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Traditional Japanese medicines, i.e., Kampo medicines, consist of crude drugs (mostly plants) that have empirical pharmacological functions (‘Yakuno’ in Japanese), such as clearing heat. Crude drugs with cold properties, such as Phellodendron bark, have the empirical function of clearing heat as they cool the body. Because we found that anti-inflammatory compounds were present in several crude drugs for clearing heat, it is speculated that the empirical function of clearing heat may be linked to anti-inflammatory activities. When 10 typical crude drugs were selected from 22 herbal crude drugs for clearing heat, we identified anti-inflammatory compounds in five crude drugs, including Phellodendron bark. In this study, the other crude drugs were extracted and partitioned with ethyl acetate (EtOAc) and n-butanol to obtain three crude fractions. All the EtOAc-soluble fractions, except that from Forsythia fruits, inhibited interleukin (IL)-1β-induced nitric oxide (NO) production in primary-cultured rat hepatocytes. Anti-inflammatory compounds were identified from these EtOAc-soluble fractions: baicalein from Scutellaria roots, (−)-nyasol from Anemarrhena rhizomes, and loniflavone from Lonicera leaves and stems. (+)-Phillygenin was purified from Forsythia fruits by removing cytotoxic oleanolic and betulinic acids. These compounds suppressed the production of NO and cytokines in hepatocytes. Anti-inflammatory compounds were not purified from the EtOAc-soluble fraction of Rehmannia roots because of their low abundance. Collectively, these findings indicate that anti-inflammatory compounds are present in all 10 crude drugs for clearing heat, confirming that these anti-inflammatory compounds in crude drugs provide the empirical functions for clearing heat. Other empirical functions of Kampo medicine can also be explained by modern pharmacological activities.

Background Multiple prolonged symptoms observed in patients who recovered from COVID-19 are defined as long COVID. Although diverse phenotypic combinations are possible, they remain unclear. This study aimed to perform a cluster analysis of long COVID in Japan and clarify the association between its characteristics and background factors and quality of life (QOL).Methods This multicentre prospective cohort study collected various symptoms and QOL after COVID-19 from January 2020 to February 2021. This study included 935 patients aged ≥18 years with COVID-19 at 26 participating medical facilities. Hierarchical cluster analysis was performed using 24 long COVID symptom at 3 months after diagnosis.Results Participants were divided into the following five clusters: numerous symptoms across multiple organs (cluster 1, n=54); no or minor symptoms (cluster 2, n=546); taste and olfactory disorders (cluster 3, n=76); fatigue, psychoneurotic symptoms and dyspnoea (low prevalence of cough and sputum) (cluster 4, n=207) and fatigue and dyspnoea (high prevalence of cough and sputum) (cluster 5, n=52). Cluster 1 included elderly patients with severe symptoms, while cluster 3 included young female with mild symptoms. No significant differences were observed in the comorbidities. Cluster 1 showed the most impaired QOL, followed by clusters 4 and 5; these changes as well as the composition of symptoms were observed over 1 year.Conclusions We identified patients with long COVID with diverse characteristics into five clusters. Future analysis of these different pathologies could result in individualised treatment of long COVID.Trial registration number The study protocol is registered at UMIN clinical trials registry (UMIN000042299).

Key Clinical Message Ochrobactrum anthropi (O. anthropi), a rare opportunistic pathogen, caused sepsis in a malnourished 15‐month‐old African child. Early detection and appropriate antibiotics led to full recovery, highlighting the importance of robust surveillance for emerging pathogens in vulnerable populations. Abstract While rarely causing infections, O. anthropi, a non‐fermenting, obligately aerobic, flagellated gram‐negative bacillus, demonstrates oxidase positivity and indole negativity. Traditionally, Ochrobactrum spp is considered a low threat due to its environmental abundance and mild virulence. It is, however, a multidrug‐resistant bacteria known for causing opportunistic infections in humans. O. anthropi is typically associated with catheter‐related bloodstream infections. The first documented case was in 1998; most cases have been reported in developed countries. We present a case of O. anthropi sepsis in a malnourished child in sub‐Saharan Africa. We report a case involving a 15‐month‐old African female who presented with symptoms and signs of protein‐energy malnutrition and sepsis. The blood culture revealed O.anthropi. We treated the child with the empirical first‐line antibiotics per the national guidelines, intravenous ampicillin and gentamicin for a week, and the child fully recovered. This report describes a rare case of O. anthropi sepsis with malnutrition in an African female child. O. anthropi is an emerging pathogen causing opportunistic infections in both immunocompetent and immunocompromised patients. We report that early bacterial detection, appropriate antibiotic susceptibility and antimicrobial management based on local antibiogram data may be essential for excellent patient outcomes. Additionally, we recommend more robust surveillance to detect such rare emerging pathogens.

We present a genome assembly from an individual male Platypus cylindrus (the oak pinhole borer; Arthropoda; Insecta; Coleoptera; Curculionidae). The genome sequence is 147.5 megabases in span. Most of the assembly is scaffolded into 8 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 19.29 kilobases in length. Gene annotation of this assembly on Ensembl identified 13,468 protein coding genes.

