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An inventory management problem is theoretically discussed for a factory having effects of lead times in replenishing the inventory, where it stocks materials used for its products. It is assumed that the factory can dynamically control the size of ordering materials. By applying the stochastic control theory, the optimal control of the ordering size is derived, in which the expected total cost up to an expiration time is minimized. First, a new stochastic model is constructed for describing an inventory fluctuation of the factory by the use of a non-diffusive stochastic differential equation, where an analytic time is introduced so that the inventory process can be a Markov process even though it is affected by lead times. Next, an optimal control is formulated by introducing an evaluation function quantifying total costs. Based upon them, the Hamilton-Jacobi-Bellman (HJB) equation is derived, whose solution gives the optimal control. Finally, the optimal control is quantitatively examined through numerical solutions of the HJB equation. Numerical results indicate that if time up to an expiration time is short then the optimal control is affected by it, otherwise, the optimal control does not depend on it.

Introduction: Patients with inflammatory bowel disease (IBD) are increasingly using online platforms to communicate with other patients and healthcare professionals seeking disease-related information and support. Free-text posts on these platforms could provide insights into patients’ everyday lives, which could help to improve patient care. In this proof-of-concept study, we applied text-mining to extract patient needs from free-text posts on a community forum in Japan, and holistically visualized the patients’ perceptions and their connections, and explored the patient characteristic-dependent trends in the use of words. Methods: Free-text posts written between May 11, 2020 and May 31, 2022 on the community forum were retrieved and subjected to text-mining analysis. Trends in the use of words were extracted from the posts for correspondence and co-occurrence network analyses using KH Coder open-source text-mining software. Results: Seventy-four posts were analyzed. Using text mining methods, we successfully extracted and visualized a variety of patient concerns and their connections. The correspondence and co-occurrence analyses revealed patient segment-dependent trends in the use of words. For example, patients with a disease duration of ≤5 yrs were more likely to use words related to emotions or their desire to change or quit their job, such as ‘anxiety’ and ‘resignation.’ Patients with a disease duration of >10 yrs were more likely to use words showing that they are finding ways to live with or accept their disease, and are getting used to the lifestyle but some patients continued to experience worsening disease. Conclusions: We found that free texts posted on an IBD community forum can be a useful source of information to capture the wide variety of thoughts of patients. Text mining procedures can help to visualize the relative importance of the topics identified from free text posts. Our findings of this proof-of-concept study will be useful for generating new hypotheses to better understand and address the needs of patients with IBD.

Abstract Background Concurrent chemoradiotherapy is the standard therapy for locally advanced non‐small cell lung cancer (NSCLC). However, there is little evidence supporting its use in older adults. Low‐dose daily carboplatin combined with thoracic radiotherapy is considered a standard regimen for this population. To establish a simple and feasible carboplatin administration method, we conducted a study of weekly carboplatin and concurrent radiotherapy for older adults with locally advanced NSCLC. Methods This prospective, single‐arm, multicenter, phase II clinical trial included patients aged ≥75 years with unresectable stage III NSCLC and Eastern Cooperative Oncology Group performance status 0–1. Patients received chemoradiotherapy (60 Gy/30 fractions plus concurrent weekly carboplatin at an area under curve of 2 mg mL−1 min−1). The primary endpoint was the overall response rate (ORR). Key secondary endpoints included progression‐free survival (PFS), overall survival (OS), and safety. Results From July 2020 to June 2022, 37 patients were enrolled from 15 institutions, and 36 patients were evaluable for efficacy and safety. The ORR was 63.9% (95% confidence interval [CI] = 47.6–77.5). Median PFS was 14.6 months (95% CI = 9.1–18.1). Median OS was 25.5 months (95% CI = 17.4–not reached). Grade 4 leucopenia, neutropenia, and thrombocytopenia were observed in one patient (2.8%) each. Conclusion Weekly carboplatin and concurrent radiation therapy was safe in older adults with locally advanced NSCLC, and promising activity was observed.

Abstract A technique for predicting the secular variation (SV) of the geomagnetic field based on the echo state network (ESN) model is proposed. SV is controlled by the geodynamo process in the Earth’s outer core, and modeling its nonlinear behaviors can be challenging. This study employs an ESN to represent the short-term temporal evolution of the geomagnetic field on the Earth’s surface. The hindcast results demonstrate that the ESN enables us to predict SV for a duration of several years with satisfactory accuracy. It is also found that the prediction is robust to the length of the the training data period. This suggests that the recent features of the SV are important for short-term prediction and that the ESN effectively learns these features. Graphical Abstract

Abstract The Covid-19 pandemic, caused by the SARS-Cov2- virus, has transformed our lives. To combat the spread of the infection, remote work has become a widespread practice. However, this shift has led to various work-related problems, including prolonged working hours, mental health issues, and communication difficulties. One particular challenge faced by team members is the inability to accurately gauge the work engagement (WE) levels of subordinates, such as their absorption, dedication, and vigor, due to the limited number of in-person interactions that occur in remote work settings. To address this issue, online communication systems utilizing text-based chat tools such as Slack and Microsoft Teams have gained popularity as substitutes for face-to-face communication. In this paper, we propose a novel approach that uses graph neural networks (GNNs) to estimate the work engagement levels (WELs) of users on text-based chat platforms. Specifically, our method involves embedding users in a feature space based solely on the structural information of the utilized communication network, without considering the contents of the conversations that take place. We conduct two studies using Slack data to evaluate our proposal. The first study reveals that the properties of communication networks play a more significant role when estimating WELs than do conversation contents. Building upon this result, the second study involves the development of a machine learning model that estimates WELs using only the architectural features of the employed communication network. In this network representation, each node corresponds to a human user, and edges represent communication logs; i.e., if person A talks to person B, the edge between node A and node B is stretched. Notably, our model achieves a correlation coefficient of 0.60 between the observed and predicted WEL values. Importantly, our proposed approach relies solely on communication network data and does not require linguistic information. This makes it particularly valuable for real-world business situations.

