Tranexamic acid and blood loss in pancreaticoduodenectomy: TAC-PD randomized clinical trial.

BACKGROUND: Tranexamic acid (TXA) may reduce intraoperative blood loss, but it has not been investigated in pancreaticoduodenectomy (PD). METHODS: A pragmatic, multicentre, randomized, blinded, placebo-controlled trial was conducted. Adult patients undergoing planned PD for biliary, duodenal, or pancreatic diseases were randomly assigned to TXA or placebo groups. Patients in the TXA group were administered 1 g TXA before incision, followed by a maintenance infusion of 125 mg/h TXA. Patients in the placebo group were administered the same volume of saline as those in the placebo group. The primary outcome was blood loss during PD. The secondary outcomes included perioperative blood transfusions, operating time, morbidity, and mortality. RESULTS: Between September 2019 and May 2021, 218 patients were randomly assigned and underwent surgery (108 in the TXA group and 110 in the placebo group). Mean intraoperative blood loss was 659 ml in the TXA group and 701 ml in the placebo group (mean difference -42 ml, 95 per cent c.i. -191 to 106). Of the 218 patients, 202 received the intervention and underwent PD, and the mean blood loss during PD was 667 ml in the TXA group and 744 ml in the placebo group (mean difference -77 ml, 95 per cent c.i. -226 to 72). The secondary outcomes were comparable between the two groups. CONCLUSION: Perioperative TXA use did not reduce blood loss during PD. REGISTRATION NUMBER: jRCTs041190062 (https://jrct.niph.go.jp).

Removing part of the pancreas is an operation with a risk of major blood loss. Tranexamic acid is a drug thought to reduce blood loss. This study asked the question, 'Does tranexamic acid reduce blood loss during surgery on the pancreas?' Half of patients received tranexamic acid during surgery. The other half received only standard care. This study showed that tranexamic acid did not decrease the blood loss during the surgery and may have little effect in patients having a pancreaticoduodenectomy.

Impact of chest subcutaneous fat on the occurrence of central venous port-related infectious complications in cancer patients.

PURPOSE: There is no concrete evidence to support the association between the amount of subcutaneous fat area (SFA) in the central venous port-insertion site (precordium) and port-related complications. We aimed to investigate the relationship between SFA in the midclavicular line and postoperative infectious complications in patients undergoing port-insertion surgery. METHODS: This was a single-institute and historical cohort study of 174 patients who underwent first central venous port implantation surgery for chemotherapy between January 2014 and December 2018. SFA in the midclavicular line was measured using preoperative computed tomography scans. The patients were divided into three groups according to SFA amount tertiles, and we investigated the association of SFA with infectious and all-cause complication events within 1 year. RESULTS: Within a median follow-up of 306 days, the patients with intermediate SFA had significantly higher infection-free survival than those with low and high SFA (low vs. intermediate vs. high: 80.4% vs. 97.7% vs. 83.4%, respectively, p=0.034). In contrast, there was no significant difference in the overall complication-free survival among the groups (low vs. intermediate vs. high: 80.4% vs. 88.9% vs. 81.8%, respectively, p=0.29). Low SFA was independently associated with high risk of infectious complications (hazard ratio, 9.45; 95% confidence interval, 1.07-83.22, p=0.043). CONCLUSION: Low SFA in the midclavicular line was an independent risk factor for infectious complications in the chemotherapy setting. This practical indicator can be useful for optimizing patients' nutritional status and when considering other types of vascular access to support administration of intravenous chemotherapy.

Impact of the preoperative body composition indexes on intraoperative blood loss in patients undergoing pancreatoduodenectomy.

PURPOSES: This study sought to identify any significant predictors of blood loss during pancreatoduodenectomy (PD) among preoperative variables, including the body composition indexes. METHODS: The preoperative data of patients undergoing PD were retrospectively reviewed. The objective variable was the percentage of blood loss during PD to the estimated circulating blood volume (proportional blood loss: PBL). The circulating blood volume was estimated using Nadler's formula. The total psoas area, average Hounsfield units of psoas area (psoas muscle density: PMD), and visceral to subcutaneous adipose tissue area ratio (VSR) were measured at the third vertebra using preoperative plain computed tomography images. A univariate analysis and multiple linear regression analysis for PBL were conducted using the preoperative variables. RESULTS: A total of 415 patients were analyzed. The median PBL was 24.5%. The PMD (coefficient - 0.267; 95% CI - 0.518, - 0.015), VSR (coefficient 2.719; 95% CI 0.238, 5.201), serum albumin level (coefficient - 8.458; 95% CI - 13.02, - 3.898), neoadjuvant therapy (coefficient 9.605; 95% CI 1.722, 17.49), and prothrombin time-international normalized ratio (PT-INR, coefficient 38.63; 95% CI 10.94, 66.31) were independently associated with PBL. CONCLUSIONS: The preoperative PMD, VSR, serum albumin level, neoadjuvant therapy, and PT-INR independently affected PBL. These factors could therefore be potential targets to reduce blood loss during PD.

