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Abstract Background and Aim Percutaneous endoscopic gastrostomy (PEG) is often associated with early mortality. We therefore investigated factors associated with early death after PEG. Methods The present study comprised patients who had undergone PEG between April 2014 and March 2020. Patients were divided into two groups: an early mortality group who died within 1 month of PEG, and a non‐mortality group whose clinical course could be followed for more than 1 month after the procedure. Patient background, hematological data, and procedural duration were compared between groups. Results Univariate analysis identified older age, high blood urea nitrogen (BUN), low prognostic nutritional index (PNI), and high controlling nutritional status (CONUT) score as factors associated with early death after PEG. In multivariate analysis, high CONUT score remained an independent prognostic factor (P = 0.0035). Conclusion A high CONUT score may be a prognostic factor for early mortality after PEG.

Abstract NMN is the direct precursor of nicotinamide adenine dinucleotide (NAD+) and is considered as a key factor for increasing NAD+ levels and mitochondrial activity in cells. In this study, based on transcriptome analysis, we showed that NMN alleviates the poly(I:C)-induced inflammatory response in cultures of two types of human primary cells, human pulmonary microvascular endothelial cells (HPMECs) and human coronary artery endothelial cells (HCAECs). Major inflammatory mediators, including IL6 and PARP family members, were grouped into coexpressed gene modules and significantly downregulated under NMN exposure in poly(I:C)-activated conditions in both cell types. The Bayesian network analysis of module hub genes predicted common genes, including eukaryotic translation initiation factor 4B (EIF4B), and distinct genes, such as platelet-derived growth factor binding molecules, in HCAECs, which potentially regulate the identified inflammation modules. These results suggest a robust regulatory mechanism by which NMN alleviates inflammatory pathway activation, which may open up the possibility of a new role for NMN replenishment in the treatment of chronic or acute inflammation.

Abstract Tephra rings that surround maar craters are typically inferred from field observations to have been emplaced rapidly over a time period of days to years and thus monogenetic, which is, however, rarely assessed quantitatively. This paper describes a polycyclic origin of the Mamiyadake tephra ring (Japan), comparing the paleomagnetic directions obtained from throughout the stratigraphy. The new data show that the paleomagnetic directions change systematically with stratigraphic height through the sections, which is interpreted to record paleosecular variation (PSV) of the geomagnetic field during formation of the tephra ring. The paleomagnetic results, together with using an average rate of PSV in Japan, indicate that the Mamiyadake tephra ring was constructed episodically with five major eruptive episodes, separated by centuries or longer, over a period of at least 1000 years. The findings demonstrate that detailed paleomagnetic characterization can uncover the temporal evolution of tephra rings, providing a useful criterion for identifying time breaks, even where field evidence is lacking, and a minimum estimate of the time interval for their emplacement. The approach used here may be applicable to volcanoes of any type. Graphical Abstract

Imidazole dipeptides (IDPs) and taurine (Tau) have several health benefits and are known to be contained in natural seafoods. However, their levels vary widely in different natural seafoods, making their simultaneous determination desirable. Herein, we employ a liquid chromatography–tandem mass spectrometry approach using a novel amino group derivatization reagent, succinimidyl 2-(3-((benzyloxy)carbonyl)-1-methyl-5-oxoimidazolidin-4-yl) acetate ((R)-CIMa-OSu), for the simultaneous quantification of IDPs (carnosine (Car) and anserine (Ans)), their related amino acids, and Tau in natural seafoods. Each seafood sample contained different concentrations of IDPs (Car: ND to 1.48 mmol/100 g-wet, Ans: ND to 4.67 mmol/100 g-wet). The Car levels were considerably higher in eel, while Tau was more abundant in squid, boiled octopus, and scallop. Thus, the derivatization reagent (R)-CIMa-OSu provides a new approach to accurately assess the nutritional composition of seafoods, thereby providing valuable insight into its dietary benefits.

Japan’s susceptibility to and severity of floods have necessitated flood control policies by the government. “Overflowing flood control”, in which the floods due to torrential rains are systematically diverted to agricultural lands in the upper to middle reaches, is one of them. More information is needed on the public assessment of the overflowing flood control policy, and this research seeks to bridge this gap. Data evaluating rice affected by the policy were collected from a random nth-price auction using a developed online system. The sample consisted of 47 consumers living in the downstream areas of the Edogawa River, one of Japan’s first-class, or prime, rivers. Data on their attitudes toward the policy were collected with a questionnaire. Multiple ordered probit models are used for regression analysis. The results show that the sample respondents were willing to pay an average of JPY 1578 for 5 kg of rice, slightly higher than the national average rice production cost, and that 36% of the sample agreed with the flood control policy, which is positively associated with large families or owning many assets.

Background: Endometriosis-associated ovarian cancer (EAOC) is a well-known type of cancer that arises from ovarian endometrioma (OE). OE contains iron-rich fluid in its cysts due to repeated hemorrhages in the ovaries. However, distinguishing between benign and malignant tumors can be challenging. We conducted a retrospective study on magnetic resonance (MR) relaxometry of cyst fluid to distinguish EAOC from OE and reported that this method showed good accuracy. The purpose of this study is to evaluate the accuracy of a non-invasive method in re-evaluating pre-surgical diagnosis of malignancy by a prospective multicenter cohort study. Methods: After the standard diagnosis process, the R2 values were obtained using a 3T system. Data on the patients were then collected through the Case Report Form (CRF). Between December 2018 and March 2023, six hospitals enrolled 109 patients. Out of these, 81 patients met the criteria required for the study. Results: The R2 values calculated using MR relaxometry showed good discriminating ability with a cut-off of 15.74 (sensitivity 80.6%, specificity 75.0%, AUC = 0.750, p < 0.001) when considering atypical or borderline tumors as EAOC. When atypical and borderline cases were grouped as OE, EAOC could be distinguished with a cut-off of 16.87 (sensitivity 87.0%, specificity 61.1%). Conclusions: MR relaxometry has proven to be an effective tool for discriminating EAOC from OE. Regular use of this method is expected to provide significant insights for clinical practice.

Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-β-activated kinase-1 (TAK1) activation, inflammatory cytokine-induced muscle wasting may be ameliorated by the inhibition of TAK1 activity. The present study was undertaken to clarify whether TAK1 inhibition can ameliorate inflammation-induced muscle wasting. SKG/Jcl mice as an autoimmune arthritis animal model were treated with a small amount of mannan as an adjuvant to enhance the production of TNF-α and IL-1β. The increase in these inflammatory cytokines caused a reduction in muscle mass and strength along with an induction of arthritis in SKG/Jcl mice. Those changes in muscle fibers were mediated via the phosphorylation of TAK1, which activated the downstream signaling cascade via NF-κB, p38 MAPK, and ERK pathways, resulting in an increase in myostatin expression. Myostatin then reduced the expression of muscle proteins not only via a reduction in MyoD1 expression but also via an enhancement of Atrogin-1 and Murf1 expression. TAK1 inhibitor, LL-Z1640-2, prevented all the cytokine-induced changes in muscle wasting. Thus, TAK1 inhibition can be a new therapeutic target of not only joint destruction but also muscle wasting induced by inflammatory cytokines.

Objectives: Although acute anterior cruciate ligament reconstruction (ACLR) is often avoided because of postoperative joint stiffness, delayed ACLR can lead to a longer recovery time and can have a negative impact on physical function due to detraining. This study aimed to determine the effects of acute ACLR on postoperative outcomes, including muscle strength, performance, and return to sports. Methods: A total of 110 patients who underwent anatomical ACLR using hamstring autografts were included in this study and were divided into three groups: acute (ACLR performed within 2 weeks after ACL injury), 2–6 weeks (ACLR performed between 2 and 6 weeks after injury), and 6–12 weeks (ACLR performed between 6 and 12 weeks after injury). Several parameters were evaluated, including range of motion, knee joint stability, isokinetic knee strength, performance, and return to sports. Results: No significant differences were found in the range of motion or knee joint stability between the groups. The acute group exhibited significantly greater quadriceps strength at 3 months postoperatively than the other groups (p < 0.05). The single-leg hop test showed that 66.7%, 38.7%, and 33.3% of the patients in the acute, 2–6 weeks, and 6–12 weeks groups, respectively, recovered to an LSI of 90% or greater (p = 0.09, Cramer’s V = 0.27). All patients in the acute group were able to return to sports (p = 0.14; Cramer’s V = 0.28). Conclusions: Acute ACLR is advantageous for the early recovery of strength and performance without adverse events. Acute ACLR may shorten the time spent away from sports activities.

The excessive intake of sodium (Na) and insufficient intake of potassium (K) are major concerns in the prevention of hypertension. Using low-Na/K seasonings (reducing 25% of the NaCl and adding K salt) may improve the dietary Na/K ratio and help prevent hypertension. To devise an intervention study using low-Na/K seasonings at a company cafeteria, we calculated the Na and K contents of the meals served at the cafeteria and estimated changes in the intakes when suitable low-Na/K seasonings were used. We also considered using milk as a good source of K. We used an ingredient list of a company cafeteria and calculated Na and K contents in each dish. The average amounts of NaCl and K per use were 5.04 g and 718 mg, respectively. Seasonings contributed 70.9% of the NaCl. With the use of low-Na/K seasonings, an estimated reduction in NaCl of 0.8 g/day and an estimated increase in K of 308 mg/day was achieved. With an additional serving (200 mL) of milk, NaCl was reduced by 0.57 g/day and K was increased by 610 mg/day, with an overall decrease in the dietary Na/K ratio from 3.20 to 2.40. The use of low-Na/K seasonings and dairy may improve the dietary Na/K ratio among cafeteria users and help prevent hypertension.

Cellular senescence is an irreversible growth arrest that acts as a barrier to cancer initiation and progression. Histone alteration is one of the major events during replicative senescence. However, little is known about the function of H3.3 in cellular senescence. Here we found that the downregulation of H3.3 induced growth suppression with senescence-like phenotypes such as senescence-associated heterochromatin foci (SAHF) and β-galactosidase (SA-β-gal) activity. Furthermore, H3.3 depletion induced senescence-like phenotypes with the p53/p21-depedent pathway. In addition, we identified miR-22-3p, tumor suppressive miRNA, as an upstream regulator of the H3F3B (H3 histone, family 3B) gene which is the histone variant H3.3 and replaces conventional H3 in active genes. Therefore, our results reveal for the first time the molecular mechanisms for cellular senescence which are regulated by H3.3 abundance. Taken together, our studies suggest that H3.3 exerts functional roles in regulating cellular senescence and is a promising target for cancer therapy.

Oxytocin, a significant pleiotropic neuropeptide, regulates psychological stress adaptation and social communication, as well as peripheral actions, such as uterine contraction and milk ejection. Recently, a Japanese Kampo medicine called Kamikihito (KKT) has been reported to stimulate oxytocin neurons to induce oxytocin secretion. Two-pore-domain potassium channels (K2P) regulate the resting potential of excitable cells, and their inhibition results in accelerated depolarization that elicits neuronal and endocrine cell activation. We assessed the effects of KKT and 14 of its components on a specific K2P, the potassium channel subfamily K member 2 (TREK-1), which is predominantly expressed in oxytocin neurons in the central nervous system (CNS). KKT inhibited the activity of TREK-1 induced via the channel activator ML335. Six of the 14 components of KKT inhibited TREK-1 activity. Additionally, we identified that 22 of the 41 compounds in the six components exhibited TREK-1 inhibitory effects. In summary, several compounds included in KKT partially activated oxytocin neurons by inhibiting TREK-1. The pharmacological effects of KKT, including antistress effects, may be partially mediated through the oxytocin pathway.