Abstract Purpose Astaxanthin (AX), commonly used for dermal applications, exhibits anti-inflammatory and antioxidant activities; however, it has poor water solubility. In this study, we investigated the physicochemical properties of AX-containing particulates formulated using the amphiphilic graft copolymer Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer: Sol) and polyethylene glycol-2000 (PEG 2000); in addition, the stability and skin applications of AX particulates were investigated. Methods AX, Sol, and PEG were mixed by weight to prepare AX particles using the hydration method. The prepared particles were subjected to stability evaluations including particle size distribution, zeta potential estimation, and fluorescence spectroscopy as well as physical evaluations including 1H-1H NOESY NMR spectral measurement, powder X-ray diffraction, and differential scanning calorimetry. Functional evaluations included singlet oxygen scavenging, skin permeation test, and fluorescence microscopy. Results Relatively stable particles of Sol/AX and Sol/PEG 2000/AX, approximately 100 nm and 125 nm in size, respectively, were formed at a mixed weight ratio (9/1) of 0.1 M Ascorbic Acid solution (0.1 M ASC) and a mixed weight ratio (8/1/1) of 0.1 M ASC, respectively, at 25 °C after storage for 14 days under light-shielded condition. Stability evaluations revealed a decrease in fluorescence intensity and color fading for Sol/AX = 9/1 and Sol/PEG 2000/AX = 8/1/1 (dispersion medium: distilled water); however, no change in fluorescence intensity of AX was observed immediately after preparation in Sol/AX = 9/1 and Sol/PEG 2000/AX = 8/1/1 (dispersion medium: 0.1 M ASC). The fluorescence intensity of AX did not fluctuate significantly immediately after adjustment, and the particles remained stable, showing a bright orange color with time. NMR spectra of Sol/AX = 9/1 and Sol/PEG 2000/AX (dispersion medium: 0.1 M ASC) showed the interactions between the CH3 group e from Sol (1.8 ~ 2.0 ppm) and the CH groups H-15,11 from AX (6.7 ~ 6.8 ppm), 8’,12’ (6.4 ~ 6.5 ppm), H-10,14 (6.4 ~ 6.5 ppm), and 7,7’ (6.2 ~ 6.3 ppm), indicating the disappearance of cross peaks. Furthermore, new cross peaks were identified for the CH3 group e of Sol (1.8 ~ 2.0 ppm), the 7-membered ring z of Sol (1.5 ~ 1.8 ppm), the 5-membered ring S of ASC (3.5 ~ 3.6 ppm), the CH group T (3.8 ~ 3.9 ppm), and the CH group U (4.7 ppm). Fluorescence microscopy observations of microparticles formulated with Sol/PEG 2000/AX showed a slight improvement in skin penetration. Conclusion New AX particulates were formed using Sol/PEG 2000/AX = 8/1/1, suggesting that Sol/PEG 2000/AX maintained the stability and improved the skin penetration of AX.

Malignant glomus tumors are rare mesenchymal tumors arising from the smooth muscle cells of the glomus body. Primary malignant glomus tumors of the thyroid are atypical. An 80-year-old man presented with a right thyroid tumor on computed tomography (CT) and was suspected of having multiple bilateral pulmonary metastases. The right lobe of the thyroid gland was accompanied by a low-density tumor and calcification inside, and infiltration into the trachea and cervical esophagus was deduced. Core needle biopsy (CNB) confirmed that round to polygonal atypical cells were growing in sheet form around the vascular endothelial cells. Immunohistochemistry results were positive for vimentin and smooth muscle actin (SMA) but negative for pan-cytokeratin and S-100 protein. Chemotherapy with doxorubicin was initiated. However, due to the progression of the disease, doxorubicin was replaced with pazopanib. His condition deteriorated further, and he died 3 months after the treatment. Overall, this disease has a poor prognosis.

Abstract Introduction The study aimed to determine the efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) in the treatment of polymyalgia rheumatica (PMR) complicated by rheumatoid arthritis (RA). Methods Patients with PMR which could be classified as RA and who were treated with bDMARDs were included in the analysis. The primary endpoint was the clinical Polymyalgia Rheumatica Activity Score (Clin-PMR-AS) after 26 weeks of treatment, and the secondary endpoint was adverse events during the observation period. Results A total of 203 patients with PMR which was resistant or intolerant to glucocorticoids and could be classified as RA were receiving bDMARDs and were enrolled in the study. There were 83, 82, and 38 patients in the tumor necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL-6Ri), and cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4-Ig) groups, respectively. Twenty-six weeks after bDMARD initiation, Clin-PMR-AS levels were significantly lower in the IL-6Ri group as compared to other groups. Multiple regression analysis was performed with Clin-PMR-AS as the objective variable. Body mass index (BMI), history of bDMARDs, and IL-6Ri use were identified as factors involved in Clin-PMR-AS. After adjustment for group characteristics using inverse probability of treatment weighting with propensity scores, the Clin-PMR-AS score at 26 weeks was significantly lower in the IL-6Ri group (9.0) than in both the TNFi (12.4, p = 0.004) and CTLA4-Ig (15.9, p = 0.003) group. Conclusion IL-6Ri may potentially improve the disease activity of PMR compared to other bDMARDs.

Abstract The idea of utilizing unused oocytes present in the ovaries has been tested in various ways to produce offspring. However, only a limited number of studies succeeded in offspring generation. They include transplantation of ovaries into autologous or allogeneic animals, and acquisition of pups from oocytes obtained by transplanting mouse ovaries into immunodeficient rats. Here we report successful production of rat oocytes by transplanting rat ovaries under the kidney capsule of immunodeficient mice with addition of hormone administration to the mice. In addition, these oocytes were developed by in vitro fertilization, and transplanted into the oviducts of pseudopregnant rats, resulting in successful delivery of pups. The modified gene of the donor rat was confirmed to be correctly inherited to the pups. These results show that xenotransplantation of ovarian tissue makes it possible to leave offspring, beginning a new phase in developmental engineering.

ABSTRACT Dietary therapy is crucial for diabetes care with the aim of preventing the onset and progression of diabetes and its complications. The traditional approach to dietary therapy for diabetes has primarily focused on restricting the intake of the three major nutrients and rigorously controlling blood glucose levels. However, advancements in nutritional science have shown that within the three major nutrients – carbohydrates, proteins and lipids – there exist multiple types, each with distinct impacts on type 2 diabetes and its complications, sometimes even showing conflicting effects. In light of this, the present review shifts its focus from the quantity to the quality of the three major nutrients. It aims to provide an overview of how the differences in nutrient quality can influence onset and progression of type 2 diabetes and diabetic kidney disease, highlighting the diverse effects and, at times, contradictory impacts associated with each nutrient type.

