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Background: Gelatin hydrogel nonwoven fabrics (Genocel) are three-dimensional gelatin scaffolds that provide cells with space for proliferation, migration, and differentiation. They are expected to be an effective wound healing modality to treat intractable wounds, such as diabetic foot ulcers, because they enhance early neovascularization when used as a skin substitute. In this study, we explored the healing process of Genocel applied to skin defects in diabetic mice and compared it with that of a conventional skin substitute, Pelnac. Methods: Genocel and Pelnac sheets were used to treat skin defects on the backs of diabetic mice. On days 7 and 14, the remaining wound area was evaluated and specimens were harvested for HE, Azan, anti-CD31, CD68, and CD163 staining to assess neoepithelialization, granulation tissue formation, capillary formation, and macrophage infiltration. Results: Wounds treated with Genocel showed a wound healing process comparable to that of wounds treated with Pelnac. No significant differences were observed in the remaining wound area, neoepithelial length, granulation formation, number of pan-macrophages, or M2 ratio on days 7 and 14. The only significant difference was the number of induced M2 macrophages, which was higher in Pelnac group than in the Genocel group on day 7 (p

Abstract Clostridioides difficile, a cause of healthcare-associated infections, poses a significant global health threat. This multi-institutional retrospective study focuses on epidemic dynamics, emphasizing minor and toxin-negative clinical isolates through high-resolution genotyping. The genotype of the C. difficile clinical isolates during 2005 to 2022 was gathered from 14 hospitals across Japan (N = 982). The total number of unique genotypes was 294. Some genotypes were identified in every hospital (cross-regional genotypes), while others were unique to a specific hospital or those in close geographic proximity (region-specific genotypes). Notably, a hospital located in a sparsely populated prefecture exhibited the highest prevalence of region-specific genotypes. The isolation rate of cross-regional genotypes positively correlated with the human mobility flow. A 6-month interval analysis at a university hospital from 2019 to 2021 revealed a temporal transition of the genotype dominance. The frequent isolation of identical genotypes over a brief timeframe did not always align with the current criteria for defining nosocomial outbreaks. This study highlights the presence of diverse indigenous C. difficile strains in regional environments. The cross-regional strains may have a higher competency to spread in the human community. The longitudinal analysis underscores the need for further investigation into potential nosocomial spread.

Background: Breast cancer is the most common cancer among women. Partial mastectomy is an alternative to mastectomy in early-stage breast cancer to restore a poor quality of life (QOL). However, the aesthetic satisfaction with this procedure is inadequate. The standard methods for breast reconstruction have certain limitations. We developed bioabsorbable implants consisting of an outer mesh composed of poly L-lactic acid (PLLA) and an inner component filled with a collagen sponge (CS). These implants were designed to promote and sustain adipogenesis in vivo, without the addition of exogenous cells or growth factors. In this study, we used PLLA mesh implants to investigate the effects of irradiation on fat formation, which is important in partial mastectomy. Methods: The implants were inserted into both the inguinal regions of the rats. One month after the implantation, a dose of 13 Gy was delivered to the left-side implants. We compared adipose tissue formation in the non-irradiated and irradiated groups at 6 and 12 months after irradiation. Results: Irradiation of implants did not lead to malignant tumor formation. The newly formed tissues and adipose tissue were not significantly different between the two groups at 6 and 12 months after irradiation. Conclusions: PLLA mesh implants containing CS are desirable bioabsorbable implants that can be replaced with autologous adipose tissue after in vivo implantation under irradiation. These implants serve as an effective material for partial mastectomy and have the potential to improve the QOL of patients after mastectomy.

In the process of investigating synaptic changes happening to mutants lacking postsynaptic receptors in the neuromuscular junction, we focused on a hitherto uncharacterized zebrafish gene zgc153932 whose expression was increased in the RNAseq and droplet digital PCR (ddPCR) analysis of a paralyzed mutant sofa potato. The zgc153932 gene which we named omcin5 (omc5) showed amino acid sequence similarity to human uromodulin and GP2, which are expressed in epithelial cells of the kidney and the gut respectively and bind to bacteria pili. omc5 had 14 paralogues in a ∼400 KB region on the chromosome 12 of the zebrafish genome. These genes, named omcin1 through 15, constitute a gene cluster which presumably arose from recent gene duplications in the zebrafish lineage. An antibody raised against the epitope common to 6–9 genes in the omcin family revealed expression in the cloaca of 1 day post fertilization (dpf) embryos which broadened to the urinary and digestive tracts by 5 dpf. Expression of omc5 was increased by exposure of embryos to Escherichia coli (E. coli). Survival of omc5 mutant embryos was shortened in the presence of E. coli, or when they were not maintained in germ-free conditions. Adults omc5 mutants also exhibited susceptibility to infection. Other teleost species which had omcin-like genes in their genomes showed a range of gene duplication, resulting in clusters of 1 to >15 omcin-like genes. We hereby identified a new gene family specific to teleost that include a microbial induced gene which confers resistance to bacterial infection.

Introduction Reducing neonatal deaths in premature infants in low- and middle-income countries is key to reducing global neonatal mortality. International neonatal networks, along with patient registries of premature infants, have contributed to improving the quality of neonatal care; however, the involvement of low-to-middle-income countries was limited. This project aims to form an international collaboration among neonatal networks in Asia (AsianNeo), including low-, middle- and high-income countries (or regions). Specifically, it aims to determine outcomes in sick newborn infants, especially very low birth weight (VLBW) infants or very preterm infants, with a view to improving the quality of care for such infants.Methods and analysis Currently, AsianNeo comprises nine neonatal networks from Indonesia, Japan, Malaysia, Philippines, Singapore, South Korea, Sri Lanka, Taiwan and Thailand. AsianNeo will undertake the following four studies: (1) institutional questionnaire surveys investigating neonatal intensive care unit resources and the clinical management of sick newborn infants, with a focus on VLBW infants (nine countries/regions); (2) a retrospective cohort study to describe and compare the outcomes of VLBW infants among Asian countries and regions (four countries/regions); (3) a prospective cohort study to develop the AsianNeo registry of VLBW infants (six countries/regions); and (4) implementation and evaluation of educational and quality improvement projects in AsianNeo countries and regions (nine countries/regions).Ethics and dissemination The study protocol was approved by the Research Ethics Board of the National Center for Child Health and Development, Tokyo, Japan (reference number 2020–244, 2022–156). The study findings will be disseminated through educational programmes, quality improvement activities, conference presentations and medical journal publications.

RNA-dependent RNA polymerase (RdRp) is a marker gene for RNA viruses; thus, it is widely used to identify RNA viruses from metatranscriptome data. However, because of the high diversity of RdRp domains, it remains difficult to identify RNA viruses using RdRp sequences. To overcome this problem, we created a NeoRdRp database containing 1,182 hidden Markov model (HMM) profiles utilizing 12,502 RdRp domain sequences. Since the development of this database, more RNA viruses have been discovered, mainly through metatranscriptome sequencing analyses. To identify RNA viruses comprehensively and specifically, we updated the NeoRdRp by incorporating recently reported RNA viruses. To this end, 557,197 RdRp-containing sequences were used as seed RdRp datasets. These sequences were processed through deduplication, clustering, alignment, and splitting, thereby generating 19,394 HMM profiles. We validated the updated NeoRdRp database, using the UniProtKB dataset and found that the recall and specificity rates were improved to 99.4% and 81.6%, from 97.2% and 76.8% in the previous version, respectively. Comparisons of eight different RdRp search tools showed that NeoRdRp2 exhibited balanced RdRp and nonspecific detection power. Expansion of the annotated RdRp datasets is expected to further accelerate the discovery of novel RNA viruses from various transcriptome datasets. The HMM profiles of NeoRdRp2 and their annotations are available at https://github.com/shoichisakaguchi/NeoRdRp.

