[A case of R0 resection in conversion surgery after duodenal stent placement for locally advanced unresectable pancreatic cancer with duodenal stenosis].

A 67-year-old man presented to our hospital with vomiting. Esophagogastroduodenoscopy revealed duodenal stenosis and atypical epithelium. A tumor in the pancreatic head, about 30mm in size, involving the superior mesenteric artery and a superior mesenteric vein was identified using abdominal contrast computed tomography (CT). Locally advanced pancreatic cancer was diagnosed in the patient through an endoscopic biopsy. Due to the duodenal stenosis complication, duodenal stent placement was conducted. After stent placement, oral intake was resumed, and improvement of the systemic condition led to chemotherapy (modified FOLFIRINOX). After chemotherapy, CT revealed decreased carcinoma progression and vascular invasion. Conversion surgery was improved, and R0 resection was achieved. Our study showed that duodenal stent placement could enhance prognosis;as a result, it was regarded as a good choice for multidisciplinary therapy.

Distributed Implementation of Full Configuration Interaction for One Trillion Determinants.

Full configuration interaction (FCI) can provide an exact molecular ground-state energy within a given basis set and serve as a benchmark for approximate methods in quantum chemical calculations, including the emerging variational quantum eigensolver. However, its exponential computational and memory requirements easily exceed the capability of a single server and limit its applicability to large molecules. In this paper, we present a distributed FCI implementation employing a hybrid parallelization scheme with multithreading and multiprocessing to expand FCI's applicability. We optimize this scheme to minimize the bottlenecks arising from interprocess communications and interthread data management. Our implementation achieves higher scalability than the naive combination of prior works and successfully calculates the exact energy of C3H8/STO-3G with 1.31 trillion determinants, which is the largest FCI calculation to the best of our knowledge. Furthermore, we provide a comprehensive list of FCI results with 136 combinations of molecules and basis sets for future evaluation and development of approximate methods.

Presenteeism in front-line physicians involved in COVID-19-related clinical practice: a national survey of employed physician members of the Japan Medical Association.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic may have increased the rate of presenteeism among front-line physicians. Presenteeism is the term used to describe attendance at work despite ill health that would normally prompt rest or absence from work. This study aimed to examine the associations between COVID-19 clinical practice and presenteeism among physicians. METHODS: A cross-sectional study was conducted from December 2021 to January 2022. The questionnaires were distributed to 21,737 employed physicians who were members of the Japan Medical Association. Presenteeism was measured by the Work Functioning Impairment Scale. Multiple logistic regression analysis was used to evaluate the association between COVID-19 clinical practice and presenteeism. RESULTS: Overall, 3,968 participants were included in the analysis, and presenteeism was observed in 13.9% of them. The rate of presenteeism significantly increased with both the number of COVID-19 patients treated and the percentage of work time spent treating these patients (both P values for trend < 0.001). In comparison to those not currently engaged in the treatment of COVID-19 patients, presenteeism was significantly higher among front-line (adjusted odds ratio [aOR] = 1.71, 95% confidence interval [CI]: 1.16-2.53) and second-line physicians supporting those in the front-line (aOR = 1.45, 95% CI: 1.17-1.78). There was no association between involvement in COVID-19 vaccination services and presenteeism. CONCLUSIONS: The burden on front-line and second-line physicians in COVID-19 clinical practice must be minimized. Employed physicians also need to recognize the importance of communicating with their workplaces about presenteeism.

Awareness, Attitudes, and Concerns Regarding Heated Tobacco Products Among Physicians in Japan.

BACKGROUND: New tobacco products, particularly heated tobacco products (HTPs), have been introduced across several international markets as alternatives to combustible products, such as cigarettes. However, there are limited studies on physicians' perceptions of HTPs. This study analyzes the awareness of HTPs among physicians and assesses their concerns and attitudes toward patients using HTPs. METHODS: A self-administered questionnaire was sent to a sample of 7,500 member physicians (6,000 male and 1,500 female) from the Japan Medical Association (JMA). The smoking status of physicians was categorized as never smokers, ever HTP smokers, current HTP smokers, and ever and current smokers of other products. Physicians' awareness and attitudes toward patients using HTPs were analyzed using descriptive statistics. The correlation between the outcomes was examined using logistic regression models, whereas physicians' concerns about HTPs were analyzed using descriptive statistics. RESULTS: Data were obtained from 5,492 physicians (21.9% women; aged 60.4; standard deviation, 12.1 years) with a response rate of 74.6%. Overall, 76.7% of the physicians had awareness of HTP, and about half of whom asked patients about using HTPs. Physicians who took longer to discuss cessation were more likely to discourage patient use. Smoking status was associated with discouraging HTP use in patients. Physicians who had experience with HTP use were primarily concerned about the products' long-term safety and less about product regulation. CONCLUSION: Japanese physicians do not have sufficient information and knowledge about HTPs. Therefore, evidence-based guidelines are required to support physicians in advising patients against HTP use.

