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Abstract Background/Aim For patients treated with osimertinib as first-line therapy, there have been no studies comparing both progression-free survival (PFS) and overall survival (OS) according to performance status (PS). Furthermore, no studies have examined differences in baseline genetic abnormalities between patients with poor and good PS. Therefore, we aimed to investigate differences in baseline genetic abnormalities and treatment effects between patients with poor and good PS who received osimertinib as the primary treatment. Patients and methods This is a secondary analysis of the ELUCIDATOR study, which is a multi-center prospective observational study in Japan that assessed mechanisms underlying resistance to osimertinib as first-line treatment for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Results There were 153 and 25 patients in the good and poor PS groups, respectively. Multivariate analysis revealed no significant between-group differences in PFS (hazards ratio [HR]: 0.98, 95% confidence interval [CI]: 0.52–1.72, p = 0.946). Multivariate analysis of OS revealed that poor PS was a poor prognostic factor (HR: 2.67, 95% CI: 1.43–4.73, p = 0.003). Regarding baseline genetic abnormalities, there was a significant increase in APC-positive cases (20.0% vs. 2.2%, p = 0.009) and a trend toward more CTNNB1-positive cases in the poor PS group than in the good PS group (14.3% vs. 2.9%, p = 0.062). Conclusion There was no between-group difference in PFS, although OS was significantly inferior in the poor PS group. Additionally, there was a significant increase in APC-positive cases and a trend toward more CTNNB1-positive cases in the poor PS group.

Seafood is an important high-protein and low-fat food source prone to spoilage and may harbor food poisoning bacteria. Vibrio parahaemolyticus is a gram-negative halophilic bacterium that causes food poisoning. It is heat labile and can be eliminated through heating; however, V. parahaemolyticus may be present in seafood for raw consumption, such as sashimi. Recently, the use of bacteriophages or phages has been proposed as a non-thermal inactivation method for microbial control. Here, we characterized VF16, a novel phage that infects V. parahaemolyticus, and evaluated the effectiveness of the combination of VF16 with the antimicrobial amino acid d‑serine in controlling V. parahaemolyticus through antimicrobial testing in broth cultures and raw scallops. The morphology of VF16 was examined using transmission electron microscopy, which demonstrated that it had a long, flexible tail characteristic of a siphovirus. Genome sequencing revealed that VF16 is a novel phage belonging to the family Demerecviridae, subfamily Ermolyevavirinae, and genus Vipunavirus. Analysis of adsorption and one-step growth curve in a liquid medium indicated that Ca2+ and Mg2+ are necessary for one or more subsequent replication processes of VF16 but are not essential for its adsorption. The combination of VF16 and d‑serine completely inhibited the regrowth of V. parahaemolyticus in the liquid medium and effectively suppressed its growth in the scallop samples. No VF16-resistant mutants were isolated from the scallop samples treated with VF16 alone or in combination with d‑serine. The combination of phages and d-amino acids is an effective non-thermal inactivation method for controlling foodborne pathogens.

Introduction: Metallic stents are widely used to prevent airway obstruction for tracheal stenosis caused by malignant diseases. Although their efficacy has been recognized, there is no established evidence surrounding their long-term safety. We report a case of airway stenosis caused by a metallic tracheal stent. Removal of the stent to secure the airway was difficult and extremely complicated. Case Presentation: A 50-year-old male suffering from dyspnea caused by malignant lymphoma (diffuse large B-cell lymphoma) of the thyroid gland was treated with a metallic tracheal stent. After remission of the lymphoma, stenosis of the stent lumen developed gradually, and the patient complained of dyspnea. Tracheostomy could not be performed due to the metallic stent. Since the patient was unable to intubate, the stent was removed under general anesthesia with partial percutaneous cardiopulmonary support 9 years after the stent placement. Conclusion: Otolaryngologists should be aware of the possibility of severe stenosis following the long-term placement of a metallic tracheal stent.

Abstract Background Immunotherapy has become a standard‐of‐care for patients with non‐small‐cell lung cancer (NSCLC). Although several biomarkers, such as programmed cell death‐1, have been shown to be useful in selecting patients likely to benefit from immune checkpoint inhibitors (ICIs), more useful and reliable ones should be investigated. The prognostic nutritional index (PNI) is a marker of the immune and nutritional status of the host, and is derived from serum albumin level and peripheral lymphocyte count. Although several groups reported its prognostic role in patients with NSCLC receiving a single ICI, there exist no reports which have demonstrated its role in the first‐line ICI combined with or without chemotherapy. Materials and Methods Two‐hundred and eighteen patients with NSCLC were included in the current study and received pembrolizumab alone or chemoimmunotherapy as the first‐line therapy. Cutoff value of the pretreatment PNI was set as 42.17. Results Among 218 patients, 123 (56.4%) had a high PNI (≥42.17), while 95 (43.6%) had a low PNI (

Abstract Background Long‐term survival can be achieved with radical local therapy in some cases of postoperative recurrence of non‐small cell lung cancer (NSCLC). Here, we evaluated post‐recurrence survival (PRS) after treatment of postoperative recurrent epidermal growth factor receptor (EGFR) mutated NSCLC and examined the effectiveness of radical local therapy. Methods This multicenter prospective cohort study was conducted in 14 hospitals. The inclusion criteria for this study were patients with recurrence after radical resection for NSCLC. Information about the patient characteristics at recurrence, tumor‐related variables, primary surgery, and treatment for recurrence was collected. After registration, follow‐up data (e.g., treatment and survival outcomes) were obtained and analyzed. Results From 2010 to 2015, 505 patients with recurrent NSCLC were enrolled into the study, and 154 EGFR mutation‐positive cases were included. As the initial treatment for recurrence, 111 patients (72%) received chemotherapy, 14 (9%) received chemoradiotherapy, 14 (9%) received definitive radiotherapy, and seven (5%) received surgical resection. The remaining eight patients (5%) received supportive care. The median PRS and 5‐year survival rates for all cases were 64 months and 53.2%, respectively. The 5‐year survival rate according to the initial treatment was as follows: supportive care, 0%; chemotherapy, 53.3% and radical local therapy, 60.1%. The six patients who received radical local treatment remained recurrence‐free for more than 3 years after recurrence with only initial treatment. Conclusions Although radical local therapy may be curative in some patients, chemotherapy including EGFR‐TKI treatment is expected to provide long‐term survival comparable to that of radical local therapy.

