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BACKGROUND: Various biomarkers have been developed and evaluated to predict the prognosis and complications of allogeneic hematopoietic cell transplantation (HCT). Most previous studies conducted on different biomarkers evaluated single effects such as those associated with inflammation, immunology, iron metabolism, and nutrition, and only a few studies have comprehensively analyzed markers. OBJECTIVE: The study aimed to survey comprehensive multiple markers prior to HCT and extract those that significantly predict the outcomes. STUDY DESIGN: A prospective multicenter observational study was performed. (UMIN000013506) Patients undergoing HCT for hematologic diseases were consecutively enrolled. Besides the usual clinical biomarkers, serum samples for extra-clinical biomarkers were collected and cryopreserved before starting the conditioning regimen. A total of 32 candidate biomarkers were selected, 23 from hematology, biochemistry, immunology, nutrition, and iron metabolism, and 9 from composite markers. Based on the area under the curve (AUC) values for survival, promising biomarkers was extracted. Internal validation for these markers was applied based on bootstrap methods. Setting the cut-off values for them, log-rank test was applied and outcomes including overall survival (OS), relapse, and non-relapse mortality (NRM) were evaluated using multivariate analyses. Furthermore, detailed analysis including transplant-related complications and external validation were conducted focusing on C-reactive protein (CRP) to platelet (Plt) ratio. RESULTS: A total of 152 patients with hematologic malignancies were enrolled from April 2014 to March 2017. CRP, soluble interleukin-2 receptor (IL2R), CRP to albumin (Alb) ratio, CRP to Plt ratio, Plt to IL2R ratio, and IL2R to Alb ratio were identified as promising markers. Internal validation successfully confirmed their reliability of AUC and multivariate analysis demonstrated the statistical significance between the higher and the lower markers. Above all, a higher CRP to Plt ratio was significantly associated with a lower OS (hazard ratio [HR] 2.77; 95% confidence interval [CI] 1.30-5.91; P = 0.008) and higher non-relapse mortality rates (HR 2.79; 95%CI 1.14-6.80; P = 0.024) at 180 days. Furthermore, univariate analysis showed that a higher CRP to Plt ratio was significantly associated with a higher incidence of sinusoidal obstructive syndrome (P < 0.001) and bloodstream infection (P = 0.027). An external validation test confirmed the significance of the CRP to Plt ratio for these outcomes. CONCLUSION: The multicenter prospective observational study successfully identified significant biomarkers in patients with hematologic malignancies who received HCT. In particular, CRP to Plt ratio was identified as a novel and useful biomarker for predicting transplant outcomes. Further investigations are needed to validate the novel markers, analysis of the pathophysiology, and application to treatment settings other than HCT.

DOI： 10.1016/j.jcyt.2024.03.490

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Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .

DOI： 10.1038/s41591-023-02791-w

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OBJECTIVE: In Japan, perioperative prophylaxis of pulmonary embolism (PE) in gynecologic cancer patients with preoperative asymptomatic venous thromboembolism (VTE) has not been well established yet. The GOTIC-VTE trial was a prospective, multi-center, single-arm clinical trial to investigate the prevention of postoperative symptomatic PE onset by seamless anticoagulant therapy from the preoperative period to 4 weeks after surgery instead of using intermittent pneumatic compression. METHODS: Anticoagulant therapy was started immediately after asymptomatic VTE diagnosis and stopped preoperatively according to the rules of each institution. Unfractionated heparin administration was resumed within 12 hours postoperatively, and this was followed by the switch to low-molecular-weight heparin and subsequently, edoxaban; this cycle was continued for 28 days. Primary outcome was the occurrence of symptomatic PE in 28 days postoperatively. Secondary outcomes were the incidence of VTE-related events in 28 days and 6 months postoperatively and protocol-related adverse events. RESULTS: Between February 2018 and September 2020, 99 patients were enrolled; of these, 82 patients were assessed as the full analysis set, including 58 for ovarian cancer, fallopian tube, or peritoneal cancer; 21 for endometrial cancer; and 3 for cervical cancer. No symptomatic PE was observed within 28 days postoperatively; two patients had bleeding events (major bleeding and clinically relevant nonmajor bleeding) and three had grade 3 adverse events (increased alanine transaminase, aspartate aminotransferase, or gamma-glutamyl transferase). CONCLUSION: The multifaceted perioperative management for gynecologic malignancies with asymptomatic VTE effectively prevented postoperative symptomatic PE. TRIAL REGISTRATION: JRCT Identifier: jRCTs031180124.

DOI： 10.3802/jgo.2024.35.e37

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The clinical implications of recipient bone marrow nucleated cell count (NCC) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unknown. We conducted a multicenter retrospective study to evaluate the clinical significance of bone marrow NCC prior to allo-HSCT in patients with acute lymphoblastic leukemia. Patients who were in remission and underwent the initial allo-HSCT were included and stratified into high- and low-NCC groups using an NCC of 10 × 104/µL as the cut-off. The 3-year overall survival (OS), non-relapse mortality (NRM), and relapse rates for the high- and low-NCC groups were 51.2 vs. 84.5% (p < 0.001), 27.5 vs. 6.5% (p < 0.001), and 31.1 vs. 24.4% (p = 0.322), respectively. The high-NCC group had significantly poorer OS and higher NRM when compared with the low-NCC group. In summary, high recipient bone marrow NCC is associated with higher NRM and lower OS following allo-HSCT.

DOI： 10.1007/s12185-023-03688-7

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Positive and negative predictive values are useful to quantify the performance of medical tests, and both are often used simultaneously. Although there are several methods to test the equality of these predictive values between two medical tests, these approaches separately compare positive and negative predictive values. Therefore, we propose a testing procedure that combines the approximate likelihood ratio test defined by Tang et al. with the non-inferiority test for predictive values. The procedure can confirm that compared to an existing test, a new medical test is non-inferior in terms of both positive and negative predictive values, as well as superior regarding at least one of these values. It can make a comprehensive judgment of the performance of the new test based on both measures. A simulation study showed that the performance of the proposed testing procedure is appropriate, and the procedure is considered useful for evaluating the performance of predictive values of medical tests.

DOI： 10.1080/02664763.2024.2335564

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Aims: Physicians determine the treatment regimen for metastatic colorectal cancer on a case-by-case bases, according to the individual disease characteristics. We retrospectively compared the baseline characteristics and efficacies of first-line treatment among patients with metastatic colorectal cancer who received intensive therapy involving fluoropyrimidine plus oxaliplatin and/or irinotecan, potentially with molecularly targeted agents as well, versus less intensive fluoropyrimidine and/or bevacizumab therapy. Materials & methods: Data were collected from a medical claims database. The efficacy outcomes were: time to treatment failure, time to first subsequent therapy and overall survival. Results: The less intensive therapy group (n = 633) had higher median age, lower daily activity levels and shorter time to treatment failure, time to first subsequent therapy and overall survival than the intensive therapy group (n = 3829). Combination therapy with molecularly targeted agents and bevacizumab improved treatment efficacy outcomes in the intensive and less intensive groups, respectively. Conclusion: Patient age and daily activity levels were important factors for determining treatment intensity.

DOI： 10.2217/fon-2022-1284

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IMPORTANCE: Substantial heterogeneity exists in treatment recommendations across molecular tumor boards (MTBs), especially for biomarkers with low evidence levels; therefore, the learning program is essential. OBJECTIVE: To determine whether a learning program sharing treatment recommendations for biomarkers with low evidence levels contributes to the standardization of MTBs and to investigate the efficacy of an artificial intelligence (AI)-based annotation system. DESIGN, SETTING, AND PARTICIPANTS: This prospective quality improvement study used 50 simulated cases to assess concordance of treatment recommendations between a central committee and participants. Forty-seven participants applied from April 7 to May 13, 2021. Fifty simulated cases were randomly divided into prelearning and postlearning evaluation groups to assess similar concordance based on previous investigations. Participants included MTBs at hub hospitals, treating physicians at core hospitals, and AI systems. Each participant made treatment recommendations for each prelearning case from registration to June 30, 2021; participated in the learning program on July 18, 2021; and made treatment recommendations for each postlearning case from August 3 to September 30, 2021. Data were analyzed from September 2 to December 10, 2021. EXPOSURES: The learning program shared the methodology of making appropriate treatment recommendations, especially for biomarkers with low evidence levels. MAIN OUTCOMES AND MEASURES: The primary end point was the proportion of MTBs that met prespecified accreditation criteria for postlearning evaluations (approximately 90% concordance with high evidence levels and approximately 40% with low evidence levels). Key secondary end points were chronological enhancements in the concordance of treatment recommendations on postlearning evaluations from prelearning evaluations. Concordance of treatment recommendations by an AI system was an exploratory end point. RESULTS: Of the 47 participants who applied, 42 were eligible. The accreditation rate of the MTBs was 55.6% (95% CI, 35.3%-74.5%; P < .001). Concordance in MTBs increased from 58.7% (95% CI, 52.8%-64.4%) to 67.9% (95% CI, 61.0%-74.1%) (odds ratio, 1.40 [95% CI, 1.06-1.86]; P = .02). In postlearning evaluations, the concordance of treatment recommendations by the AI system was significantly higher than that of MTBs (88.0% [95% CI, 68.7%-96.1%]; P = .03). CONCLUSIONS AND RELEVANCE: The findings of this quality improvement study suggest that use of a learning program improved the concordance of treatment recommendations provided by MTBs to central ones. Treatment recommendations made by an AI system showed higher concordance than that for MTBs, indicating the potential clinical utility of the AI system.

DOI： 10.1001/jamaoncol.2023.5120

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BACKGROUND: Computed tomography (CT)-derived extracellular volume fraction (ECV) is a noninvasive method to quantify myocardial fibrosis. Although studies suggest CT is a suitable measure of ECV, clinical use remains limited. OBJECTIVES: A meta-analysis was performed to determine the clinical value of CT-derived ECV in cardiovascular diseases. METHODS: Electronic database searches of PubMed, Web of Science Core Collection, Cochrane advanced search, and EMBASE were performed. The most pivotal analysis entailed the comparison of ECV ascertained through CT-ECV among the control, aortic stenosis, and cardiac amyloidosis cohorts. The diagnostic test accuracy for detecting cardiac amyloidosis was assessed using summary receiver-operating characteristics curve. RESULTS: Pooled CT-derived ECV values were 28.5% (95% CI: 27.3%-29.7%) in the control, 31.9 (95% CI: 30.2%-33.8%) in the aortic stenosis, and 48.9% (95% CI: 44.5%-53.3%) in the cardiac amyloidosis group. ECV was significantly elevated in aortic stenosis (P = 0.002; vs controls) but further elevated in cardiac amyloidosis (P < 0.001; vs aortic stenosis). CT-derived ECV had a high diagnostic accuracy for cardiac amyloidosis, with sensitivity of 92.8% (95% CI: 86.7%-96.2%), specificity of 84.8% (95% CI: 68.6%-93.4%), and area under the summary receiver-operating characteristic curve of 0.94 (95% CI: 0.88-1.00). CONCLUSIONS: This study is the first comprehensive systematic review and meta-analysis of CT-derived ECV evaluation in cardiac disease. The high diagnostic accuracy of CT-ECV suggests the usefulness of CT-ECV in the diagnosis of cardiac amyloidosis in preoperative CT planning for transcatheter aortic valve replacement.

DOI： 10.1016/j.jcmg.2023.10.008

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This study retrospectively evaluated the mid-term outcomes of surgical aortic valve replacement (SAVR) using a stented porcine aortic valve bioprosthesis (Mosaic; Medtronic Inc., Minneapolis, MN, USA) with concomitant mitral valve (MV) repair. From 1999 to 2014, 157 patients (median [interquartile range] age, 75 [70-79] years; 47% women) underwent SAVR with concomitant MV repair (SAVR + MV repair), and 1045 patients (median [interquartile range] age, 76 [70-80] years; 54% women) underwent SAVR only at 10 centers in Japan as part of the long-term multicenter Japan Mosaic valve (J-MOVE) study. The 5-year overall survival rate was 81.5% ± 4.1% in the SAVR + MV repair group and 85.1% ± 1.4% in the SAVR only group, and the 8-year overall survival rates were 75.2% ± 5.7% and 78.1% ± 2.1%, respectively. Cox proportional hazards analysis showed no significant difference in the survival rates between the two groups (hazard ratio, 0.87; 95% confidence interval, 0.54-1.40; P = 0.576). Among women with mild or moderate mitral regurgitation who were not receiving dialysis, those who underwent SAVR + MV repair, were aged > 75 years, and had a preoperative left ventricular ejection fraction of 30-75% tended to have a lower mortality risk. In conclusion, this subgroup analysis of the J-MOVE cohort showed relevant mid-term outcomes after SAVR + MV repair.

DOI： 10.1007/s00380-023-02325-x

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In modern medicine, medical tests are used for various purposes including diagnosis, disease screening, prognosis, and risk prediction. To quantify the performance of the binary medical test, we often use sensitivity, specificity, and negative and positive predictive values as measures. Additionally, the F 1 $$ {F}_1 $$ -score, which is defined as the harmonic mean of precision (positive predictive value) and recall (sensitivity), has come to be used in the medical field due to its favorable characteristics. The F 1 $$ {F}_1 $$ -score has been extended for multi-class classification, and two types of F 1 $$ {F}_1 $$ -scores have been proposed for multi-class classification: a micro-averaged F 1 $$ {F}_1 $$ -score and a macro-averaged F 1 $$ {F}_1 $$ -score. The micro-averaged F 1 $$ {F}_1 $$ -score pools per-sample classifications across classes and then calculates the overall F 1 $$ {F}_1 $$ -score, whereas the macro-averaged F 1 $$ {F}_1 $$ -score computes an arithmetic mean of the F 1 $$ {F}_1 $$ -scores for each class. Additionally, Sokolova and Lapalme 1 $$ {}^1 $$ gave an alternative definition of the macro-averaged F 1 $$ {F}_1 $$ -score as the harmonic mean of the arithmetic means of the precision and recall over classes. Although some statistical methods of inference for binary and multi-class F 1 $$ {F}_1 $$ -scores have been proposed, the methodology development of hypothesis testing procedure for them has not been fully progressing yet. Therefore, we aim to develop hypothesis testing procedure for comparing two F 1 $$ {F}_1 $$ -scores in paired study design based on the large sample multivariate central limit theorem.

DOI： 10.1002/sim.9853

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OBJECTIVE: The aim of the present study was to investigate which treatment, neoadjuvant chemoradiotherapy (NAC-RT) with S-1 or combination neoadjuvant chemotherapy with gemcitabine and S-1 (NAC-GS), is more promising as neoadjuvant treatment (NAT) for resectable pancreatic cancer in terms of effectiveness and safety. METHODS: In the NAC-RT with S-1 group, the patients received a total radiation dose of 50.4 Gy in 28 fractions with oral S-1. In the NAC-GS group, the patients received intravenous gemcitabine at a dose of 1000 mg/m2 with oral S-1 for two cycles. The primary endpoint was the 2-year progression-free survival (PFS) rate. The trial was registered with the UMIN Clinical Trial Registry as UMIN000014894. RESULTS: From April 2014 to April 2017, a total of 103 patients were enrolled. After exclusion of one patient because of ineligibility, 51 patients were included in the NAC-RT with S-1 group, and 51 patients were included in the NAC-GS group in the intention-to-treat analysis. The 2-year PFS rate was 45.0% (90% confidence interval [CI]: 33.3%-56.0%) in the NAC-RT with S-1 group and 54.9% (42.8%-65.5%) in the NAC-GS group (p = .350). The 2-year overall survival rate was 66.7% in the NAC-RT with S-1 group and 72.4% in the NAC-GS group (p = .300). Although leukopenia and neutropenia rates were significantly higher in the NAC-GS group than in the NAC-RT with S-1 group (p = .023 and p < .001), other adverse events of NAT and postoperative complications were comparable between the two groups. CONCLUSION: Both NAC-RT with S-1 and NAC-GS are considered promising treatments for resectable pancreatic cancer.

DOI： 10.1002/jhbp.1353

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INTRODUCTION: Three randomized controlled trials have resulted in extremely extensive application of the strategy of using neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) for patients with advanced epithelial ovarian cancer in Japan. This study aimed to evaluate the status and effectiveness of treatment strategies using NAC followed by IDS in Japanese clinical practice. PATIENTS AND METHODS: We conducted a multi-institutional observational study of 940 women with Federation of Gynecology and Obstetrics (FIGO) stages III-IV epithelial ovarian cancer treated at one of nine centers between 2010 and 2015. Progression-free survival (PFS) and overall survival (OS) were compared between 486 propensity-score matched participants who underwent NAC followed by IDS and primary debulking surgery (PDS) followed by adjuvant chemotherapy. RESULTS: Patients with FIGO stage IIIC receiving NAC had a shorter OS (median OS: 48.1 vs. 68.2 months, hazard ratio [HR]: 1.34; 95% confidence interval [CI] 0.99-1.82, p = 0.06) but not PFS (median PFS: 19.7 vs. 19.4 months, HR: 1.02; 95% CI: 0.80-1.31, p = 0.88). However, patients with FIGO stage IV receiving NAC and PDS had comparable PFS (median PFS: 16.6 vs. 14.7 months, HR: 1.07 95% CI: 0.74-1.53, p = 0.73) and OS (median PFS: 45.2 vs. 35.7 months, HR: 0.98; 95% CI: 0.65-1.47, p = 0.93). CONCLUSIONS: NAC followed by IDS did not improve survival. In patients with FIGO stage IIIC, NAC may be associated with a shorter OS.

DOI： 10.1007/s10147-023-02329-7

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Intraperitoneal Carboplatin for Ovarian CancerThis trial compared intravenous weekly paclitaxel administered with intraperitoneal or intravenous carboplatin. There was a statistically significant increase in progression-free survival in patients with ovarian cancer treated with intraperitoneal versus intravenous carboplatin and paclitaxel, with no difference in overall survival between groups.

DOI： 10.1056/EVIDoa2200225

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IMPORTANCE: For patients with RAS wild-type metastatic colorectal cancer, adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined. OBJECTIVE: To evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015-January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022). INTERVENTIONS: Panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days. MAIN OUTCOMES AND MEASURES: The primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resection rate. RESULTS: In the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0%-12.3%) and 16.5% vs 10.9% overall (difference, 5.6%; 95% CI, 1.0%-10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%). CONCLUSIONS AND RELEVANCE: Among patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02394795.

DOI： 10.1001/jama.2023.4428

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DOI： 10.1016/j.jaad.2022.08.066

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BACKGROUND: To explore the predictive value of the Thompson score during the first 4 days of life for estimating short-term adverse outcomes in neonatal encephalopathy. METHODS: This observational study evaluated infants with neonatal encephalopathy (≥36 weeks of gestation) registered in a multicenter cohort of cooled infants in Japan. The Thompson score was evaluated at 0-24, 24-48, 48-72, and 72-90 h of age. Adverse outcomes included death, survival with respiratory impairment (requiring tracheostomy), or survival with feeding impairment (requiring gavage feeding) at discharge. RESULTS: Of the 632 infants, 21 (3.3%) died, 59 (9.3%) survived with respiratory impairment, and 113 (17.9%) survived with feeding impairment. The Thompson score throughout the first 4 days accurately predicted death, respiratory impairment, or feeding impairment. The 72-90 h score showed the highest accuracy. A cutoff of ≥15 had a sensitivity of 0.85 and specificity of 0.92 for death or respiratory impairment, while a cutoff of ≥14 had a sensitivity of 0.71 and a specificity of 0.92 for death, respiratory or feeding impairment. CONCLUSION: A high Thompson score during the first 4 days of life, especially at 72-90 h could thus be useful for estimating the need for prolonged life support. IMPACT: The Thompson score on days 1-4 of age was useful in predicting death and respiratory or feeding impairments. The 72-90 h Thompson score showed the highest predictive capability. Owing to the rarity of withdrawal of life-sustaining treatment in Japan, 43% of infants with persistent severe encephalopathy with a Thompson score of ≥15 at 72-90 h of age could regain spontaneous breathing, be extubated, and survive without tracheostomy. Meanwhile, approximately 50% of infants who survived without tracheostomy required gavage feeding. Our results could provide useful information for clinical decision making regarding infants with persistent severe encephalopathy.