Severe Acute Respiratory Syndrome Coronavirus 2 Prevalence, Seroprevalence, and Exposure among Evacuees from Wuhan, China, 2020.

To determine prevalence of, seroprevalence of, and potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among a cohort of evacuees returning to the United States from Wuhan, China, in January 2020, we conducted a cross-sectional study of quarantined evacuees from 1 repatriation flight. Overall, 193 of 195 evacuees completed exposure surveys and submitted upper respiratory or serum specimens or both at arrival in the United States. Nearly all evacuees had taken preventive measures to limit potential exposure while in Wuhan, and none had detectable SARS-CoV-2 in upper respiratory tract specimens, suggesting the absence of asymptomatic respiratory shedding among this group at the time of testing. Evidence of antibodies to SARS-CoV-2 was detected in 1 evacuee, who reported experiencing no symptoms or high-risk exposures in the previous 2 months. These findings demonstrated that this group of evacuees posed a low risk of introducing SARS-CoV-2 to the United States.

Characteristics of primary and repeated recurrent retroperitoneal liposarcoma: outcomes after aggressive surgeries at a single institution.

OBJECTIVE: This study sought to investigate the characteristics of primary and repeated recurrent retroperitoneal liposarcoma. METHODS: Patients treated with primary or recurrent retroperitoneal liposarcoma between 2005 and 2018 were retrospectively reviewed. Survival time analysis of recurrence-free survival and overall survival was conducted using Kaplan-Meier analysis and log-rank test. RESULTS: Fifty-two patients with primary retroperitoneal liposarcoma were analysed. Amongst them, 46 patients (88%) had undergone surgery. Histologic grades included well-differentiated (n = 21), dedifferentiated (n = 21), myxoid (n = 3) and pleomorphic (n = 1) subtypes. The patients undergoing R0 resection in the first surgery had significantly higher recurrence-free survival rates compared with the patients undergoing non-R0 resection (3-year recurrence-free survival: 80 versus 38%; 5-year recurrence-free survival: 49 versus 29%, P = 0.033). Although overall survival rates tended to be higher in the patients undergoing R0 resection compared with the non-R0 resection, it did not reach to a statistical significant difference (5-year overall survival: 93 versus 75%; 10-year overall survival: 93 versus 59%, P = 0.124). The recurrence rates were 65, 67, 73 and 100%, and the median recurrence-free survival times were 46, 20, 9 and 3 months after the first, second, third and fourth surgeries, respectively. The 5-year overall survival rates were 82, 69, 40 and 0% after the first, second, third and fourth surgeries, respectively. CONCLUSIONS: With repeated recurrence and surgeries, the time to recurrence decreased and the recurrence rate increased. R0 resection in the first surgery was considered the most important for longer recurrence-free survival and radical cure.

Melanogenesis-Inhibitory Activities of Isomeric C-seco Limonoids and Deesterified Limonoids.

Treatment of eight C-seco limonoids including six of salannin-type, 1 - 6, and two of nimbin-type, 7 and 8, with a combination of BF3 · Et2 O and iodide ion yielded the isomeric C-seco derivatives, i.e., six isosalannins, 1a - 6a, and two isonimbins, 7a and 8a, respectively. Ohchinin (1) was further subjected to LiAlH4 reduction which yielded a deesterified trihydroxy limonoid, nimbidinol (9). In addition, ten limonoids including seven of azadirone-type, 10 - 16, and three of gedunin-type, 17 - 19, all of which possess no ester functionality in the molecule, were obtained from the neutral fraction of Azadirachta indica seed extract after alkaline hydrolysis. Among the above, twelve compounds, i.e., 1a - 4a, 6a, 9, 13 - 16, 18, and 19, were new compounds, and their structures were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. Upon evaluation of all these limonoids for their inhibitory activities against melanogenesis in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), five structurally modified limonoids, 3-deacetyl-28-oxosalannin (6a), 9, 17-epi-17-hydroxynimbocinol (14), 17-epi-17-hydroxy-15-methoxynimbocinol (15), and 7-deacetyl-17-epinimolicinol (18), in addition to a natural limonoid, 1, exhibited potent inhibitory activities with 26 - 66% reduction of melanin content at 100 µm concentration with almost no or low toxicity to the B16 melanoma cells (70 - 99% cell viability at 100 µm).