The recovery of apex consumers increases the need for coexistence efforts, and it is important to understand how apex consumers respond to human-modified landscapes. Roads can restrict movement and gene flow as well as increase mortality risk, however, can also provide attractive food resources along roadside and enhance movement efficiency of apex consumer. To investigate the selectivity (preference/avoidance) and movement patterns of an apex consumer in relation to roads, we carried out an integrated step selection analysis of GPS data from Asiatic black bears (Ursus thibetanus) in the Ashio-Nikko Mountains, Japan. During the reproductive season, adult males preferred areas near all types of roads, but preferred areas further from roads during the day compared to the night. Also, adult males displayed slower movements as well as avoided less dense vegetation near main roads and faster movement near minor roads. In comparison, adult females avoided areas near main roads and preferred areas near minor roads. In addition, adult females preferred areas further from minor roads during the day compared to the night. In the hyperphagia season, neither sex exhibited any selectivity in relation to roads in general, but preferred areas farther from all types of roads during the day. Our results suggest that Asiatic black bears not only generally perceive roads as a risk but also may use areas near roads for food resources or travel routes depending on sex, season, and human activity level. To minimize bear-human encounters near roads, we propose that management of roadside vegetation focuses on creating habitats with high visibility and plant species unattractive for bears.

Abstract Background Cancer immunotherapy with immune checkpoint inhibitors (ICIs) is an innovative treatment for non‐small cell lung cancer (NSCLC). Recently, the specific composition of the gut microbiome before initiation of cancer immunotherapy has been highlighted as a predictive biomarker in patients undergoing cancer immunotherapy, mainly in the US or Europe. However, the fact gut microbiome status is completely different in races or countries has been revealed. In addition, how the microbiome composition and diversity chronologically change during cancer immunotherapy is still unclear. Methods This multicenter, prospective observational study will analyze the association between the gut microbiome and therapeutic response in NSCLC patients who received atezolizumab‐based immunotherapy. The aim of the present study is to clarify not only how the specific composition of the gut microbiome influences clinical response in NSCLC patients but the chronological changes of gut microbiota during atezolizumab‐based immunotherapy. The gut microbiota will be analyzed using 16S rRNA gene sequencing. The main inclusion criteria are as follows: (1) Pathologically‐ or cytologically‐confirmed stage IV or postoperative recurrent NSCLC. (2) Patients ≥20 years old at the time of informed consent. (3) Planned to treat with atezolizumab‐based immunotherapy combined with platinum‐based chemotherapy (cohort 1) and monotherapy (cohort 2) as a first immunotherapy. (4) Patients to provide fecal samples. A total of 60 patients will be enrolled prospectively. Enrollment will begin in 2020 and the final analyses will be completed by 2024. Discussion This trial will provide more evidence of how gut microbiota composition and diversity chronologically change during cancer immunotherapy and contribute to the development of biomarkers to predict ICI response as well as biotic therapies which enhance the ICI response.

Abstract Scavenging is a common feeding behavior that provides ecosystem services by removing potentially infectious waste from the landscape. The importance of facultative scavenging is often overlooked, but likely becomes especially important in ecosystems without obligate scavengers. Here, we investigated the ecological function of vertebrate facultative scavengers in removing ungulate carcasses from Japanese forests that lack obligate scavengers. We found that mammals detected carcasses first more often than birds, and that raccoon dogs (Nyctereutes procyonoides) were the most frequent scavenger to first detect carcasses. However, we found no evidence of there being species that signal the location of carrion to other species via social cues. Instead, higher temperatures promoted earlier detection of the carcasses by scavengers, likely related to increased olfactory signals. The carcasses were completely consumed on average in 7.0 days, reasonably similar to other systems regardless of habitat, indicating that facultative scavengers are providing ecosystem services. Larger carcasses tended to take longer to deplete, but carcasses were consumed faster in warmer temperatures. Our results indicate that facultative scavengers were capable of consuming carrion and contributing ecosystem services in a forest ecosystem that lacks obligate scavengers.

Summary: Small cell lung cancer (SCLC) is one of the deadliest human cancers, with a 5-year survival rate of ∼7%. Here, we performed a targeted proteomics analysis of human SCLC samples and thereby identified hypoxanthine phosphoribosyltransferase 1 (HPRT1) in the salvage purine synthesis pathway as a factor that contributes to SCLC malignancy by promoting cell survival in a glutamine-starved environment. Inhibition of HPRT1 by 6-mercaptopurine (6-MP) in combination with methotrexate (MTX), which blocks the de novo purine synthesis pathway, attenuated the growth of SCLC in mouse xenograft models. Moreover, modulation of host glutamine anabolism with the glutamine synthetase inhibitor methionine sulfoximine (MSO) in combination with 6-MP and MTX treatment resulted in marked tumor suppression and prolongation of host survival. Our results thus suggest that modulation of host glutamine anabolism combined with simultaneous inhibition of the de novo and salvage purine synthesis pathways may be of therapeutic benefit for SCLC.

