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Simple Summary: Multilevel societies are the most complex social structures in animals. They are social structures with nested levels of social organization, where stable "core units" gather to form higher-level groups. Such multiple-unit groups usually become very large (usually 100–1000 individuals), making it difficult to conduct observations. Most previous studies lack numerical definitions and descriptions; thus, it is largely unknown how and why animals, including humans, form multilevel societies. Aerial observation from unmanned aerial vehicles (drones) is a powerful method of capturing the spatial structures and movements of large animal groups. Recent advances in drone technology and its application have led to new discoveries, such as the spatial structure of multiunit groups and the underlying mechanisms of collective behavior. We review how previous studies have utilized drones and how drone applications have contributed to the understanding of multilevel societies. We will further discuss the potential opportunities and challenges with regard to drone observations in future studies. Unmanned aerial vehicles (drones) have recently been used in various behavioral ecology studies. However, their application has been limited to single groups, and most studies have not implemented individual identification. A multilevel society refers to a social structure in which small stable "core units" gather and make a larger, multiple-unit group. Here, we introduce recent applications of drone technology and individual identification to complex social structures involving multiple groups, such as multilevel societies. Drones made it possible to obtain the identification, accurate positioning, or movement of more than a hundred individuals in a multilevel social group. In addition, in multilevel social groups, drones facilitate the observation of heterogeneous spatial positioning patterns and mechanisms of behavioral propagation, which are different from those in a single-level group. Such findings may contribute to the quantitative definition and assessment of multilevel societies and enhance our understanding of mechanisms of multiple group aggregation. The application of drones to various species may resolve various questions related to multilevel societies. [ABSTRACT FROM AUTHOR]

Key Clinical Message: A rare missense mutation was identified as a reversion mutation using cancer genomic profiling and a suspected mechanism underlying resistance to olaparib in breast cancer. A 34‐year‐old woman with breast cancer and BRCA2: p.Gln3047Ter was treated with olaparib. After tumor progression, cancer genomic profiling testing using liquid biopsy revealed BRCA2 p.Gln3047Ter and p.Gln3047Tyr, with 48.9% and 0.37% allele frequency, respectively. These findings shed light on reversion mutation as a mechanism of resistance to olaparib in breast cancer. [ABSTRACT FROM AUTHOR]

To reconstruct the historical trend of lake productivity and trophic status in mountain lakes over the past 60 years, we examined the diatom and cladoceran zooplankton remains, fossil pigments, and organic geochemical proxies in a sediment core from Lake Yamanaka, Japan. The fluxes of fossil pigments and total diatom valves, as well as diatom assemblages, did not show any marked changes from the 1960s to the mid-1970s, suggesting that the anthropogenic nutrient input was insufficient for changing the lake trophic status, despite the increased anthropogenic activities around the lake along with the concurrent rapid economic growth in Japan. After the 1990s, the increased fluxes of fossil pigments and percentage of eutrophic diatom species were suggestive of nutrient enrichment in the lake water. After the late 1990s, the stable nitrogen isotope ratios of bulk sediment (δ15Nbulk) gradually decreased with concurrent increases in the total nitrogen (TN) flux, thereby suggesting enhanced atmospheric nutrient deposition. In addition, the reconstructed Chl-a flux considered for post-burial degradation was significantly positively correlated with the summer surface water temperature since 2006. These findings suggest that, in recent decades, not only the anthropogenic nutrient loadings, but also climate warming might have significantly affected the eutrophication in Lake Yamanaka. [ABSTRACT FROM AUTHOR]

Granulomatous mastitis (GM) is a rare disease, particularly among men. Herein, we present a case of GM diagnosed in a 63‐year‐old male patient who showed reduction in the tumor size during 3 months of observation. [ABSTRACT FROM AUTHOR]

Yamaguchi et al. summarized pioneering studies using I Drosophila i models that linked ALS and CMT to epigenetic regulation associated with post-translational histone modifications and noncoding RNAs [[8]]. Indeed, the authors discuss that genetic approaches using I Drosophila i models identified several epigenetic regulators as important modifiers of phenotypes seen in ALS and CMT model flies. Further characterization of these factors in relation to these diseases would be an important future direction, not only for ALS and CMT research but also for studies related to other types of neurological and neurodegenerative disorders. The fruit fly I Drosophila melanogaster i is a highly tractable animal model to study various human diseases [[1]]. [Extracted from the article]

Background: Aureobasidium melanigenum is a ubiquitous dematiaceous fungus that rarely causes invasive human infections. Here, we present a case of Aureobasidium melanigenum bloodstream infection in a 20-year-old man with long-term catheter use.Case Presentation: A 20-year-old man receiving home care with severe disabilities due to cerebral palsy and short bowel syndrome, resulting in long-term central venous catheter use, was referred to our hospital with a fever. After the detection of yeast-like cells in blood cultures on day 3, antifungal therapy was initiated. Two identification tests performed at a clinical microbiological laboratory showed different identification results: Aureobasidium pullulans from matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and Cryptococcus albidus from a VITEK2 system. Therefore, we changed the antifungal drug to liposomal amphotericin B. The fungus was identified as A. melanigenum by DNA sequence-based analysis. The patient recovered with antifungal therapy and long-term catheter removal.Conclusion: It is difficult to correctly identify A. melanigenum by routine microbiological testing. Clinicians must pay attention to the process of identification of yeast-like cells and retain A. melanigenum in cases of refractory fungal infection. [ABSTRACT FROM AUTHOR]

In this review, we propose that the social dynamics of founder populations in novel and newly available environments can have critical effects in shaping species' sociality and can produce long‐lasting changes in social structure and behavior. For founder populations which expand into an underexploited niche separated from the parent population, the necessity of bond formation with strangers, lack of clear territories, and initial abundance of resources can lead to altered initial social dynamics to which subsequent generations adapt. We call this the founder sociality hypothesis. After specifying the theoretical reasoning and mechanism of effect, we focus on three particular cases where the social dynamics of founder populations may have a central role in explaining their modern behavioral ecology. In particular, we develop and review evidence for three predictions of the founder sociality hypothesis in territorial, mixed‐sex group forming species: relatively stronger social bonds in the dispersing sex with relatively weaker bonds in the nondispersing sex, reduced territoriality, and increased social tolerance. We briefly touch on the implications for human evolution given our species' evolutionary history marked by frequent expansion and adaptation to novel environments. We conclude by proposing several experiments and models with testable predictions following from the founder sociality hypothesis. [ABSTRACT FROM AUTHOR]