Abstract Ramucirumab plus docetaxel (RD) can cause febrile neutropenia (FN), which frequently requires the prophylactic administration of pegfilgrastim. However, the effects of prophylactic pegfilgrastim on FN prevention, therapeutic efficacy, and prognosis after RD have not been fully evaluated in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred and eighty-eight patients with advanced NSCLC who received RD as second-line therapy after platinum-based chemotherapy plus PD-1 blockade were included. Patients were divided into groups with and without prophylactic pegfilgrastim, and adverse events, efficacy, and prognosis were compared between both groups. Of the 288 patients, 247 received prophylactic pegfilgrastim and 41 did not. The frequency of grade 3/4 neutropenia was 62 patients (25.1%) in the pegfilgrastim group and 28 (68.3%) in the control group (p

Abstract Circulation of SARS-CoV-2 Omicron XBB has resulted in the emergence of XBB.1.5, a new Variant of Interest. Our phylogenetic analysis suggests that XBB.1.5 evolved from XBB.1 by acquiring the S486P spike (S) mutation, subsequent to the acquisition of a nonsense mutation in ORF8. Neutralization assays showed similar abilities of immune escape between XBB.1.5 and XBB.1. We determine the structural basis for the interaction between human ACE2 and the S protein of XBB.1.5, showing similar overall structures between the S proteins of XBB.1 and XBB.1.5. We provide the intrinsic pathogenicity of XBB.1 and XBB.1.5 in hamsters. Importantly, we find that the ORF8 nonsense mutation of XBB.1.5 resulted in impairment of MHC suppression. In vivo experiments using recombinant viruses reveal that the XBB.1.5 mutations are involved with reduced virulence of XBB.1.5. Together, our study identifies the two viral functions defined the difference between XBB.1 and XBB.1.5.

Abstract Background Which patients benefit from the addition of immune checkpoint inhibitors (ICIs) to chemotherapy for small cell lung cancer (SCLC) remains unclear. There have been few reports on the efficacy of ICIs based on conventional immunohistochemical neuroendocrine (NE) markers (synaptophysin, chromogranin A, and neural cell adhesion molecule [NCAM]). In the present study, we aimed to analyze the relationship between the expression of immunohistochemical NE markers and the efficacy of ICIs in patients with extensive disease (ED)‐SCLC, to assess whether conventional NE markers are predictive of ICIs. Methods Patients with untreated ED‐SCLC who received first‐line therapy at the Shizuoka Cancer Center between November 2002 and July 2021 were retrospectively reviewed. We evaluated the efficacy of first‐line chemotherapy according to the expression status of each immunohistochemical NE marker in patients treated with ICI plus chemotherapy (ICI‐chemo group) and with chemotherapy alone (chemo group). Results A total of 227 patients were included in the ICI‐chemo and chemo groups, respectively. The progression‐free survival (PFS) tended to be better in patients in the ICI‐chemo group than those treated with chemotherapy alone in patients with NE marker‐positive SCLC. In particular, it was statistically significant in patients with chromogranin A‐positive SCLC (p = 0.036). In patients with NE marker‐negative SCLC, no significant differences were observed in PFS between the two groups. There were no significant differences in overall survival (OS), regardless of the expression of any conventional NE marker. Conclusion Our study suggests that the efficacy of ICIs in addition to chemotherapy may be poor in patients with NE marker‐negative SCLC.

We report the publication of 953 DNA barcodes of forest leaf litter beetles from central Taiwan, in total representing 334 species of 36 beetle families. This is the first bulk of data from the Taiwanese Leaf Litter beetles project focused on uncovering the under-explored diversity of leaf litter beetles across Taiwan. Based on these data, we provide the first records of the following taxa for Taiwan: family Sphindidae (genus Aspidiphorus Ziegler, 1821); tribes Trichonychini, Ctenistini, and Bythinoplectini (all Staphylinidae: Pselaphinae); genera Gyrelon Hinton, 1942, Thyroderus Sharp, 1885, Cautomus Sharp, 1885 (all Cerylonidae), Dermatohomoeus Hlisnikovský, 1963 (Leiodidae), Paraploderus Herman, 1970 (Staphylinidae: Oxytelinae), Thinocharis Kraatz, 1859 (Staphylinidae: Paederinae), Cephennodes Reitter, 1884, Napoconnus Franz, 1957 (both Staphylinidae: Scydmaeninae), Bicava Belon, 1884 (Latridiidae), Otibazo Morimoto, 1961, Seleuca Pascoe, 1871 and Acallinus Morimoto, 1962 (all Curculionidae); species Oodes (Lachnocrepis) japonicus (Bates, 1873) (Carabidae: Licininae), Drusilla obliqua (Bernhauer, 1916) (Staphylinidae: Aleocharinae) and Coccotrypes advena Blandford, 1894 (Curculionidae: Scolytinae). The records of Anapleus Horn, 1873 (Histeridae) and Batraxis Reitter, 1882 (Staphylinidae: Pselaphinae) have been confirmed. The male of Sivacrypticus taiwanicus Kaszab, 1964 (Archeocrypticidae) is described for the first time. Gyrelon jenpani Hu, Fikáček & Matsumoto, sp. nov. (Cerylonidae) is described, illustrated, and compared with related species. DNA barcodes associated larvae of 42 species with adults, we are concisely illustrating some of these: Oodes japonicus, Perigona cf. nigriceps Dejean, 1831 (both Carabidae), Ptilodactyla sp. (Ptilodactylidae), Maltypus ryukyuanus Wittmer, 1970 (Cantharidae), Drusilla obliqua, Myrmecocephalus brevisulcus (Pace, 2008), Diochus sp., Mimopinophilus sp. (all Staphylinidae), Stelidota multiguttata Reitter, 1877, Lasiodites inaequalis (Grouvelle, 1914) (both Nitidulidae), Lagria scutellaris Pic, 1910, and Anaedus spinicornis Kaszab, 1973 (both Tenebrionidae). We also report the first cases of Rickettsia infections in Scydmaeninae and Pselaphinae. All data (sequences, metadata, and voucher photos) are made public in BOLD database and in a Zenodo Archive.

