First report of surgery for congenital biliary dilatation using the hinotori™ Surgical Robot System (with video).

Robot-assisted surgery for congenital biliary dilatation has been evolving primarily with the da Vinci® Surgical System. The hinotori™ Surgical Robot System, developed in Japan, received approval for gastroenterological surgery in 2022. We present the inaugural case of congenital biliary dilatation surgery utilizing the hinotori™ system. A 57-year-old woman was referred to our institution for evaluation and treatment of common bile duct dilatation classified under Todani Type Ia congenital biliary dilatation. Robotic resection of the extrahepatic bile duct and hepaticojejunostomy with Roux-en-Y were performed. The operation lasted 292 min with minimal blood loss (10 mL). The patient had an uneventful postoperative course and was discharged 10 days after surgery. Robotic surgery using the hinotori™ system for congenital biliary dilatation can be safely performed.

Metabolic reprogramming by mutant GNAS creates an actionable dependency in intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: Oncogenic 'hotspot' mutations of KRAS and GNAS are two major driver alterations in intraductal papillary mucinous neoplasms (IPMNs), which are bona fide precursors to pancreatic ductal adenocarcinoma. We previously reported that pancreas-specific Kras G12D and Gnas R201C co-expression in p48Cre; KrasLSL-G12D; Rosa26LSL-rtTA; Tg (TetO-GnasR201C) mice ('Kras;Gnas' mice) caused development of cystic lesions recapitulating IPMNs. OBJECTIVE: We aim to unveil the consequences of mutant Gnas R201C expression on phenotype, transcriptomic profile and genomic dependencies. DESIGN: We performed multimodal transcriptional profiling (bulk RNA sequencing, single-cell RNA sequencing and spatial transcriptomics) in the 'Kras;Gnas' autochthonous model and tumour-derived cell lines (Kras;Gnas cells), where Gnas R201C expression is inducible. A genome-wide CRISPR/Cas9 screen was conducted to identify potential vulnerabilities in KrasG12D;GnasR201C co-expressing cells. RESULTS: Induction of Gnas R201C-and resulting G(s)alpha signalling-leads to the emergence of a gene signature of gastric (pyloric type) metaplasia in pancreatic neoplastic epithelial cells. CRISPR screening identified the synthetic essentiality of glycolysis-related genes Gpi1 and Slc2a1 in Kras G12D;Gnas R201C co-expressing cells. Real-time metabolic analyses in Kras;Gnas cells and autochthonous Kras;Gnas model confirmed enhanced glycolysis on Gnas R201C induction. Induction of Gnas R201C made Kras G12D expressing cells more dependent on glycolysis for their survival. Protein kinase A-dependent phosphorylation of the glycolytic intermediate enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) was a driver of increased glycolysis on Gnas R201C induction. CONCLUSION: Multiple orthogonal approaches demonstrate that Kras G12D and Gnas R201C co-expression results in a gene signature of gastric pyloric metaplasia and glycolytic dependency during IPMN pathogenesis. The observed metabolic reprogramming may provide a potential target for therapeutics and interception of IPMNs.

Generation of human iPSC-derived 3D bile duct within liver organoid by incorporating human iPSC-derived blood vessel.

In fetal development, tissue interaction such as the interplay between blood vessel (BV) and epithelial tissue is crucial for organogenesis. Here we recapitulate the spatial arrangement between liver epithelial tissue and the portal vein to observe the formation of intrahepatic bile ducts (BDs) from human induced pluripotent stem cells (hiPSC). We co-culture hiPSC-liver progenitors on the artificial BV consisting of immature smooth muscle cells and endothelial cells, both derived from hiPSCs. After 3 weeks, liver progenitors within hiPSC-BV-incorporated liver organoids (BVLO) differentiate to cholangiocytes and acquire epithelial characteristics, including intercellular junctions, microvilli on the apical membrane, and secretory functions. Furthermore, liver surface transplanted-BVLO temporarily attenuates cholestatic injury symptoms. Single cell RNA sequence analysis suggests that BD interact with the BV in BVLO through TGFß and Notch pathways. Knocking out JAG1 in hiPSC-BV significantly attenuates bile duct formation, highlighting BVLO potential as a model for Alagille syndrome, a congenital biliary disease. Overall, we develop a novel 3D co-culture method that successfully establishes functional human BDs by emulating liver epithelial-BV interaction.

