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Abstract Background and Aims Hemophilia was diagnosed in precedence research of clot waveform analysis (CWA) using the activated partial thromboplastin time (APTT). In patients with antiphospholipid syndrome (APS), lupus anticoagulant (LA) causes an increase in APTT, suggesting that the waveform would probably be distorted. Therefore, we evaluated using clinical samples. CWA may be useful low cost for clinical detection of LA. We assessed the clinical value of CWA for detection of LA and coagulation using clinical blood samples collected from patients with a prolonged APTT. Methods We used patient samples inspected between April 2011 and March 2013 in Yamagata University Hospital. CWA was performed using the ACL TOP coagulation analyzer, and the associated software program was used to calculate APTT clotting endpoints. An atypical peak was defined as a derivative plot that did not conform to the normal S‐shaped clot reaction curve. Results In total, 162 patients, including 66 men and 96 women, with an average age of 46 years (range: 24‐89 years) were included. We also collected control samples from unmatched healthy donors. All 162 patients were divided according to medication history or condition into the following five groups: heparin (n = 20), warfarin (n = 23), hepatic dysfunction (n = 13), normal (n = 20), and LA‐positive antiphospholipid syndrome (APS; n = 86). Twenty healthy individuals were included as controls. Eighty patients had an atypical peak. Among all, 78 patients (90.6%) were LA‐positive, and 2 patients (2.5%) were treated with warfarin. The remaining two patients had prothrombin time international normalized ratios (PT‐INR) >4.0 while taking warfarin. Those who were APS LA positive with thrombosis and without thrombosis had split the reaction of clotting time, deceleration/acceleration time (D/A) ratio of 2.36 (1.99,3.24) vs 2.34 (2.04,2.86), respectively. Conclusion The significant atypical peak and D/A ratio extension may be explained by the clotting waveforms observed specifically in patients with LA‐positive APS.

Abstract Background Maternally inherited diabetes and deafness (MIDD), a mitochondrial genetic disorder, typically affects the kidneys and results in end-stage renal disease. Early diagnosis of MIDD is challenging when renal manifestations precede other key clinical features such as diabetes and deafness and/or when the disease is complicated by other renal pathologies. Case presentation Here, we present the case of a 33-year-old Japanese woman who had initially been diagnosed with IgA nephropathy but was found to have MIDD 6 years later. Two renal biopsies were conducted six years apart. While assessment of the first biopsy specimen with the monoclonal antibody (KM55) revealed mesangial IgA deposits (containing the galactose-deficient IgA1 variant [Gd-IgA1]), examination of the second specimen showed no mesangial IgA deposits and newly-developed glomerular global scleroses and tubular damage. Granular swollen epithelial cells (GSECs), characterised by abnormal mitochondria, were observed among the tubules and collecting ducts in both biopsy specimens. Mitochondrial DNA analysis revealed an m.3243A > G mutation. Conclusions We rediscovered the usefulness of GSECs as a pathologically distinctive feature of mitochondrial nephropathy and reviewed the literature regarding MIDD complicated by mesangial IgA deposition. Furthermore, we demonstrate that the mesangial IgA deposits in this patient consisted of the galactose-deficient IgA1 variant. The monoclonal antibody (KM55) might be a useful tool to distinguish IgAN from latent IgA deposits.

Background: The mean 5-6-month survival after failed standard chemotherapy for metastatic colorectal cancer (mCRC) necessitates more effective treatments for refractory mCRC. For untreated mCRC, S-1 + oral leucovorin (SL) therapy offers promising results without severe toxicity. The ML18147 trial demonstrated that bevacizumab (Bev) prolongs overall survival after mCRC progression. We conducted a single-centre phase-II trial to evaluate the safety and efficacy of SL/Bev combination chemotherapy as mCRC salvage therapy. Methods: Major eligibility criteria were confirmed adenocarcinoma diagnosis; age >20 years; Eastern Cooperative Oncology Group performance status, 0-2; and progression after administration/intolerance of/to approved drugs for mCRC. (5-FU, oxaliplatin, irinotecan, Bev, and anti-EGFR antibody, if KRAS wild-type). S-1 (80-120 mg/body) and leucovorin (25 mg) were orally administered in a 1-week-on/1-week-off schedule. Bev (5 mg/kg) was administered on day 1 of every 2-week cycle. The primary endpoint was disease control rate (DCR). Results: A total of 31 patients were enrolled. DCR was 65% [95% confidence interval (CI), 48-100%] and the response rate was 7% (95% CI, 0.7-22%). One patient showing partial response to SL/Bev had a BRAF-mutant tumor. Median progression-free survival and overall survivals were 5.3 [95% CI, 2.1-9.3] and 9.9 [95% CI, 7.4-NA] months, respectively. The most-frequent grade-3/4 adverse events were mucositis (26%) and diarrhea (11%), which were manageable by dose reduction/interruption. Conclusions: SL/Bev showed impressive activity in refractory mCRC and was tolerable, suggesting its potential as an alternative chemotherapy for refractory mCRC. [ABSTRACT FROM AUTHOR]