Background/Aims A previous study demonstrated that half of patients started oral corticosteroids (OCS) for ulcerative colitis (UC) exacerbations at lower doses than recommended by Japanese treatment guidelines (initial OCS prednisolone equivalent dose, 30–40 mg). This may relate to physician’s concern about infection, especially pneumonia including Pneumocystis jirovecii pneumonia (PJP), from high OCS doses. We assessed whether pneumonia incidence is increased with guideline-recommended OCS initial doses. Methods This retrospective cohort study used the Japan Medical Data Center claims database (2012–2021). The whole cohort consisted of all UC patients who started OCS during the study period meeting the inclusion and exclusion criteria. The matched cohort was created by propensity score matching; the lower (initial OCS dose < 30 mg), guideline-recommended (30–40 mg), and higher groups ( > 40 mg) in a 2:2:1 ratio. Pneumonia incidence in the primary analysis was evaluated in the matched cohort. A Poisson regression model determined pneumonia-related risk factors in the whole cohort. Results After screening, 3,349 patients comprised the whole cohort; 1,775 patients comprised the matched cohort (lower dose, n = 710; guideline-recommended dose, n = 710; higher dose, n = 355). The incidence of any pneumonia was low; no differences were observed in incidence rates across these dose subgroups. In total, 3 PJP cases were found in the whole cohort, but not detected in the matched cohort. Several risk factors for any pneumonia were identified, including age, higher comorbidities index, treatment in large facility and hospitalization. Conclusions The incidence of pneumonia, including PJP, in UC patients was low across initial OCS dose treatment subgroups.

Abstract Background Perioperative management of patients on dialysis is critical for controlling bleeding and thrombotic risk, in addition to infection control. Postoperative anticoagulation is often difficult to control, and different institutions have different policies. Therefore, in this study, we aimed to investigate factors associated with postoperative bleeding events and whether warfarin (WF) therapy affects the incidence of postoperative bleeding events, total mortality, and stroke. Methods Patients who were admitted to the cardiovascular surgery department and underwent valve replacement or plasty were included, and those who underwent mechanical valve introduction were excluded. Thirty-nine patients were included in the study. The primary endpoint was to identify factors associated with the composite endpoint of postoperative bleeding events, and the secondary endpoint was to determine the effect size of WF therapy on postoperative bleeding events, all-cause mortality, and stroke and the strength of association between the crossed endpoints. The strength of the association between the crossed items was examined. Results Low body weight (p = 0.038) was identified as a factor associated with the primary endpoint of postoperative bleeding events. The secondary endpoint of whether or not patients received WF therapy was largely unrelated to bleeding events, all-cause mortality, and postoperative stroke up to 90 days after surgery. Conclusions Preliminary studies suggest that low body weight is a risk factor for postoperative bleeding events in patients on dialysis, although further exploration of other factors will be necessary with the accumulation of similar cases.

Abstract Microalgae are considered to be more useful and effective to use in biomass production than other photosynthesis organisms. However, microalgae need to be altered to acquire more desirable traits for the relevant purpose. Although neutron radiation is known to induce DNA mutations, there have been few studies on its application to microalgae, and the optimal relationship between irradiation intensity and mutation occurrence has not been established. In this study, using the unicellular red alga Cyanidioschyzon merolae as a model, we analyzed the relationship between the absorbed dose of two types of neutrons, high-energy (above 1 MeV) and thermal (around 25 meV) neutrons, and mutation occurrence while monitoring mutations in URA5.3 gene encoding UMP synthase. As a result, the highest mutational occurrence was observed when the cells were irradiated with 20 Gy of high-energy neutrons and 13 Gy of thermal neutrons. Using these optimal neutron irradiation conditions, we next attempted to improve the lipid accumulation of Euglena gracilis, which is a candidate strain for biofuel feedstock production. As a result, we obtained several strains with a maximum 1.3-fold increase in lipid accumulation compared with the wild-type. These results indicate that microalgae breeding by neutron irradiation is effective.

Abstract The prenatal diagnosis of fetal heart disease potentially influences parental decision-making regarding pregnancy termination. Existing literature indicates that the severity, whether in complexity or lethality, significantly influences parental decisions concerning abortion. However, questions remain as to how fetal heart disease severity impacts parental decisions, given recent advancements in postsurgical outcomes. Therefore, we investigated risk factors associated with parents’ decision-making regarding abortion following a prenatal diagnosis of fetal heart disease. Our analysis included 73 (terminated: n = 37; continued: n = 36) pregnancies with a fetal heart disease diagnosed before 22 weeks of gestation. Increased gestational age at diagnosis reduced the likelihood of parents’ decision on termination (Model 1: adjusted odds ratio, 0.94; 95% confidence interval 0.89–0.99; Model 2: 0.95 0.90–0.997). Critical disease (5.25; 1.09–25.19) and concurrent extracardiac or genetic abnormalities (Model 1: 4.19, 1.21–14.53; Model 2: 5.47, 1.50–19.96) increased the likelihood of choosing abortion. Notably, complex disease did not significantly influence parental decisions (0.56; 0.14–2.20). These results suggest that parental decision-making regarding abortion may be influenced by earlier gestational age at diagnosis, the lethality of heart disease, and extracardiac or genetic abnormalities, but not its complexity if prenatal diagnosis and parental counseling are provided at a cardiovascular-specialized facility.

Abstract There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory cells. We characterized the specific distribution of myeloid cells of both human type A AAD samples and a murine AAD model generated using angiotensin II (ANGII) and β-aminopropionitrile (BAPN) by single-cell RNA sequencing (scRNA-seq). We also examined the effect of an anti-interleukin-1β (IL-1β) antibody in the murine AAD model. IL1B+ inflammatory macrophages and classical monocytes were increased in human AAD samples. Trajectory analysis demonstrated that IL1B+ inflammatory macrophages differentiated from S100A8/9/12+ classical monocytes uniquely observed in the aorta of AAD. We found increased infiltration of neutrophils and monocytes with the expression of inflammatory cytokines in the aorta and accumulation of inflammatory macrophages before the onset of macroscopic AAD in the murine AAD model. In blocking experiments using an anti-IL-1β antibody, it improved survival of murine AAD model by preventing elastin degradation. We observed the accumulation of inflammatory macrophages expressing IL-1β in both human AAD samples and in a murine AAD model. Anti-IL-1β antibody could improve the mortality rate in mice, suggesting that it may be a treatment option for AAD.