Working hours, side work, and depressive symptoms in physicians: A nationwide cross-sectional study in Japan.

OBJECTIVES: Long working hours in Japan is a social concern. This is also true for the working hours of physicians, who often do side work in addition to working at their main hospital. New physician work regulations to be implemented in Japan require work-hour management, including side work. This study examined the association between physicians' overtime and side work hours and their health outcomes. METHODS: We conducted a cross-sectional study using data from a survey of working physicians conducted by the Japan Medical Association from 2021 to 2022. Questionnaires completed by 2906 full-time working physicians aged 24-69, excluding junior resident doctors, were analyzed. Depressive symptoms and the presence of thoughts of death or suicide using the Quick Inventory of Depressive Symptomatology - Japanese version was used to assess health outcomes. Logistic regression analysis was performed using overtime at the main place of employment and side work hours as exposure factors. RESULTS: Both depressive symptoms and thoughts of death or suicide increased in the group with longer overtime hours at the main place of work. A similar tendency was observed for side work but adjusting for overtime hours eliminated the association. In other words, total working hours had an impact on health, regardless of whether overtime work at the main place of employment or side work. CONCLUSIONS: Despite the existence of multiple hurdles to managing working hours, including side work, the working environment for physicians needs to be improved to protect their health and quality of medical care.

Gut-liver-axis microphysiological system for studying cellular fluidic shear stress and inter-tissue interaction.

To clarify the physiological and pathological roles of gut-liver-axis (GLA) in the human body, a GLA microphysiological system (GLA-MPS) holds great potential. However, in current GLA-MPSs, the importance of a physiologically relevant flow for gut and liver cells' cultivation is not fully addressed. In addition, the integration of individual organ perfusion, circulation flow, and organ tissue functions in a single device has not been achieved. Here, we introduce a GLA-MPS by integrating two cell-culture chambers with individually applied perfusion flows and a circulation channel with an on-chip pneumatic micropump under cell-culture chambers via a porous membrane for interconnecting them. We analyzed the fluid shear stress (FSS) with computational fluid dynamics simulations and confirmed that the physiologically relevant FSS could be applied to the gut (Caco-2) (8 × 10-3 dyn cm-2) and liver (HepG2) cells (1.2 × 10-7 dyn cm-2). Under the physiologically relevant flow, the Caco-2 and HepG2 cells in the GLA-MPS maintained a cell survival rate of 95% and 92%, respectively. Furthermore, the expression of functional proteins such as zonula occludens 1 (in Caco-2) and albumin (in HepG2) was enhanced. To demonstrate the GLA interaction, the inflammatory bowel disease was recapitulated by applying lipopolysaccharide for only Caco-2 cells. The inflammatory proteins, such as inducible nitric oxide synthase, were induced in Caco-2 and HepG2 cells. The presented GLA-MPS can be adapted as an advanced in vitro model in various applications for disease modeling associated with inter-tissue interactions, such as inflammatory disease.

In vitro culture at 39 °C during hepatic maturation of human ES cells facilitates hepatocyte-like cell functions.

Hepatocyte-like cells derived from human pluripotent stem cells (hPSC-HLCs) offer an alternative to primary hepatocytes commonly used for drug screenings and toxicological tests. However, these cells do not have hepatic functions comparable to those of hepatocytes in vivo due to insufficient hepatic differentiation. Here we showed that the hepatic functions of hPSC-HLCs were facilitated by applying physiological liver temperatures during hepatic differentiation. We identified the optimal temperature by treating HLCs derived from H9 human embryonic stem cells (hESC-HLCs) at 39 °C; the 42 °C treatment caused significantly greater cell death than the 39 °C treatment. We confirmed the improvement of hepatic functions, such as albumin secretion, cytochrome P450 3A activity, and collagen production, without severe cell damage. In combination with existing hepatic differentiation protocols, the method proposed here may further improve hepatic functions for hPSCs and lead to the realization of drug discovery efforts and drug toxicological tests.

