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Background Tranexamic acid (TXA) reduces surgical bleeding and reduces death from bleeding after trauma and childbirth. However, its effects on thrombotic events and seizures are less clear. We conducted a systematic review and meta-analysis to examine the safety of TXA in bleeding patients. Methods For this systematic review and meta-analysis, we searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled trials from inception until June 1, 2020. We included randomized trials comparing intravenous tranexamic acid and placebo or no intervention in bleeding patients. The primary outcomes were thrombotic events, venous thromboembolism, acute coronary syndrome, stroke and seizures. A meta-analysis was performed using a random effects model and meta-regression analysis was performed to evaluate how effects vary by dose. We assessed the certainty of evidence using the grading of recommendations, assessment, development and evaluations (GRADE) approach. Results A total of 234 studies with 102,681 patients were included in the meta-analysis. In bleeding patients, there was no evidence that TXA increased the risk of thrombotic events (RR = 1.00 [95% CI 0.93–1.08]), seizures (1.18 [0.91–1.53]), venous thromboembolism (1.04 [0.92–1.17]), acute coronary syndrome (0.88 [0.78–1.00]) or stroke (1.12 [0.98–1.27]). In a dose-by-dose sensitivity analysis, seizures were increased in patients receiving more than 2 g/day of TXA (3.05 [1.01–9.20]). Meta-regression showed an increased risk of seizures with increased dose of TXA ( p  = 0.011). Conclusion Tranexamic acid did not appear to increase the risk of thrombotic events in bleeding patients. However, because there may be dose-dependent increase in the risk of seizures, very high doses should be avoided.

IntroductionTranexamic acid (TXA) is a synthetic derivative of the amino acid lysine that inhibits fibrinolysis by blocking lysine-binding sites on plasminogen, which contribute to reduced bleeding, the need for transfusion and mortality. Although there is reliable evidence of the efficacy of TXA, its effects on other important outcomes, adverse events, including thrombotic events and seizure, remain uncertain.Methods and analysisWe will conduct a systematic review and meta-analysis of randomised controlled trials with the objective of evaluating the incidence of thrombotic adverse events and seizure and how the effect of TXA varies by dose and underlying disease. We will include patients with bleeding in any underlying disease. We will search MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials for randomised controlled trials. The planned date of our systematic search is 1 June 2020. We will follow the recommendations of the Cochrane Collaboration and the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. Subgroup and sensitivity analyses will be performed to explore residual heterogeneity and inconsistency. Meta-regression analysis will be carried out to investigate the association between the incidence of adverse events and the TXA dose. The risk of systematic errors (bias) and random errors will be assessed and the overall quality of evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach.Ethics and disseminationThis study will not involve primary data collection, and formal ethics approval will therefore not be required. We aim to publish this systematic review in a peer-review journal.Trial registration numberUMIN000039611.

Barley accumulates proanthocyanidins (PA), a type of flavonoid compound, in the testa layer. The accumulated PA have a detrimental effect on the quality of beer and pearled barley. Therefore, controlling PA accumulation in the testa layer is an important breeding objective in barley. PA accumulation is regulated by a ternary complex consisting of MYB, basic helix–loop–helix (bHLH), and WD40 transcription factors (MBW complex) in various plant species. The MBW complex regulates the transcription of structural genes encoding enzymes in the flavonoid biosynthesis pathway. Although HvMYB10 and HvWD40‐1 have been identified as regulators of PA accumulation in the barley testa layer, the bHLH transcription factor regulating it remains unclear. In this study, we isolated a novel PA‐defective mutant, TK113, using sodium azide mutagenesis. Expression analysis revealed that the expression levels of multiple structural genes decreased in the seed coat of TK113. Single nucleotide polymorphism (SNP)‐index analysis with a candidate gene approach identified a mutation causing amino acid substitution in HvTT8, which encodes the bHLH transcription factor, of TK113 associated with the PA‐defective phenotype. The mutation was located in a highly conserved domain among TT8 orthologs, indicating that it is the most likely causal mutation for the PA‐defective phenotype of TK113.

Background Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium–glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity. Methods This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency–to–high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT. Results Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was – 0.57 and – 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed. Conclusions This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events. Trial Registration: The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442 .