Abstract Background The factors that predict the clinical response to ramucirumab plus docetaxel (RD) after first‐line chemoimmunotherapy are unresolved. We explored whether the therapeutic efficacy of prior chemoimmunotherapy could predict the outcome of RD as sequential therapy in patients with advanced non‐small cell lung cancer (NSCLC). Methods Our study comprised 288 patients with advanced NSCLC who received RD as the second‐line treatment after first‐line chemoimmunotherapy at 62 Japanese institutions. Chemoimmunotherapy consisted of a platinum‐based regimen and immune checkpoint inhibitors (ICIs). The association between several variables and the therapeutic outcome of RD was determined via logistic regression analysis. Results Of the 288 patients, 225 (78.1%) received maintenance therapy and 108 (37.5%) received both ICI treatment for >180 days and maintenance therapy. All of 108 patients having ICIs for >180 days received maintenance therapy. Univariate analysis identified performance status, histology (adenocarcinoma), maintenance therapy, and ICI treatment >180 days as significant predictors of better progression‐free survival (PFS) and overall survival (OS) after RD administration. Multivariate analysis confirmed that these factors independently predicted favorable PFS and OS. The therapeutic response and PD‐L1 expression were not closely associated with outcome after RD treatment. In particular, maintenance therapy >4 cycles was more predictive of the better prognosis for RD treatment. Conclusion Extended ICI treatment after chemoimmunotherapy and maintenance therapy enhanced the efficacy of second‐line RD treatment in patients with advanced NSCLC.

Abstract Background The study introduces the application of negative pressure wound therapy (NPWT) in pediatric stoma closure, emphasizing the importance of enhancing aesthetics and minimizing surgical site infections (SSI). Case presentation The case series involves four infants undergoing non-umbilical stoma closure with a combination of purse-string closure (PSC) and NPWT, focusing on aesthetic outcomes and infection prevention. NPWT was initiated immediately after surgery, and patients were monitored every 3–4 days. Notably, none of the four infants experienced SSI or other complications. The patients adequately tolerated NPWT, with no significant adverse events. Furthermore, Manchester Scar Scale (MSS) was 9 [7–10], and Patient and Observer Scar Assessment Scale (POSAS) (observer) was 12.5 [12–19], POSAS (patient) was 12.5 [11–16] (all median values [minimum–maximum]), indicating that excellent aesthetic outcomes were achieved. Discussion We emphasizes the significance of aesthetics in pediatric patients; in addition, our findings demonstrate that four infants who received NPWT combined with PSC achieved superior outcomes that did the most recent four infants who underwent PSC only at our institution. It also addresses the risk of SSI in stoma closure and discusses the pros and potential cons of using NPWT in pediatric cases, underlining the need for further research and the accumulation of additional reports. Conclusions This is the inaugural report of prophylactic NPWT for pediatric stoma closure, emphasizing the effectiveness of combining PSC and NPWT for SSI prevention and improved aesthetics. The study calls for additional research and reports on NPWT in pediatric cases to further solidify its benefits in this patient population.

Abstract Background Accurate evaluation of tumor invasion depth is essential to determine the appropriate treatment strategy for patients with superficial esophageal cancer. The pretreatment tumor depth diagnosis currently relies on the magnifying endoscopic classification established by the Japan Esophageal Society (JES). However, the diagnostic accuracy of tumors involving the muscularis mucosa (MM) or those invading the upper third of the submucosal layer (SM1), which correspond to Type B2 vessels in the JES classification, remains insufficient. Previous retrospective studies have reported improved accuracy by considering additional findings, such as the size and macroscopic type of the Type B2 vessel area, in evaluating tumor invasion depth. Therefore, this study aimed to investigate whether incorporating the size and/or macroscopic type of the Type B2 vessel area improves the diagnostic accuracy of preoperative tumor invasion depth prediction based on the JES classification. Methods This multicenter prospective observational study will include patients diagnosed with MM/SM1 esophageal squamous cell carcinoma based on the Type B2 vessels of the JES classification. The tumor invasion depth will be evaluated using both the standard JES classification (standard-depth evaluation) and the JES classification with additional findings (hypothetical-depth evaluation) for the same set of patients. Data from both endoscopic depth evaluations will be electronically collected and stored in a cloud-based database before endoscopic resection or esophagectomy. This study’s primary endpoint is accuracy, defined as the proportion of cases in which the preoperative depth diagnosis matched the histological depth diagnosis after resection. Outcomes of standard- and hypothetical-depth evaluation will be compared. Discussion Collecting reliable prospective data on the JES classification, explicitly concerning the B2 vessel category, has the potential to provide valuable insights. Incorporating additional findings into the in-depth evaluation process may guide clinical decision-making and promote evidence-based medicine practices in managing superficial esophageal cancer. Trial registration This trial was registered in the Clinical Trials Registry of the University Hospital Medical Information Network (UMIN-CTR) under the identifier UMIN000051145, registered on 23/5/2023.