DOI： 10.1038/s41390-022-02212-7

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BACKGROUND: Transcatheter arterial embolization (TAE) has long been used for hemostasis of traumatic or postoperative hemorrhage and embolization of tumors. Previous retrospective studies of TAE for painful bone metastases showed 60%-80% pain reduction with a median time to response of 1-2 days. Compared with radiotherapy and bisphosphonates, time to response appeared earlier than that of radiotherapy or bone-modifying agents. However, few prospective studies have examined TAE for this indication. Here, we describe the protocol for a confirmatory study designed to clarify the efficacy and safety profile of TAE. METHODS: This study will be a multicenter, single-arm confirmatory study (phase 2-3 design). Patients with painful bone metastases from any primary tumor are eligible for enrollment. TAE will be the main intervention. Following puncture of the femoral artery under local anesthesia and insertion of an angiographic sheath, angiography will confirm that the injected region includes tumor vasculature. Catheter position will be adjusted so that the embolization range does not include non-target tissues. Spherical embolic material will then be slowly injected into the artery to embolize it. The primary endpoint (efficacy) is the proportion of subjects with pain relief at 72 h after TAE and the secondary endpoint (safety) is the incidence of all NCI Common Terminology Criteria for Adverse Events version 5.0 Grade 4 adverse events and Grade ≥ 3 necrosis of the central nervous system. DISCUSSION: If the primary and secondary endpoints are met, TAE can be a treatment choice for painful bone metastases. Trial registry number is UMIN-CTR ID: UMIN000040794. TRIAL REGISTRATION: The study is ongoing, and patients are currently being enrolled. Enrollment started in March 2021. A total of 36 patients have participated as of Aug 2022. PROTOCOL VERSION: Ver1.4, 13/07/2022.

DOI： 10.1186/s12885-023-10538-6

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Objectives: For suspected common bile duct stone (CBDS) missed on computed tomography (CT), there is no clear evidence on whether endoscopic ultrasound (EUS) or magnetic resonance cholangiopancreatography (MRCP) is the better diagnostic tool. We aimed to compare the diagnostic accuracy of EUS and MRCP for cases of missed CBDS on CT. Methods: Patients suspected of having CBDS were enrolled and randomly allocated to the EUS or MRCP group. Upon the initial examination, those having CBDS or sludge formation underwent endoscopic retrograde cholangiopancreatography (ERCP), while those who were CBDS-negative underwent a second examination with either MRCP or EUS, which was distinct from the initial diagnostic procedure. The primary outcome was diagnostic accuracy, and the secondary outcomes were diagnostic ability, detection rate and characteristics of CBDS in the second examination, and the frequency of adverse events. Results: Between April 2019 and January 2021, 50 patients were enrolled in the study. The accuracy was 92.3% for EUS and 68.4% for MRCP (P = 0.055). EUS showed 100% sensitivity, 88.2% specificity, 81.8% positive predictive value, and 100% negative predictive value, and MRCP showed 33.3% sensitivity, 84.6% specificity, 50% positive predictive value, and 73.3% negative predictive value. The CBDS detection rate in the second examination was 0% for MRCP after a negative EUS and 35.7% for EUS after a negative MRCP (P=0.041). No adverse events occurred in any of the patients. Conclusions: Endoscopic ultrasound may be a superior diagnostic tool compared to MRCP for the detection of CBDS that are undetected on CT. (UMIN000036357).

DOI： 10.11280/gee.65.486

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Objective. Although data accumulated in clinical trials have higher accuracy compared to real-world data and are irreplaceably valuable, most previous clinical trial data have been left unutilized. Methods. The Japan Lung Cancer Society (JLCS) asked six clinical trial groups that conducted randomized clinical trials on curative chemoradiation for locally advanced non-small cell lung cancer (NSCLC) to provide data. After obtaining consent from all six groups, data were collected from August 2019 to June 2021. Results. Eight trials, JCOG9812, JCOG 0301, NJLCG0601, OLCSG0007, WJTOG0105, WJOG5008L, SPECTRA, and TORG1018, were included. More than 3000 data items were integrated into 408 items by adjusting their definitions and units. The total number of collected cases was 1288: median age (range), 66 (30-93) years; sex (male/female) 1064/224; histological type (squamous cell carcinoma/adenocarcinoma/other NSCLC/unknown) 517/629/138/4; and stage IIIA/B, 536/752. The median overall survival was 24.6 months, with 2-, 5-, and 10-year survival rates of 51.1%, 22.5%, and 13.8%, respectively, in all enrollments. The median progression-free survival (PFS) was 9.5 months, with 2-, 5-, and 10-year PFS rates of 22.4%, 13.0%, and 9.1%, respectively. Part of the information in the database has been made available on the JLCS web page, and the JLCS members were provided the right to propose research using the database. Conclusion. The integration and sharing of clinical trial data for research purposes was made real by the nonprofit, academic organization, the JLCS. This database will lead to innovative researches and contribute to the improvement of lung cancer treatment and future research.

DOI： 10.2482/haigan.63.161

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In some situations, square contingency tables with ordered categories are analyzed by considering collapsed tables where adjacent categories are combined. This study proposes measures to represent the degree of departure from symmetry using collapsed tables. The proposed measures are defined as the arithmetic mean of submeasures of each collapsed 3 × 3 table. Additionally, a theorem affirms that the value of the measure for symmetry is equal to the sum of the value of the proposed measures. Finally, examples are given.

DOI： 10.1080/03610926.2023.2233152

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IMPORTANCE: Quality assurance of molecular tumor boards (MTBs) is crucial in cancer genome medicine. OBJECTIVE: To evaluate the concordance of recommendations by MTBs and centrally developed consensus treatment recommendations at all 12 leading institutions for cancer genomic medicine in Japan using 50 simulated cases. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective quality improvement study of 50 simulated cancer cases. Molecular tumor boards from 12 core hospitals independently recommended treatment for 50 cases blinded to the centrally developed consensus treatment recommendations. The study's central committee consisted of representatives from all 12 core hospitals in Japan who selected the 50 simulated cases from The Cancer Genome Atlas database, including frequently observed genomic alterations. The central committee recommended centrally developed consensus treatment. The concordance rate for genomically matched treatments between MTBs and centrally developed consensus treatment recommendations was evaluated. Data analysis was conducted from January 22 to March 3, 2021. EXPOSURES: Simulated cases of cancer. MAIN OUTCOMES AND MEASURES: The primary outcome was concordance, defined as the proportion of recommendations by MTBs concordant with centrally developed consensus treatment recommendations. A mixed-effects logistic regression model, adjusted for institutes as a random intercept, was applied. High evidence levels were defined as established biomarkers for which the treatment was ready for routine use in clinical practice, and low evidence levels were defined as biomarkers for genomically matched treatment that were under investigation. RESULTS: The Clinical Practice Guidance for Next-Generation Sequencing in Cancer Diagnosis and Treatment (edition 2.1) was used for evidence-level definition. The mean concordance between MTBs and centrally developed consensus treatment recommendations was 62% (95% CI, 57%-65%). Each MTB concordance varied from 48% to 86%. The concordance rate was higher in the subset of patients with colorectal cancer (100%; 95% CI, 94.0%-100%), ROS1 fusion (100%; 95% CI, 85.5%-100%), and high evidence level A/R (A: 88%; 95% CI, 81.8%-93.0%; R:100%; 95% CI, 92.6%-100%). Conversely, the concordance rate was lower in cases of cervical cancer (11%; 95% CI, 3.1%-26.1%), TP53 mutation (16%; 95% CI, 12.5%-19.9%), and low evidence level C/D/E (C: 30%; 95% CI, 24.7%-35.9%; D: 25%; 95% CI, 5.5%-57.2%; and E: 18%; 95% CI, 13.8%-23.0%). Multivariate analysis showed that evidence level (high [A/R] vs low [C/D/E]: odds ratio, 4.4; 95% CI, 1.8-10.8) and TP53 alteration (yes vs no: odds ratio, 0.06; 95% CI, 0.03-0.10) were significantly associated with concordance. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that genomically matched treatment recommendations differ among MTBs, particularly in genomic alterations with low evidence levels wherein treatment is being investigated. Sharing information on matched therapy for low evidence levels may be needed to improve the quality of MTBs.

DOI： 10.1001/jamanetworkopen.2022.45081

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DOI： 10.1136/ijgc-2022-igcs.481

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BACKGROUND: Chronic constipation leads to poor quality of life, and treatment remains unsatisfactory for patients. In Japan, magnesium oxide has been commonly used as the first choice of treatment for constipation; however, there are some cases of low satisfaction with magnesium oxide treatment. Linaclotide has recently been used to treat chronic constipation. In this study, we will examine whether linaclotide improves symptoms and quality of life in patients showing insufficient response to magnesium oxide. METHODS: This is an exploratory multicenter open-label study. The target number of patients is 64: 32 patients with and 32 without abdominal symptoms. Patients with chronic idiopathic constipation or irritate bowel syndrome with constipation diagnosed according to the Rome-IV criteria are eligible. Patients prescribed 0.99-2 g/day of magnesium oxide for at least 4 weeks will be included. Those who consent to the study will continue taking magnesium oxide for 2-4 weeks, and defecation will be documented. Patients who meet the criteria will be prescribed linaclotide (0.5 mg) daily for 12 weeks. The primary endpoint is a change in the Japanese version of the Patient Assessment of Constipation Quality of Life (JPAC-QOL) score after 12 weeks of treatment. CONCLUSION: This is the first study to investigate the usefulness of linaclotide as a second-line treatment for chronic constipation. We will test the efficacy of treatment of constipation in patients with inadequate response to magnesium oxide. TRIAL REGISTRATION: This study is registered with the Japan Registry of Clinical Trials (jRCT, jRCTs031200048).

DOI： 10.1016/j.conctc.2022.101019

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This study investigated the incidence and risk factors of perioperative clinical seizure and epilepsy in children after operation for CHD. We included 777 consecutive children who underwent operation from January 2013 to December 2016 at Kanagawa Children's Medical Center, Kanagawa, Japan. Perinatal, perioperative, and follow-up medical data were collected. Elastic net regression and mediation analysis were performed to investigate risk factors of perioperative clinical seizure and epilepsy. Anatomic CHD classification was performed based on the preoperative echocardiograms; cardiac surgery was evaluated using Risk Adjustment in Congenital Heart Surgery 1. Twenty-three (3.0%) and 15 (1.9%) patients experienced perioperative clinical seizure and epilepsy, respectively. Partial regression coefficient with epilepsy as the objective variable for anatomical CHD classification, Risk Adjustment in Congenital Heart Surgery 1, and the number of surgeries was 0.367, 0.014, and 0.142, respectively. The proportion of indirect effects on epilepsy via perioperative clinical seizure was 22.0, 21.0, and 33.0%, respectively. The 15 patients with epilepsy included eight cases with cerebral infarction, two cases with cerebral haemorrhage, and three cases with hypoxic-ischaemic encephalopathy; white matter integrity was not found. Anatomical complexity of CHD, high-risk cardiac surgery, and multiple cardiac surgeries were identified as potential risk factors for developing epilepsy, with a low rate of indirect involvement via perioperative clinical seizure and a high rate of direct involvement independently of perioperative clinical seizure. Unlike white matter integrity, stroke and hypoxic-ischaemic encephalopathy were identified as potential factors for developing epilepsy.

DOI： 10.1017/S1047951121005011

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A 2-step approach, Fibrosis-4 index (FIB-4) followed by vibration-controlled transient elastography (VCTE), has been proposed to predict advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to develop a novel 3-step approach for predicting advanced fibrosis. We enrolled 284 biopsy-confirmed NAFLD patients from two tertiary care centers and developed subgroups (n = 190), including 3.7% of patients with advanced fibrosis, assuming a primary care setting. In the 3-step approach, patients with intermediate-to-high FIB-4 in the first step underwent an enhanced liver fibrosis test or measurement of type IV collagen 7S domain as the second step, and VCTE was performed if the second step value was higher than the cutoff. In 284 cases, a tertiary care cohort with 36.3% advanced fibrosis, the 3-step approach showed significantly higher specificity and positive predictive value than the 2-step approach. In the subgroup with 3.7% advanced fibrosis, the 3-step approach significantly reduced the referral rate to specialists, the number of high-risk patients (i.e., liver biopsy candidates), and healthcare costs by 12.5% to 15.8%. The 3-step approach may improve the diagnostic performance to predict advanced fibrosis in NAFLD, which could lower rates of referrals to specialists, liver biopsies, and medical costs.

DOI： 10.1038/s41598-022-22767-z

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Clinical studies often collect longitudinal and time-to-event data for each subject. Joint modeling is a powerful methodology for evaluating the association between these data. The existing models, however, have not sufficiently addressed the problem of missing data, which are commonly encountered in longitudinal studies. In this paper, we introduce a novel joint model with shared random effects for incomplete longitudinal data and time-to-event data. Our proposed joint model consists of three submodels: a linear mixed model for the longitudinal data, a Cox proportional hazard model for the time-to-event data, and a Cox proportional hazard model for the time-to-dropout from the study. By simultaneously estimating the parameters included in these submodels, the biases of estimators are expected to decrease under two missing scenarios. We estimated the proposed model by Bayesian approach, and the performance of our method was evaluated through Monte Carlo simulation studies.

DOI： 10.3390/math10193656

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In square contingency table analysis, we consider a partial measure that represents the degree of departure from symmetry for each of several pairs. It may be useful to pool the values of the measure into a single summary measure of partial asymmetry. We show that the estimator of partial measures is asymptotically mutually independent for a large sample size. The present paper proposes a symmetry measure in the class of weighted averages that is different from previous studies. The proposed measure is an approximation of the measure in the class of weighted averages that has the smallest variance.

DOI： 10.3390/sym14091936

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Language：English   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

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OBJECTIVES: For suspected common bile duct stone (CBDS) missed on computed tomography (CT), there is no clear evidence on whether endoscopic ultrasound (EUS) or magnetic resonance cholangiopancreatography (MRCP) is the better diagnostic tool. We aimed to compare the diagnostic accuracy of EUS and MRCP for cases of missed CBDS on CT. METHODS: Patients suspected of having CBDS were enrolled and randomly allocated to the EUS or MRCP group. Upon the initial examination, those having CBDS or sludge formation underwent endoscopic retrograde cholangiopancreatography (ERCP), while those who were CBDS-negative underwent a second examination with either MRCP or EUS, which was distinct from the initial diagnostic procedure. The primary outcome was diagnostic accuracy, and the secondary outcomes were diagnostic ability, detection rate and characteristics of CBDS in the second examination, and the frequency of adverse events. RESULTS: Between April 2019 and January 2021, 50 patients were enrolled in the study. The accuracy was 92.3% for EUS and 68.4% for MRCP (P = 0.055). EUS showed 100% sensitivity, 88.2% specificity, 81.8% positive predictive value, and 100% negative predictive value, and MRCP showed 33.3% sensitivity, 84.6% specificity, 50% positive predictive value, and 73.3% negative predictive value. The CBDS detection rate in the second examination was 0% for MRCP after a negative EUS and 35.7% for EUS after a negative MRCP (P = 0.041). No adverse events occurred in any of the patients. CONCLUSIONS: Endoscopic ultrasound may be a superior diagnostic tool compared to MRCP for the detection of CBDS that are undetected on CT. (UMIN000036357).

DOI： 10.1111/den.14193

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BACKGROUND: The development of chemotherapy and treatment strategies for metastatic colorectal cancer (mCRC) have provided patients with significant survival benefits. Currently, molecular targeting agents and late-line treatment with regorafenib and trifluridine/tipiracil (FTD/TPI) are available. However, the impact of this increase in drug availability on overall survival (OS) in mCRC remains a clinical question. METHODS: We retrospectively collected data on consecutive mCRC patients who were treated at three institutions in Japan. We divided the patients into three cohorts: patients who initiated first-line treatment from Jan 2005 to Dec 2006 (cohort A: only cytotoxic drugs available), Jan 2007 to Dec 2011 (cohort B: molecular targeting drugs available), and Jan 2012 to Sep 2016 (cohort C: late-line treatment available). RESULTS: A total of 1409 consecutive patients were analyzed. The median survival time (MST) in cohorts A, B, and C was 18.6, 25.4, and 26.4 months, respectively. The hazard ratio (HR) for cohort B versus A was 0.81 (95% CI 0.68-0.97), for cohort C versus A was 0.74 (95% CI 0.61-0.89), and for cohort C versus B was 0.92 (0.81-1.03). The median number of administered drugs (range) was 3 (1-5) in cohort A, 4 (1-7) in cohort B, and 4 (1-7) in cohort C. The increase in drug availability extended the MST from 15.5 months in patients treated with ≤3 drugs to 36.0-37.3 months in patients treated with six to seven drugs. CONCLUSION: The development of chemotherapy including late-line treatments could improve the prognosis of mCRC patients.

DOI： 10.1002/cam4.4599

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Furlow double-opposing Z-plasty (FDOZ) as primary palatoplasty for the bilateral cleft lip and palate (BCLP) closure often leads to a palatal fistula formation in cases with wide clefts. We examined the utility of the calculated maximum closable cleft width to determine the feasibility of a direct palatal closure without lateral incisions. In this retrospective study, we analyzed consecutive patients with a BCLP who were treated for 5 years from 2009. In sixty-three BCLP patients, the following dimensions were measured preoperatively: an actual distance between maxillary tuberosities (Actual X); actual cleft height, calculated from the line joining the maxillary tuberosities to the cleft edge (Actual Y); and actual cleft width at the hard-soft palate junction (Actual Z) and calculated maximum cleft width requiring a direct closure (CMZ). Six months postoperatively, the relationships between the fistula occurrence and actual Z/CMZ were examined. Median values (interquartile range) of Actual X, Y, and Z and CMZ were 35.0 (33.0-39.0) mm, 7.0 (6.0-8.0) mm, 10.0 (8.0-11.0) mm, and 4.6 (2.7-5.7) mm, respectively. The median age at operation was 8.0 (7.0-17.0) months. Fistulae at the hard-soft palate junction developed postoperatively in three cases with more than a 10-mm cleft width (4.76%). A receiver operating characteristic (ROC) curve analysis indicated that actual Z was a better predictor of a postoperative fistula formation than CMZ. An actual cleft width was a better predictor of the fistula occurrence than a calculated maximum cleft width after FDOZ for a BCLP repair. The low fistula rate of FDOZ suggested that FDOZ could be used to close the palate with less than a 10-mm cleft width.

