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Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'II: foundational building blocks-context, community and health', authors address the following themes: 'Context-grounding family medicine in time, place and being', 'Recentring community', 'Community-oriented primary care', 'Embeddedness in practice', 'The meaning of health', 'Disease, illness and sickness-core concepts', 'The biopsychosocial model', 'The biopsychosocial approach' and 'Family medicine as social medicine.' May readers grasp new implications for medical education and practice in these essays., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tuberculosis (TB) incidence rates in the Republic of the Marshall Islands are among the highest in the world, 480/100,000 in 2017. In response, the Health Ministry completed islandwide screening in Ebeye Island in 2017., Methods: Participants were interviewed to obtain TB history, exposures, and symptoms. TB assessment included chest radiography with sputum collection for GeneXpert® MTB-RIF if indicated. TB diagnosis was made by consensus of visiting TB experts. Participants were also screened for Hansen's disease (HD) and diabetes mellitus (DM). For persons aged ≥21 years, blood pressure, cholesterol, and blood glucose were assessed., Results: A total of 5,166 persons (90.0 % of target population) completed screening leading to the identification of 39 new cases of TB (755/100,000) and 14 persons with HD (270/100,000). DM was detected in 1,096 persons (27 %), including in 351 persons not previously diagnosed. The rate of hypertension was 61 % and of hypercholesterolemia was 15 %. New or prevalent TB diagnosis was associated with newly diagnosed or history of DM (aOR 4.68, 2.15-10.20)., Conclusions: In Ebeye, an integrated TB screening campaign found TB, HD, DM, and hypertension. TB and DM were strongly associated., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Long non-coding RNA (lncRNA) plays an important role in the regulation of gene expression in normal and cancer cells. We previously discovered a novel tumor-suppressive lncRNA, DRAIC , in prostate cancer cells. Subsequent studies have demonstrated that DRAIC is dysregulated in various malignancies and exhibits a tumor-suppressive or pro-oncogenic function. However, details regarding its expression pattern in normal and cancerous tissues remain largely unknown. In this study, we performed chromogenic in situ hybridization (CISH) using RNAscope technology to assess DRAIC expression in formalin-fixed paraffin-embedded (FFPE) specimens. In the neuroendocrine-differentiated cancer cell line VMRC-LCD, CISH revealed a diffuse localization of DRAIC in the cytoplasm as well as specific accumulation in the nuclear compartment. DRAIC expression was comprehensively analyzed using tissue microarrays containing 89 normal and 155 tumor tissue samples. DRAIC was weakly expressed in normal epithelial cells of the colon, bronchiole, kidney, prostate, and testis. Conversely, DRAIC was moderately to highly expressed in some cancer tissues, including prostate adenocarcinoma, invasive ductal carcinoma of the breast, neuroendocrine carcinoma of the esophagus, lung adenocarcinoma, and small cell lung carcinoma. While DRAIC knockdown did not affect VMRC-LCD cellular viability and invasive ability, gene expression related to the neuroendocrine and cancer-related pathways was altered. Our expression analysis revealed the specific expression pattern of DRAIC in normal and cancerous FFPE tissues. The results presented here may lead to the elucidation of additional novel functions of DRAIC ., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Direct DNA double-strand breaks result in phosphorylation of H2AX, a variant of the histone H2 protein. Phosphorylated H2AX (γH2AX) may be a potential indicator in the evaluation of genotoxicity and hepatocarcinogenicity. In this study, γH2AX and Ki-67 were detected in the short-term responses (24 h after chemical administration) to classify genotoxic hepatocarcinogens (GHs) from non-GH chemicals. One hundred and thirty-five 6-week-old Crl: CD(SD) (SPF) male rats were treated with 22 chemicals including 11 GH and 11 non-GH, sacrificed 24 h later, and immunostained with γH2AX and Ki-67. Positivity rates of these markers were measured in the 3 liver ZONEs 1-3; portal, lobular, and central venous regions. These values were input into 3 machine learning models-Naïve Bayes, Random Forest, and k-Nearest Neighbor to classify GH and non-GH using a 10-fold cross-validation method. All 11 and 10 out of 11 GH caused significant increase in γH2AX and Ki-67 levels, respectively (P < .05). Of the 3 machine learning models, Random Forest performed the best. GH were identified with 95.0% sensitivity (76/80 GH-treated rats), 90.9% specificity (50/55 non-GH-treated rats), and 90.0% overall correct response rate using γH2AX staining, and 96.2% sensitivity (77/80), 81.8% specificity (45/55), and 90.4% overall correct response rate using Ki-67 labeling. Random Forest model using γH2AX and Ki-67 could independently predict GH in the early stage with high accuracy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Distinguishing between central nervous system lymphoma (CNSL) and CNS infectious and/or demyelinating diseases, although clinically important, is sometimes difficult even using imaging strategies and conventional cerebrospinal fluid (CSF) analyses. To determine whether detection of genetic mutations enables differentiation between these diseases and the early detection of CNSL, we performed mutational analysis using CSF liquid biopsy technique., Methods: In this study, we extracted cell-free DNA from the CSF (CSF-cfDNA) of CNSL (N = 10), CNS infectious disease (N = 10), and demyelinating disease (N = 10) patients, and performed quantitative mutational analysis by droplet-digital PCR. Conventional analyses were also performed using peripheral blood and CSF to confirm the characteristics of each disease., Results: Blood hemoglobin and albumin levels were significantly lower in CNSL than CNS infectious and demyelinating diseases, CSF cell counts were significantly higher in infectious diseases than CNSL and demyelinating diseases, and CSF-cfDNA concentrations were significantly higher in infectious diseases than CNSL and demyelinating diseases. Mutation analysis using CSF-cfDNA detected MYD88 L265P and CD79 Y196 mutations in 60% of CNSLs each, with either mutation detected in 80% of cases. Mutual existence of both mutations was identified in 40% of cases. These mutations were not detected in either infectious or demyelinating diseases, and the sensitivity and specificity of detecting either MYD88/CD79B mutations in CNSL were 80% and 100%, respectively. In the four cases biopsied, the median time from collecting CSF with the detected mutations to definitive diagnosis by conventional methods was 22.5 days (range, 18-93 days)., Conclusions: These results suggest that mutation analysis using CSF-cfDNA might be useful for differentiating CNSL from CNS infectious/demyelinating diseases and for early detection of CNSL, even in cases where brain biopsy is difficult to perform., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