Effect of short- and long-term melatonin treatments on the reproductive activity of the tropical damselfish Chrysiptera cyanea.

Photoperiod plays a role in controlling the initiation and termination of reproduction in fish. Melatonin is an internal transducer of environmental photoperiod and is involved in regulating reproduction. The present study aimed to examine how melatonin impacts the transcript levels of kisspeptin (kiss1 and kiss2), gonadotropin-releasing hormones (gnrh1), and the ß-subunit of gonadotropins (fshß and lhß) in the brain of the sapphire devil, a tropical damselfish with long photoperiod preference. Feeding mature females with melatonin-containing pellets inhibited increases in the transcript levels of kiss1, gnrh1, and lhß within 3 h. Continuous melatonin treatment for 1 week resulted in oocyte regression and downregulation of kiss2, gnrh1, fshß, and lhß. When the transcript levels of kiss1 and gnrh1 were measured at 4-h intervals in the brain of sapphire devil, a day-high/night-low fluctuation was observed. The hypothalamic-pituitary-gonadal (HPG) axis may be influenced by melatonin, exerting a negative effect at night because the transcript levels of aralkylamine N-acetyltransferase (aanat2) increased during the scotophase. The expression of aanat2 was higher under short-day than long-day conditions, suggesting that there is a seasonal change in melatonin levels at night. It was concluded that change in photoperiod becomes a key factor for controlling the hormone synthesis in the HPG axis through melatonin.

Testis development in the Japanese eel is affected by photic signals through melatonin secretion.

OBJECTIVE: According to reported spawning characteristics of Japanese eel, Anguilla japonica, which exhibit spawning and migration patterns that are synchronized with lunar cycles and photoperiod, we hypothesized that a close association exists between specific photic signals (daylight, daylength, and moonlight) and endocrinological regulation. Given the photic control in melatonin secretion, this hypothesis was tested by investigating whether melatonin signals act as mediators relaying photic signals during testis development in the eel. METHODS: We examined changes in melatonin-secretion patterns using time-resolved fluorescence immunoassays in sexually immature and mature male Japanese eels under the condition of a new moon (NM) and a full moon (FM). RESULTS: The eye and plasma melatonin levels exhibited a nocturnal pattern under a 12-h light: dark cycle (12L12D) or under constant darkness (DD), but not with constant light (LL). Eye melatonin levels were similar under the 12L12D and short-day (9L15D) conditions. In the long-day condition (15L9D), secreted plasma melatonin levels were stable, whereas short-day melatonin secretion began when darkness commenced. Sexual maturation began at 8 weeks following intraperitoneal injection of human chorionic gonadotropin (hCG), and NM exposure led to significantly higher eye and plasma melatonin levels compared with those detected under FM exposure.

Cyclo olefin polymer-based solvent-free mass-productive microphysiological systems.

A microphysiological system (MPS) holds great promise for drug screening and toxicological testing as an alternative to animal models. However, this platform faces several challenges in terms of the materials used (e.g. polydimethylsiloxane; PDMS). For instance, absorption of drug candidates and fluorescent dyes into PDMS, as well as the effect elicited by materials on cultured cells, can cause inaccurate or misleading results in cell assays. The use of PDMS also poses challenges for mass production and long-term storage of fabricated MPSs. Hence, to circumvent these issues, herein we describe the development of a cyclo olefin polymer (COP)-based MPS using photobonding processes and vacuum ultraviolet (VUV), designated as COP-VUV-MPS. COP is an amorphous polymer with chemical/physical stability, high purity and optical clarity. Due to the thermostability and high modulus of COP, the metal molding processes was applied for mass production of MPSs without deformation of microstructures and with quick fabrication cycle time (approx. 10 min/cycle). Moreover, VUV photobonding process with an excimer light at a 172nm wavelength allowed assembling COP materials without the use of additional solvents and tapes, which might cause cell damages. In comparison with the conventional MPS made of PDMS (PDMS-MPS), COP-VUV-MPS showed improved chemical resistance without causing molecule absorption. Moreover, COP-VUV-MPS maintained the stemness of environmentally sensitive human-induced pluripotent stem cells without causing undesired cellular phenotypes or gene expression. These results suggest that COP-VUV-MPS may be broadly applicable for the advancement of MPS and applications in drug development, as well asin vitrotoxicological testing.