[A Case of BRAF Mutant Cecal Cancer Treated with Encorafenib, Binimetinib, and Cetuximab Triple Therapy].

A Japanese woman in her early 70's presented to our hospital with abdominal pain and nausea. Abdominal computed tomography showed irregular wall thickening of the ileocecal region and small intestine dilatation. Colonoscopy revealed a tumor lesion at the ileocecal valve and adenocarcinoma was detected in the biopsy specimen. Accordingly, the diagnosis was cecal cancer and bowel obstruction. Right hemicolectomy was performed as palliative surgery, and laparotomy findings revealed peritoneal dissemination. The final staging was pT4a, pN2b, pM1c, pStage Ⅳc, harboring a BRAFV600E mutation. Rapid postoperative tumor progression occurred, leading to multiple liver metastases and ascites. Encorafenib, binimetinib, and cetuximab triple therapy was started as a second line regimen. The therapy was extremely effective. CA19-9 level decreased to within normal range, and the liver tumor size was visibly diminished. After receiving treatment for 2 months in outpatient care, she had to discontinue the treatment due to carcinomatous peritonitis. Unfortunately, she died 6 months after initial diagnosis. BRAF-mutated colon cancer is associated with poor prognosis. In Japan, encorafenib, binimetinib, and cetuximab triple therapy is a new BRAF targeting regimen approved in 2020. We report this clinical course in hopes of eventually achieving better outcomes for patients with this aggressive disease.

Monoallelic KRAS (G13C) mutation triggers dysregulated expansion in induced pluripotent stem cell-derived hematopoietic progenitor cells.

BACKGROUND: Although oncogenic RAS mutants are thought to exert mutagenic effects upon blood cells, it remains uncertain how a single oncogenic RAS impacts non-transformed multipotent hematopoietic stem or progenitor cells (HPCs). Such potential pre-malignant status may characterize HPCs in patients with RAS-associated autoimmune lymphoproliferative syndrome-like disease (RALD). This study sought to elucidate the biological and molecular alterations in human HPCs carrying monoallelic mutant KRAS (G13C) with no other oncogene mutations. METHODS: We utilized induced pluripotent stem cells (iPSCs) derived from two unrelated RALD patients. Isogenic HPC pairs harboring either wild-type KRAS or monoallelic KRAS (G13C) alone obtained following differentiation enabled reliable comparative analyses. The compound screening was conducted with an established platform using KRAS (G13C) iPSCs and differentiated HPCs. RESULTS: Cell culture assays revealed that monoallelic KRAS (G13C) impacted both myeloid differentiation and expansion characteristics of iPSC-derived HPCs. Comprehensive RNA-sequencing analysis depicted close clustering of HPC samples within the isogenic group, warranting that comparative studies should be performed within the same genetic background. When compared with no stimulation, iPSC-derived KRAS (G13C)-HPCs showed marked similarity with the wild-type isogenic control in transcriptomic profiles. After stimulation with cytokines, however, KRAS (G13C)-HPCs exhibited obvious aberrant cell-cycle and apoptosis responses, compatible with "dysregulated expansion," demonstrated by molecular and biological assessment. Increased BCL-xL expression was identified amongst other molecular changes unique to mutant HPCs. With screening platforms established for therapeutic intervention, we observed selective activity against KRAS (G13C)-HPC expansion in several candidate compounds, most notably in a MEK- and a BCL-2/BCL-xL-inhibitor. These two compounds demonstrated selective inhibitory effects on KRAS (G13C)-HPCs even with primary patient samples when combined. CONCLUSIONS: Our findings indicate that a monoallelic oncogenic KRAS can confer dysregulated expansion characteristics to non-transformed HPCs, which may constitute a pathological condition in RALD hematopoiesis. The use of iPSC-based screening platforms will lead to discovering treatments that enable selective inhibition of RAS-mutated HPC clones.

Integration of Kupffer cells into human iPSC-derived liver organoids for modeling liver dysfunction in sepsis.