As AI technologies progress, social acceptance of AI agents, including intelligent virtual agents and robots, is becoming even more important for more applications of AI in human society. One way to improve the relationship between humans and anthropomorphic agents is to have humans empathize with the agents. By empathizing, humans act positively and kindly toward agents, which makes it easier for them to accept the agents. In this study, we focus on self-disclosure from agents to humans in order to increase empathy felt by humans toward anthropomorphic agents. We experimentally investigate the possibility that self-disclosure from an agent facilitates human empathy. We formulate hypotheses and experimentally analyze and discuss the conditions in which humans have more empathy toward agents. Experiments were conducted with a three-way mixed plan, and the factors were the agents' appearance (human, robot), self-disclosure (high-relevance self-disclosure, low-relevance self-disclosure, no self-disclosure), and empathy before/after a video stimulus. An analysis of variance (ANOVA) was performed using data from 918 participants. We found that the appearance factor did not have a main effect, and self-disclosure that was highly relevant to the scenario used facilitated more human empathy with a statistically significant difference. We also found that no self-disclosure suppressed empathy. These results support our hypotheses. This study reveals that self-disclosure represents an important characteristic of anthropomorphic agents which helps humans to accept them., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Tsumura, Yamada. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Distinguishing primary central nervous system lymphoma (PCNSL) from glioblastoma, isocitrate dehydrogenase (IDH)-wildtype is sometimes hard. Because the role of operation on them varies, accurate preoperative diagnosis is crucial. In this study, we evaluated whether a specific kind of chemical exchange saturation transfer imaging, i.e., amide proton transfer-weighted (APTw) imaging, was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. A total of 14 PCNSL and 27 glioblastoma, IDH-wildtype cases were evaluated. There was no significant difference in the mean APTw signal values between the two groups. However, the percentile values from the 1st percentile to the 20th percentile APTw signals and the width 1-100 APTw signals significantly differed. The highest area under the curve was 0.796, which was obtained from the width 1-100 APTw signal values. The sensitivity and specificity values were 64.3% and 88.9%, respectively. APTw imaging was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. To avoid unnecessary aggressive surgical resection, APTw imaging is recommended for cases in which PCNSL is one of the differential diagnoses.

Increasing numbers of medical students participate in international electives. However, this recent trend has yet to be examined in non-Western high-income countries such as Japan. The aim of this study is to assess recent trends in Japan, and to suggest ways in which those trends might be influenced. A retrospective cross-sectional analysis of responses to an 8-item questionnaire sent in August 2019 to 82 medical schools in Japan is reported. The responses were received in September 2019. Narrative responses were obtained regarding rationales for exchange programs, participant feedback, and challenges encountered. Responses were translated into English and categorized into themes. Of 82 Japanese medical schools, 56 (68%) responded to the questionnaire. Both the number of incoming and outgoing exchange students had increased steadily over the preceding 3-year period. The leading destinations for Japanese students were the United States (30%), other Asian (36%), and European countries (24%). Narrative responses reveal different rationales from those reported by medical schools in Western high-income countries. Only a few Japanese students chose low or middle-income countries as their destinations, as opposed to the trend seen in Western high-income countries. The reported challenges encountered by the exchange programs may provide insights for improvement. Exchanges have been greatly affected by the coronavirus disease 2019 pandemic. The results can serve as pre-pandemic baseline data and should promote further international collaboration for medical education under current circumstances., (©Copyright 2022 by University Health Partners of Hawai‘i (UHP Hawai‘i).)

Background: A leiomyosarcoma of the gastrointestinal tract is extremely rare. We report a case of jejunal leiomyosarcoma with intestinal intussusception at the angle of Treitz that was successfully treated with laparoscopic resection followed by intracorporeal reconstruction using a delta-shaped anastomosis., Case Presentation: A 54-year-old man was referred to our hospital due to fatigue and loss of appetite. Blood tests showed anemia. Enteroscopy and subsequent enterography using meglumine sodium amidotrizoate showed easily hemorrhagic tumor (10 cm in diameter) in the jejunum just beyond the angle of Treitz. Contrast-enhanced computed tomography revealed jejunojejunal intussusception. Histopathological examination of a biopsy specimen revealed a leiomyosarcoma. Laparoscopic resection of the tumor without reduction of the intussusception was performed. The resected line of the proximal intestine was very close to the ligament of Treitz in the present case. Intracorporeal jejunojejunostomy was completed using a delta-shaped anastomosis, wherein anastomosis was performed between the posterior walls of the proximal and distal jejunums after minimal mobilization around the ligament of Treitz. The patient's postoperative course was uneventful, and he was discharged at 10 days postoperatively. No recurrence has been observed within 2 years after surgery., Conclusions: We present a case in which a totally laparoscopic surgery for leiomyosarcoma located at the angle of Treitz with jejunojejunal intussusception was performed successfully., (© 2022. The Author(s).)