Cytotoxic and melanogenesis-inhibitory activities of limonoids from the leaves of Azadirachta indica (Neem).

Seventeen limonoids (tetranortriterpenoids), 1-17, including three new compounds, i.e., 17-defurano-17-(2,5-dihydro-2-oxofuran-3-yl)-28-deoxonimbolide (14), 17-defurano-17-(2ξ-2,5-dihydro-2-hydroxy-5-oxofuran-3-yl)-28-deoxonimbolide (15), and 17-defurano-17-(5ξ-2,5-dihydro-5-hydroxy-2-oxofuran-3-yl)-2',3'-dehydrosalannol (17), were isolated from an EtOH extract of the leaf of neem (Azadirachta indica). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses and comparison with literature. Upon evaluation of the cytotoxic activities of these compounds against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines, seven compounds, i.e., 1-3, 12, 13, 15, and 16, exhibited potent cytotoxicities with IC50 values in the range of 0.1-9.9 µM against one or more cell lines. Among these compounds, cytotoxicity of nimonol (1; IC50 2.8 µM) against HL60 cells was demonstrated to be mainly due to the induction of apoptosis by flow cytometry. Western blot analysis suggested that compound 1 induced apoptosis via both the mitochondrial and death receptor-mediated pathways in HL60 cells. In addition, when compounds 1-17 were evaluated for their inhibitory activities against melanogenesis in B16 melanoma cells, induced with α-melanocyte-stimulating hormone (α-MSH), seven compounds, 1, 2, 4-6, 15, and 16, exhibited inhibitory activities with 31-94% reduction of melanin content at 10 µM concentration with no or low toxicity to the cells (82-112% of cell viability at 10 µM). All 17 compounds were further evaluated for their inhibitory effects against the EpsteinBarr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells.

Cytotoxic and apoptosis-inducing activities, and anti-tumor-promoting effects of cyanogenated and oxygenated triterpenes.

Two of each semisynthetic lanostane- and cycloartane-type triterpenes with a cyano-enone functionality, i.e., 13 and 18, and 23 and 28, respectively, sixteen of their synthetic intermediates, 9-12, 14-17, 19-22, and 24-27, along with seven semisynthetic oxygenated triterpene acetates, 29-35, and eight natural hydroxy triterpenes, 1-8, were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines. One natural triterpene, 8, and ten semisynthetic triterpenes, 9, 13, 15, 18, 23, 25, 28, 29, 32, and 33, exhibited potent cytotoxicities against one or more cell lines with IC50 values in the range of 1.4-9.9 µM. Two lanostane-type triterpenes with a cyano-enone functionality, 3-oxolanosta-1,8,24-triene-2-carbonitrile (13) and 3-oxolanosta-1,8-diene-2-carbonitrile (18), induced apoptosis in HL60 cells, as observed by membrane phospholipid exposure in flow cytometry. Western blot analysis showed that 13 and 18 significantly reduced procaspases-3, -8, and -9, and increased cleaved caspases-3, -8, and -9. These findings indicated that compounds 13 and 18 induced apoptosis in HL60 cells via both the mitochondrial and the death receptor-mediated pathways. In addition, upon evaluation of the inhibitory effects on EpsteinBarr virus early antigen (EBV-EA) activation induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, seven natural triterpenes, 1-6 and 8, and ten semisynthetic triterpenes, 9, 10, 14, 15, 19, 20, 24, 25, 29, and 30, exhibited inhibitory effects which were higher than that of ß-carotene, a vitamin A precursor studied widely in cancer-chemoprevention animal models.

Limonoids from Azadirachta indica var. siamensis extracts and their cytotoxic and melanogenesis-inhibitory activities.