The higher-order structure (HOS) is a critical quality attribute of recombinant adeno-associated viruses (rAAVs). Evaluating the HOS of the entire rAAV capsid is challenging because of the flexibility and/or less folded nature of the VP1 unique (VP1u) and VP1/VP2 common regions, which are structural features essential for these regions to exert their functions following viral infection. In this study, hydrogen/deuterium exchange mass spectrometry (HDX-MS) was used for the structural analysis of full and empty rAAV8 capsids. We obtained 486 peptides representing 85% sequence coverage. Surprisingly, the VP1u region showed rapid deuterium uptake even though this region contains the phospholipase A2 domain composed primarily of α-helices. The comparison of deuterium uptake between full and empty capsids showed significant protection from hydrogen/deuterium exchange in the full capsid at the channel structure of the 5-fold symmetry axis. This corresponds to cryo-electron microscopy studies in which the extended densities were observed only in the full capsid. In addition, deuterium uptake was reduced in the VP1u region of the full capsid, suggesting the folding and/or interaction of this region with the encapsidated genome. This study demonstrated HDX-MS as a powerful method for probing the structure of the entire rAAV capsid.

Non-structural members, such as roofs and ceilings, become affixed to main beams that are known as structural members. When such main beams experience bending or compressive forces that lead to lateral buckling, non-structural members may act to restrain the resulting lateral buckling deformation. Nevertheless, neither Japanese nor European guidelines advocate for the utilization of non-structural members as lateral buckling stiffeners for beams. Additionally, local buckling ensues near the bolt apertures in the beam–roof folded plate connection due to the torsional deformation induced by the lateral buckling of the H beam, thereby reducing the rotational stiffness of the roof folded plate to a percentage of its ideal stiffness. This paper conducts torsional experiments on roof folded plates, and with various connection methods between these plates and the beams, to comprehend the deformation mechanism of roof folded plates and the relationship between their rotational stiffness and the torsional moment. Then, the relationship between the demand values against restraining the lateral buckling of the main beam and the experimentally determined bearing capacity of the roof folded plate is elucidated. Results indicate the efficacy of utilizing the roof folded plate as a continuous brace. The lateral buckling design capacity of H beams that are continuously stiffened by roof folded plates is elucidated via application of a connection method that ensures joint stiffness between the roof folded plate and the beam while using Japanese and European design codes.

The usefulness of comprehensive genomic profiling (CGP) in the Japanese healthcare insurance system remains underexplored. Therefore, this large-scale study aimed to determine the usefulness of CGP in diagnosing digestive cancers. Patients with various cancer types recruited between March 2020 and October 2022 underwent the FoundationOne® CDx assay at the Keio PleSSision Group (19 hospitals in Japan). A scoring system was developed to identify potentially actionable genomic alterations of biological significance and actionable genomic alterations. The detection rates for potentially actionable genomic alterations, actionable genomic alterations, and alterations equivalent to companion diagnosis (CDx), as well as the signaling pathways associated with these alterations in each digestive cancer, were analyzed. Among the 1587 patients, 547 had digestive cancer. The detection rates of potentially actionable genomic alterations, actionable genomic alterations, and alterations equivalent to CDx were 99.5%, 62.5%, and 11.5%, respectively. APC, KRAS, and CDKN2A alterations were frequently observed in colorectal, pancreatic, and biliary cancers, respectively. Most digestive cancers, except esophageal cancer, were adenocarcinomas. Thus, the classification flowchart for digestive adenocarcinomas proposed in this study may facilitate precise diagnosis. CGP has clinical and diagnostic utility in digestive cancers.

Parasite growth in hosts depends on their hosts’ nutritional status. This study examined whether the body size of the strepsipteran parasite Xenos oxyodontes, which parasitizes the eusocial wasp Vespa analis, is affected by several key factors, including host body size. We collected V. analis using bait traps for three years in Niigata, Japan, and evaluated the number of male and female X. oxyodontes parasites throughout the seasons. A total of 185 female parasites were collected, and their cephalothorax widths were measured. The widths of female parasites did not statistically vary among seasons and were positively correlated with the head widths of female host wasps but negatively correlated with the number of parasites per host wasp. In addition, we examined whether the reproductive conditions of post-hibernation solitary queens affected the cephalothorax width of female parasites. The widths of the female parasites were greater when the queens had less-developed ovaries. These results suggested that nutrient availability by female parasites depends on the host wasp and competition with conspecific individuals.

Abstract Background Second malignant neoplasms (SMNs) are one of the most severe late complications after pediatric cancer treatment. However, the effect of genetic variation on SMNs remains unclear. In this study, we revealed germline genetic factors that contribute to the development of SMNs after treatment of pediatric solid tumors. Methods We performed whole‐exome sequencing in 14 pediatric patients with SMNs, including three brain tumors. Results Our analysis revealed that five of 14 (35.7%) patients had pathogenic germline variants in cancer‐predisposing genes (CPGs), which was significantly higher than in the control cohort (p

Abstract In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022. XBB.1 is the variant most profoundly resistant to BA.2/5 breakthrough infection sera to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of spike, and each region of the recombinant spike confers immune evasion and increases fusogenicity. We further provide the structural basis for the interaction between XBB.1 spike and human ACE2. Finally, the intrinsic pathogenicity of XBB.1 in male hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than substitutions.