Macrophages are classified into two phenotypes, M1 and M2, based on their roles. M2 macrophages suppress inflammation and increase in proportion to the malignancy of brain tumors. Recently, macrophage extracellular traps (METs), which change into a network, have been reported as a unique form of macrophage cell death. In this study, immunohistochemical analysis of macrophages in METs in human glioblastoma was performed. To distinguish between M1 and M2 macrophages, multiple immunostainings with Iba1 combined with CD163 or CD204 were performed. M2 macrophages were present in small amounts in normal and borderline areas but showed an increasing trend as they shifted to tumor areas, and most of them were the activated- or phagocytic-type. We also successfully detected METs coexisting with fibrin and lactoferrin near the border between the tumor and necrotic area. M2 macrophages not only suppressed inflammation but also were involved in the formation of METs. This study found that M2 macrophages play various roles in unstable situations., Competing Interests: VThe authors declare that they have no conflicts of interest., (2022 The Japan Society of Histochemistry and Cytochemistry.)

Meningiomas are a common pathology in the central nervous system requiring complete surgical resection. However, in cases of recurrence and post-irradiation, accurate identification of tumor remnants and a dural tail under bright light remains challenging. We aimed to perform real-time intraoperative visualization of the meningioma and dural tail using a delayed-window indocyanine green (ICG) technique with microscopy. Fifteen patients with intracranial meningioma received 0.5 mg/kg ICG a few hours before observation during the surgery. We used near-infrared (NIR) fluorescence to identify the tumor location. NIR fluorescence could visualize meningiomas in 12 out of 15 cases. Near-infrared visualization during the surgery ranged from 1 to 4 h after the administration of ICG. The mean signal-to-background ratio (SBR) of the intracranial meningioma in delayed-window ICG (DWIG) was 3.3 ± 2.6. The ratio of gadolinium-enhanced T1 tumor signal to the brain (T1BR) (2.5 ± 0.9) was significantly correlated with the tumor SBR ( p = 0.016). K trans , indicating blood-brain barrier permeability, was significantly correlated with tumor SBR ( p < 0.0001) and T1BR ( p = 0.013) on dynamic contrast-enhanced magnetic resonance imaging (MRI). DWIG demonstrated a sensitivity of 94%, specificity of 38%, positive predictive value (PPV) of 76%, and negative predictive value (NPV) of 75% for meningiomas. This is the first pilot study in which DWIG fluorescence-guided surgery was used to visualize meningioma and dural tail intraoperatively with microscopy. DWIG is comparable with second-window ICG in terms of mean SBR. Gadolinium-enhanced T1 tumor signal may predict NIR fluorescence of the intracranial meningioma. Blood-brain barrier permeability as shown by K trans on dynamic contrast-enhanced MRI can contribute to gadolinium enhancement on MRI and to ICG retention and tumor fluorescence by NIR., Competing Interests: JL owned stock options in Visionsense. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Muto, Mine, Nishiyama, Murayama, Yamada, Kojima, Hayakawa, Adachi, Hasegawa, Lee and Hirose.)

This study updates the previously-reported impact of the University of Hawai'i Family Medicine Residency Program (UHFMRP) on the state of Hawai'i family physician workforce. This study is a retrospective examination of all UHFMRP graduates from the program between 1996 and 2020. Graduate data regarding country or state of medical school, allopathic versus osteopathic training, current clinical practice, zip code of current clinical practice, current board certification, and current fellowship status were recorded between May and July 2020. Overall, 146 UHFMRP graduates completed the program between 1996 and 2020. Currently, 126 UHFMRP graduates have active medical licenses, with 121 graduates (96%, n=126) practicing in the United States, of whom 83 (69%, n=121) are practicing in Hawai'i. Of the 83 UHFMRP graduates practicing in Hawai'i, 67 graduates (81%, n=83) practice on O'ahu. UHFMRP graduates with active medical licenses in Hawai'i represent 23% (83 of 364) of the entire current family physician workforce in Hawai'i. The UHFMRP continues to make an impact on the Hawai'i State family physician workforce, and the retention rate of graduates in Hawai'i has remained relatively stable since 1996., (©Copyright 2022 by University Health Partners of Hawai‘i (UHP Hawai‘i).)

Pancreatic neuroendocrine neoplasms (PNENs) are relatively rare with a reported incidence of 1-2/100,000 and generally thought to originate from the precursor of the neuroendocrine cells including the islet and the pancreatic duct cells. About 65% of PNENs are non-functional. While insulinomas and gastrinomas are the most common functional PNENs, ACTH-producing PNENs are extremely rare. We herein present an extremely rare case of a patient with Cushing's syndrome caused by PNEN. A 46-year-old woman with edema in bilateral lower extremities and moon face was admitted with a suspicious pancreatic tumor. Enhanced computed tomography and endoscopic ultrasonography revealed a pancreatic tumor. The final diagnosis of ACTH-producing PNEN with Cushing's syndrome was based on clinical and biochemical test results and endocrinological studies. The symptoms associated Cushing's syndrome improved after pancreaticoduodenectomy for PNEN., (© 2022. Japanese Society of Gastroenterology.)