Maximizing the potential of human liver organoids (LOs) for modeling human septic liver requires the integration of innate immune cells, particularly resident macrophage Kupffer cells. In this study, we present a strategy to generate LOs containing Kupffer cells (KuLOs) by recapitulating fetal liver hematopoiesis using human induced pluripotent stem cell (hiPSC)-derived erythro-myeloid progenitors (EMPs), the origin of tissue-resident macrophages, and hiPSC-derived LOs. Remarkably, LOs actively promote EMP hematopoiesis toward myeloid and erythroid lineages. Moreover, supplementing with macrophage colony-stimulating factor (M-CSF) proves crucial in sustaining the hematopoietic population during the establishment of KuLOs. Exposing KuLOs to sepsis-like endotoxins leads to significant organoid dysfunction that closely resembles the pathological characteristics of the human septic liver. Furthermore, we observe a notable functional recovery in KuLOs upon endotoxin elimination, which is accelerated by using Toll-like receptor-4-directed endotoxin antagonist. Our study represents a comprehensive framework for integrating hematopoietic cells into organoids, facilitating in-depth investigations into inflammation-mediated liver pathologies.

Functional evaluation of rare OASL variants by analysis of SLE patient-derived iPSCs.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by genetic heterogeneity and an interferon (IFN) signature. The overall landscapes of the heritability of SLE remains unclear. OBJECTIVES: To identify and elucidate the biological functions of rare variants underlying SLE, we conducted analyses of patient-derived induced pluripotent stem cells (iPSCs) in combination with genetic analysis. METHODS: Two familial SLE patient- and two healthy donor (HD)-derived iPSCs were established. Type 1 IFN-secreting dendritic cells (DCs) were differentiated from iPSCs. Genetic analyses of SLE-iPSCs, and 117 SLE patients and 107 HDs in the ImmuNexUT database were performed independently. Genome editing of the variants on iPSCs was performed with the CRISPR/Cas9 system. RESULTS: Type 1 IFN secretion was significantly increased in DCs differentiated from SLE-iPSCs compared to HD-iPSCs. Genetic analyses revealed a rare variant in the 2'-5'-Oligoadenylate Synthetase Like (OASL) shared between SLE-iPSCs and another independent SLE patient, and significant accumulation of OASL variants among SLE patients (HD 0.93%, SLE 6.84%, OR 8.387) in the database. Genome editing of mutated OASL 202Q to wild-type 202 R or wild-type OASL 202 R to mutated 202Q resulted in reduced or enhanced Type 1 IFN secretion of DCs. Three other OASL variants (R60W, T261S and A447V) accumulated in SLE patients had also capacities to enhance Type 1 IFN secretion in response to dsRNA. CONCLUSIONS: We established a patient-derived iPSC-based strategy to investigate the linkage of genotype and phenotype in autoimmune diseases. Detailed case-based investigations using patient-derived iPSCs provide information to unveil the heritability of the pathogenesis of autoimmune diseases.

PDGF Receptors and Signaling Are Required for 3D-Structure Formation and Differentiation of Human iPSC-Derived Hepatic Spheroids.

Human iPSC-derived liver organoids (LO) or hepatic spheroids (HS) have attracted widespread interest, and the numerous studies on them have recently provided various production protocols. However, the mechanism by which the 3D structures of LO and HS are formed from the 2D-cultured cells and the mechanism of the LO and HS maturation remain largely unknown. In this study, we demonstrate that PDGFRA is specifically induced in the cells that are suitable for HS formation and that PDGF receptors and signaling are required for HS formation and maturation. Additionally, in vivo, we show that the localization of PDGFRα is in complete agreement with mouse E9.5 hepatoblasts, which begin to form the 3D-structural liver bud from the single layer. Our results present that PDGFRA play important roles for 3D structure formation and maturation of hepatocytes in vitro and in vivo and provide a clue to elucidate the hepatocyte differentiation mechanism.

The Drosophila AWP1 ortholog Doctor No regulates JAK/STAT signaling for left-right asymmetry in the gut by promoting receptor endocytosis.

Many organs of Drosophila show stereotypical left-right (LR) asymmetry; however, the underlying mechanisms remain elusive. Here, we have identified an evolutionarily conserved ubiquitin-binding protein, AWP1/Doctor No (Drn), as a factor required for LR asymmetry in the embryonic anterior gut. We found that drn is essential in the circular visceral muscle cells of the midgut for JAK/STAT signaling, which contributes to the first known cue for anterior gut lateralization via LR asymmetric nuclear rearrangement. Embryos homozygous for drn and lacking its maternal contribution showed phenotypes similar to those with depleted JAK/STAT signaling, suggesting that Drn is a general component of JAK/STAT signaling. Absence of Drn resulted in specific accumulation of Domeless (Dome), the receptor for ligands in the JAK/STAT signaling pathway, in intracellular compartments, including ubiquitylated cargos. Dome colocalized with Drn in wild-type Drosophila. These results suggest that Drn is required for the endocytic trafficking of Dome, which is a crucial step for activation of JAK/STAT signaling and the subsequent degradation of Dome. The roles of AWP1/Drn in activating JAK/STAT signaling and in LR asymmetric development may be conserved in various organisms.