Introduction: The effects of first-line single-agent chemotherapy on overall survival (OS) might be confounded by subsequent treatments in elderly patients with nonsmall cell lung cancer (NSCLC). We, therefore, aimed to evaluate whether progression-free survival (PFS), postprogression survival (PPS), or tumor response might be a valid surrogate endpoint for OS in this patient population.Patients and Methods: We retrospectively reviewed the clinical data of 58 elderly patients with advanced NSCLC, who received first-line single-agent cytotoxic chemotherapy at our institution between October 2003 and November 2013. The relationships of PFS, PPS, and tumor response with OS were individually analyzed.Results: The study cohort included 46 men and 12 women with a median age of 79 years (range: 75-87 years). There were 30 adenocarcinomas, 22 squamous cell carcinomas, and 6 other histologic types with 1 stage IIIA, 9 IIIB, and 48 IV cases. The performance status (PS) scores were 0, 1, and 2 in 18, 35, and 5 patients, respectively. The median PFS and OS were 2.8 and 5.4 months, respectively. Our analyses revealed a strong correlation of PPS and PFS with OS, whereas that between tumor shrinkage and OS was weak. Tumor stage and PS after initial treatment were significantly associated with PPS. Individual analysis indicated that PPS might serve as a surrogate for OS in elderly patients with advanced NSCLC receiving first-line single-agent chemotherapy.Conclusion: Our findings suggested that the disease course after progression following first-line single-agent chemotherapy might influence the OS of elderly patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

The effects of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with small cell lung cancer (SCLC). We examined whether progression-free survival (PFS), post-progression survival (PPS), and tumor response could be valid surrogate endpoints for OS after first-line chemotherapies for patients with extensive SCLC using individual-level data. METHODS: Between September 2002 and November 2012, we analyzed 49 cases of patients with extensive SCLC who were treated with cisplatin and irinotecan as first-line chemotherapy. The relationships of PFS, PPS, and tumor response with OS were analyzed at the individual level. RESULTS: Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r = 0.97, p < 0.05, R2 = 0.94), PFS was moderately correlated with OS (r = 0.58, p < 0.05, R2 = 0.24), and tumor shrinkage was weakly correlated with OS (r = 0.37, p < 0.05, R2 = 0.13). The best response to second-line treatment, and the number of regimens employed after progression beyond first-line chemotherapy were both significantly associated with PPS (p ≤ 0.05). CONCLUSION: PPS is a potential surrogate for OS in patients with extensive SCLC. Our findings also suggest that subsequent treatment after disease progression following first-line chemotherapy may greatly influence OS. [ABSTRACT FROM AUTHOR]

Background: Despite considerable recent progress in the treatment of lung adenocarcinoma, there has been little progress in the development of efficacious molecular targeted therapies for squamous cell lung cancer. In addition to the recent comprehensive genome-wide characterization of squamous cell lung cancer, it is also important to genotype this form of cancer. We therefore conducted the Shizuoka Lung Cancer Mutation Study to analyze driver mutations in patients with thoracic malignancies. Here we report the results of genotyping in patients with squamous cell lung cancer. Methods: Based on the biobanking system, in conjunction with the clinic and pathology lab, we developed a genotyping panel designed to assess 24 mutations in 10 genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, HER2 and DDR2), EGFR, MET, PIK3CA, FGFR1 and FGFR2 copy numbers, and EML4-ALK and ROS1 translocations, using pyrosequencing plus capillary electrophoresis, quantitative polymerase chain reaction (PCR) and reverse-transcription PCR, respectively. Results: A total of 129 patients with squamous cell lung cancer and adenosquamous carcinoma were enrolled in this study between July 2011 and November 2012. We detected genetic alterations in 40% of all cases. Gene alterations included: EGFR mutations, 6%; KRAS mutations, 4%; PIK3CA mutations, 13%; NRAS mutations, 1%; KIF5b-RET fusion gene, 1%; EGFR copy number gain, 5%; PIK3CA copy number gain, 15%; and FGFR1 copy number gain, 5%. Twelve patients (9%) harbored simultaneous genetic alterations. Genetic alterations were detected more frequently in surgically-resected, snap-frozen samples than in formalin-fixed, paraffin-embedded samples (50% vs. 29%). In addition, patients aged ≤70 years old and never-smokers showed high frequencies of genetic alterations. Conclusions: This study represents one of the largest prospective tumor-genotyping studies to be performed in Asian patients with squamous cell lung cancer. These results suggest that incorporation of genetic profiling into lung cancer clinical practice may facilitate the administration of personalized cancer treatments in patients with squamous cell lung cancer. [ABSTRACT FROM AUTHOR]