Objective This study aimed to verify the utility of simple, safe, and effective venous thromboembolism (VTE) prophylaxis and implement it with few adverse events during cesarean delivery. Methods This single-center, prospective study involved pregnant women who underwent cesarean deliveries from August 3, 2020 to March 31, 2022. Patients with VTE risk factors were initially administered unfractionated heparin (5,000 international unit [IU] subcutaneously, twice daily), 6 hours after cesarean delivery. Subsequently, they were administered enoxaparin (2,000 IU subcutaneously, twice daily). They were not administered anticoagulants if one or more of the exclusion criteria were met. The primary efficacy outcome was the incidence of symptomatic VTE. The primary safety outcome was the incidence of major bleeding. Results Out of the 850 women eligible for this study, 551 (64.9%) had one or more VTE risk factors and 299 (35.1%) had no risk factors. Of the 551 women with one or more VTE risk factors, 15 met one or more exclusion criteria for enoxaparin administration. A total of 314 women received only perioperative mechanical prophylaxis, including 15 who met the exclusion criteria for anticoagulants and 299 without VTE risk factors. During implementation of the protocol, no woman developed symptomatic VTE after cesarean delivery. Major bleeding occurred in only one woman who received postoperative anticoagulants. Conclusion This protocol, which clarified the administration of anticoagulants according to VTE risk factors and dose reduction/discontinuation criteria, may be an effective and safe VTE prophylaxis for cesarean deliveries.

Abstract The COVID-19 pandemic has affected all domains of human life, including the economic and social fabric of societies. One of the central strategies for managing public health throughout the pandemic has been through persuasive messaging and collective behaviour change. To help scholars better understand the social and moral psychology behind public health behaviour, we present a dataset comprising of 51,404 individuals from 69 countries. This dataset was collected for the International Collaboration on Social & Moral Psychology of COVID-19 project (ICSMP COVID-19). This social science survey invited participants around the world to complete a series of moral and psychological measures and public health attitudes about COVID-19 during an early phase of the COVID-19 pandemic (between April and June 2020). The survey included seven broad categories of questions: COVID-19 beliefs and compliance behaviours; identity and social attitudes; ideology; health and well-being; moral beliefs and motivation; personality traits; and demographic variables. We report both raw and cleaned data, along with all survey materials, data visualisations, and psychometric evaluations of key variables.

Abstract Root penetration into the soil is essential for plants to access water and nutrients, as well as to mechanically support aboveground structures. This requires a combination of healthy plant growth, adequate soil mechanical properties, and compatible plant–soil interactions. Despite the current knowledge of the static rheology driving the interactions at the root–soil interface, few theoretical approaches have attempted to describe root penetration with dynamic rheology. In this work, we experimentally showed that radish roots in contact with soil of specific density during a specific growth stage fail to penetrate the soil. To explore the mechanism of root penetration into the soil, we constructed a theoretical model to explore the relevant conditions amenable to root entry into the soil. The theory indicates that dimensionless parameters such as root growth anisotropy, static root–soil competition, and dynamic root–soil competition are important for root penetration. The consequent theoretical expectations were supported by finite element analysis, and a potential mechanism of root penetration into the soil is discussed.

Abstract In late 2022, various Omicron subvariants emerged and cocirculated worldwide. These variants convergently acquired amino acid substitutions at critical residues in the spike protein, including residues R346, K444, L452, N460, and F486. Here, we characterize the convergent evolution of Omicron subvariants and the properties of one recent lineage of concern, BQ.1.1. Our phylogenetic analysis suggests that these five substitutions are recurrently acquired, particularly in younger Omicron lineages. Epidemic dynamics modelling suggests that the five substitutions increase viral fitness, and a large proportion of the fitness variation within Omicron lineages can be explained by these substitutions. Compared to BA.5, BQ.1.1 evades breakthrough BA.2 and BA.5 infection sera more efficiently, as demonstrated by neutralization assays. The pathogenicity of BQ.1.1 in hamsters is lower than that of BA.5. Our multiscale investigations illuminate the evolutionary rules governing the convergent evolution for known Omicron lineages as of 2022.

In-plane stress distribution in a spinning free-clamped slicing blade is studied analytically. The blade is subjected to a stationary, distributed, in-plane slicing load along the inner periphery, while it is clamped and tensioned initially in the radial direction along the outer boundary. The radial, hoop, and shear stresses in the blade are given by sum of the stresses from the tensioning, spinning, and edge loading. The solution is obtained by introducing the Lame potential functions and the two- dimensional elasticity theory. Numerical results are presented for an actual SUS301 blade cutting a 6-in.-diameter silicon ingot at 1550 rpm. Results obtained show that the contribution of the slicing load on the stress distribution is not significant; further the overall stress distribution is approximated by that of the initial tensioning except for the case of the shear stress distribution.

Background Common regional anesthesia approaches for video-assisted thoracoscopic surgery (VATS) include paravertebral block (PVB) and erector spinae plane block (ESPB). PVB is considered a deep nerve block which is contraindicated in antithrombotic therapy. ESPB is effective when administered as a bolus, as well as continuously. However, the recently proposed intertransverse process block (ITPB) ensures more effective diffusion of the local anesthetic into the paravertebral space. Case We report cases of three patients who received bolus ITPB (costotransverse foramen block and mid-point transverse process-to-pleura block in one and two cases, respectively) combined with continuous ESPB when a deep nerve block could not be administered. Opioids were not required postoperatively, and all postoperative numerical rating scale scores (0–10) at rest were maintained below 4. Conclusions The combination of bolus ITPB and continuous ESPB may be an alternative analgesic method when deep nerve blocks are contraindicated in VATS.

