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This study examined the ability of a computer-based cognitive assessment tool (CompBased-CAT) to predict mild cognitive impairment (MCI) in community-dwelling older adults. A two-year longitudinal study was conducted using data from 2016 to 2018 from the Otassha study cohort of community-dwelling older adults. MCI was defined as a Mini-Mental Status Examination (MMSE) score of <27. The CompBased-CAT was used at baseline, with each subtest score converted into a Z-score. Subsequently, the total Z-scores were calculated. Participants were divided into robust and MCI groups, and all variables were compared using the t-test or χ2 test. Receiver operating characteristic (ROC) curves and logistic regression analyses were conducted, with MCI and total Z-scores as dependent and independent variables, respectively. Among the 455 participants (median age, 72 years; range, 65-89 years; 282 women and 173 men), 32 developed MCI after two years. The participants in the MCI group were significantly older. They had lower maximal gait speed, baseline MMSE scores, subtest Z-scores, and total Z-scores than those in the robust group. The area under the ROC curve was 0.79 (95% confidence interval: 0.70-0.87; P <0.01). The sensitivity was 0.76, and the specificity was 0.75. The logistic regression analysis showed an odds ratio of 1.34 (95% confidence interval: 1.18-1.52; P <0.01). This study showed that CompBased-CAT can detect MCI, which is an early stage of dementia. Thus, CompBased-CAT can be used in future community health checkups and events for older adults., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Takahashi et al. 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.)

Intraoperative magnesium has the effect of reducing postoperative opiate requirement, pain, and agitation. However, its effect on postoperative sedation and delirium is unclear. This study investigated the effect of magnesium on the postoperative Richmond Agitation-Sedation Scale (RASS) score and delirium following endovascular repair of aortic aneurysm (EVAR). Sixty-three consecutive patients diagnosed with abdominal (45) and thoracic (18) aortic aneurysm who underwent EVAR under general anesthesia were eligible. Patients were allocated randomly to the magnesium group (infusion of 30 mg•kg-1 magnesium in the first hour followed by 10 mg•kg-1 h-1 until the end of surgical procedure, targeting total 60 mg•kg-1) or the control group (0.9% saline at the same volume and rate). The primary outcome was whether magnesium had an effect on RASS score of patients at postoperative ICU admission. Secondary outcomes were effects on RASS score, numerical rating scale (NRS) score, Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) until 24 h after postoperative ICU transfer, and length of ICU stay. At postoperative ICU admission, magnesium had no significant effect on the RASS score (0[-0.5 to 0] vs 0[0 to 0]; P = 0.114), but at 1 h the NRS score was statistically different, 2[0 to 4] vs 4[0 to 5] (P = 0.0406). However, other data (RASS score, NRS score, CAM-ICU and length of ICU stay) did not show a significant difference. Our results did not show that intraoperative magnesium of target total 60 mg•kg-1 affected postoperative RASS score for undergoing EVAR. Trial registration: The current study was registered according to WHO and ICMJE standards on 4 July 2018, under registration number the Japan Registry of Clinical Trials, iRCTs041190013., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kanamori et al. 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.)

This study examined the differences in medical and long-term care costs over 18 months between pet owners and non-owners among community-dwelling older Japanese. Pet ownership data were collected from 460 community-dwelling adults age 65 years and older. These data were matched with data from the National Health Insurance, health insurance for older people, and Long-Term Care Insurance beneficiaries for 17 months back from the survey on pet ownership. Pet-ownership group-specific trajectories in monthly medical and long-term care costs were modeled by a generalized estimating equation. Among pet owners (n = 96, 20.9%) and non-pet owners (n = 364, 79.1%) there were no significant differences in baseline demographic or health characteristics including chronic disease and self-reported long-term care level. At baseline, pet owners had estimated monthly medical costs of ¥48,054 (SE = 0.11; $418), compared to ¥42,260 (SE = 0.06; $367) for non-pet owners. The monthly medical costs did not differ significantly between the two groups during the 18-month follow-up period. At baseline, estimated monthly long-term care costs of pet owners and non-pet owners were ¥676 (SE = 0.75; $6) and ¥1,420 (SE = 0.52; $12), respectively. During the follow-up period, the non-pet owner to owner ratio of monthly long-term care costs was 1.2 at minimum and 2.3 at maximum. This study showed that monthly long-term care costs for pet owners were approximately half those of non-pet owners. Pet owners might use long-term care services less frequently, or use lighter care services., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Taniguchi et al. 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.)

Endoscopic mucosal healing (MH) is an important treatment goal for patients with ulcerative colitis (UC). The neutrophil-to-lymphocyte ratio (NLR) reflects systemic inflammation and has been reported to be a useful predictive marker for UC. This study aimed to evaluate the clinical utility of the NLR for predicting clinical relapse in UC patients with MH. We retrospectively enrolled patients with UC who underwent colonoscopy at the Osaka City University Hospital between January 2010 and December 2010, whose Mayo Endoscopic Subscore was 0 or 1. The correlation between the incidence of relapse and demographic factors, including the NLR, was analyzed. We included 129 patients in the present study. The median NLR at the time of endoscopy was 1.98, and differences in the high NLR group and the low NLR group were compared. During a median follow-up period of 46.4 months, 58 patients (45.0%) experienced relapse. The cumulative relapse-free rate was significantly higher in the low NLR group than in the high NLR group (P = 0.03, log-rank test). Multivariate analysis identified high NLR as an independent prognostic factor for clinical relapse (hazard ratio, 1.74; 95% confidence interval, 1.02-2.98; P = 0.04). NLR is a novel and useful predictor of clinical relapse in UC patients with MH, and it can potentially be a strong indicator to determine the appropriate treatment strategy and decision-making in clinical practice., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kurimoto et al. 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.)

Background: Autonomic dysfunction is a factor in irritable bowel syndrome (IBS). However, there are no reports of autonomic nervous system (ANS) activity during natural defecation in patients with IBS. We aimed to clarify the relationship between ANS activity and life events, such as defecation and abdominal symptoms, using real-time recording., Methods: Six patients with IBS and 14 healthy controls were enrolled in this prospective multicenter study. ANS activity was recorded for 24 h using a T-shirt wearable device, and life events were recorded simultaneously in real time using a smartphone application software. Low frequency/high frequency (LF/HF) and HF calculated by power spectrum analysis were defined as activity indicators of the sympathetic and parasympathetic nerves, respectively., Results: The means of LF/HF and HF in the period with positive symptoms were comparable between the groups; however, the sum of LF/HF, sum of ΔLF/HF, and the maximum variation in ΔLF/HF were significantly higher in the IBS group. In the IBS group, the sum of ΔLF/HF and LF/HF increased significantly from 2 min before defecation, and the sum of LF/HF remained significantly higher until 9 min after defecation. The sum of ΔLF/HF at 2 min before defecation was significantly positively correlated with the intensity of abdominal pain and diarrhea and constipation scores. In contrast, it was significantly negatively correlated with defecation satisfaction and health-related quality of life., Conclusions: In patients with IBS, sympathetic nerve activity was activated 2 min before defecation, which was correlated with abdominal symptoms and lower QOL., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Nakata et al. 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.)

Participation in sports groups has health benefits for older adults, such as preventing functional limitations and social isolation. Encouraging participation in sports groups may be an important means of health promotion in older adults. However, there is insufficient research on the determinants of new participation in sports groups to consider effective interventions to promote participation in these groups. We investigated this using data from a 1-year prospective study. Data were obtained from "The Otassha Study" that assessed a cohort of community-dwelling older adults living in an urban area of Japan. Of 769 older adults who participated in a baseline health survey in 2018, 557 participated in a follow-up survey in 2019. We excluded 184 individuals who already participated in sports groups at baseline and 36 with missing data. Participation in sports groups was defined as that occurring more than once a week. Logistic regression analysis was used to identify the determinants of new participation in sports groups, with sociodemographic factors, lifestyle habits, physical functions, cognitive functions, psychological factors, and social factors as independent variables. Forty-one (12.2%) individuals participated in sports groups at follow-up. In the multiple adjusted logistic regression model, new participation in sports groups was significantly associated with female sex (odds ratio [OR] = 5.57, 95% confidence interval [CI]: 1.61‒19.26), engagement in regular exercise (OR = 2.23, 95%CI: 1.03‒4.84), and having a large social network (OR = 1.12, 95%CI: 1.04‒1.20). Physical functions were not associated with new participation. Determinants of new participation were lifestyle habits and social factors, rather than physical functions. Intervention through social networks may be effective in encouraging new participation in sports groups, which, in turn, may facilitate healthy aging., Competing Interests: The authors have declared that no competing interests exist.