DOI： 10.1016/j.bjps.2022.01.038

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INTRODUCTION: Although data accumulated in clinical trials have higher accuracy compared with real-world data and are irreplaceably valuable, most previous clinical trial data have been left unused. METHODS: The Japan Lung Cancer Society (JLCS) asked six clinical trial groups that conducted randomized clinical trials on curative chemoradiation for locally advanced NSCLC to provide data. After obtaining consent from all six groups, data were collected from August 2019 to June 2021. RESULTS: A total of eight trials, JCOG9812, JCOG0301, NJLCG0601, OLCSG0007, WJTOG0105, WJOG5008L, SPECTRA, and TORG1018, were included. More than 3000 data items were integrated into 408 items by adjusting their definitions and units. The total number of collected cases was 1288: median age (range), 66 (30-93) years; sex (male/female) 1064/224; pathological type (squamous cell carcinoma, adenocarcinoma, other NSCLC, and unknown) 517, 629, 138, and 4; and stage IIIA and B, 536 and 752. The median overall survival was 26.0 months, with 2-, 5-, and 10-year survival rates of 53.7%, 24.8%, and 15.2%, respectively, in all enrollments. The median progression-free survival was 9.6 months, with 2-, 5-, and 10-year progression-free survival rates of 23.6%, 14.0%, and 9.4%, respectively. Part of the information in the database has been made available on the JLCS web page, and the JLCS members were provided the right to propose research using the database. CONCLUSIONS: The integration and sharing of clinical trial data for research purposes was made real by the nonprofit, academic organization, the JLCS. This database will lead to innovative researches and contribute to the improvement of lung cancer treatment and future research.

DOI： 10.1016/j.jtocrr.2022.100317

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INTRODUCTION: Outcomes of immune checkpoint inhibitor (ICI) rechallenge in NSCLC remain uncertain. This study estimated the safety and efficacy of ICI rechallenge and compared rechallenge benefit among different reasons of initial ICI discontinuation in NSCLC. METHODS: PubMed, EMBASE, and Cochrane Library were searched for studies on NSCLC retreated with ICI. Immune-related adverse events (irAEs), overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) at initial ICI and rechallenge were analyzed. RESULTS: A total of 15 studies including 442 patients between 2018 and 2022 were eligible for meta-analysis. The incidence of grade 3 or 4 irAE was lower in rechallenge than initial ICI (8.6% versus 17.8%, p < 0.001). Patients rechallenged with ICI had lower ORR and DCR than initial ICI (13.2% versus 42.4%, p < 0.001; 51.1% versus 74.0%, p < 0.001). The ORR and DCR to ICI rechallenge were both higher in patients who experienced disease progression after stopping ICI or irAE than patients with disease progression during ICI treatment (ORR: 46.2% versus 20% versus 11.4%, p = 0.003; DCR: 84.6% versus 90.0% versus 55.0%, p = 0.002). In addition, 34.7% of 69 patients with individual response to ICI and PFS experienced the same or better response to ICI rechallenge in comparison with initial ICI, although PFS in initial ICI was longer than that in ICI rechallenge (median: 8.90 versus 3.67 mo, hazard ratio = 0.44, 95% confidence interval: 0.33-0.59). CONCLUSIONS: ICI rechallenge had less severe toxicity than initial ICI treatment. Patients undergoing disease progression after ICI cessation or ICI discontinuation owing to irAE are more likely to benefit from ICI rechallenge in NSCLC.

DOI： 10.1016/j.jtocrr.2022.100309

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

A binary classification problem is common in medical field, and we often use sensitivity, specificity, accuracy, negative and positive predictive values as measures of performance of a binary predictor. In computer science, a classifier is usually evaluated with precision (positive predictive value) and recall (sensitivity). As a single summary measure of a classifier's performance, F 1 score, defined as the harmonic mean of precision and recall, is widely used in the context of information retrieval and information extraction evaluation since it possesses favorable characteristics, especially when the prevalence is low. Some statistical methods for inference have been developed for the F 1 score in binary classification problems; however, they have not been extended to the problem of multi-class classification. There are three types of F 1 scores, and statistical properties of these F 1 scores have hardly ever been discussed. We propose methods based on the large sample multivariate central limit theorem for estimating F 1 scores with confidence intervals.

DOI： 10.1007/s10489-021-02635-5

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BACKGROUND: This study retrospectively evaluated the long-term patient outcomes and durability of the Mosaic mitral porcine bioprosthesis in the Japan Mosaic valve long-term multicenter study.Methods and Results:The medical records of 390 patients who underwent mitral valve replacement with the Mosaic bioprosthesis at 10 centers in Japan (1999-2014) were reviewed. Patient data were collected using the Research Electronic Data Capture software. Patient survival was determined using the Kaplan-Meier method. Freedom from structural valve deterioration (SVD) and valve-related reoperation and death were determined using actuarial methods. The median (interquartile range [IQR]) age of the cohort was 73 (69-77) years. The median (IQR) follow-up period was 4.83 (1.84-8.26) years. The longest follow-up period was 15.8 years. The 30-day mortality rate was 5.4%. The 12-year actuarial survival rate was 54.1±4.5%, and the freedom from valve-related death was 85.3±3.4%. The freedom from reoperation at 12 years was 74.3±5.7%. The freedom from SVD at 12 years was 81.4±6.6% for patients aged ≥65 years and 71.6±11.1% for those aged <65 years. The median (IQR) mean pressure gradient was 4.1 (3.0-6.0) and 5.6 (4.0-6.7) mmHg at 1 and 10 years, respectively. The median (IQR) effective orifice area was 1.7 (1.4-2.0) and 1.4 (1.2-1.6) cm2at 1 and 10 years, respectively. CONCLUSIONS: The Mosaic porcine bioprosthesis offered satisfactory long-term outcomes for up to 12 years.

DOI： 10.1253/circj.CJ-21-0528

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BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection elicits varying degrees of protective immunity conferred by neutralizing antibodies (nAbs). In this study, we report the persistence of nAb responses over 12 months after infection despite their decreasing trend noticed from 6 months. METHODS: The study included sera from 497 individuals who had been infected with SARS-CoV-2 between January and August 2020. Samples were collected at 6 and 12 months after onset. The titers of immunoglobulin (Ig)G to the viral nucleocapsid protein (NP) and receptor-binding domain (RBD) of the spike protein were measured by chemiluminescence enzyme immunoassay. The nAb titer was determined using lentivirus-based pseudovirus or authentic virus. RESULTS: Antibody titers of NP-IgG, RBD-IgG, and nAbs were higher in severe and moderate cases than in mild cases at 12 months after onset. Although the nAb levels were likely to confer adequate protection against wild-type viral infection, the neutralization activity to recently circulating variants in some of the mild cases (~30%) was undermined, implying the susceptibility to reinfection with the variants of concerns (VOCs). CONCLUSIONS: Coronavirus disease 2019 convalescent individuals have robust humoral immunity even at 12 months after infection albeit that the medical history and background of patients could affect the function and dynamics of antibody response to the VOCs.

DOI： 10.1093/ofid/ofab626

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BACKGROUND: Although childhood undervaccination among single mother families is a concern for child healthcare, their association is still under debate. This study aimed to investigate the association between maternal marital status and the risk of childhood undervaccination and determine the mediating effect of household income. METHODS: We utilised prospective birth cohort from the Japan Environment and Children's Study (JECS). Of 104,062 foetal records (children) from 97,413 mothers, 82,462 that included mothers recruited between 2011 and 2014, were analysed. Childhood undervaccination was defined as not having been vaccinated with at least one routine vaccine. A log-binomial regression analysis was used to estimate the risk ratio (RR) for the association between maternal marital status and the risk of childhood undervaccination. A causal mediation analysis was further performed to investigate the proportion of the association mediated by household income. RESULTS: Among 82,462 children, 3188 and 79,274 had unmarried and married mothers, respectively. Childhood undervaccination was observed in 1053 (33.0%) and 16,901 (21.3%) children of unmarried and married mothers, respectively. Maternal marital status was associated with a higher risk of childhood undervaccination (adjusted risk ratio [aRR], 1.34; 95% confidence interval [CI], 1.27 to 1.41). Compared with married and older mothers, both unmarried and older (aRR, 1.54; 95% CI, 1.35 to 1.77) and unmarried and younger (aRR, 1.66; 95% CI, 1.54 to 1.79) mothers were associated with a higher risk of childhood undervaccination. The causal mediation analysis showed that the proportion mediated by household income was 10.5% (95% CI, 9.9 to 11.0%). CONCLUSIONS: This nationwide, prospective, large-scale birth cohort study found that a household with a single mother was associated with an increased risk of childhood undervaccination, and 10% of this association was explained by household income. These findings underscore the importance of improving the social environment among single mother families, including not only poverty but also working conditions.

DOI： 10.1186/s12889-022-12511-7

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BACKGROUND: Endoscopic resection, especially endoscopic submucosal dissection (ESD), is increasingly performed in elderly patients with early gastric cancer, and lesions beyond the expanded indications are also resected endoscopically in some patients. It is essential to assess whether gastric ESD is safe and suitable for elderly patients and investigate what type of lesions carry an increased risk of ESD-related complications. AIM: To assess the efficacy and feasibility of gastric ESD for elderly patients, and define high-risk lesions and prognostic indicators. METHODS: Among a total of 1169 sessions of gastric ESD performed in Kanagawa Cancer Center Hospital from 2006 to 2014, 179 sessions (15.3%) were performed in patients aged ≥ 80 years, and 172 of these sessions were done in patients with a final diagnosis of gastric cancer. These patients were studied retrospectively to evaluate short-term outcomes and survival. The short-term outcomes included the rates of en bloc resection and curative resection, complications, and procedure-related mortality. Curability was assessed according to the Japanese Gastric Cancer Treatment Guidelines 2010. Fisher's exact test was used to statistically analyze risk factors. Clinical characteristics of each group were compared using Fisher's exact test and Mann-Whitney U test. Survival rates at each time point were based on Kaplan-Meier estimation. Overall survival rates were compared between patients with gastric cancer in each group with use of the log-rank test. To identify prognostic factors that jointly predict the hazard of death while controlling for model overfitting, we used the least absolute shrinkage and selection operator (LASSO) Cox regression model including factors curative/ noncurative, age, gender, body mass index, prognostic nutritional index, Charlson comorbidity index (CCI), Glasgow prognostic score, neutrophil-to-lymphocyte ratio, and antithrombotic agent use. We selected the LASSO Cox regression model that resulted in minimal prediction error in 10-fold cross-validation. P < 0.05 was considered statistically significant. RESULTS: The en bloc dissection rate was 97.1%, indicating that a high quality of treatment was achieved even in elderly patients. As for complications, the rates of bleeding, perforation and aspiration pneumonitis were 3.4%, 1.1% and 0.6%, respectively. These complication rates indicated that ESD was not associated with a particularly higher risk in elderly patients than in nonelderly patients. A dissection incision > 40 mm, lesions associated with depressions, and lesions with ulcers were risk factors for post-ESD bleeding, and location of the lesion in the upper third of the stomach was a risk factor for perforation in elderly patients (P < 0.05). Location of the lesion in the lower third of the stomach tended to be associated with a higher risk of bleeding. The overall survival (OS) did not differ significantly between curative and noncurative ESD (P = 0.69). In patients without additional surgery, OS rate was significantly lower in patients with a high CCI (≥ 2) than in those with a low CCI (≤ 1) (P < 0.001). CONCLUSION: Gastric ESD is feasible even in patients aged ≥ 80 years. Observation without additional surgery after noncurative ESD is reasonable, especially in elderly patients with CCI ≥ 2.

DOI： 10.4253/wjge.v14.i1.49

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AIMS: There is a paucity of comparative data on the use of sorafenib and lenvatinib for unresectable hepatocellular carcinoma. We assessed the real-world treatment outcomes between using sorafenib and lenvatinib for unresectable hepatocellular carcinoma in the multiple molecular-targeted therapy era. METHODS AND RESULTS: We enrolled 386 patients treated with sorafenib or lenvatinib as the first-line therapy for unresectable hepatocellular carcinoma at multiple centers. Propensity score matching was performed to adjust for differences in baseline and tumor characteristics between the two groups. Propensity score matching identified 110 patients in each treatment group. The median overall survival was similar between lenvatinib and sorafenib (14.8 and 13.0 months, respectively; P = 0.352). The median progression-free survival was longer with lenvatinib than with sorafenib (7.6 and 3.9 months, respectively; P < 0.001). The overall response rate (P < 0.001) and disease control rate (P = 0.015), as defined by the modified Response Evaluation Criteria in Solid Tumors, were significantly better with lenvatinib than with sorafenib. The median overall survival was longer in patients who received subsequent treatment than in those who did not in the sorafenib group (23.1 and 5.7 months, respectively; P < 0.001), whereas the median overall survival with or without subsequent treatment did not differ significantly in the lenvatinib group (17.8 and 14.7 months, respectively; P = 0.439). CONCLUSION: Overall survival with sorafenib and lenvatinib was not significantly different. However, patients who received subsequent treatments had longer overall survival than those who received only first-line treatment with sorafenib, whereas lenvatinib did not show this effect.

DOI： 10.1002/jgh3.12691

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Introduction: Given that coronavirus disease 2019(COVID-19)aggravation is associated with an excessive host immune response, complementary anti-inflammatory treatment is recommended in severe disease. Although dexamethasone is a widely used anti-inflammatory agent in COVID-19 patients with respiratory failure, its use in patients with mild COVID-19 not receiving oxygen could have harmful effects. Colchicine, an anti-inflammatory drug, blocks the upstream immune response by inhibiting NALP3 inflammasome activation. This study aimed to assess the efficacy and safety of low-dose colchicine(DRC 3633)in mild COVID-19. Methods: This study is a prospective, multicenter, placebo-controlled, double-blind randomized, phase 2 clinical trial patients with moderate COVID-19 admitted at nine hospitals in Japan (jRCT2071200078). The primary endpoint is area under the curve(AUC)for the amount of change of serum hypersensitive C-reactive protein(hs-CRP)from baseline to 1, 2, and 4 weeks after initiating investigational drug. Study participants will be randomly assigned to the colchicine or placebo group at a 1:1 ratio. On day 1, patients in the colchicine group will receive 1 mg of colchicine, followed by 0.5 mg of colchicine after 2 h barring gastrointestinal complications. From day 2 to 28, 0.5 mg of colchicine will be administered once daily. Discussion: An appropriate anti-inflammatory strategy is critical to improve the outcome of severe COVID-19 patients. This study will assess the efficacy of low-dose colchicine not only by the AUC of the amount of change in serum hs-CRP from baseline to several time points, but also by evaluating whether the result of the primary endpoint is consistent with other relevant biomarkers and clinical parameters measured as secondary endpoints.

DOI： 10.3999/jscpt.53.6_199

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGERNATURE  

In clinical trials, two or more binary responses obtained by dichotomizing continuous responses are often employed as multiple primary endpoints. Testing procedures for multiple binary variables with latent distribution have not yet been adequately discussed. Based on the association measure among latent variables, we provide a statistic for testing the superiority of at least one binary endpoint. In addition, we propose a testing procedure with a framework in which the trial efficacy is confirmed only when there is superiority of at least one endpoint and non-inferiority of the remaining endpoints. The performance of the proposed procedure is evaluated through simulations.

DOI： 10.1007/s44199-021-00003-3

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For square contingency tables with ordered categories, the marginal homogeneity model is represented by various expressions, and some extensions of the marginal homogeneity model were proposed. Herein we consider the marginal continuation-ratio to examine a new expression of the marginal homogeneity model. We also propose an extension of the marginal homogeneity model using the ratio of marginal continuation-ratios; namely, the marginal continuation odds ratio. The proposed model can be interpreted in various ways. Additionally, we propose a generalization of it, and decompose the marginal homogeneity model using the generalized model. Furthermore, we extend the models and decompositions into multi-way contingency tables.

DOI： 10.1007/s13571-020-00228-9

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The COVID-19 pandemic is an unprecedented threat to humanity that has provoked global health concerns. Since the etiopathogenesis of this illness is not fully characterized, the prognostic factors enabling treatment decisions have not been well documented. Accurately predicting the progression of the disease would aid in appropriate patient categorization and thus help determine the best treatment option. Here, we have introduced a proteomic approach utilizing data-independent acquisition mass spectrometry (DIA-MS) to identify the serum proteins that are closely associated with COVID-19 prognosis. Twenty-seven proteins were differentially expressed between severely ill COVID-19 patients with an adverse or favorable prognosis. Ingenuity Pathway Analysis revealed that 15 of the 27 proteins might be regulated by cytokine signaling relevant to interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF), and their differential expression was implicated in the systemic inflammatory response and in cardiovascular disorders. We further evaluated practical predictors of the clinical prognosis of severe COVID-19 patients. Subsequent ELISA assays revealed that CHI3L1 and IGFALS may serve as highly sensitive prognostic markers. Our findings can help formulate a diagnostic approach for accurately identifying COVID-19 patients with severe disease and for providing appropriate treatment based on their predicted prognosis.

DOI： 10.1038/s41598-021-98253-9

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OBJECTIVES: the prevalence of intracranial aneurysms and arachnoid cysts is higher in patients with autosomal dominant polycystic kidney disease (ADPKD) than in the general population. A genotype correlation was reported for intracranial aneurysms, but it is unclear for arachnoid cysts. Therefore, the genotype correlation with intracranial aneurysms and arachnoid cysts was investigated in ADPKD. MATERIALS AND METHODS: intracranial aneurysms and arachnoid cysts were screened by magnetic resonance imaging (MRI), and PKD genotypes were examined using next-generation sequencing for 169 patients with ADPKD. RESULTS: PKD1-, PKD2- and no-mutation were identified in 137, 24 and 8 patients, respectively. Intracranial aneurysms and arachnoid cysts were found in 34 and 25 patients, respectively, with no significant difference in frequency. Genotype, sex, estimated glomerular filtration rate and age at ADPKD diagnosis significantly affected the age at brain MRI. The proportional hazard risk analyzed using the age at brain MRI adjusted by these four variables was 5.0-times higher in the PKD1 group than in the PKD2 group for arachnoid cysts (P = 0.0357), but it was not different for intracranial aneurysms (P = 0.1605). Arachnoid cysts were diagnosed earlier in the PKD1 group than in the PKD2 group (54.8 vs 67.7 years, P = 0.0231), but no difference was found for intracranial aneurysms (P = 0.4738) by Kaplan-Meier analysis. CONCLUSIONS: this study demonstrated the correlation between arachnoid cysts and PKD1 mutation. The reported association of arachnoid cysts with advanced renal disease may be due to the common correlation of these factors with PKD1 mutation.

DOI： 10.1016/j.jstrokecerebrovasdis.2021.105943

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BACKGROUND: Predicting the prognosis of early-onset otitis media with effusion (OME) in children is difficult. OBJECTIVES: To investigate the prognostic factors of OME in children undergoing tympanostomy at 1 year of age. MATERIAL AND METHODS: We examined 66 children (123 ears) followed up to 6 years of age. OME prognosis was determined by a history of re-tympanostomy at the last examination. We retrospectively analysed the prognostic factors based on the duration of first ventilation tube (VT) placed, history of otorrhea, asthma, adenoidectomy, and mastoid air cell system (MACS) size at 1 year before tympanostomy and at 3 years. RESULTS: While 25 ears underwent re-tympanostomy (group 1), 98 did not (group 2). The mean duration of VT placed was 21 months and 25, and the mean MACS size at 3 years was 314 mm2 and 441, respectively, in the corresponding groups. MACS size at 3 years was significantly smaller in group 1 than in group 2. The combination of MACS size at 3 years and duration of VT placed showed the best value of area under the curve. CONCLUSION AND SIGNIFICANCE: The most probable prognostic factor was the combination of the MACS size at 3 years and duration of VT placed.