We propose an AI-assisted design concept exploration tool, the "Character Space Construction" ("CSC"). Concept designers explore and articulate the target product aesthetics and semantics in language, which is expressed using "Design Concept Phrases" ("DCPs"), that is, compound adjective phrases, and contrasting terms that convey what are not their target design concepts. Designers often utilize this dichotomy technique to communicate the nature of their aesthetic and semantic design concepts with stakeholders, especially in an early design development phase. The CSC assists this designers' cognitive activity by constructing a "Character Space" ("CS"), which is a semantic quadrant system, in a structured manner. A CS created by designers with the assistance of the CSC enables them to discern and explain their design concepts in contrast with opposing terms. These terms in a CS are retrieved and combined in the CSC by using a knowledge graph. The CSC presents terms and phrases as lists of candidates to users from which users will choose in order to define the target design concept, which is then visualized in a CS. The participants in our experiment, who were in the "arts and design" profession, were given two conditions under which to create DCPs and explain them. One group created and explained the DCPs with the assistance of the proposed CSC, and the other did the same task without this assistance, given the freedom to use any publicly available web search tools instead. The result showed that the group assisted by the CSC indicated their tasks were supported significantly better, especially in exploration, as measured by the Creativity Support Index (CSI)., Competing Interests: SS was employed by Toyota Motor Corporation and its North American subsidiary, Calty Design Research, Inc. between April 1992 and July 2007. SS was hired as a design consultant between January 2015 and July 2020 for the Concept-i project, which is introduced as an industry case study in the introduction section of this paper. This research is independent of any part of that project and the authors received no funding for the cost of this research. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sano and Yamada.)

Primary central nervous system lymphomas (PCNSLs) rarely exhibit intratumoral hemorrhage. The differential diagnosis of hemorrhagic neoplasms of the central nervous system (CNS) currently includes metastatic carcinomas, melanomas, choriocarcinomas, oligodendrogliomas, and glioblastomas. Here we present the clinical, radiological, pathological, and molecular genetic features of six cases of PCNSL associated with intratumoral hemorrhage. The median age of patients was 75 years, with male predominance. While conventional PCNSLs were associated with low cerebral blood volume (CBV), perfusion magnetic resonance imaging (MRI) revealed elevated CBV in three cases, consistent with vascular proliferation. All six cases were diagnosed pathologically as having diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell-like (non-GCB) phenotype; marked histiocytic infiltrates and abundant non-neoplastic T-cells were observed in most cases. Expression of vascular endothelial growth factor and CD105 in the lymphoma cells and the small vessels, respectively, suggested angiogenesis within the neoplasms. Neoplastic cells were immunohistochemically negative for programmed cell death ligand 1 (PD-L1), while immune cells in the microenvironment were positive for PD-L1. Mutations in the MYD88 gene (MYD88) (L265P) and the CD79B gene (CD79B) were detected in five and one case, respectively. As therapeutic modalities used for PCNSLs differ from those that target conventional hemorrhagic neoplasms, full tissue diagnoses of all hemorrhagic CNS tumors are clearly warranted., (© 2021 Japanese Society of Neuropathology.)

The human-agent team, which is a problem in which humans and autonomous agents collaborate to achieve one task, is typical in human-AI collaboration. For effective collaboration, humans want to have an effective plan, but in realistic situations, they might have difficulty calculating the best plan due to cognitive limitations. In this case, guidance from an agent that has many computational resources may be useful. However, if an agent guides the human behavior explicitly, the human may feel that they have lost autonomy and are being controlled by the agent. We therefore investigated implicit guidance offered by means of an agent's behavior. With this type of guidance, the agent acts in a way that makes it easy for the human to find an effective plan for a collaborative task, and the human can then improve the plan. Since the human improves their plan voluntarily, he or she maintains autonomy. We modeled a collaborative agent with implicit guidance by integrating the Bayesian Theory of Mind into existing collaborative-planning algorithms and demonstrated through a behavioral experiment that implicit guidance is effective for enabling humans to maintain a balance between improving their plans and retaining autonomy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nakahashi and Yamada.)

Isocitrate dehydrogenase (IDH) wild-type diffuse astrocytic tumors tend to be pathologically diagnosed as glioblastomas (GBMs). We previously reported that myoinositol to total choline (Ins/Cho) ratio in GBMs on magnetic resonance (MR) spectroscopy was significantly lower than that in IDH-mutant gliomas. We then hypothesized that a low Ins/Cho ratio is a poor prognosis factor in patients with GBMs, IDH-wild-type. In the present study, we calculated the Ins/Cho ratios of patients with GBMs and investigated their progression-free survival (PFS) and overall survival (OS) to determine their utility as prognostic marker. We classified patients with GBMs harboring wild-type IDH (n = 27) into two groups based on the Ins/Cho ratio, and compared patient backgrounds, pathological findings, PFS, OS, and copy number aberrations between the high and low Ins/Cho groups. Patients with GBMs in the low Ins/Cho ratio group indicated shorter PFS (P = 0.021) and OS (P = 0.048) than those in the high Ins/Cho group. Multivariate analysis demonstrated that the Ins/Cho ratio was significantly correlated with PFS (hazard ratio 0.24, P = 0.028). In conclusion, the preoperative Ins/Cho ratio can be used as a novel potential prognostic factor for GBM, IDH-wild-type.

Seizures are common in patients with gliomas; however, the mechanisms of epileptogenesis in gliomas have not been fully understood. This study hypothesized that analyzing quantified metabolites using magnetic resonance spectroscopy (MRS) might provide novel insights to better understand the epileptogenesis in gliomas, and specific metabolites might be indicators of preoperative seizures in gliomas. We retrospectively investigated patient information (gender, age at diagnosis of tumor, their survival time) and tumor information (location, histology, genetic features, and metabolites according to MRS) in patients with gliomas. The data were correlated with the incidence of seizure and analyzed statistically. Of 146 adult supratentorial gliomas, isocitrate dehydrogenase (IDH) mutant tumors significantly indicated higher incidence of preoperative seizures than IDH wild-type gliomas. However, MRS study indicated that glutamate concentration in IDH wild-type gliomas was higher than that in IDH mutant gliomas. Glutamate was not associated with high frequency of preoperative seizures in patients with gliomas. Instead, increased total N-acetyl-L-aspartate (tNAA) was significantly associated with them. Moreover, multivariable analysis indicated that increased level of tNAA was an independent predictor of preoperative seizures. According to MRS analysis, tNAA, rather than glutamate, might be a useful to detect preoperative seizures in patient with supratentorial gliomas.