Some journals require users to register before accessing a scientific paper, despite labelling that content as open access (OA) and free-of-charge. We refer to such cases as members-only OA (MOOA), which we contend is not ‘free’ since users are forced to ‘pay’ with personal data. Scholarly content may be accessible via MOOA to either the in-browser text (HTML) or to the archival-friendly version (PDF), or both. We suggest a four-tier typology to capture the degree of openness based on this observation. We believe that technical guidelines of OA implementation should not permit MOOA.

Abstract Black band disease (BBD) in corals is characterized by a distinctive, band-like microbial mat, which spreads across the tissues and often kills infected colonies. The microbial mat is dominated by cyanobacteria but also commonly contains sulfide-oxidizing bacteria (SOB), sulfate-reducing bacteria (SRB), and other microbes. The migration rate in BBD varies across different environmental conditions, including temperature, light, and pH. However, whether variations in the migration rates reflect differences in the microbial consortium within the BBD mat remains unknown. Here, we show that the micro-scale surface structure, bacterial composition, and spatial distribution differed across BBD lesions with different migration rates. The migration rate was positively correlated with the relative abundance of potential SOBs belonging to Arcobacteraceae localized in the middle layer within the mat and negatively correlated with the relative abundance of other potential SOBs belonging to Rhodobacteraceae. Our study highlights the microbial composition in BBD as an important determinant of virulence.

Vibration and deflection of a silicon-wafer slicer cutting the crystal ingot is studied analytically. The blade is clamped and then tensioned in the radial direction at the outer boundary. The inner periphery is under the action of distributed in-plane and lateral slicing loads from the workpiece. The stresses from tensioning, spinning, and loading from the workpiece are taken into account in the in-plane stress evaluation of the blade. The solution is obtained by introducing the multi-modal expansion and applying the Galerkin method to the governing equation of the blade. Numerical results are presented for an actual SUS 301 blade cutting a 15.24 cm (6 in.) diameter silicon ingot. Results obtained show that the initial tensioning has a significant effect on the natural frequencies of the blade, while the lateral deflection of the blade is much affected by the lateral reaction force from the ingot.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, continues to spread around the world with serious cases and deaths. It has also been suggested that different genetic variants in the human genome affect both the susceptibility to infection and severity of disease in COVID-19 patients. Angiotensin-converting enzyme 2 (ACE2) has been identified as a cell surface receptor for SARS-CoV and SARS-CoV-2 entry into cells. The construction of an experimental model system using human iPS cells would enable further studies of the association between viral characteristics and genetic variants. Airway and alveolar epithelial cells are cell types of the lung that express high levels of ACE2 and are suitable for in vitro infection experiments. Here, we show that human iPS cell-derived airway and alveolar epithelial cells are highly susceptible to viral infection of SARS-CoV-2. Using gene knockout with CRISPR-Cas9 in human iPS cells we demonstrate that ACE2 plays an essential role in the airway and alveolar epithelial cell entry of SARS-CoV-2 in vitro. Replication of SARS-CoV-2 was strongly suppressed in ACE2 knockout (KO) lung cells. Our model system based on human iPS cell-derived lung cells may be applied to understand the molecular biology regulating viral respiratory infection leading to potential therapeutic developments for COVID-19 and the prevention of future pandemics.

Background Olive fruit is rich in bioactive pentacyclic triterpenoids, primarily maslinic acid (MA). Previous studies have demonstrated that MA exhibits anti-inflammatory and anti-oxidative effects; however, it is unclear whether MA intake during training inhibits perceptual fatigue and muscle soreness in athletes. This study analyzed the effects of MA supplementation during athletic training on perceptual fatigue and muscle soreness. Methods This randomized, double-blind, cross-over, and placebo-controlled trial involved 12 young, healthy male water polo athletes. After daily training for seven days, they ingested either olive fruit extract, containing 60 mg/day MA, or a placebo. We measured perceptual fatigue and muscle soreness during the intervention using a visual analog scale and inflammatory and oxidative stress-related proteins. Results Perceptual fatigue and muscle soreness and the area under the curve during the training period were significantly lower (main effect of MA; P

Background: Nursing shortage is a global and priority issue. Affective commitment has been identified as a key to retention in the workplace. Exploring the way to promote the nurse's affective commitment is necessary to maintain the nursing workforce and care quality. The staff nurse's organizational justice (procedural and interactional justice) and the manager's condition of mental health have the potential to be related to the staff nurse's affective commitment. Objective: To explore the impact on the nurse's affective commitment from procedural and interactional justices at individual and unit levels and the manager's mental health. Design: A multi-site longitudinal design. Setting(s): Nine Japanese hospitals with more than 200 beds and located in an area with more than 150,000 people. Participants: 385 staff nurses and their 42 nurse managers who completed both surveys in 2016 and 2017. Methods: We analyzed the data from a two-year national survey of the Work Environment for hospital Nurses in Japan part II. Nurse staff and their managers completed the surveys. This multilevel analysis performed four random intercept models on affective commitment and entered the variables of procedural and interactional justices and manager mental health into the models. Results: The staff nurse's affective commitment was positively associated with procedural justice climate (unit level), interactional justice climate (unit-level), and the perception of interactional justice (individual justice). The manager's mental health (psychological distress) had a negative relationship with affective commitment. Conclusions: The climates of procedural and interactional justice, the individual perception of interactional justice, and the manager's mental health impacted the nurses’ affective commitment as a predictor of retention. Moreover, the perception of interactional justice and the organizational contexts (organizational justice climates and managers’ psychological distress) were mediated by affective commitment. Thus, support to maintain the manager's mental health is required to promote staff's affective commitment related to retention. Registration: None. Tweetable abstract: Nurse staff's affective commitment was stimulated by interactional justice, two types of organizational justice climate, and the manager's mental health.