DOI： 10.1080/00016489.2021.1956690

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BACKGROUND: Naples prognostic score (NPS) is a scoring system based on albumin, cholesterol concentration, lymphocyte-to-monocyte ratio, and neutrophil-to-lymphocyte ratio reflecting host systemic inflammation, malnutrition, and survival for several malignancies. This study was designed to assess the prognostic significance of NPS in patients with locally advanced esophageal squamous cell carcinoma (ESCC) and to compare its prognostic accuracy with that of other systemic inflammatory and nutritional index. METHODS: We retrospectively examined 165 patients with locally advanced ESCC who underwent neoadjuvant therapy followed by curative resection between January 2011 and September 2019. Patients were divided into three groups based on their NPS before neoadjuvant therapy (Group 0: NPS = 0; Group 1: NPS = 1-2; Group 2: NPS = 3-4). We compared the clinicopathological characteristics and survival rates among the groups. RESULTS: The 5-year recurrence-free survival (RFS) and overall survival (OS) rates were significantly different between the groups (P < 0.001). The NPS was superior to other systemic inflammatory and nutritional index for predicting prognoses, as determined using area under the curves (P < 0.05). Multivariate analysis demonstrated that the NPS was a significant predictor of poor RFS (Group 1: hazard ratio [HR] 1.897, P = 0.049; Group 2: HR 3.979, P < 0.001) and OS (Group 1: HR 2.152, P = 0.033; Group 2: HR 3.239, P = 0.006). CONCLUSIONS: The present study demonstrated that NPS was an independent prognostic factor in patients with locally advanced ESCC and more reliable and accurate than the other systemic inflammatory and nutritional index.

DOI： 10.1245/s10434-020-09549-5

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Language：English   Publisher：ELSEVIER  

DOI： 10.1016/j.annonc.2021.05.680

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Cancer cells upregulate the expression levels of glycolytic enzymes in order to reach the increased glycolysis required. One such upregulated glycolytic enzyme is glyoxalase 1 (GLO 1), which catalyzes the conversion of toxic methylglyoxal to nontoxic S-D-lactoylglutathione. Protein kinase Cλ (PKCλ) is also upregulated in various types of cancer and is involved in cancer progression. In the present study, the association between enhanced glycolysis and PKCλ in breast cancer was investigated. In human breast cancer, high GLO 1 expression was associated with high PKCλ expression at the protein (P<0.01) and mRNA levels (P<0.01). Furthermore, Wilcoxon and Cox regression model analysis revealed that patients with stage III-IV tumors with high GLO 1 and PKCλ expression had poor overall survival compared with patients expressing lower levels of these genes [P=0.040 (Gehan-Breslow generalized Wilcoxon test) and P=0.031 (hazard ratio, 2.36; 95% confidence interval, 1.08-5.16), respectively]. Treatment of MDA-MB-157 and MDA-MB-468 human basal-like breast cancer cells with TLSC702 (a GLO 1 inhibitor) and/or aurothiomalate (a PKCλ inhibitor) reduced both cell viability and tumor-sphere formation. These results suggested that GLO 1 and PKCλ were cooperatively involved in cancer progression and contributed to a poor prognosis in breast cancer. In conclusion, GLO 1 and PKCλ serve as potentially effective therapeutic targets for treatment of late-stage human breast cancer.

DOI： 10.3892/ol.2021.12808

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BACKGROUND: The lymph node (LN) ratio (LNR) and the log odds of positive LNs (LODDS) have been proposed as sensitive prognosticators in patients with primary gastric cancer, especially in patients with an insufficient number of harvested LNs. We investigated the association of LNR and LODDS with survival in patients with remnant gastric cancer (RGC) and explored whether these staging methods are prognostic factors in patients with an insufficient number of harvested LNs. METHODS: The present study retrospectively examined 95 patients with RGC who received gastrectomy between January 2000 and December 2018. The patients were classified according to the adjusted X-tile cutoff for LNR and LODDS. The association between survival rates and clinicopathological features was investigated. The predictive accuracy of the LNR and LODDS was compared with that of the Union for International Cancer Control pathological N factor. RESULTS: Multivariate analysis revealed that the LNR and LODDS were independent risk factors for recurrence-free survival (RFS) [hazard ratio (HR) 2.623, p = 0.020; HR 3.404, p = 0.004, respectively] and overall survival (OS) (HR 3.694, p = 0.003; HR 2.895, p = 0.022, respectively) in patients with RGC. Moreover, even in patients with 15 or fewer harvested LNs, only the LNR was a significant independent risk factor for RFS (HR 21.890, p < 0.001) and OS (HR 6.597, p = 0.002). The receiver operating characteristic curves revealed that the prognostic accuracy of the three methods was comparable (p > 0.05). CONCLUSION: LNR has significant prognostic value for patients with RGC, including those with an insufficient number of harvested LNs.

DOI： 10.1245/s10434-020-09433-2

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Objectives We investigated the 5-year disease-related mortality risk, including that associated with neoplasms, mental/behavioral/neurodevelopmental disorders, and diseases of the circulatory system and respiratory system,in ambulatory frail Japanese older adults.Methods We retrospectively analyzed long-term care and health insurance claims data in this cohort study performed between April 2012 and March 2017. The primary outcome was mortality, and the secondary outcome was care-need level decline. Risk factors were determined based on the International Statistical Classification of Disease and Related Health Problems, 10th Revision codes, hospitalization, and institutionalization. The study included 1,239 ambulatory frail older adults newly certified as needing Support-Level care at baseline (April 2012-March 2013) across three Japanese municipalities.Results Of the 1,239 participants, 454 (36.6%) died. Neoplasms (hazard ratio [HR] 2.69, 95% confidence interval [CI] 1.97-3.68) or respiratory system diseases (HR 1.62, 95%CI 1.26-2.08) were independently associated with mortality. Mental/behavioral/neurodevelopmental disorders (HR 1.39, 95%CI 1.17-1.66) or diseases of the respiratory system(HR 86, 95%CI 75-99) were independently associated with care-need level decline.Conclusions This study suggests that neoplasms or respiratory system diseases were associated with a high mortality risk and that mental/behavioral/neurodevelopmental disorders were associated with care-need level decline among ambulatory frail older adults. Optimal disease management and effective long-term care are important to delay the onset of these events in older adults certified as needing Support-Level care.

DOI： 10.11236/jph.20-002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

The test treatment in confirmatory clinical trials is often assessed using multiple primary endpoints. We considered that trial efficacy is confirmed only when there is superiority of at least one endpoint and non-inferiority of the remaining endpoints. Some researchers proposed testing procedures for multiple primary endpoints that are continuous variables. However, there has not yet been discussion of the case in which a trial has multiple binary endpoints in the above framework. In this study, we consider a testing procedure for multiple primary endpoints that are binary, and evaluate the performance of the proposed method through simulations.

DOI： 10.1080/03610926.2021.1912766

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WALTER DE GRUYTER GMBH  

OBJECTIVES: Gastroesophageal reflux may exacerbate chronic lung disease in preterm infants. We evaluated the short-term effects of transpyloric feeding on respiratory status in preterm infants during mechanical ventilation. METHODS: We retrospectively collected data from the hospital information management system. To evaluate the effect of transpyloric feeding on oxygenation, we compared changes in SpO2/FiO2 ratios before and after commencing transpyloric feeding by a piecewise linear regression model. RESULTS: We examined 33 infants (median gestational age, 25.4 weeks; median birth weight, 656 g) who underwent transpyloric feeding. All tubes were placed at the bedside without fluoroscopy. No cases of unsuccessful placement, gastroduodenal perforation, or tracheal misinsertion occurred. Transpyloric feeding began at a median age of 18 (interquartile range, 15-23) days. Mean SpO2/FiO2 (±SD) ratios were 391 (±49), 371 (±51), 365 (±56), and 366 (±53) 72-96 h before, 0-24 h before, 48-72 h after, and 96-120 h after starting transpyloric feeding, respectively. The rate of change per hour of SpO2/FiO2 ratios increased 48-120 h after compared with 0-96 h before transpyloric feeding (0.03 [95% confidence interval, -0.10 to 0.17] vs. -0.29 [-0.47 to -0.12]) (p=0.007). No apparent changes occurred in the mean airway pressure, amplitude pressure, or pCO2. CONCLUSIONS: Transpyloric feeding during mechanical ventilation can prevent the deterioration of oxygenation without major complications at the stage of respiratory exacerbation in preterm infants.

DOI： 10.1515/jpm-2020-0243

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Phenylketonuria (PKU) and hyperphenylalaninemia (HPA), both identified in newborn screening, are attributable to variants in PAH. Reportedly, the p.R53H(c.158G>A) variant is common in patients with HPA in East Asia. Here, we aimed to define the association between p.R53H and HPA phenotype, and study the long-term outcome of patients with HPA carrying p.R53H. We retrospectively reviewed the genotype in 370 patients detected by newborn screening, and identified the phenotype in 280 (117, HPA; 163, PKU). p.R413P(c.1238G>C) was the most frequently found (n = 117, 31.6%) variant, followed by p.R53H (n = 89, 24.1%). The odds ratio for heterozygous p.R53H to cause HPA was 48.3 (95% CI 19.410-120.004). Furthermore, we assessed the non-linear association between the phenylalanine (Phe) value and elapsed time using the follow-up data of the blood Phe levels of 73 patients with HPA carrying p.R53H. The predicted levels peaked at 161.9 μmol (95% CI 152.088-172.343) at 50-60 months of age and did not exceed 360 μmol/L during the 210-month long observation period. The findings suggest that patients with HPA, carrying p.R53H, do not need frequent Phe monitoring as against those with PKU. Our study provides convincing evidence to determine clinical management of patients detected through newborn screening in Japan.

DOI： 10.3390/ijns7010017

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Language：Japanese   Publisher：(公社)日本薬学会  

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BACKGROUND: Anti-programmed death-1 (PD-1) immunotherapy can cause immune-related pneumonitis, also known as checkpoint inhibitor pneumonitis (CIP). CIP that develops early after the initiation of anti-PD-1 immunotherapy is important because it is more severe than CIP that develops later. However, only a few studies have examined the risk factors for early-onset CIP. Previous studies have reported several risk factors for CIP, including imaging findings of airway obstruction adjacent to lung tumors. However, the utility of this factor is debatable. Therefore, we investigated potential risk factors for early-onset CIP, including tumor invasion in the central airway (TICA), in patients with non-small cell lung cancer (NSCLC) receiving anti-PD-1 therapy. METHODS: We retrospectively analyzed the medical records and chest computed tomography scans of patients with NSCLC treated with anti-PD-1 antibodies at the Kanagawa Cancer Center in Japan between 1 January 2016, and 30 June 2018. The clinical characteristics and imaging findings, including TICA, were compared between patients with and without early-onset CIP. RESULTS: Data from 181 eligible patients (114 receiving nivolumab and 67 receiving pembrolizumab) were analyzed. Early-onset CIP occurred in 13 of 79 patients (16.5%) with TICA and 2 of 102 patients (2.0%) without TICA. In multivariate analysis, the odds ratio of early-onset CIP for patients with TICA was 8.2 (95% confidence interval [CI]: 1.98-34.0, P = 0.0037). CONCLUSIONS: TICA was strongly associated with early-onset CIP in patients with NSCLC. Clinicians should carefully observe patients with TICA, especially within three months of anti-PD-1 antibody administration because of high CIP risk. KEY POINTS: Significant study findings Tumor invasion in the central airway (TICA) was a predictor of early-onset checkpoint inhibitor pneumonitis (CIP) TICA had good interobserver variability, indicating its utility in clinical practice Patients with TICA might have a higher immune status than patients without What this study adds This is the first study focusing on risk factors for CIP limited to early-onset CIP.

DOI： 10.1111/1759-7714.13703

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BACKGROUND: BK-SE36 is blood-stage malaria vaccine candidate that is undergoing clinical trials. Here, the safety and immunogenicity of BK-SE36 with a novel adjuvant, CpG-ODN(K3) (thus, BK-SE36/CpG) was assessed in a phase 1a trial in Japan. METHODS: An investigator-initiated, randomised, single-blind, placebo-controlled, dose-escalation study was conducted at Osaka University Hospital with 26 healthy malaria naïve Japanese male adults. The trial was conducted in two stages: Stage/Group 1, half-dose (n = 7 for BK-SE36/CpG and n = 3 for control) and Stage/Group 2, full-dose (n = 11 for BK-SE36/CpG and n = 5 for control). There were two intramuscular vaccinations 21 days apart for both half-dose (0.5 ml: 50 µg SE36 + 500 µg aluminum + 500 µg K3) and full-dose (1.0 ml: 100 µg SE36 + 1000 µg aluminum + 1000 µg K3). A one-year follow-up was done to monitor changes in autoimmune markers and vaccine-induced antibody response. RESULTS: BK-SE36/CpG was well tolerated. Vaccination site reactions were similar to those observed with BK-SE36. During the trial and follow-up period, no subject had clinical evidence of autoimmune disease. The full-dose group had significantly higher titres than the half-dose group (Student's t-test, p = 0.002) at 21 days post-second vaccination. Antibody titres remained above baseline values during 12 months of follow-up. The vaccine induced antibody was mostly composed of IgG1 and IgM, and recognised epitopes close to the polyserine region located in the middle of SE36. CONCLUSIONS: BK-SE36/CpG has an acceptable safety profile. Use of CpG-ODN(K3) greatly enhanced immunogenicity in malaria naïve Japanese adults when compared to BK-SE36 alone. The utility of BK-SE36/CpG is currently under evaluation in a malaria endemic setting in West Africa. TRIAL REGISTRATION: JMACCT Clinical Trial Registry JMA-IIA00109.

DOI： 10.1016/j.vaccine.2020.09.056

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BACKGROUND: Lymph node ratio (LNR), defined as the ratio of metastatic nodes to the total number of examined lymph nodes, has been proposed as a sensitive prognostic factor in patients with gastric cancer (GC). We investigate its association with survival in pathological stage (pStage) II/III GC and explore whether this is a prognostic factor in each Union for International Cancer Control pStage (7th edition). PATIENTS AND METHODS: We retrospectively examined 838 patients with pStage II/III GC who underwent curative gastrectomy between June 2000 and December 2018. Patients were classified into low-LNR (L-LNR), middle-LNR (M-LNR), and high-LNR (H-LNR) groups according to adjusted X-tile cutoff values of 0.1 and 0.25 for LNR, and their clinicopathological characteristics and survival rates were compared. RESULTS: The 5-year recurrence-free survival (RFS) and overall survival (OS) rates postsurgery showed significant differences among the groups (P < 0.001). Multivariate analysis demonstrated that LNR was a significant predictor of poor RFS [M-LNR: hazard ratio (HR) 3.128, 95% confidence interval (CI) 2.254-4.342, P < 0.001; H-LNR: HR 5.148, 95% CI 3.546-7.474, P < 0.001] and OS (M-LNR: HR 2.749, 95% CI 2.038-3.708, P < 0.001; H-LNR: HR 4.654, 95% CI 3.288-6.588, P < 0.001). On subset analysis stratified by pStage, significant differences were observed between the groups in terms of the RFS curves of pStage II and III GC (P < 0.001 and < 0.001, respectively) and OS curves of pStage II and III GC (P = 0.001 and < 0.001, respectively). CONCLUSIONS: High LNR is a predictor of worse prognosis in pStage II/III GC, including each substage.

DOI： 10.1245/s10434-020-08616-1

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Language：English   Publisher：(一社)日本癌治療学会  

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INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) pathogenesis involves abnormal metabolism of cholesterol and hepatic accumulation of toxic free-cholesterol. Elobixibat (EXB) inhibits the ileal bile acid (BA) transporter. EXB and cholestyramine (CTM) facilitate the removal of free cholesterol from the liver by decreasing BA recirculation to the liver, thereby stimulating novel BA synthesis from cholesterol. In this randomised, double-blind, placebo-controlled, parallel-group, phase IIa study, we aim to provide a proof-of-concept assessment by evaluating the efficacy and safety of EXB in combination with CTM in patients with NAFLD. METHODS AND ANALYSIS: A total of 100 adult patients with NAFLD, diagnosed based on low-density lipoprotein cholesterol (LDL-C) level of >120 mg/dL and liver fat content of ≥8% by MRI-based proton density fat fraction (MRI-PDFF), who meet the inclusion/exclusion criteria will be enrolled. The patients will be randomly assigned to receive the combination therapy of 10 mg EXB and 9 g CTM powder (4 g CTM), 10 mg EXB monotherapy, 9 g CTM powder monotherapy or a placebo treatment (n=25 per group). Blood tests and MRIs will be performed 16 weeks following treatment initiation. The primary study endpoint will be the absolute LDL-C level change at week 16 after treatment initiation. The exploratory endpoint will include absolute changes in the liver fat fraction as measured by MRI-PDFF. This proof-of-concept study will determine whether the combination therapy of EXB and CTM is effective and safe for patients with NAFLD. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of Yokohama City University Hospital before participant enrolment. The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences. TRIAL REGISTRATION NUMBER: NCT04235205.

DOI： 10.1136/bmjopen-2020-037961

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INTRODUCTION: Defecation desire (DD) is an important physiological component of normal defecation. However, knowledge of DD in the general population and in individuals with chronic constipation (CC) is lacking. We aimed to assess the prevalence of DD in the general population and individuals with CC and to understand the impact of treatment on DD among individuals with CC. METHODS: We conducted an online questionnaire survey targeting the Japanese general population in 2019. DD was reported as never, rarely, usually, or always. Individuals who self-reported constipation and met the Rome IV criteria for functional constipation but did not for irritable bowel syndrome were included in the CC group, while the same number of age-/sex-matched controls who met neither functional constipation nor irritable bowel syndrome criteria was included in the non-CC group. Individuals who reported DD as rarely or never were defined as having loss of DD (LODD). RESULTS: Of the 20,986 participants, 2,587 were included in the CC group (12.3%). LODD was significantly higher in the CC individuals than in the non-CC controls (57.4% vs 8.3%, respectively, P < 0.001, odds ratio 14.84 [95% confidence interval 12.65-17.42]). Satisfaction with treatment for constipation was lower in individuals with persistent LODD (25.9%) compared with those with improved LODD (56.5%) on treatment (P < 0.001, odds ratio 2.48 [1.39-4.43]). DISCUSSION: LODD is common in CC and is associated with decreased satisfaction to treatment. Greater attention should be paid to DD when treating patients with CC.