Background: The extent of resection has been reported to be associated with overall survival in gliomas. The use of 5-aminolevulinic acid (5-ALA) has been recognized to increase the extent of tumor resection., Objective: To evaluate what factors affect the intraoperative fluorescence after administration of 5-ALA in gliomas., Methods: Correlation of intraoperative fluorescence and several clinical, radiographic, molecular biologic, and histopathologic characters was retrospectively evaluated in 104 patients (53 males and 51 females; mean age 54.2 yr) with gliomas at our institution. To clarify the mechanisms that mutant isocitrate dehydrogenase (IDH) affect the intraoperative fluorescence, in Vitro experiments using genetically engineered glioma cells harboring mutant IDH1 were performed., Results: Intraoperative fluorescence was observed in 82 patients (78.8%). In addition to age, magnetic resonance imaging enhancement, World Health Organization grades, and MIB-1 index, the status of IDH was revealed to be correlated with intraoperative fluorescence. In Vitro assay revealed that mutant IDH indirectly reduced the amount of exogenous 5-ALA-derived protoporphyrinogen IX in glioma cells by increasing activity of ferrochelatase and heme oxygenase 1., Conclusion: Mutant IDH1/2-induced metabolite changes of exogenous 5-ALA were suggested to contribute to the lesser intraoperative fluorescence in gliomas with mutant IDH1/2 than in those without., (Copyright © 2019 by the Congress of Neurological Surgeons.)

The CIC-DUX4 translocation is the most common genetic alteration of small round cell sarcomas without EWSR1 rearrangement. These "Ewing-like sarcomas" usually occur in peripheral soft tissues, and rare primary central nervous system (CNS) tumors have been described. We report a rare case of primary spinal intramedullary Ewing-like sarcoma harboring CIC-DUX4 translocation. A 23-year-old man presented with weakness in the extremities. Magnetic resonance imaging revealed a large intramedullary tumor spanning C3-C5 with heterogeneous enhancement following gadolinium administration. Histologically, most of the tumor displayed dense myeloid proliferation composed of medium- to slightly small-sized primitive cells. Postoperatively, he received local adjuvant radiation therapy without tumor progression for 10 months. Target RNA sequencing analysis revealed the CIC-DUX4 fusion gene. Methylation array analysis resulted in a diagnosis of "methylation class CNS Ewing sarcoma family tumor with CIC alteration". Although this tumor lacked characteristic histological features such as lobular structures in association with desmoplastic stroma, relatively uniform nuclei with prominent nucleoli and eosinophilic cytoplasm, which are often found in CIC-rearranged sarcomas of soft tissue, were identified. Recently, many CNS and soft tissue tumors require genetic analysis for precise diagnosis. To consider certain molecular testing, careful histological examination is essential.

Superficial siderosis is a rare disease resulting from the deposited hemosiderin owing to repeated subarachnoid hemorrhage. It has been reported that hemosiderin deposits on the brain surface and brain parenchyma causes nerve disorder, resulting in progressive and irreversible hearing loss, cerebellar ataxia and pyramidal disorder. The brain tumor is one of the cause of superficial siderosis. A 16-year-old female present a nearby hospital with complaints of absence seizure. A magnetic resonance imaging (MRI) revealed a heterogeneously enhanced mass at the right temporal lobe. Susceptibility-weighted imaging revealed diffuse and extensive superficial siderosis on the brain surface. The tumor was gross totally removed and diagnosed as glioneuronal tumor. The patient had been well, although susceptibility-weighted imaging performed one year after the surgery showed superficial siderosis remained. Early diagnosis and prevention of bleeding sources are recommended to prevent symptom progression associated with superficial siderosis. Susceptibility-weighted imaging is considered useful for early detection of superficial siderosis., Competing Interests: None

According to the 2016 World Health Organization (WHO) classification of central nervous system tumors, diffuse astrocytic and oligodendroglial tumors are differentiated by the presence of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and the combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 (1p/19q co-deletion). IDH-mutant astrocytoma often has p53 and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutation, showing the alternative lengthening of telomeres (ALT) phenotype, while IDH-mutant and 1p/19q-co-deleted oligodendroglioma often have wild-type p53 and telomerase reverse transcriptase (TERT) promoter mutation, showing telomerase activation. This study analyzed IDH, ATRX, and TERT promoter mutations, and the correlation between them. Immortalized cells overcome the telomere-related crisis by activating telomerase or ALT. In glioma, telomerase is mainly activated by TERT promoter mutation, while ALT is usually associated with ATRX mutation. Although the mechanism of how ATRX mutation induces ALT remains unclear, ATRX loss alone is believed to be insufficient to induce ALT. Treatments targeting telomere maintenance are promising.

