicenter, randomized controlled trial that demonstrated the capability of LCI for detecting neoplastic lesions in the upper gastrointestinal tract. Patients and methods Data from the LCI-FIND prospective trial were used. In the LCI-FIND trial, 1502 patients with a history of gastrointestinal cancer were randomly assigned to two groups based on examination methods: white light imaging (WLI) followed by LCI (WLI group) and LCI followed by WLI (LCI group). The present exploratory analysis investigated the outcomes of patients who underwent ultraslim and standard endoscopies. Results Ultraslim endoscopes were used in 223 patients and standard endoscopes in 1279 patients. The primary endpoint of the LCI-FIND trial was the percentage of patients diagnosed with a neoplastic lesion using WLI or LCI. The corresponding percentage tended to be higher with LCI than with WLI among patients who underwent ultraslim endoscopy and among those who underwent standard endoscopy; the crude risk ratio was 2.21 [95 % confidence interval (CI): 1.06–4.67], and the adjusted odds ratio was 2.46 (95 % CI: 1.07–5.63). Conclusions Our exploratory analysis of data from the LCI-FIND trial showed that LCI is useful in identifying neoplastic lesions, when used in ultraslim endoscopy.