Introductions: Silk elastin, a recombinant protein with repeats of elastin and silk fibroin, possesses a self-gelling ability and is a potential wound dressing material. The aim of this study is to elucidate the mechanism of the wound healing-promoting effect of silk elastin by comparing its in vivo behavior in a mouse wound model with that of a collagen sponge. Methods: Skin defects (8 mm in diameter) were created on the backs of C57BL/6J and BKS.Cg- + Lepr/+Lepr db male mice. Silk elastin sponges of 2.5 or 5.0 mm thickness, as well as collagen sponges, were placed on the wounds and secured with a polyurethane film. In the control group, only the polyurethane film was applied. The remaining wound area was grossly evaluated, and tissue samples were collected after 7, 14, and 21 days for histological evaluation, including neoepithelialization, wound contraction, granulation tissue formation, newly formed capillaries, and macrophages. Genetic analysis was conducted using real-time polymerase chain reaction. Results: In the study with C57BL/6J, there were no significant differences between the silk elastin and collagen sponge groups. Similarly, in the study using BKS.Cg- + Lepr/+Lepr db, no significant differences were found in the remaining wound area and granulation tissue formation between the silk elastin and collagen sponge groups. However, on day 14, the 5.0-mm-thick silk elastin sponge group showed increased macrophages, longer neoepithelialization, and more frequent angiogenesis compared to other groups. Gene expression of inducible nitric oxide synthase and arginase-1 was also higher in the 5.0 mm thick silk elastin sponge group. Conclusions: Silk elastin sponges demonstrated superior neoepithelialization and angiogenesis compared to collagen sponges. The results suggest that silk elastin and collagen sponges promote wound healing through different mechanisms, with silk elastin possibly enhancing wound healing by facilitating increased macrophage migration. Further studies are needed, but silk elastin shows great potential as a versatile wound dressing material.

Introduction: The regeneration of adipose tissue in patients after breast cancer surgery would be desirable without the use of growth factors or cells to avoid potential recurrence and metastasis. We reported that prolate spheroidal-shaped poly-L-lactic acid (PLLA) mesh implants of approximately 18-mm polar diameter and 7.5-mm greatest equatorial diameter containing collagen sponge (CS) would be replaced by regenerated adipose tissue after implantation, thereby suggesting an innovative method for breast reconstruction. Our study aimed to evaluate the adipose tissue regeneration ability of implant aggregates in a porcine model. Methods: We prepared implant aggregates consisting of thirty PLLA mesh implants containing CS packed in a woven poly (glycolic acid) bag. The implant aggregates were inserted under the mammary glands in the porcine abdomen for a year. Single and double groups were classified by inserting either one or two implant aggregates on each side of the abdomen, respectively. Results: In both groups, the volume of the implant aggregates decreased over time, and the formation of adipose tissue peaked between 6 and 9 months. Histologically, the formation of adipose tissue was confirmed in the area that was in contact with native adipose tissue. Conclusions: Our implant aggregates could induce the autologous adipose tissue after long term implantation in vivo, without the use of any growth factor or cell treatment, presenting a potential novel method of breast reconstruction.

Poly-L-lactic acid (PLLA) mesh implants containing collagen sponge (CS) were replaced with autologous adipose tissue regeneration in vivo. Herein, we investigated the optimal external frames and internal fillings using poly (lactic-co-ε-caprolactone) (P (LA/CL)), PLLA, and low-molecular-weight PLLA (LMW-PLLA) as the external frame and polyglycolic acid (PGA) nanosheets and CS as the internal filling. We prepared six implants: P (LA/CL) with PGA nano, PLLA with PGA nano, PLLA with CS, PLLA with 1/2 CS, PLLA with 1/4 CS, and LMW-PLLA with CS, and evaluated adipogenesis at 6 and 12 months using a rat inguinal model. The internal spaces in the P (LA/CL) and LMW-PLLA implants collapsed at 6 months, whereas those in the other four implants collapsed at 12 months. Adipose tissue regeneration was not significantly different between the PLLA-implanted groups at 6 and 12 months and was greater than that in the P (LA/CL) with PGA nano and LMW-PLLA with CS groups. The PGA nanosheet inside PLLA was comparable to the CS inside PLLA in the regeneration of adipose tissue and macrophage infiltration. In summary, PLLA is a promising external frame material in which the internal space can be replaced with adipose tissue. Thus, PGA nanosheets are an alternative internal filling material for adipose tissue regeneration.

Background: A novel treatment has been developed to reconstruct large skin defects caused by the excision of giant congenital melanocytic nevi. It involves the reimplantation of high-hydrostatic pressurized nevus tissue as a cell-inactivated autologous scaffold for dermal regeneration, followed by the implantation of cultured epithelial autografts on the regenerated dermis. Because this treatment has shown promise in a first-in-human clinical trial which used a prototype pressure machine, a novel pressure device was specifically designed for clinical use. Methods: In a prospective investigator-initiated clinical trial involving three patients, we evaluated the safety and efficacy of the skin regeneration treatment using a pressure device. All three patients underwent surgical excision of the nevus tissue, primary reimplantation of the inactivated nevus tissue, and secondary implantation of cultured epithelial autografts. Results: Engraftment of inactivated nevus tissue and cultured epithelial autografts was successful in all three cases, with over 90% epithelialization at 8 weeks post-surgery. No serious adverse events or device malfunction were observed during the trial. Conclusion: The novel pressure device safely and effectively enabled dermal regeneration using the nevus tissue as an autologous scaffold. This innovative approach offers several advantages, including reduced invasiveness due to minimal sacrifice of normal skin for skin grafting and high curative potential resulting from full-thickness removal of the nevus tissue.

Abstract Gastric cancer is one of the leading causes of death worldwide, and resections are performed to cure the disease. We have previously reported the changes in the gastric microbiota after gastric cancer resection, which may be associated with the oral microbiota; however, the changes in the oral microbiota remain uncharacterized. This study aimed to characterize the changes in the salivary microbiota caused by gastric cancer resection and to evaluate their association with the gastric fluid microbiota. Saliva and gastric fluid samples were collected from 63 patients who underwent gastrectomy before and after surgery, and a 16S rRNA metagenomic analysis was performed to compare the microbiota composition. The number of bacterial species in the salivary microbiota decreased, and the bacterial composition changed after the resection of gastric cancer. In addition, we identified several bacterial genera that varied significantly in the salivary microbiota, some of which also showed similar changes in the gastric fluid microbiota. These findings indicate that changes in the gastric environment affect the oral microbiota, emphasizing the close association between the oral and gastric fluid microbiota. Our study signifies the importance of focusing on the oral microbiota in the perioperative period of gastrectomy in patients with gastric cancer.

Abstract The typical seasonally dry forests in Southeast Asia are the mixed deciduous forest (MDF), dry dipterocarp (deciduous) forest (DDF), and dry evergreen forest (DEF). We obtained 21 physiological traits in the top/sunlit leaves of 107, 65 and 51 tree species in MDF, DEF and DDF, respectively. Approximately 70%, 95% and 95% of canopy tree species which consist of MDF, DEF and DDF are sampled, respectively. Light-saturated photosynthetic rates (A sat) exhibit a positive correlation with foliar nitrogen (N) and phosphorus (P) on leaf mass and area bases across tree species. Decreased leaf mass-based P reduces the positive slope of the mass-based N and A sat relationship across species and habitats. The differences in nutrient and water use and leaf habits are well matched to the variation in soil properties among the forest types, highlighting the reliability of this comprehensive database for revealing the mechanism of niche segregation based on edaphic factors.