Six new limonoids, 7-benzoyl-17-epinimbocinol (5), 3-acetyl-7-tigloylnimbidinin (8), 1-isovaleroyl-1-detigloylsalanninolide (15), 2,3-dihydro-3α-methoxynimbolide (16), deacetyl-20,21-epoxy-20,22-dihydro-21-deoxyisonimbinolide (26), and deacetyl-20,21,22,23-tetrahydro-20,22-dihydroxy-21,23-dimethoxynimbin (27), along with 28 known limonoids, 1-4, 6, 7, 9-14, 17-25, and 28-34, and two known flavonoids, 35 and 36, have been isolated from the extracts of bark, leaves, roots, and seeds of Azadirachta indica A. Juss. var. siamensis Valeton (Siamese neem tree; Meliaceae). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. All of these compounds were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines. Eleven compounds, 1, 2, 4-7, 13, 16, 17, 29, and 30, exhibited potent cytotoxicities against one or more cell lines with IC50 values in the range of 0.1-9.3 µM. Compound 16 induced apoptotic cell death in AZ521 cells upon evaluation of the apoptosis-inducing activity by flow cytometric analysis. Western blot analysis on AZ521 cells revealed that compound 16 activated caspases-3, -8, and -9, while increasing the ratio of Bax/Bcl-2. This suggested that 16 induced apoptosis via both mitochondrial and death receptor pathways in AZ521. In addition, upon evaluation of all compounds against the melanogenesis in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), 20 limonoids, i.e., 1-3, 6, 9-11, 18, 19, 21-29, 32, and 34, and two flavonoids, 35 and 36, exhibited melanogenesis-inhibitory activities, with no, or almost no, toxicities to the cells at lower and/or higher concentrations, which were more potent than the reference arbutin, a known melanogenesis inhibitor. Western blot analysis showed that nimbin (18) reduced the protein levels of microphtalmia-associated transcription factor (MITF), tyrosinase, tyrosine-related protein 1 (TRP-1), and TRP-2 mostly in a concentration-dependent manner, indicating that 18 inhibits melanogenesis on a α-MSH-stimulated B16 melanoma cells by, at least in part, inhibiting the expression of MITF, followed by decreasing the expression of tyrosinase, TRP-1, and TRP-2.

Limonoids and flavonoids from the flowers of Azadirachta indica var. siamensis, and their melanogenesis-inhibitory and cytotoxic activities.

A new limonoid, 7-O-acetyl-7-O-debenzoyl-22-hydroxy-21-methoxylimocinin (2), and two new flavonoids, 3'-(3-hydroxy-3-methylbutyl)naringenin (7) and 4'-O-methyllespedezaflavanone C (9), along with nine known compounds, including two limonoids, 1 and 3, and seven flavonoids, 4-6, 8, and 10-12, were isolated from a MeOH extract of the flowers of Azadirachta indica A.Juss. var. siamensis Valeton (Siamese neem tree; Meliaceae). The structures of new compounds were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. All of these compounds were evaluated for their melanogenesis-inhibitory activities in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH). Compound 2 (16.9% melanin content at 30 µM), 6-deacetylnimbin (3; 49.6% melanin content at 100 µM), and kaempferide (10; 41.7% melanin content at 10 µM) exhibited inhibitory effects with no, or almost no, toxicity to the cells (81.0-111.7% cell viability). In addition, evaluation of their cytotoxic activities against HL60, A549, AZ521, and SK-BR-3 human cancer cell lines, isoazadironolide (1), 4'-O-methyl-8-prenylnaringenin (5), euchrestaflavanone A (8), 9, and 3-methoxy-3'-prenylnaringenin (12) revealed potent cytotoxicities against one or more cell lines with IC50 values in the range of 4.5-9.9 µM.

Cytotoxic activities of amino acid-conjugate derivatives of abietane-type diterpenoids against human cancer cell lines.

Nine amino acid conjugate derivatives, each 2-10 and 12-20, were prepared from abietic acid (1) and dehydroabietic acid (11), respectively, and they were evaluated for their cytotoxicities against four human cancer cell lines, i.e., leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3). All compounds showed cytotoxicities against HL60 with IC50 values in the range of 2.3-37.3 µM. In addition, most of the derivatives exhibited moderate cytotoxicities against the other cancer cell lines. Among the derivatives, methyl N-[18-oxoabieta-8,11,13-trien-18-yl]-L-tyrosinate (19) exhibited potent cytotoxic activities against four cancer cell lines with IC50 values of 2.3 (HL60), 7.1 (A549), 3.9 (AZ521), and 8.1 µM (SK-BR-3). Furthermore, all derivatives were shown to possess high selective cytotoxic activities for leukemia cells, since they exhibited only weak cytotoxicities against normal lymphocyte cell line RPMI1788.