CIRO: COVID-19 infection risk ontology.

Public health authorities perform contact tracing for highly contagious agents to identify close contacts with the infected cases. However, during the pandemic caused by coronavirus disease 2019 (COVID-19), this operation was not employed in countries with high patient volumes. Meanwhile, the Japanese government conducted this operation, thereby contributing to the control of infections, at the cost of arduous manual labor by public health officials. To ease the burden of the officials, this study attempted to automate the assessment of each person's infection risk through an ontology, called COVID-19 Infection Risk Ontology (CIRO). This ontology expresses infection risks of COVID-19 formulated by the Japanese government, toward automated assessment of infection risks of individuals, using Resource Description Framework (RDF) and SPARQL (SPARQL Protocol and RDF Query Language) queries. For evaluation, we demonstrated that the knowledge graph built could infer the risks, formulated by the government. Moreover, we conducted reasoning experiments to analyze the computational efficiency. The experiments demonstrated usefulness of the knowledge processing, and identified issues left for deployment.

Patients' acceptance of placebo antibiotics in Japan: a prescription for antimicrobial resistance.

BACKGROUND: The generalized use of antibiotics has led to the emergence of bacteria which are resistant to antimicrobial agents. This stems in part from the patient's tendencies to seek antibiotics for diseases when not necessary. Hence, this article investigated patient acceptance of prescribing placebos as a substitute for unnecessary antibiotics in Japan, where physicians are under severe time constraints and are unable to offer explanations and persuade patients who demand unnecessary antibiotics prescription. METHODS: A web-based questionnaire was administered to assess patients' acceptance of the placebo treatment under informed consent. One thousand participants representing all genders and age-class were randomly selected from the online panel of a web-survey company. RESULTS: The results showed that 67.9% of the participants were "satisfied" to receive such treatments, whereas 20.6% indicated acceptance of the prescription but without satisfaction. In total, 88.5% of the participants accepted the prescription of placebo, a result consistent with that of a preceding study on placebo treatments conducted in the United States. In the survey, tone of persuasion did not affect the patients' attitudes; however, patients who were loyal to their physicians exhibited lower refusal rates. CONCLUSION: The survey results showed that the prescription of "ethical placebos" could be an acceptable option for the patients in Japan. For ethical concerns, an additional literature survey was conducted and the result suggested that such a radical treatment option could be justified, provided that the prescription benefits patients and informed consent is properly obtained. Albeit it is impractical to use, because of ethical and operational concerns, it would be worth further investigation to ensure diversity in the countermeasures for antimicrobial resistance, a major public health threat nowadays.

Loss of Rnf43 Accelerates Kras-Mediated Neoplasia and Remodels the Tumor Immune Microenvironment in Pancreatic Adenocarcinoma.

BACKGROUND & AIMS: RNF43 is an E3 ubiquitin ligase that is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC) and precursor cystic neoplasms of the pancreas. The impact of RNF43 mutations on PDAC is poorly understood and autochthonous models have not been characterized sufficiently. In this study, we describe a genetically engineered mouse model (GEMM) of PDAC with conditional expression of oncogenic Kras and deletion of the catalytic domain of Rnf43 in exocrine cells. METHODS: We generated Ptf1a-Cre;LSL-KrasG12D;Rnf43flox/flox (KRC) and Ptf1a-Cre; LSL-KrasG12D (KC) mice and animal survival was assessed. KRC mice were sacrificed at 2 months, 4 months, and at moribund status followed by analysis of pancreata by single-cell RNA sequencing. Comparative analyses between moribund KRC and a moribund Kras/Tp53-driven PDAC GEMM (KPC) was performed. Cell lines were isolated from KRC and KC tumors and interrogated by cytokine array analyses, ATAC sequencing, and in vitro drug assays. KRC GEMMs were also treated with an anti-CTLA4 neutralizing antibody with treatment response measured by magnetic response imaging. RESULTS: We demonstrate that KRC mice display a marked increase in incidence of high-grade cystic lesions of the pancreas and PDAC compared with KC. Importantly, KRC mice have a significantly decreased survival compared with KC mice. Using single-cell RNA sequencing, we demonstrated that KRC tumor progression is accompanied by a decrease in macrophages, as well as an increase in T and B lymphocytes, with evidence of increased immune checkpoint molecule expression and affinity maturation, respectively. This was in stark contrast to the tumor immune microenvironment observed in the KPC PDAC GEMM. Furthermore, expression of the chemokine CXCL5 was found to be specifically decreased in KRC cancer cells by means of epigenetic regulation and emerged as a putative candidate for mediating the unique KRC immune landscape. CONCLUSIONS: The KRC GEMM establishes RNF43 as a bona fide tumor suppressor gene in PDAC. This GEMM features a markedly different immune microenvironment compared with previously reported PDAC GEMMs and puts forth a rationale for an immunotherapy approach in this subset of PDAC cases.