Background: Non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) need to be approached carefully given the high incidence of pulmonary toxicity. Pemetrexed (PEM) is the key drug for the treatment of NSCLC. However, its safety, especially with respect to the exacerbation of ILD, and efficacy in NSCLC patients with ILD have yet to be established. Method: We investigated the safety and efficacy of PEM monotherapy in NSCLC patients with or without idiopathic interstitial pneumonia (IIPs). The medical charts of these patients were retrospectively reviewed. Results: Twenty-five patients diagnosed as having IIPs (IIPs group) and 88 patients without ILD (non-ILD group) were treated with PEM monotherapy at Juntendo University Hospital between 2009 and 2013. In the IIPs group, 12 patients were found to have usual interstitial pneumonitis (UIP) on chest computed tomography (CT) (UIP group) and the other 13 patients showed a non-UIP pattern on chest CT (non-UIP IIPs group). Three patients in the IIPs group (2 in the UIP group and 1 in the non-UIP IIPs group) and 1 in the non-ILD group developed pulmonary toxicity during treatment (3.5% overall, 12.0% in the IIPs group versus 1.1% in the non-ILD group). Moreover, all 3 patients in the IIPs group died of pulmonary toxicity. Overall survival tended to be longer in the non-ILD group than in the IIPs group (p = 0.08). Multivariate analyses demonstrated that IIPs was the only significant independent risk factor for PEM-related pulmonary toxicity. Conclusion: We found that the incidence of PEM-related pulmonary toxicity was significantly higher amongst NSCLC patients with IIPs than among those without IIPs. Particular care must be taken when administering PEM to treat NSCLC patients with IIPs. [ABSTRACT FROM AUTHOR]

Background: Serum CYFRA 21-1 is one of the most important serum markers in the diagnosis of non-small cell lung cancer (NSCLC), especially squamous-cell carcinoma. However, it remains unknown whether pretreatment serum CYFRA 21-1 values (PCV) may also have prognostic implications in patients with advanced lung adenocarcinoma.Methods: We retrospectively reviewed the data of 284 patients (pts) who were diagnosed as having advanced lung adenocarcinoma and had received initial therapy.Results: Of the study subjects, 121 pts (43%) had activating epidermal growth factor receptor (EGFR) mutations (Mt+), while the remaining 163 pts (57%) had wild-type EGFR (Mt-). Univariate analysis identified gender (male/ female), ECOG performance status (PS) (0-1/ ≥2), PCV (<2.2 ng/ml/ ≥2.2 ng/ml), EGFR mutation status (Mt+/ Mt-), pretreatment serum CEA values (<5.0 ng/ml/ ≥5.0 ng/ml), smoking history (yes/ no) and EGFR-TKI treatment (yes/ no) as prognostic factors (p = .008, p < .0001, p < .0001, p < .0001, p = .036, p = .0012, p < .0001 respectively). Cox's multivariate regression analysis identified PCV < 2.2ng/ml as the only factor significantly associated with prolonged survival (p < .0001, hazard ratio: 0.43, 95% CI 0.31-0.59), after adjustments for PS (p < .0001), EGFR mutation status (p = .0069), date of start of initial therapy (p = .07), gender (p = .75), serum CEA level (p = .63), smoking history (p = .39) and EGFR-TKI treatment (p = .20). Furthermore, pts with Mt+ and PCV of <2.2 ng/ml had a more favorable prognosis than those with Mt+ and PCV of ≥2.2 ng/ml (MST: 67.0 vs. 21.0 months, p < .0001), and patients with Mt- and PCV of <2.2 ng/ml had a more favorable prognosis than those with Mt- and PCV of ≥2.2 ng/ml (MST: 24.1 vs. 10.2 months, p < .0001).Conclusion: PCV may be a potential independent prognostic factor in both Mt+ and Mt- patients with advanced lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Abstract This document is an executive summary of the APSIC Guide for Prevention of Central Line Associated Bloodstream Infections (CLABSI). It describes key evidence-based care components of the Central Line Insertion and Maintenance Bundles and its implementation using the quality improvement methodology, namely the Plan-Do-Study-Act (PDSA) methodology involving multidisciplinary process and stakeholders. Monitoring of improvement over time with timely feedback to stakeholders is a key component to ensure the success of implementing best practices. A surveillance program is recommended to monitor outcomes and adherence to evidence-based central line insertion and maintenance practices (compliance rate) and identify quality improvement opportunities and strategically targeting interventions for the reduction of CLABSI.