Abstract Background Amrubicin (AMR) regimens have shown efficacy as second‐line treatment in patients with small cell lung cancer (SCLC); however, adverse events such as febrile neutropenia (FN) sometimes preclude their use. Further, the safety and efficacy of AMR with primary prophylactic pegfilgrastim (P‐PEG) have not been sufficiently evaluated. In this study, we evaluated the safety and efficacy of AMR with or without P‐PEG as second‐line chemotherapy for SCLC. Methods We retrospectively reviewed patients with SCLC who received AMR as second‐line chemotherapy at Shizuoka Cancer Center, between December 2014 and November 2021. Based on presence/absence of P‐PEG in their regimen, patients (n = 60) were divided into P‐PEG (n = 21) and non‐P‐PEG groups, and their clinical outcomes were evaluated. Results Median of AMR treatment cycles was five (range: 1–39 cycles) in P‐PEG group and four (range: 1–15 cycles) in non‐P‐PEG group. The incidence of FN (4.8% vs. 30.8%; p = 0.02) and AMR dose reduction because of adverse events (4.8% vs. 25.6%; p = 0.08) were lower in the P‐PEG group than in the non‐P‐PEG group. The objective response rates were 52.4% and 30.8%, and median progression‐free and overall survival were 4.7 and 3.0 months, and 9.6 and 6.8 months, in the P‐PEG and non‐P‐PEG groups, respectively. Conclusions AMR with P‐PEG as second‐line chemotherapy for SCLC reduced the incidence of FN at a maintained AMR dose intensity and was associated with favorable tumor responses and survival outcomes. P‐PEG should be considered for patients treated with AMR for SCLC including refractory relapsed SCLC.

Abstract Oral lichen planus (OLP) is a chronic inflammatory disease associated with T cell infiltration. The crosstalk between oral epithelium and mucosal T cells was considered to be crucial in the pathogenesis of OLP. Here, we selectively extracted the normal epithelium (NE) and lesional epithelium (LE) of buccal mucosa specimens from three patients with OLP by laser capture microdissection due to identify the pathogenic factors. Cathepsin K (CTSK) was identified as one of common upregulated genes in the LE by DNA microarray. Immunohistochemically, CTSK was distinctly detected in and around the LE, while it was rarely seen in the NE. Recent studies showed that CTSK enhanced Toll-like receptor 9 (TLR9) signaling in antigen-presenting cells, leading to Th17 cell differentiation. TLR9 expression mainly co-localized with CD123+ plasmacytoid dendritic cells (pDCs). The number of RORγt-positive cells correlated with that of CTSK-positive cells in OLP tissues. CD123+ pDCs induced the production of Th17-related cytokines (IL-6, IL-23, and TGF-β) upon stimulation with TLR9 agonist CpG DNA. Moreover, single cell RNA-sequencing analysis revealed that TLR9-positive pDCs enhanced in genes associated with Th17 cell differentiation in comparison with TLR9-negative pDCs. CTSK could induce Th17-related production of CD123+ pDCs via TLR9 signaling to promote the pathogenesis of OLP.

Abstract Background In open thoracoabdominal aortic aneurysm (TAAA) repair, we have been performing vascular reconstruction under moderate to deep hypothermia and assisted circulation using simultaneous upper and lower body perfusion. This method is effective for protecting the spinal cord and the brain, heart, and abdominal organs and for avoiding lung damage. Methods TAAA repair was performed under hypothermia at 20–28 °C in 18 cases (Crawford type I in 0 cases, type II in 5, type III in 3, type IV in 4, and Safi V in 6) between October 2014 and January 2023. Cardiopulmonary bypass was conducted by combined upper and lower body perfusion, with perfusion both via the femoral artery and either transapically or via the descending aorta or the left brachial artery. Results The ischemic time for the artery of Adamkiewicz and the main segmental arteries was 40–124 min (75 ± 33 min). No spinal cord ischemic injury or brain or heart complications occurred. One patient with postoperative right renal artery occlusion and one with an infected aneurysm required tracheostomy, but the intubation time for the other 16 was 32 ± 33 h. The duration of postoperative intensive care unit stay was 6.5 ± 6.2 days, the length of hospital stay was 29 ± 15 days, and no in-hospital deaths occurred. Conclusions Simultaneous upper and lower body perfusion under moderate to deep hypothermia during thoracoabdominal aortic surgery may avoid not only spinal cord injury, but also cardiac and brain complications.