Abstract Aim Postmortem brain research is necessary for elucidating the pathology of schizophrenia; an increasing number of studies require a combination of suitable tissue samples preserved at multiple brain banks. In this study, we examined whether a comparative study of protein expression levels can be conducted using postmortem brain samples preserved in different facilities. Methods We compared the demographic factors of postmortem brain samples preserved in two institutions and measured and compared the expression levels of glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) and glial fibrillary acidic protein (GFAP) in the prefrontal cortex and superior temporal gyrus. GAPDH is generally used as a loading control for western blotting, and GFAP is considered as an astrocyte marker in the brain. Results We found significant differences between the two institutions in postmortem interval, age at death, and preservation time. To reduce the effects of these differences on our measurements, the parameters were set as covariates in our analyses of covariance. Subsequently, no differences in GAPDH and GFAP expression were found between institutions. Conclusions When studies are conducted using brain samples preserved in different brain banks, differences in demographic factors should be carefully considered and taken into account by statistical methods to minimize their impact as much as possible. Since there was no significant difference in the protein expression levels of GAPDH and GFAP in either region between the two institutions that preserved the postmortem brains, we concluded that it is possible to perform protein quantitative analysis assuming that there is no effect of difference between two institutions.

A robot hand-arm that can perform various tasks with the unaffected arm could ease the daily lives of patients with a single upper-limb dysfunction. A smooth interaction between robot and patient is desirable since their other arm functions normally. If the robot can move in response to the user’s intentions and cooperate with the unaffected arm, even without detailed operation, it can effectively assist with daily tasks. This study aims to propose and develop a cybernic robot hand-arm with the following features: 1) input of user intention via bioelectrical signals from the paralyzed arm, the unaffected arm’s motion, and voice; 2) autonomous control of support movements; 3) a control system that integrates voluntary and autonomous control by combining 1) and 2) to thus allow smooth work support in cooperation with the unaffected arm, reflecting intention as a part of the body; and 4) a learning function to provide work support across various tasks in daily use. We confirmed the feasibility and usefulness of the proposed system through a pilot study involving three patients. The system learned to support new tasks by working with the user through an operating function that does not require the involvement of the unaffected arm. The system divides the support actions into movement phases and learns the phase-shift conditions from the sensor information about the user’s intention. After learning, the system autonomously performs learned support actions through voluntary phase shifts based on input about the user’s intention via bioelectrical signals, the unaffected arm’s motion, and by voice, enabling smooth collaborative movement with the unaffected arm. Experiments with patients demonstrated that the system could learn and provide smooth work support in cooperation with the unaffected arm to successfully complete tasks they find difficult. Additionally, the questionnaire subjectively confirmed that cooperative work according to the user’s intention was achieved and that work time was within a feasible range for daily life. Furthermore, it was observed that participants who used bioelectrical signals from their paralyzed arm perceived the system as part of their body. We thus confirmed the feasibility and usefulness of various cooperative task supports using the proposed method.

Abstract Aim To examine the association of the combination of taking neuropsychiatric medications from the onset of pregnancy to mid‐pregnancy and maternal psychological distress at mid‐pregnancy, with children's behavioral problems. Methods Neuropsychiatric medication use from the onset of pregnancy to mid‐pregnancy was defined by the self‐reported name of the neuropsychiatric medication in the questionnaire in early and mid‐pregnancy. Maternal psychological distress was defined by the Kessler Psychological Distress Scale (K6) ≥13 on the questionnaire in mid‐pregnancy. We classified the participants into four categories based on the combination of taking neuropsychiatric medications and psychological distress: “None,” “Medications only,” “K6 ≥ 13 only,” and “Both.” Children's behavioral problems were assessed using the Child Behavior Checklist for Ages 1½–5 (CBCL) at 2 years of age. The clinical ranges of the internalizing and externalizing scales of the CBCL were defined as behavioral problems. We conducted a multivariable logistic regression analysis to examine the associations between the four categories of maternal exposure and children's behavioral problems. Results Compared with the “None” category (n = 9873), the “K6 ≥ 13 only” category (n = 308) was statistically significantly associated with internalizing and externalizing problems. In contrast, the “Medications only” (n = 93) and “Both” (n = 22) categories were not statistically significantly associated with internalizing and externalizing problems, although the point estimates of the odds ratio in the “Both” category were relatively high (1.58 for the internalizing problem and 2.50 for the externalizing problem). Conclusion The category of mothers taking neuropsychiatric medications and having no psychological distress during pregnancy was not associated with children's behavioral problems in the present population.

Objectives: To clarify the infection route in maternal death due to invasive group A streptococcal (GAS) infection and toxic shock syndrome (TSS). Methods: A retrospective study was conducted on maternal deaths due to GAS-TSS in Japan between January 2010 and March 2024. The final causal diagnosis of maternal death and the infection routes of GAS were analysed using medical records, laboratory data and autopsy findings. Results: Among the 616 maternal deaths during the study period, 48 (8%) involved infectious diseases. The most common infection was invasive GAS (56%, n = 27), 21 (78%) and six cases occurred during the antepartum and puerperium periods, respectively. In the GAS-TSS group, 71% (15/21) infections were originated the upper respiratory tract. However, in the puerperium cases, 67% (4/6) were infected from the genital tract. In addition, no maternal deaths due to GAS-TSS were reported during the COVID-19 pandemic period in Japan from 2020 to 2023. Conclusion: Most antepartum GAS infections were from the upper respiratory tract. They may be reduced by preventive measures, including frequent disinfection, wearing masks and isolation from persons at high risk of carrying GAS, such as symptomatic children. On the other hand, GAS-TSS during puerperium infection via the genital tract.