Abstract Castleman disease is a rare disease borne of a B cell lymphoproliferative disorder of uncertain cause. Standard therapy for the unicentric type of Castleman disease localized as a single mass or single lymph‐node station is surgical extirpation. Nevertheless, in the thoracic cavity, unresectable cases or cases of incomplete extirpation of the tumor without lung scarring owing to tumor size/location have been noted. In such cases, lung resection (e.g., lobectomy, pneumonectomy) or additional therapy (immunotherapy, chemotherapy, radiotherapy) after resection is required. However, few instances of patients receiving induction immunotherapy or chemotherapy followed by surgery have been reported. Here, we describe a 21‐year‐old woman with unicentric Castleman disease originating from the left hilum. The tumor seemed to involve/be in contact with the pulmonary vein and bronchus. Tumor location indicated that initial resection was necessary to sacrifice upper and lower pulmonary lobes. To avoid these pulmonary resections, induction therapy followed by surgery was selected. Induction therapy using rituximab was very efficacious. Resection after induction therapy was completed only by tumor extirpation, and resulted in preservation of pulmonary function. Thoracic surgeons might consider induction therapy followed by resection if the tumor is resectable UCAD, but initial resection is needed and sacrifices a large amount of pulmonary function.

Objectives: The optimal treatment for recurrent non–small cell lung cancer (NSCLC) has not been standardized. In this prospective cohort study, we evaluated post-recurrence survival (PRS) after treatment of recurrent NSCLC and identified prognostic factors after recurrence. Methods: This multicenter prospective cohort study was conducted in 14 hospitals. The inclusion criteria for this study were patients with recurrence after radical resection for NSCLC. Information about the patient characteristics at recurrence, tumor-related variables, primary surgery, and treatment for recurrence was collected. After registration, follow-up data, such as treatment and survival outcomes, were obtained every 3 months. Results: From 2010 to 2015, 505 cases were enrolled, and 495 cases were analyzed. As initial treatment for recurrence, 263 patients (53%) received chemotherapy, 46 (9%) received chemoradiotherapy, 98 (20%) had definitive radiotherapy, 14 (3%) received palliative radiotherapy, and 31 (6%) underwent surgical resection. The remaining 43 patients (9%) received supportive care. The median PRS and 5-year survival rates for all cases were 30 months and 31.9%, respectively. The median PRS according to the initial treatment was as follows: supportive care, 8 months; palliative radiotherapy, 16 months; definitive radiotherapy, 30 months; chemotherapy, 31 months; chemoradiotherapy, 35 months; and surgery, not reached. A multivariate analysis showed that the age, gender, performance status, histology presence of symptoms, duration from primary surgery to recurrence, and number of recurrent foci were independent prognostic factors for PRS. Conclusions: The PRS of patients with recurrent NSCLC was different depending on the patient's background characteristics and initial treatment for recurrence.

Large carnivores have long fascinated human societies and have profound influences on ecosystems. However, their conservation represents one of the greatest challenges of our time, particularly where attacks on humans occur. Where human recreational and/or livelihood activities overlap with large carnivore ranges, conflicts can become particularly serious. Two different scenarios are responsible for such overlap: In some regions of the world, increasing human populations lead to extended encroachment into large carnivore ranges, which are subject to increasing contraction, fragmentation, and degradation. In other regions, human and large carnivore populations are expanding, thus exacerbating conflicts, especially in those areas where these species were extirpated and are now returning. We thus face the problem of learning how to live with species that can pose serious threats to humans. We collected a total of 5,440 large carnivore (Felidae, Canidae, and Ursidae; 12 species) attacks worldwide between 1950 and 2019. The number of reported attacks increased over time, especially in lower-income countries. Most attacks (68%) resulted in human injuries, whereas 32% were fatal. Although attack scenarios varied greatly within and among species, as well as in different areas of the world, factors triggering large carnivore attacks on humans largely depend on the socioeconomic context, with people being at risk mainly during recreational activities in high-income countries and during livelihood activities in low-income countries. The specific combination of local socioeconomic and ecological factors is thus a risky mix triggering large carnivore attacks on humans, whose circumstances and frequencies cannot only be ascribed to the animal species. This also implies that effective measures to reduce large carnivore attacks must also consider the diverse local ecological and social contexts.

A slow-down in warming and ice loss in Greenland over the past decade is linked to a shift in El Niño events towards the central Pacific through an atmospheric remote forcing, according to analyses of observations and simulations with an atmospheric circulation model.

In endozoochorous seed dispersal, the ecological characteristics of each disperser determine the quantitative and qualitative aspects of the dispersal mechanism. To understand the role of different frugivores in multispecies seed dispersal networks, it is necessary to focus on the community structure and investigate where in the landscape seed deposition occurs. The aim of this research was to assess the quantitative and qualitative aspects of a mammalian endozoochorous seed dispersal network in a temperate forest ecosystem and identify the seasonal dispersal niche of each member of the assemblage. We hypothesized that differences among dispersers and seasons would occur in (H1) the proportion of scats that contain seeds, seed abundance in scats, and the number of seed species dispersed per scat, and in (H2) the probability of dispersing seeds to suitable microsites for germination of each species and seed abundance. We also hypothesized (H3) that the microhabitat variables of deposition sites would vary among dispersers, and (H4) that complementary structures would occur in terms of dispersers, dispersed species, and deposition sites. From summer (June–August) to autumn (September–November) in 2003 and 2004, we collected scats of five mammalian frugivorous species and recorded eight microhabitat variables at each deposition site in central Japan. We recorded the presence and number of seeds in scats and identified all seed at the species level. We considered a deposition site as suitable when the habitat type (interior forest, treefall gap, forest edge, and outside the forest) at a deposition site matched the microhabitat required for the for the dispersed species to germinate and survive as seedlings. A total of 341 scats containing seeds of 16 fleshy-fruited species were collected. Among these, 213 (62.5 %) scats were dispersed to suitable habitats (summer: 68.8 %, autumn: 54.8 %). We found that the seed abundance in the scat varied among dispersers and was higher in autumn (H1–2). The probability of dispersing seeds to suitable microsites switched among dispersers from summer to autumn (H2). The distinctive microhabitat variables and variation in microhabitat at deposition sites differed among dispersers across seasons (H3). Disperser-plant and disperser-deposition site networks were specialized and modular in structure compared to random networks during both seasons, but there was a less nested structure in summer compared to autumn (H4). The five mammal species showed differences and seasonality in seed dispersal niches. Because of these differences, these mammal species may play redundant and complementary roles in the seed dispersal network.

