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Disease-related cells differentiated from patient-derived iPSCs are useful for elucidating the pathophysiological mechanisms underlying these diseases. In this study, four iPSC lines were established from independent patients with sensorineural hearing loss and a mutation in EYA4. These iPSCs showed pluripotency, the capacity to differentiate into three germ layers, and normal karyotypes, suggesting that these lines are useful for the pathological study of sensorineural hearing loss and drug screening for ear disorders.

Summary: Background: Meropenem (MEPM) holds significance in treating severe infections and drug-resistant bacteria. There are concerns that antimicrobial shortages may lead to the use of alternative antimicrobials that are less effective and safer. We have responded to the MEPM shortage with post-prescription monitoring and feedback (PPRF) with no restrictions on MEPM initiation. We aimed to assess the impact of the MEPM shortage and the PPRF on broad-spectrum antimicrobial use and mortality. Methods: This retrospective study was conducted in a single hospital in Japan. The period from October 2021 to August 2022 was defined as the period before the MEPM shortage, and the period from September 2022 to March 2023 was defined as the period during the MEPM shortage. To support the appropriate use of antimicrobials during MEPM shortages, the antimicrobial stewardship team (AST) developed a list of alternatives to MEPM. An interrupted time series analysis was used to assess changes in use and mortality among patients receiving broad-spectrum antimicrobials over the study period. Discussion: The shortage of MEPM and PPRF temporarily increased the use of alternative cefepime; however, the subsequent change in days of therapy and days of coverage of broad-spectrum antimicrobials suggests a decrease in the use of these antimicrobials. Despite these shifts, the mortality rates remained stable, suggesting that the response to the shortage did not adversely affect treatment outcomes. Conclusion: In the context of antimicrobial shortages, AST support plays an important role in enabling physicians to make optimal use of antimicrobials.

Abstract The advent of Artificial Intelligence (AI)-based object detection technology has made identification of position coordinates of surgical instruments from videos possible. This study aimed to find kinematic differences by surgical skill level. An AI algorithm was developed to identify X and Y coordinates of surgical instrument tips accurately from video. Kinematic analysis including fluctuation analysis was performed on 18 laparoscopic distal gastrectomy videos from three expert and three novice surgeons (3 videos/surgeon, 11.6 h, 1,254,010 frames). Analysis showed the expert surgeon cohort moved more efficiently and regularly, with significantly less operation time and total travel distance. Instrument tip movement did not differ in velocity, acceleration, or jerk between skill levels. The evaluation index of fluctuation β was significantly higher in experts. ROC curve cutoff value at 1.4 determined sensitivity and specificity of 77.8% for experts and novices. Despite the small sample, this study suggests AI-based object detection with fluctuation analysis is promising because skill evaluation can be calculated in real time with potential for peri-operational evaluation.

Abstract Maternal immunoglobulin (Ig)G is present in breast milk and has been shown to contribute to the development of the immune system in infants. In contrast, maternal IgG has no known effect on early childhood brain development. We found maternal IgG immunoreactivity in microglia, which are resident macrophages of the central nervous system of the pup brain, peaking at postnatal one week. Strong IgG immunoreactivity was observed in microglia in the corpus callosum and cerebellar white matter. IgG stimulation of primary cultured microglia activated the type I interferon feedback loop by Syk. Analysis of neonatal Fc receptor knockout (FcRn KO) mice that could not take up IgG from their mothers revealed abnormalities in the proliferation and/or survival of microglia, oligodendrocytes, and some types of interneurons. Moreover, FcRn KO mice also exhibited abnormalities in social behavior and lower locomotor activity in their home cages. Thus, changes in the mother-derived IgG levels affect brain development in offsprings.

Abstract Furan compounds, including 5-hydroxymethylfurfural and furfural, can be synthesized from biomass and have garnered attention for their potential applications in biofuels and resin precursors. In this study, the synthesis of the furan compounds from rice straw was explored using a combined approach of ionic liquid treatment, specifically 1-methylimidazolium hydrogen sulfate ([MIM]HSO4), and vacuum steam distillation. Through the optimization of various processing parameters, we established that the best conditions for the furan compound production include: a cold trap cooling temperature of – 196 ℃, a system pressure of 10 hPa, a treatment temperature of 180 ℃, a reaction duration of 30 min, a sample loading of 1wt%, and a particle size range of 45–90 µm. Under these conditions, the resultant yield of the furan compounds was quantified at 27.9wt%. Additionally, the recyclability of the utilized ionic liquid was evaluated. Notably, even after four recycling cycles (encompassing a total of five reactions), the yield of the furan compounds remained consistent, underscoring the viability of ionic liquid reuse.