Cryptoassets flow among players as recorded in the ledger of blockchain for all the transactions, comprising a network of players as nodes and flows as edges. The last decade, on the other hand, has witnessed repeating bubbles and crashes of the price of cryptoassets in exchange markets with fiat currencies and other cryptos. We study the relationship between these two important aspects of dynamics, one in the bubble/crash of price and the other in the daily network of crypto, by investigating Bitcoin and XRP. We focus on "regular players" who frequently appear on a weekly basis during a period of time including bubble/crash, and quantify each player's role with respect to outgoing and incoming flows by defining flow-weighted frequency. During the most significant period of one-year starting from the winter of 2017, we discovered the structure of three groups of players in the diagram of flow-weighted frequency, which is common to Bitcoin and XRP in spite of the different nature of the two cryptos. By examining the identity and business activity of some regular players in the case of Bitcoin, we can observe different roles of them, namely the players balancing surplus and deficit of cryptoassets (Bal-branch), those accumulating the cryptoassets (In-branch), and those reducing it (Out-branch). Using this information, we found that the regime switching among Bal-, In-, Out-branches was presumably brought about by the regular players who are not necessarily dominant and stable in the case of Bitcoin, while such players are simply absent in the case of XRP. We further discuss how one can understand the temporal transitions among the three branches., Competing Interests: The authors have declared that no competing interests exist.

The aim of this study is to investigate the prognostic significance of geriatric nutritional risk index (GNRI) at the time of recurrence in patients with recurrent pancreatic cancer, and the relationship between GNRI and skeletal muscle mass for survival outcomes after recurrence. This study enrolled 77 patients who developed postoperative recurrence. The skeletal muscle mass index (SMI) was used in this study. The patients were divided into a high-GNRI group (n = 36) and a low-GNRI group (n = 41) for the GNRI, and were divided into a high-SMI group (n = 38) and a low-SMI group (n = 39) for SMI. The 2-year post-recurrence overall survival of patients in the high-GNRI group was significantly longer than that of patients in the low-GNRI group (P = 0.001). No significant difference for the 2-year post-recurrence OS curves between the high-SMI group and the low-SMI group was observed (P = 0.125). Upon stratifying the patients with high GNRI or low GNRI according to SMI, There was no significant difference in the 2-year post-recurrence OS curves between the patients with both high GNRI and high SMI and the patients with high GNRI and low SMI (P = 0.399). Similarly, There was no significant difference in the 2-year post-recurrence OS curves between the patients with low GNRI and high SMI and the patients with both low GNRI and low SMI (P = 0.256). Multivariate analysis revealed that the GNRI at the time of recurrence was an independent prognostic risk factor in patients with recurrent pancreatic cancer (P = 0.019). The GNRI at the time of recurrence is useful for predicting the prognosis in patients with recurrence pancreatic cancer. Skeletal muscle mass at the time of recurrence is not contributed to predict post-recurrence survival of patients with recurrent pancreatic cancer., Competing Interests: The authors received no specific funding for this work.

Objective: Our aim is to determine the strong predictors of the onset of instrumental activities of daily living (IADL) decline in community-dwelling older people., Design: A prospective cohort study with a two-year follow-up., Setting: Kashiwa City, Chiba Prefecture, Japan and Toshima Ward, Tokyo Metropolitan, Japan., Participants: The data were acquired from two cohorts. The final sample comprised 1,523 community-dwelling older people aged 65-94 years (681 men, 842 women). They were individuals who were independent in IADL at baseline and participated in follow-up IADL assessments two years later., Measurements: At baseline, comprehensive assessments were performed including: health interview, gait function, hand-grip strength, skeletal muscle mass, balance function, oral function, dietary lifestyle, cognitive function, quality of life, mental status, and social network. When the two-year follow-up was performed, IADL declines were observed in 53 out of 1,523 people. The association of each Z-transformed parameter with the occurrence of IADL decline was examined by employing a binominal logistic regression model adjusting for age, gender, body weight, body height, and medical history. An odds ratio (OR) and a 95% confidence interval were calculated and compared between different parameters., Results: A decrease in walking speed and one-legged stance time, whereas an increased timed up & go test time was associated with significant ORs for the occurrence of IADL decline., Conclusion: Gait-related parameters appear to be the strong predictors of the onset of IADL decline in community-dwelling older people., Competing Interests: The authors have declared that no competing interests exist.

Nurse practitioners are increasingly now members of intensive care teams in Japan, but no data exist about their effect on the outcomes for critically ill patients. This study aimed to compare the outcomes of postoperative patients on mechanical ventilators before and after the participation of nurse practitioners in intensive care teams. We retrospectively identified 387 patients who underwent postoperative mechanical ventilation at a University Hospital in Japan, using data from medical records from 1 April 2015 to 31 March 2017. We extracted data and compared patients' length of stay in the intensive care unit and the hospital, mechanical ventilation days, postoperative rehabilitation start date, rehabilitation prescription, intensive care unit and hospital mortality, and intensive care unit readmission. Multiple regression analysis was used to analyze the factors affecting length of stay in the intensive care unit. Patients who received care from nurse practitioners and physicians had significantly shorter stays in intensive care (4.8 ± 4.8 days versus 6.7 ± 10.3 days, p < 0.021). Mechanical ventilation days, total length of hospital stay, rehabilitation prescription, mortality in intensive care and hospital, and readmission to intensive care were all similar to those who received care only from physicians. The multiple regression analysis suggests that participation of nurse practitioners in intensive care reduced the length of stay in the unit by 2.6 days (p = 0.003). These findings could help to increase use of non-physician healthcare providers in intensive care. Our results demonstrated that it is both effective and safe for nurse practitioners to participate in intensive care teams that provide care for postoperative patients receiving mechanical ventilation., Competing Interests: The authors have declared that no competing interests exist.

Epigenome research has employed various methods to identify the genomic location of proteins of interest, such as transcription factors and histone modifications. A recently established method called CUT&Tag uses a Protein-A Tn5 transposase fusion protein, which cuts the genome and inserts adapter sequences nearby the target protein. Throughout most of the CUT&Tag procedure, cells are held on concanavalin A (con A)-conjugated magnetic beads. Proper holding of cells would be decisive for the accessibility of Tn5 to the chromatin, and efficacy of the procedure of washing cells. However, BioMag®Plus ConA magnetic beads, used in the original CUT&Tag protocol, often exhibit poor suspendability and severe aggregation. Here, we compared the BioMag beads and Dynabeads® magnetic particles of which conjugation of con A was done by our hands, and examined the performance of these magnetic beads in CUT&Tag. Among tested, one of the Dynabeads, MyOne-T1, kept excessive suspendability in a buffer even after overnight incubation. Furthermore, the MyOne-T1 beads notably improved the sensitivity in CUT&Tag assay for H3K4me3. In conclusion, the arrangement and the selection of MyOne-T1 refine the suspendability of beads, which improves the association of chromatin with Tn5, which enhances the sensitivity in CUT&Tag assay., Competing Interests: The authors report that there were material support and technical advice from VERITAS corporation for this study that could have influenced its outcome and that one of the authors, Y.T. is its employee. This does not alter our adherence to PLOS ONE policies on sharing data and materials." We believe our revised manuscript would suffice the reviewer’s concerns. It would be greatly appreciated if the editorial office and reviewers could consider this revision. All the authors have read the manuscript and have approved this submission. All study participants provided informed consent, and the study design was approved by an ethics review board.

Previous studies have reported qualitative characteristics of myelopathy hand, but few studies have reported quantitative kinematic parameters of this condition. Our purpose of this study was to quantitatively evaluate the abnormal finger movements in patients with cervical compressive myelopathy (CCM) (termed myelopathy hand) and to understand the characteristics of myelopathy hand during the grip and release test (GRT) using gyro sensors. Sixty patients with CCM (severe: n = 30; mild-to-moderate: n = 30) and sixty healthy adults (age-matched control: n = 30; young control: n = 30) were included in this study. All participants performed the GRT. The index and little fingers' and the wrist's movements during the GRT were recorded using three gyro sensors. The number of cycles, switching time-delay, time per cycle, and peak angular velocity were calculated and compared between groups. Patients with severe CCM had the lowest number of cycles and longest switching time-delays, followed by patients with mild-to-moderate CCM, the age-matched control group, and the young control group. The time per cycle and the peak angular velocities of fingers in participants with severe CCM were significantly lower than those in participants with mild-to-moderate CCM; however, there were no significant differences between the control groups. The peak angular velocities of fingers were significantly lower during extension motions than during flexion motions in participants with CCM. Participants with CCM have lower peak angular velocities during finger movement. Finger extension also is impaired in participants with CCM. Abnormal finger movements and the severity of myelopathy in participants with CCM can be assessed using gyro sensors., Competing Interests: The authors have declared that no competing interests exist.