DOI： 10.14309/ctg.0000000000000230

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Language：Japanese   Publisher：(一社)日本インターベンショナルラジオロジー学会  

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Language：Japanese   Publisher：(NPO)日本緩和医療学会  

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BACKGROUND: This study retrospectively evaluated the long-term patient outcomes and durability of the Mosaic aortic porcine bioprosthesis in the Japan Mosaic valve long-term multicenter study.Methods and Results:We reviewed the records of 1,202 patients who underwent aortic valve replacement with the Mosaic bioprosthesis at 10 centers in Japan (1999-2014). Patient data were collected using Research Electronic Data Capture. Patient survival was determined by Kaplan-Meier methodology. Freedom from structural valve deterioration (SVD) and valve-related reoperation and death were determined by actuarial methods. The median (interquartile range [IQR]) age of the cohort was 76 (70-80) years. The median (IQR) follow-up period was 3.52 (1.71-5.35) years. The longest follow-up was 15.8 years. The 30-day mortality rate was 2.3%. The 12-year actuarial survival rate was 59.9±7.5%, and the freedom from valve-related death was 81.1±7.9%. The freedom from reoperation was 86.4±2.6% at 12 years. The freedom from SVD at 12 years was 93.5±2.9% for patients aged ≥65 years and 98.2±1.8% for those aged <65 years. The median (IQR) systolic pressure gradient was 17 (12-23) and 19 (12-25) mmHg at 1 and 10 years, respectively. The median (IQR) effective orifice area was 1.2 (1.1-1.5) and 1.1 (1-1.5) cm2at 1 and 10 years, respectively. CONCLUSIONS: The Mosaic porcine bioprosthesis showed satisfactory long-term outcomes over 12 years.

DOI： 10.1253/circj.CJ-19-1113

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AIM: Bile salt export pump (BSEP) deficiency manifests a form of progressive intrahepatic cholestasis. This study aimed to establish a scoring system of liver histology for the uncommon genetic condition. METHODS: After a roundtable discussion and histology review, a scoring system for BSEP deficiency was established. Eleven tissue samples were independently evaluated by three pathologists based on the proposed standard for an interobserver agreement analysis. In four cases with serial tissue samples available, correlation between changes in histology scores and clinical outcome was examined. RESULTS: Of 14 initially listed histopathological findings, 12 were selected for scoring and grouped into the following four categories: cholestasis, parenchymal changes, portal tract changes and fibrosis. Each category consisted of two to four microscopic findings that were further divided into three to six scores; therefore, each category had a maximum score of 8-11. Interobserver agreement was highest for pericellular fibrosis (κ = 0.849) and lowest for hepatocellular cholestasis (κ = 0.241) with the mean and median κ values of the 12 parameters being 0.561 and 0.602, respectively. For two patients whose clinical features worsened, score changes between two time points were interpreted as deteriorated. In two patients, who showed a good clinical response to preprandial treatment with sodium 4-phenylbutyrate, histological changes were evaluated as improved or unchanged. CONCLUSIONS: The proposed histology-based scoring system for BSEP deficiency with moderate interobserver agreement may be useful not only for monitoring microscopic changes in clinical practice but also for a surrogate endpoint in clinical trials.

DOI： 10.1111/hepr.13494

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ATLANTIS PRESS  

For square contingency tables with ordered categories, there would be some situations that one would like to analyze them by using collapsed 3 x 3 tables combining some adjacent categories in the original table. This paper considers the marginal homogeneity for collapsed tables and proposes a measure which represents the degree of departure from the marginal homogeneity. The proposed measure lies between 0 and 1, and it takes zero when the marginal homogeneity holds. Examples are given. (c) 2020 The Authors. Published by Atlantis Press SARL.

DOI： 10.2991/jsta.d.200507.001

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PURPOSE: We assessed the association of tumor size with patient survival following diagnosis of solitary hepatocellular carcinoma without vascular invasion. METHODS: The overall population comprised 638 patients who initially underwent hepatic resection with curative intent for a solitary hepatocellular carcinoma without macroscopic vascular invasion (487 had no microscopic vascular invasion). We set 5 cm as the tumor cutoff size for a solitary tumor based on the Milan criteria, and we used a multivariate Cox proportional hazards model and propensity score matching to evaluate the impact of tumor size on survival. RESULTS: Tumor size was significantly associated with a proportional increase in cancer-specific survival in the overall population (P = 0.001) and the subgroup with no microscopic vascular invasion (P = 0.029); however, multivariate analysis revealed no significant risk associated with recurrence-free survival (P = 0.055 and 0.59, respectively). After propensity score matching, the cancer-specific survival of patients with tumors > 5 cm was significantly worse than for those with tumors ≤ 5 cm in the overall population (P = 0.0077); the corresponding 2-year cumulative recurrence rates were 45.8% and 23.5%, respectively (P = 0.0027). Finally, the proportions of extrahepatic to total recurrences were 8% for those with tumors ≤ 5 cm and 29.1% for those with tumors > 5 cm in the unmatched overall population (P < 0.001). CONCLUSION: Tumor size was associated with recurrence within 2 years of surgery and with poor cancer-specific survival in patients with solitary hepatocellular carcinoma, even in the absence of microscopic vascular invasion.

DOI： 10.1007/s11605-019-04273-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

We evaluated impact of a small-sized Mosaic porcine bioprosthesis on hemodynamic performance and outcomes in patients with aortic stenosis (AS) and low left ventricular ejection fraction (LVEF) in a Japan multicenter cohort. Of 1,202 patients enrolled, 105 (8.7%) who had LVEF < 50% and AS underwent aortic valve replacement (AVR). Fifty-two patients received Mosaic porcine bioprosthesis ≤ 21 mm (S-AVR), and 53 received a bioprosthesis ≥ 23 mm (L-AVR). The median follow-up period was 3.1 [1.2, 5.1] years. At 5 years, LVEF significantly improved from median 41.2 [33.8, 45.9]% to 64.2 [49.8, 72.5]% in S-AVR (p < 0.001) and from median 43.2 [37.3, 46.8]% to 61.2 [47.2, 68.0]% in L-AVR (p < 0.001). The left ventricular mass index significantly decreased from median 158.4 [122.2, 194.9] to 110.0 [83.6, 129.4] gm/m in S-AVR (p < 0.001) and from median 169.8 [132.2, 203.6] to 109.6 [101.8, 132.4] gm/m in L-AVR (p < 0.001). There were no significant differences between S-AVR and L-AVR groups regarding freedom from cardiac death (93.1 ± 3.9% vs. 96.2 ± 3.8%; p = 0.119) and valve-related death (97.6 ± 2.4% vs. 100.0 ± 0.0%; p = 0.953). Clinical outcomes and improved hemodynamic performance were similar in both groups.

DOI： 10.1097/MAT.0000000000001040

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Language：English   Publisher：TAYLOR & FRANCIS LTD  

In clinical researches, various clinical scales with ordered categories are used to evaluate the efficacy and safety/toxicity of treatments. Such the clinical scales are sometimes summarized on the transition between the baseline and the study end point as a square contingency table. Also, clinical scales may be reclassified into three groups. However, the cutpoints can be varied depending on clinical researches or clinicians. Hence, this paper proposes a measure which is expressed by using same weights for collapsed tables and which can see the directionality for two kinds of asymmetries. Also, this paper shows an application of the proposed measure to clinical data, and that the proposed measure is a useful statistical method for analyzing ordered categorical data.

DOI： 10.1080/02664763.2019.1673325

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Other Link： https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17H04446/

Language：English   Publishing type：Research paper (scientific journal)  

Background We developed a novel high-sensitive assay for plasma xanthine oxidoreductase (XOR) activity that is not affected by the original serum uric acid level. However, the association of plasma XOR activity with that level has not been fully examined. Methods This cross-sectional study included 191 subjects (91 males, 100 females) registered in the MedCity21 health examination registry. Plasma XOR activity was determined using our assay for plasma XOR activity with [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. Serum levels of uric acid and adiponectin, and visceral fat area (VFA) obtained by computed tomography were measured, and insulin resistance was determined based on the homeostasis model assessment (HOMA-IR) index. Results The median values for uric acid and plasma XOR activity were 333 μmol/L and 26.1 pmol/h/mL, respectively. Multivariable linear regression analysis showed a significant and positive association of serum uric acid level (coefficient: 26.503; 95% confidence interval: 2.06, 50.945; p = 0.035) with plasma XOR activity independent of VFA and HOMA-IR, and also age, gender, alcohol drinking habit, systolic blood pressure, estimated glomerular filtration rate (eGFR), glycated hemoglobin A1c, triglyceride, and adiponectin levels. The "gender*XOR activity" interaction was not significant (p = 0.91), providing no evidence that gender modifies the relationship between plasma XOR activity and serum uric acid level. Conclusions Plasma XOR activity was found to be positively associated with serum uric acid level independent of other known confounding factors affecting that level, including gender difference, eGFR, adiponectin level, VFA, and HOMA-IR.

DOI： 10.1515/cclm-2019-0199

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Publisher：Taylor & Francis  

Positive and negative predictive values describe the clinical performance of the diagnostic test when it is applied to a cohort of individuals. Testing non-inferiority of predictive values may be adequate in some cases due to the simplicity of the examination and the invasiveness of the test, but no non-inferiority test for predictive values has been proposed yet. In this study, we propose a non-inferiority test that investigates the non-inferiority of predictive values in paired designs, and formulae for the calculation of sample size to execute the non-inferiority test of two predictive values. Simulation studies showed that the proposed non-inferiority test is useful for comparing two predictive values in clinical trials.

DOI： 10.1080/23737484.2020.1719559

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Other Link： https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18K11195/

Language：English   Publisher：AMER SOC CLINICAL ONCOLOGY  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Positive and negative predictive values describe the performance of a diagnostic test. There are several methods to test the equality of predictive values in paired designs. However, these methods were premised on large sample theory, and they may not be suitable for small-size clinical trials because of inflation of the type 1 error rate. In this study, we propose an exact test to control the type 1 error rate strictly for conducting a small-size clinical trial that investigates the equality of predictive values in paired designs. In addition, we execute simulation studies to evaluate the performance of the proposed exact test and existing methods in small-size clinical trials. The proposed test can calculate the exact P value, and as a result of simulations, the empirical type 1 error rate for the proposed test did not exceed the significance level regardless of the setting, and the empirical power for the proposed test is not much different from the other methods based on large-sample theory. Therefore, it is considered that the proposed exact test is useful when the type 1 error rate needs to be controlled strictly.

DOI： 10.1002/pst.1968

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DOI： 10.3324/haematol.2018.208876

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Objective Therapeutic predictors derived from the venous pressure before therapy have not been identified for Budd-Chiari syndrome (BCS). The aim of this study was to determine whether or not measuring the distal pressure or pressure gradient was useful for predicting treatment efficacy in BCS. Methods We retrospectively analyzed seven consecutive patients diagnosed with symptomatic BCS at our hospital between 2008 and 2017. Distal and proximal venous pressures at occlusion sites of BCS were measured before treatment in all cases. The pressure gradient was defined as the difference between distal and proximal venous pressures. A receiver operating characteristics (ROC) analysis was performed for venous pressures. Results Percutaneous old balloon angioplasty (POBA) was performed in seven cases, with technical success achieved in all cases (100%). No complications were encountered. The median primary patency was 574 (interquartile range, 439.5-1,056.5) days. The 1-year primary patency rate was 71.73%. Six cases (85.7%) showed resolution of symptoms, representing clinical success. The ROC analysis revealed a high distal pressure (area under the ROC curve = 0.83, cut-off=12 mmHg) as a predictor of treatment efficacy of POBA for symptomatic BCS. In addition, the pressure gradient was considered significant from a clinical perspective, because the 6 successful cases with resolution of symptoms showed a large pressure gradient (range, 8-21 mmHg) before treatment, whereas the failed case showed a relatively small pressure gradient (7 mmHg). Conclusion High distal pressure and a large pressure gradient might predict the treatment efficacy of balloon angioplasty for symptomatic BCS.

DOI： 10.2169/internalmedicine.2704-19

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AIM: To investigate the frequency and risk factors of perioperative, symptomatic venous thromboembolism (VTE) after gastroenterological surgery. METHODS: We assessed the frequency of and risk factors for VTE after eight gastroenterological procedures (total 516 217 cases including, gastrectomy, total gastrectomy, hepatectomy, esophagectomy, right hemicolectomy, low anterior resection, pancreaticoduodenectomy, and acute pan-peritonitis surgery) based on data from the National Clinical Database. Data collected between 2011 and 2013 (382 124 cases) were used as a test set, and data from 2014 (134 093 cases) were used as a validation set. RESULTS: The frequency of deep vein thrombosis (DVT) was 0.3% (382 124 cases), and the incidence of pulmonary embolism (PE) was 0.2% (382 124 cases) ranging from 0.1% to 0.7% for DVT and from 0.1% and 0.3% for PE among eight surgeries, respectively. Analyses using pre-and intra-operative factors identified the top three risk factors for VTE as esophagectomy, pancreaticoduodenectomy, and hepatectomy. Using pre-, intra-, and postoperative factors, the second through fourth risk factors were sepsis, prolonged ventilation >48 hours and readmission within 30 days. The highest risks factor for PE using pre-, intra-, and postoperative factors were any cardiac events. Unplanned intubation was the fourth risk factor. CONCLUSION: The risk for DVT and PE differed for each surgical procedure. VTE and PE risk factors changed after considering postoperative factors. It may be necessary to reconsider the prophylaxis depending on whether the complication occurs after surgery, particularly breathing and cardiac complications.

DOI： 10.1002/ags3.12275

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OBJECTIVE: The Risk Assessment Profile (RAP) score is used as a tool of risk prediction in post-traumatic venous thromboembolism (VTE), but this scoring system is complicated to use in clinical settings due to its many variables. The objective of this study was to validate the utility of the RAP model and to develop a simpler risk prediction model for post-traumatic VTE. METHODS: We conducted an observational study at two emergency and critical care centres in Japan between 2013 and 2016. Consecutive adult trauma patients who survived for 24 h or more after admission to the hospital were enroled. One prediction model (quick RAP model) was created with 6 variables based on clinical utility, experience, and thrombogenic mechanism from 17 variables in the conventional RAP model. We calculated diagnostic performance with 95% confidence interval (95% CI) by exact method. RESULTS: We identified and analysed 859 patients. Twenty-six patients (3.0%) had VTE (17 with deep venous thrombosis alone, 2 with pulmonary embolism alone, and 7 with both). In the external validation, the RAP model had a sensitivity of 100% (95% CI, 86.8-100%) and specificity of 37.9% (95% CI, 34.6-41.3%). In contrast, the qRAP model had a sensitivity of 96.2% (95% CI, 80.4-99.9%) and specificity of 56.2% (95% CI, 52.7-59.6%). In the internal validation, receiver-operating characteristic curve analysis showed that the two models had similar area under the curve values that were not significantly different (0.832 and 0.800, respectively; RAP vs qRAP, p = 0.477). CONCLUSIONS: We developed a practical, modified predictive model for VTE, the qRAP model, which appeared only slightly less accurate than the conventional RAP model and had the advantage of being simpler to use to predict VTE. In our dataset, the conventional RAP model was also evaluated as useful for the prediction of post-traumatic VTE.

DOI： 10.1016/j.injury.2019.06.020

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BACKGROUND: We examined whether inferior thyroid artery peak systolic velocity (ITA-PSV) predicts an increase in levothyroxine (LT4) dosage in pregnant women with Hashimoto's thyroiditis. METHODS: Twenty-two women with Hashimoto's thyroiditis who were planning and later achieved pregnancy or confirmed as pregnant were enrolled in this retrospective longitudinal observational study. ITA-PSV and thyroid volume were measured using ultrasonography. Serum concentrations of free thyroxine (F-T4), free triiodothyronine (F-T3), and thyroid stimulating hormone (TSH) were simultaneously determined. We adjusted LT4 dosage to maintain serum TSH at < 2.5 μIU/mL (1st trimester) and later at < 3 μIU/mL (2nd, 3rd trimester). RESULTS: Eighteen patients (81.8%) required an increase in LT4 dosage during pregnancy, of whom 7 (31.8%) required an increase ≥50 μg. Multivariable regression analysis showed that TSH (β = 0.507, p = 0.008) and ITA-PSV (β = - 0.362, p = 0.047), but not thyroid volume, F-T4, or F-T3, were independently associated with increased LT4 dosage. Receiver-operating characteristic analysis for predicting an increase in LT4 ≥ 50 μg/day showed that the area under the curve (0.905) for ITA-PSV with TSH was not significantly increased (p = 0.123) as compared to that (0.743) for TSH alone, whereas integrated discrimination improvement was significantly increased (27.9%, p = 0.009). CONCLUSIONS: In pregnant patients with Hashimoto's thyroiditis, ITA-PSV was a significant predictor of increase in LT4 dosage independent of TSH level, while ITA-PSV plus TSH showed significantly improved predictability as compared to TSH alone. These results suggest that ITA-PSV reflects residual thyroid function and is useful for evaluating the need for increased thyroid hormone production in pregnant patients with Hashimoto's thyroiditis.

DOI： 10.1186/s12884-019-2389-1

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Language：Japanese   Publisher：(一社)日本痛風・尿酸核酸学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J07281&link_issn=&doc_id=20190828010034&doc_link_id=10.14867%2Fgnamtsunyo.43.1_72&url=https%3A%2F%2Fdoi.org%2F10.14867%2Fgnamtsunyo.43.1_72&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(一社)日本老年医学会  

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Background and study aims  An increasing number of patients have been using anticoagulants including anti-vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs); however, in patients using anticoagulants, limited data are available with regard to the risks of gastrointestinal bleeding and thromboembolic events during the peri-endoscopic period. We aimed to evaluate the peri-endoscopic bleeding and thrombotic risks in patients administered VKAs or DOACs. Patients and methods  Consecutive patients using anticoagulants who underwent endoscopic biopsy, mucosal resection, or submucosal dissection were prospectively enrolled across 11 hospitals. The primary outcome assessed was difference in incidence of post-procedural gastrointestinal bleeding in patients using VKAs and DOACs. Duration of hospitalization and peri-procedural thromboembolic events were also compared. Results  We enrolled 174 patients using VKAs and 37 using DOACs. In total, 16 patients using VKA were excluded from the analysis because of cancellation of endoscopic procedures and contraindications to the use of DOACs; 128 (81 %) patients using VKAs and 17 (46 %) using DOACs received heparin-bridging therapy (HB). The rate of post-procedural gastrointestinal bleeding in DOAC users was similar to that in VKA users (16.2 % vs. 16.4 %, P  = 1.000). Duration of hospitalization was significantly longer in patients using VKAs than in those using DOACs (median 15 vs. 7 days, P  < 0.0001). Myocardial infarction occurred during pre-endoscopic HB in one patient using VKAs. Conclusion  DOAC administration showed similar post-procedural gastrointestinal bleeding risk to VKA administration in patients undergoing endoscopic procedures, but it shortened the hospital stay.

DOI： 10.1055/a-0754-1997

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Language：Japanese   Publisher：(一社)日本痛風・尿酸核酸学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

BACKGROUND: The Mayo Clinic Image Classification (MIC) was proposed as a renal prognosis prediction model for autosomal dominant polycystic kidney disease (ADPKD). MIC is based on the assumption of exponential constant increase in height-adjusted total kidney volume (HtTKV). HtTKV growth rate is calculated by one-time measurement of HtTKV and age. We named it as an age-adjusted HtTKV growth rate (AHTKV-α). AHTKV-α was compared with HtTKV slope measured by at least two HtTKV values. METHODS: Comparison of repeatability between AHTKV-α and HtTKV slope, correlation of subgroups divided according to baseline AHTKV-α and HtTKV slope with disease manifestations, estimated glomerular filtration rate (eGFR) slope, and renal survival were analyzed in 296 patients with ADPKD. PKD genotype influences were compared between AHTKV-α and HtTKV slope in 88 patients with characterized PKD mutations. RESULTS: Absolute differences between baseline and follow-up measures were significantly larger for the HtTKV slope than for AHTKV-α (P < 0.0001). From baseline AHTKV-α-based subgroups A-E according to MIC, disease manifestations occurred earlier and future eGFR slopes became steeper (P < 0.0001). Multivariate hazard ratios of renal survival differed significantly among baseline AHTKV-α-based subgroups. Inter-subgroup differences in these predictors were less evident during baseline HtTKV slope-based classification. AHTKV-α values, but not HtTKV slopes, were significantly higher for PKD1 mutation carriers than for PKD2 mutation carriers (P < 0.0001). CONCLUSION: MIC is a good renal prediction model applicable to Japanese patients also. AHTKV-α can be a more sensitive and reliable indicator in TKV growth rate than HtTKV slope.