Background: Nonepisodic angioedema with eosinophilia (NEAE) is a condition marked by angioedema and significant eosinophilia and often linked with atopic dermatitis. It predominantly affects young Asian women and occurs more frequently in the autumn and winter. Despite over 100 reported cases, its etiology and pathogenesis remain unclear. Case presentation: A 23-year-old Japanese female florist presented with acute arm swelling following rose-thorn pricks to her hands and fingers in spring. One week later, she developed progressive symmetrical non-pitting edema in her lower legs and a 3 kg weight gain without any rash. She had a history of oral allergy syndrome to apples and pears for which allergen-specific IgE were previously detected. Blood tests showed significant eosinophilia (14,930 cells/μL) and elevated thymus and activation-regulated chemokine (TARC) levels (12,864 pg/mL). Thyroid disease, autoimmune disorders, and hematologic malignancies were ruled out. Normal cardiac markers and a whole-body computed tomography excluded visceral organ involvement. She was diagnosed with NEAE and treated with oral prednisolone, which resolved the edema within 10 days. Prednisolone was tapered gradually on an outpatient basis without recurrence. Conclusion: A review of the literature indicates that NEAE triggered by subcutaneous antigen exposure may not follow the typical age or seasonal patterns. Direct subcutaneous antigen exposure, including rose-thorn pricks, can trigger NEAE. Clinicians should consider NEAE in atypical presentations and thoroughly investigate preceding episodes.

Abstract Wastewater surveillance is an effective tool for monitoring community spread of COVID-19 and other diseases. Quantitative PCR (qPCR) analysis for wastewater surveillance is more susceptible to mutations in target genome regions than binary PCR analysis for clinical surveillance. The SARS-CoV-2 concentrations in wastewater estimated by N1 and N2 qPCR assays started to diverge around July 2022 in data from different sampling sites, analytical methods, and analytical laboratories in Japan. On the basis of clinical genomic surveillance data and experimental data, we demonstrate that the divergence is due to two mutations in the N1 probe region, which can cause underestimation of viral concentrations. We further show that this inaccuracy can be alleviated if the qPCR data are analyzed with the second derivative method or the Cy0 method instead of the crossing point method.

Abstract Catalytic antibodies possess a dual function that enables both antigen recognition and degradation. However, their time-consuming preparation is a significant drawback. This study developed a new method for quickly converting mice monoclonal antibodies into catalytic antibodies using site-directed mutagenesis. Three mice type monoclonal antibodies targeting hemagglutinin molecule of influenza A virus could be transformed into the catalytic antibodies by deleting Pro95 in CDR-3 of the light chain. No catalytic activity was observed for monoclonal antibodies and light chains. In contrast, the Pro95-deleted light chains exhibited a catalytic activity to cleave the antigenic peptide including the portion of conserved region of hemagglutinin molecule. The affinity of the Pro95-deleted light chains to the antigen increased approximately 100-fold compared to the wild-type light chains. In the mutants, three residues (Asp1, Ser92, and His93) come closer to the appropriate position to create the catalytic site and contributing to the enhancement of both catalytic function and immunoreactivity. Notably, the Pro95-deleted catalytic light chains could suppress influenza virus infection in vitro assay, whereas the parent antibody and the light chain did not. This strategy offers a rapid and efficient way to create catalytic antibodies from existing antibodies, accelerating the development for various applications in diagnostic and therapeutic applications.

Abstract Heterogeneity of Helicobacter pylori communities contributes to its pathogenicity and diverse clinical outcomes. We conducted drug-susceptibility tests using four antibiotics, clarithromycin (CLR), amoxicillin (AMX), metronidazole and sitafloxacin, to examine H. pylori population diversity. We also analyzed genes associated with resistance to CLR and AMX. We examined multiple isolates from 42 Japanese patients, including 28 patients in whom primary eradication with CLR and AMX had failed, and 14 treatment-naïve patients. We identified some patients with coexistence of drug resistant- and sensitive-isolates (drug-heteroR/S-patients). More than 60% of patients were drug-heteroR/S to all four drugs, indicating extensive heterogeneity. For the four drugs except AMX, the rates of drug-heteroR/S-patients were higher in treatment-naïve patients than in primary eradication-failure patients. In primary eradication-failure patients, isolates multi-resistant to all four drugs existed among other isolates. In primary eradication-failure drug-heteroR/S-patients, CLR- and AMX-resistant isolates were preferentially distributed to the corpus and antrum with different minimum inhibitory concentrations, respectively. We found two mutations in PBP1A, G591K and A480V, and analyzed these in recombinants to directly demonstrate their association with AMX resistance. Assessment of multiple isolates from different stomach regions will improve accurate assessment of H. pylori colonization status in the stomach.

Abstract Background Immunoglobulin (Ig)G4-related disease affects nearly every organ, and its clinical course varies depending on the involved organ; however, its occurrence in the mediastinum is rarely reported. Case presentation A 58-year-old woman presented with a posterior mediastinal tumor along the thoracic spine on imaging. Based on her elevated serum IgG4 level of 349.7 mg/dL, IgG4-related disease was suspected. Since the tumor was growing and malignancy could not be excluded, surgical resection was performed for definitive diagnosis. Robot-assisted thoracoscopic surgery was performed via the left semipronation and right thoracic approaches. The irregularly-shaped tumor was located on the level of the seventh to ninth thoracic vertebra, along the sympathetic nerve. A malignancy was not excluded based on the appearance of the tumor. The tumor had poor mobility. The sympathetic nerves, intercostal arteries, and veins were also excised. In this case, the articulated forceps, used during the robotic surgery, were useful in achieving complete tumor resection along the vertebral body. The pathological examination revealed IgG4-positive plasma infiltration, which fulfilled the criteria for IgG4-related diseases. The postoperative course was uneventful, and the patient underwent follow-up on an outpatient basis without additional medications. Conclusion The clinical presentation of IgG4-related disease varies, based on the involved organs. This case was rare because the mediastinum was involved, and it emphasized the effectiveness of surgical resection.