IntroductionAddresing vaccine hesitancy is considered an important goal in management of the COVID-19 pandemic. We sought to understand what factors influenced people, especially those initially hesitant, to receive two or more vaccine doses within a year of the vaccine’s release.MethodsWe conducted longitudinal Web-based observational studies of 3,870 individuals. The surveys were conducted at four different time points: January 2021, June 2021, September 2021, and December 2021. In the baseline survey (January 2021), we assessed vaccination intention (i.e., “strongly agree” or “agree” [acceptance], “neutral” [not sure], and “disagree” or “strongly disagree” [hesitance]), and assumptions about coronavirus disease (COVID-19), COVID-19 vaccine, COVID-19-related health preventive behavior, and COVID-19 vaccine reliability. In subsequent surveys (December 2021), we assessed vaccination completion (i.e., ≥2 vaccinations). To investigate the relationship between predictors of COVID-19 vaccination completion, a multivariable logistic regression model was applied. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated while adjusting for gender, age, marital status, presence of children, household income category, and presence of diseases under treatment. In a stratified analysis, predictors were determined based on vaccination intention.ResultsApproximately 96, 87, and 72% of those who demonstrated acceptance, were not sure, or hesitated had been vaccinated after 1 year, respectively. Overall, significant factors associated with COVID-19 vaccine compliance included the influence of others close to the index participant (social norms) (AOR, 1.80; 95% CI, 1.56–2.08; p

Introduction: From previous research, an emerging material composed of gelatin hydrogel nonwoven fabric (Genocel) has shown potential as a skin substitute, by improving neovascularization promotion in the early phase of wound healing. However, Genocel was inferior in terms of granulation formation compared to Pelnac. To solve this problem, we modified the manufacturing process of Genocel to reduce its water content, extend the degradation time (Genocel-L), and evaluate its healing process as a skin substitute. Methods: Genocel with a low water content (Genocel-L) was prepared and the difference in water content compared to that of the conventional Genocel was confirmed. Degradation tests were performed using collagenase and compared among Genocel-L, Genocel, and Pelnac sheets. In the in vivo study, sheets of Genocel-L or Pelnac were applied to skin defects created on the backs of C57BL/6JJcl mice. On days 7, 14, and 21, the remaining wound area was evaluated and specimens were harvested for Hematoxylin and Eosin, Azan, anti-CD31, CD68, and CD163 staining to assess neoepithelialization, granulation tissue, capillary formation, and macrophage infiltration. Results: Genocel-L had a lower water content than the conventional Genocel and a slower degradation than Genocel and Pelnac. In the in vivo experiment, no significant differences were observed between Genocel-L and Pelnac in relation to the wound area, neoepithelium length, granulation formation, and the number of newly formed capillaries. The area of newly formed capillaries in the Pelnac group was significantly larger than that in the Genocel-L group on day 21 (p

Cellular immunity is critical for the regulation of viral diseases, including coronavirus disease 2019 (COVID-19), and is generally considered immature in childhood. However, the details of cellular immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among children are unclear. We assessed cellular immunity in eight children post-vaccination against SARS-CoV-2 and 11 children after SARS-CoV-2 infection using the T-SPOT®.COVID assay for the spike (S) and nucleocapsid (N) proteins. In the vaccinated group, the T-SPOT®.COVID assay for the S protein yielded positive results in seven children. In the post-infection group, the assay for the N protein was positive for 5 of 11 children, with 3 of these 5 children requiring hospitalization, including 2 who needed mechanical ventilation. The T-SPOT®.COVID assay is thus valuable for assessing cellular immunity against SARS-CoV-2, and most children infected with SARS-CoV-2 may not develop such immunity unless the disease severity is significant.

Surgical resection of malignant bone tumors leads to significant defects in the normal surrounding tissues that should be reconstructed to avoid amputation. Our research aimed to inactivate osteosarcoma (OS)-affected bone to obtain autologous bone grafts for bone defect reconstruction using a novel therapy called high hydrostatic pressurization (HHP) therapy. The key points are complete tumor death and preservation of the non-denatured native extracellular matrix (ECM) and bone tissue by HHP. Previously, we found that HHP at 200 MPa for 10 min can completely inactivate cells in normal skin and skin tumors, including malignant melanoma and squamous cell carcinoma while maintaining their original biochemical properties and biological components. Based on our previous research, this study used HHP at 200 MPa for 10 min to eradicate OS. We prepared an OS cell line (LM8), pressurized it at 200 MPa for 10 min, and confirmed its inactivation through morphological observation, WST-8 assay, and live/dead assay. We then injected OS cells with or without HHP into the bone marrow of the murine tibia, after which we implanted tumor tissues with or without HHP into the anterior surface of the tibia. After HHP, OS cells did not proliferate and were assessed using a live/dead assay. The pressurized cells and tumors did not grow after implantation. The pressurized bone was well prepared as tumor-free autologous bone tissues, resulting in the complete eradication of OS. This straightforward and short-pressing treatment was proven to process the tumor-affected bone to make a transplantable and tumor-free autologous bone substitute.

Introduction: Autologous cultured epidermis (CE) is an effective approach for overcoming the deficiency of donor sites to treat extensive burns. However, the production of autologous CE takes 3–4 weeks, which prevents its use during the life-threatening period of severe burns. In contrast, allogeneic CE can be prepared in advance and used as a wound dressing, releasing several growth factors stimulating the activity of recipient cells at the application site. Dried CE is prepared by drying CEs under controlled temperature and humidity conditions until all the water is completely removed and no viable cells are present. Dried CE accelerates wound healing in a murine skin defect model and is potentially a new therapeutic strategy. However, the dried CE safety and efficacy have not yet been studied in large animal models. Therefore, we studied the safety and efficacy of human-dried CE in wound healing using a miniature swine model. Methods: Human CE was manufactured using Green's method from donor keratinocytes. Three types of CEs (Fresh, Cryopreserved, and Dried) were prepared, and the ability of each CE to promote keratinocyte proliferation was confirmed in vitro. Extracts of the three CEs were added to keratinocytes seeded in 12-well plates, and cell proliferation was evaluated using the WST-8 assay for 7 days. Next, we prepared a partial-thickness skin defect on the back of a miniature swine and applied three types of human CE to evaluate wound healing promotion. On days 4 and 7, the specimens were harvested for hematoxylin-eosin, AZAN, and anti-CD31 staining to assess epithelialization, granulation tissue, and capillary formation. Results: The conditioned medium containing dried CE extract significantly enhanced keratinocyte proliferation compared to the control group (P

Introduction: Genocel is an emerging material, used in cell culture, with high mechanical strength and good cytocompatibility. Based on these characteristics, Genocel is considered a promising skin substitute for wound healing. In this study, we explored the possibility of using Genocel as a skin substitute for murine skin defects and compared it with a conventional skin substitute. Methods: Sheets of Genocel and Pelnac were applied to skin defects created on the backs of mice. On days 7, 14, and 21, the remaining wound area was evaluated and specimens were harvested for HE, Azan, anti-CD31, CD68, and CD163 staining to assess neoepithelialization, granulation tissue, capillary formation, and macrophage infiltration. Results: No significant differences in the wound area or neoepithelium length were observed between groups. The number of newly formed capillaries in the Genocel group was significantly higher than that in the Pelnac group on day 7 (p

Summary:. Indocyanine green (ICG) fluorescence imaging is useful for assessing flap viability; however, it is associated with a risk of anaphylactic shock, even in patients with no history of drug allergies. SnapshotNIR is a noncontact, camera-type handheld tissue oximeter that can measure the tissue oxygen saturation of the body surface. The device emits red and near infrared light wavelengths and then optimizes the measurement of the differential reflectance from oxygenated and deoxygenated hemoglobin, and StO2 is calculated. A 20 × 15 cm surgical field can be evaluated in less than 3 seconds by holding the camera at a distance of 30 cm. We applied this device at zone II in a deep inferior epigastric perforator (DIEP) flap, and compared the findings with the border of flap perfusion detected by ICG imaging. Left breast reconstruction using a free DIEP flap was performed for a 60-year-old woman. The DIEP flap was vascularized by a perforator vessel coursing to the right abdominis muscle. First, Diagnogreen (5 mg; Daiichi Sankyo Co., Tokyo, Japan) was intravenously injected, and the ICG fluorescence perfusion border detected by PDE-neo (Hamamatsu Photonics, Hamamatsu City, Shizuoka, Japan) was determined. The ICG border was defined by two reconstructive surgeons after fluorescence had spread out for 2 minutes. Next, zones Ⅱ and Ⅳ of the DIEP flap, contralateral to the perforator, were evaluated using photographs obtained by SnapshotNIR. There were significant StO2 value differences between the ICG-negative area and ICG-positive area. This device can be widely applied in the noninvasive evaluation of flap viability.