Background: We aimed to establish an external validation of the Briganti 2019 nomogram in a Japanese cohort to preoperatively evaluate the probability of lymph node invasion in patients with high-risk, clinically localized prostate cancer. Methods: The cohort consisted of 278 patients with prostate cancer diagnosed using magnetic resonance imaging-targeted biopsy who underwent radical prostatectomy and extended pelvic lymph node dissection from 2012 to 2020. Patients were rated using the Briganti 2019 nomogram, which evaluates the probability of lymph node invasion. We used the area under curve of the receiver operating characteristic analysis to quantify the accuracy of the nomogram. Results: Nineteen (6.8%) patients had lymph node invasion. The median number of lymph nodes removed was 18. The area under the curve for the Briganti 2019 was 0.71. When the cutoff was set at 7%, 84 (30.2%) patients with extended pelvic lymph node dissection could be omitted, and only 1 (1.2%) patient with lymph node invasion would be missed. Sensitivity, specificity, and negative predictive values at the 7% cutoff were 94.7, 32.0, and 98.8%, respectively. Conclusion: This external validation showed that the Briganti 2019 nomogram was accurate, although there may still be scope for individual adjustments. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is a leading cause of severe respiratory illness worldwide, particularly in infants and older adults. Vaccines targeting the fusion glycoprotein (F protein) —one of the surface antigens of RSV— are highly effective in preventing RSV-associated severe lower respiratory tract disease. However, the efficacy of these vaccines against upper respiratory tract challenge needs improvement. Here, we aimed to examine the efficacy of F protein vaccines with or without CpG oligodeoxynucleotide (CpG ODN) as an adjuvant in the upper and lower respiratory tracts in mice. F + CpG ODN induced higher levels of F-specific IgG than that induced by F alone; however, levels of neutralizing antibodies did not increase compared to those induced by F alone. F + CpG ODN induced T helper 1 (Th1) cells while F alone induced T helper 2 (Th2) cells. Moreover, F + CpG ODN improved the protection against RSV challenge in the upper respiratory tract compared to F alone, which was largely dependent on CD4+ T cells. Meanwhile, both F + CpG ODN and F alone protected the lower respiratory tract. In conclusion, we demonstrated that induction of F-specific Th1 cells is an effective strategy to prevent RSV challenge in the upper respiratory tract in F protein vaccines. These data support the development of novel F protein vaccines. • F protein vaccine efficacy in the upper respiratory tract (URT) needs improvement. • We examined the potential of CpG ODN to improve F protein efficacy in mice. • F + CpG ODN increases F-specific Th1 cells but not neutralizing antibody levels. • F + CpG ODN improves protection against RSV challenge in the URT. • CD4+ T cells help protect against RSV challenge in the URT. [ABSTRACT FROM AUTHOR]

In Japan, mowing work on ridges of farms that cultivate rice is difficult for farmers, especially in hilly and mountainous areas. Moreover, geographical information on ridges in paddy fields has not been prepared; such information includes the slope angle, the ridge area, and the ridge rate of the total paddy field area. This issue causes a level of uncertainty in management analysis in terms of labor costs, including mowing costs, particularly when farmers and agricultural corporations are starting or expanding farm businesses. Therefore, this research developed a method for creating planting area and ridge area polygons in paddy fields to measure the actual areas of both sites using slope angle information and calculating the ridge rates in paddy fields. This study adopts artificial intelligence, geographical information system (GIS), and precision digital elevation model techniques as strategy implementation tools with data prepared by an aerial laser survey of Nagano Prefecture. The model generated using the proposed machine learning tool can automatically detect the planting and ridge areas of paddy fields through aerial images of farmland with more than 96% accuracy. Then, polygons can be created for use in GIS. Furthermore, these polygons can be created for most of the understudied paddy fields, approximately 35 000 hectares throughout Nagano Prefecture, in only 2 to 3 weeks. Therefore, based on these techniques, the slope angles of ridges, the ridge areas, and the ridge rates of paddy areas can be measured through polygons. [ABSTRACT FROM AUTHOR]

In this review, we reorganize the concept and highlight the importance of prestige in humans and non-human animals by introducing key characteristics of dominance and prestige and related theories. Previous studies with non-human animals have mainly focused on dominance, presuming prestige as a human-unique social trait. However, to deepen our understanding of the evolution of prestige, comparative studies with non-human animals, especially our evolutionary closest relatives, chimpanzees and bonobos, are essential. We propose the direction of future studies to investigate how prestige has emerged as a viable strategy for gaining social rank while diverging from dominance, which will establish a foundation for investigating the impact of prestige on propensities towards large-scale cooperation and cumulative culture which are still considered unique to humans. Such comparative viewpoints on prestige, along with some hypotheses of species differences, will provide powerful guidance for understanding the evolution of social hierarchies. • Both dominance and prestige are utilized as a viable strategy for acquiring higher social rank in human social hierarchy. • In non-human animals, only dominance, but not prestige, has been assumed as a viable strategy for attaining social rank. • Exploring prestige-like traits in non-human animals may provide insights into the evolution of human social hierarchy. • We propose hypotheses about possible differences in prestige between chimpanzees and bonobos. [ABSTRACT FROM AUTHOR]

The number of clinical diagnoses of autism spectrum disorder (ASD) is increasing annually. Interestingly, the human body temperature has also been reported to gradually decrease over the decades. An imbalance in the activation of the excitatory and inhibitory neurons is assumed to be involved in the pathogenesis of ASD. Neurophysiological evidence showed that brain activity decreases as cortical temperature increases, suggesting that an increase in brain temperature enhances the inhibitory neural mechanisms. Behavioral characteristics specific to clinical ASD were observed to be moderated when people with the diagnoses had a fever. To explore the possible relationship between ASD and body temperature in the general population, we conducted a survey study using a large population-based sample (N ~ 2000, in the age groups 20s to 70s). Through two surveys, multiple regression analyses did not show significant relationships between axillary temperatures and autistic traits measured by questionnaires (Autism Spectrum (AQ) and Empathy/Systemizing Quotients), controlling for covariates of age and self-reported circadian rhythms. Conversely, we consistently observed a negative relationship between AQ and age. People with higher AQ scores tended to have stronger eveningness. Our findings contribute to the understanding of age-related malleability and the irregularity of circadian rhythms related to autistic traits. [ABSTRACT FROM AUTHOR]

Several studies have shown that horses have the ability to cross-modally recognize humans by associating their voice with their physical appearance. However, it remains unclear whether horses are able to differentiate humans according to different criteria, such as the fact that they are women or men. Horses might recognize some human characteristics, such as sex, and use these characteristics to classify them into different categories. The aim of this study was to explore whether domesticated horses are able to cross-modally recognize women and men according to visual and auditory cues, using a preferential looking paradigm. We simultaneously presented two videos of women and men's faces, while playing a recording of a human voice belonging to one of these two categories through a loudspeaker. The results showed that the horses looked significantly more towards the congruent video than towards the incongruent video, suggesting that they are able to associate women's voices with women's faces and men's voices with men's faces. Further investigation is necessary to determine the mechanism underlying this recognition, as it might be interesting to determine which characteristics horses use to categorize humans. These results suggest a novel perspective that could allow us to better understand how horses perceive humans. [ABSTRACT FROM AUTHOR]