Abstract Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection in young children and the second leading cause of infant death worldwide. While global circulation has been extensively studied for respiratory viruses such as seasonal influenza, and more recently also in great detail for SARS-CoV-2, a lack of global multi-annual sampling of complete RSV genomes limits our understanding of RSV molecular epidemiology. Here, we capitalise on the genomic surveillance by the INFORM-RSV study and apply phylodynamic approaches to uncover how selection and neutral epidemiological processes shape RSV diversity. Using complete viral genome sequences, we show similar patterns of site-specific diversifying selection among RSVA and RSVB and recover the imprint of non-neutral epidemic processes on their genealogies. Using a phylogeographic approach, we provide evidence for air travel governing the global patterns of RSVA and RSVB spread, which results in a considerable degree of phylogenetic mixing across countries. Our findings highlight the potential of systematic global RSV genomic surveillance for transforming our understanding of global RSV spread.

Abstract The vagus nerve is the only pathway for transmitting parasympathetic signals between the brain and thoracoabdominal organs, thereby exhibiting anti-inflammatory functions through the cholinergic anti-inflammatory pathway. Despite often being resected during lymph node dissection in upper gastrointestinal cancer surgery, the impact of vagotomy on postoperative outcomes in gastric cancer patients remains unclear. Sub-diaphragmatic vagotomy was performed on C57BL/6 mice. Three weeks later, syngeneic murine gastric cancer cell line YTN16P was injected into the peritoneal cavity, and the number of peritoneal metastases (PM) on the mesentery and omentum compared with control mice. The phenotypes of immune cells in peritoneal lavage and omental milky spots one day after tumor inoculation were analyzed using flow cytometry and immunohistochemistry. Intraperitoneal transfer of 3 × 105 YTN16P significantly increased the number of metastatic nodules on the mesentery in the vagotomy group compared to the control group. The omental metastasis grade was also significantly higher in the vagotomy group. Phenotypic analysis of immune cells in peritoneal lavage did not reveal significant differences after vagotomy. However, vagotomized mice exhibited a notable increase in milky spot area, with a higher presence of cytokeratin(+) tumor cells, F4/80(+) macrophages, and CD3(+) T cells. Vagus nerve signaling appears to regulate the immune response dynamics within milky spots against disseminated tumor cells and inhibits the development of PM. Preserving the vagus nerve may offer advantages in advanced gastric cancer surgery to reduce peritoneal recurrence.

Abstract The association between daily breakfast habits during pregnancy and offspring neurodevelopment remains unknown. We evaluated the association between breakfast habits during pregnancy and offspring neurodevelopment. Data of 72,260 women with singleton deliveries at and after 37 weeks of gestation enrolled during 2011–2014 in the Japan Environment and Children’s Study were analysed. Offspring neurodevelopmental delays at 3 years of age were evaluated using the Ages and Stages Questionnaire, Third Edition (ASQ-3). Participants were stratified by tertiles of maternal daily energy intake (DEI) (Groups 1, 2, and 3:

A man in his 60 s, who had experienced sustained abdominal pain intermittently for three years, lost consciousness and was transferred to an emergency hospital, where he was pronounced dead. In the forensic autopsy, a giant bladder stone measuring 6.5 × 6.0 × 4.0 cm was found adhering to an aluminum eyeliner that penetrated the anterior wall of his rectum. This might have induced pyelonephritis in the left kidney, resulting in sepsis. The deceased may have inserted the eyeliner for sexual stimulation. However, the eyeliner did not injure the peritoneum and no peritonitis occurred, which probably prevented acute sepsis immediately after insertion. The exact time of penetration was undetermined; however, the rectal foreign body may have been retained for three years. This case suggests that sexual activity should be considered a possible manner of death, even if it took place several years previously.

A man in his forties with two lacerations in the occiput was found in a river. A forensic autopsy revealed that the cause of death was drowning, and the blood ethanol concentration was 1.5 mg/mL. The whole brain was fixed with formalin for 15 days using the standard immersion method to evaluate this. The fixed brains showed large holes in the deep white matter as artifacts. Research suggests that formalin-fixed brains from drowning cases tend to have “Swiss cheese-like” holes in the deep white matter. However, this study is the first to report a case that focuses on large holes as artifacts. The holes in the fixed brain may have been caused by postmortem invasion of freshwater indigenous bacteria and gas formation.