Abstract Kidney organoids have shown promise as evaluation tools, but their in vitro maturity remains limited. Transplantation into adult mice has aided in maturation; however, their lack of urinary tract connection limits long-term viability. Thus, long-term viable generated nephrons have not been demonstrated. In this study, we present an approachable method in which mouse and rat renal progenitor cells are injected into the developing kidneys of neonatal mice, resulting in the generation of chimeric nephrons integrated with the host urinary tracts. These chimeric nephrons exhibit similar maturation to the host nephrons, long-term viability with excretion and reabsorption functions, and cisplatin-induced renal injury in both acute and chronic phases, as confirmed by single-cell RNA-sequencing. Additionally, induced human nephron progenitor cells differentiate into nephrons within the neonatal kidneys. Collectively, neonatal injection represents a promising approach for in vivo nephron generation, with potential applications in kidney regeneration, drug screening, and pathological analysis.

Abstract Mosquitoes interact with various organisms in the environment, and female mosquitoes in particular serve as vectors that directly transmit a number of microorganisms to humans and animals by blood-sucking. Comprehensive analysis of mosquito-borne viruses has led to the understanding of the existence of diverse viral species and to the identification of zoonotic arboviruses responsible for significant outbreaks and epidemics. In the present study on mosquito-borne bunyaviruses we employed a broad-spectrum RT-PCR approach and identified eighteen different additional species in the Phenuiviridae family and also a number of related but unclassified bunyaviruses in mosquitoes collected in Zambia. The entire RNA genome segments of the newly identified viruses were further analyzed by RNA sequencing with a ribonuclease R (RNase R) treatment to reduce host-derived RNAs and enrich viral RNAs, taking advantage of the dsRNA panhandle structure of the bunyavirus genome. All three or four genome segments were identified in eight bunyavirus species. Furthermore, L segments of three different novel viruses related to the Leishbunyaviridae were found in mosquitoes together with genes from the suspected host, the Crithidia parasite. In summary, our virus detection approach using a combination of broad-spectrum RT-PCR and RNA sequencing analysis with a simple virus enrichment method allowed the discovery of novel bunyaviruses. The diversity of bunyaviruses is still expanding and studies on this will allow a better understanding of the ecology of hematophagous mosquitoes.

Vehicular Ad Hoc Networks (VANETs) have gained significant attention due to their potential to enhance road safety, traffic efficiency, and passenger comfort through vehicle-to-vehicle and vehicle-to-infrastructure communication. However, VANETs face resource management challenges due to the dynamic and resource constrained nature of vehicular environments. Integrating cloud-fog-edge computing and Software-Defined Networking (SDN) with VANETs can harness the computational capabilities and resources available at different tiers to efficiently process and manage vehicular data. In this work, we used this paradigm and proposed an intelligent approach based on Fuzzy Logic (FL) to evaluate the processing and storage capability of vehicles for helping other vehicles in need of additional resources. The effectiveness of the proposed system is evaluated through extensive simulations and a testbed. Performance analysis between the simulation results and the testbed offers a comprehensive understanding of the proposed system and its performance and feasibility.

Abstract Background The ALTA-1L study compared brigatinib with crizotinib in untreated ALK-rearranged non-small cell lung cancer (NSCLC) patients, demonstrating the efficacy of brigatinib. Although the median progression-free survival (PFS) of brigatinib group was 24.0 months, the one-year PFS rate was 70%. In the NEJ009 study, patients with EGFR mutations showed improved outcomes with gefitinib plus chemotherapy compared with gefitinib monotherapy. To evaluate the efficacy of the combination of brigatinib with chemotherapy for patients with ALK-rearranged NSCLC, we designed B-DASH study (WJOG 14720L). Methods B-DASH study is a multicenter, two-arm, phase II study. Eligible patients have untreated stage IIIB, stage IIIC, stage IV, or postoperative relapse ALK-rearranged nonsquamous NSCLC. Patients will be randomized in a 1:1 ratio to receive brigatinib (180 mg once daily with a 7-day lead-in period at 90 mg) monotherapy or carboplatin (area under the curve = 5 on day 1) plus pemetrexed (500 mg/m2 on day 1) and brigatinib in a 3-week cycle for up to four cycles, followed by pemetrexed and brigatinib as maintenance therapy. The target hazard ratio of 0.62 is set based on the NEJ009 study. With one-sided alpha = 0.20 and power = 0.8, the sample size for the B-DASH study was calculated to be 110, considering the possibility of patients dropping out. The primary endpoint is PFS. The key secondary endpoints are the overall response rate and overall survival. We will evaluate tumor-derived DNA from plasma specimens before treatment, 42 days after administering the study drug, and on the day of progressive disease. Recruitment began in November 2021 and is ongoing. Discussion The efficacy of combination therapy with tyrosine kinase inhibitors and cytotoxic chemotherapy was demonstrated in patients with EGFR mutations but remains unclear in patients with ALK-rearranged NSCLC. The B-DASH study is the only trial of brigatinib combined with chemotherapy in patients with untreated ALK-rearranged NSCLC. Trial registration jRCT identifier: jRCTs041210103.

Abstract Refining out-of-hospital cardiopulmonary arrest (OHCA) resuscitation protocols for local emergency practices is vital. The lack of comprehensive evaluation methods for individualized protocols impedes targeted improvements. Thus, we employed machine learning to assess emergency medical service (EMS) records for examining regional disparities in time reduction strategies. In this retrospective study, we examined Japanese EMS records and neurological outcomes from 2015 to 2020 using nationwide data. We included patients aged ≥ 18 years with cardiogenic OHCA and visualized EMS activity time variations across prefectures. A five-layer neural network generated a neurological outcome predictive model that was trained on 80% of the data and tested on the remaining 20%. We evaluated interventions associated with changes in prognosis by simulating these changes after adjusting for time factors, including EMS contact to hospital arrival and initial defibrillation or drug administration. The study encompassed 460,540 patients, with the model’s area under the curve and accuracy being 0.96 and 0.95, respectively. Reducing transport time and defibrillation improved outcomes universally, while combining transport time and drug administration showed varied efficacy. In conclusion, the association of emergency activity time with neurological outcomes varied across Japanese prefectures, suggesting the need to set targets for reducing activity time in localized emergency protocols.