To determine whether preoperative white blood cell (WBC) counts reflect risk of anastomotic leak (AL) for patients with colorectal cancer (CRC), we retrospectively examined data from records of 208 consecutive patients who had undergone resections for left-sided CRC, including their clinicopathological parameters and preoperative laboratory data. The diagnostic value of WBC count for AL was evaluated and compared with those of neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio and platelet count × C-reactive protein level multiplier (P-CRP) value; optimal cut-off values were derived from receiver operating characteristic curves. AL was observed in 11 of the 208 patients (5.3%). Compared with the no-AL group, the AL group had a significantly higher mean WBC count and smoking rate. In multivariate analysis, WBC count and smoking were independent risk factors for AL. Compared with the other tested inflammatory indicators, the cut-off value for WBC (6,200/μL) had the highest sensitivity (81.8%) and negative predictive value (98.4%), as well as the lowest likelihood ratio (0.289). Preoperative WBC count could therefore be a convenient predictor of AL in patients with left-sided CRC., Competing Interests: The authors have declared that no competing interests exist.

Aging of the population has led to an increase in the prevalence of cancer among older adults. In Japan, single agent chemotherapy was recommended for advanced non-small cell lung cancer (NSCLC) for those, who were aged ≥75 years, while the Western guidelines did not recommend a specific regimen. In clinical practice, physicians are required to decide the treatment based on a lack of enough evidence. This study aimed to examine the prescribing patterns of first-line chemotherapy according to age in the real-world practice. Data from the survey database of Diagnostic Procedure Combination and hospital-based cancer registries of designated cancer centers nationwide were used. The first-line chemotherapy regimens among 9,737 patients who were diagnosed with advanced lung cancer between January and December 2013, were identified and compared based on age. We found that the proportion of patients receiving chemotherapy decreased with age; 80.0%, 70.4%, 50.6%, and 30.2% of patients aged 70-74, 75-79, 80-84, and ≥ 85 years, respectively, received chemotherapy. Among them, platinum doublets were prescribed for 62.7% of the patients who were aged ≥ 70 years, and 60.7% of the patients who were aged ≥ 75 years with no driver mutations in NSCLC; only 37.6% of them received single agents. Patients who were aged ≥ 80 years also preferred platinum doublets (35.6%). Carboplatin was commonly prescribed in all age groups; only 28.4% of those receiving platinum doublets selected cisplatin. In this study, platinum doublets were identified as the most commonly prescribed regimen in those who were aged ≥ 70 years. Despite recommendations of Japanese guidelines for NSCLC, 60.7% of those who were aged ≥75 years received platinum doublets. Additionally, patients who were aged ≥ 80 years also received systemic chemotherapy, including platinum doublets; age did not solely influence regimen selection., Competing Interests: I have read journal’s policy and the authors of this manuscript have the following competing interests: Ayako Okuyama reports grants and other from National Cancer Center in Japan, during the conduct of the study. Akihiro Hirakawa reports grants and personal fees from Ono Pharmaceutical, and personal fees from Astellas Pharma, AbbVie, Nippon Boehringer Ingelheim, Kissei Pharmaceutical, Pfizer, and Nippon Shinyaku, outside the submitted work. Yasushi Goto reports grants and personal fees from Eli Lilly, Chugai, Taiho Pharmaceutical, Pfizer, Novartis, MSD, Guardant Health, and Ono Pharmaceutical, and grants from Kyorin, and Dai-ichi Sankyo, and personal fees from Boehringer Ingelheim, AstraZeneca, and Glaxo Smith Kline, outside the submitted work. Yasuhiro Fujiwara reports grants and committee member from Japan Agency for Medical Research and Development, and The Ministry of Health Labor and Welfare, Japan, during the conduct of the study, and lecture fee from Astra Zeneca KK, Daiichi Sankyo Co., Ltd, Taiho Pharmaceutical Co., Ltd, Chugai Pharmaceutical Co., Ltd, Novartis Pharma KK, SRL Inc, Bristol-Myers Squibb KK, and Santen Pharmaceutical Co., Ltd, outside the submitted work. Takahiro Higashi is employed by the National Cancer Center Japan, which is responsible for operating hospital-based cancer registries nationwide, during the conduct of the study, and the data collection was funded by the internal grant of National Cancer Center. Kan Yonemori reports personal fees from Novartis, Pfizer, Chugai, Eisai, Taiho, and AstraZeneca, outside the submitted work. Shoko Noda-Narita, Asuka Kawachi, and Ryo Sadachi, have nothing to disclose. The competing interests stated do not alter our adherence to PLOS ONE policies on sharing data and materials.

Resolvin D1, a specialized pro-resolving lipid mediator produced from docosahexaenoic acid by 15- and 5-lipoxygenase, exerts anti-inflammatory effects driving to the resolution of inflammation. The present study aimed to elucidate its role in small intestinal damage induced by nonsteroidal anti-inflammatory drug (NSAID). Indomethacin was administered orally to C57BL/6J male mice, which were sacrificed 24 h later to collect small intestine specimens. Before administration of indomethacin, mice were subjected to intraperitoneal treatment with resolvin D1 or oral administration of baicalein, a 15-lipoxygenase inhibitor. Small intestinal damage induced by indomethacin was attenuated by pretreatment with resolvin D1. Furthermore, resolvin D1 reduced the gene expression levels of interleukin-1β, tumor necrosis factor-α, and CXCL1/keratinocyte chemoattractant. Conversely, the inhibition of 15-lipoxygenase activity by baicalein increased the expression of genes coding for these inflammatory cytokines and chemokine, leading to exacerbated small intestinal damage, and reduced the concentration of resolvin D1 in the small intestinal tissue. Exogenous treatment with resolvin D1 negated the deleterious effect of baicalein. 15-lipoxygenase was mainly expressed in the epithelium and inflammatory cells of the small intestine, and its gene and protein expression was not affected by the administration of indomethacin. Inhibition of the resolvin D1 receptor, lipoxin A4 receptor /formyl peptide receptor 2, by its specific inhibitors Boc-1 and WRW4 aggravated indomethacin-induced small intestinal damage. Collectively, these results indicate that resolvin D1 produced by 15-lipoxygenase contributes to mucoprotection against NSAID-induced small intestinal damage through its anti-inflammatory effect., Competing Interests: The authors have declared that no competing interests exist.

Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)-25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)-24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2-25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2-25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac., Competing Interests: The authors have declared that no competing interests exist.

Background and Aims: We investigated the usefulness of combining two-dimensional shear wave elastography and the ultrasound-guided attenuation parameter for assessing the risk of progressive non-alcoholic steatohepatitis, defined as non-alcoholic steatohepatitis with a non-alcoholic fatty liver disease activity score of ≥4 and a fibrosis stage of ≥2., Methods: This prospective study included 202 patients with non-alcoholic fatty liver disease who underwent two-dimensional shear wave elastography, ultrasound-guided attenuation parameter, vibration-controlled transient elastography, the controlled attenuation parameter, and liver biopsy on the same day. Patients were grouped according to liver stiffness measurement using two-dimensional shear wave elastography and the attenuation coefficient, assessed using the ultrasound-guided attenuation parameter: A, low liver stiffness measurement/low attenuation coefficient; B, low liver stiffness measurement/high attenuation coefficient; C, high liver stiffness measurement/low attenuation coefficient; and D, high liver stiffness measurement/high attenuation coefficient., Results: Two-dimensional shear wave elastography and vibration-controlled transient elastography had equivalent diagnostic performance for fibrosis. The areas under the curve of the ultrasound-guided attenuation parameter for identifying steatosis grades ≥S1, ≥S2, and S3 were 0.89, 0.91, and 0.92, respectively, which were significantly better than those of the controlled attenuation parameter (P<0.05). The percentages of progressive non-alcoholic steatohepatitis in Groups A, B, C, and D were 0.0%, 7.7%, 35.7%, and 50.0%, respectively (P<0.001). The prediction model was established as logit (p) = 0.5414 × liver stiffness measurement (kPa) + 7.791 × attenuation coefficient (dB/cm/MHz)-8.401, with area under the receiver operating characteristic curve, sensitivity, and specificity values of 0.832, 80.9%, and 74.6%, respectively; there was no significant difference from the FibroScan-aspartate aminotransferase score., Conclusion: Combined assessment by two-dimensional shear wave elastography and the ultrasound-guided attenuation parameter is useful for risk stratification of progressive non-alcoholic steatohepatitis and may be convenient for evaluating the necessity of specialist referral and liver biopsy., Competing Interests: The authors have read the journal’s policy, and the authors of this manuscript have the following competing interests: T.O., S.N. and N.K. are paid employees of GE Healthcare Japan. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors declare that they have no competing interests. There are no products in development or marketing products to declare.