A pituitary adenylate cyclase-activating polypeptide (PACAP)-specific receptor, PAC1R, is coupled with multiple signal transduction pathways including stimulation of adenylate cyclase, phospholipase C and extracellular-signal regulated kinase (ERK)1/2. PAC1R has been shown to exert its long-lasting and potent signals via β-arrestin1 and β-arrestin2. However, the precise roles of the two β-arrestin isoforms in PACAP-PAC1R signaling remain unclear. Here we examined the interaction between the two β-arrestin isoforms and PAC1R, β-arrestin-dependent PAC1R subcellular localization and ERK1/2 activation. Upon PACAP stimulation, although PAC1R similarly interacted with β-arrestin1 and β-arrestin2 in HEK293T cells, the complex of PAC1R and β-arrestin2 was translocated from the cell surface into cytosol, but that of β-arrestin1 remained in the cell surface regions in HeLa cells and mouse primary cultured neurons. Silencing of β-arrestin2 blocked PACAP-induced PAC1R internalization and ERK1/2 phosphorylation, but silencing of β-arrestin1 increased ERK1/2 phosphorylation. These results show that β-arrestin1 and β-arrestin2 exert differential actions on PAC1R internalization and PAC1R-dependent ERK1/2 activation, and suggest that the two β-arrestin isoforms may be involved in fine and precise tuning of the PAC1R signaling pathways.

INTRODUCTION: Underwater endoscopic mucosal resection (UEMR) and cold snare polypectomy (CSP) are novel endoscopic procedures for superficial nonampullary duodenal epithelial tumors (SNADET). However, consensus on how to use both procedures appropriately has not been established. In this study, we evaluated treatment outcomes of both procedures, including resectability. METHODS: In this single-center randomized controlled study conducted between January 2020 and June 2022, patients with SNADET £12 mm were randomly allocated to UEMR and CSP groups. The primary end point was sufficient vertical R0 resection (SVR0), which was defined as R0 resection including a sufficient submucosal layer. We compared treatment outcomes including SVR0 rate between groups. RESULTS: The SVR0 rate was significantly higher in theUEMRgroup than in the CSP group (65.6% vs 41.5%, P5 0.01). By contrast, theR0resection rate was not significantly different between study groups (70.3% vs 61.5%, P50.29). The submucosal layer thickness was significantly greater in theUEMR group than in the CSP group (median 546 [range, 309--833] mm vs 69 [0--295] mm, P < 0.01). CSP had a shorter total procedure time (median 12 [range, 8--16] min vs 1 [1--3] min, P < 0.01) and fewer total bleeding events (9.4% vs 1.5%, P 5 0.06). DISCUSSION: UEMR has superior vertical resectability compared with CSP, but CSP has a shorter procedure time and fewer bleeding events. Although CSP is preferable for most small SNADET, UEMR should be selected for lesions that cannot be definitively diagnosed as mucosal low-grade neoplasias. [ABSTRACT FROM AUTHOR]