Recapitulation of Human Embryonic Heartbeat to Promote Differentiation of Hepatic Endoderm to Hepatoblasts.

Hepatic development requires multiple sequential physicochemical environmental changes in an embryo, and human pluripotent stem cells (hPSCs) allow for the elucidation of this embryonic developmental process. However, the current in vitro methods for hPSC-hepatic differentiation, which employ various biochemical substances, produce hPSC-derived hepatocytes with less functionality than primary hepatocytes, due to a lack of physical stimuli, such as heart beating. Here, we developed a microfluidic platform that recapitulates the beating of a human embryonic heart to improve the functionality of hepatoblasts derived from hepatic endoderm (HE) in vitro. This microfluidic platform facilitates the application of multiple mechanical stretching forces, to mimic heart beating, to cultured hepatic endoderm cells to identify the optimal stimuli. Results show that stimulated HE-derived hepatoblasts increased cytochrome P450 3A (CYP3A) metabolic activity, as well as the expression of hepatoblast functional markers (albumin, cytokeratin 19 and CYP3A7), compared to unstimulated hepatoblasts. This approach of hepatic differentiation from hPSCs with the application of mechanical stimuli will facilitate improved methods for studying human embryonic liver development, as well as accurate pharmacological testing with functional liver cells.

Expression profiles of types 2 and 3 iodothyronine deiodinase genes in relation to vitellogenesis in a tropical damselfish, Chrysiptera cyanea.

Thyroid hormone (TH) is involved in regulating the reproduction of vertebrates. Its physiological action in the target tissues is due to the conversion of TH by iodothyronine deiodinases. In this study, we aimed to clone and characterize type 2 (sdDio2) and type 3 (sdDio3) of the sapphire devil Chrysiptera cyanea, a tropical damselfish that undergoes active reproduction under long-day conditions, and to study the involvement of THs in the ovarian development of this species. When the cDNAs of sdDio2 and sdDio3 were partially cloned, they had deduced amino acid sequences of lengths 271 and 267, respectively, both of which were characterized by one selenocysteine residue. Real-time quantitative PCR (qPCR) revealed that both genes are highly expressed in the whole brain, and sdDio2 and sdDio3 are highly transcribed in the liver and ovary, respectively. In situ hybridization analyses showed positive signals of sdDio2 and sdDio3 transcripts in the hypothalamic area of the brain. Little change in mRNA abundance of sdDio2 and sdDio3 in the brain was observed during the vitellogenic phases. It is assumed that simultaneous activation and inactivation of THs occur in this area because oral administration of triiodothyronine (T3), but not of thyroxine (T4), upregulated mRNA abundance of both genes in the brain. The transcript levels of sdDio2 in the liver and sdDio3 in the ovary increased as vitellogenesis progressed, suggesting that, through the metabolism of THs, sdDio2 and sdDio3 play a role in vitellogenin synthesis in the liver and yolk accumulation/E2 synthesis in the ovary. Taken together, these results suggest that iodothyronine deiodinases act as a driver for vitellogenesis in tropical damselfish by conversion of THs in certain peripheral tissues.

The mRNA expression patterns of kisspeptins, GnRHs, and gonadotropins in the brain and pituitary gland of a tropical damselfish, Chrysiptera cyanea, during the reproductive cycle.