Exploring optimal granularity for extractive summarization of unstructured health records: Analysis of the largest multi-institutional archive of health records in Japan.

Automated summarization of clinical texts can reduce the burden of medical professionals. "Discharge summaries" are one promising application of the summarization, because they can be generated from daily inpatient records. Our preliminary experiment suggests that 20-31% of the descriptions in discharge summaries overlap with the content of the inpatient records. However, it remains unclear how the summaries should be generated from the unstructured source. To decompose the physician's summarization process, this study aimed to identify the optimal granularity in summarization. We first defined three types of summarization units with different granularities to compare the performance of the discharge summary generation: whole sentences, clinical segments, and clauses. We defined clinical segments in this study, aiming to express the smallest medically meaningful concepts. To obtain the clinical segments, it was necessary to automatically split the texts in the first stage of the pipeline. Accordingly, we compared rule-based methods and a machine learning method, and the latter outperformed the formers with an F1 score of 0.846 in the splitting task. Next, we experimentally measured the accuracy of extractive summarization using the three types of units, based on the ROUGE-1 metric, on a multi-institutional national archive of health records in Japan. The measured accuracies of extractive summarization using whole sentences, clinical segments, and clauses were 31.91, 36.15, and 25.18, respectively. We found that the clinical segments yielded higher accuracy than sentences and clauses. This result indicates that summarization of inpatient records demands finer granularity than sentence-oriented processing. Although we used only Japanese health records, it can be interpreted as follows: physicians extract "concepts of medical significance" from patient records and recombine them in new contexts when summarizing chronological clinical records, rather than simply copying and pasting topic sentences. This observation suggests that a discharge summary is created by higher-order information processing over concepts on sub-sentence level, which may guide future research in this field.

Is artificial intelligence capable of generating hospital discharge summaries from inpatient records?

Medical professionals have been burdened by clerical work, and artificial intelligence may efficiently support physicians by generating clinical summaries. However, whether hospital discharge summaries can be generated automatically from inpatient records stored in electronic health records remains unclear. Therefore, this study investigated the sources of information in discharge summaries. First, the discharge summaries were automatically split into fine-grained segments, such as those representing medical expressions, using a machine learning model from a previous study. Second, these segments in the discharge summaries that did not originate from inpatient records were filtered out. This was performed by calculating the n-gram overlap between inpatient records and discharge summaries. The final source origin decision was made manually. Finally, to reveal the specific sources (e.g., referral documents, prescriptions, and physician's memory) from which the segments originated, they were manually classified by consulting medical professionals. For further and deeper analysis, this study designed and annotated clinical role labels that represent the subjectivity of the expressions and builds a machine learning model to assign them automatically. The analysis results revealed the following: First, 39% of the information in the discharge summary originated from external sources other than inpatient records. Second, patient's past clinical records constituted 43%, and patient referral documents constituted 18% of the expressions derived from external sources. Third, 11% of the missing information was not derived from any documents. These are possibly derived from physicians' memories or reasoning. According to these results, end-to-end summarization using machine learning is considered infeasible. Machine summarization with an assisted post-editing process is the best fit for this problem domain.

Alteration in meibum lipid composition and subjective symptoms due to aging and meibomian gland dysfunction.