Sexually dimorphic brain development and behavior are known to be influenced by sex hormones exposure in prenatal periods. On the other hand, second-to forth digit ratio (2D/4D) has been used as an indirect method to investigate the putative effects of prenatal exposure to androgen. In the present study, we herein investigated the relationship between gender-role play behavior and the second-to-fourth digit ratio (2D/4D), which has been used as an indirect method to investigate the putative effects of prenatal exposure to androgens, in school-aged children. Among 4981 children who became 8 years old by November 2014 and were contactable for this survey by The Hokkaido Study of Environment and Children's Health, 1631 (32.7%), who had data for 2D/4D and Pre-school Activities Inventory (PSAI) as well as data for the survey at baseline, were available for analysis. Parents sent reports of PSAI on the sex-typical characteristics, preferred toys, and play activities of children, and black and white photocopies of the left and right hand palms via mail. PSAI consisted of 12 masculine items and 12 feminine items, and a composite score was created by subtracting the feminine score from the masculine score, with higher scores representing masculine-typical behavior. While composite scores in PSAI were significantly higher in boys than in girls, 2D/4D was significantly lower in boys than in girls. Although the presence or absence of brothers or sisters affected the composite, masculine, and feminine scored of PSAI, a multivariate regression model revealed that 2D/4D negatively correlated with the composite scores of PSAI in boys, whereas no correlation was found in girls. Although 2D/4D negatively correlated with the masculine score in boys and girls, no correlation was observed between 2D/4D and the feminine score. In conclusion, although social factors, such as the existence of brother or sisters, affect dimorphic brain development and behavior in childhood, the present study revealed that the prenatal hormonal environment was an important factor influencing masculine-typical dimorphic brain development and behavior in school-aged children.

The purpose of the study is to design a woody biomass energy system and application to coal co-firing, and to evaluate the system considering the three dimensions of energy, economic, and environmental impact. The study targets five types of woody biomass; forest wood residues, forest thinnings, sawmill wood residues, construction wastes and pruned branches of fruit trees. The system contains of collecting of biomass, transporting raw materials, producing wood fuels, transporting wood fuels, and coal co-firing. The study evaluates six cases that differ in wood fuel production location and the type of wood fuel. The results of case study show that the potential of the biomass resource is 37 PJ/year and the availability is 3.6 PJ/year in Tohoku area. The case that pellets produced at the resource generation points has the lowest amount of energy consumption 0.9 PJ/year, wood fuel supply cost 3.2 JPY/MJ and CO2 emissions 0.66×103 t-CO2/year. It is also obtained that the drying process and transportation process have dominant effect on energy consumption and cost.

Prenatal sex hormones can induce abnormalities in the reproductive system and adversely impact on genital development. We investigated whether sex hormones in cord blood influenced the ratio of the second to fourth digit lengths (2D/4D) in school-aged children. Of the 514 children who participated in a prospective cohort study on birth in Sapporo between 2002 and 2005, the following sex hormone levels were measured in 294 stored cord blood samples (135 boys and 159 girls); testosterone (T), estradiol (E), progesterone, LH, FSH, inhibin B, and insulin-like factor 3 (INSL3). A total of 350 children, who were of school age and could be contacted for this survey, were then requested via mail to send black-and-white photocopies of the palms of both the left and right hands. 2D/4D was calculated in 190 children (88 boys and 102 girls) using photocopies and derived from participants with the characteristics of older mothers, a higher annual household income, higher educational level, and fewer smokers among family members. 2D/4D was significantly lower in males than in females (p

INTRODUCTION: One-piece endoscopic mucosal resection (EMR) for lesions >15 mm is still unsatisfactory, and attempted 1-piece EMR for lesions >25 mm can increase perforation risk. Therefore, modifications to ensure 1-piece EMR of 15- to 25-mm lesions would be beneficial. The aim of this study was to investigate whether Tip-in EMR, which anchors the snare tip within the submucosal layer, increases en bloc resection for 15- to 25-mm colorectal lesions compared with EMR. METHODS: In this prospective randomized controlled trial, patients with nonpolypoid colorectal neoplasms of 15-25 mm in size were recruited and randomly assigned in a 1:1 ratio to undergo Tip-in EMR or standard EMR, stratified by age, sex, tumor size category, and tumor location. The primary endpoint was the odds ratio of en bloc resection adjusted by location and size category. Adverse events and procedure time were also evaluated. RESULTS: We analyzed 41 lesions in the Tip-inEMRgroup and 41 lesions in theEMRgroup. En bloc resection was achieved in 37 (90.2%) patients undergoing Tip-in EMR and 30 (73.1%) who had EMR. The adjusted odds ratio of en bloc resection in Tip-in EMR vs EMR was 3.46 (95% confidence interval: 1.06-13.6, P = 0.040). The Tip-in EMR and EMR groups did not differ significantly in adverse event rates (0%vs 4.8%) or median procedure times (7 vs 5 minutes). DISCUSSION: In this single-center randomized controlled trial, we found that Tip-in EMR significantly improved the en bloc resection rate for nonpolypoid lesions 15-25 mm in size, with no increase in adverse events or procedure time. [ABSTRACT FROM AUTHOR]