Abstract Background First-line chemotherapy with maintenance therapy is expected to be well-tolerated and improve survival in patients with metastatic colorectal cancer (mCRC). This study evaluated the efficacy and safety of trifluridine/tipiracil (TAS-102) plus bevacizumab (Bev) as maintenance therapy for mCRC, omitting both oxaliplatin and fluoropyrimidines. Materials and Methods Patients with untreated mCRC initially received induction chemotherapy with fluoropyrimidine, oxaliplatin plus bevacizumab for 3-4 months. After achieving stable disease or better on imaging, 52 patients transitioned to maintenance therapy with TAS+Bev: TAS-102 (35 mg/m2, twice daily on days 1-5 and 8-12) plus Bev (5.0 mg/kg on Days 1 and 15, intravenously). Progression-free survival 1 (PFS1), defined as the time from the start of maintenance therapy to disease progression or death, was evaluated as the primary endpoint. Results The median cumulative dose of oxaliplatin during induction was 529 mg/m2. Median PFS1 during TAS+Bev maintenance was 8.7 months (95% CI: 5.5-12.3). The response rate and disease control rate during maintenance were 59.6% and 94.2%, respectively. Oxaliplatin reintroduction was feasible in 53.8% (28/52) of patient with a median total first-line chemotherapy duration was 16.2 months (95% CI: 14.5-20.6). Safety outcomes, including dose intensity and adverse events, were acceptable. Conclusion This strategy of switching to first-line maintenance therapy with TAS+Bev demonstrated promising efficacy and safety. This strategy effectively avoided cumulative neurotoxicity, preserved quality of life and enabled reintroduction of oxaliplatin, suggesting it may represent a promising alternative strategy for patients ineligible for prolonged oxaliplatin-based treatment. Overall survival analysis is currently ongoing. [UMIN Trial ID: UMIN000031317]

This phase II study (MCSGO-1202) aimed to evaluate the initial dose reduction of oxaliplatin in XELOX plus bevacizumab therapy. This was a phase II, multicenter, open-label, single-arm, prospective, study conducted at 14 Japanese institutions. The study included patients with metastatic colorectal cancer (mCRC) with performance status (PS) of 1 or 2 who had not undergone chemotherapy. Patients received oxaliplatin (100 mg/m ) plus bevacizumab (7.5 mg/kg) on day 1 and capecitabine (2,000 mg/m2/day) on days 1-14 of a 21-day cycle. The primary endpoint was the objective response rate. The secondary endpoints were progression-free and overall survival, 1-year survival rate, disease control rate, dose intensity, and adverse events. Between April 2012 and March 2016, 56 patients were enrolled. The median age was 71 years (range=44-85 years), and the majority (90.6%) had a PS of 1. A complete response was observed in three patients (5.7%), partial response in 24 (45.3%), stable disease in 22 (43.4%), and progressive disease in one (1.9%). The median progression-free survival and overall survival were 11.4 and 26.5 months, respectively. The most common grade 3-4 adverse events were leucopenia (15.1%), neutropenia (9.4%), neuropathy (9.4%). The dose-reduction strategy of oxaliplatin was effective for elderly or vulnerable patients with mCRC.

We aimed to compare longitudinal brain atrophy in patients with neuromyelitis optica spectrum disorder (NMOSD) with healthy controls (HCs). The atrophy rate in patients with anti-aquaporin-4 antibody-positive NMOSD (AQP4 + NMOSD) was compared with age-sex-matched HCs recruited from the Japanese Alzheimer’s Disease Neuroimaging Initiative study and another study performed at Chiba University. Twenty-nine patients with AQP4 + NMOSD and 29 HCs were enrolled in the study. The time between magnetic resonance imaging (MRI) scans was longer in the AQP4 + NMOSD group compared with the HCs (median; 3.2 vs. 2.9 years, P  = 0.009). The annualized normalized white matter volume (NWV) atrophy rate was higher in the AQP4 + NMOSD group compared with the HCs (median; 0.37 vs. − 0.14, P  = 0.018). The maximum spinal cord lesion length negatively correlated with NWV at baseline MRI in patients with AQP4 + NMOSD (Spearman’s rho =  − 0.41, P  = 0.027). The annualized NWV atrophy rate negatively correlated with the time between initiation of persistent prednisolone usage and baseline MRI in patients with AQP4 + NMOSD (Spearman’s rho =  − 0.43, P  = 0.019). Patients with AQP4 + NMOSD had a greater annualized NWV atrophy rate than HCs. Suppressing disease activity may prevent brain atrophy in patients with AQP4 + NMOSD.