PURPOSE: To investigate the alteration in lipid composition of meibum, objective clinical signs, and subjective symptoms associated with aging and meibomian gland (MG) dysfunction (MGD). METHODS: In 10 MGD patients [4 males/6 females, mean age: 65.6 ± 7.9 years (range: 50-79 years)] and 24 healthy volunteer subjects [young subjects: 6 males/6 females, mean age: 25.7 ± 3.8 years (range: 20-35 years), elderly subjects: 6 males/6 females, mean age: 58.4 ± 7.5 years (range: 50-79 years)], three objective clinical signs were evaluated: MG orifice obstruction, meibum score, and tear film lipid layer interference pattern. Subjective symptoms were analyzed via a 15-item questionnaire. After careful collection of meibum samples, comprehensive lipid analysis was performed via liquid chromatography-mass spectrometry. Data was analyzed via JMP® ver. 13 (SAS Institute, Inc., Cary, NC) statistical analysis software. RESULTS: In the MGD patients and elderly subjects, there was a significant decrease in non-polar lipids such as cholesterol esters (ChEs), while a significant increase in polar lipids [cholesterol (Ch), (O-acyl)-ω-hydroxy fatty acid (OAHFA), and free fatty acid (FA)] in total lipids (Tukey-Kramer test: p < 0.05). Triglyceride was significantly increased only in MGD patients (p < 0.05). Symptom scores representative of vision quality (i.e., blurred vision/haziness) were significantly negatively-correlated with the ratio of the non-polar lipid ChE, while significantly positively correlated with the polar lipids Ch, OAHFA, and FA (Spearman's rank correlation coefficient: p < 0.05). CONCLUSIONS: Our findings revealed that both MGD and aging affect the composition ratio of major meibum lipids, resulting in the appearance of subjective symptoms.

Membrane-bound MMP-14 protease-activatable adeno-associated viral vectors for gene delivery to pancreatic tumors.

Adeno-associated virus' (AAV) relatively simple structure makes it accommodating for engineering into controllable delivery platforms. Cancer, such as pancreatic ductal adenocarcinoma (PDAC), are often characterized by upregulation of membrane-bound proteins, such as MMP-14, that propagate survival integrin signaling. In order to target tumors, we have engineered an MMP-14 protease-activatable AAV vector that responds to both membrane-bound and extracellularly active MMPs. This "provector" was generated by inserting a tetra-aspartic acid inactivating motif flanked by the MMP-14 cleavage sequence IPESLRAG into the capsid subunits. The MMP-14 provector shows lower background transduction than previously developed provectors, leading to a 9.5-fold increase in transduction ability. In a murine model of PDAC, the MMP-14 provector shows increased delivery to an allograft tumor. This proof-of-concept study illustrates the possibilities of membrane-bound protease-activatable gene therapies to target tumors.

Improvement of Evaporative Dry Eye With Meibomian Gland Dysfunction in Model Mice by Treatment With Ophthalmic Solution Containing Mineral Oil.

Purpose: Meibomian gland dysfunction (MGD) is a major cause of evaporative dry eye. The purpose of this study is to assess the efficacy of a mineral oil-containing ophthalmic solution (MO) in mitigating the evaporative dry eye phenotypes in a mouse model in which fatty acid elongase Elovl1 is disrupted. Methods: Elovl1-deficient mice were assessed in terms of number of plugged meibomian gland orifices, tear film breakup time (BUT), corneal fluorescein staining (CFS) score, tear quantity, and histology. The effects of the MO on the dry eye phenotypes were compared with those in groups not treated or treated with blank ophthalmic solution (BL). Results: Untreated Elovl1-deficient mice exhibited dry eye phenotypes with MGD symptoms such as plugging of meibomian gland orifices (P = 0.002 compared with control mice), high CFS scores (P = 0.002), and shortened BUT (P < 0.001). Among three groups of Elovl1-deficient mice (MO treated, BL treated, and untreated), the MO-treated group exhibited fewer plugged orifices (MO treated, 7.6; BL treated, 10.5 [P = 0.033]; untreated, 13.0 [P < 0.001]), lower CFS scores (MO treated, 1.1; BL treated, 2.7 [P = 0.013]; untreated, 2.5 [P = 0.050]), and improved BUT (MO treated, 19.4 seconds; BL treated, 8.3 seconds [P = 0.098]; untreated, 1.5 seconds [P = 0.008]). Conclusions: Elovl1-deficient mice exhibited multiple MGD symptoms, which were improved by MO. Translational Relevance: Our findings reveal the usefulness of Elovl1-deficient mice as a model for dry eye with MGD and suggest the potential of mineral oil eye drops as a treatment for this condition.

Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic reaction caused by cancer-associated fibroblasts (CAFs), which provokes treatment resistance. CAFs are newly proposed to be heterogeneous populations with different functions within the PDAC microenvironment. The most direct sources of CAFs are resident tissue fibroblasts and mesenchymal stem cells, however, the origins and functions of CAF subtypes remain unclear. Here, we established allogeneic bone marrow (BM) transplantation models using spontaneous PDAC mice, and then investigated what subtype cells derived from BM modulate the tumor microenvironment and affect the behavior of pancreatic cancer cells (PCCs). BM-derived multilineage hematopoietic cells were engrafted in recipient pancreas, and accumulated at the invasive front and central lesion of PDAC. We identified BM macrophages-derived CAFs in tumors. BM-derived macrophages treated with PCC-conditioned media expressed CAF markers. BM-derived macrophages led the local invasion of PCCs in vitro and enhanced the tumor invasive growth in vivo. Our data suggest that BM-derived cells are recruited to the pancreas during carcinogenesis and that the specific subpopulation of BM-derived macrophages partially converted into CAF-like cells, acted as leading cells, and facilitated pancreatic cancer progression. The control of the conversion of BM-derived macrophages into CAF-like cells may be a novel therapeutic strategy to suppress tumor growth.

Strategies for the efficient use of diagnostic resource under constraints: a model-based study on overflow of patients and insufficient diagnostic kits.

This article addresses an optimisation problem of distributing rapid diagnostic kits among patients when the demands far surpass the supplies. This problem has not been given much attention in the field, and therefore, this article aims to provide a preliminary result in this problem domain. First, we describe the problem and define the goal of the optimisation by introducing an evaluation metric that measures the efficiency of the distribution strategies. Then, we propose two simple strategies, and a strategy that incorporates a prediction of patients' visits utilising a standard epidemic model. The strategies were evaluated using the metric, with past statistics in Kitami City, Hokkaido, Japan, and the prediction-based strategy outperformed the other distribution strategies. We discuss the properties of the strategies and the limitations of the proposed approach. Although the problem must be generalised before the actual deployment of the suggested strategy, the preliminary result is promising in its ability to address the shortage of diagnostic capacity currently observed worldwide because of the ongoing coronavirus disease pandemic.

De-identifying free text of Japanese electronic health records.

BACKGROUND: Recently, more electronic data sources are becoming available in the healthcare domain. Electronic health records (EHRs), with their vast amounts of potentially available data, can greatly improve healthcare. Although EHR de-identification is necessary to protect personal information, automatic de-identification of Japanese language EHRs has not been studied sufficiently. This study was conducted to raise de-identification performance for Japanese EHRs through classic machine learning, deep learning, and rule-based methods, depending on the dataset. RESULTS: Using three datasets, we implemented de-identification systems for Japanese EHRs and compared the de-identification performances found for rule-based, Conditional Random Fields (CRF), and Long-Short Term Memory (LSTM)-based methods. Gold standard tags for de-identification are annotated manually for age, hospital, person, sex, and time. We used different combinations of our datasets to train and evaluate our three methods. Our best F1-scores were 84.23, 68.19, and 81.67 points, respectively, for evaluations of the MedNLP dataset, a dummy EHR dataset that was virtually written by a medical doctor, and a Pathology Report dataset. Our LSTM-based method was the best performing, except for the MedNLP dataset. The rule-based method was best for the MedNLP dataset. The LSTM-based method achieved a good score of 83.07 points for this MedNLP dataset, which differs by 1.16 points from the best score obtained using the rule-based method. Results suggest that LSTM adapted well to different characteristics of our datasets. Our LSTM-based method performed better than our CRF-based method, yielding a 7.41 point F1-score, when applied to our Pathology Report dataset. This report is the first of study applying this LSTM-based method to any de-identification task of a Japanese EHR. CONCLUSIONS: Our LSTM-based machine learning method was able to extract named entities to be de-identified with better performance, in general, than that of our rule-based methods. However, machine learning methods are inadequate for processing expressions with low occurrence. Our future work will specifically examine the combination of LSTM and rule-based methods to achieve better performance. Our currently achieved level of performance is sufficiently higher than that of publicly available Japanese de-identification tools. Therefore, our system will be applied to actual de-identification tasks in hospitals.