DOI： 10.1007/s10157-018-1617-8

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BACKGROUND: Higher levels of uric acid production have been reported in individuals with visceral fat obesity, and obesity is known to enhance xanthine oxidoreductase (XOR) activity, although the precise mechanism remains unclear. We investigated the associations of visceral fat area (VFA), serum adiponectin level, and insulin resistance with plasma XOR activity using our novel highly sensitive assay based on [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. METHODS: This cross-sectional study included 193 subjects (92 males and 101 females) registered in the MedCity21 health examination registry. Plasma XOR activity, serum adiponectin level, and VFA obtained by computed tomography were measured, and insulin resistance was determined based on the homeostasis model assessment (HOMA-IR) index. RESULTS: The mean values for VFA, log HOMA-IR, and log plasma XOR activity were 76.8 ± 45.8 cm2, 0.14 ± 0.30, and 1.50 ± 0.44 pmol/h/mL, respectively. Multiple regression analysis showed that HOMA-IR was significantly (p=0.020) associated with plasma XOR activity independent of other factors, including VFA and adiponectin level, as well as age, sex, alcohol drinking habit, smoking habit, alanine transaminase, HbA1c, and eGFR. The "sex∗HOMA - IR" interaction was not significant (p=0.020) associated with plasma XOR activity independent of other factors, including VFA and adiponectin level, as well as age, sex, alcohol drinking habit, smoking habit, alanine transaminase, HbA1c, and eGFR. The ". CONCLUSIONS: Our results indicate that insulin resistance is associated with plasma XOR activity and that relationship is independent of visceral adiposity and adiponectin level, suggesting that the development of insulin resistance resulting from increased visceral adiposity and/or reduced serum adiponectin contributes to increased uric acid production by stimulating XOR activity.

DOI： 10.1155/2019/1762161

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BACKGROUND: Active surveillance has the potential to prevent nosocomial transmission of carbapenem-resistant Acinetobacter baumannii (CRAB). We assessed whether rapid diagnosis using clinical specimen-direct loop-mediated isothermal amplification (LAMP), a rapid molecular diagnostic assay, and subsequent intervention, could reduce CRAB nosocomial transmission in intensive care units (ICUs). METHODS: A before and after (quasi-experimental) study was conducted in two ICUs at the Mahidol University Faculty of Medicine Ramathibodi Hospital with 3 months of observational period followed by 9 months of interventional period. All patients were screened for CRAB using both the culture and LAMP method from rectal swab and/or bronchial aspirates (intubated patients only) upon admission, weekly thereafter, and upon discharge. During the pre-intervention period, we performed contact precautions based on culture results. In contrast, during the intervention period, we initiated contact precautions within a few hours after sample collection on the basis of LAMP results. RESULTS: A total of 1335 patients were admitted to the ICUs, of which 866 patients (pre-intervention period: 187; intervention period: 679) were eligible for this study. Incidence rate of CRAB infection decreased to 20.9 per 1000 patient-days in the intervention period from 35.2 in the pre-intervention period (P < 0.02). The calculated hazard ratio of CRAB transmission was 0.65 (95% confidence interval [CI], 0.44-0.97). Risk factors for CRAB acquisition included exposure to carbapenem (hazard ratio, 2.54 [95% CI: 1.61-5.57]). CONCLUSIONS: LAMP screening for CRAB upon ICU admission proved feasible for routine clinical practice. Rapid screening using LAMP followed by early intervention may reduce CRAB transmission rates in ICUs when compared to conventional intervention.

DOI： 10.1186/s13756-019-0564-9

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Glyoxalase 1 (GLO1) is a ubiquitous enzyme involved in the detoxification of methylglyoxal, a cytotoxic byproduct of glycolysis that induces apoptosis. In this study, we found that GLO1 gene expression correlates with neoplasm histologic grade (χ 2 test, p = 0.002) and is elevated in human basal-like breast cancer tissues. Approximately 90% of basal-like cancers were grade 3 tumors highly expressing both GLO1 and the cancer stem cell marker ALDH1A3. ALDH1high cells derived from the MDA-MB 157 and MDA-MB 468 human basal-like breast cancer cell lines showed elevated GLO1 activity. GLO1 inhibition using TLSC702 suppressed ALDH1high cell viability as well as the formation of tumor-spheres by ALDH1high cells. GLO1 knockdown using specific siRNAs also suppressed ALDH1high cell viability, and both TLSC702 and GLO1 siRNA induced apoptosis in ALDH1high cells. These results suggest GLO1 is essential for the survival of ALDH1-positive breast cancer stem cells. We therefore conclude that GLO1 is a potential therapeutic target for treatment of basal-like breast cancers.

DOI： 10.18632/oncotarget.26369

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PURPOSE: Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive corneal dystrophy that causes severe vision loss. Because of its poor prognosis, there is a demand for novel treatments for GDLD. Here, we establish a new in vitro disease model of GDLD based on immortalized human corneal epithelial (HCE-T) cells. METHODS: By using transcription activator-like effector nuclease plasmids, tumor-associated calcium signal transducer 2 (TACSTD2) and its paralogous gene, epithelial cell adhesion molecule (EpCAM), were knocked out in HCE-T cells. Fluorescence-activated cell sorting was performed to obtain cells in which both TACSTD2 and EpCAM were knocked out (DKO cells). In DKO cells, the expression levels and subcellular localizations of claudin (CLDN) 1, 4, and 7, and ZO-1 were investigated, along with epithelial barrier function. By using DKO cells, the feasibility of gene therapy for GDLD was also investigated. RESULTS: DKO cells exhibited decreased expression and aberrant subcellular localization of CLDN1 and CLDN7 proteins, as well as decreased epithelial barrier function. Transduction of the TACSTD2 gene into DKO cells nearly normalized expression levels and subcellular localization of CLDN1 and CLDN7 proteins, while significantly increasing epithelial barrier function. CONCLUSIONS: We established an in vitro disease model of GDLD by knocking out TACSTD2 and its paralogous gene, EpCAM, in HCE-T cells. This cell line accurately reflected pathological aspects of GDLD. TRANSLATIONAL RELEVANCE: We expect that the cell line will be useful to elucidate the pathogenesis of GDLD and develop novel treatments for GDLD.

DOI： 10.1167/tvst.7.6.30

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Language：Japanese   Publisher：(一社)日本肥満学会  

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BACKGROUND: Erythropoietin (EPO) has antiapoptotic and tissue-protective effects, but previous clinical studies using high-dose EPO have not shown cardioprotective effects, probably because of platelet activation and a lack of knowledge regarding the optimal dose. In contrast, a small pilot study using low-dose EPO has shown improvement in left ventricular function without adverse cardiovascular events.Methods and Results:We performed a multicenter (25 hospitals), prospective, randomized, double-blind, placebo-controlled, dose-finding study to clarify the efficacy and safety of low-dose EPO in patients with ST-segment elevation myocardial infarction (STEMI) under the Evaluation System of Investigational Medical Care of the Ministry of Health, Labor and Welfare of Japan. In total, 198 STEMI patients with low left ventricular ejection fraction (LVEF <50%) were randomly assigned to receive intravenous administration of EPO (6,000 or 12,000 IU) or placebo within 6 h of successful percutaneous coronary intervention. At 6 months, there was no significant dose-response relationship in LVEF improvement among the 3 groups tested (EPO 12,000 IU: 5.4±9.3%, EPO 6,000 IU: 7.3±7.7%, Placebo: 8.1±8.3%, P=0.862). Low-dose EPO also did not improve cardiac function, as evaluated by 99 mTc-MIBI SPECT or NT-proBNP at 6 months and did not increase adverse events. CONCLUSIONS: Administration of low-dose EPO did not improve LVEF at 6 months in STEMI patients (UMIN000005721).

DOI： 10.1253/circj.CJ-17-0889

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BACKGROUND AND AIM: Esophageal endoscopic submucosal dissection (ESD) to resect widespread lesions has increased the incidence of strictures, and some patients develop strictures despite receiving prophylactic locoregional triamcinolone injections. The present study evaluated the predictive factors for esophageal stricture formation in patients given prophylactic triamcinolone injections after ESD. METHODS: This was a retrospective observational study. Of 552 consecutive patients who underwent ESD, those who received prophylactic triamcinolone injections immediately after ESD were enrolled. Primary outcome was predictive factors for esophageal stricture formation in patients given prophylactic triamcinolone injections. RESULTS: We evaluated 101 en bloc resections involving 144 lesions in 96 patients. Strictures occurred following 17 (16.8%) resections. Wider circumferential mucosal defect (odds ratio [OR] 2.42, 95% confidence interval [CI]: 1.01-5.80; P = 0.048) was an independent predictive factor for stricture development. Cut-off value associated with stricture formation was five-sixths of the circumferential mucosal defect. Propensity analysis determined that frequency of esophageal strictures increased in patients with circumferential mucosal defects of more than five-sixths compared with those less than five-sixths (OR = 5.70, 95% CI: 1.61-20.18; P = 0.007). CONCLUSION: Resections involving circumferential mucosal defects of more than five-sixths increased the likelihood of stricture formation in patients given prophylactic locoregional triamcinolone injections after esophageal ESD.

DOI： 10.1111/den.12946

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PURPOSE: One of the pathophysiological processes in sepsis is endothelial dysfunction, which leads to disseminated intravascular coagulation (DIC). Syndecan-1 is a major structural component of the endothelium and plays a key role in endothelial function. The purpose of this study was to assess the value of syndecan-1 as a predictive marker for DIC in sepsis. METHODS: We performed a prospective observational study of patients with sepsis from February 2014 to July 2015. Serial change of hemostatic markers, anticoagulant and fibrinolytic markers (antithrombin, PAI-1), endothelial markers (syndecan-1, VCAM-1, E-selectin), and inflammatory markers (IL-1β, IL-6, IL-8, HMGB-1, histone-H3) were analyzed. Clinical data including APACHE II, SOFA, and DIC scores and 28-day mortality were also evaluated. RESULTS: During the study, 39 septic patients and 15 healthy controls were included. Syndecan-1 levels were significantly increased in the septic patients compared with the healthy controls. Of the septic patients, non-survivors had higher syndecan-1 levels than did the survivors on days 1, 2, and 4. Significant correlations on day 1 were found between syndecan-1 levels and APACHE II, SOFA, and DIC scores, hemostatic markers, IL-1β, IL-8, and PAI-1. Syndecan-1 levels on day 1 were also significantly higher in patients with than without DIC and had strong discriminative power for the prediction of both DIC development and subsequent mortality, with AUCs of 0.79 and 0.85, respectively. CONCLUSION: Syndecan-1 levels were associated with not only the severity of illness and mortality but also DIC development in sepsis, suggesting that syndecan-1 could be a predictive marker of DIC.

DOI： 10.1016/j.jcrc.2017.07.049

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Language：English   Publisher：UNIV TSUKUBA  

The performance of randomization methods in consideration of the impact of a prognostic factor that has an interaction and baseline characteristics that have no effect on the outcome has not been clarified, especially for small sized clinical trials. We conducted numerical simulations to identify the difference in behaviour of the empirical power and the empirical type 1 error rate among some randomization methods and statistical analyses when we use a prognostic factor that has an interaction or baseline characteristics that have no effect on the outcome for small sized randomized controlled trials. The empirical power was higher when using a prognostic factor that had an interaction. Also, by using stratified blocked randomization (ST) or minimization (MI) with the multiple regression, the empirical power was further increased. On the other hand, the empirical power was lower when using baseline characteristics that had no effect on the outcome. We recommend conducting ST or MI, multiple regression and using a prognostic factor that has an interaction in small-size randomized controlled trials.

DOI： 10.5183/jjscs.1707001_236

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Other Link： http://id.ndl.go.jp/bib/030633057

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Background The prevalence of carbapenem-resistant Enterobacteriaceae (CRE) has been reported to be lower in Japan than in many other countries. However, extensive surveillance for CRE carriage has not been performed in Japan. Aim To investigate the prevalence of CRE carriage in Japan among convalescent patients considered to be at high risk of being CRE carriers using an improved selective culture medium. Methods A cross-sectional survey was conducted in 22 acute care hospitals (ACHs) and 21 long-term care hospitals (LTCHs) in northern Osaka from December 2015 to January 2016. Patients who used incontinence aids, an enteral feeding tube or a urinary catheter were enrolled. Faecal specimens were examined using the newly developed M-ECC for imipenemase (IMP)-producing CRE, which is the most prevalent form of CRE in Japan. The positive isolates were analysed by polymerase chain reaction and sequencing. Risk factors associated with carriage were analysed by logistic regression. Findings Among 1507 patients, 184 (12.2%) carried CRE. The percentage of positive patients was significantly higher in LTCHs (14.9%) than in ACHs (3.6%) (P<0.001). Risk factors for CRE carriage were longer hospital stay [odds ratio (OR) 2.59; 95% confidence interval (CI) 1.87–3.60], enteral feeding (OR 3.03, 95% CI 2.08–4.42) and antibiotic exposure (OR 2.00, 95% CI 1.40–2.87). Among the 233 CRE isolates identified, 223 were IMP producers; the remaining isolates did not produce carbapenemase. Conclusions This is the first Japanese report to demonstrate the significant spread of CRE in both ACHs and LTCHs using an improved selective medium. A coordinated regional approach may help to prevent further spread.

DOI： 10.1016/j.jhin.2017.07.015

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

BACKGROUND: Coronary artery bypass grafting (CABG) reduces functional mitral regurgitation (MR) associated with ischemic heart disease, although the predictive factors or mechanisms of reversibility of functional MR after CABG are not fully understood.We investigated whether mitral valve structure is associated with the outcome of functional MR after CABG.Methods and Results:From a consecutive series of 98 patients with mild-moderate functional MR preoperatively who underwent isolated CABG, we enrolled 66 patients who were followed up for >1 year postoperatively using echocardiography. The degree of MR was reduced in 34 patients (52%) postoperatively, in association with a lower rate of in-hospital treatment for cardiac failure in the long term, compared with the 32 patients (48%) with residual MR postoperatively. The patients with reduced MR postoperatively had longer estimated coaptation length and more anteriorly or centrally directed MR jets than those without reduced MR. On statistical analysis, the addition of estimated coaptation length and jet direction to the reported predictors (ejection fraction, left ventricular end-diastolic dimension, and tenting height) more accurately predicted changes in post-CABG MR than the reported 3 factors alone. CONCLUSIONS: Residual MR was associated with the emergence of congestive heart failure in the long term after CABG. A specific mitral valve structure, such as large mitral leaflet size or predominant tethering of the posterior leaflet, was a predictive factor for the reversibility of post-CABG functional MR.

DOI： 10.1253/circj.CJ-16-1280

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We discuss the important role of biostatisticians in clinical research. In addition, the biases that occur in a study, especially "confounding" in an observational study, are discussed using a real example. Finally, the manuscript provides an overview of propensity score matching, a method to eliminate confounding.

DOI： 10.11477/mf.1416200829

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BACKGROUND AND STUDY AIMS:  Endoscopic local steroid injection (LSI) has been used to prevent esophageal strictures after endoscopic submucosal dissection (ESD) for superficial esophageal neoplasms (SENs). This study aimed to evaluate the safety and efficacy of LSI therapy. PATIENTS AND METHODS:  From May 2007 to September 2014, at four institutions, 40 consecutive patients with SENs were treated with ESD that left a mucosal defect of more than three-quarters of the esophageal circumference. Two patients who underwent esophagectomy after ESD were excluded, and 38 patients were analyzed. The incidence of post-ESD strictures and adverse events associated with LSI were retrospectively investigated. RESULTS:  Prophylactic LSI was administered in 28 patients (LSI group), and not administered in 10 patients (Non-prevention group). Post-ESD stricture rates were significantly lower in the LSI group (43 %) than in the Non-prevention group (90 %) ( P  = 0.012). Endoscopic balloon dilation (EBD) was conducted in 11 patients (39 %) in the LSI group and in 7 (70 %) in the Non-prevention group. In the LSI group, perforation caused by EBD occurred in five patients, while in the Non-prevention group, it occurred in only one patient who had received subsequent LSI before the perforation. Four patients with perforation successfully recovered after conservative therapy, but the other two patients required surgical treatment. A review of follow-up examinations with endoscopic ultrasonography and narrow-band imaging showed impaired ulcer-healing process after LSI. CONCLUSION:  LSI is useful for preventing post-ESD strictures, but it appears to increase the risk of perforation in cases of EBD.

DOI： 10.1055/s-0043-110077

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AbstractStreptococcus suis is an important zoonotic pathogen in swine and humans that causes sepsis and meningitis. Our previous study in Thailand showed that the prevalence of S. suis infection in humans, especially in northern areas of Thailand, and the transmission of the pathogen occurred mainly through the consumption of traditional raw pork products. Considering the high incidence proportion and mortality rate of the disease as an important public health problem, we implemented a food safety campaign in the Phayao Province in northern Thailand in 2011. We evaluated the effects of a food safety campaign by comparing the sociodemographic, clinical, and bacteriological characteristics of cases before and after the campaign. The follow-up study showed a marked decrease of the incidence proportion in the first 2 years, indicating the effectiveness of the campaign. In the third year, however, the incidence proportion slightly increased again, indicating the existence of deep-rooted cultural behaviors and the necessity of continuous public health intervention. Furthermore, epidemiological analysis of the cases made it possible to estimate the infectivity of the pathogen via the oral route of infection. In the present study, we showed the effectiveness of the food safety campaign for controlling the S. suis infection, and we present a role model public health intervention for prevalent areas affected by S. suis infection in humans.

DOI： 10.4269/ajtmh.16-0456

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ PUBLISHING GROUP  

Objectives: Evidence on the safety and long-term efficacy of super selective bronchial artery embolisation (ssBAE) using platinum coils in patients with haemoptysis is insufficient. The objective of the present study was to evaluate the safety and the 3-year postprocedure haemoptysis-free survival rate of de novo elective ssBAE using platinum coils rather than particles for the treatment of haemoptysis.
Design: A single-centre retrospective observational study.
Setting: Hemoptysis and Pulmonary Circulation Center in Japan.
Participants: A total of 489 consecutive patients with massive and non-massive haemoptysis who underwent de novo elective ssBAE without malignancy or haemodialysis.
Interventions: ssBAE using platinum coils. All patients underwent CT angiography before the procedure for identifying haemoptysis-related arteries (HRAs) and for procedural planning.
Primary and secondary outcome measures: The composite of the 3-year recurrence of haemoptysis and mortality from the day of the last ssBAE session. Each component of the primary end point and procedural success defined as successful embolisation of all target HRAs were also evaluated.
Results: The median patient age was 69 years, and 46.4% were men. The total number of target vessels was 4 (quartile 2-7), and the procedural success rate was 93.4%. There were 8 (1.6%) major complications: 1 aortic dissection, 2 symptomatic cerebellar infarctions and 5 mediastinal haematoma cases. The haemoptysis-free survival rates were estimated by the Kaplan-Meier analysis at 86.9% (95% CI 83.7% to 90.2%) at 1 year, 79.4% (74.8% to 84.3%) at 2 years and 57.6% (45.1% to 73.4%) at 3 years. Although not statistically significant by the adjusted analysis of variance with multiple imputation of missing variables, cryptogenic haemoptysis tended to show the most favourable outcome and non-tuberculous mycobacterium showed the worst outcome (adjusted p=0.250).
Conclusions: We demonstrated the safety and long-term efficacy of elective ssBAE using platinum coils and established that it can be a valuable therapeutic option for treating patients with haemoptysis.