IntroductionThe literature suggests that people can accurately infer dark triad (DT) personality traits from other peoples’ faces. Using a self-report scale, this study investigated the impact of participants’ DT personality traits on their ability to accurately infer other peoples’ DT traits from facial cues.MethodsWe created composite facial photographs of Japanese people with varying Machiavellianism, psychopathy, and narcissism scores. The Japanese participants (N = 170) assessed these three DT traits in the facial photographs and completed a questionnaire that assessed their own DT traits.ResultsThe results indicated that the participants could accurately infer all three DT traits from female faces but not from male faces. Male participants showed a positive correlation between accurate inferences of other men’s Machiavellianism and their own DT traits. In contrast, female participants showed a negative correlation between correct inferences of men’s DT traits and their own DT traits.DiscussionThese findings offer novel insights into human evolutionary and social adaptations.

The high prevalence of obesity has become a pressing global public health problem and there exists a strong association between increased BMI and mortality at a BMI of 25 kg/m2 or higher. The prevalence of obesity is higher among middle-aged adults than among younger groups and the combination of aging and obesity exacerbate systemic inflammation. Increased inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha (TNFα) are hallmarks of obesity, and promote the secretion of hepatic C-reactive protein (CRP) which further induces systematic inflammation. The neuropeptide oxytocin has been shown to have anti-obesity and anti-inflammation effects, and also suppress sweet-tasting carbohydrate consumption in mammals. Previously, we have shown that the Japanese herbal medicine Kamikihito (KKT), which is used to treat neuropsychological stress disorders in Japan, functions as an oxytocin receptors agonist. In the present study, we further investigated the effect of KKT on body weight (BW), food intake, inflammation, and sweet preferences in middle-aged obese mice. KKT oral administration for 12 days decreased the expression of pro-inflammatory cytokines in the liver, and the plasma CRP and TNFα levels in obese mice. The effect of KKT administration was found to be different between male and female mice. In the absence of sucrose, KKT administration decreased food intake only in male mice. However, while having access to a 30% sucrose solution, both BW and food intake was decreased by KKT administration in male and female mice; but sucrose intake was decreased in female mice alone. In addition, KKT administration decreased sucrose intake in oxytocin deficient lean mice, but not in the WT lean mice. The present study demonstrates that KKT ameliorates chronic inflammation, which is strongly associated with aging and obesity, and decreases food intake in male mice as well as sucrose intake in female mice; in an oxytocin receptor dependent manner.

Without complete data on under-5 mortality, tracking progress towards achieving Sustainable Development Goal 3.2 will be challenging. Such data are also needed to ensure proper planning and prioritisation of scarce resources in low-income and middle-income countries. However, most low-income and middle-income countries have weak Civil Registration and Vital Statistics (CRVS) systems, leaving a critical gap in understanding under-5 mortality dynamics. This paper outlines a community-based approach to enhance under-5 mortality surveillance in low-income countries, using The Gambia as a case study. The methodology involves Health and Demographic Surveillance Systems (HDSSs) in Basse and Fuladu West, employing unique identification numbers, periodical household visits and collaboration with communities, village reporters and project field workers to ensure comprehensive data collection. Verbal autopsies (VAs) are conducted by trained field workers, and causes of death are determined using the physician-certified VA method. Between 1 September 2019 and 1 September 2023, 1333 deaths were detected, for which causes of death were determined for 97.1% (1294 of 1333). The most common causes of death detected were acute respiratory infections including pneumonia, sepsis, diarrhoeal diseases and birth asphyxia. Challenges include the cost of maintaining the HDSSs, poor road infrastructure, Electronic Data Capture transition challenges, and the need for national integration of HDSS data into the CRVS system. The success of this model highlights its potential for scalable and adaptable under-5 mortality surveillance in resource-limited settings.

This study analyzed a social problem-solving workation in Kamaishi, Japan, focusing on the “hitohada nugu” experience, a cross-boundary and other-oriented contribution and relationship-building experience. The results of interviews with stakeholders of the work experience, including company managers and participants, intermediaries in the host local community, and government officials, as well as a questionnaire survey of all participants, indicated that employees who participated in the program learned and grew through their inexperience in Kamaishi, which was different from their work experience. On the other hand, the local community and companies that plan and operate the program face a dilemma in explaining the effects of the workation on the company's business, the solution to local issues, and the learning and growth of employees.