Abstract Intercostal cavernous hemangioma is extremely rare among benign vascular tumors. Achieving a definitive diagnosis preoperatively by radiographic examination alone is difficult; surgical resection is usually needed. Occasional cases are found as giant tumors, and some grow substantially during observation without treatment. Such tumors require extended surgical resection; however, small tumors can be completely resected by tumor extirpation alone. Thus, immediate surgical resection while the tumor is small might help to avoid invasive surgery. We herein describe cases of intercostal cavernous hemangioma with no invasion to the surrounding tissues, successfully treated by complete tumor resection using robot‐assisted thoracic surgery.

Cancer immunotherapy including immune checkpoint inhibitors (ICI) has revolutionized non-small cell lung cancer (NSCLC) therapy. Recently, the microbiota status “before” initiation of ICI therapy has been emphasized as a predictive biomarker in patients undergoing ICI therapy. However, the microbiota diversity and composition “during” ICI therapy is unknown. This multicenter, prospective observational study analyzed both saliva and feces from 28 patients with NSCLC. We performed 16S ribosomal RNA gene sequencing, then analyzed associations of oral and gut microbiota diversity or composition with ICI response. At the genus level, the alpha diversity of the gut microbiota was significantly greater in responders (n = 17) than in non-responders (n = 11) (Chao 1, p = 0.0174; PD whole tree, p = 0.0219; observed species, p = 0.0238; Shannon, p = 0.0362), while the beta diversity of the gut microbiota was significantly different (principal coordinates analysis, p = 0.035). Compositional differences in the gut microbiota were observed between the two groups; in particular, g_Blautia was enriched in responders, whereas o_RF32 order unclassified was enriched in non-responders. The progression-free survival (PFS) of patients enriched gut microbiota of g_Blautia was significantly longer [median survival time (MST): not reached vs. 549 days, p = 0.0480] and the PFS of patients with gut microbiota of o_RF32 unclassified was significantly shorter (MST: 49 vs. 757 days, p = 0.0205). There were no significant differences between groups in the oral microbiota. This study revealed a strong association between gut microbiota diversity and ICI response in NSCLC patients. Moreover, specific gut microbiota compositions may influence the ICI response. These findings might be useful in identifying biomarkers to predict ICI response.

Abstract Immune checkpoint inhibitors with chemotherapy have been shown to exhibit remarkable efficacy for advanced non‐small‐cell lung carcinoma and are under investigation as an induction therapy. However, the significance of preoperative therapy with pembrolizumab + chemotherapy for surgically resectable non‐small‐cell lung carcinoma still remains unclear. Here, we report a case of stage IIIB non‐small‐cell lung carcinoma that underwent salvage surgery after three cycles of pembrolizumab + carboplatin + nab‐paclitaxel. Computed tomography revealed the remarkable decrease in tumor volume by 81%. A pathological examination showed that viable neoplastic cells were observed in

Abstract Background Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced or recurrent non‐small cell lung cancer (NSCLC). They cause immune‐related adverse events (irAEs), but the underlying mechanisms and predictors remain to be fully elucidated. In this retrospective study, we investigated the association between pretreatment neutrophil‐to‐lymphocyte ratio (NLR) and the occurrence of irAEs. Methods The study involved 115 patients with NSCLC who started ICI‐only treatment in our hospital between January 2016 and April 2020. Results Forty‐five patients (39.1%) had irAEs, and pretreatment NLR was significantly lower in the irAEs group than in the non‐irAEs group (2.8 vs. 4.1; p = 0.036). The cutoff value of the NLR was 2.86 (area under curve, 0.62; sensitivity, 0.56; specificity, 0.71), and the incidence rate of irAEs was significantly higher in the NLR

Abstract Previous studies on the mating system of the Asian black bear (Ursus thibetanus) have been limited to observations of captive populations and estimations of multiple paternities. Hence, the mating system of wild bears remains poorly understood. Animal‐borne camera systems (i.e., cameras mounted on animals) provide novel tools to study the behavior of elusive animals. Here, we used an animal‐borne video system to record the activities of wild bears during the mating season. Video camera collars were attached to four adult Asian black bears (male “A” and “B,” and female “A” and “B”) captured in Tokyo, central Japan, in May and June 2018. The collars were retrieved in July 2018, after which the video data were downloaded and analyzed in terms of bear activity and mating behavior. All the bears were found to interact with other uniquely identifiable bears for some of the time (range 9–22 days) during the deployment period (range 36–45 days), and multiple mating in males was documented. Both males and females exhibited different behaviors on social days (i.e., days when the bear interacted with conspecifics) compared with solitary days (i.e., days with no observed interactions with conspecifics). Compared with solitary days, the bears spent a lower proportion of time on foraging activities and higher proportion of time on resting activities on social days. Our results suggest that Asian black bears have a polygamous mating system, as both sexes consort and potentially mate with multiple partners during a given mating season. Furthermore, bears appeared to reduce their foraging activities on social days and engaged more in social interactions.