The current study aimed to evaluate the outcomes of patients with adenocarcinoma (AC) of the uterine cervix after definitive radiotherapy (RT) and to evaluate prognostic factors, including immunity-related molecules. A total of 71 patients with AC of the uterine cervix from multiple Japanese institutions were retrospectively analysed. Histological subtypes were diagnosed according to the 2014 World Health Organization classification. All patients underwent definitive RT comprising external beam RT and intracavitary brachytherapy with or without concurrent chemotherapy. Immunohistochemical studies were performed to detect the expression of programmed cell death-ligand 1(PD-L1) and CD8. The 5-year locoregional control (LC), overall survival (OS) and progression-free survival (PFS) rates for all patients were 61.8, 49.7 and 36.1%, respectively. The LC, OS and PFS rates were not significantly different among the histological subtypes. Membranous PD-L1 expression was not significantly associated with prognosis. Patients with CD8-positive tumor-infiltrating lymphocytes (CD8+TILs) in the tumor nests had significantly better OS than patients without CD8+TILs in the tumor nests (5-year OS: 53.8 vs 23.8%, P = 0.038). As expected, the International Federation of Gynecology and Obstetrics (FIGO) stage (2008) III-IVA and maximum tumor diameter > 40 mm were significantly associated with worse prognosis. In summary, the presence of CD8+TILs in the tumor nests has the potential to be an independent favorable prognostic factor for patients with AC of the uterine cervix after definitive RT., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Safety and efficiency of human-AI collaboration often depend on how humans could appropriately calibrate their trust towards the AI agents. Over-trusting the autonomous system sometimes causes serious safety issues. Although many studies focused on the importance of system transparency in keeping proper trust calibration, the research in detecting and mitigating improper trust calibration remains very limited. To fill these research gaps, we propose a method of adaptive trust calibration that consists of a framework for detecting the inappropriate calibration status by monitoring the user's reliance behavior and cognitive cues called "trust calibration cues" to prompt the user to reinitiate trust calibration. We evaluated our framework and four types of trust calibration cues in an online experiment using a drone simulator. A total of 116 participants performed pothole inspection tasks by using the drone's automatic inspection, the reliability of which could fluctuate depending upon the weather conditions. The participants needed to decide whether to rely on automatic inspection or to do the inspection manually. The results showed that adaptively presenting simple cues could significantly promote trust calibration during over-trust., Competing Interests: The authors have declared that no competing interests exist.

The genetic features of isocitrate dehydrogenase-wild-type (IDH-wt) lower-grade gliomas (LGGs; World Health Organization grades II and III) are not well defined. This study analyzed the genetic and other features of IDH-wt LGGs to develop a subclassification that can be used to predict their prognosis. Clinical, histopathological, and genetic features of 35 cases of diffuse IDH-wt astrocytoma and IDH-wt anaplastic astrocytoma were analyzed. The following genetic factors were examined: mutations of B-rapidly accelerated fibrosarcoma, telomerase reverse transcriptase promoter (TERTp), histone 3 family 3A, and alpha-thalassemia/mental retardation syndrome, X-linked; and copy number aberrations. In the univariate analysis, the following factors were associated with poor overall survival (OS): the histopathological diagnosis, TERTp mutation, the gain of chromosome 7 (+ 7), and the loss of chromosome 10q (- 10q). In the multivariate analysis, + 7, - 10q, and TERTp mutation were independent prognostic factors associated with poor OS. The median OS was significantly worse for patients who harbored at least one of these factors than for those without any of them (18.5 vs. 54.5 months, P = 0.002). The subclassification of IDH-wt LGGs according to the genetic factors + 7, - 10q, and TERTp mutation is potentially useful for predicting the prognosis.

Objective: Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) and meningioma exhibit similar radiographic features; however, they differ in their prognoses. Preoperative differentiation between them is important for determining the treatment and follow-up plan. The aim of this study was to determine the factors that can be used to differentiate SFT/HPC from meningioma and World Health Organization (WHO) grade I from grade II meningioma., Methods: The analysis included 84 cases: 5 of SFT/HPC, 72 of WHO grade I meningioma, and 7 of WHO grade II meningioma. Clinical characteristics and conventional magnetic resonance imaging, perfusion magnetic resonance imaging, and magnetic resonance spectroscopy (MRS) LCModel parameters were evaluated via multivariate logistic regression analysis to identify the factors that distinguish SFT/HPC from meningioma., Results: Patients with SFT/HPC were mostly men and were younger than those with meningioma. The percentage of T2-weighted images in meningioma was greater than that in SFT/HPC. There were significant differences between SFT/HPC and meningioma in levels of glutamate, phosphocholine, myo-inositol, or glycerophosphocholine + phosphocholine derived from long echo-time MRS, and myo-inositol derived from short echo-time MRS. Stepwise logistic regression analysis revealed that the age of <45 years and myo-inositol in short echo-time MRS of ≧6.347 were associated with a diagnosis of SFT/HPC with high sensitivity and specificity. However, no factors were found that differentiated WHO grade I meningioma from WHO grade II meningioma., Conclusions: Age and myo-inositol level calculated from MRS are useful factors for distinguishing SFT/HPC from meningioma preoperatively., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: c-Met has been shown to be associated with tumor growth in several human cancers. This study aims to evaluate the correlation between the c-Met expression and histopathologic/clinical characteristics., Methods: A total of 153 patients with histologically defined World Health Organization grade II-IV diffuse astrocytic and oligodendroglial tumors were analyzed., Results: For each histopathologic diagnosis, the number of cases and positive rate of c-Met expression are as follows: oligodendroglioma, IDH-mutant, and 1p19q codeletion (OD): 16 cases, 6.3%; anaplastic oligodendroglioma, IDH-mutant, and 1p19q codeletion (AO): 11 cases, 36.4%; diffuse astrocytoma (DA), IDH-mutant: 21 cases, 28.6%; anaplastic astrocytoma (AA), IDH- mutant: 15 cases, 20%; glioblastoma, IDH-mutant: 2, 100%, DA, IDH-wildtype: 9 cases, 33.3%; AA, IDH-wildtype: 20 cases, 30.0%; and glioblastoma, IDH-wildtype: 59 cases, 52.5%. c-Met expression was correlated with progression-free survival in oligodendroglial tumors and glioblastoma, IDH-wildtype. Furthermore, it was correlated with overall survival in AO, oligodendroglial tumors, DA, IDH-mutant, DA, IDH-wildtype, and glioblastoma, IDH-wildtype, and tend to be correlated with overall survival in IDH-mutant lower-grade astrocytic tumors., Conclusions: c-Met expression was revealed to be a useful marker for prognosis prediction in IDH-mutant lower-grade gliomas and glioblastoma, IDH-wildtype, representing a new independent prognostic marker that can be easily measured., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Anthropomorphic agents used in online-shopping need to be trusted by users so that users feel comfortable buying products. In this paper, we propose a model for designing trustworthy agents by assuming two factors of trust, that is, emotion and knowledgeableness perceived. Our hypothesis is that when a user feels happy and perceives an agent as being highly knowledgeable, a high level of trust results between the user and agent. We conducted four experiments with participants to verify this hypothesis by preparing transition operators utilizing emotional contagion and knowledgeable utterances. As a result, we verified that users' internal states transitioned as expected and that the two factors significantly influenced their trust states.