Recently, research on domestic mammals' sociocognitive skills toward humans has been prolific, allowing us to better understand the human–animal relationship. For example, horses have been shown to distinguish human beings on the basis of photographs and voices and to have cross-modal mental representations of individual humans and human emotions. This leads to questions such as the extent to which horses can differentiate human attributes such as age. Here, we tested whether horses discriminate human adults from children. In a cross-modal paradigm, we presented 31 female horses with two simultaneous muted videos of a child and an adult saying the same neutral sentence, accompanied by the sound of an adult's or child's voice speaking the sentence. The horses looked significantly longer at the videos that were incongruent with the heard voice than at the congruent videos. We conclude that horses can match adults' and children's faces and voices cross-modally. Moreover, their heart rates increased during children's vocalizations but not during adults'. This suggests that in addition to having mental representations of adults and children, horses have a stronger emotional response to children's voices than adults' voices. [ABSTRACT FROM AUTHOR]

The Geriatric Nutritional Risk Index (GNRI) has been reported as a screening tool to assess the nutrition-related risk with mortality in older patients and those with the various diseases. However, the prognostic value of GNRI in metastatic renal cell carcinoma (mRCC) patients receiving nivolumab therapy remains unclear. Fifty-six consecutive patients with mRCC receiving nivolumab between September 2013 and August 2020 at our institution were retrospectively analyzed. The survival outcomes and prognostic factors associated with overall survival (OS) were statistically analyzed. Thirteen and forty-three patients were classified with low (GNRI < 92) and high (GNRI ≥ 92) GNRI, respectively. Patients with low GNRI demonstrated significantly shorter OS (P = 0.0002) than those with high GNRI. In multivariate analysis, GNRI at the time of nivolumab (P = 0.008) was extracted as the predictor for OS in addition to Karnofsky performance status (KPS) (P = 0.016). Integration of the GNRI into the International Metastatic Renal Cell Cancer Database Consortium (IMDC) risk classification improved the c-index from 0.761 to 0.833 (combination of GNRI with IMDC risk classification) and to 0.778 (substitution of GNRI with KPS in IMDC risk classification). GNRI was a significant prognostic biomarker in mRCC patients receiving nivolumab. [ABSTRACT FROM AUTHOR]

Background Cryptococcosis is a notable infectious complication of liver transplantation. Currently, there is no recommendation for screening serum cryptococcal antigen (CrAg) levels in solid organ transplant recipients. We aimed to explore the role of serum CrAg in liver transplant recipients at an institution where posttransplant serum CrAg has been widely tested. Methods This retrospective study was conducted at a tertiary care center in Japan. All liver transplant recipients with serum CrAg measured either for screening or for diagnostic testing at least once after transplantation between April 2005 and March 2022 were included. For participants with either a positive CrAg test result or positive culture for Cryptococcus , we manually reviewed clinical manifestations, management, and prognosis from the medical records. Results During the study period, 12 885 serum CrAg tests (median, 16 tests per patient) were performed in 468 liver transplant recipients. The 1-year posttransplant incidence of positive serum CrAg test results and culture-proven cryptococcosis was 1.9% (9/468) and 0.6% (3/468), respectively. No patient with persistently negative serum CrAg test results showed growth of Cryptococcus in culture. Four patients had clinical manifestations consistent with cryptococcosis, of whom 2 (50.0%) started antifungal therapy promptly based on a positive serum CrAg test result. In contrast, 5 patients had no clinical manifestations. Three of the 5 (60.0%) patients did not receive antifungal therapy and remained free of clinical manifestations. Conclusions Serum CrAg test was more sensitive than culture among liver transplant recipients and prompted early diagnosis and antifungal therapy in symptomatic patients. However, serial screening of serum CrAg in asymptomatic patients may be of little value, with the potential for false-positive results. [ABSTRACT FROM AUTHOR]

Background Non-culture-based fungal assays (NCBFAs) have been used increasingly to help diagnose invasive fungal diseases. However, little is known about inappropriate use of NCBFAs. We aimed to investigate inappropriate use of NCBFAs in a tertiary academic hospital. Methods This retrospective cohort study included patients who underwent testing with beta-D glucan (BDG) between January and March 2018 or with galactomannan antigen (GMA) or cryptococcal antigen (CRAG) between January and June 2018. Testing was deemed appropriate if the clinical presentation was compatible with a fungal infection and there was a predisposing host factor at the time of ordering. We compared patients with appropriate and inappropriate use of NCBFAs using multivariate logistic regression analysis. Results Four hundred seventy patients (BDG, 394; GMA, 138; CRAG, 164) met inclusion criteria and were evaluated. About 80% of NCBFAs were deemed inappropriate. Ordering by transplant medicine physicians, repetitions of the test, the absence of predisposing factors for fungal infections, and the absence of recommendations from infectious diseases consultants were associated with an increased risk of inappropriate NCBFA use. Conclusions We found that a large proportion of NCBFAs were deemed inappropriate. There is an opportunity for diagnostic stewardship to reduce avoidable fungal testing among patients at low risk for fungal infection. [ABSTRACT FROM AUTHOR]

Although oxytocin (OT) plays a role in bonding between heterospecifics and conspecifics, the effects of OT on the formation of such interspecific social behavior have only been investigated between humans and dogs (Canis familiaris). In this study, for comparative evaluation of the effects of OT between dog–human and cat–human social interaction, we investigated the effects of exogenous OT on the behavior of domestic cats (Felis silvestris catus) toward humans. We intranasally administered OT or saline to 30 cats using a nebulizer and recorded their behavior (gaze, touch, vocalization, and proximity). The results showed an interaction between the administration condition and sex for gaze duration. Post hoc analyses revealed a significant increase in gaze in the OT condition in male cats but not in females. There were no significant differences in gaze toward owners and strangers in any condition or sex. The male-specific OT-mediated increase in gaze toward humans observed in this study differs from previous research on dogs wherein such effects were observed only in females. These findings suggest an overall effect of exogenous OT on cats' social relationship with humans as well as the possibility of different mechanisms between cat–human and dog–human relationships. [ABSTRACT FROM AUTHOR]