Background: Both negative and positive associations between social networking service (SNS) usage and mental health have been suggested by previous studies; however, their differences by type of SNS and age remain unclear. We addressed this issue based on the frequency of traditional communication such as face-to-face and non-face-to-face communication (e.g., phone, email, and letters)., Methods: In total, 8,576 individuals participated, including 2,543 aged 18-39, 3,048 aged 40-64, and 2,985 aged over 65 years. They were asked to indicate their frequency of SNS usage, both for posting and checking, of LINE (a popular message application in Japan), Facebook, Twitter, and Instagram, with frequent usage defined as posting or checking more than a few times a week. To determine mental health status, WHO-5 (i.e., well-being), K6 (i.e., distress symptoms), and feelings of loneliness were assessed. Multiple and logistic regression analyses were adjusted for the frequency of traditional communication. To avoid type 1 error, a Bonferroni correction of p ≤ 0.002 was applied in the regression models (p = 0.05/18, a number of regression models)., Results: The most frequently used SNS across the three age groups was LINE; frequent usage (both posting and checking) among older adults was independently associated with better well-being. Frequent posting on Facebook was associated with better well-being in middle-aged adults. Young adults who frequently checked on Instagram showed a tendency toward better well-being and lower distress symptoms. On the contrary, frequent usage of Twitter was associated with distress symptoms or feelings of loneliness across all three age groups., Conclusions: We found generational and SNS-type-dependent negative and positive associations between SNS use and mental health, indicating the possible influences of SNS use and the importance of non-SNS communication., Competing Interests: The authors have declared that no competing interests exist.

Today's consumer goods markets are rapidly evolving with significant growth in the number of information media as well as the number of competitive products. In this environment, obtaining a quantitative grasp of heterogeneous interactions of firms and customers, which have attracted interest of management scientists and economists, requires the analysis of extremely high-dimensional data. Existing approaches in quantitative research could not handle such data without any reliable prior knowledge nor strong assumptions. Alternatively, we propose a novel method called complex Hilbert principal component analysis (CHPCA) and construct a synchronization network using Hodge decomposition. CHPCA enables us to extract significant comovements with a time lead/delay in the data, and Hodge decomposition is useful for identifying the time-structure of correlations. We apply this method to the Japanese beer market data and reveal comovement of variables related to the consumer choice process across multiple products. Furthermore, we find remarkable customer heterogeneity by calculating the coordinates of each customer in the space derived from the results of CHPCA. Lastly, we discuss the policy and managerial implications, limitations, and further development of the proposed method., Competing Interests: The authors have declared that no competing interests exist.

Non-steroidal anti-inflammatory drugs (NSAIDs) induce small intestinal damage. It has been reported that rebamipide, a mucoprotective drug, exerts a protective effect against NSAID-induced small intestinal damage; however, the underlying mechanism remains unknown. In this study, we investigated the significance of the small intestinal microbiota in the protective effect of rebamipide against indomethacin-induced small intestinal damage in mice. A comprehensive analysis of the 16S rRNA gene sequencing revealed an alteration in the composition of the small intestinal microbiota at the species level, modulated by the administration of rebamipide and omeprazole. The transplantation of the small intestinal microbiota of the mice treated with rebamipide suppressed the indomethacin-induced small intestinal damage. Omeprazole, a proton pump inhibitor, exacerbated the indomethacin-induced small intestinal damage, which was accompanied by the alteration of the small intestinal microbiota. We found that the transplantation of the small intestinal microbiota of the rebamipide-treated mice ameliorated indomethacin-induced small intestinal damage and the omeprazole-induced exacerbation of the damage. These results suggest that rebamipide exerts a protective effect against NSAID-induced small intestinal damage via the modulation of the small intestinal microbiota, and that its ameliorating effect extends also to the exacerbation of NSAID-induced small intestinal damage by proton pump inhibitors., Competing Interests: The authors have declared that no competing interests exist.

Background: Endoscopic ultrasonography (EUS) is proven to be a more specific and sensitive method for detecting pancreatic lesions. However, usefulness of EUS after pancreatectomy has not been reported. This study aimed to evaluate the observational capability of EUS for the remnant pancreas (RP) after pancreatectomy., Patient and Methods: This single-center, retrospective study enrolled 395 patients who underwent pancreatectomy at Onomichi General Hospital between December 2002 and March 2016, 45 patients who underwent EUS for RP were included for analysis. We evaluated the usefulness of EUS for RP using logistic regression analysis., Results: Complete observation of the RP was done in 42 patients (93%). In the initial surgical procedure, 21 patients underwent pancreaticoduodenectomy (PD), and 24 patients underwent distal pancreatectomy (DP). PD and DP were observed in 85% (18/21) and 100% (24/24) cases, respectively. A comparison of the detection capability of EUS and contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) showed that EUS was significantly superior to contrast-enhanced CT or MRI (p < 0.01). Eight of the 45 patients showed recurrence lesions in the RP. The median recurrence period was 33 months. Predictive factors for recurrence in the univariate and multivariate analyses were significantly different in space occupying lesion with EUS findings (p < 0.01) and elevated CA19-9(p < 0.01)., Conclusions: EUS was able to observe the RP in almost all cases. In addition, the detection capability of EUS was significantly superior to those of CT or MRI. We recommend that all patients with RP should undergo EUS, and a longer follow-up must be performed., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Pouchitis is a major complication after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC). Although there have been many investigations of the neutrophil-to-lymphocyte ratio (NLR) in various diseases, its role in predicting the development of pouchitis remains unclear. We aimed to evaluate the clinical utility of the NLR for predicting the development of pouchitis after IPAA in UC patients., Materials and Methods: UC patients who underwent IPAA at Osaka City University Hospital between May 2006 and March 2019 were included. The incidence of pouchitis was estimated using the Kaplan-Meier method. Potential preoperative, intraoperative, and postoperative predictors for pouchitis, including various demographic and clinical variables, were analyzed. The combined impact of the NLR and other known prognostic factors were investigated using Cox proportional hazard regression with inverse probability of treatment weighting (IPTW)., Results: Forty-nine patients with UC who underwent IPAA were included. The median follow-up period was 18.3 months (interquartile range: 10.7-47.2 months). Eighteen patients (36.7%) developed pouchitis. The incidence of pouchitis was 19.2%, 32.6%, and 45.9% at 1, 2, and 5 years, respectively. NLR was significantly associated with the development of pouchitis in the univariate Cox regression analysis (hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.01-1.28; P = 0.03). The NLR cutoff value of 2.15 was predictive of the development of pouchitis according to receiver operating characteristic analysis (specificity: 67.7%, sensitivity: 72.2%). The incidence of pouchitis was significantly lower in the low NLR group than that in the high NLR group (P = 0.01, log-rank test). Cox regression analyses using IPTW also identified NLR as a prognostic factor for the development of pouchitis by statistically adjusting for background factors (HR, 3.60; 95% CI, 1.31-9.89; P = 0.01)., Conclusions: NLR may be a novel and useful indicator for predicting the development of pouchitis after IPAA in UC and should be introduced in clinical practice., Competing Interests: The authors have declared that no competing interests exist.

Every nation prioritizes the inclusive economic growth and development of all regions. However, we observe that economic activities are clustered in space, which results in a disparity in per-capita income among different regions. A complexity-based method was proposed by Hidalgo and Hausmann [PNAS 106, 10570-10575 (2009)] to explain the large gaps in per-capita income across countries. Although there have been extensive studies on countries' economic complexity using international export data, studies on economic complexity at the regional level are relatively less studied. Here, we study the industrial sector complexity of prefectures in Japan based on the basic information of more than one million firms. We aggregate the data as a bipartite network of prefectures and industrial sectors. We decompose the bipartite network as a prefecture-prefecture network and sector-sector network, which reveals the relationships among them. Similarities among the prefectures and among the sectors are measured using a metric. From these similarity matrices, we cluster the prefectures and sectors using the minimal spanning tree technique. The computed economic complexity index from the structure of the bipartite network shows a high correlation with macroeconomic indicators, such as per-capita gross prefectural product and prefectural income per person. We argue that this index reflects the present economic performance and hidden potential of the prefectures for future growth., Competing Interests: The authors have declared that no competing interests exist.