Abstract Background A technical qualification system was developed in 2004 by the Japan Society for Endoscopic Surgery. An analysis of the EnSSURE study on 3188 stage II–III rectal cancer patients, which was performed by including the participation of qualified surgeons as assistants and advisers without restricting their participation as operators, revealed that the participation of technically qualified surgeons in surgery improved the technical and oncological safety of laparoscopic rectal resection. Aim This secondary retrospective analysis of the EnSSURE study examined the advantage of qualified surgeons participating in laparoscopic low anterior resection (LAR). Methods The outcomes of low anterior resection were compared between groups with and without the participation of surgeons qualified by the Endoscopic Surgical Skill Qualification System (Q and non‐Q groups, respectively). We used propensity score matching to generate paired cohorts at a one‐to‐one ratio. The postoperative complication rate, short‐term results (hemorrhage volume, operative time, number of dissected lymph nodes, open conversion rate, intraoperative complication rate, and R0 resection rate), and long‐term results (disease‐free survival rate, local recurrence rate, and overall survival rate) were evaluated. Results The frequencies of postoperative complications, anastomotic bleeding, and intraperitoneal abscess were significantly lower, the operative time was significantly shorter, the postoperative hospital stay was significantly shorter, and the number of dissected lymph nodes was higher in the Q group. No significant differences were observed in disease‐free survival, local recurrence, or overall survival rate rates between the groups. Conclusion The participation of qualified surgeons in LAR is technically advantageous.

Abstract Introduction This study aimed to develop low-cost models using machine learning approaches predicting the achievement of Clinical Disease Activity Index (CDAI) remission 6 months after initiation of tumor necrosis factor inhibitors (TNFi) as primary biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) for rheumatoid arthritis (RA). Methods Data of patients with RA initiating TNFi as first b/tsDMARD after unsuccessful methotrexate treatment were collected from the FIRST registry (August 2003 to October 2022). Baseline characteristics and 6-month CDAI were collected. The analysis used various machine learning approaches including logistic regression with stepwise variable selection, decision tree, support vector machine, and lasso logistic regression (Lasso), with 48 factors accessible in routine clinical practice for the prediction model. Robustness was ensured by k-fold cross validation. Results Among the approaches tested, Lasso showed the advantages in predicting CDAI remission: with a mean area under the curve 0.704, sensitivity 61.7%, and specificity 69.9%. Predicted TNFi responders achieved CDAI remission at an average rate of 53.2%, while only 26.4% of predicted TNFi non-responders achieved remission. Encouragingly, the models generated relied solely on patient-reported outcomes and quantitative parameters, excluding subjective physician input. Conclusions While external cohort validation is warranted for broader applicability, this study highlights the potential for a low-cost predictive model to predict CDAI remission following TNFi treatment. The approach of the study using only baseline data and 6-month CDAI measures, suggests the feasibility of establishing regional cohorts to generate low-cost models tailored to specific regions or institutions. This may facilitate the application of regional/in-house precision medicine strategies in RA management.

Abstract Background A team approach is essential for effective trauma management. Close collaboration between interventional radiologists and surgeons during the initial management of trauma patients is important for prompt and accurate trauma care. This study aimed to determine whether trauma patients benefit from close collaboration between interventional radiology (IR) and surgical teams during the primary trauma survey. Methods A retrospective observational study was conducted between 2014 and 2021 at a single institution. Patients were assigned to an embolization group (EG), a surgery group (SG), or a combination group (CG) according to their treatment. The primary and secondary outcomes were survival at hospital discharge compared with the probability of survival (Ps) and the time course of treatment. Results The analysis included 197 patients, consisting of 135 men and 62 women, with a median age of 56 [IQR, 38–72] years and an injury severity score of 20 [10–29]. The EG, SG, and CG included 114, 48, and 35 patients, respectively. Differences in organ injury patterns were observed between the three groups. In-hospital survival rates in all three groups were higher than the Ps. In particular, the survival rate in the CG was 15.5% higher than the Ps (95% CI: 7.5–23.6%; p

Abstract Background Autoimmune pulmonary alveolar proteinosis (APAP) is a diffuse lung disease that causes abnormal accumulation of lipoproteins in the alveoli; however, its pathogenesis remains unclear. Recently, APAP cases have been reported during the course of dermatomyositis. The combination of these two diseases may be coincidental; however, it may have been overlooked because differentiating APAP from a flare-up of interstitial pneumonia associated with dermatomyositis is challenging. This didactic case demonstrates the need for early APAP scrutiny. Case presentation A 50-year-old woman was diagnosed with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatitis and interstitial pneumonia in April 2021. The patient was treated with corticosteroids, tacrolimus, and cyclophosphamide pulse therapy for interstitial pneumonia complicated by MDA5 antibody-positive dermatitis, which improved the symptoms and interstitial pneumonia. Eight months after the start of treatment, a new interstitial shadow appeared that worsened. Therefore, three additional courses of cyclophosphamide pulse therapy were administered; however, the respiratory symptoms and interstitial shadows did not improve. Respiratory failure progressed, and 14 months after treatment initiation, bronchoscopy revealed turbid alveolar lavage fluid, numerous foamy macrophages, and numerous periodic acid–Schiff-positive unstructured materials. Blood test results revealed high anti-granulocyte–macrophage colony-stimulating factor (GM-CSF) antibody levels, leading to a diagnosis of APAP. The patient underwent whole-lung lavage, and the respiratory disturbance promptly improved. Anti-GM-CSF antibodies were measured from the cryopreserved serum samples collected at the time of diagnosis of anti-MDA5 antibody-positive dermatitis, and 10 months later, both values were significantly higher than normal. Conclusions This is the first report of anti-MDA5 antibody-positive dermatomyositis complicated by interstitial pneumonia with APAP, which may develop during immunosuppressive therapy and be misdiagnosed as a re-exacerbation of interstitial pneumonia. In anti-MDA5 antibody-positive dermatomyositis, APAP comorbidity may have been overlooked, and early evaluation with bronchoalveolar lavage fluid and anti-GM-CSF antibody measurements should be considered, keeping the development of APAP in mind.

Abstract Aberrant glycosylation is a crucial strategy employed by cancer cells to evade cellular immunity. However, it’s unclear whether homologous recombination (HR) status-dependent glycosylation can be therapeutically explored. Here, we show that the inhibition of branched N-glycans sensitizes HR-proficient, but not HR-deficient, epithelial ovarian cancers (EOCs) to immune checkpoint blockade (ICB). In contrast to fucosylation whose inhibition sensitizes EOCs to anti-PD-L1 immunotherapy regardless of HR-status, we observe an enrichment of branched N-glycans on HR-proficient compared to HR-deficient EOCs. Mechanistically, BRCA1/2 transcriptionally promotes the expression of MGAT5, the enzyme responsible for catalyzing branched N-glycans. The branched N-glycans on HR-proficient tumors augment their resistance to anti-PD-L1 by enhancing its binding with PD-1 on CD8+ T cells. In orthotopic, syngeneic EOC models in female mice, inhibiting branched N-glycans using 2-Deoxy-D-glucose sensitizes HR-proficient, but not HR-deficient EOCs, to anti-PD-L1. These findings indicate branched N-glycans as promising therapeutic targets whose inhibition sensitizes HR-proficient EOCs to ICB by overcoming immune evasion.