Background: Proteinuria is a common adverse event observed during treatment with antivascular endothelial growth factor (VEGF) antibodies. Proteinuria is a risk factor for renal dysfunction and cardiovascular complications in patients with chronic kidney disease. However, the association between anti-VEGF antibody-induced proteinuria and renal dysfunction or cardiovascular complications remains unclear. Methods: This retrospective, observational study included patients with cancer that were treated with bevacizumab (BV) at Kyoto University Hospital (Kyoto, Japan) between January 2006 and March 2018. Adverse event rates were compared between patients who developed qualitative ≥ 2 + proteinuria and those who developed < 1 + proteinuria. Adverse events were defined as renal dysfunction (i.e., ≥ 57% decrease in the eGFR, compared to the rate at the initial treatment) and hospitalization due to BV-associated cardiovascular complications and other adverse events. Results: In total, 734 patients were included in this analysis. Renal dysfunction was more common in patients with ≥ 2 + proteinuria than in those with < 1 + proteinuria (13/199, 6.5% vs. 12/535, 2.3%). Seven of these 13 patients with ≥ 2 + proteinuria had transient reversible renal dysfunction. Only four (2.0%) patients had BV-associated renal dysfunction. Of the 734 patients, six patients, 16 patients, and 13 patients were hospitalized because of the adverse events of cardiovascular complications, thromboembolisms, and cerebrovascular complications, respectively. No relationship was observed between these adverse events and proteinuria. Conclusion: BV treatment-induced proteinuria was not associated with renal dysfunction or other adverse events. Continuing BV with caution is a possible treatment option, even after proteinuria develops, in patients with cancer and a limited prognosis. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusions The objective of the study was to describe the surgical outcome of robot‐assisted radical cystectomy and predictive factors for major complications in real‐world clinical practice at a single institution in Japan.We retrospectively analyzed 208 consecutive patients undergoing robot‐assisted radical cystectomy at our institution between 2019 and 2023. Patient and disease characteristics, intraoperative details, and perioperative outcomes were reviewed. Postoperative complications were defined as minor complications (Clavien–Dindo grades 1–2) or major complications (grades 3–5). Predictors of complications were examined using multivariable logistic analysis.Overall, 147 men and 61 women, median age 70 years (interquartile range, 62–77), were included in this study. Median operative time and estimated blood loss were 8.4 h and 185 mL, respectively; 11 patients (5%) received intraoperative blood transfusions. For urinary diversions, ileal conduit, neobladder, and cutaneous ureterostomy were performed in 153 (74%), 49 (24%), and 6 (3%) patients, respectively. Urinary diversions were primarily performed with extracorporeal urinary diversion. In total, 140 complications occurred in 111 patients (53%) within 30 days. Of these patients, 31 major complications occurred in 28 patients, and one perioperative death (0.5%) with a postoperative cardiovascular event. Multivariable analysis showed only prolonged operative time (odds ratio: 4.34, 95% confidence interval: 1.82–10.35, p < 0.01) was the independent risk factor for major complications.This study reports surgical outcomes at our single institution. Prolonged operative time was a significant prognostic factor for major complications. As far as we know, this study reports the largest number of robot‐assisted radical cystectomy cases at a single center in Japan. [ABSTRACT FROM AUTHOR]

Johnston's organ, the Drosophila auditory organ, is anatomically very different from the mammalian organ of Corti. However, recent evidence indicates significant cellular and molecular similarities exist between vertebrate and invertebrate hearing, suggesting that Drosophila may be a useful platform to determine the function of the many mammalian deafness genes whose underlying biological mechanisms are poorly characterized. Our goal was a comprehensive screen of all known orthologues of mammalian deafness genes in the fruit fly to better understand conservation of hearing mechanisms between the insect and the fly and ultimately gain insight into human hereditary deafness. We used bioinformatic comparisons to screen previously reported human and mouse deafness genes and found that 156 of them have orthologues in Drosophila melanogaster. We used fluorescent imaging of T2A-GAL4 gene trap and GFP or YFP fluorescent protein trap lines for 54 of the Drosophila genes and found 38 to be expressed in different cell types in Johnston's organ. We phenotypically characterized the function of strong loss-of-function mutants in three genes expressed in Johnston's organ (Cad99C, Msp-300, and Koi) using a courtship assay and electrophysiological recordings of sound-evoked potentials. Cad99C and Koi were found to have significant courtship defects. However, when we tested these genes for electrophysiological defects in hearing response, we did not see a significant difference suggesting the courtship defects were not caused by hearing deficiencies. Furthermore, we used a UAS/RNAi approach to test the function of seven genes and found two additional genes, CG5921 and Myo10a, that gave a statistically significant delay in courtship but not in sound-evoked potentials. Our results suggest that many mammalian deafness genes have Drosophila homologues expressed in the Johnston's organ, but that their requirement for hearing may not necessarily be the same as in mammals. [ABSTRACT FROM AUTHOR]

• This study proposed an embedded concrete hinge RC column (ECH-RC). • This study proposed an ECH-RC with unbonded bar (ECH-UBRC). • ECH-RC had a Mesnager hinge embedded at the base of an RC column. • The uncertainty in the failure behavior of ECH-RC columns could be minimized. • The high-strength bars in ECH-UBRC can improve the stability of the column. In Japan, since the 2011 Tohoku Earthquake, there has been a growing interest in addressing earthquakes that exceed design assumptions. Consequently, the concept of "anti-catastrophe" has been proposed as a new approach to the seismic design of infrastructures. This approach necessitates considering the conditions after significant structural damage, a concept not explicitly addressed in current seismic design codes. This study proposes two types of reinforced concrete (RC) columns: Embedded Concrete Hinge RC column (ECH-RC) and Embedded Concrete Hinge unbonded bar RC column (ECH-UBRC) to minimize the uncertainty of failure behaviors of RC columns during Beyond Design-Basis Events (BDBE) while ensuring high ductility during Design-Basis Events (DBE). ECH-RC features a Mesnager hinge embedded at its base, while ECH-UBRC incorporates unbonded high-strength bars in addition to a Mesnager hinge. ECH-RC and ECH-UBRC are designed for bridge columns subjected to low axial loads. To ensure the stability of the entire bridge structure during BDBE, providing lateral restraints at large displacements is essential. Results from cyclic loading tests revealed that embedded Mesnager hinges effectively prevented the uncontrollable failure of RC columns during BDBE by limiting axial and shear deformation at the plastic hinge, while the unbonded bars enhanced the stability of RC columns. [ABSTRACT FROM AUTHOR]

The scale of volcanic eruptions influences the effects of wide-ranging disasters involving ashfall, such as the disruption of lifelines and paralysis of urban functions. This highlights the importance of vehicle availability on ash-covered roads for disaster management personnel involved in rescue and recovery efforts and for citizens who must evacuate or continue their social lives. We conducted tests to scientifically verify the running ability of vehicles on ash-covered roads. Results revealed that all-wheel-drive vehicles showed better running performance than two-wheel-drive vehicles, which get stuck when ashfall thickness exceeds 10 cm. Most of the vehicle's drive power is consumed as energy to scrape ash grains from under the tires, hindering sufficient propulsion. In addition, the tires sink into the ash layer, which increases driving resistance and causes the vehicle to get stuck. Running ability on ash-covered roads is mainly determined by the relation between the "drive system" of the vehicle and the "thickness of ash" on the roads. In addition, road surface conditions, including ash thickness, could change in time and space because of traffic volume and weather conditions. [ABSTRACT FROM AUTHOR]