Today's computers are becoming ever more versatile. They are used in various applications, such as for education, entertainment, and information services. In other words, computers are often required to not only inform users of information but also communicate with them socially. Previous studies explored the design of ambient light displays and suggested that such systems can convey information to people in the periphery of their attention without distracting them from their primary work. However, they mainly focused on using ambient lights to convey certain information. It is still unclear whether and how the lights can influence people's perception and decision-making. To explore this, we performed three experiments using a ping-pong game, Ultimatum game, and Give-Some game, in which we attached an LED strip to the front-bottom of a computer monitor and had it display a set of light expressions. Our evaluation of the results suggested that expressive lights do affect human perception and decision-making. Participants liked and anthropomorphized the computer more when it displayed light animations. Particularly, they perceived the computer as positive and friendlier when it displayed green and low intensity light animation, while red and high intensity light animation was perceived as negative and more hostile. They consequently behaved with more tolerance and cooperation to the computer when it was positive compared with when it was negative. The findings can open up possibilities for the design of ambient light systems for various applications where human-machine interaction is needed.

Competing Interests: COI: None declared

Molecular irreversibleness with Helicobacter pylori (H. pylori) infection might have a role in gastric tumorigenesis after H. pylori eradication. We performed comprehensive DNA methylation profiling of gastric mucosa after H. pylori eradication with or without gastric cancer. Using four different groups of biopsies obtained from gastric body without history of H. pylori infection (Hp-), gastric body without cancer after H. pylori eradication (cancer-free body), gastric body with early gastric cancer diagnosed after H. pylori eradication (EGC body) and their paired samples from adjacent mucosa of cancer (EGC ADJ), methylation status of five candidate genes (MYOD1, SLC16A12, IGF2, RORA and PRDM5) was examined by the bisulfite pyrosequencing. An Infinium Methylation EPIC BeadChip array was also used to characterize the methylation status of greater than 850,000 CpG sites. The EGC ADJ group showed highest methylation levels of five candidate genes among the four groups of biopsies. In the gastric body (cancer-free body + EGC body), methylation levels were significantly decreased in patients with longer period after eradication, while such association was not observed in EGC ADJ group. Hyper methylated samples were associated with shorter telomere, an indicator for rapid cell turnover, and higher DNMT1 protein expression, an enzyme related to methyl transfer reaction. The genome-wide methylation analysis demonstrated strikingly higher methylation levels especially at CpG islands in the EGC ADJ group. Exclusively hypermethylated promoter CpG islands in the same group frequently coded zinc finger proteins. Our data show that DNA methylation accumulation is associated with molecular irreversibleness and gastric carcinogenesis after H. pylori eradication., (© 2018 UICC.)

This commentary outlines the health insurance disparities of Compact of Free Association (COFA) migrants living in the United States. Compact of Free Association migrants are citizens of the Republic of the Marshall Islands, the Federated States of Micronesia, and the Republic of Palau who can live, work, and study in the United States without a visa. Compact of Free Association migrants make up a significant proportion of the rapidly growing Pacific Islander population in the United States. This article describes the historical and current relationships between the United States and the Compact nations and examines national policy barriers constraining health insurance access for COFA migrants. In addition, the commentary describes the state-level health policies of Arkansas, Hawai'i, and Oregon, which are the states where the majority of COFA migrants reside. Finally, policy recommendations are provided to improve health equity for COFA migrants.

Background: Single-gene mutation syndromes account for some familial glioma (FG); however, they make up only a small fraction of glioma families. Gliomas can be classified into 3 major molecular subtypes based on isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion. We hypothesized that the prevalence of molecular subtypes might differ in familial versus sporadic gliomas and that tumors in the same family should have the same molecular subtype., Methods: Participants in the FG study (Gliogene) provided samples for germline DNA analysis. Formalin-fixed, paraffin-embedded tumors were obtained from a subset of FG cases, and DNA was extracted. We analyzed tissue from 75 families, including 10 families containing a second affected family member. Copy number variation data were obtained using a first-generation Affymetrix molecular inversion probe (MIP) array., Results: Samples from 62 of 75 (83%) FG cases could be classified into the 3 subtypes. The prevalence of the molecular subtypes was: 30 (48%) IDH-wildtype, 21 (34%) IDH-mutant non-codeleted, and 11 (19%) IDH-mutant and 1p/19q codeleted. This distribution of molecular subtypes was not statistically different from that of sporadic gliomas (P = 0.54). Of 10 paired FG samples, molecular subtypes were concordant for 7 (κ = 0.59): 3 IDH-mutant non-codeleted, 2 IDH-wildtype, and 2 IDH-mutant and 1p/19q codeleted gliomas., Conclusions: Our data suggest that within individual families, patients develop gliomas of the same molecular subtype. However, we did not observe differences in the prevalence of the molecular subtypes in FG compared with sporadic gliomas. These observations provide further insight into the distribution of molecular subtypes in FG.