Abstract Cerebrospinal fluid (CSF) leakage is a rare but severe complication during dacryocystorhinostomy (DCR). Understanding the details of the anatomy of the lacrimal drainage system and skull base is essential to avoid this complication. We examined the positional relationship between the lacrimal sac and skull base using 16 cadavers (22 sides) and using computed tomographic images taken in 81 patients (81 sides). Consequently, the frontal sinus intervened between the lacrimal sac and skull base in 81.8–90.1% of cases. The lacrimal sac fundus and posterior lacrimal crest were far from the skull base/cribriform plate, and the skull base above the lacrimal sac was considerably thick. These results indicate that the risk of skull base injury and consequent CSF leakage during DCR is extremely low. However, surgeons should be cautious of this complication by indirect injury due to a twisting movement of a bone rongeur applied to the maxillary bone during creation of a bony window in patients with no interposition of the frontal and ethmoid sinuses between the lacrimal sac and skull base.

Purpose: Understanding the immune response during radiation therapy (RT) in a clinical setting is imperative for maximizing the efficacy of combined RT and immunotherapy. Calreticulin, a major damage-associated molecular pattern that is exposed on the cell surface after RT, is presumed to be associated with the tumor-specific immune response. Here, we examined changes in calreticulin expression in clinical specimens obtained before and during RT and analyzed its relationship with the density of CD8+ T cells in the same patient set. Methods and Materials: This retrospective analysis evaluated 67 patients with cervical squamous cell carcinoma who were treated with definitive RT. Tumor biopsy specimens were collected before RT and after 10 Gy irradiation. Calreticulin expression in tumor cells was evaluated via immunohistochemical staining. Subsequently, the patients were divided into 2 groups according to the level of calreticulin expression, and the clinical outcomes were compared. Finally, the correlation between calreticulin levels and density of stromal CD8+ T cells was evaluated. Results: The calreticulin expression significantly increased after 10 Gy (82% of patients showed an increase; P < .01). Patients with increased calreticulin levels tended to show better progression-free survival, but this was not statistically significant (P = .09). In patients with high expression of calreticulin, a positive trend was observed between calreticulin and CD8+ T cell density, but the association was not statistically significant (P = .06). Conclusions: Calreticulin expression increased after 10 Gy irradiation in tissue biopsies of patients with cervical cancer. Higher calreticulin expression levels are potentially associated with better progression-free survival and greater T cell positivity, but there was no statistically significant relationship between calreticulin upregulation and clinical outcomes or CD8+ T cell density. Further analysis will be required to clarify mechanisms underlying the immune response to RT and to optimize the RT and immunotherapy combination approach.

Abstract The changes in gastric microbiota following reconstruction after gastrectomy have not been reported. This study aimed to compare the gastric microbiota following Billroth I and Roux-en-Y reconstructions after distal gastrectomy. We enrolled 71 gastrectomized patients with gastric cancer; 31 and 40 underwent Billroth I and Roux-en-Y reconstructions, respectively. During upper gastrointestinal endoscopy, gastric fluid was collected immediately before and 6 months after distal gastrectomy. Deoxyribonucleic acid isolated from each sample was evaluated using 16S ribosomal ribonucleic acid metagenomic analysis. Analysis revealed that the gastric microbiota’s species richness (expressed as the alpha diversity) was significantly lower after than before distal gastrectomy (operational taxonomic units, p = 0.001; Shannon index, p = 0.03). The interindividual diversity (beta diversity) was significantly different before and after distal gastrectomy (unweighted UniFrac distances, p = 0.04; weighted UniFrac distances, p = 0.001; Bray–Curtis, p = 0.001). Alpha and beta diversity were not significantly different between Billroth I and Roux-en-Y reconstructions (observed operational taxonomic units, p = 0.58; Shannon index, p = 0.95; unweighted UniFrac distances, p = 0.65; weighted UniFrac distances, p = 0.67; Bray–Curtis, p = 0.63). Our study demonstrated significant differences in gastric microbiota diversity, composition, and community before and after distal gastrectomy but no difference between Billroth I and Roux-en-Y reconstruction after distal gastrectomy.

Abstract Background There are limited studies on the risk of secondary cancers after carbon‐ion radiotherapy (CIRT). We assessed the incidence of secondary cancers in patients treated with CIRT for cervical cancer. We also evaluated the incidence of secondary cancers in patients who received standard photon radiotherapy (RT) throughout the same period. Methods This retrospective study included patients with cervical cancer who underwent curative RT at our hospital. All cancers discovered for the first time after RT were classified as secondary cancers. To compare the risk of secondary cancers among cervical cancer survivors to the general population, standardized incidence ratios (SIRs) were calculated. Results The analysis included a total of 197 and 417 patients in the CIRT and photon RT groups, respectively. The total person‐years during the observation period were 1052.4 in the CIRT group and 2481.5 in the photon RT group. The SIR for all secondary cancers was 1.1 (95% confidence interval [CI], 0.6–2.1) in the CIRT group and 1.4 (95% CI, 1.0–2.1) in the photon RT group. The 10‐year cumulative incidence of all secondary cancers was 9.5% (95% CI, 4.0–21.5) in the CIRT group and 9.4% (95% CI, 6.2–14.1) in the photon RT group. The CIRT and photon RT groups were not significantly different in incidence (p = 0.268). Conclusions The incidence of secondary cancers after CIRT for cervical cancer was similar to that after photon RT. Validation of our findings after long‐term observation is warranted.

Abstract Cryopreserved allogeneic cultured epidermis (CE) is used for treating second-degree burn wounds and diabetic foot ulcers; however, the need for cryopreservation limits its use. We have previously reported that CE accelerates wound healing irrespective of its viability and hypothesized that dehydrated CEs lacking living cells may act as an effective wound dressing. We prepared dried CE and investigated its morphological and physical properties and wound-healing effects and compared them with those of cryopreserved CE. Hematoxylin–eosin staining, immunostaining for basement membrane, and electron microscopy revealed that the morphologies of dried CE and cryopreserved CE were comparable and that the membrane structure was not damaged. The breaking strength, modulus of elasticity, and water permeability of dried CE were comparable with those of the cryopreserved CE. Furthermore, the levels of various active cytokines and chemokines in dried CE were comparable with those in cryopreserved CE. Dried CE applied to skin defect in diabetic mice significantly reduced the wound area and increased the new epithelium length 4 and 7 days after implantation, similar to that observed for cryopreserved CE. Consequently, dried CE had similar morphological and physical properties and wound-healing effects compared with those of cryopreserved CE and can be a physiological and versatile wound-dressing.