EZH1, a polycomb repressive complex-2 component, is involved in a myriad of cellular processes. EZH1 represses transcription of downstream target genes through histone 3 lysine27 (H3K27) trimethylation (H3K27me3). Genetic variants in histone modifiers have been associated with developmental disorders, while EZH1 has not yet been linked to any human disease. However, the paralog EZH2 is associated with Weaver syndrome. Here we report a previously undiagnosed individual with a novel neurodevelopmental phenotype identified to have a de novo missense variant in EZH1 through exome sequencing. The individual presented in infancy with neurodevelopmental delay and hypotonia and was later noted to have proximal muscle weakness. The variant, p.A678G, is in the SET domain, known for its methyltransferase activity, and an analogous somatic or germline mutation in EZH2 has been reported in patients with B-cell lymphoma or Weaver syndrome, respectively. Human EZH1/2 are homologous to fly Enhancer of zeste (E(z)), an essential gene in Drosophila, and the affected residue (p.A678 in humans, p.A691 in flies) is conserved. To further study this variant, we obtained null alleles and generated transgenic flies expressing wildtype [E(z)WT] and the variant [E(z)A691G]. When expressed ubiquitously the variant rescues null-lethality similar to the wildtype. Overexpression of E(z)WT induces homeotic patterning defects but notably the E(z)A691G variant leads to dramatically stronger morphological phenotypes. We also note a dramatic loss of H3K27me2 and a corresponding increase in H3K27me3 in flies expressing E(z)A691G, suggesting this acts as a gain-of-function allele. In conclusion, here we present a novel EZH1 de novo variant associated with a neurodevelopmental disorder. Furthermore, we found that this variant has a functional impact in Drosophila. [ABSTRACT FROM AUTHOR]

Background: The mucosa serves as the first defence against pathogens and facilitates the surveillance and elimination of symbiotic bacteria by mucosal immunity. Recently, the mRNA vaccine against SARS-CoV-2 has been demonstrated to induce secretory antibodies in the oral and nasal cavities in addition to a systemic immune response. However, the mechanism of induced immune stimulation effect on mucosal immunity and commensal bacteria profile remains unclear. Methods: Here, we longitudinally analysed the changing nasal microbiota and both systemic and nasal immune response upon SARS-CoV-2 mRNA vaccination, and evaluated how mRNA vaccination influenced nasal microbiota in 18 healthy participants who had received the third BNT162b. Results: The nasal S-RBD IgG level correlated significantly with plasma IgG levels until 1 month and the levels were sustained for 3 months post-vaccination. In contrast, nasal S-RBD IgA induction peaked at 1 month, albeit slightly, and correlated only with plasma IgA, but the induction level decreased markedly at 3 months post-vaccination. 16 S rRNA sequencing of the nasal microbiota post-vaccination revealed not an overall change, but a decrease in certain opportunistic bacteria, mainly Fusobacterium. The decrease in these bacteria was more pronounced in those who exhibited nasal S-RBD IgA induction, and those with higher S-RBD IgA induction had lower relative amounts of potentially pathogenic bacteria such as Pseudomonas pre-vaccination. In addition, plasma and mucosal S-RBD IgG levels correlated with decreased commensal pathogens such as Finegoldia. Conclusions: These findings suggest that the third dose of SARS-CoV-2 mRNA vaccination induced S-RBD antibodies in the nasal mucosa and may have stimulated mucosal immunity against opportunistic bacterial pathogens. This effect, albeit probably secondary, may be considered one of the benefits of mRNA vaccination. Furthermore, our data suggest that a cooperative function of mucosal and systemic immunity in the reduction of bacteria and provides a better understanding of the symbiotic relationship between the host and bacteria in the nasal mucosa. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer (BC) in adolescents and young adults (AYA) has unique biological qualities, but the details of these features remain unclear, and treatment options are comparable to those of other age groups. In this study, we identified a gene that demonstrates a strong association with patient prognosis solely in AYA patients, despite the fact that its expression does not differ by age group. Although this gene, GALNT1, has no prognostic significance in whole BC, when examined in AYA BC, high GALNT1 was significantly associated with worse survival. Furthermore, high GALNT1 expression was found to be an independent factor for survival among several clinical features of AYA patients. Finally, high GALNT1 BC is associated with increased EMT, angiogenesis, and protein secretion in AYA patients, but not in the elderly. We report the clinical relevance of the GALNT1 gene in AYA BC. It is well established that genetic information differs amongst the adolescent and young adult population (AYA) and older patients. Although several studies on genetic information have been conducted, no current prognostic biomarker exists to help differentiate survival outcomes amongst AYA patients. The GALNT family of genes have been associated with several cancer etiologies, such as the Tn antigen and epithelial-mesenchymal transition (EMT); however, the clinical significance of GALNT1 expression in breast cancer (BC) remains unclear. We investigated the clinical relevance of GALNT1 expression in BC using two large independent cohorts. We found that, although triple-negative BC (TNBC) had the highest GALNT1 expression compared to ER-positive/HER2-negative BC, GALNT1 levels in BC were not associated with clinical aggressiveness, including histological grade, AJCC stage and N-category, and patient survival, consistently in both the METABRIC and GSE96058 cohorts. There was also no biological difference between low- and high-GALNT1 expression BC, as analyzed by hallmark gene sets via gene set enrichment analysis (GSEA). Further, no significant difference was found in GALNT1 expression levels among AYAs and older patients. However, high GALNT1 expression was associated with significantly worse survival in AYA patients, in both cohorts. Furthermore, high GALNT1 expression was found to be an independent factor among several clinical features, including subtype, histological grade, AJCC T and N-category, in AYA patients. In both cohorts, BC with high GALNT1 expression demonstrated low levels of CD8+ T-cell infiltration, but not other anti-cancerous or pro-cancerous immune cells. Finally, high levels of GALNT1 BC demonstrated increased EMT, angiogenesis, and protein secretion in the AYA population, but not in older patients. In conclusion, our findings demonstrate that GALNT1 expression was found to be associated with angiogenesis and EMT, and may have potential as prognostic biomarker, specifically in AYA patients. [ABSTRACT FROM AUTHOR]

BK polyomavirus-associated nephropathy occurs in kidney transplant recipients under immunosuppressive treatment. BK polyomavirus is implicated in cancer development and invasion, and case reports of renal cell carcinoma and urothelial carcinoma possibly associated with BK polyomavirus has been reported. Further, it has been suggested that the immune responses of KT-related diseases could play a role in the pathogenesis and progression of renal cell carcinoma. Thus, we thought to examine the relationship between BK polyomavirus-associated nephropathy and renal cell carcinoma in terms of gene expression. To identify the common and specific immune responses involved in kidney transplantation-related diseases with a specific focus on BK polyomavirus-associated nephropathy, we performed consensus weighted gene co-expression network analysis on gene profile datasets of renal biopsy samples from different institutions. After the identification of gene modules and validation of the obtained network by immunohistochemistry of the marker across kidney transplantation-related diseases, the relationship between prognosis of renal cell carcinoma and modules was assessed. We included the data from 248 patients and identified the 14 gene clusters across the datasets. We revealed that one cluster related to the translation regulating process and DNA damage response was specifically upregulated in BK polyomavirus-associated nephropathy. There was a significant association between the expression value of hub genes of the identified cluster including those related to cGAS-STING pathway and DNA damage response, and the prognosis of renal cell carcinoma. The study suggested the potential link between kidney transplantation-related diseases, especially specific transcriptomic signature of BK polyomavirus associated nephropathy and renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Understanding groundwater dynamics is important for projecting water resources of the Lake Kawaguchi, however, the difficulty of observation and the limited number of geochemical tracers are a problem. In this study, we investigated 14C concentration (Δ14C) of lake water for three years and employed a 14C box model to estimate the groundwater contribution. Seasonal variations of Δ14C were also observed in both 2019 and 2020, confirming that Δ14C in Lake Kawaguchi decreases from summer to fall and increases during winter. Heavy precipitation exceeding 300 mm in a few days because of tropical cyclon HAGIBIS (Typhoon#19) significantly increased Δ14C in the lake for one month and it could caused by temporal changes in the surface water pathway. The 14C box model demonstrated that 14C could semiquantitatively evaluate the groundwater flow in the lake. It is needed to add quantative evaluations inflow from rivers and other factors to understand of groundwater dynamics. [ABSTRACT FROM AUTHOR]