DOI： 10.1136/bmjopen-2016-014805

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER MEDICAL ASSOC  

IMPORTANCE Inhibitors of mammalian target of rapamycin complex 1, such as sirolimus, effectively target skin lesions in tuberous sclerosis complex (TSC). However, systemic treatment causes adverse effects, and topical sirolimus has shown promise in the treatment of facial angiofibromas.
OBJECTIVE To evaluate the efficacy, safety, and optimal concentration of a topical sirolimus gel vs placebo for treatment of facial angiofibromas in TSC.
DESIGN, SETTING, AND PARTICIPANTS A double-blind, placebo-controlled, parallel-group, dose-escalation, phase 2 randomized clinical trial using 3 sirolimus gel concentrations was performed at Osaka University Hospital, Osaka, Japan. Thirty-six patients with TSC and facial angiofibromas, including 18 aged 3 to 18 years (children) and 18 aged 19 to 65 years (adults), were enrolled from December 10, 2013, to July 17, 2014. Analysis was by intention to treat.
INTERVENTIONS The adult and child groups were each subdivided into 3 groups (n = 12 each) and randomized to receive sirolimus gel concentrations of 0.05%, 0.1%, or 0.2% or placebo using a web-response system in a 2: 1 fashion. The medication was applied to the patient's lesions twice per day for 12 weeks. Each patient underwent assessment at 2, 4, 8, and 12 weeks during treatment and at 4 weeks after discontinuation of the treatment (16 weeks).
MAIN OUTCOMES AND MEASURES The primary end point, planned before starting data collection, was an improvement factor, represented as a variable composed of tumor size reduction and a lessening of the redness of the 3 target tumors at 12 weeks relative to baseline.
RESULTS All 36 patients (13 male and 23 female; median age, 40 years; range, 6-47 years) completed the study analyses. The improvement factor was statistically significant in all active treatment groups receiving 0.2% sirolimus (mean [SD], 1.94 [0.68]; P &lt;.001) and not in the adult subgroups receiving 0.1%(mean [SD], 0.88 [0.85]; P =.31) and 0.05%(mean [SD], 1.63 [1.11]; P =.09) concentrations of sirolimus. No significant adverse effects were observed. Mild skin dryness (13 patients [36%]) and irritation (11 patients [31%]) were observed. Low blood levels of sirolimus (&lt; 0.25 ng/mL) were detected in adults (1 patient [25%] in the 0.1% adult subgroup and 2 patients [50%] in the 0.2% adult subgroup) and particularly in children (1 patient [25%] in the 0.05% child subgroup, 2 patients [50%] in the 0.1% child subgroup, and 4 patients [100%] in the 0.2% child subgroup).
CONCLUSIONS AND RELEVANCE Topical sirolimus gel is safe and effective for facial angiofibromas in TSC. The optimal concentration of sirolimus was 0.2%.

DOI： 10.1001/jamadermatol.2016.3545

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OBJECTIVE: Dynamic susceptibility contrast magnetic resonance imaging is widely used to assess glioma grade; histogram analyses are used for precise tumor perfusion evaluations. We evaluated the effect of vessel contamination in normalized cerebral blood volume (nCBV) to differentiate high- and low-grade gliomas. METHODS: Thirty-four patients with gliomas underwent dynamic susceptibility contrast magnetic resonance imaging. Both traditional and vessel-masked nCBV maps were constructed. Histogram analyses of whole tumors and statistical comparisons were performed to compare traditional and vessel-masked images. RESULTS: Mean values of all the histogram metrics were lower in vessel-masked images than in traditional images. Receiver operating characteristic curve analyses for every histogram metric showed a higher area under the curve for vessel-masked images than for traditional images. The integrated discrimination improvement showed that the vessel-masked images were superior to the traditional images significantly for predicting the glioma grading. CONCLUSIONS: Vessel-masked nCBV maps can prevent overestimations of CBV measurements and can improve diagnostic accuracy for glioma grading.

DOI： 10.1097/RCT.0000000000000614

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OBJECTIVE: Acute mesenteric ischemia (AMI) is a potentially fatal vascular emergency, and several computed tomographic (CT) findings have been introduced to determine the presence of intestinal ischemia or necrosis, although the most useful finding is unknown. METHODS: We retrospectively analyzed data of 43 consecutive patients with AMI who were treated during the period from 2006 to 2015. Study patients included both superior mesenteric artery dissection (n = 29) and thrombosis (SMAT, n = 14). Epidemiological data, CT findings, and the primary end point defined as the composite of intestinal ischemia or necrosis based on surgical finding and in-hospital mortality were investigated. The classification and regression tree was used to assess determinants of the primary end point, and area under the curve of receiver operating characteristics was used to evaluate discriminating accuracy. RESULTS: In total, the primary end point occurred in 27.9% (0.0% in superior mesenteric artery dissection and 85.7% in SMAT). Classification and regression tree demonstrated that the baseline disease was the only and strong determinant of the primary outcome (P< .001), which was also confirmed by the highest area under the curve of 0.968 (95% confidence interval, 0.924-1.000). CONCLUSIONS: The baseline disease rather than CT findings is the most important determinant of the primary end point. In patients with AMI, SMAT should undergo exploratory surgery and subsequent surgical treatment without delay.

DOI： 10.1016/j.ajem.2016.08.016

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BACKGROUND: The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor involved in the pathogenesis of inflammatory diseases. However, the significance of the soluble isoform of RAGE (sRAGE) has not been clarified in critical illness. We investigated circulating sRAGE in blood samples from septic patients. METHODS: In this cross-sectional study, criteria for inclusion were patients with severe sepsis and age older than 18 years. Samples were collected within 24 hours after the diagnosis of sepsis and also from healthy volunteers. The levels of sRAGE and RAGE signaling pathway-associated biologic parameters were measured with an enzyme-linked immunosorbent assay kit. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were calculated at the time of patient enrollment. We used the International Society of Thrombosis and Haemostasis (ISTH) overt disseminated intravascular coagulation (DIC) diagnostic criteria algorithm to assess coagulopathy. RESULTS: Included were 24 septic patients and 12 healthy volunteers. Serum sRAGE level was significantly increased in the patients compared with healthy controls. Significant correlations were found between sRAGE levels and APACHE II, SOFA, and ISTH DIC scores. The increase in sRAGE levels also correlated with the upregulation of interleukin-6, soluble vascular adhesion molecule 1, and plasminogen activator inhibitor 1 levels and a reduction in platelet count. The fraction of sRAGE other than the endogenous secreted form of RAGE (esRAGE) was augmented in the patients. CONCLUSION: We demonstrated for the first time that the serum level of sRAGE increased with the progression of DIC and the severity of sepsis, suggesting that circulating sRAGE reflects RAGE signaling pathway activity, which induces the excessive inflammatory response involved in endothelial injury and coagulopathy and that its measurement may be useful as a biomarker for sepis. LEVEL OF EVIDENCE: Prognostic study, level IV.

DOI： 10.1097/TA.0000000000000651

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

BACKGROUND
Previous studies have shown that trauma systems decrease morbidity and mortality after injury, but progress in system development has been slow and inconsistent. This study evaluated the progress in 20 state or regional systems following a consultative visit conducted by the Trauma Systems Evaluation and Planning Committee (TSEPC) of the Committee on Trauma, expanding on a previous study published in 2008, which demonstrated significant progress in six systems following consultation.
METHODS
Twenty trauma systems that underwent TSEPC consultation between 2004 and 2010 were studied. Status was assessed using a set of 16 objective indicators. Baseline scores for 14 regions were calculated during the consultation visit and taken from the 2008 study for the remaining six. Postconsultation status was assessed during facilitated teleconferences. Progress was assessed by comparing changes in indicator scores.
RESULTS
There was significant improvement in approximately 80% of systems evaluated within 60 months following the consultation. There was no progress in five of six systems reevaluated over 80 months after consultation, and all four systems evaluated over 100 months after consultation showed erosion of progress. Significant improvements were seen in 10 of the 16 individual indicators, with the greatest gains related to system standards, data systems, performance improvement, prehospital triage criteria, and linkages with public health. Consistent with the 2008 study, the two indicators related to financing for the trauma system showed no improvement.
CONCLUSION
The TSEPC consultation process continues to be associated with improvements in trauma system development in approximately 80% of cases, consistent with the 2008 study, but gains are not self-sustaining. There was a stagnation in progress and a deterioration in total score over time, suggesting that a repeat consultation may be beneficial. System funding remains a challenge and was the area most likely to suffer setbacks over during study period.
LEVEL OF EVIDENCE
Care management study, level V.

DOI： 10.1097/TA.0000000000000653

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

For square contingency tables with ordered categories, there may be some cases that one wants to analyze them by considering collapsed tables with some adjacent categories combined in the original table. This paper considers the symmetry model for collapsed square contingency tables and proposes a measure to represent the degree of departure from symmetry. The proposed measure is defined as the arithmetic mean of submeasures each of which represents the degree of departure from symmetry for each collapsed 3x3 table. Each submeasure also represents the mean of power-divergence or diversity index for each collapsed table. Examples are given.

DOI： 10.1080/02664763.2014.993362

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI PUBLISHING CORP  

Recently, it has been reported that circulating free DNA (cf-DNA) in the blood is increased in various infectious diseases, including sepsis. Moreover, a relationship between cf-DNA and neutrophil extracellular traps (NETs) has been suggested. However, it is still unclear what the source and physiological role of cf-DNA in sepsis are. In this study, we examined the source of cf-DNA by detecting citrullinated histone H3, a characteristic feature of NET formation, in cecal ligation and puncture-(CLP-) operated mice. In addition, neutrophil depletion using anti-Ly6G antibodies was performed to assess the association between neutrophils and cf-DNA. Increased cf-DNA levels were observed only in CLP mice and not in the control groups; the qPCR findings revealed that the cf-DNA was mainly host-derived, even in bacteremic conditions. Citrullinated histone H3 was not increased in the neutrophils upon CLP, and the depletion of neutrophils showed limited effects on decreasing the amount of cf-DNA. Taken together, these results suggested that elevated cf-DNA levels during early-phase sepsis may represent a candidate biomarker for the severity of sepsis and that, contrary to previous findings, cf-DNA is not derived from neutrophils or NETs.

DOI： 10.1155/2015/614518

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Neutrophil extracellular traps (NETs), a newly identified immune mechanism, are induced by inflammatory stimuli. Modification by citrullination of histone H3 is thought to be involved in the in vitro formation of NETs. The purposes of this study were to evaluate whether NETs and citrullinated histone H3 (Cit-H3) are present in the bloodstream of critically ill patients and to identify correlations with clinical and biological parameters. Blood samples were collected from intubated patients at the time of ICU admission from April to June 2011. To identify NETs, DNA and histone H3 were visualized simultaneously by immunofluorescence in blood smears. Cit-H3 was detected using a specific antibody. We assessed relationships of the presence of NETs and Cit-H3 with the existence of bacteria in tracheal aspirate, SIRS, diagnosis, WBC count, and concentrations of IL-8, TNF-alpha, cf-DNA, lactate, and HMGB1. Forty-nine patients were included. The median of age was 66.0 (IQR: 52.5-76.0) years. The diagnoses included trauma (7, 14.3%), infection (14, 28.6%), resuscitation from cardiopulmonary arrest (8, 16.3%), acute poisoning (4, 8.1%), heart disease (4, 8.1%), brain stroke (8, 16.3%), heat stroke (2, 4.1%), and others (2, 4.1%). We identified NETs in 5 patients and Cit-H3 in 11 patients. NETs and/or Cit-H3 were observed more frequently in "the presence of bacteria in tracheal aspirate'' group (11/22, 50.0%) than in "the absence of bacteria in tracheal aspirate'' group (4/27, 14.8%) (p&lt;.01). Multiple logistic regression analysis showed tht only the presence of bacteria in tracheal aspirate was significantly associated with the presence of NETs and/or Cit-H3. The presence of bacteria in tracheal aspirate may be one important factor associated with NET formation. NETs may play a pivotal role in the biological defense against the dissemination of pathogens from the respiratory tract to the bloodstream in potentially infected patients.

DOI： 10.1371/journal.pone.0111755

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

For the analysis of square contingency tables with ordinal categories, Tahata, Yamamoto and Tomizawa (2009) considered the normal distribution type symmetry model, which may be appropriate if it is reasonable to assume an underlying bivariate normal distribution with equal marginal variances. The present paper proposes a new model which may be appropriate for a square ordinal table if it is reasonable to assume an underlying bivariate skew normal distribution with equal marginal variances. Simulations are used to investigate the fitting of new model for bivariate skew normal distribution. The decayed teeth data are analyzed by using the new model. (C) 2014 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.csda.2014.04.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

For square contingency tables, we propose a quasi-symmetry model with an exponential form along subdiagonal and give the theorem that Tomizawa's (1992) diagonal exponent symmetry model holds if and only if the proposed model and marginal means equality model hold with the orthogonality of test statistics. (C) 2014 The Authors. Published by Elsevier B.V.

DOI： 10.1016/j.spl.2014.04.029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

Neutrophil extracellular traps (NETs) are structures composed of DNA and granular proteins, which rapidly trap and kill pathogens. The formation of NETs has been detected during infection in animal experiments, but their role in humans is unclear. The purposes of this study were to quantitatively evaluate the production of NETs during acute respiratory infection and to study the relationship between the NET length and various inflammatory mediators.
We examined bronchial aspirates collected from nine intubated patients in an intensive care unit. Samples were collected at the onset of acute respiratory infection (day 0) and on days 1, 3-5, and 6-8. The NET length was visualised by immunohistochemistry and quantified using computer tracing software.
The NET length was measured and compared at each time point. The length differed significantly between time points (p&lt;0.001). NETs were significantly longer on day 1 than on day 0 (p&lt;0.001). Neutrophils released NETs abundantly in response to respiratory infection and regression analysis showed that NET length correlated with six clinical parameters (white blood cells, platelets, lactate, CXC ligand-2, interleukin-8, and procalcitonin) as the explanatory variables.
NETs in bronchial aspirates may reflect disease progression of respiratory infections. Quantification of NETs in bronchial aspirates may provide a new indicator of inflammation.

DOI： 10.1183/09031936.00139813

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Background: The 2010 Consensus on Science and Treatment Recommendations Statement recommended that short video/computer self-instruction courses, with minimal or no instructor coaching, combined with hands-on practice can be considered an effective alternative to instructor-led basic life support courses. The purpose of this study was to examine the effectiveness of a simplified cardiopulmonary resuscitation (CPR) training program for non-medical staff working at a university hospital.Methods: Before and immediately after a 45-min CPR training program consisting of instruction on chest compression and automated external defibrillator (AED) use with a personal training manikin, CPR skills were automatically recorded and evaluated. Participants' attitudes towards CPR were evaluated by a questionnaire survey.Results: From September 2011 through March 2013, 161 participants attended the program. We evaluated chest compression technique in 109 of these participants. The number of chest compressions delivered after the program versus that before was significantly greater (110.8 ± 13.0/min vs 94.2 ± 27.4/min, p < 0.0001), interruption of chest compressions was significantly shorter (0.05 ± 0.34 sec/30 sec vs 0.89 ± 3.52 sec/30 sec, p < 0.05), mean depth of chest compressions was significantly greater (57.6 ± 6.8 mm vs 52.2 ± 9.4 mm, p < 0.0001), and the proportion of incomplete chest compressions of <5 cm among all chest compressions was significantly decreased (8.9 ± 23.2% vs 38.6 ± 42.9%, p < 0.0001). Of the 159 participants who responded to the questionnaire survey after the program, the proportion of participants who answered 'I can check for a response,' 'I can perform chest compressions,' and 'I can absolutely or I think I can use an AED' increased versus that before the program (81.8% vs 19.5%, 77.4% vs 10.1%, 84.3% vs 23.3%, respectively).Conclusions: A 45-min simplified CPR training program on chest compression and AED use improved CPR quality and the attitude towards CPR and AED use of non-medical staff of a university hospital. © 2014 Hirose et al.; licensee BioMed Central Ltd.

DOI： 10.1186/1757-7241-22-31

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUSHPA PUBLISHING HOUSE  

For two-way contingency tables, Yamamoto et al. [10] considered a measure that represents the degree of departure from marginal pointsymmetry. The present paper extends the measure to multi-way tables. The proposed measure is expressed by using the Cressie-Read powerdivergence or the Patil-Taillie diversity index. The measure could be useful for comparing the degrees of departure from marginal pointsymmetry in several multi-way tables. Examples are given.

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Language：Japanese   Publisher：(一社)日本臨床救急医学会  

目的:大学病院非医療従事職員を対象に胸骨圧迫とAED使用に特化した簡易型心肺蘇生講習会を実施し、その教育効果を調べること。対象・方法:2011年9月から2012年1月の間に受講した56名に対し、胸骨圧迫とAED実施に関する質問紙調査を行った。うち29名の胸骨圧迫手技を客観的に評価した。結果:講習会前後で「反応の確認ができる」と答えた人が9名(16%)から48名(86%)(p<0.0001)に、「胸骨圧迫ができる」と答えた人が5名(9%)から46名(82%)(p<0.0001)に、「AEDを使用できる」と答えた人が14名(25%)から50名(89%)(p<0.0001)に増加した。また、胸骨圧迫回数が89.6±31.0回/分から107.8±16.3回/分(p<0.01)に、圧迫中断時間が2.7±6.2秒から0.2±0.7秒(p<0.05)に、5cm未満の不完全圧迫回数/総圧迫回数(%)は18.0±31.8%から5.6±19.0%(p<0.05)へと改善した。結語:簡易型心肺蘇生講習会により胸骨圧迫とAEDを実施する自信が向上し、胸骨圧迫手技の技術が改善した。(著者抄録)

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Language：Japanese   Publisher：(一社)日本Shock学会  

NETs(Neutrophil Extracellular Traps)とは、活性化された好中球が能動的に放出する網目状の構造物である。クロマチンを主成分とし、感染防御のために病原体を捕獲して排除する機構を備えているが、ヒトにおけるNETsと臨床病態との関連はいまだ明らかにされていない。このためわれわれは、集中治療を要する患者から採取した痰、血液のスメア標本を作製し、免疫組織化学的にNETsを同定することで、ヒトの生体侵襲応答におけるNETsの関与を検討した。その結果、急性呼吸器感染発症時には喀痰中にNETsが著明に出現し、血液中では、健常人には全く認められないNETsがSIRS患者において有意に誘導されることが明らかになった。NETsはさまざまな生体侵襲に対する制御機構として重要な役割を果たしていると考えられる。(著者抄録)

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Language：Japanese   Publisher：日本計算機統計学会  

DOI： 10.20551/jscssymo.28.0_41

CiNii Books

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For square contingency tables with nominal categories, Tomizawa (1994), and Tomizawa, Seo and Yamamoto (1998) considered the power-divergence-type measures to represent the degree of departure from symmetry. The present paper proposes the Wald-type measure to represent the degree of departure from symmetry. In sample version the proposed measure is obtained by modifying the Wald test statistic by the upper limit with fixed sample size. The paper also describes the relationship between the proposed measure and asymmetry models, and the relationship between the measure and the bivariate normal distribution. Examples are given.