Background: Mumps deafness causes serious problems, and incidence data are needed to identify its disease burden. However, such data are limited, and the reported incidence is highly variable. Nationwide studies in Japan with a large age range are lacking. Methods: This was a retrospective observational investigation of the 2005–2017 mumps burden using employment-based health insurance claims data. Data were analyzed for 5,190,326 people aged 0–64 years to estimate the incidence of mumps deafness. Results: Of 68,112 patients with mumps (36,423 males; 31,689 females), 102 (48 males; 54 females) developed mumps deafness—an incidence of 15.0 per 10,000 patients (1 in 668 patients). Fifty-four (52.9%) patients had mumps deafness in childhood (0–15 years), and 48 (47.1%) had mumps deafness in adolescence and adulthood (16–64 years); most cases occurred in childhood, the peak period for mumps onset. The incidence of mumps deafness per 10,000 patients was 73.6 in adolescence and adulthood, 8.4 times higher than the incidence of 8.8 in childhood (P < 0.001). In childhood, the incidence of mumps deafness was 7.2 times higher among 6–15-year-olds (13.8; 95% CI, 10.2–18.2) than among 0–5-year-olds (1.9; 95% CI, 0.6–4.5), and this difference was statistically significant (P < 0.001). No sex difference was observed. Conclusions: The incidence of mumps deafness per 10,000 patients aged 0–64 years was 15.0 (1 in 668 patients). A secondary risk of deafness following mumps virus infection was identified not only for children, but also for adolescents and adults.

Oral microbiota may be associated with serious local or systemic medical conditions resulting from chemotherapy. This study was conducted to evaluate the changes in the oral microbiota following the initiation of chemotherapy in patients with hematopoietic malignancies and to identify the characteristics of the oral microbiota associated with oral mucositis. Oral samples were collected from 57 patients with hematopoietic malignancies at 2 time points: before the start of chemotherapy and 8 to 20 days after the start of chemotherapy, when chemotherapy-induced oral mucositis often occurs, and 16S rRNA metagenomic analyses were performed. Comparative and linear discriminant analysis effect size (LEfSe) analyses were used to determine the characteristic bacterial groups before and after the initiation of chemotherapy and in those who developed oral mucositis. The alpha and beta diversities of oral microbiota before and after the initiation of chemotherapy differed significantly (operational taxonomic unit index, P

Background:. A micrograft (MG) suspension produced by the Rigenera protocol has been used to stimulate tissue regeneration. Recently, a combination therapy of an artificial dermis and skin MG has been used to promote angiogenesis and granulation tissue formation in the artificial dermis. There are no reports comparing the differences in MG impregnation efficiency between different artificial dermis products. Therefore, we compared the impregnation of skin MG in Pelnac Gplus and Integra. Methods:. Skin MG was prepared from the skin of C57BL/6JJcl mice using Rigeneracons and administered onto Pelnac Gplus and Integra sheets. The amount of MG suspension impregnated in Pelnac Gplus and Integra was evaluated. Pelnac Gplus and Integra sheets combined with MG were applied to murine defects, and wound area, neoepithelium length, granulation tissue formation, and newly formed capillaries were compared with the control groups on days 7 and 14. Results:. The weight percentage of the MG absorbed by Pelnac Gplus and Integra was 88.8% ± 3.5% and 28.2% ± 7.0%, respectively (P < 0.05). In the in vivo experiment, the area of newly formed granulation tissue and both the number and area of newly formed capillaries in the PelnacG + MG group were significantly larger than those in the control group at 14 days after implantation (P < 0.05). Conclusions:. Skin MG was successfully impregnated into Pelnac Gplus by simple administration but not into Integra. Administration of skin MG into the Pelnac Gplus promoted granulation formation and angiogenesis. Pelnac Gplus was more suitable than Integra in the combination therapy.

Objective Using a prospective observational design, we assessed adverse events (AEs) after COVID-19 vaccination in Japanese patients. Methods Two doses of the mRNA-1273 (SPIKEVAX®) or BNT162b2 (COMIRNATY®) vaccine were administered to participants aged 12 to 18 years, and AEs after each dose were recorded for 14 days. Data on the duration and nature (local vs. systemic) of AEs were collected using a questionnaire. Sex-based differences in AE frequency were also analyzed. Results After the first and second doses, 152 and 135 vaccinees were enrolled, respectively. After the first dose, fever (>37.1°C) occurred in 38.9% of males and 50.0% of females, whereas local pain occurred in 89.8% and 97.7% of males and females, respectively (only SPIKEVAX® was used as the first dose). After the second dose, fever (>37.1°C) occurred in 77.8% and 82.6% of males vaccinated with COMIRNATY® and SPIKEVAX®, respectively, and 82.6% of females (all received SPIKEVAX®). The local pain rates in these groups were 80.6%, 76.3%, and 100%, respectively. After the second dose, local pain, fever (>38.1°C) and headache were significantly more common in female participants, and the median symptom duration was 3 days. Conclusions AEs were more frequent after the second dose and in females.

Background: Mumps vaccination coverage is low in Japan, partly because of its voluntary nature. Although pediatric cases of mumps virus infection are captured by the National Epidemiological Surveillance of Infectious Diseases program under the Infectious Disease Law, there are currently no data regarding the occurrence of mumps and its complications in adults. Methods: We investigated the annual incidence rates of mumps and its complications based on health insurance reimbursement data for 5,209,660 individuals aged 0–64 years for 2005–2017, obtained from JMDC Inc., to estimate the mumps-related disease burden during this period. Results: There were three mumps outbreaks (2006, 2010, and 2016) during 2005–2017. The annual incidence of mumps was highest in individuals aged 0–5 years (808–3,792 per 100,000 persons), followed by those aged 6–15 years (658–2,141 per 100,000 persons). The incidence of mumps was higher in females than in males (male/female ratio, 0.90). Among mumps-related complications, the overall incidence (per 1,000 mumps cases) was highest for orchitis (6.6), followed by meningitis (5.8), deafness (1.3), pancreatitis (0.5), and encephalitis (0.3). No cases of oophoritis were noted. The overall incidence of mumps-related complications was 2.5 times higher in males than in females. Conclusions: This study revealed the disease burden due to mumps and its complications in Japan during 2005–2017. These data suggest the need for mumps-prevention measures in adolescents and adults, as well as in children.

Abstract Background The optimal management of clinical T4 (cT4) prostate cancer (PC) is still uncertain. At our institution, carbon ion radiotherapy (CIRT) for nonmetastatic PC, including tumors invading the bladder, has been performed since 2010. Since carbon ion beams provide a sharp dose distribution with minimal penumbra and have biological advantages over photon radiotherapy, CIRT may provide a therapeutic benefit for PC with bladder invasion. Hence, we evaluated CIRT for PC with bladder invasion in terms of the safety and efficacy. Methods Between March 2010 and December 2016, a total of 1337 patients with nonmetastatic PC received CIRT at a total dose of 57.6 Gy (RBE) in 16 fractions over 4 weeks. Among them, seven patients who had locally advanced PC with bladder invasion were identified. Long-term androgen-deprivation therapy (ADT) was also administered to these patients. Adverse events were graded according to the Common Terminology Criteria for Adverse Event version 5.0. Results At the completion of our study, all the patients with cT4 PC were alive with a median follow-up period of 78 months. Grade 2 acute urinary disorders were observed in only one patient. Regarding late toxicities, only one patient developed grade 2 hematuria and urinary urgency. There was no grade 3 or worse toxicity, and gastrointestinal toxicity was not observed. Six (85.7%) patients had no recurrence or metastasis. One patient had biochemical and local failures 42 and 45 months after CIRT, respectively. However, the recurrent disease has been well controlled by salvage ADT. Conclusions Seven patients with locally advanced PC invading the bladder treated with CIRT were evaluated. Our findings seem to suggest positive safety and efficacy profiles for CIRT.