Simple Summary: Cats (Felis silvestris catus) live with humans as domesticated animals. However, it is not clear how they have evolved from African wildcats (Felis silvestris lybica) through domestication. In this study, we compared the facial morphology of cats and wildcats to determine how the facial morphology of cats has changed in relation to their interactions with humans. Cats kept by humans had a smaller nose length and a lower eye angle compared with wildcats and feral cats, and these changes were found to influence cuteness ratings. The facial morphology of feral cats not living with humans was not significantly different from that of wildcats, suggesting that this change is due to the process of feralization. We aimed to clarify the changes in facial morphology of cats in relation to their interactions with humans. In Study 1, we compared the facial morphology of cats (feral mixed breed, owned domestic mixed breed, and owned domestic purebreds) with that of African wildcats. After collecting 3295 photos, we found that owned domestic cats' noses were significantly shorter than those of African wildcats and feral mixed breed, and there were no significant differences between the latter two. The eye angles were significantly more gradual in owned domestic purebreds than in the other groups. In Study 2, we examined the correlation between facial morphology and years with the owner, and found that the former is not affected by the latter. This suggests that changes in facial morphology are possibly transgenerational changes. The difference in facial morphology between wildcats and owned cats might be caused by domestication, and that between feral cats and owned cats might be due to feralization. In Study 3, we investigated whether cats' facial features affect cuteness ratings. We asked human participants to evaluate the cuteness of cats' face images and found that faces with shorter nose lengths were considered cuter. This suggests that owned domestic cats' facial morphology is preferred by humans. [ABSTRACT FROM AUTHOR]

Notch signaling plays various roles in cell-fate specification through direct cell–cell interactions. Notch receptors are evolutionarily conserved transmembrane proteins with multiple epidermal growth factor (EGF)-like repeats. Drosophila Notch has 36 EGF-like repeats, and while some play a role in Notch signaling, the specific functions of most remain unclear. To investigate the role of each EGF-like repeat, we used 19 previously identified missense mutations of Notch with unique amino acid substitutions in various EGF-like repeats and a transmembrane domain; 17 of these were identified through a single genetic screen. We assessed these mutants' phenotypes in the nervous system and hindgut during embryogenesis, and found that 10 of the 19 Notch mutants had defects in both lateral inhibition and inductive Notch signaling, showing context dependency. Of these 10 mutants, six accumulated Notch in the endoplasmic reticulum (ER), and these six were located in EGF-like repeats 8–10 or 25. Mutations with cysteine substitutions were not always coupled with ER accumulation. This suggests that certain EGF-like repeats may be particularly susceptible to structural perturbation, resulting in a misfolded and inactive Notch product that accumulates in the ER. Thus, we propose that these EGF-like repeats may be integral to Notch folding. [ABSTRACT FROM AUTHOR]

Oxytocin has attracted research attention due to its role in promoting social bonding. In bonobos and chimpanzees, the two species most closely related to humans, urinary oxytocin is known to correlate with key behaviours related to social bonding such as social grooming in chimpanzees and female‐female sexual behaviour in bonobos. However, no study has demonstrated that the administration of oxytocin promotes real‐life social interactions in Pan, leaving it unclear whether oxytocin is merely correlated with social behaviors or does affect them in these species. To test this, we administered nebulized oxytocin or saline placebo to a group of female bonobos and subsequently observed changes in their gross behavior during free interaction. We found an overall effect of more frequent grooming in the oxytocin condition. However, on the individual level this effect remained significant for only one participant in our follow‐up models, suggesting future work should explore interindividual variation. Our results provide some experimental support for the biobehavioural feedback loop hypothesis, which posits that some functions of the oxytocin system support the formation and maintenance of social bonds through a positive feedback loop; however, further tests with a larger number of individuals are required. Our results, at a minimum, demonstrated that oxytocin affects spontaneous, naturalistic social interactions of at least some female bonobos, adding to accumulating evidence that oxytocin modulates complex social behaviors of Pan. Highlights: We administered oxytocin or saline placebo to whole subgroups of bonobos simultaneously. Our overall model finds higher rates of grooming in the oxytocin condition, however, this was only significant in one participant in individual level analysis. This provides some support to the biobehavioural feedback loop hypothesis of oxytocin in bonobo social bonding, while future work should explore individual, group, and species level variation. [ABSTRACT FROM AUTHOR]

On influenza virus infection or vaccination, immune responses occur, including the production of antibodies with various functions that contribute to protection from seasonal influenza virus infection. In the current study, we attempted to identify the antibody functions that play a central role in preventing the onset of seasonal influenza by comparing the levels of several antibody titers for different antibody functions between 5 subclinically infected individuals and 16 patients infected with seasonal H3N2 virus. For antibody titers before influenza virus exposure, we found that the nAb titers and enzyme-linked immunosorbent assay titers against hemagglutinin and neuraminidase (NA) proteins in the subclinically infected individuals were significantly higher than those in the patients, whereas the NA inhibition titers and antibody-dependent cellular cytotoxicity activities did not significantly differ between subclinically infected individuals and infected patients. These results suggest that nAb and enzyme-linked immunosorbent assay titers against hemagglutinin and NA serve as correlates of symptomatic influenza infection. [ABSTRACT FROM AUTHOR]

The pseudoaneurysm in Case 4 was confirmed to have regressed spontaneously by CECT at 4 months after surgery. gl As shown in Figure 1a, DUS as a screening test identified four cases of asymptomatic RAP. Abbreviations and Acronyms CECT contrast-enhanced computed tomography DUS Doppler ultrasonography DVT deep venous thrombosis PN partial nephrectomy POD postoperative day RAP renal artery pseudoaneurysm Where technically feasible, partial nephrectomy (PN) is increasingly considered the gold standard for localized renal cell carcinomas. Doppler ultrasonography as a screening test for the detection of asymptomatic renal artery pseudoaneurysms following partial nephrectomy: A 15-year single-institution experience. [Extracted from the article]