This article proposes a constrained clustering algorithm with competitive performance and less computation time to the state-of-the-art methods, which consists of a constrained k-means algorithm enhanced by the boosting principle. Constrained k-means clustering using constraints as background knowledge, although easy to implement and quick, has insufficient performance compared with metric learning-based methods. Since it simply adds a function into the data assignment process of the k-means algorithm to check for constraint violations, it often exploits only a small number of constraints. Metric learning-based methods, which exploit constraints to create a new metric for data similarity, have shown promising results although the methods proposed so far are often slow depending on the amount of data or number of feature dimensions. We present a method that exploits the advantages of the constrained k-means and metric learning approaches. It incorporates a mechanism for accepting constraint priorities and a metric learning framework based on the boosting principle into a constrained k-means algorithm. In the framework, a metric is learned in the form of a kernel matrix that integrates weak cluster hypotheses produced by the constrained k-means algorithm, which works as a weak learner under the boosting principle. Experimental results for 12 data sets from 3 data sources demonstrated that our method has performance competitive to those of state-of-the-art constrained clustering methods for most data sets and that it takes much less computation time. Experimental evaluation demonstrated the effectiveness of controlling the constraint priorities by using the boosting principle and that our constrained k-means algorithm functions correctly as a weak learner of boosting., (Copyright © 2018 Okabe and Yamada.)

Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy-number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A-PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n = 33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%-60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A-PXA (93%), BRAF V600E (87%), and wild-type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n = 15), +2 (n = 11), +5 (n = 10), +21 (n = 10), +20 (n = 9), +12 (n = 8), +15 (n = 8), and losses -22 (n = 11), -14 (n = 7), -13 (n = 5). Losses and copy-neutral loss of heterozygosity were significantly more common in A-PXA, involving chromosomes 22 (P = 0.009) and 14 (P = 0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P = 0.003), while other copy-number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A-PXA with areas of distinct low- and high-grade morphology (n = 2), matched primary/tumor recurrence (n = 7), or both (n = 1). Copy-number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy-number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA., (© 2017 International Society of Neuropathology.)

Humans use two distinct cognitive strategies separately to understand and predict other humans' behavior. One is mind-reading, in which an internal state such as an intention or an emotional state is assumed to be a source of a variety of behaviors. The other is behavior-reading, in which an actor's behavior is modeled based on stimulus-response associations without assuming internal states behind the behavior. We hypothesize that anthropomorphic features are key for an observer switching between these two cognitive strategies in a competitive situation. We provide support for this hypothesis through two studies using four agents with different appearances. We show that only a human agent was thought to possess both the ability to generate a variety of behaviors and internal mental states, such as minds and emotions (Study 1). We also show that humans used mixed (opposing) strategies against a human agent and exploitative strategies against the agents with mechanical appearances when they played a repeated zero-sum game (Study 2). Our findings show that humans understand that human behavior is varied; that humans have internal states, such as minds and emotions; that the behavior of machines is governed by a limited number of fixed rules; and that machines do not possess internal mental states. Our findings also suggest that the function of mind-reading is to trigger a strategy for use against agents with variable behavior and that humans exploit others who lack behavioral variability based on behavior-reading in a competitive situation.

Objectives: We compared the age at admission and the severity of illness of hospitalized Micronesians with 3 other racial/ethnic groups in Hawaii., Methods: With Hawaii Health Information Corporation inpatient data, we determined the age at admission and the severity of illness for 162,152 adult, non-pregnancy-related hospital discharges in Hawaii from 2010 to 2012. We performed multivariable linear regression analyses within major disease categories by racial/ethnic group. We created disease categories with all patient refined-diagnosis related groups., Results: Hospitalized Micronesians were significantly younger at admission than were comparison racial/ethnic groups across all patient refined-diagnosis related group categories. The severity of illness for Micronesians was significantly higher than was that of all comparison racial/ethnic groups for cardiac and infectious diseases, higher than was that of Whites and Japanese for cancer and endocrine hospitalizations, and higher than was that of Native Hawaiians for substance abuse hospitalizations., Conclusions: Micronesians were hospitalized significantly younger and often sicker than were comparison populations. Our results will be useful to researchers, state governments, and hospitals, providers, and health systems for this vulnerable group.

Approximately one in two hundred persons in the Marshall Islands have active tuberculosis (TB). We examine the historical antecedents of this situation in order to assign ethical responsibility for the present situation. Examining the antecedents in terms of Galtung's dialectic of personal versus structural violence, we can identify instances in the history of the Marshall Islands when individual subjects made decisions (personal violence) with large-scale ecologic, social, and health consequences. The roles of medical experimenters, military commanders, captains of the weapons industry in particular, and industrial capitalism in general (as the cause of global warming) are examined. In that, together with Lewontin, we also identify industrial capitalism as the cause of tuberculosis, we note that the distinction between personal versus structural violence is difficult to maintain. By identifying the cause of the tuberculosis in the Marshall Islands, we also identify what needs be done to treat and prevent it.