Abstract Background Children with influenza virus infections are prone to complications and are common sources of influenza transmission. Baloxavir marboxil inhibits cap-dependent endonuclease and was approved for influenza treatment in adolescent, adult, and pediatric patients in Japan. The miniSTONE-2 study included pediatric patients with influenza (1 to

Scintillators emit visible luminescence when irradiated with X-rays and may enable remote optogenetic control of neurons deep in the brain. The authors inject an inorganic scintillator to activate and inhibit midbrain dopamine neurons in freely moving mice by X-ray irradiation to modulate place preference behavior.

Abstract Background Daily anatomical deviations may distort the dose distribution in carbon ion radiotherapy (CIRT), which may cause treatment failure. Therefore, this study aimed to perform re-planning to maintain the dose coverage in patients with pancreatic cancer with passive scattering CIRT. Methods Eight patients with pancreatic cancer and 95 daily computed tomography (CT) sets were examined. Two types of adaptive plans based on new range compensators (RCs) (AP-1) and initial RCs (AP-2) were generated. In AP-2, each beam was optimized by manually adjusting the range shifter thickness and spread-out Bragg peak size to make dose reduction by

Abstract Background Adenoid cystic carcinoma (ACC) is a rare malignant tumor involving mostly the head and neck region, and frequently the salivary glands. The development of lung metastasis after treatment of the primary tumor is a common occurrence in ACC. Although lung metastases show a slow rate of growth, approximately 10% of patients die from distant metastases. The radioresistance of ACC limits the efficacy of conventional radiotherapy for lung metastases, and the optimal dose remains to be determined. Stereotactic body radiotherapy (SBRT) using CyberKnife can deliver a high dose to the lung tumor, while sparing the surrounding normal lung tissues, leading to favorable local control in non-squamous cell lung cancer and metastatic lung tumors. We report a case of lung metastases from ACC treated successfully with SBRT using CyberKnife. Case presentation A 76-year-old Japanese man with ACC who was treated with carbon ion radiotherapy for a primary oropharynx tumor presented with three metastatic lesions in the lung. The tumor masses were located in the right upper, right lower, and left lower lobes of the lungs. Surgical resection was not indicated because of the presence of multiple tumors. The patient underwent SBRT at 60 Gy in 10 sequential fractions for each tumor. The biologically effective dose based on an alpha/beta ratio of 2 Gy was 240 Gy per tumor. The percentage of the total lung volume irradiated with >20 Gy was 4.9%, 3.2%, and 2.6% for each tumor. The patient developed acute radiation pneumonitis during the initial therapy, which resolved at 6 months after the CyberKnife treatment. At 21 months after the first CyberKnife treatment, three tumors showed no signs of recurrence. No late toxicity was observed. Conclusions SBRT using CyberKnife is an effective and feasible approach to the management of multiple lung metastases of ACC.

Abstract Background In this study, we aim to present the clinical outcomes of radiotherapy (RT) in clinical pelvic lymph node‐positive prostate cancer (cN1) patients. We also analyze the prognostic factors with focus on RT dose escalation to metastatic lymph nodes (LN). Methods We retrospectively analyzed the data from cN1 patients who were treated with definitive RT and androgen deprivation therapy (ADT) between June 2004 and February 2016. All patients received localized irradiation to the prostate region and whole pelvis irradiation. Some patients received intensity‐modulated radiation therapy with RT dose escalation to metastatic LN. Univariate analyses using log‐rank test were performed to find prognostic factors between patient subgroups. Results Fifty‐one consecutive patients were identified. The median follow‐up period for all patients was 88 (range 20‐157) months. Primary Gleason pattern and LN RT dose were statistically significant prognostic factors for relapse‐free survival (RFS) and distant metastasis‐free survival (DMFS). Especially, RT dose escalation (60 Gy or more) to metastatic LN significantly improved RFS and DMFS compared with standard dose RT (4‐year RFS 90.6% vs 82.1%, 7‐year RFS 90.6% vs 58.0%, P = .015; 4‐year DMFS 90.6% vs 82.1%, 7‐year DMFS 90.6% vs 62.8%, P = .023). The following factors were all statistically significant for biochemical relapse‐free survival (BRFS): T stage, LN RT dose, local RT dose, and ADT duration period. Any significantly different toxicity was not seen for each LN or local RT dose except for the incident rate of grade 2 or more acute urinary retention, which was significantly higher in the higher LN RT dose (60 Gy or more) group by the Chi‐square test. Conclusions RT dose escalation to metastatic LN in cN1 patients improves BRFS, RFS, and DMFS at 4 and 7 years, without increasing severe adverse events.

Abstract Background Hepatocellular carcinoma (HCC) involving a major branch of the portal or hepatic vein is in a locally advanced stage and remains difficult to cure. This study aimed to evaluate the clinical effects of carbon ion radiotherapy (C-ion RT) in locally advanced HCC (LAHCC). Methods The data of 11 consecutive patients with LAHCC who received C-ion RT were analyzed. The C-ion RT doses of 52.8 Gy (relative biological effectiveness [RBE]) and 60.0 Gy (RBE) were delivered in 4 fractions for standard cases, and the 60.0 Gy dose was delivered in 12 fractions for close-to-gastrointestinal-tract cases. Survival and local control probabilities were calculated using the Kaplan-Meier method. Results The median follow-up duration after C-ion RT was 36.4 months. The median age at the time of registration for C-ion RT was 76 years. The median tumor size was 53 mm. The numbers of treatment-naive and recurrent HCC patients were 1 and 10, respectively. Direct invasion of the major branch of the portal vein, hepatic vein, or both portal and hepatic veins was observed in three, five, and three patients, respectively. The 3-year overall survival, local control, and progression-free survival rates were 64, 78, and 18%, respectively. No patient developed radiation-induced liver diseases or grade 3 or higher toxicities in the acute and late phases. Conclusions C-ion RT showed favorable clinical outcomes with a high rate of local control and minimal toxicities in LAHCC. Our findings suggest that C-ion RT is a promising multidisciplinary treatment option in LAHCC.

Abstract Background Although carbon‐ion radiotherapy (C‐ion RT) with concurrent chemotherapy (chemo‐C‐ion RT) is a promising treatment for adenocarcinoma (AC) of the uterine cervix, its long‐term efficacy remains unclear. We evaluated the long‐term significance of concurrent weekly cisplatin and C‐ion RT for locally advanced AC of the uterine cervix. Methods We performed a pooled analysis of patients with stage IIB–IVA AC of the uterine cervix who underwent C‐ion RT alone or chemo‐C‐ion RT between September 2007 and December 2018 at our institution. Patients received 74.4 Gy (relative biological effectiveness) with or without cisplatin (40 mg/m2 per week for up to 5 weeks), underwent no prior pelvic RT or systemic therapy, and had a performance status of 0‐2. Propensity score matching was based on the year of diagnosis, regional lymph node metastasis, and stage. Results The matched cohort contained 26 patients who underwent C‐ion RT and 26 who underwent chemo‐C‐ion RT. The median age and follow‐up period were 57 (range, 28‐79) years and 34 (range, 2‐126) months, respectively. The 5‐year overall survival rate was significantly better in the chemo‐C‐ion RT group (72%) than in the C‐ion RT group (46%; P = .041). The 5‐year distant metastatic‐free rate was also significantly better in the chemo‐C‐ion RT group (66%) than in the C‐ion RT group (41%; P = .048). The incidence of grade ≥ 3 late toxicities was comparable between the two groups. Conclusions Chemo‐C‐ion RT for locally advanced AC of the uterine cervix is associated with a long‐term survival benefit.