The sapphire devil (Chrysiptera cyanea) is a tropical damselfish that undergoes active reproduction under long-day conditions. To elucidate the physiological regulation of the brain-pituitary-gonadal axis in female sapphire devil, we cloned and characterized the genes of two kisspeptins (kiss1 and kiss2), three gonadotropin-releasing hormones (gnrh1, gnrh2, gnrh3), and the ß-subunit of two gonadotropins (fshß and lhß) and investigated the gene expression changes during ovarian development. Quantitative polymerase chain reaction analyses in various brain parts revealed high expression levels of kiss1, kiss2, and gnrh2 in the diencephalon; gnrh2 and gnrh3 in the telencephalon; and fshß and lhß in the pituitary. In situ hybridization (ISH) analyses revealed positive signals of kiss1 in the dorsal and ventral habenular nucleus and of kiss2 in the dorsal and ventral parts of the nucleus of the lateral recess. This analysis showed gnrh1 expression in the preoptic area (POA), suggesting that GnRH1 plays a stimulating role in the secretion of gonadotropins from the pituitary of the sapphire devil. High transcription levels of kiss1, kiss2, gnrh1, gnrh2, fshß, and lhß were observed in the brain during the late vitellogenic stage, suggesting their involvement in the physiological processes of vitellogenesis. Immersion of fish in estradiol-17ß (E2)-containing seawater resulted in increased expression of kiss2 and gnrh1 in their brains. This study showed that kiss-expressing neurons in the diencephalon are influenced by E2, leading to upregulation of gnrh1 in the POA and of fshß and lhß in the pituitary during vitellogenesis.

Plasma polyunsaturated fatty acid profile is associated with vascular endothelial function in patients with type 2 diabetes.

Decreased plasma n-3 polyunsaturated fatty acid levels or the n-3/n-6 polyunsaturated fatty acid ratios are associated with a risk of cardiovascular events. In this cross-sectional study, we measured plasma levels of eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid and investigated the association between the plasma polyunsaturated fatty acid profile and vascular endothelial function in 396 patients with type 2 diabetes. Endothelium-dependent, flow-mediated dilatation of the brachial artery was measured using ultrasonography. Multiple regression analyses, including age, sex, body mass index, and other cardiovascular risk factors, revealed that plasma eicosapentaenoic acid levels ( ß = 0.140, p = 0.008) and the eicosapentaenoic acid/arachidonic acid ratio ( ß = 0.127, p = 0.019), but not plasma docosahexaenoic acid levels ( ß = 0.067, p = 0.220) or the docosahexaenoic acid/arachidonic acid ratio ( ß = 0.034, p = 0.559), were independently and positively associated with flow-mediated dilatation. In conclusion, plasma eicosapentaenoic acid levels and the eicosapentaenoic acid/arachidonic acid ratio are independently associated with endothelial function in patients with type 2 diabetes. This study indicates a positive association between eicosapentaenoic acid, rather than docosahexaenoic acid, and endothelial function in type 2 diabetes.

Interaction Between Syntactic Structure and Information Structure in the Processing of a Head-Final Language.

The effects of syntactic and information structures on sentence processing load were investigated using two reading comprehension experiments in Japanese, a head-final SOV language. In the first experiment, we discovered the main effects of syntactic and information structures, as well as their interaction, showing that interaction of these two factors is not restricted to head-initial languages. The second experiment revealed that the interaction between syntactic structure and information structure occurs at the second NP (O of SOV and S of OSV), which, crucially, is a pre-head position, suggesting the incremental nature of the processing of both syntactic structure and information structure in head-final languages.

Molecular cloning of kisspeptin receptor genes (gpr54-1 and gpr54-2) and their expression profiles in the brain of a tropical damselfish during different gonadal stages.

The kisspeptin receptor (GPR54) mediates neuroendocrine control of kisspeptin in the brain and acts as a gateway for a pulsatile release of hypothalamic gonadotropin-releasing hormone. This study aimed to clone two GPR54 genes (gpr54-1 and gpr54-2) from the brain of the sapphire devil Chrysiptera cyanea, a tropical damselfish, and to study their involvement in reproduction. The partial sequences of the sapphire devil gpr54-1 cDNA (1059bp) and gpr54-2 cDNA (1098bp) each had an open reading frame encoding a protein of 353 and 366 amino acids, respectively, both of which had structural features of a G-protein-coupled receptor. The expression of gpr54-1 mRNA was observed in the diencephalon and telencephalon, and gpr54-2 mRNA was found in the optic tectum of sapphire devil. When gpr54-1 and gpr54-2 mRNA levels were examined in the brain of sapphire devil by real-time quantitative polymerase chain reaction (qPCR), they were found to increase during late vitellogenesis and post-spawning. Treatment of fish with estradiol-17ß (Ε2) resulted in an increase in gpr54-1 and gpr54-2 expression in the brain of sapphire devil. Thus, kisspeptin receptors likely mediate the activity of kisspeptin in the brain and are involved in controlling reproductive events in a tropical damselfish.