Abstract The incidence of central nervous system (CNS) metastases in patients with anaplastic lymphoma kinase (ALK) fusion gene‐positive (ALK+) non‐small cell lung cancer (NSCLC) is high, ranging from approximately 20%–70%. Although ALK inhibitors (ALKis) are generally effective for CNS metastases in patients with ALK+ NSCLC, relapse with CNS metastases is frequently observed. A 37‐year‐old woman with a high level of carcinoembryonic antigen was diagnosed with right lung adenocarcinoma (pathological stage IIIA) and underwent right lower lobectomy. Despite the administration of postoperative chemotherapy, her carcinoembryonic antigen (CEA) level remained elevated. Although crizotinib was administered due to the positivity for ALK fusion, brain metastases appeared at 19.0 months after the start of treatment. Treatment with alectinib following crizotinib resulted in the complete disappearance of brain metastases. However, brain metastases relapsed, and meningeal dissemination appeared at 38.3 months after the start of treatment with alectinib. Although ceritinib, brigatinib, and alectinib rechallenge were attempted, the CNS lesions worsened. Lorlatinib was then administered, resulting in the normalization of the CEA level (4.5 ng/ml) 4.1 months after the start of lorlatinib. The brain metastases and meningeal dissemination almost disappeared. The overall time from the start of crizotinib to lorlatinib is 89.5 months at present, and the patient continues to be treated with lorlatinib without relapse. Lorlatinib was effective in this case with brain metastases and meningeal dissemination after resistance to first‐ and second‐generation ALKis. Appropriate sequential treatment with first‐, second‐ and third‐generation ALKis can lead to a long‐term survival in ALK+ patients with brain metastases and meningeal dissemination.

Abstract The differentiation between major histological types of lung cancer, such as adenocarcinoma (ADC), squamous cell carcinoma (SCC), and small-cell lung cancer (SCLC) is of crucial importance for determining optimum cancer treatment. Hematoxylin and Eosin (H&E)-stained slides of small transbronchial lung biopsy (TBLB) are one of the primary sources for making a diagnosis; however, a subset of cases present a challenge for pathologists to diagnose from H&E-stained slides alone, and these either require further immunohistochemistry or are deferred to surgical resection for definitive diagnosis. We trained a deep learning model to classify H&E-stained Whole Slide Images of TBLB specimens into ADC, SCC, SCLC, and non-neoplastic using a training set of 579 WSIs. The trained model was capable of classifying an independent test set of 83 challenging indeterminate cases with a receiver operator curve area under the curve (AUC) of 0.99. We further evaluated the model on four independent test sets—one TBLB and three surgical, with combined total of 2407 WSIs—demonstrating highly promising results with AUCs ranging from 0.94 to 0.99.

Comparative analysis of animal behaviour using locomotion data such as GPS data is difficult because the large amount of data makes it difficult to contrast group differences. Here the authors apply deep learning to detect and highlight trajectories characteristic of a group across scales of millimetres to hundreds of kilometres.

Abstract Lung cancer is one of the major causes of cancer-related deaths in many countries around the world, and its histopathological diagnosis is crucial for deciding on optimum treatment strategies. Recently, Artificial Intelligence (AI) deep learning models have been widely shown to be useful in various medical fields, particularly image and pathological diagnoses; however, AI models for the pathological diagnosis of pulmonary lesions that have been validated on large-scale test sets are yet to be seen. We trained a Convolution Neural Network (CNN) based on the EfficientNet-B3 architecture, using transfer learning and weakly-supervised learning, to predict carcinoma in Whole Slide Images (WSIs) using a training dataset of 3,554 WSIs. We obtained highly promising results for differentiating between lung carcinoma and non-neoplastic with high Receiver Operator Curve (ROC) area under the curves (AUCs) on four independent test sets (ROC AUCs of 0.975, 0.974, 0.988, and 0.981, respectively). Development and validation of algorithms such as ours are important initial steps in the development of software suites that could be adopted in routine pathological practices and potentially help reduce the burden on pathologists.

Abstract Scavenging is a common feeding behavior by many species that plays an important role in ecosystem stability and function while also providing ecosystem services. Despite its importance, facultative scavenging on large animal carcasses has generally been overlooked in Asian temperate forest ecosystems. The aim of this study was to determine the composition and feeding behavior of the facultative scavenger guild as it relates to sika deer (Cervus nippon) carcasses in Japanese forests. There are no obligate scavengers or large predators that kill adult ungulates, but humans fill the role of large predators by culling deer for population management. We documented nine vertebrate species scavenging on deer carcasses and found that mammals were more frequent scavengers than birds and also fed for longer durations. This result suggests that there is a facultative scavenger guild composed mainly of mammals in our forest ecosystem and that carcass utilization by birds was restricted to only forest species. Raccoon dogs (Nyctereutes procyonoides) and Asian black bears (Ursus thibetanus) were the most frequent scavenger species and also fed for longer durations than other scavengers. There were significant seasonal differences in scavenging by Asian black bear, Japanese marten (Martes melampus), and mountain hawk‐eagle (Nisaetus nipalensis), suggesting the availability of other food resources may alter facultative scavenging by each species. Our results support that scavenging is widespread in this system and likely has important functions including building links in the food web.