ABSTRACTSleep is essential for our health. Short sleep is known to increase disease risks via imbalance of intestinal microbiota, dysbiosis. However, mechanisms by which short sleep induces dysbiosis remain unknown. Small intestinal Paneth cell regulates the intestinal microbiota by secreting antimicrobial peptides including α-defensin, human defensin 5 (HD5). Disruption of circadian rhythm mediating sleep-wake cycle induces Paneth cell failure. We aim to clarify effects of short sleep on HD5 secretion and the intestinal microbiota. Fecal samples and self-reported sleep time were obtained from 35 healthy middle-aged Japanese (41 to 60-year-old). Shorter sleep time was associated with lower fecal HD5 concentration (r = 0.354, p = 0.037), lower centered log ratio (CLR)-transformed abundance of short-chain fatty acid (SCFA) producers in the intestinal microbiota such as [Ruminococcus] gnavus group (r = 0.504, p = 0.002) and Butyricicoccus (r = 0.484, p = 0.003), and lower fecal SCFA concentration. Furthermore, fecal HD5 positively correlated with the abundance of these genera and SCFA concentration. These findings suggest that short sleep relates to disturbance of the intestinal microbiota via decreased HD5 secretion.

Abstract Deep learning has recently gained attention in the atmospheric and oceanic sciences for its potential to improve the accuracy of numerical simulations or to reduce computational costs. Super‐resolution is one such technique for high‐resolution inference from low‐resolution data. This paper proposes a new scheme, called four‐dimensional super‐resolution data assimilation (4D‐SRDA). This framework calculates the time evolution of a system from low‐resolution simulations using a physics‐based model, while a trained neural network simultaneously performs data assimilation and spatio‐temporal super‐resolution. The use of low‐resolution simulations without ensemble members reduces the computational cost of obtaining inferences at high spatio‐temporal resolution. In 4D‐SRDA, physics‐based simulations and neural‐network inferences are performed alternately, possibly causing a domain shift, that is, a statistical difference between the training and test data, especially in offline training. Domain shifts can reduce the accuracy of inference. To mitigate this risk, we developed super‐resolution mixup (SR‐mixup)–a data augmentation method for domain generalization. SR‐mixup creates a linear combination of randomly sampled inputs, resulting in synthetic data with a different distribution from the original data. The proposed methods were validated using an idealized barotropic ocean jet with supervised learning. The results suggest that the combination of 4D‐SRDA and SR‐mixup is effective for robust inference cycles. This study highlights the potential of super‐resolution and domain‐generalization techniques, in the field of data assimilation, especially for the integration of physics‐based and data‐driven models.

Scientists write research articles, process ethics reviews, evaluate proposals and research, and seek funding. Several strategies have been proposed to optimize these operations and to decentralize access to research resources and opportunities. For instance, we previously proposed the trinity review method, combining registered reports with financing and research ethics assessments. However, previously proposed systems have a number of shortcomings, including how to implement them, e.g., who manages them, how incentives for reviewers are paid, etc. Various solutions have been proposed to address these issues, employing methods based on blockchain technologies, called “decentralized science (DeSci)”. Decentralized approaches that exploit these developments offer potentially profound improvements to the troubled scientific ecosystem. Here, we propose a system that integrates ethics reviews, peer reviews, and funding in a decentralized manner, based on Web3 technology. This new method, named ABCDEF publishing, would enhance the speed, fairness, and transparency of scientific research and publishing.

An immunochromatographic kit using antibodies against recombinant N protein of an omicron B.1.1.529 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was developed to detect SARS-CoV-2 omicron variants. The kit detected omicron variants (BA.1.18, BA.1.1, BA.2, BA.2.12.1, BA.2.75, BA.4.1, BA.4.6, BE.1, BA.5.2.1, XE, BF.7, BF.7.4.1, XBB.1, XBB.1.5 and BQ.1.1) as well as Wuhan strain and a delta variant.

Key message Although intrathoracic extramedullary haematopoiesis (EMH) is rare, its nodular lesions should be differentiated from malignancy. 111In‐bone marrow scintigraphy can be useful for the non‐invasive diagnosis of intrathoracic EMH because extramedullary accumulation of 111In can be determined as EMH.

Summary: Interstitial lung disease (ILD) represents a large group of diseases characterized by chronic inflammation and fibrosis of the lungs, for which therapeutic options are limited. Among several causative genes of familial ILD with autosomal dominant inheritance, the mutations in the BRICHOS domain of SFTPC cause protein accumulation and endoplasmic reticulum stress by misfolding its proprotein. Through a screening system using these two phenotypes in HEK293 cells and evaluation using alveolar epithelial type 2 (AT2) cells differentiated from patient-derived induced pluripotent stem cells (iPSCs), we identified Cryptotanshinone (CPT) as a potential therapeutic agent for ILD. CPT decreased cell death induced by mutant SFTPC overexpression in A549 and HEK293 cells and ameliorated the bleomycin-induced contraction of the matrix in fibroblast-dependent alveolar organoids derived from iPSCs with SFTPC mutation. CPT and this screening strategy can apply to abnormal protein-folding-associated ILD and other protein-misfolding diseases.