Objectives: To investigate the tumor shrinkage patterns of patients with metastatic renal cell carcinoma treated with nivolumab monotherapy. Methods: Forty‐four consecutive patients with metastatic renal cell carcinoma treated with nivolumab monotherapy (81 metastatic and four primary lesions) between September 2013 and December 2020 were retrospectively analyzed. The tumor shrinkage rate of individual visceral and lymph node metastatic lesions and the primary site lesions treated with nivolumab monotherapy, as well as the association between overall survival and pretreatment tumor size, were statistically assessed. Results: Pretreatment tumor size for the total and individual target lesions, which included kidneys, lungs, pancreas, and lymph nodes, were not correlated with tumor shrinkage rate. The tumor shrinkage rate was found to have no significant association with pretreatment tumor size between any organ. In addition, there is no significant difference in tumor shrinkage rate between larger (>median value) and smaller (

Objective: To clarify the diagnostic performance of the three-dimensional reconstructed virtual image (3D-RVI) in evaluating RENAL nephrometry score (RENAL-NS).Methods: This study included 130 patients who underwent preoperative contrast-enhanced computed tomography followed by partial nephrectomy for renal tumors suggestive of renal cell carcinoma. RENAL-NS was calculated prior to the surgery, and tumor resection was performed referring to the score. We retrospectively reviewed preoperative contrast-enhanced computed tomography images. We calculated the inter-observer variability of RENAL-NS using 3D-RVI vs two-dimensional (2D) imaging and compared the ability of RENAL-NS using 3D-RVI vs 2D imaging to predict the risk of opening of the urinary collecting system. We also compared the two modalities for the time required to evaluate RENAL-NS.Results: RENAL-NS evaluated using 3D-RVI showed a higher inter-observer agreement compared to 2D-imaging (rs = 0.85 vs rs = 0.65). The "nearness to sinus" score was more strongly associated with the opening of the urinary collecting system when evaluated using 3D-RVI than 2D-imaging (AUC = 0.71 vs AUC = 0.57, P = .016). RENAL-NS using 2D-imaging required a significantly longer time compared to 3D-RVI (P = .036).Conclusion: Using 3D-RVI improves the accuracy, reliability and efficiency of RENAL-NS evaluation in preoperative assessment and can play an important role in preoperative assessment and intraoperative navigation. [ABSTRACT FROM AUTHOR]

FZR1, which encodes the Cdh1 subunit of the anaphase-promoting complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Whole-exome sequencing in 39 patient-parent trios and subsequent targeted sequencing in an additional cohort of 211 patients was performed to identify novel genes involved in developmental and epileptic encephalopathy. Functional studies in Drosophila were performed using three different mutant alleles of the Drosophila homologue of FZR1 fzr. All three individuals carrying de novo variants in FZR1 had childhood-onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference. Two individuals were diagnosed with the developmental and epileptic encephalopathy subtype myoclonic atonic epilepsy. We provide genetic-association testing using two independent statistical tests to support FZR1 association with developmental and epileptic encephalopathies. Further, we provide functional evidence that the missense variants are loss-of-function alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homologue fzr and overexpression studies, we show that patient variants can affect proper neurodevelopment. With the recent report of a patient with neonatal-onset with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and developmental and epileptic encephalopathy and expands the associated phenotype. We conclude that heterozygous loss-of-function of FZR1 leads to developmental and epileptic encephalopathies associated with a spectrum of neonatal to childhood-onset seizure types, developmental delay and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed myoclonic atonic epilepsy or developmental and epileptic encephalopathy cases. [ABSTRACT FROM AUTHOR]

Purpose: Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients.Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry.We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1 g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1 g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1 g/g or higher compared to those with less than 1 g/g. In patients with UPCR 1 g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase.This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs.Methods: Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients.Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry.We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1 g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1 g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1 g/g or higher compared to those with less than 1 g/g. In patients with UPCR 1 g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase.This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs.Results: Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients.Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry.We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1 g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1 g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1 g/g or higher compared to those with less than 1 g/g. In patients with UPCR 1 g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase.This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs.Conclusion: Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients.Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry.We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1 g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1 g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1 g/g or higher compared to those with less than 1 g/g. In patients with UPCR 1 g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase.This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs. [ABSTRACT FROM AUTHOR]

TM2 domain containing (TM2D) proteins are conserved in metazoans and encoded by three separate genes in each model organism species that has been sequenced. Rare variants in TM2D3 are associated with Alzheimer's disease (AD) and its fly ortholog almondex is required for embryonic Notch signaling. However, the functions of this gene family remain elusive. We knocked-out all three TM2D genes (almondex, CG11103/amaretto, CG10795/biscotti) in Drosophila and found that they share the same maternal-effect neurogenic defect. Triple null animals are not phenotypically worse than single nulls, suggesting these genes function together. Overexpression of the most conserved region of the TM2D proteins acts as a potent inhibitor of Notch signaling at the γ-secretase cleavage step. Lastly, Almondex is detected in the brain and its loss causes shortened lifespan accompanied by progressive motor and electrophysiological defects. The functional links between all three TM2D genes are likely to be evolutionarily conserved, suggesting that this entire gene family may be involved in AD. Author summary: Alzheimer's disease (AD) is the most common neurodegenerative disease affecting the aging population. Although many genetic factors have been implicated in its pathogenesis, in vivo functions of many of these genes have not been well defined. In this study, we investigated the function of TM2D3, a conserved gene that has been implicated in late-onset AD through an exome-wide association study, and two closely related genes, TM2D1 and TM2D2, using the fruit fly Drosophila melanogaster. In addition to exhibiting a previously reported maternal-effect neuurodevelopmental phenotype caused by Notch signaling defects during embryogenesis, fly TM2D3 mutants are short lived and display age-dependent motor and electrophysiological defects, providing the first link between this gene and age-dependent neurological phenotypes. Furthermore, TM2D1 and TM2D2 knockout flies phenotypically mimic the loss of TM2D3. Triple knockout of all three TM2D genes resemble the single knockouts, suggesting that these genes likely function together. Together with functional data that implicates TM2D3 in a biological process that is liked to the γ-secretase, a protease that is involved in AD in addition to being required for proper Notch signaling, we propose that all three TM2D family genes may be involved in AD pathogenesis, which warrants further investigation through human genetics studies. [ABSTRACT FROM AUTHOR]

Behavioural synchrony among individuals is essential for group-living organisms. The functioning of synchronization in a multilevel society, which is a nested assemblage of multiple social levels between many individuals, remains largely unknown. The aim of the present study was to build a model that explained the synchronization of activity in a multilevel society of feral horses. Multi-agent-based models were used based on four hypotheses: A) horses do not synchronize, B) horses synchronize with any individual in any unit, C) horses synchronize only within units, and D) horses synchronize across and within units, but internal synchronization is stronger. The empirical data obtained from drone observations best supported hypothesis D. This result suggests that animals in a multilevel society coordinate with other conspecifics not only within a unit but also at an inter-unit level. In this case, inter-individual distances are much longer than those in most previous models which only considered local interaction within a few body lengths. [ABSTRACT FROM AUTHOR]