The connection between Arctic sea ice loss and mid-latitude cooling in Eurasia has been widely debated. Here, model experiments reveal that the persistence of sea ice loss-related snow and soil temperature anomalies in Eurasia may lead to further cooling in the following winters.

Abstract Background We present a cellular phone-enhanced GPS tracking system (GPS mobile with CTG-001G receiver triangulation) suitable for urban carnivores, in tandem with appropriate home range analysis, as an additional tracking technology option in metropolitan settings. We conduct this proof-of-concept study working with the management of introduced invasive raccoons in Japan (and conditions implicit to this control program). Results Each tracking period averaged 17 days, and a tracking accuracy of

Abstract Background Across China and Southeast Asia, an estimated 17,000 bears are currently farmed for bile, primarily for traditional medicines. Depending on country, bile is extracted daily via transabdominal gallbladder fistulas, indwelling catheters, or needle aspiration. Despite claims that bears do not develop adverse effects from bile extraction, health issues identified in bears removed from bile farms include bile-extraction site infections, abdominal hernias, peritonitis, cholecystitis, hepatic neoplasia, cardiac disease, skeletal abnormalities, and abnormal behaviors. We present a comprehensive assessment of the effects of bile farming by comparing serum biochemical and hematological values of bears from farms that were bile-extracted (BE) and bears from farms not bile-extracted (FNE) with bears from non-farm captive (ZOO) and free-range (FR) environments. We hypothesized BE bears would have significant laboratory abnormalities compared to all non-extracted bear groups. We also hypothesized BE bears would have reduced long-term survival compared to FNE bears despite removal from farms. Results BE bears exhibited the highest values and greatest variation (on a population level) in laboratory parameters compared to all non-extracted bear groups particularly for alanine transaminase, gamma glutamyltransferase (GGT), total bilirubin (TBIL), alkaline phosphatase (ALKP), blood urea nitrogen, creatinine (CREA), and total white blood cell count. Significant differences were detected between bear groups when accounting for season, sex, and/or age. BE bears exhibited greater mean serum GGT compared to all non-extracted bear groups, and the odds of having elevated TBIL were 7.3 times greater for BE bears, consistent with hepatobiliary disease. Biochemical parameter elevations in BE bears persisted up to 14 years post-rescue, consistent with long-term effects of bile-extraction. BE bears that arrived with elevated CREA and ALKP had median survival times of 1 and 4 years respectively, and regardless of laboratory abnormalities, BE bears had significantly shorter survival times compared to FNE bears. Conclusions Our results provide strong evidence that bile extraction practices not only represent a temporary constraint for bears’ welfare, but confer distinct long-term adverse health consequences. Routine laboratory panels may be insensitive to detect the extent of underlying illness in BE bears as these bears have significantly reduced survival regardless of biochemical assessment compared to FNE bears.

BackgroundPreoperative nutritional status is an important host-related prognostic factor for non-small cell lung carcinoma (NSCLC); however, the significance of postoperative changes in nutritional status remains unclear. This study aimed to elucidate the significance of postoperative decreases in serum albumin (ΔAlb) on the outcomes of early-stage NSCLC.MethodsWe analyzed 443 training cohort (TC) and 642 validation cohort (VC) patients with pStage IA NSCLC who underwent surgery and did not recur within 1 year. We measured preoperative serum albumin levels (preAlb) and postoperative levels 1 year after surgery (postAlb), and calculated ΔAlb as (preAlb - postAlb)/preAlb × 100%. A cutoff value of 11% for ΔAlb was defined on the basis of the receiver operating characteristic curve for the TC.ResultsPatients were divided into ΔAlb-Decreased and ΔAlb-Stable groups, including 100 (22.6%) and 343 (77.4%) in the TC, and 58 (9.0%) and 584 (90.1%) in the VC. ΔAlb-Decreased was associated with male sex (p = 0.0490), smoking (p = 0.0156), and non-adenocarcinoma (pConclusionWe demonstrated a negative impact of postoperative decrease of the serum albumin on the prognosis of patients with early-stage NSCLC. Postoperative changes in nutritional status might be important in NSCLC outcomes.

The present study aimed to investigate the nutritional aspects of the bear diet quantitatively, in order to understand plant food selection in spring. Bears were observed directly from April to July in 2013 and 2014, to visually recognize plant species consumed by bears, and to describe the foraging period in the Ashio-Nikko Mountains, central Japan. Leaves were collected from eight dominant tree species, regardless of whether bears fed on them in spring, and their key nutritional components analyzed: crude protein (CP), neutral detergent fiber (NDF), and total energy. Bears tended to consume fresh leaves of specific species in May, and nutritional analysis revealed that these leaves had higher CP and lower NDF than other non-food leaves. However, CP in consumed leaves gradually decreased, and NDF increased from May to July, when the bears’ food item preference changed from plant materials to ants. Bears may consume tree leaves with high CP and low NDF after hibernation to rebuild muscle mass.