Abstract Odor environments in living spaces can influence human physiological and psychological states. To elucidate the effect of volatile organic compounds (VOCs) of wood in living spaces on the modulations of cognitive processing, we built two experimental huts to simulate wooden construction living spaces. One hut was made of cedarwood (Cryptomeria japonica), and the other was made of resin. We used cedarwood and resin, because they are often used as construction materials in Japan. In both huts, we measured the participants’ first positivity in the early visual cortex (P1), the third positivity elicited by voluntary attention (P3b), and the automatic occipital negativity to infrequent visual stimuli in event-related potentials (ERPs), while they performed a visual discrimination task. The VOCs in both huts were measured by gas chromatography–mass spectrometry. The concentration of volatile sesquiterpenes was significantly increased in the cedarwood hut. Neither P1 nor P3b was affected by the cedarwood hut. Compared to the resin hut, we observed significantly larger occipital negativities to the infrequent stimuli in the cedarwood hut in the time windows of 280–300 ms at the mid-occipital region. These findings suggest that the increased concentration of volatile sesquiterpenes emitted from cedarwood facilitates the human brain’s response to changes in visual stimuli.

Abstract Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fibrosis that develops from fatty liver. Disruption of intestinal microbiota homeostasis, dysbiosis, is associated with fibrosis development in NASH. An antimicrobial peptide α-defensin secreted by Paneth cells in the small intestine is known to regulate composition of the intestinal microbiota. However, involvement of α-defensin in NASH remains unknown. Here, we show that in diet-induced NASH model mice, decrease of fecal α-defensin along with dysbiosis occurs before NASH onset. When α-defensin levels in the intestinal lumen are restored by intravenous administration of R-Spondin1 to induce Paneth cell regeneration or by oral administration of α-defensins, liver fibrosis is ameliorated with dissolving dysbiosis. Furthermore, R-Spondin1 and α-defensin improved liver pathologies together with different features in the intestinal microbiota. These results indicate that decreased α-defensin secretion induces liver fibrosis through dysbiosis, further suggesting Paneth cell α-defensin as a potential therapeutic target for NASH.

Abstract Periprosthetic joint infection (PJI) is characterized by biofilm infection, which is difficult to alleviate while preserving implant integrity. Furthermore, long-term antibiotic therapy may increase the prevalence of drug-resistant bacterial strains, necessitating a non-antibacterial approach. Adipose-derived stem cells (ADSCs) exert antibacterial effects; however, their efficacy in PJI remains unclear. This study investigates the efficacy of combined intravenous ADSCs and antibiotic therapy in comparison to antibiotic monotherapy in a methicillin-sensitive Staphylococcus aureus (MSSA)-infected PJI rat model. The rats were randomly assigned and equally divided into 3 groups: no-treatment group, antibiotic group, ADSCs with antibiotic group. The ADSCs with antibiotic group exhibited the fastest recovery from weight loss, with lower bacterial counts (p = 0.013 vs. no-treatment group; p = 0.024 vs. antibiotic group) and less bone density loss around the implants (p = 0.015 vs. no-treatment group; p = 0.025 vs. antibiotic group). The modified Rissing score was used to evaluate localized infection on postoperative day 14 and was the lowest in the ADSCs with antibiotic group; however, no significant difference was observed between the antibiotic group and ADSCs with antibiotic group (p < 0.001 vs. no-treatment group; p = 0.359 vs. antibiotic group). Histological analysis revealed a clear, thin, and continuous bony envelope, a homogeneous bone marrow, and a defined, normal interface in the ADSCs with antibiotic group. Moreover, the expression of cathelicidin expression was significantly higher (p = 0.002 vs. no-treatment group; p = 0.049 vs. antibiotic group), whereas that of tumor necrosis factor (TNF)-α and interleukin(IL)-6 was lower in the ADSCs with antibiotic group than in the no-treatment group (TNF-α, p = 0.010 vs. no-treatment group; IL-6, p = 0.010 vs. no-treatment group). Thus, the combined intravenous ADSCs and antibiotic therapy induced a stronger antibacterial effect than antibiotic monotherapy in a MSSA-infected PJI rat model. This strong antibacterial effect may be related to the increased cathelicidin expression and decreased inflammatory cytokine expression at the site of infection.

Abstract Aims/Introduction To investigate the genetic background of Japanese patients with suspected maturity‐onset diabetes of the young (MODY). Materials and Methods On 340 proband patients referred from across Japan, genomic variants were analyzed using a targeted multigene panel analysis combined with the multiplex ligation probe amplification (MLPA) analysis, mitochondrial m.3243A > G analysis and methylation‐specific polymerase chain reaction of the imprinted 6q24 locus. Pathogenic/likely pathogenic variants were listed according to the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Additionally, variants with a population frequency 20 (CS >20) were listed as rare variants of uncertain significance‐CS >20. Results A total of 157 pathogenic/likely pathogenic variants and 44 rare variants of uncertain significance‐CS >20 were identified. In the pathogenic/likely pathogenic variants, alterations in the GCK gene were the most common (82, 52.2%) followed by HNF1A (29, 18.5%), HNF4A (13, 8.3%) and HNF1B (13, 8.3%). One patient was a 29.5% mosaic with a truncating INSR variant. In the rare variants of uncertain significance‐CS >20, 20 (45.5%) were in the genes coding for the adenosine triphosphate‐sensitive potassium channel, KCNJ11 or ABCC8, and four were in the genes of the insulin‐signaling pathway, INSR and PIK3R1. Four variants in ABCC8 were previously reported in patients with congenital hyperinsulinism, suggesting the inactivating nature of these variants, and at least two of our patients had a history of congenital hyperinsulinism evolving into diabetes. In two patients with INSR or PIK3R1 variants, insulin resistance was evident at diagnosis. Conclusions Causative genomic variants could be identified in at least 46.2% of clinically suspected MODY patients. ABCC8‐MODY with inactivating variants could represent a distinct category of MODY. Genes of insulin resistance should be included in the sequencing panel for MODY.