This study aims to clarify the factors associated with the gradual withdrawal from society in older adults. We defined the stages of follow-up difficulty based on four follow-up surveys on non-respondents of longitudinal mail surveys in community-dwelling older adults to examine the main factors associated with the stages of follow-up difficulty. We conducted a follow-up mail survey (FL1) with respondents of a baseline survey, and three more follow-up surveys with the non-respondents of each previous survey: simplified mail (FL2), postcard (FL3), and home visit surveys (FL4). The respondents of each follow-up survey were defined as a stage of follow-up difficulty; their characteristics concerning social participation and interaction at baseline in each stage were analyzed. The number of respondents in the FL1, FL2, FL3, and FL4 stages and non-respondents (NR) were as follows: 2,361; 462; 234; 84; and 101, respectively. Participation in hobby groups in FL2 and FL3, sports groups in FL4, and neighborhood association and social isolation in NR were significantly associated with the stage of follow-up difficulty. Based on these results, we conclude that the following factors are associated with each stage of follow-up difficulty: 1) a decline in instrumental activities of daily living in the FL2 and FL3 stages, 2) dislike for participating in physical activity such as sports in the FL4 stage, and 3) social isolation, not even belonging to a neighborhood association due to low social interaction in the NR group., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To investigate the association between different stages of posterior vitreous detachment (PVD) and macular microvasculature in the elderly., Methods: Swept-source optical coherence tomography (OCT), OCT angiography, and color fundus images of 490 eyes without retinal pathologies of 322 participants aged ≥65 years were evaluated. PVD was classified using enhanced vitreous visualization mode as no apparent PVD (stage 0/1), vitreous adhesions at the fovea and optic disc (stage 2), adhesion at the optic disc (stage 3), or complete PVD (stage 4). Microvascular parameters, including foveal avascular zone (FAZ) and vessel density (VD), were analyzed for their associations with complete PVD. Additionally, the association between PVD and central retinal thickness (CRT) was also addressed., Results: Overall, 80, 31, 31, and 349 eyes were categorized into stages 0/1, 2, 3, and 4, respectively. Using multivariate mixed-effects model, the mean superficial FAZ area was smaller in stage 4 compared with stages 0-3 (0.29 vs. 0.32 mm2; P = 0.014), and the mean superficial VD was lower in stage 4 compared with stages 0-3 (34.96% vs. 35.24%; P = 0.0089). However, PVD was not significantly associated with deep macular microvascular parameters or CRT., Conclusions: Complete PVD was associated with smaller FAZ area and lower VD in superficial macular microvasculature, while it was not associated with central retinal thickness., Competing Interests: Topcon (www.topcon.co.jp), supported our condut of the present research, which does not alter our adherence to PLOS ONE policies on sharing data and materials.

The interactions among macroprices with leads and lags play a significant role in explaining the behavior of an aggregate price index. Thus, to understand inflation and deflation, it is essential to explore the mechanism according to which these macroprices interact with each other. On the basis of a new method, we show that, irrespective of the sources of shocks, a robust flow of changes occurs in domestic prices from upstream to downstream. Moreover, we demonstrate that macroprices change in clusters, and we identify these clusters. Firms are not symmetric. Overall, our analysis suggests that the inertia arising from input/output linkages in production explains the behavior of aggregate prices., Competing Interests: The authors have declared that no competing interests exist.

Background: Critical care nurses need a high level of medical competence, especially with regard to patient safety. There are several tools to measure general and critical care nursing competence, but the usability of these tools is inadequate because they include large numbers of questions. To maintain quality and safety in intensive care units (ICUs), it is necessary to be able to easily measure and evaluate critical care nursing competence. The purpose of this study was to develop an easy-to-use questionnaire assessing critical care nursing competence related to patient safety., Methods: A cross-sectional, descriptive, explorative study was designed to collect data from nurses working in six ICUs in tertiary hospitals in Japan. Data were collected from August 2017 to December 2018. The Critical Care Nursing Competence Questionnaire for Patient Safety (C3Q-safety) is a 22-item instrument designed to assess nursing competence related to patient safety in ICUs. Items were developed based on previous work related to critical care nursing competence and were adjusted based on a pilot study., Results: A total of 211 nurses working in ICUs participated in this study. Through descriptive statistics and factor analysis, the number of questions was reduced from 24 to 22. The C3Q-safety had four factors: decision making, collaboration, nursing intervention, and principles of nursing care. Cronbach's alpha ranged from 0.73 to 0.83. The four factors showed positive correlations with each other (0.47 to 0.72). Nurses licensed as certified nurses in intensive care and those with longer ICU work experience showed significantly higher scores on all four factors., Conclusions: We developed an easy-to-use questionnaire to assess critical care nursing competence related to patient safety. The C3Q-safety was able to detect four areas of competence. The C3Q-safety will make it possible to easily measure critical care nursing competence and can be utilized for efficient education., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Social isolation is a particular problem among older people and social participation may reduce future isolation. However, it is unclear which types of activities and which level of participation are effective. This study examines the relationship between social participation and isolation among Japanese older people by employing a 3-year longitudinal study., Methods: A mail survey was sent to 3,518 community-dwelling older people in an urban area in 2014 (baseline: BL). We then conducted follow-up mail survey on respondents who were non-isolated at BL in 2017 (follow-up: FL), with isolation being defined as being in contact with others less than once a week. An analysis was carried out on 1,070 subjects (398 men and 672 women). Social participation is defined by participation in group activities (community, senior club, hobbies, sports, volunteering, politics, industry, and religion). A logistic regression analysis was conducted to determine the association between the types of social participation and the number of organization types at BL, and isolation at FL., Results: At FL, 75 men (18.8%) and 59 women (8.8%) were considered to be isolated. Among the men, participation in a hobby group and sports group both significantly reduced the degree of isolation. Moreover, participation in two organizations and three or more organizations significantly lowered the risk of isolation when compared to non-participants. Among women, there were no significant associations among particular types of social activities and isolation. On the other hand, participation in one organization and three or more organizations significantly reduced their isolation when compared to non-participants. There was a significant linear trend between the number of types of organizations and isolation, regardless of gender., Conclusions: Participation in social activities reduces future isolation in older people. Encouraging participation in social activities could help reduce negative health outcomes associated with social isolation later in life., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Although tacrolimus is useful as an induction therapy in patients with ulcerative colitis (UC), information regarding the long-term outcome after tacrolimus therapy is insufficient. The aim of this study was to evaluate the clinical significance of the pretreatment neutrophil-to-lymphocyte ratio (NLR) as a prognostic factor in patients with UC receiving tacrolimus, to aid treatment selection., Materials and Methods: Patients with moderate-to-severe active UC who received oral tacrolimus induction therapy and subsequent immunomodulatory maintenance therapy at our hospital between 2009 and 2017 and who showed clinical response at week 12, were retrospectively enrolled. Cox regression analysis was conducted to study the prognostic role of the pretreatment NLR. The combined impact of the NLR and other known prognostic factors was investigated with multivariate regression., Results: Among 45 patients included in this study, 21 patients experienced relapse during a median follow-up period of 16.6 months. Multivariate Cox regression analysis identified the pretreatment NLR (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.72-0.94, P < 0.01) and the use of immunomodulators at the start of tacrolimus treatment (HR: 0.18, 95% CI: 0.05-0.66, P = 0.01) as independent predictors of clinical relapse., Conclusions: The pretreatment NLR is an independent prognostic factor in patients with UC treated with tacrolimus., Competing Interests: The following authors Tetsuya Tanigawa, Toshio Watanabe, and Yasuhiro Fujiwara were previously faculty members of a course sponsored by Eisai Co., Ltd, up to last year. They are now no longer faculty members of this course. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Gliadin, a component of wheat gluten known to be an important factor in the etiology of celiac disease, is related to several other diseases through its enhancing effect on intestinal paracellular permeability. We investigated the significance of gliadin in non-steroidal anti-inflammatory drug (NSAID)-induced small-intestinal damage in mice. 7-week-old C57BL/6 male mice were divided into the following groups: standard diet group, in which mice were fed with wheat-containing standard rodent diet (CE-2); gluten-free diet group, in which mice were fed with gluten-free diet (AIN-76A); and gliadin-administered group, in which mice fed with gluten-free diet were administered with gliadin (~250 mg/kg BW). Each group was subdivided into negative, healthy control group and NSAID-treated group. To some mice fed with gluten-free diet and administered with gliadin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor was administered for clarification of the significance of EGFR in NSAID-induced small intestinal damage and intestinal permeability. In mice fed with a gluten-free diet, indomethacin or diclofenac induced very mild mucosal damage in the small intestine compared with that in mice fed with a wheat-containing standard diet. Gliadin exacerbated the NSAID-induced small-intestinal damage in mice fed with a gluten-free diet. With the administration of indomethacin, MPO activity, a marker of neutrophil infiltration into the mucosa and mRNA expression level of tumor necrosis factor α and interleukin-1β in the small intestine were higher in the gliadin-administered mice. Gliadin increased the intestinal paracellular permeability without indomethacin administration (4.3-fold) and further increased the permeability after indomethacin administration (2.1-fold). Gliadin induced phosphorylation of epidermal growth factor receptor (EGFR) in small-intestinal tissues, and erlotinib (an EGFR tyrosine kinase inhibitor) attenuated the indomethacin-induced intestinal damage and permeability exacerbated by gliadin, accompanied by inhibition of EGFR phosphorylation. These results suggest that gliadin plays an important role in the induction and exacerbation of NSAID-induced small-intestinal damage, and that increase in intestinal permeability via the EGFR signalling pathway is involved in its mechanism., Competing Interests: The authors have declared that no competing interests exist.