Abstract Energy balance (i.e., energy intake minus energy expenditure) is an essential factor when evaluating an animal's nutritional state. We aimed to identify periods of the year that are most important for Asian black bears (Ursus thibetanus) in terms of energy balance. We estimated bears’ daily energy balance by estimating energy intake based on the energy content (kcal/g) of major food items, their average ingestion rate (g/min), and daily feeding time (min) and by estimating energy expenditure using an equation for the costs of resting, traveling, and feeding based on behavioral data of 34 bears fitted with GPS collars in central Japan. Because food habits of bears change seasonally, we estimated daily energy balance for each month. And, because bears change their feeding behavior depending on the availability of hard mast, we made separate estimations for years of good and poor mast conditions during autumn. We identified major food items from fecal analysis and calculated the gross energy content per unit for each item. Based on direct observation of bears feeding over 10 yr, we measured ingestion rates of the major food items; Quercus crispula acorns on the tree had the highest ingestion rate, whereas the values of other items did not show notable characteristics. The variability of energy expenditure rose moderately in good mast years, except for males. On the other hand, there was a bimodal pattern of energy intake and energy balance, declining from May to July, rising again from August to October, and declining in November. The peak of energy intake and energy balance was larger in good mast years than in poor mast years only for females, whereas the cumulative energy balance in good mast years was larger than in poor mast years for both sexes. After poor mast years, the cumulative energy balance of males becomes negative in February, during hibernation, and did not exceed zero until August, even if they could start feeding in May. Thus, further longitudinal studies that examine cumulative energy balance, rather than energy balance alone, are necessary to clarify the seasonal change in the nutritional state of Asian black bears.

Cementum annuli widths in mammals are is influenced by the nutrition of mammals. Reproductive stress has been is suggested to reduce the width of lead to narrower cementum annuli widths in female Asian black bears (Ursus thibetanus); however, food availability in autumn strongly impacts bear nutrition and likely impacts cementum widths as well. This study aimed to test how cementum annuli widths and the formation of false annuli were influenced by hard mast production. We established two hypotheses: (1) cementum annuli widths become narrower in poor mast years owing to inadequate nutritional conditions and (2) false annuli occur more frequently in poor mast years. We used teeth samples from male bears to avoid reproductive influences and separated width data into "adult" and "subadult" groups. We calculated the proportional width index (PWI) and used linear mixed models to estimate the masting effects on PWI. Generalized linear mixed models estimated the masting effects on false annuli frequency. True annuli widths and false annuli formation showed no significant relationship with mast production in adults. In subadults, poor mast production weak negative influence on false annuli formation. These new data resolve previous questions, allowing us to deduce that cementum annuli widths are a reliable index of reproductive success in female bears.

In Mitchell’s chemiosmotic theory, a proton (H+) motive force across the membrane (Δp), generated by the respiratory chain, drives F1Fo-ATPase for ATP production in various organisms. The bulk-base chemiosmotic theory cannot account for ATP production in alkaliphilic bacteria. However, alkaliphiles thrive in environments with a H+ concentrations that are one-thousandth (ca. pH 10) the concentration required by neutralophiles. This situation is similar to the production of electricity by hydroelectric turbines under conditions of very limited water. Alkaliphiles manage their metabolism via various strategies involving the cell wall structure, solute transport systems and molecular mechanisms on the outer surface membrane. Our experimental results indicate that efficient ATP production in alkaliphilic Bacillus spp. is attributable to a high membrane electrical potential (ΔΨ) generated for an attractive force for H+ on the outer surface membrane. In addition, the enhanced F1Fo-ATPase driving force per H+ is derived from the high ΔΨ. However, it is difficult to explain the reasons for high ΔΨ formation based on the respiratory rate. The Donnan effect (which is observed when charged particles that are unable to pass through a semipermeable membrane create an uneven electrical charge) likely contributes to the formation of the high ΔΨ because the intracellular negative ion capacities of alkaliphiles are much higher than those of neutralophiles. There are several variations in the adaptation to alkaline environments by bacteria. However, it could be difficult to utilize high ΔΨ in the low aeration condition due to the low activity of respiration. To explain the efficient ATP production occurring in H+-less and air-limited environments in alkaliphilic bacteria, we propose a cytochrome c-associated “H+ capacitor mechanism” as an alkaline adaptation strategy. As an outer surface protein, cytochrome c-550 from Bacillusclarkii possesses an extra Asn-rich segment between the region anchored to the membrane and the main body of the cytochrome c. This structure may contribute to the formation of the proton-binding network to transfer H+ at the outer surface membrane in obligate alkaliphiles. The H+ capacitor mechanism is further enhanced under low-aeration conditions in both alkaliphilic Bacillus spp. and the Gram-negative alkaliphile Pseudomonas alcaliphila.

The sensitivity of postoperative pleural air leakage (PAL) after pulmonary resection is evaluated by a simple subjective grading method in clinical practice. A new electronic digital chest drainage evaluation system (DCS) recently became clinically available. This study was designed to evaluate the clinical application of the DCS in monitoring the airflow volume and managing postoperative PAL.We prospectively enrolled 25 patients who underwent pulmonary resection. Postoperative PAL was evaluated using both conventional PAL grading based on the physician's visual judgment (analog chest drainage evaluation system [ACS]: Level 0 = no leakage to 4 = continuous leakage) and the DCS. The DCS digital measurement was recorded as the flow volume (ml/min), which was taken once daily from postoperative day 1 to the day of chest drainage tube removal.In total, 45 measurements were performed on 25 patients during the evaluation period. Postoperative PAL was observed in five patients (20.0%) and judged as ACS Level >1. The mean DCS values corresponding to ACS Levels 0, 1, 2, and 3 were 2.42 (0.0-11.3), 48.6 (35.4-67.9), 95.6 (79.7-111.5), and 405.3 (150.3-715.6), respectively. The Spearman correlation test showed a significant positive correlation between the ACS PAL level and DCS flow volume (R = 0.8477, p < 0.001).A relationship between the visual PAL level by the ACS and the digital value by the DCS was identified in this study. The numeric volume obtained by the DCS has been successful in information-sharing with all staff. The digital PAL value evaluated by the DCS is appropriate, and the use of the DCS is promising in the treatment of postoperative PAL after pulmonary resection.