Abstract In this paper, we address the problem of earthquake declustering, and propose a k-nearest neighbors approach based on the selection of multiple-parent nodes with respect to each of the given earthquakes, which can be regarded as a natural extension of the conventional correlation-metric method based on the selection of a single-parent node. Based on this approach, we develop a centrality measure that exploits link weight assigned by a logarithmic-distance scheme and a technique of individually visualizing each set of child nodes with respect to given target earthquakes. For experimental evaluation, we used an earthquake catalog covering Japan and selected 24 earthquakes that caused considerable damage or casualties. We first show that our proposed centrality measure using a logarithmic-distance scheme can rank these 24 major earthquakes higher than four link-weighting schemes (i.e., uniform, magnitude, inverse-distance, and normalized-inverse-distance weighting) and conventional single-parent selection. We then show that unlike the conventional approach to simultaneously visualizing all the events in the catalog, our proposed technique can produce a naturally interpretable classification result for these 24 major earthquakes, by individually visualizing each set of the first to k-th child nodes with different colored markers plotted in the directly interpretable spatio and temporal metrics. As a consequence, we confirm that our approach based on multiple-parent selection is vital and promising.

Abstract We aimed to assess the reliability and validity of OpenPose, a posture estimation algorithm, for measuring hip-knee-ankle (HKA) angle in patients with knee osteoarthritis, by comparing it with radiography. In this prospective study, we analysed 60 knees (30 patients) with knee osteoarthritis. We measured HKA angle using OpenPose and radiography before or after total knee arthroplasty and assessed the test–retest reliability of each method with intraclass correlation coefficient (1, 1). We evaluated the ability to estimate the radiographic measurement values from the OpenPose values using linear regression analysis and used intraclass correlation coefficients (2, 1) and Bland–Altman analyses to evaluate the agreement and error between OpenPose and radiographic measurements. OpenPose had excellent test–retest reliability (intraclass correlation coefficient (1, 1) = 1.000) and excellent agreement with radiography (intraclass correlation coefficient (2, 1) = 0.915), with regression analysis indicating a large correlation (R2 = 0.865). OpenPose also had a 1.1° fixed error and no systematic error when compared with radiography. This is the first study to validate the use of OpenPose for the estimation of HKA angle in patients with knee osteoarthritis. OpenPose is a reliable and valid tool for measuring HKA angle in patients with knee osteoarthritis. OpenPose, which enables non-invasive and simple measurements, may be a useful tool to assess changes in HKA angle and monitor the progression and post-operative course of knee osteoarthritis. Furthermore, this validated tool can be used not only in clinics and hospitals, but also at home and in training gyms; thus, its use could potentially be expanded to include self-assessment/monitoring.

Abstract Background The shared decision-making model has been proposed as the ideal treatment decision-making process in medical encounters. However, the decision to participate in clinical trials rarely involves shared decision-making. In this study, we investigated the perceptions of Japanese clinical research coordinators who routinely support the informed consent process. Methods This study aimed to (1) identify clinical research coordinators’ perceptions of the current status of shared decision-making implementation and its influencing factors, and (2) obtain suggestions to enhance the shared decision-making process in clinical trials. A cross-sectional survey was conducted using a web questionnaire based on the Theory of Planned behaviour. Invitations were sent to 1087 Japanese medical institutions, and responses from the participants were captured via the web. The shared decision-making process in clinical trials was defined according to the Shared Decision-Making Questionnaire for Doctors. The effect of the attitudes toward shared decision-making, clinical research coordinators’ subjective norms towards its implementation, perceived barriers to autonomous decision-making, and the number of difficult steps in the shared decision-making process on the shared decision-making current status as the shared decision-making intention was assessed by multiple regression analysis. Results In total, 373 clinical research coordinators responded to the questionnaire. Many believed that they were already implementing shared decision-making. Attitudes toward shared decision-making (t = 3.400, p

Abstract Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have yet to be established. We previously reported that a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, ZSTK474, was effective for the treatment of sarcomas in a phase I clinical trial. We also demonstrated the efficacy of ZSTK474 in a preclinical model, particularly in cell lines from synovial sarcoma (SS), Ewing’s sarcoma (ES) and alveolar rhabdomyosarcoma (ARMS), all of which harbor chromosomal translocations. ZSTK474 selectively induced apoptosis in all these sarcoma cell lines, although the precise mechanism underlying the induction of apoptosis remained unclear. In the present study, we aimed to determine the antitumor effect of PI3K inhibitors, particularly with regards to the induction of apoptosis, against various TRS subtypes using cell lines and patient-derived cells (PDCs). All of the cell lines derived from SS (six), ES (two) and ARMS (one) underwent apoptosis accompanied by the cleavage of poly-(ADP-ribose) polymerase (PARP) and the loss of mitochondrial membrane potential. We also observed apoptotic progression in PDCs from SS, ES and clear cell sarcoma (CCS). Transcriptional analyses revealed that PI3K inhibitors triggered the induction of PUMA and BIM and the knockdown of these genes by RNA interference efficiently suppressed apoptosis, suggesting their functional involvement in the progression of apoptosis. In contrast, TRS-derived cell lines/PDCs from alveolar soft part sarcoma (ASPS), CIC-DUX4 sarcoma and dermatofibrosarcoma protuberans failed to undergo apoptosis nor induce PUMA and BIM expression, as well as cell lines derived from non-TRSs and carcinomas. Thus, we conclude that PI3K inhibitors induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and the subsequent loss of mitochondrial membrane potential. This represents proof of concept for PI3K-targeted therapy, particularly such TRS patients.

Abstract Background Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) requires a large amount of economic and human resources. The presence of bystander cardiopulmonary resuscitation (CPR) was focused on selecting appropriate V-A ECMO candidates. Result This study retrospectively enrolled 39 patients with V-A ECMO due to out-of-hospital cardiac arrest (CA) between January 2010 and March 2019. The introduction criteria of V-A ECMO included the following: (1)