Background: We previously conducted a genome-wide linkage analysis of Japanese nuclear families affected with prostate cancer and showed that the susceptibility to prostate cancer was closely linked to D8S550 at 8p23. The role of farnesyl diphosphate farnesyltransferase ( FDFT1 ), which is located under the peak marker D8S550 at 8p23, and squalene synthase, the enzyme encoded by FDFT1 , in prostate cancer was studied. Methods: The association among common variants of FDFT1 with prostate cancer risk, the promoter activities of FDFT1 with different genotypes and the effects of inhibition of squalene synthase were studied, and the FDFT1 transcript levels of human prostate samples were quantified. Results: The A allele of rs2645429 was significantly associated with prostate cancer risk in a Japanese familial prostate cancer population. Rs2645429 was located in the promoter region of FDFT1 , and the AA genotype showed significantly increased promoter activity. The knockdown of FDFT1 mRNA expression or squalene synthase inhibition led to a significant decrease in prostate cancer cell proliferation. Additionally, human prostate cancer specimens expressed significantly higher levels of FDFT1 mRNA compared with noncancerous specimens. Finally, aggressive cancers showed higher transcript levels. Conclusions: FDFT1 and its encoded enzyme, squalene synthase, may play an important role in prostate cancer development and its aggressive phenotypes.

Aims Risk‐scoring systems for colorectal liver metastasis (CRLM) after hepatectomy allow prognoses to be predicted preoperatively. We investigated the clinical outcomes of neoadjuvant chemotherapy for resectable CRLM according to patient risk status, aiming to determine the subgroup of patients who could benefit from neoadjuvant chemotherapy. Methods In this multi‐institutional retrospective analysis, the preoperative risk score was calculated from six previously reported factors: synchronous metastases, primary lymph node positivity, tumor number, largest tumor diameter, extrahepatic metastasis, and the preoperative carbohydrate antigen 19–9 level. Patients were divided into three groups according to their risk scores: low risk (score = 0), intermediate risk (score 1–10), and high risk (score ≥11). Overall and recurrence‐free survival curves were calculated using the Kaplan–Meier method. After propensity‐score matching in the intermediate‐risk group, we compared clinicopathological features and outcomes. Results There were 318 cases, from 20 institutions. The preoperative risk score could be calculated in 277 cases. There were 34, 192, and 51 patients in the low‐, intermediate‐, and high‐risk groups, respectively. Intermediate‐risk group patients who received neoadjuvant chemotherapy had significantly better recurrence‐free survival than that of patients without neoadjuvant chemotherapy (P = .0453). After propensity‐score matching in the intermediate‐risk group, the recurrence‐free survival rate was better in patients who received neoadjuvant chemotherapy (P = .0261). But the overall survival rate was not improved after the matching. Conclusion Neoadjuvant chemotherapy for resectable CRLM might prolong the recurrence‐free survival period for intermediate‐risk patients with preoperative risk scores in the range of 1–10, but the overall survival was not improved by neoadjuvant chemotherapy. Neoadjuvant chemotherapy for resectable CRLM might prolong the recurrence‐free survival period for intermediate‐risk patients with preoperative risk scores in the range of 1‐10.

Sulfation is a key pathway in xenobiotic metabolism and chemical defense, and phenol sulfotransferase SULT1A1 plays a central role in this reaction. Genetic polymorphism of the SULT1A1 gene, SULT1A1, was reported to be associated with risks of several cancers; however, one study showed no significant relation between SULT1A1 genotype with prostate cancer risk. The present study was conducted to confirm the association of a G638A polymorphism, Arg213His, in SULT1A1 with familial prostate cancer risk in a Japanese population. A case–control study consisting of 126 cases and 119 controls was performed. In controls, GG, GA, and AA genotypes were observed in 85 (71.4%), 32 (26.9%), and 2 (1.7%), respectively; whereas, GG, GA, and AA genotypes were observed in 94 (74.6%), 32 (25.4%), and 0 cases, respectively. No significant differences were found in genotypic frequencies among cases and controls. Furthermore, stratification of cases according to clinical stages (localized or metastatic), pathological grades (Gleason score <7, or >7), age at diagnosis (<70 years or >70) and the number of affected relatives (2 or >2) did not show any significant differences among categories. These findings suggested that genetic polymorphism of SULT1A1 might not be involved in genetic susceptibility to prostate cancer.