Introduction: Primary malignant melanoma of the esophagus is a very rare disease with a poor prognosis. We herein report a patient with primary malignant melanoma of the esophagus who underwent surgical resection. Case Presentation: A 73-year-old female underwent an upper gastrointestinal endoscopy during follow-up for colonic diverticulitis. An endoscopic examination and constructed radiography revealed a slightly elevated black pigmented lesion in the upper esophagus and a black pigmented area in the esophagogastric junction. Through a preoperative endoscopic biopsy, she was diagnosed with malignant melanoma of the esophagus. We performed thoracoscopy-assisted and laparoscopy-assisted subtotal esophagectomy with lymphadenectomy. The surgical specimens were subjected to immunohistochemical analysis, resulting in a diagnosis of malignant melanoma. The tumor cells were positive for Melan-A and HMB-45 diffusely, supporting that diagnosis. We performed surgical resection in a case of primary malignant melanoma of the esophagus, and the patient has remained disease free for 2 years since the surgery. Conclusion: Early diagnosis and radical resection may be essential for long-term survival in patients with malignant melanoma of the esophagus.

Abstract Determinants of HIV-1 latency establishment are yet to be elucidated. HIV reservoir comprises a rare fraction of infected cells that can survive host and virus-mediated killing. In vitro reporter models so far offered a feasible means to inspect this population, but with limited capabilities to dissect provirus silencing dynamics. Here, we describe a new HIV reporter model, HIV-Timer of cell kinetics and activity (HIV-Tocky) with dual fluorescence spontaneous shifting to reveal provirus silencing and reactivation dynamics. This unique feature allows, for the first time, identifying two latent populations: a directly latent, and a recently silenced subset, with the latter having integration features suggestive of stable latency. Our proposed model can help address the heterogeneous nature of HIV reservoirs and offers new possibilities for evaluating eradication strategies.

Abstract Background Rice bran a by-product of the rice milling process is currently underutilized. Recent studies have shown that plant-derived nanoparticles (pdNPs) can be mass-produced at a low cost and exhibit biological and therapeutic activities. Rice bran contains various anti-cancer compounds, including γ-oryzanol and γ-tocotrienol, and rice bran-derived nanoparticles (rbNPs) can be employed as novel therapeutic agents for cancer treatment. Results Koshihikari rice bran was suspended in water, and the suspension was centrifuged and filtered through a 0.45-µm-pore size syringe filter. The filtrate was ultracentrifuged, and the precipitates were suspended to obtain rbNPs. The rbNPs were negatively charged exosome-like nanoparticles with an average diameter of approximately 130 nm. The rbNPs exhibited cytotoxic activities against cancer cells but not against normal cells. The cytotoxic activity of rbNPs to murine colon adenocarcinoma colon26 cells was significantly greater than DOXIL® or other pdNPs. The rbNPs induced cell cycle arrest and apoptosis, and reduced the expression of proliferative proteins, including β-catenin and cyclin D1. Intraperitoneal injections of rbNPs into mice bearing peritoneal dissemination of colon26 cells significantly suppressed tumor growth with no significant adverse effects. Conclusion These results indicated that rbNPs are promising nanoparticles, hold significant potential for anti-cancer applications, and are expected to play a vital role in cancer treatment.

Abstract The role of extratropical atmosphere-ocean coupling in generating and maintaining large-scale atmospheric low-frequency variability remains an open question owing to vigorous atmospheric internal fluctuations. Here, we use coupled and uncoupled large-ensemble global model simulations to clarify how the coupling intensifies atmospheric teleconnection patterns in the Northern Hemisphere winter. We show that the extratropical coupling selectively enhances the variance of three principal modes of variability, explaining 13%, 11%, and 10% of the total variance of Pacific/North American, North Atlantic Oscillation, and Warm-Arctic Cold-Eurasian patterns, respectively. Atmosphere-ocean coupling reduces damping to lower-tropospheric available potential energy, which in turn increases kinetic energy by changing energy transfer within the mode. The extratropical ocean is overall passive (adjustable) to large-scale atmospheric variation, thus contributing to the prominence of these modes. The geographical dependence of available potential energy damping suggests the existence of mode-specific sweet spots where the influence of coupling operates efficiently, providing a clue to improving the model biases in variance and signal-to-noise ratio of these modes.

Abstract Aim The etiology of bipolar disorder (BD) remains unknown; however, lipid abnormalities in BD have received increasing attention in recent years. In this study, we examined the expression levels of enzyme proteins associated with the metabolic pathway of phosphoinositides (PIs) and their downstream effectors, protein kinase B (Akt1) and glycogen synthase kinase 3β (GSK3β), which have been assumed to be the targets of mood stabilizers such as lithium, in the postmortem brains of patients with BD. Methods The protein expression levels of phosphatidylinositol 4‐phosphate 5‐kinase type‐1 gamma (PIP5K1C), phosphatidylinositol 4‐kinase alpha (PIK4CA), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), Akt1, and GSK3β were measured using enzyme‐linked immunosorbent assays and multiplex fluorescent bead‐based immunoassays in the prefrontal cortex (PFC). Specifically, PTEN, Akt1, GSK3β, and PIP5K1C were measured in seven BD patients and 48 controls. Additionally, PIK4CA was analyzed in 10 cases and 34 controls. Results PTEN expression levels were markedly decreased in the PFCs of patients with BD, whereas those of Akt and GSK3β were prominently elevated. Moreover, patients medicated with lithium exhibited higher Akt1 expression levels and lower PTEN expression levels in comparison with the untreated group. Conclusion Our results suggest that the expression levels of Akt1/GSK3β and its upstream regulator PTEN are considerably altered.