Abstract Background Carbon ion Radiotherapy for prostate cancer is widely used, however reports are limited from single institute or short follow up. We performed a prospective observational study (GUNMA0702) to evaluate the feasibility and efficacy of carbon ion radiotherapy for localized and locally advanced prostate cancer. Methods Between June 2010 and August 2013, 304 patients with localized prostate cancer were treated, with a median follow-up duration of 60 months. All patients received carbon ion radiotherapy with 57.6 Gy (RBE) in 16 fractions over 4 weeks. Hormonal therapy was given according to the risk group. Toxicity was reported according to the Common Toxicity Criteria for Adverse Event, Version 4.0 by the National Cancer Institute. Results The overall 5-year biochemical relapse-free rate was 92.7%, with rates of 91.7, 93.4, and 92.0% in low-risk, intermediate-risk, and high-risk patients, respectively. The 5-year local control and overall survival rates were 98.4 and 96.6%, respectively. Acute grade 3 or greater toxicity was not observed. Late grade 2 and grade 3 genitourinary and gastrointestinal toxicity rates were 9 and 0.3%, and 0.3, and 0%, respectively. Conclusions The present protocol of carbon ion radiotherapy for prostate cancer provided low genitourinary and gastrointestinal toxicity with good biochemical control within 5 years. Trial registration University Medical Information Network Clinical Trial Registry number: UMIN000003827.

Glutaraldehyde, a germicide for reprocessing endoscopes that is important for hygiene in the clinic, might be hazardous to humans. Electrolyzed acid water (EAW) has a broad anti-microbial spectrum and safety profile and might be a glutaraldehyde alternative. We sought to assess EAW disinfection of flexible endoscopes in clinical otorhinolaryngological settings and its in vitro inactivation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and bacteria commonly isolated in otorhinolaryngology. Ninety endoscopes were tested for bacterial contamination before and after endoscope disinfection with EAW. The species and strains of bacteria were studied. The in vitro inactivation of bacteria and SARS-CoV-2 by EAW was investigated to determine the efficacy of endoscope disinfection. More than 20 colony-forming units of bacteria at one or more sampling sites were detected in 75/90 microbiological cultures of samples from clinically used endoscopes (83.3%). The most common genus detected was Staphylococcus followed by Cutibacterium and Corynebacterium at all sites including the ears, noses, and throats. In the in vitro study, more than 107 CFU/mL of all bacterial species examined were reduced to below the detection limit ( 105 PFU) was decreased to less than 5 PFU. Effective inactivation of SARS-CoV-2 was also observed with a 19:1 ratio of EAW to the virus. EAW effectively reprocessed flexible endoscopes contributing to infection control in medical institutions in the era of the coronavirus disease 2019 pandemic.

BACKGROUND: Although digital learning devices have become increasingly more common in medical education settings, it remains unclear how they influence medical student learning styles and various outcome measures. This study aimed to assess student learning styles, specifically as they relate to digital dependency, writing habits, and group learning practices among current medical students. MATERIALS AND METHODS: This questionnaire study was approved by the Research Ethics Committee of Osaka Medical and Pharmaceutical University. We conducted a questionnaire survey of 109 medical students who were 5th year students during the 2021 school year. Medical students were asked about their level of digital dependency, writing by hand, and group learning practices. We also analyzed the correlation between student learning styles and their respective outcomes on several summative evaluations. RESULTS: Of the 109 students targeted, we received responses from 62 (response rate, 56.8%). Among the respondents, digital dependency was 83.4 ± 18.6%, while hand writing ratio 39.8 ± 29.9% and group learning ratio 33.5 ± 30.5%. We also assessed correlations between these learning styles and scores on the CBT, OSCE, CC, and CC Integrative Test. Only writing by hand showed a small positive correlation with CC Integrative Test scores. CONCLUSION: Our questionnaire survey assessed the rates of digital dependency, writing by hand, and group learning practices, and analyzed the correlations between these learning styles and respective outcomes. Current medical students exhibited high digital dependency which was not correlated with performance outcomes.

Neurofeedback (NF) aptitude, which refers to an individual's ability to change brain activity through NF training, has been reported to vary significantly from person to person. The prediction of individual NF aptitudes is critical in clinical applications to screen patients suitable for NF treatment. In the present study, we extracted the resting-state functional brain connectivity (FC) markers of NF aptitude, independent of NF-targeting brain regions. We combined the data from fMRI-NF studies targeting four different brain regions at two independent sites (obtained from 59 healthy adults and six patients with major depressive disorder) to collect resting-state fMRI data associated with aptitude scores in subsequent fMRI-NF training. We then trained the multiple regression models to predict the individual NF aptitude scores from the resting-state fMRI data using a discovery dataset from one site and identified six resting-state FCs that predicted NF aptitude. Subsequently, the reproducibility of the prediction model was validated using independent test data from another site. The identified FC model revealed that the posterior cingulate cortex was the functional hub among the brain regions and formed predictive resting-state FCs, suggesting that NF aptitude may be involved in the attentional mode-orientation modulation system's characteristics in task-free resting-state brain activity.

Our current understanding of melancholic depression is shaped by its position in the depression spectrum. The lack of consensus on how it should be treated—whether as a subtype of depression, or as a distinct disorder altogethe—interferes with the recovery of suffering patients. In this study, we analyzed brain state energy landscape models of melancholic depression, in contrast to healthy and non-melancholic energy landscapes. Our analyses showed significant group differences on basin energy, basin frequency, and transition dynamics in several functional brain networks such as basal ganglia, dorsal default mode, and left executive control networks. Furthermore, we found evidences suggesting the connection between energy landscape characteristics (basin characteristics) and depressive symptom scores (BDI-II and SHAPS). These results indicate that melancholic depression is distinguishable from its non-melancholic counterpart, not only in terms of depression severity, but also in brain dynamics.

Macrolide-resistant Mycoplasma pneumoniae (MRMP) infections have become increasingly prevalent, especially in East Asia. Whereas MRMP strains have point mutations that are implicated in conferring resistance, monitoring the antibiotic susceptibility of M. pneumoniae and identifying mutations in the resistant strains is crucial for effective disease management. Therefore, we investigated antimicrobial susceptibilities among M. pneumoniae isolates obtained from Japanese children since 2011. To establish the current susceptibility trend, we analyzed the minimum inhibitory concentrations (MICs) of M. pneumoniae in recent years (2017–2020) in comparison with past data. Our observation of 122 M. pneumoniae strains suggested that 76 were macrolide-susceptible M. pneumoniae (MSMP) and 46 were macrolide-resistant. The MIC ranges (µg/mL) of clarithromycin (CAM), azithromycin (AZM), tosufloxacin (TFLX), and minocycline (MINO) to all M. pneumoniae isolates were 0.001–>128, 0.00012–>128, 0.25–0.5, and 0.125–4 µg/mL, respectively. None of the strains was resistant to TFLX or MINO. The MIC distributions of CAM and AZM to MSMP and MINO to all M. pneumoniae isolates were significantly lower, but that of TFLX was significantly higher than that reported in all previous data concordant with the amount of recent antimicrobial use. Therefore, continuation of appropriate antimicrobial use for M. pneumoniae infection is important.