Background: In this study, we investigated the association between the early response of serum and hematological variables and the outcome of cabazitaxel therapy. Patients and methods: The medical records of 59 consecutive patients who had previously received docetaxel chemotherapy for the treatment of metastatic castration-resistant prostate cancer (CRPC) and who received cabazitaxel at our hospital between January 2011 and March 2020 were retrospectively reviewed and statistically analyzed. Results: The median follow-up period after cabazitaxel initiation was 15.2 months. The 30% prostate-specific antigen (PSA) response rate, median PSA progression-free survival period, and overall survival (OS) period were 45.8%, 4.3 months, and 22.6 months, respectively. Within 1 to 2 cycles of cabazitaxel, we were unable to identify hematological or serum kinetics that had a relationship with OS. Analysis of the variables after 3 cycles of cabazitaxel, however, revealed two factors, PSA decline > 30% (p = 0.016) and neutrophil–lymphocyte ratio (NLR) decline > 30% (p = 0.044), as the predictors of favorable outcome for OS. We established a prognostic model for predicting the OS period composed of these two factors, which exhibited distinctly separated OS curves (p = 0.004). The C-index of a model incorporating these two factors was 0.703. Conclusions: This is the first study to demonstrate that PSA and NLR decline 3 cycles after the initiation of cabazitaxel were associated with favorable outcome in patients with CRPC. Also, 3 cycles of cabazitaxel might be necessary to assess the efficacy of cabazitaxel therapy. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the efficacy and safety profiles of first‐line etoposide, ifosfamide and cisplatin and primary prophylaxis with pegfilgrastim as first‐line chemotherapy for disseminated germ cell cancer. Methods: This study reviewed 154 consecutive patients with previously untreated disseminated germ cell cancer who received first‐line etoposide, ifosfamide and cisplatin between 1995 and 2020. Of these, 54 patients were managed with primary prophylaxis using pegfilgrastim (primary prophylaxis group), and 100 were managed with the therapeutic use of short‐acting granulocyte colony‐stimulating factor (non‐primary prophylaxis group). Results: The International Germ Cell Cancer Collaborative Group classification identified 90 (58%)/40 (26%)/24 (16%) patients with good/intermediate/poor prognosis, respectively. Overall, 139 patients (90%) were disease free after etoposide, ifosfamide and cisplatin with/without post‐chemotherapy surgery. The median relative dose intensity of etoposide, ifosfamide and cisplatin was 96%, and there was a significant difference between the primary prophylaxis and non‐primary prophylaxis groups (100% vs 90%, P < 0.01). The 5‐year salvage treatment‐free and overall survival rates were 83% and 94%, respectively. In total, 138 patients (90%) developed grade 4 hematological toxicities, and there were no treatment‐related deaths due to myelosuppression. Grade 4 neutropenia was less commonly observed in the primary prophylaxis group compared with the non‐primary prophylaxis group (80% vs 95%, P < 0.01). Conclusions: This is the largest study of first‐line etoposide, ifosfamide and cisplatin, and its sufficient efficacy and safety profiles are confirmed in current clinical practice. Primary prophylaxis using pegfilgrastim might further improve the feasibility of etoposide, ifosfamide and cisplatin. [ABSTRACT FROM AUTHOR]

Pyoderma gangrenosum (PG) is a relatively rare inflammatory skin disease that progressively causes necrotic ulceration mainly on the lower extremities and trunk. Systemic corticosteroid is considered a first-line treatment for PG as it facilitates wound healing; however, several cases where tumor necrosis factor-α inhibitors, adalimumab and infliximab, were administered showed good response. For intractable PG with a large ulcer or problematic epithelization, chemical or mechanical debridement of necrotic tissue in combination with skin grafting may be necessary to promote wound healing. Our report presents a case of intractable ulcerative PG requiring oral prednisolone and skin grafting. Although mechanical debridement was performed, granulation was poor; therefore, after the PG activity became quiescent, we utilized a vacuum-assisted closure (VAC) system to promote granulation and adaptation of the grafted skin. Although more cases are required for a definitive conclusion, the VAC system may be a choice for PG with large ulcers. [ABSTRACT FROM AUTHOR]

When interacting with humans, domesticated species may respond to communicative gestures, such as pointing. However, it is currently unknown, except for in dogs, if species comprehend the communicative nature of such cues. Here, we investigated whether horses could follow the pointing of a human informant by evaluating the credibility of the information about the food-hiding place provided by the pointing of two informants. Using an object-choice task, we manipulated the attentional state of the two informants during food-hiding events and differentiated their knowledge about the location of the hidden food. Furthermore, we investigated the horses' visual attention levels towards human behaviour to evaluate the relationship between their motivation and their performance of the task. The result showed that horses that sustained high attention levels could evaluate the credibility of the information and followed the pointing of an informant who knew where food was hidden (Z = − 2.281, P = 0.002, n = 36). This suggests that horses are highly sensitive to the attentional state and pointing gestures of humans, and that they perceive pointing as a communicative cue. This study also indicates that the motivation for the task should be investigated to determine the socio-cognitive abilities of animals. [ABSTRACT FROM AUTHOR]

Sentinel lymph node (SLN) biopsy has been the standard modality for breast cancer patients with clinically node negative disease. In patients who undergo axillary lymph node dissection (ALND) due to SLN metastasis, the harvested nodes (non-SLNs) often contain no metastasis. Here, we evaluated the predictive factors associated with non-SLN metastasis in breast cancer patients. This was a retrospective study of patients with operable cT1-3, cN0 invasive breast cancer who underwent SLN biopsy followed by ALND due to SLN metastasis. The clinicopathologic factors and predictive factors of non-SLN metastasis were analyzed. The optimal cutoff for the Ki67 index and the number of positive and negative SLNs that were predictive of non-SLN metastasis were evaluated using receiver operating characteristic curves. The median number of SLN and non-SLN was 3 and 11, respectively. Of the 150 patients, 52 (35.0%) had metastases in non-SLNs. The optimal cutoffs for the Ki67 index and the number of positive and negative SLNs were of 12%, 2, and 1, respectively. In the univariate analysis, the Ki67 index and the number of positive SLNs≥2 and negative SLNs≤1 were higher in the non-SLN + group than that in the non-SLN – group. The number of negative SLNs was as a predictive factor for non-SLNs metastasis in the multivariate analysis. The number of negative SLNs predicts the risk of non-SLN metastasis in breast cancer. When deciding on whether to omit ALND, the number of positive and negative SLNs should be considered. [ABSTRACT FROM AUTHOR]

Invasive meningococcal disease (IMD) can occur in travelers returning from mass-gathering events or endemic regions. We present a 60-year-old Argentine traveler to Tokyo who developed IMD by Neisseria meningitidis Serogroup W135 during her stay in Japan. N. meningitidis serogroup W135 infection has become common in Argentina, whereas IMD less commonly occurs in Japan. Considering the prevalence, the patient most likely acquired the infection in Argentina, and it developed in Japan. Air travel enables passengers to reach the four corners of the world within a few days. IMD should be considered in travelers due to its potential to induce rapid clinical deterioration and transmission. [ABSTRACT FROM AUTHOR]