Abstract Aims Many patients who are transferred to the convalescent rehabilitation ward of Kawasaki Kokoro Hospital (hereinafter, our hospital) are on psychotropics prescribed for delirium by their physicians at acute care hospitals. In this study, psychiatrists and pharmacists collaborated with rehabilitation physicians to reduce the use of psychotropics. Methods The basic information and psychotropics prescription statuses of 88 patients discharged from the convalescent rehabilitation ward of our hospital between April 1, 2021 and March 31, 2022 were derived from their medical records. Results At admission, psychotropics were prescribed to 55 patients and the number of prescribed drugs was 2 (median). At discharge, psychotropics were prescribed to 41 patients and the number of prescribed drugs was 1 (median), showing a significant decrease (p

Abstract Background Gastric cancer is primarily treated by surgery; however, little is known about the changes in the intraperitoneal immune environment and the prognostic impact of surgery. Surgical stress and cancer-associated inflammation cause immune cells to mobilize into the abdominal cavity via numerous cytokines. One such cytokine, CX3CR1, has various immune-related functions that remain to be fully explained. We characterized the intraperitoneal immune environment by investigating CX3CR1+ cells in intraperitoneal lavage fluid during gastric cancer surgery. Methods Lavage fluid samples were obtained from a total of 41 patients who underwent gastrectomy. The relative expression of various genes was analyzed using quantitative real-time PCR. The association of each gene expression with clinicopathological features and surgical outcomes was examined. The fraction of CX3CR1+ cells was analyzed by flow cytometry. Cytokine profiles in lavage fluid samples were investigated using a cytometric beads array. Results CX3CR1high patients exhibited higher levels of perioperative inflammation in blood tests and more recurrences than CX3CR1low patients. CX3CR1high patients tended to exhibit higher pathological T and N stage than CX3CR1low patients. CX3CR1 was primarily expressed on myeloid-derived suppressor cells and tumor-associated macrophages. In particular, polymorphonuclear myeloid-derived suppressor cells were associated with perioperative inflammation, pathological N, and recurrences. These immunosuppressive cells were associated with a trend toward unfavorable prognosis. Moreover, CX3CR1 expression was correlated with programmed death–1 expression. Conclusions Our results suggest that CX3CR1+ cells are associated with an acute inflammatory response, tumor-promotion, and recurrence. CX3CR1 expression could be taken advantage of as a beneficial therapeutic target for improving immunosuppressive state in the future. In addition, analysis of intra-abdominal CX3CR1+ cells could be useful for characterizing the immune environment after gastric cancer surgery.

Abstract Aim Carcinoma of the ampulla of Vater (CAV) shows a favorable prognosis compared to that with the other periampullary tumors, while some cases have a poor prognosis. The aims of the present study are to clarify the clinicopathological factors associated with poor recurrence‐free survival (RFS) in patients with CAV after curative resection and to validate the usefulness of adjuvant chemotherapy (AC). Patients The study design is a multicenter retrospective cohort study. Patients with CAV who underwent pancreaticoduodenectomy between January 2008 and December 2020 at 26 hospitals were analyzed. The 30 clinicopathological factors were evaluated. A propensity score matching (PSM) was used to compare between patients with and without AC. Results Finally, 460 patients were analyzed. Median duration of follow‐up was 47.2 months. Twenty‐one prognostic factors associated with poor RFS were identified by univariate analysis. In multivariate analysis, aged ≥71, tumor diameter ≥12 mm, pT2 or higher stage (pT≥2), portal vein invasion (PV+), venous invasion(V+), and node positive disease (pN+) were independent prognostic factors for poor RFS. Out of 80 patients who received AC, 63 patients were assigned to analysis for PSM. The results showed no beneficial effect of AC on RFS. The preoperative factors potentially predicting pT≥2, V+, and/or N+ were at least one of following; (1) CA19‐9 > 37 IU/mL, (2) ulcerative or mixed type appearance, (3) except for well‐differentiated tumor, or (4) except for intestinal subtype of histology. Conclusions Aged ≥71, tumor diameter ≥12 mm, pT≥2, PV+, V+, and pN+ were independent prognostic factors for poor RFS in patients with CAV. An additional therapeutic strategy may be desirable in CAV patients at high risk for recurrence.

Background Although there is increasing awareness of the health risks of air pollution as a global issue, few studies have focused on the methods for assessing individuals’ perceptions of these risks. This scoping review aimed to identify previous research evaluating individuals’ perceptions of air pollution and its health effects, and to explore the measurement of perceptions, as a key resource for health behaviour. Methods The review followed the methodological framework proposed by Arksey and O’Malley. PubMed and Web of Science were searched. After initial and full-text screening, we further selected studies with standardised scales that had previously been tested for reliability and validity in assessing awareness and perceptions. Results After full-text screening, 95 studies were identified. ‘Perception/awareness of air quality’ was often measured, as well as ‘Perception of health risk.’ Only nine studies (9.5%) used validated scaled questionnaires. There was considerable variation in the scales used to measure the multiple dimensions of risk perception for air pollution. Conclusion Few studies used structured scales to quantify individuals’ perceptions, limiting comparisons among studies. Standardised methods for measuring health risk perception are needed.

Background During the coronavirus disease (COVID-19) pandemic, caesarean section (CS) has been the preferred deliver method for pregnant women with COVID-19 in order to limit the use of hospital beds and prevent morbidity among healthcare workers.Methods To evaluate delivery methods used during the COVID-19 pandemic as well as the rates of adverse events and healthcare worker morbidity associated with caesarean deliveries.Methods We investigated maternal and neonatal backgrounds, delivery methods, indications and complication rates among pregnant women with COVID-19 from December 2020 to August 2022 in Mie Prefecture, Japan. The predominant mutation period was classified as the pre-Delta, Delta and Omicron epoch.Results Of the 1291 pregnant women with COVID-19, 59 delivered; 23 had a vaginal delivery and 36 underwent CS. Thirteen underwent CS with no medical indications other than mild COVID-19, all during the Omicron epoch. Neonatal complications occurred significantly more often in CS than in vaginal delivery. COVID-19 in healthcare workers was not attributable to the delivery process.Conclusion The number of CS with no medical indications and neonatal complications related to CS increased during the COVID-19 pandemic. Although this study included centres that performed vaginal deliveries during COVID-19, there were no cases of COVID-19 in healthcare workers. It is possible that the number of CS and neonatal complications could have been reduced by establishing a system for vaginal delivery in pregnant women with recent-onset COVID-19, given that there were no cases of COVID-19 among the healthcare workers included in the study.