Liver sinusoidal endothelial cells (LSECs) play a pivotal role in hepatic function and homeostasis. LSEC dysfunction has been recognized to be closely involved in various liver diseases, including non-alcoholic steatohepatitis (NASH), but not much is known about the fate of the scavenger receptors in LSECs during NASH. Fc gamma receptor IIb (FcγRIIb), known as a scavenger receptor, contributes to receptor-mediated endocytosis and immune complexes clearance. In this study, to elucidate the fate of FcγRIIb in the progression of non-alcoholic fatty liver disease (NAFLD), we examined FcγRIIb levels in NAFLD biopsy specimens by immunohistochemistry, and investigated their correlation with the exacerbation of biological indexes and clinicopathological scores of NASH. The FcγRIIb expression levels indicated significant negative correlations with serum levels of blood lipids (triglyceride, total cholesterol, high-density lipoprotein-cholesterol), type 4 collagen and hyaluronic acid, which are involved in hepatic lipid metabolism disorder, fibrosis, and inflammation, respectively. However, there was no significant difference of FcγRIIb expression levels among the pathological grades of NAFLD. During NAFLD progression, inflammation and fibrosis may influence the expression of FcγRIIb and their scavenger functions to maintain hepatic homeostasis., Competing Interests: The authors have declared that no competing interests exist.

Tuberculosis causes the highest mortality among all single infections. Asymptomatic tuberculosis, afflicting one third of the global human population, is the major source as 5-10% of asymptomatic cases develop active tuberculosis during their lifetime. Thus it is one of important issues to develop diagnostic tools for accurately detecting asymptomatic infection. Mycobacterial DNA-binding protein 1 (MDP1) is a major protein in persistent Mycobacterium tuberculosis and has potential for diagnostic use in detecting asymptomatic infection. However, a previous ELISA-based study revealed a specificity problem; IgGs against MDP1 were detected in both M. tuberculosis-infected and uninfected individuals. Although the tertiary structures of an antigen are known to influence antibody recognition, the MDP1 structural details have not yet been investigated. The N-terminal half of MDP1, homologous to bacterial histone-like protein HU, is predicted to be responsible for DNA-binding, while the C-terminal half is assumed as totally intrinsically disordered regions. To clarify the relationship between the MDP1 tertiary structure and IgG recognition, we refined the purification method, which allow us to obtain a recombinant protein with the predicted structure. Furthermore, we showed that an IgG-ELISA using MDP1 purified by our refined method is indeed useful in the detection of asymptomatic tuberculosis., Competing Interests: The authors have declared that no competing interests exist.

This paper studies the structure of the Japanese production network, which includes one million firms and five million supplier-customer links. This study finds that this network forms a tightly-knit structure with a core giant strongly connected component (GSCC) surrounded by IN and OUT components constituting two half-shells of the GSCC, which we call awalnut structure because of its shape. The hierarchical structure of the communities is studied by the Infomap method, and most of the irreducible communities are found to be at the second level. The composition of some of the major communities, including overexpressions regarding their industrial or regional nature, and the connections that exist between the communities are studied in detail. The findings obtained here cause us to question the validity and accuracy of using the conventional input-output analysis, which is expected to be useful when firms in the same sectors are highly connected to each other., Competing Interests: The authors have declared that no competing interests exist.

Background & Aims: Advanced techniques have been developed to overcome difficult cannulation cases in endoscopic retrograde cholangiopancreatography (ERCP). Pancreatic duct guidewire placement method (PGW) is performed in difficult cannulation cases; it is possible that it places patients at risk of post-ERCP pancreatitis (PEP). The mechanism of PEP is still unclear, but pancreatic duct pressure and injury of pancreatic duct are known causes of PEP. Therefore, we hypothesized a relationship between pancreatic duct diameter and PEP and predicted that PGW would increase the risk of PEP in patients with non-dilated pancreatic ducts. This study aimed to investigate whether PGW increased the risk of PEP in patients with pancreatic duct diameter ≤ 3 mm., Methods: We analyzed 332 patients with pancreatic duct ≤ 3 mm who performed first time ERCP session. The primary endpoint was the rate of adverse event of PEP. We evaluated the risk of PEP in patients who had undergone PGW compared to those who had not, using the inverse probability of treatment weighting (IPTW) analysis., Results: PGW was found to be an independent risk factor for PEP by univariate analysis (odds ratio [OR], 2.45; 95% confidence interval [CI], 1.12-5.38; p = 0.03) after IPTW in patients with pancreatic duct diameter ≤ 3 mm. Adjusted for all covariates, PGW remained an independent risk factor for PEP (OR, 3.12; 95% CI, 1.33-7.33; p = 0.01)., Conclusion: Our results indicate that PGW in patients with pancreatic duct diameter ≤ 3 mm increases the risk of PEP.

This work aims to study and explain the business cycle correlations of the Japanese production network. We consider the supplier-customer network, which is a directed network representing the trading links between Japanese firms (links from suppliers to customers). The community structure of this network is determined by applying the Infomap algorithm. Each community is defined by its GDP and its associated business cycle. Business cycle correlations between communities are estimated based on copula theory. Then, based on firms' attributes and network topology, these correlations are explained through linear econometric models. The results show strong evidence of business cycle correlations in the Japanese production network. A significant systemic risk is found for high negative or positive shocks. These correlations are explained mainly by the sector and by geographic similarities. Moreover, our results highlight the higher vulnerability of small communities and small firms, which is explained by the disassortative mixing of the production network.

Objective: Studies have suggested that frequent participation in social groups contributes to the well-being of older people. The primary aim of this study was to identify the number of days older adults should participate in the activities of social groups to maintain their health for 4 years. This study also aimed to examine whether the effective frequency differs by the type of social group activity., Method: We examined a prospective cohort of 1,320 community-dwelling older adults over 65 years of age, who responded to both a baseline and a follow-up mail survey, in a suburban city of Tokyo, Japan. The dependent variable was the change in functional competence during 4 years. Logistic regression analyses were conducted to examine the effects of participation in the activities of the 5 most common social groups among older Japanese on maintaining functional competence., Results: Nine hundred and ninety-four participants (76.5%) maintained their functional competence for 4 years. The results of the logistic regression analyses showed that participating in alumni groups less than once a month and being an inactive member were associated with higher odds of maintaining functional competence, after controlling for socioeconomic, demographic and baseline health status. Additionally, the odds of maintaining functional competence for 4 years increased upon participating in volunteer groups once a month or more. These results were also confirmed using logistic regression analysis, even after adjustment for the effects of participation in other social groups., Discussion: The results indicated the effectiveness of volunteer activities that fulfill a social role in maintaining health. Therefore, older adults should be encouraged to participate in activities of volunteer groups at least once a month. Additionally, older adults can obtain positive health outcomes through less frequent participation in alumni groups, compared with the activities of volunteer groups.