Most Japanese adults are vaccinated twice with the Sabin trivalent oral polio vaccine. Booster vaccination is recommended for Japanese travelers to polio-endemic/high-risk countries. We assessed the catch-up immunization of healthy Japanese adults aged ≥20 years with two doses of standalone conventional inactivated polio vaccine (cIPV). Immunogenicity was evaluated by serum neutralization titers (pre-booster vaccination, 4–6 weeks after each vaccination) against type 1, 2, and 3 poliovirus strains. The participants were 61 healthy Japanese adults (26 men/35 women; mean age ± standard deviation age 35.8 ± 8.0 years). Seropositivity rates (percentage of participants with anti-poliovirus antibody titers ≥1:8) pre-vaccination were 88.5%, 95.1%, and 52.5% for Sabin strains (type 1, 2, and 3); 72.1%, 93.4%, and 31.1% for virulent poliovirus strains (type 1: Mahoney; type 2: MEF-1; and type 3: Saukett); and 93.4%, 93.4%, 93.4%, and 88.5% for type 2 vaccine-derived poliovirus strains (SV3128, SV3130, 11,196, and 11,198). After one cIPV dose, all seropositivity rates increased to 98.4–100.0%. After two cIPV doses, the seropositivity rates reached 100% for all strains. cIPV was well tolerated, with no safety concerns. Catch-up immunization with standalone cIPV induced robust immune responses in Japanese adults, indicating that one booster dose boosted serum-neutralizing antibodies to many strains.

ABSTRACT Nonalcoholic fatty liver disease (NAFLD), characterized by excessive fat deposition in the liver unrelated to alcohol consumption, is highly prevalent worldwide. However, effective therapeutic agents approved for NAFLD treatment are lacking. An ileal bile acid transporter inhibitor (IBATi), which represents a new mode of treatment of chronic idiopathic constipation, leads to increased delivery of bile acids to the colon. We investigated the effect of IBATi against NAFLD through modification of the gut microbiota in mice. IBATi treatment significantly suppressed body weight gain, liver dysfunction, and serum low-density lipoprotein levels and significantly decreased NAFLD activity scores in high-fat diet (HFD) mice. Treatment with IBATi ameliorated the decreased hepatic cholesterol 7-a-monooxygenase (Cyp7a1) and increased ileal fibroblast growth factor 15 (Fgf15) mRNA expression in HFD mice. Further, IBATi treatment changed the α-diversity in the gut microbiota reduced by HFD, which was analyzed in feces using 16S rRNA sequencing. To establish the mechanism underlying improvement in NAFLD induced by IBATi, we recolonized antibiotic solution-treated mice by fecal microbiome transplantation (FMT) using stool from HFD or HFD plus IBATi mice. This is the first report that fecally transplanted gut microbiota from HFD plus IBATi mice prevented hepatic steatosis caused by HFD. In conclusion, IBATi improved hepatic steatosis by ameliorating gut microbiota dysbiosis in NAFLD model mice, suggesting a potential therapeutic agent for NAFLD treatment. IMPORTANCE NAFLD is an increasingly recognized condition that may progress to liver cirrhosis and hepatocellular carcinoma, and community surveys have assessed that the prevalence is 14 to 32% worldwide. The first line of treatment for NAFLD is lifestyle modification to achieve weight reduction, particularly through diet and exercise. However, weight reduction is difficult to achieve and maintain, and pharmacological agents approved for the treatment of NAFLD are lacking. This study investigated the influence of the gut microbiota and the effect of an IBATi on NAFLD using a murine model. Treatment with IBATi significantly improved NAFLD in HFD mice. Further, fecal microbiome transplantation using stool from HFD plus IBATi mice prevented hepatic steatosis caused by HFD. Our study makes a significant contribution to the literature because the study findings suggest a potential treatment strategy for NAFLD patients by ameliorating gut microbiota dysbiosis.

Abstract This study aimed to evaluate the efficacy of carbon‐ion radiotherapy in combination with chemotherapy using dacarbazine, nimustine, and vincristine (DAV therapy) in mucosal melanoma. Twenty‐one patients with clinically localized mucosal melanoma of the head and neck were enrolled. The primary endpoint was 3‐year overall survival (OS). Secondary endpoints included local control, progression‐free survival (PFS), and adverse event occurrence. Carbon‐ion radiotherapy with a dose of 57.6‐64.0 Gy (relative biological effectiveness) in 16 fractions was delivered concurrently with DAV therapy, and 2 cycles of adjuvant DAV therapy were administered every 6 weeks. The median follow‐up periods were 15.5 months for all patients, and 31.2 months for 12 surviving patients. All patients had locally advanced T4a or T4b disease in the rhino‐sinus area. In 16 patients (76.2%), 3 cycles of planned DAV therapy were completed. The 3‐year OS and PFS rates were 49.2% and 37.0% respectively. The 3‐year local control rate was 92.3%. Eleven patients (52%) developed distant metastasis, which was the most frequent pattern of the first failure. Commonly presenting acute grade 2‐3 toxicities associated with radiotherapy and chemotherapy were mucositis (11 patients [53%]) and leukopenia (9 patients [43%]), which improved with conservative therapy. None of the patients developed grade 3 or greater late toxicities. Carbon‐ion radiotherapy in combination with DAV therapy led to excellent local control for advanced mucosal melanoma within acceptable toxicities. The efficacy of additional DAV therapy in improving survival was weaker than expected as distant metastases still occurred frequently. Trial registration no. UMIN000007939.

Abstract This phase II study's aim was to confirm the efficacy and safety of hypofractionated carbon‐ion radiotherapy in patients with stage I peripheral nonsmall cell lung cancer (NSCLC). The study encompassed 37 patients with histologically proven peripheral stage I NSCLC in the period June 2010‐March 2015. All underwent the planned full dose of carbon‐ion radiotherapy, administered with relative biological effectiveness of 52.8 Gy and 60 Gy (divided into four fractions over 1 week) for T1 and T2a tumors, respectively. The 2‐year local control rate was set as the primary endpoint, while overall survival, progression‐free survival, and the incidence rates of acute and late adverse events were secondary endpoints. The patients were followed up for 56.3 months overall and 62.2 months in the surviving patients, respectively. The actuarial local control rates were 91.2% after 2 years, and 88.1% after 5 years. No differences were found between the T1 and T2a tumors in the 5‐year local control rate (90.9% vs 86.7%, P = .75). The actuarial overall survival rates achieved 91.9% for 2‐year and 74.9% for 5‐year period. T1 tumors showed actuarial 5‐year overall survival rates of 80%, compared to 66.7% in T2a tumors. Two patients with T2a tumors and either severe emphysema or bronchiectasis experienced lung toxicity ≥ grade 2, in contrast to T1 patients who only experienced mild toxicities (lower than grade 2). The findings suggest that carbon‐ion radiotherapy is effective and safe for peripheral stage I NSCLC; however, further clinical evaluations are needed to confirm its therapeutic efficacy. Trial registration: UMIN000003797. Registered 21 June 2010, prospectively registered.

Abstract Background The aim of this study was to evaluate the efficacy and safety of carbon‐ion radiation therapy for nonsquamous cell carcinomas of the oral cavity in a multicenter study. Methods Retrospective analysis of the clinicopathological features and outcomes of 76 patients with oral nonsquamous cell carcinomas with N0‐1 M0 status and were treated with carbon‐ion radiation therapy at four institutions in Japan between November 2003 and December 2014 was performed. Results Salivary gland carcinoma, mucosal melanoma, and three other carcinomas were found in 46, 27, and 3 patients, respectively. T1‐3, T4a, and T4b disease was diagnosed in 27, 18, and 31 patients, respectively. Median follow‐up period was 31.1 months (range, 3‐118 months). Three‐year local control, progression‐free survival, and overall survival of all patients were 86.8%, 63.1%, and 78.4%, respectively. Multivariate analysis showed T classification (T4) to be a significant independent poor prognostic factor for local control. Acute grade 3 mucositis was observed in 38 patients. Grades 3 and 4 late morbidities were observed in 9 and 4 patients, respectively. No grade 5 late toxicity was observed. Conclusions Oral nonsquamous cell carcinomas could be treated effectively, with acceptable toxicity, by carbon‐ion radiation therapy.