The relationship between a synoptic-scale, upper-level cold vortex and a meso-α scale polar low (PL) over the Sea of Japan, and the role played by low-level baroclinicity in the development of the PL were investigated. We examined three PLs from the perspective of potential vorticity (PV) and energy budgets, using mesoscale analysis data with a horizontal resolution of ~11 km. During the development stage of each PLs, a meso-α scale upper-level PV (UPV) anomaly, which intrudes to around the 700–600 hPa level and which is just a part of a synoptic-scale PV anomaly accompanying the cold vortex, moved to the west side of a low-level PL. The PL was located in a wide region of low static stability in the lower troposphere. These conditions suggested that the synoptic-scale cold vortex, accompanied by a cold dome and the different scales of UPV anomalies, played a role in creating a favourable environment for the PL development. One of the common characteristics of the PL cases studied here was that, in contrast to the low-level PL, the upper-level disturbance associated with the meso-α scale UPV anomaly showed no development at all. This is likely because of the mobile UPV anomaly cut off from its source. Low-level baroclinicity, which varied with time, was an important factor in differentiating the PL shape and the energy sources necessary for PL development. Furthermore, the strength of baroclinicity, through its enhancement of mesoscale fronts and convection, affected diabatic processes, as well as baroclinic development.

Although endoscopic retrograde cholangiopancreatography (ERCP) is an effective modality for the diagnosis and treatment of biliary and pancreatic diseases, it is still related with several severe complications. We report on the case of a female patient who developed liver parenchyma perforation following ERCP. She underwent ERCP with sphincterotomy and extraction of a common bile duct stone. Shortly after ERCP, abdominal distension was identified. Abdominal computed tomography revealed intraabdominal air leakage and leakage of contrast dye penetrating the liver parenchyma into the space around the spleen. Since periampullary perforation related to sphincterotomy could not be denied, she was referred for immediate surgery. Obvious perforation could not be found at surgery. Cholecystectomy, insertion of a T tube into the common bile duct, placement of a duodenostomy tube and drainage of the retroperitoneum were performed. She did well postoperatively and was discharged home on postoperative day 28. In conclusion, as it is well recognized that perforation is one of the most serious complication related to ERCP, liver parenchyma perforation should be suspected as a cause.

Dental plaque biofilms cause various dental diseases; therefore, inhibiting the growths of the dental plaque bacteria which produce biofilms can be a strategy for preventing dental disease. Certain sulfated polysaccharides from marine algae exert antimicrobial activities against human bacterial pathogens in addition to their physiological benefits. On the basis of these observations, the antimicrobial and antibiofilm activities of sulfated polysaccharides from different marine algae were evaluated against dental plaque bacteria. Among the sulfated polysaccharides, a fucoidan from Fucus vesiculosus showed notable antimicrobial activities against the selected dental plaque bacteria, including some foodborne pathogenic bacteria. The minimum inhibitory concentrations were of 125 to 1000 µg mL−1. Regarding the antibiofilm activity, the fucoidan at the concentrations of above 250 µg mL−1 completely suppressed the biofilm formations and planktonic cell growths of Streptococcus mutans and S. sobrinus. However, no eliminative effect on the completed biofilm was observed. The fucoidan consisted of almost fucose base polysaccharide containing approximately 14.0% sulfate content. The average molecular weight of the fucoidan was changed by heat treatment (121 °C for 15 min) and it affected the antimicrobial activity.

ABSTRACT: To examine effects of volatile anesthetics (VAs) on steroidogenesis, cell suspensions of isolated bovine adrenocortical cells were incubated with several steroidogenic agents in the presence or absence of halothane and sevoflurane. The adrenocortical cells were dispersed by trypsin digestion of bovine adrenal cortex. The cortisol level was measured fluorometrically. VAs inhibited adrenocorticotropic hormone-, acetylcholine-, angiotensin-II-, and KCl-stimulated steroidogenesis in a concentration-dependent manner with extracellular Ca2+. However, dibutyryl cyclic adenosine monophosphate-stimulated steroidogenesis was not inhibited by VAs. These results suggest that VAs inhibit steroidogenesis by blocking Ca2+-influx from the extracellular space without influencing the action of intracellular cyclic nucleotides.

Precipitable water, total moisture flux and its convergence are calculated based on the 6-year (1986-1991) twice-daily U.S. NMC data to investigate the atmospheric water circulation in the Antarctic region. The precipitable water becomes large in summer, but the zonal mean poleward moisture flux and its convergence, which corresponds to "precipitation minus evaporation", become large in winter and they also exhibit semi-annual variation. This is because the seasonal variation of moisture flux and its convergence is mainly controlled by the cyclonic activity in the Antarctic region. The westward moisture flux, which does not exist in the Arctic region, is seen poleward of 70° along the Antarctic continent and it is significant in summer. It is found that the atmospheric water circulation in the Antarctic region is very active compared with the global mean, especially in winter.

The climate memory of a land surface generally persists for only a few months, but analysis of surface meteorological data revealed a longer-term climate memory carried by soil freeze–thaw processes in Siberia. Surface temperature variability during the snowmelt season corresponds reasonably well with that in the summer of the following year, when most stations show a secondary autocorrelation peak. The surface temperature memory is thought to be stored as variations in the amount of snowmelt water held in the soil, and through soil freezing, which emerges as latent heat variations in the near-surface atmosphere during soil thawing approximately one year later. The ground conditions are dry in the longer-term climate memory regions, such as eastern Siberia, where less snow cover (higher surface air temperature) in spring results in less snowmelt water or lower soil moisture in the summer. Consequently, through soil freezing, it will require less latent heat to thaw in the summer of the following year, resulting in higher surface air temperature. In addition to soil moisture and snow cover, soil freeze–thaw processes can also act as agents of climate memory in the near-surface atmosphere.