Background: Increasing plasma glucose levels and insulin resistance can alter the distribution pattern of fluorine-18-labeled fluorodeoxyglucose (18F-FDG) in the brain and relatively reduce 18F-FDG uptake in Alzheimer's disease (AD)-related hypometabolic regions, leading to the appearance of an AD-like pattern. However, its relationship with plasma insulin levels is unclear. We aimed to compare the effects of plasma glucose levels, plasma insulin levels and insulin resistance on the appearance of the AD-like pattern in 18F-FDG images., Methods: Fifty-nine cognitively normal older subjects (age = 75.7 ± 6.4 years) underwent 18F-FDG positron emission tomography along with measurement of plasma glucose and insulin levels. As an index of insulin resistance, the Homeostasis model assessment of Insulin Resistance (HOMA-IR) was calculated., Results: Plasma glucose levels, plasma insulin levels, and HOMA-IR were 102.2 ± 8.1 mg/dL, 4.1 ± 1.9 μU/mL, and 1.0 ± 0.5, respectively. Whole-brain voxelwise analysis showed a negative correlation of 18F-FDG uptake with plasma glucose levels in the precuneus and lateral parietotemporal regions (cluster-corrected p < 0.05), and no correlation with plasma insulin levels or HOMA-IR. In the significant cluster, 18F-FDG uptake decreased by approximately 4-5% when plasma glucose levels increased by 20 mg/dL. In the precuneus region, volume-of-interest analysis confirmed a negative correlation of 18F-FDG uptake with plasma glucose levels (r = -0.376, p = 0.002), and no correlation with plasma insulin levels (r = 0.156, p = 0.12) or HOMA-IR (r = 0.096, p = 0.24)., Conclusion: This study suggests that, of the three parameters, plasma glucose levels have the greatest effect on the appearance of the AD-like pattern in 18F-FDG images.

Objectives: Neutrophil-to-lymphocyte ratio (NLR) has been used to determine the outcome in malignancies and coronary heart disease. Some reports considered the value of NLR as a predictor of response to infliximab in patients with Crohn's disease or rheumatoid arthritis; however, no similar studies have been reported for ulcerative colitis (UC). This study aimed to evaluate the clinical significance of the baseline NLR in patients with UC treated by infliximab., Materials and Methods: Patients with moderate-to-severe active UC who received the first infliximab infusion in our hospital between 2010 and 2015, who showed clinical response during the induction period, were retrospectively evaluated for long-term outcomes and risk factors for loss of response (LOR) during infliximab maintenance therapy. Baseline inflammatory markers including NLR were measured within one week before the initiation of infliximab., Results: Fifty-nine patients with moderate-to-severe active UC started treatment with infliximab and 37 patients (62.7%) experienced clinical response after induction therapy. Fourteen of 37 patients on maintenance therapy lost the response during follow-up. Baseline NLR of patients with LOR was significantly higher than in patients with sustained response. The NLR cut-off value of 4.488 was predictive of LOR, using receiver operating characteristic analysis (sensitivity: 78.6%, specificity: 78.3%). A univariate analysis revealed a significant relationship between relapse-free survival and the NLR (P = 0.018). Multivariate analysis indicated the NLR as an independent prognostic factor for LOR (hazard ratio = 3.86, 95% confidence interval: 1.20-12.4, P = 0.023)., Conclusions: Baseline NLR is a useful prognostic marker in patients with moderate-to-severe active UC treated with infliximab, and may contribute to appropriate use of infliximab., Competing Interests: Tetsuya Tanigawa, Toshio Watanabe, Kazunari Tominaga, and Yasuhiro Fujiwara are faculty members of a course sponsored by Eisai Co., Ltd. The other authors declare that they have no conflicts of interest, and that there were no external funding sources for this study. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Sevoflurane exposure impairs the long-term memory in neonates. Whether the exposure to animals in adolescence affects the memory, however, has been unclear. A small hydrolase enzyme of guanosine triphosphate (GTPase) rac1 plays a role in the F-actin dynamics related to the synaptic plasticity, as well as superoxide production via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. The current study was designed to examine whether sevoflurane exposure to mice in early adolescence modifies the long-term learning ability concomitantly with the changes in F-actin constitution as well as superoxide production in the hippocampus according to the levels of rac1 protein expression. Four-week-old mice were subjected to the evaluation of long-term learning ability for three days. On day one, each mouse was allowed to enter a dark chamber for five min to acclimatization. On day two, the procedure was repeated with the addition of an electric shock as soon as a mouse entered the dark chamber. All mice subsequently inhaled 2 L/min air with (Sevoflurane group) and without (Control group) 2.5% sevoflurane for three hours. On day three, each mouse was placed on the platform and retention time, which is the latency to enter the dark chamber, was examined. The brain removed after the behavior test, was used for analyses of immunofluorescence, Western immunoblotting and intracellular levels of superoxide. Sevoflurane exposure significantly prolonged retention time, indicating the enhanced long-term memory. Sevoflurane inhalation augmented F-actin constitution coexisting with the rac1 protein overexpression in the hippocampus whereas it did not alter the levels of superoxide. Sevoflurane exposure to 4-week-old mice accelerates the long-term memory concomitantly with the enhanced F-actin constitution coexisting with the small GTPase rac1 overexpression in the hippocampus. These results suggest that sevoflurane inhalation may amplify long-term memory consolidation via the increased cytoskeleton constitution in the hippocampus of animals in early adolescence., Competing Interests: The authors have declared that no competing interests exist.

Purpose of the Study: This study aims to clarify the job seeking process of the elderly people through the local employment support facility known as the Active Senior Employment Support Center (ASESC)"AKUTIBU SINIA SHUGYO SIEN SENTAA" in the Tokyo metropolitan area, and evaluate the performance as a complement to the national support systems., Methods: We conducted 6 waves of longitudinal mail surveys over 38 weeks to 235 older job seekers (146 males and 89 females, average age 63.7, SD 5.6), who visited two ASESCs for the first time, to clarify their living situation, health condition, and changes in their job seeking process., Results: These older job seekers tended to be at a relatively low education level and on low income, as well as tended to seek jobs for earning living expenses rather than for well-being. Half of them found employment in 35.0 days; however, 23.8% couldn't find any job in 38 weeks, especially those who were younger and with higher education., Implications: ASESCs are functioning to assist older job seekers who are mainly seeking jobs for earning living expenses, which can be attained in a short time span and enable them to earn some money. These facilities are expected to be consulting services, not only for employment support but also for general living, because it is important to maintain contact with people who are at risk of social isolation, serious financial difficulty, or suicide. We consider it very helpful to encourage and re-activate these mismatched people, by supporting them to engage in highly contributional services to our society and the next generation, such as providing child-care support or daily life support, the demands for which are rapidly increasing due to recent governmental policies.

Arterial transit time (ATT) is most crucial for measuring absolute cerebral blood flow (CBF) by arterial spin labeling (ASL), a noninvasive magnetic resonance (MR) perfusion assessment technique, in patients with chronic occlusive cerebrovascular disease. We validated ASL-CBF and ASL-ATT maps calculated by pulsed continuous ASL (pCASL) with multiple post-label delay acquisitions in patients with occlusive cerebrovascular disease. Fifteen patients underwent MR scans, including pCASL, and positron emission tomography (PET) scans with 15O-water to obtain PET-CBF. MR acquisitions with different post-label delays (1.0, 1.5, 2.0, 2.5 and 3.0 sec) were also obtained for ATT correction. The theoretical framework of 2-compartmental model (2CM) was also used for the delay compensation. ASL-CBF and ASL-ATT were calculated based on the proposed 2CM, and the effect on the CBF values and the ATT correction characteristics were discussed. Linear regression analyses were performed both on pixel-by-pixel and region-of-interest bases in the middle cerebral artery (MCA) territory. There were significant correlations between ASL-CBF and PET-CBF both for voxel values (r = 0.74 ± 0.08, slope: 0.87 ± 0.22, intercept: 6.1 ± 4.9) and for the MCA territorial comparison in both affected (R2 = 0.67, y = 0.83x + 6.3) and contralateral sides (R2 = 0.66, y = 0.74x + 6.3). ASL-ATTs in the affected side were significantly longer than those in the contralateral side (1.51 ± 0.41 sec and 1.12 ± 0.30 sec, respectively, p <0.0005). CBF measurement using pCASL with delay compensation was feasible and fairly accurate even in altered hemodynamic states.