IntroductionThe severe acute respiratory syndrome coronavirus (SARS-CoV-2) spike (S) protein is essential in mediating membrane fusion of the virus with the target cells. Several reports demonstrated that SARS-CoV-2 S protein fusogenicity is reportedly closely associated with the intrinsic pathogenicity of the virus determined using hamster models. However, the association between S protein fusogenicity and other virological parameters remains elusive.MethodsIn this study, we investigated the virological parameters (e.g., S1/S2 cleavage efficiency, plaque size, pseudoviral infectivity, pseudovirus entry efficiency, and viral replication kinetics) of eleven previous variants of concern (VOCs) and variants of interest (VOIs) correlating with S protein fusogenicity.Results and discussionS protein fusogenicity was found to be strongly correlated with S1/S2 cleavage efficiency and plaque size formed by clinical isolates. However, S protein fusogenicity was less associated with pseudoviral infectivity, pseudovirus entry efficiency, and viral replication kinetics. Taken together, our results suggest that S1/S2 cleavage efficiency and plaque size could be potential indicators to predict the intrinsic pathogenicity and S protein fusogenicity of newly emerged SARS-CoV-2 variants.

Emerging and reemerging tick-borne virus infections caused by orthonairoviruses (family Nairoviridae), which are genetically distinct from Crimean-Congo hemorrhagic fever virus, have been recently reported in East Asia. Here, we have established a mouse infection model using type-I/II interferon receptor-knockout mice (AG129 mice) both for a better understanding of the pathogenesis of these infections and validation of antiviral agents using Yezo virus (YEZV), a novel orthonairovirus causing febrile illnesses associated with tick bites in Japan and China. YEZV-inoculated AG129 mice developed hepatitis with body weight loss and died by 6 days post infection. Blood biochemistry tests showed elevated liver enzyme levels, similar to YEZV-infected human patients. AG129 mice treated with favipiravir survived lethal YEZV infection, demonstrating the anti-YEZV effect of this drug. The present mouse model will help us better understand the pathogenicity of the emerging tick-borne orthonairoviruses and the development of specific antiviral agents for their treatment.

We present a genome assembly from an individual male Bruchidius siliquastri (the Judas tree Seed Beetle; Arthropoda; Insecta; Coleoptera; Chrysomelidae). The genome sequence is 375.6 megabases in span. Most of the assembly is scaffolded into 11 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 15.81 kilobases in length. Gene annotation of this assembly on Ensembl identified 17,940 protein coding genes.

Objectives The present study clarified the prevalence of poor sleep quality and its relation to lifestyle habits, competitive-based activities, and psychological distress among Japanese student-athletes in the initial pandemic period (2020) and 1 year later (2021).

Abstract Many arthropods harbour bacterial symbionts, which are maintained by vertical and/or horizontal transmission. Spiroplasma is one of the most well-known symbionts of ticks and other arthropods. It is still unclear how Spiroplasma infections have spread in tick populations despite its high prevalence in some tick species. In this study, Ixodes ovatus, which has been reported to harbour Spiroplasma ixodetis at high frequencies, was examined for its vertical transmission potential under experimental conditions. Next, two isolates of tick-derived Spiroplasma, S. ixodetis and Spiroplasma mirum, were experimentally inoculated into Spiroplasma-free Haemaphysalis longicornis colonies and the presence of Spiroplasma in their eggs and larvae was tested. Our experimental data confirmed that S. ixodetis was transmitted to eggs and larvae in a vertical manner in the original host I. ovatus. In the second experiment, there was no significant difference in engorged weight, egg weight, and hatching rate between Spiroplasma-inoculated and control H. longicornis groups. This suggested that Spiroplasma infection does not affect tick reproduction. Spiroplasma DNA was only detected in the eggs and larvae derived from some individuals of S. ixodetis-inoculated groups. This has demonstrated the potential of horizontal transmission between different tick species. These findings may help understand the transmission dynamics of Spiroplasma in nature and its adaptation mechanism to host arthropod species.

Abstract Rational design of self-assembled DNA nanostructures has become one of the fastest-growing research areas in molecular science. Particular attention is focused on the development of dynamic DNA nanodevices whose configuration and function are regulated by specific chemical inputs. Herein, we demonstrate the concept of metal-mediated base-pair switching to induce inter- and intramolecular DNA strand displacement in a metal-responsive manner. The 5-hydroxyuracil (U OH ) nucleobase is employed as a metal-responsive unit, forming both a hydrogen-bonded U OH –A base pair and a metal-mediated U OH –GdIII–U OH base pair. Metal-mediated strand displacement reactions are demonstrated under isothermal conditions based on the base-pair switching between U OH –A and U OH –GdIII–U OH . Furthermore, metal-responsive DNA tweezers and allosteric DNAzymes are developed as typical models for DNA nanodevices simply by incorporating U OH bases into the sequence. The metal-mediated base-pair switching will become a versatile strategy for constructing stimuli-responsive DNA nanostructures, expanding the scope of dynamic DNA nanotechnology.

Abstract The unremitting emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants necessitates ongoing control measures. Given its rapid spread, the new Omicron subvariant BA.5 requires urgent characterization. Here, we comprehensively analyzed BA.5 with the other Omicron variants BA.1, BA.2, and ancestral B.1.1. Although in vitro growth kinetics of BA.5 was comparable among the Omicron subvariants, BA.5 was much more fusogenic than BA.1 and BA.2. Airway-on-a-chip analysis showed that, among Omicron subvariants, BA.5 had enhanced ability to disrupt the respiratory epithelial and endothelial barriers. Furthermore, in our hamster model, in vivo pathogenicity of BA.5 was slightly higher than that of the other Omicron variants and less than that of ancestral B.1.1. Notably, BA.5 gains efficient virus spread compared with BA.1 and BA.2, leading to prompt immune responses. Our findings suggest that BA.5 has low pathogenicity compared with the ancestral strain but enhanced virus spread /inflammation compared with earlier Omicron subvariants.