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

For square contingency tables with ordered categories, there may be some cases that one wants to analyze them by considering collapsed tables with some adjacent categories combined in the original table. This paper proposes three kinds of new models which have the structure of point-symmetry (PS), quasi point-symmetry and marginal point-symmetry for collapsed square tables. This paper also gives a decomposition of the PS model for collapsed square tables. The father's and his daughter's occupational mobility data are analyzed using new models.

DOI： 10.1080/02664763.2013.786028

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Language：Japanese   Publisher：(一社)日本Shock学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUSHPA PUBLISHING HOUSE  

For nominal square contingency tables, Tomizawa [9] and Tomizawa and Makii [10] considered measures to represent the degree of departure from marginal symmetry. These measures attain the maximum value when one of row and column marginal probabilities for any category is zero. The present paper proposes two kinds of generalization of these measures so that the degree of departure from marginal symmetry can attain the maximum value even when the marginal probabilities are not zeros. An example is also given.

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For the analysis of square contingency tables, many kinds of symmetry models have proposed. The present paper proposes a new kind of symmetry model, and gives a decomposition of the new model by introducing an extended model of it. Moreover, it shows the orthogonality of statistic for testing goodness-of-fit of the new model. Two unaided vision data analyses are also shown.

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：WORLD SCIENTIFIC PUBL CO PTE LTD  

For the analysis of square contingency tables with ordered categories, Tahata, Yamamoto, Nagatani and Tomizawa (2009) considered an average symmetry model and a measure of degree of departure from the model. The present paper proposes (1) the statistic to test the equality of degree of asymmetry and (2) the measure to represent the difference of degree of asymmetry between several square contingency tables. They are applied to unaided distance vision data in Britain and in Japan, and to decayed teeth data in Japan.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：EUROPEAN JOURNAL PURE & APPLIED MATHEMATICS  

For square contingency tables with ordered categories, we decompose the symmetry model into three models for cumulative probabilities. Three models are the cumulative two ratios-parameter symmetry, the global symmetry, and the marginal means equality models. An example is given.

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PURPOSE: The development of novel pharmaceutical interventions to improve the clinical outcomes of patients with acute ST-segment elevation myocardial infarction (STEMI) is an unmet medical need worldwide. In animal models, a single intravenous administration of erythropoietin (EPO) during reperfusion improves left ventricular (LV) function in the chronic stage. However, the results of recent proof-of-concept trials using high-dose EPO in patients with STEMI are inconsistent. In our pilot study, low-dose EPO after successful percutaneous coronary intervention (PCI) improved the LV ejection fraction (EF) and did not trigger severe adverse clinical events in patients with STEMI. One possible reason for this discrepancy is the dose of EPO used. METHODS AND RESULTS: We have started a double-blind, placebo-controlled, randomized, multicenter clinical trial (EPO-AMI-II) to clarify the safety and efficacy of low-dose EPO in patients with STEMI. STEMI patients who have a low LVEF (<50 %) will be randomly assigned to intravenous administration of placebo or EPO (6,000 or 12,000 IU) within 6 h after successful PCI. The primary endpoint is the difference in LVEF between the acute and chronic phases (6 months), as measured by single-photon emission computed tomography. The patient number needed for EPO-AMI-II is 600. The study will stop when superior efficacy or futility is detected by an interim analysis. This study has been approved by the Evaluation System of Investigational Medical Care. CONCLUSIONS: EPO-AMI-II study will clarify the safety and efficacy of low-dose EPO in STEMI patients with LV dysfunction in a double-blind, placebo-controlled, multicenter study. (247 words).

DOI： 10.1007/s10557-012-6410-4

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Language：Japanese   Publisher：(一社)日本救急医学会  

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For two-way contingency tables, Tomizawa (1985b) gave a theorem that the double symmetry (DS) model holds if and only if both the quasi DS and the marginal DS models hold. The present paper proposes, for multiway tables, the DS, some quasi DS and marginal DS models, and extends Tomizawa's theorem into multi-way tables. It also shows that for multi-way tables the likelihood ratio statistic for testing goodness of fit of the DS model is asymptotically equivalent to the sum of those for testing the quasi DS model with some order and the marginal DS with the corresponding order. An example is given.

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Publishing type：Research paper (scientific journal)  

For two-way contingency tables with a nominal explanatory and an ordinal response variables, Yamamoto et al. (2011) considered a proportional reduction in error measure, which describes the relative decrease in the probability of making an error in predicting the value of the responsevariable when the value of the explanatory variable is known, as opposed to when it is not known. The present paper extends the measure to a multi-way contingency table with multiple explanatory variables and an ordinal response variable. An example is shown.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INST NACIONAL ESTATISTICA-INE  

For the analysis of square contingency tables, Tomizawa, Miyamoto and Ashihara (2003) considered a measure to represent the degree of departure from marginal homogeneity. However, the maximum value of this measure cannot distinguish two kinds of marginal inhomogeneity. This paper proposes a measure which can distinguish two kinds of marginal inhomogeneity for square tables with ordered categories. The measure is constructed using the arc-cosine function of symmetric cumulative probabilities. Especially the proposed measure is useful for representing the degree of departure from marginal homogeneity when the extended marginal homogeneity model holds. Examples are given.

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Problem statement: For square contingency tables with ordered categories, this study considers four kinds of extensions of the marginal homogeneity model and gives decompositions for the ordinal quasi-symmetry model. The decompositions are extensions of some existing decompositions. Approach: This study gives a decomposition theorem that the ordinal quasisymmetry model holds if and only if the quasi-symmetry model and the proposed weighted marginal homogeneity model hold. An example is given. Results: For the data of cross-classification of father's and his son's occupational status in Denmark, the decomposition of the ordinal quasi-symmetry model is applied and the detailed analysis is given. Conclusion: When the ordinal quasi-symmetry model fits the data poorly, this decomposition is useful for seeing which of decomposed two models influences stronger. © 2011 Science Publications.

DOI： 10.3844/jmssp.2011.314.318

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TARU PUBLICATIONS  

For two-way contingency tables with a nominal explanatory and an ordinal response variables, the present paper proposes a proportional reduction in error measure, which describes the relative decrease in the probability of making an error in predicting the value of the response variable when the value of the explanatory variable is known, as opposed to when it is not known. The measure depends on the order of listing the response categories. Examples are shown.

DOI： 10.1080/09720510.2011.10701584

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：WORLD SCIENTIFIC PUBL CO PTE LTD  

For a two-way contingency table with nominal row and column variables, the measures which describe the proportional reduction in variation (PRV) from the marginal distribution of one variable to the conditional distribution given the other variable are proposed by Goodman and Kruskal (1954), Theil (1970), and Freeman (1987, p. 101). Tomizawa, Seo and Ebi (1997), and Miyamoto, Usui and Tomizawa (2005) proposed the generalization of those measures. Tomizawa, Miyamoto and Yajima (2002), and Yamamoto and Tomizawa (2009) proposed the PRV measures for a nominal-ordinal contingency table and for an ordinal-ordinal contingency table, respectively. The present paper (1) reviews these PRV measures and (2) analyzes and compares between several categorical data using these PRV measures.

DOI： 10.1142/9789814343763_0026

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：UNIV TSUKUBA  

For square contingency tables with ordered categories, Agresti (2002) considered the ordinal quasi-symmetry (OQS) model and Iki, Tahata and Tomizawa (2009) considered the ridit score type quasi-symmetry (RQS) model. The present paper proposes measures which represent the degree of departure from each of the OQS and RQS models. The proposed measures are expressed by using the Cressie-Read power-divergence or Patil-Taillie diversity index. These measures would be useful for comparing the degrees of departure from OQS and RQS in several tables. The measures are applied to the data of individual's education and father's or mother's education in Japan.

DOI： 10.5183/jjscs.1008001_190

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUSHPA PUBLISHING HOUSE  

For two-way contingency tables with nominal categories in which the explanatory and response variables are not defined clearly, the present paper proposes a generalized measure which describes the proportional reduction in variation from the marginal distribution of one variable to the conditional distributions of the variable given the value of the other variable. The measure proposed includes measures of forms of harmonic, geometric and arithmetic means. Examples are also given.

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：WORLD SCIENTIFIC PUBL CO PTE LTD  

For the analysis of square contingency tables with same row and column classifications, Stuart (1955) considered the marginal homogeneity model which indicates that the row marginal distribution is identical with the column marginal distribution. Tahata, Iwashita and Tomizawa (2006, 2008) proposed the measure of departure from the marginal homogeneity model for square contingency tables with ordered categories. The present paper (1) reviews these measures and (2) compares between several Japanese social mobility data using these measures.

DOI： 10.1142/9789814304061_0031

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Language：English   Publishing type：Research paper (scientific journal)  

A model is proposed having the structure of both symmetry and quasi-uniform association (SQU model) and provides a decomposition of the SQU model. It is also shown with examples that the test statistic for goodness-of-fit of the SQU model is asymptotically equivalent to the sum of those for the decomposed models. © 2010 JMASM, Inc.

DOI： 10.22237/jmasm/1272687840

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Language：English  

DOI： 10.2174/1876527001001010032

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CENTRE ENVIRONMENT SOCIAL & ECONOMIC RESEARCH PUBL-CESER  

For a two-way table with a nominal explanatory and a nominal response variables, Goodman and Kruskal (1954), and Theil (1970) proposed the measures which describe the proportional reduction in variation (PRV) from the marginal distribution to the conditional distributions of the response. Tomizawa, Seo and Ebi (1997) proposed a generalization of those measures. Tomizawa, Miyamoto and Yajima (2002) proposed a PRV measure for a nominal-ordinal contingency table. Tomizawa and Yukawa (2003) proposed a PRV measure for a square contingency table with ordered categories. First, we propose a PRV measure for a ordinal-ordinal contingency table in which the explanatory and response variables are not defined clearly. The measure proposed is expressed by using Patil-Taillie diversity index including Shannon entropy. Secondly, we propose a measure of degree of agreement for a square contingency table with ordered categories. The proposed measure takes a minimum value zero if and only if the independence between the classifications holds, and a maximum value unity if and only if perfect agreement occurs. The measure is different from the Cohen's Kappa measure. Examples are given.

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Publishing type：Part of collection (book)  

For the analysis of square contingency tables with the same row and column classifications, the symmetry model is applied. This paper (1) reviews the measure for representing the degree of departure from the symmetry and (2) using the measure, compares five sets of social-mobility data on the father’s and son’s occupational status (i) for British in 1954, (ii) for Denmark in 1954, (iii) for Japan in 1955, (iv) for Japan in 1965, and (v) for Japan in 1975.

DOI： 10.1142/9789814273756_0018

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AUSTRIAN STATISTICAL SOC  

For the analysis of square contingency tables, Tomizawa (1994), Tomizawa, Seo, and Yamamoto (1998), and Tomizawa, Miyamoto, and Hatanaka (2001) considered measures to represent the degree of departure from symmetry. However, the maximum value of these measures cannot distinguish two kinds of complete asymmetry (say, complete-upper-asymmetry and complete-lower-asymmetry). The present paper proposes a measure which can distinguish two kinds of complete asymmetry for square tables with ordered categories. Especially the proposed measure is useful for representing the degree of departure from symmetry when the conditional symmetry model holds. Examples are given.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI  

For 2 X 2 X K contingency tables, Tomizawa considered a Shannon entropy type measure to represent the degree of departure from a log-linear model of no three-factor interaction (the NOTFI model). This paper proposes a generalization of Tomizawa's measure for 2 X 2 X K tables. The measure proposed is expressed by using Patil-Taillie diversity index or Cressie-Read power-divergence. A special case of the proposed measure includes Tomizawa's measure. The proposed measure would be useful for comparing the degrees of departure from the NOTFI model in several tables.

DOI： 10.3390/e10040776

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUSHPA PUBLISHING HOUSE  

For square (i.e., two-way) contingency tables with ordered categories, the decomposition of the symmetry model holds into the conditional symmetry and global symmetry models (Read [8]). For three-way contingency tables, Tomizawa [11] considered the conditional symmetry model. For three-way tables with ordered categories, the present paper proposes the global symmetry model and gives the decomposition of the symmetry model into the conditional symmetry and global symmetry models. The present paper also shows that for three-way tables the likelihood ratio statistic for testing goodness-of-fit of symmetry is equal to the sum of those for testing conditional symmetry and global symmetry. The meteorological data are analyzed.

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Publishing type：Part of collection (book)  

For the analysis of square contingency tables, various models of symmetry and asymmetry are proposed by many statisticians. This paper (1) reviews various models and (2) using models, compares four kinds of data on unaided distance vision of (i) men in Britain, (ii) women in Britain, (iii) students in a university of Japan, and (iv) pupils in elementary schools in Tokyo, Japan. This paper also (3) proposes the use of ratio parameter in the conditional symmetry model for comparing the degree of asymmetry in several tables.

DOI： 10.1142/9789812793171_0025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS AS  

For the analysis of square contingency tables with ordered categories, Agresti (1983) considered the linear diagonals-parameter symmetry (LDPS) model being an extension of the symmetry (S) model, which may be appropriate for a square ordinal table if it is reasonable to assume an underlying bivariate normal distribution with equal marginal variances. This paper proposes another extension of the S model which may be appropriate for a square ordinal table if it is reasonable to assume an underlying epsilon-contaminated bivariate normal distribution with equal marginal variances included in the class of elliptical distributions. The proposed model has a structure of weighted mixture of two LDPS models. Moreover, this paper gives a theorem that the S model holds if and only if both the proposed model and the marginal means equality model hold. The simulation studies based on the epsilon-contaminated bivariate normal distribution are given.

DOI： 10.1080/15598608.2008.10411900

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For square contingency tables with ordered categories, Agresti [1] considered the linear diagonals-parameter symmetry (LDPS) model being an extension of the symmetry model. This paper proposes a measure which represents the degree of departure from the LDPS model. The measure proposed is expressed using the Cressie-Read power-divergence or Patil-Taillie diversity index. The measure is useful for comparing the degree of departure from LDPS in several tables, and it may be appropriate for comparing the degrees of departure from the equality of the marginal variances for several square ordinal tables if it is reasonable to assume underlying bivariate normal distributions. Examples are also given. © 2008 IOS Press. All rights reserved.

DOI： 10.3233/MAS-2008-3405

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INST NACIONAL ESTATISTICA-INE  

For the analysis of square contingency tables, Tomizawa and Makii (2001), and Tomizawa, Miyamoto and Ashihara (2003) considered the measures to represent the degree of departure from marginal homogeneity (MH). Tomizawa (1984) considered an extended marginal homogeneity (EMH) model for square tables with ordered categories. This paper proposes a measure to represent the degree of departure from EMH. The measure proposed is expressed by using the Cressie and Read&apos;s (1984) power-divergence or Patil and Taillie&apos;s (1982) diversity index. The measure would be useful for comparing the degree of departure from EMH in several tables. Examples are given.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

For square contingency tables with ordered categories, CAUSSINUS [Annales de la Faculte des Sciences de l'Universite de Toulouse (1965) Vol. 29, pp. 77-182] and AGRESTI [Statistics and Probability Letters (1983) Vol. 1, pp. 313-316] considered the quasi-symmetry and the linear diagonal-parameter symmetry models, respectively, which have multiplicative forms for cell probabilities. This paper proposes two kinds of models that have the similar multiplicative forms for cumulative probabilities that an observation will fall in row (column) category i or below and column (row) category j (&gt; i) or above. The endometrial cancer data are analyzed using these models.

DOI： 10.1111/j.1467-9574.2007.00353.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AUSTRIAN STATISTICAL SOC  

For the analysis of square contingency tables with ordered categories, Tomizawa et al. (2003) considered a measure to represent the degree of departure from marginal homogeneity (MH). Tomizawa (1993) considered an extended marginal homogeneity (EMH) model. This paper (i) proposes a measure to represent the degree of departure from EMH, (ii) proposes a measure from equality of marginal means (E), and (iii) gives a theorem that the value of measure for MH is equal to the sum of the value of measure for EMH and that for E.

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Publishing type：Research paper (scientific journal)  

For square contingency tables with ordered categories, Goodman (1979) considered the diagonals-parameter symmetry model for the cell probabilities. Tomizawa (1993) proposed the cumulative diagonals-parameter symmetry (D) model which has a similar form for cumulative probabilities that an observation will fall in row (column) category i or below and column (row) category j (> i) or above. First, this paper gives another expression of the D model in which the log odds (for the symmetric cumulative probabilities) have polynomial patterns of the distance j - i between the diagonal containing the cutpoint [i and j (> i )] and the main diagonal of the table. Secondly, this paper introduces the cumulative polynomial diagonals-parameter symmetry (C) model which is the parsimonious D model, and the cumulative polynomial diagonal marginal symmetry (M) model. Thirdly, this paper gives the decomposition of the C model into the D and M models.

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Language：English   Publisher：(一社)日本血液学会-東京事務局  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Publisher：Austrian Statistical Society  

<jats:p>For the analysis of square contingency tables with ordered categories, Tomizawa et al. (2003) considered a measure to represent the degree of departure from marginal homogeneity (MH). Tomizawa (1993) considered an extended marginal homogeneity (EMH) model. This paper (i) proposes a measure to represent the degree of departure from EMH, (ii) proposes a measure from equality of marginal means (E), and (iii) gives a theorem that the value of measure for MH is equal to the sum of the value of measure for EMH and that for E.</jats:p>

DOI： 10.17713/ajs.v36i2.325

DOI： 10.14490/jjss.40.097_references_DOI_IpAAJusoqLgwxa8ui4sNuo31CZm

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Publisher：Natural Sciences Publishing  

DOI： 10.12785/jsap/010306

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Other Link： https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24700282/

Publisher：SAGE Publications  

<jats:p> Abtsrcat </jats:p><jats:p> For the square contingency tables with ordered categories, there may be some cases that one wants to analyze them by considering collapsed tables with some adjacent categories combined in the original table. This paper considers some symmetry models for collapsed square contingency tables and proposes two new models which have the structure of global symmetry and that of quasi-symmetry for the collapsed square tables. Also this paper gives two kinds of decompositions of the symmetry model for collapsed square tables. The new models and decompositions are useful for analyzing the collapsed square tables. Examples are given. </jats:p>

DOI： 10.1177/0008068320120102

DOI： 10.1080/02664763.2014.993362_references_DOI_1B30na1CFQs0KKi3Vo35hEIm1m0

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Language：English   Publisher：Japanese Society of Computational Statistics  

For square contingency tables with ordered categories, Tomizawa, Miyamoto and Hatanaka (2001) considered a measure that represents the degree of departure from symmetry. This paper extends the measure to multi-way tables with ordered categories. The measure proposed is expressed by using the Cressie-Read power-divergence or the Patil-Taillie diversity index. The measure could be useful for comparing the degrees of departure from symmetry in several multi-way tables with ordered categories. Examples are given.

DOI： 10.5183/jjscs1988.20.39

DOI： 10.14490/jjss.40.097_references_DOI_JXdOX45lwTiSSHeuayItOj4dyME

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