We explore the foreign exchange and stock market networks for 48 countries from 1999 to 2012 and propose a model, based on complex Hilbert principal component analysis, for extracting significant lead-lag relationships between these markets. The global set of countries, including large and small countries in Europe, the Americas, Asia, and the Middle East, is contrasted with the limited scopes of targets, e.g., G5, G7 or the emerging Asian countries, adopted by previous works. We construct a coupled synchronization network, perform community analysis, and identify formation of four distinct network communities that are relatively stable over time. In addition to investigating the entire period, we divide the time period into into "mild crisis," (1999-2002), "calm," (2003-2006) and "severe crisis" (2007-2012) sub-periods and find that the severe crisis period behavior dominates the dynamics in the foreign exchange-equity synchronization network. We observe that in general the foreign exchange market has predictive power for the global stock market performances. In addition, the United States, German and Mexican markets have forecasting power for the performances of other global equity markets.

Objective: Smoking is associated with gastroesophageal reflux disease (GERD). Varenicline, a nicotinic receptor partial agonist, is used to aid smoking cessation. The purpose of this study was to prospectively examine the long-term benefits of smoking cessation on GERD and health-related quality of life (HR-QOL)., Methods: Patients treated with varenicline were asked to fill out a self-report questionnaire about their smoking habits, gastrointestinal symptoms, and HR-QOL before and 1 year after smoking cessation. The prevalence of GERD, frequency of symptoms, and HR-QOL scores were compared. We also investigated associations between clinical factors and newly-developed GERD., Results: A total of 141 patients achieved smoking cessation (success group) and 50 did not (failure group) at 1 year after the treatment. The GERD improvement in the success group (43.9%) was significantly higher than that in the failure group (18.2%). The frequency of reflux symptoms significantly decreased only in the success group. There were no significant associations between newly developed GERD and clinical factors including increased body mass index and successful smoking cessation. HR-QOL significantly improved only in the success group., Conclusions: Smoking cessation improved both GERD and HR-QOL. Smoking cessation should be recommended for GERD patients.

Background: Biliary tract cancer (BTC) patients who have undergone surgical resection with major hepatectomy cannot tolerate the standard gemcitabine regimen (1,000 mg/m2 on days 1, 8, and 15 every 4 weeks) due to severe toxicities such as myelosuppression. Our dose-finding study of adjuvant gemcitabine therapy for biliary tract cancer following major hepatectomy determined that the recommended dose is 1,000 mg/m2 on days 1 and 15 every 4 weeks. Here, we evaluate the pharmacokinetics and pharmacodynamics of gemcitabine in these subjects., Methods: We evaluated BTC patients scheduled to undergo surgical resection with major hepatectomy followed by gemcitabine therapy. A pharmacokinetic evaluation of gemcitabine and its main metabolite, 2',2'-difluorodeoxyuridine (dFdU), was conducted at the initial administration of gemcitabine, which was given by intravenous infusion over 30 min at a dose of 800-1,000 mg/m2. Physical examination and adverse events were monitored for 12 weeks., Results: Thirteen patients were enrolled from August 2011 to January 2013, with 12 ultimately completing the pharmacokinetic study. Eight patients had hilar cholangiocarcinoma, three had intrahepatic cholangiocarcinoma, and one had superficial spreading type cholangiocarcinoma. The median interval from surgery to first administration of gemcitabine was 65.5 days (range, 43-83 days). We observed the following toxicities: neutropenia (n = 11, 91.7%), leukopenia (n = 10, 83.3%), thrombocytopenia (n = 6, 50.0%), and infection (n = 5, 41.7%). Grade 3 or 4 neutropenia was observed in 25% (n = 3) of patients. There were differences in clearance of gemcitabine and dFdU between our subjects and the subjects who had not undergone hepatectomy., Conclusion: Major hepatectomy did not affect the pharmacokinetics of gemcitabine or dFdU., Trial Registration: UMIN-CTR in (JPRN) UMIN000005109.

Background: Working at old ages is regarded as a good way to keep one's health according to the idea of productive aging. However, there is not enough evidence yet whether retirement is good or bad, or the kind of effects it has on the health of older adults aged 65 and over. We examined it by using a recent data of Wako city, a suburb area near Tokyo in Japan., Methods: One thousand seven hundred sixty-eight participants answered to 3 waves of survey questionnaires: 2008, 2010, and 2012, successively. We considered 3 indicators of health; self-rated health, mental health (GDS15) and HLFC (Higher-Level Functional Capacity: TMIG-IC). In cross-sectional analysis, we compared these 3 indicators by three groups: full-time worker, part-time worker, and non-worker. In longitudinal analysis, we compared these three indicators by two groups: subjects who successively worked in 2008, 2010, 2012, and subjects who worked in 2008 but retired before 2010. We used one-way and two way repeated measures ANCOVA for these analyses, respectively., Results: It was significantly clear that retirement worsened both mental health and HLFC in people aged 65 years and over; especially, mental health worsened rapidly and HLFC gradually. However, these indicators didn't worsen in subjects who changed from full-time jobs to part-time jobs. Quitting from part-time jobs deteriorated mental health gradually and HLFC moderately compared to full-time jobs., Conclusion: The results support the activity theory that older adults who quit from full-time jobs deteriorated both mental health and HLFC, though at different speeds. If they make a transit to part-time jobs, the deterioration would be moderate. It shows that working is an effective way of social participation for older people aged 65 years and over in Japan.

Objectives: To determine age- and sex-specific body composition reference values and investigate age differences in these parameters for community-dwelling older Japanese men and women, using direct segmental multi-frequency bioelectrical impedance analysis., Methods: We conducted a pooled analysis of data collected in four cohort studies between 2008 and 2012: Kusatsu Longitudinal Study, Hatoyama Cohort Study, Itabashi Cohort Study, and Kashiwa Cohort Study. The pooled analysis included cross-sectional data from 4478 nondisabled, community-dwelling adults aged 65-94 years (2145 men, 2333 women; mean age: 72.9 years in men and 72.6 years in women). Body weight, fat mass (FM), percentage FM, fat-free mass (FFM), and appendicular lean soft tissue mass were measured using the InBody 720 and 430 (Biospace Co. Ltd, Seoul, Korea). The values were then normalized by height in meters squared to determine body mass index (BMI), FM index (FMI), FFM index (FFMI), and skeletal muscle mass index (SMI)., Results: Simple means (standard deviation) of BMI, percentage FM, FMI, FFMI, and SMI were 23.4 (2.9) kg/m(2), 24.9 (6.3)%, 5.96 (2.09) kg/m(2), 17.4 (1.5) kg/m(2), and 7.29 (0.76) kg/m(2), respectively, in men and 22.7 (3.3) kg/m(2), 31.7 (7.1)%, 7.40 (2.61) kg/m(2), 15.3 (1.2) kg/m(2), and 5.86 (0.67) kg/m(2), respectively, in women. We then calculated quartiles and quintiles for these indices after stratifying for sex and 5-year age group. FFMI and SMI decreased significantly with age in both sexes (P < 0.001 for trends), but FFMI remained constant among the women with only a 1% decrease up to age 84 years. Percentage FM increased significantly, with age (P < 0.001 in men and P = 0.045 in women for trends), but FMI was unchanged in both sexes (P = 0.147 in men and P = 0.176 in women for trends)., Conclusion: The present data should be useful in the clinical evaluation of body composition of older Japanese and for international comparisons. The small age-related decrease in FFMI may be a noteworthy characteristic of body composition change in older Japanese women.

Reactive oxygen species (ROS) and nitric oxide (NO) are major pathogenic molecules produced during viral lung infections, including influenza. While fluoroquinolones are widely used as antimicrobial agents for treating a variety of bacterial infections, including secondary infections associated with the influenza virus, it has been reported that they also function as anti-oxidants against ROS and as a NO regulator. Therefore, we hypothesized that levofloxacin (LVFX), one of the most frequently used fluoroquinolone derivatives, may attenuate pulmonary injuries associated with influenza virus infections by inhibiting the production of ROS species such as hydroxyl radicals and neutrophil-derived NO that is produced during an influenza viral infection. The therapeutic impact of LVFX was examined in a PR8 (H1N1) influenza virus-induced lung injury mouse model. ESR spin-trapping experiments indicated that LVFX showed scavenging activity against neutrophil-derived hydroxyl radicals. LVFX markedly improved the survival rate of mice that were infected with the influenza virus in a dose-dependent manner. In addition, the LVFX treatment resulted in a dose-dependent decrease in the level of 8-hydroxy-2'-deoxyguanosine (a marker of oxidative stress) and nitrotyrosine (a nitrative marker) in the lungs of virus-infected mice, and the nitrite/nitrate ratio (NO metabolites) and IFN-γ in BALF. These results indicate that LVFX may be of substantial benefit in the treatment of various acute inflammatory disorders such as influenza virus-induced pneumonia, by inhibiting inflammatory cell responses and suppressing the overproduction of NO in the lungs.