Background This study aimed to clarify the details of outpatient cancer rehabilitation provided by designated cancer hospitals in Japan. Materials and Methods Questionnaires were sent to 427 designated cancer hospitals in Japan. We surveyed whether outpatient rehabilitation was provided, including detailed content, such as intervention time and frequency, Dietz classification, cancer type, and intervention content. Results Responses were obtained from 235 (55.0%) surveyed facilities, of which 92 (39.1%) facilities provided outpatient cancer rehabilitation. Outpatient cancer rehabilitation was mainly provided for 20–40 minutes per session, 1–2 times per week, for the Dietz classification of restorative, supportive, and preventive phases. Breast cancer was the most common cancer type, followed by lung, colorectal, and stomach. The implementation rate of head and neck cancer and bone and soft tissue sarcoma was significantly higher at university hospitals and cancer centers than at general hospitals (P < 0.01). Resistance training was the most common intervention, followed by range of motion exercise, pulmonary rehabilitation, and support for lymphedema; and the frequency of pulmonary rehabilitation was significantly higher in general hospitals than in university hospitals (P < 0.05). Conclusions Outpatient cancer rehabilitation in Japan is less prevalent than that in inpatient settings. Many facilities provide interventions for shoulder joint dysfunction and lymphedema after breast cancer surgery, as well as prehabilitation and postoperative recovery for lung and gastrointestinal cancer. It is expected that rehabilitation tailored to each facility’s characteristics and verification of its effectiveness will contribute to its diffusion and development.

Abstract Introduction Cisplatin plus pemetrexed followed by pemetrexed is an efficacious platinum combination regimen for advanced non‐squamous, non‐small cell lung cancer (NSCLC). Data regarding the addition of bevacizumab, especially in maintenance treatment, are insufficient. Methods Eligibility criteria included: no prior chemotherapy; advanced, non‐squamous, NSCLC; performance status ≤1; and epidermal growth factor receptor mutation‐negative. Patients (N = 108) received induction chemotherapy with cisplatin, pemetrexed, and bevacizumab every 3 weeks for four cycles, and tumor response was needed to confirm four‐week response duration. Patients with at least stable disease were randomized to pemetrexed/bevacizumab or pemetrexed alone. The primary endpoint was progression‐free survival (PFS) after induction chemotherapy. Myeloid‐derived suppressor cell (MDSC) counts of peripheral blood samples were also analyzed. Results Thirty‐five patients each were randomized to the pemetrexed/bevacizumab group and the pemetrexed alone group. PFS was significantly better in the pemetrexed/bevacizumab group than in the pemetrexed alone group (7.0 vs. 5.4 months, hazard ratio: 0.56 [0.34–0.93], log‐rank p = 0.023). In patients with partial response to induction therapy, median overall survival was 23.3 months in the pemetrexed alone group and 29.6 months in the pemetrexed/bevacizumab group (log‐rank p = 0.077). Pretreatment monocytic (M)‐MDSC counts tended to be greater in the pemetrexed/bevacizumab group with poor PFS than in those with good PFS (p = 0.0724). Conclusions Addition of bevacizumab to pemetrexed as maintenance therapy prolonged PFS in patients with untreated, advanced, non‐squamous NSCLC. Furthermore, an early response to induction therapy and pretreatment M‐MDSC counts may be related to the survival benefit of the addition of bevacizumab to the combination of cisplatin and pemetrexed.

Abstract Background Cancer cachexia is a syndrome that does not fully recover with nutritional support and causes appetite loss and body weight loss. It worsens a patient's quality of life and prognosis. In this study, the epidemiology of cachexia in lung cancer, its risk factors and its impact on chemotherapy response rate and prognosis were examined using the national database of the Japan Lung Cancer Society. Understanding these things related to cancer cachexia is important as a starting point in overcoming cancer cachexia in patients with lung cancer. Methods In 2012, 12 320 patients from 314 institutions in Japan were registered in a nationwide registry database (Japanese Lung Cancer Registry Study). Of these, data on body weight loss within 6 months were available for 8489 patients. We defined the patients with body weight loss ≥ 5% within 6 months, which is one of the three criteria listed in the 2011 international consensus definition of cancer cachexia, as cachectic in this study. Results Approximately 20.4% of the 8489 patients had cancer cachexia. Sex, age, smoking history, emphysema, performance status, superior vena cava syndrome, clinical stage, site of metastasis, histology, epidermal growth factor receptor (EGFR) mutation status, primary treatment method and serum albumin levels were significantly different between patients with and without cachexia. Logistic analyses showed that smoking history, emphysema, clinical stage, site of metastasis, histology, EGFR mutation, serum calcium and albumin levels were significantly associated with cancer cachexia. The response to initial therapy, including chemotherapy, chemoradiotherapy or radiotherapy, was significantly poorer in the patients with cachexia than in those without cachexia (response rate: 49.7% vs. 41.5%, P