AbstractPurpose c-Jun N-terminal kinases (JNKs) comprise a subfamily of mitogen-activated protein kinases (MAPKs). The JNK group is known to be activated by a variety of stimuli. However, the molecular mechanism underlying heat-induced JNK activation is largely unknown. The aim of this study was to clarify how JNK activity is stimulated by heat.Methods and materials The expression levels of various MAPK members in HeLa cells, with or without hyperthermia treatment, were evaluated via western blotting. The kinase activity of MAPK members was assessed through in vitro kinase assays. Cell death was assessed in the absence or presence of siRNAs targeting MAPK-related members.Results Hyperthermia decreased the levels of MAP3Ks, such as ASK1 and MLK3 which are JNK kinase kinase members, but not those of the downstream MAP2K/SEK1 and MAPK/JNK. Despite the reduced or transient phosphorylation of ASK1, MLK3, or SEK1, downstream JNK was phosphorylated in a temperature-dependent manner. In vitro kinase assays demonstrated that heat did not directly stimulate SEK1 or JNK. However, the expression levels of DUSP16, a JNK phosphatase, were decreased upon hyperthermia treatment. DUSP16 knockdown enhanced the heat-induced activation of ASK1–SEK1–JNK pathway and apoptosis.Conclusion JNK was activated in a temperature-dependent manner despite reduced or transient phosphorylation of the upstream MAP3K and MAP2K. Hyperthermia-induced degradation of DUSP16 may induce activation of the ASK1–SEK1–JNK pathway and subsequent apoptosis.

Background This study aimed to clarify the characteristics and survival prediction value of transcranial Doppler microembolic signals (MES) in patients with acute cerebral infarction and active cancer. Methods and Results Between 2017 and 2022, 1089 cases of acute cerebral infarction were recorded within 7 days of disease onset. Among them, transcranial Doppler was successful in 33 patients who had active cancer, and these data were analyzed in this study. The primary outcomes were stroke recurrence and mortality at 3 months. The study population had the following characteristics [median (interquartile range)]: age, 70 years (63–78); body mass index, 21.6 (20–24), National Institutes of Health Stroke Scale 3 (1–6), and modified Rankin Scale score at discharge 1 (1–4). The most common cancer types were lung (24%), pancreatic (24%), and intestinal (18%). MES was present in 16 of 33 patients (48.5%). The presence and number of MES were significantly associated with the levels of D‐dimer (P

Background We aimed to clarify the predictive value of cerebral small‐vessel disease and intracranial large artery disease (LAD) observed in magnetic resonance imaging of the brain and magnetic resonance angiography on future vascular events and cognitive impairment. Methods and Results Data were derived from a Japanese cohort with evidence of cerebral vessel disease on magnetic resonance imaging. This study included 862 participants who underwent magnetic resonance angiography after excluding patients with a modified Rankin Scale score >1 and Mini‐Mental State Examination score

Abstract The spleen is a key source of circulating and tumor-infiltrating immune cells. However, the effect of splenectomy on tumor growth remains unclear. At 3 weeks after splenectomy, we subcutaneously injected LuM1 cells into BALB/c mice and evaluated the growth of primary tumors and lung metastases at 4 weeks after tumor inoculation. In addition, we examined the phenotypes of immune cells in peripheral blood by using flow cytometry and in tumor tissue by using multiplex immunohistochemistry. The growth of primary tumors was reduced in splenectomized mice compared with the sham-operated group. Conversely, splenectomized mice had more lung metastases. Splenectomized mice had fewer CD11b+cells, especially monocytic MDSCs (CD11b+Gr-1neg-lowLy6chigh), and NK cells (CD49b+CD335+). The proportion of NK cells was inversely correlated with the number of lung metastases. In splenectomized mice, the density of CD3+ and granzyme B+ CD8+ T cells was increased, with fewer M2-type macrophages in primary tumors, but NK cells were decreased markedly in lung. Splenectomy concurrently enhances T cell-mediated acquired immunity by reducing the number of monocytic MDSCs and suppresses innate immunity by decreasing the number of NK cells. Splenectomy has opposite effects on primary and metastatic lesions through differential regulation on these two immune systems.

The demand for drone-based object transportation has been rapidly growing recently. Current drones face limitations in their ability to grasp objects on the flat surface. To address this issue, our study presents a universal jamming holding system with the capability to grasp flat surfaces. In general, jamming grippers cannot grasp flat surfaces. Here we have introduced a stretchable membrane and spherical shape to the gripper, allowing our jamming gripper to grasp flat surfaces. We assumed that when the stretchable membrane attaches to an object, the stretchable membrane spontaneously forms microscopic suction cup-like structure at the contact area. Our jamming gripper then can grasp flat objects by the effect of the suction cup-like structure. Our jamming gripper is ideal for drone mounting as it maintains the center of gravity during the gripping process and can operate with low positional accuracy. In addition, our jamming gripper operate on a pneumatic circuit powered by a solenoid valve, allowing our drone to hold objects without consuming energy. Our experimental results demonstrated that an acrylic plate could support a load of 945 g on a flat surface at a filling rate of 75%. Our gripper also has a good adsorption force on metal, acrylic, ice, and other surfaces. The gripping force of our grippers is independent of the pressing force. Our jamming gripper can be mounted on a drone and controlled wirelessly to perform grasping movements autonomously, making them highly versatile. It can be applied to various situations where the shapes of objects to be grasped are uncertain, such as delivery of goods to remote areas or sample collection.