The Processing Cost of Scrambling and Topicalization in Japanese.

This article presents two reading comprehension experiments, using the sentence correctness decision task, that explore the causes of processing cost of Japanese sentences with SNOMOACCV, STOPOACCV, OACCSNOMV, and OTOPSNOMV word orders. The first experiment was conducted in order to see if either syntax or frequency plays a significant role in the processing of these sentences. The results of the first experiment have shown that both the structure-building process and frequency directly affect processing load. We observed that there was no difference in processing cost between SNOMOACCV and STOPOACCV, both of which are easier to process than OACCSNOMV, which is in turn easier to process than OTOPSNOMV: SNOMOACCV = STOPOACCV < OACCSNOMV < OTOPSNOMV. This result is the mixture of the two positions. Specifically, the structure building cost of STOPOACCV was neutralized by its high frequency. The aim of the second experiment was to investigate the interaction between syntactic structure, frequency, and information structure. The results showed that the processing cost of OACCSNOMV was facilitated by given-new ordering, but SNOMOACCV, STOPOACCV, and OTOPSNOMV were not. Thus, we can conclude that information structure also influences processing cost. In addition, the distribution of informational effects can be accounted for by Kuno's (1987, p. 212) Markedness Principle for Discourse Rule Violations: SNOMOACCV and STOPOACCV are unmarked/canonical options, and as such are not penalized even when they violate given-new ordering, OACCSNOMV is penalized when it does not maintain given-new ordering because it is a marked/non-canonical option, and OTOPSNOMV is penalized even when it obeys given-new ordering possibly because more specific contexts are needed. Another reason for the increased processing cost of OTOPSNOMV is a garden path effect; upon encountering OTOP of OTOPSNOMV, the parser preferentially (mis)interpreted it as STOP due to a subject-before-object preference. The revision of the interpretation may be the cause of the high processing cost observed in OTOPSNOMV.

Visceral Adiposity is Preferentially Associated with Vascular Stiffness Rather than Thickness in Men with Type 2 Diabetes.

AIM: Visceral fat accumulation is known to underlie the clustering of cardiovascular risk factors. However, it is not completely understood how visceral fat accumulation influences the development of cardiovascular disease. In this study, we investigated the clinical impact of visceral adiposity on vascular stiffness and thickness in patients with type 2 diabetes (T2D). METHODS: One hundred and sixty-one patients with T2D, including 92 men and 69 women, were included in this cross-sectional study. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by dual bioelectrical impedance analysis. Stiffness parameter ß and intima-media thickness (IMT) of the common carotid artery were measured by ultrasonography. RESULTS: The mean age and duration of diabetes in the study population were 61 years and 13.9 years, respectively. In men, VFA and waist circumference (WC) were positively correlated with stiffness parameter ß, whereas body mass index (BMI), WC, and SFA were negatively correlated with IMT. In contrast, in women, none of the obesity-related indices were significantly correlated with stiffness parameter ß or IMT. In multiple regression analyses, VFA as well as WC, BMI, and SFA were independently associated with stiffness parameter ß after adjustment for age and other potential confounders in men but not in women. None of the obesity-related indices were independently associated with IMT for either sex. CONCLUSION: In men with T2D, visceral adiposity is associated with carotid arterial stiffness but not thickness.

Bleeding due to acquired hemophilia A in acute pancreatitis: a case report.

Acquired hemophilia A leads to severe bleeding and is known to be related to many underlying diseases; however, it has not been reported to occur as a complication of pancreatitis. We present a case of acquired hemophilia A secondary to severe acute pancreatitis. A 76-year-old female developed a hematoma in the lower leg muscle while being treated for severe acute pancreatitis. Blood tests revealed prolonged activated partial thromboplastin time (APTT) and the presence of an autoantibody to factor VIII. The bleeding diathesis was successfully controlled by immunosuppressive therapy. This case highlights the need for careful differential diagnosis for successful management of bleeding disorders as complications of pancreatitis.