Phase-stable sub-cycle mid-infrared conical emission from filamentation in gases.

Sub-single-cycle pulses in the mid-infrared (MIR) region were generated through a conical emission from a laser-induced filament. Fundamental and second-harmonic pulses of 25-fs Ti:sapphire amplifier output were focused into argon to produce phase-stable broadband MIR pulses in a well-focusable ring-shaped beam. The beam profile and spectrum of the MIR field are accurately reproduced with a simple calculation based on a four-wave mixing process. The ring-shaped pattern of the MIR beam originates from a dramatic confocal-parameter mismatch between the MIR field and the laser beams.

Glycosidic inhibitors of melanogenesis from leaves of Momordica charantia.

Eight glycosidic compounds, 1-8, including two new compounds, (4ξ)-α-terpineol 8-O-[α-L-arabinopyranosyl-(1→6)-ß-D-glucopyranoside] (5) and myrtenol 10-O-[ß-D-apiofuranosyl-(1→6)-ß-D-glucopyranoside] (7), were isolated from the BuOH-soluble fraction of a MeOH extract of Momordica charantia leaves. The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses and comparison with literature. Upon evaluation of compounds 1-8 on the melanogenesis in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), these compounds were found to exhibit inhibitory activities with 7.1-27.0% and 23.6-46.4% reduction of melanin content at 30 µM and 100 µM, respectively, with no or almost no toxicity to the cells (80.0-103.5% of cell viability at 100 µM). Western blot analysis showed that compound 7 reduced the protein levels of MITF, tyrosinase, TRP-1, and TRP-2 mostly in a concentration-dependent manner, suggesting that this compound inhibits melanogenesis on the α-MSH-stimulated B16 melanoma cells by, at least in part, inhibiting the expression of MITF, followed by decreasing the expression of tyrosinase, TRP-1, and TRP-2.

Development of a method to determine workers' personal exposure levels to glyphosate.

OBJECTIVES: We aimed to develop a method to determine workers' personal exposure levels to N-(phosphonomethyl)glycine (glyphosate) for their risk assessments. METHODS: The proposed method was assessed as follows: recovery, stability of samples on storage, method limit of quantification, and reproducibility. Glyphosate in air was sampled using an air-sampling cassette containing a glass fiber filter. Ultrapure water was used to extract glyphosate from sampler filters. After derivation with 9-fluorenylmethyloxycarbonyl chloride, samples were analyzed by high-performance liquid chromatography using a fluorescence detector. RESULTS: Spiked samples indicated an overall recovery of 101%. After 7 days of storage at 4°C, recoveries were approximately 100%. The method limit of quantification was 0.060 µg/sample. Relative standard deviations representing overall reproducibility, defined as precision, were 1.4%-1.8%. CONCLUSIONS: The method developed in this study allows 4-h personal exposure monitoring of glyphosate at 0.250-500 µg/m3 . Thus, this method can be used to estimate worker exposure to glyphosate.

Structural biology of cell surface receptors implicated in Alzheimer's disease.

Alzheimer's disease is a common and devastating age-related disease with no effective disease-modifying treatments. Human genetics has implicated a wide range of cell surface receptors as playing a role in the disease, many of which are involved in the production or clearance of neurotoxins in the brain. Amyloid precursor protein, a membrane-bound signaling molecule, is at the very heart of the disease: hereditary mutations in its gene are associated with a greatly increased risk of getting the disease. A proteolytic breakdown product of amyloid precursor protein, the neurotoxic Aß peptide, has been the target for many drug discovery efforts. Antibodies have been designed to target Aß production with some success, although they have not proved efficacious in clinical trials with regards to cognitive benefits to date. Many of the recently identified genes associated with late-onset Alzheimer's disease risk are integral to the innate immune system. Some of these genes code for microglial proteins, such as the strongest genetic risk factor for the disease, namely APOE, and the cell surface receptors CD33 and TREM2 which are involved in clearance of the Aß peptide from the brain. In this review, we show how structural biology has provided key insights into the normal functioning of these cell surface receptors and provided a framework for developing novel treatments to combat Alzheimer's disease.

Anti-Tumor Effects of MAPK-Dependent Tumor-Selective Oncolytic Vaccinia Virus Armed with CD/UPRT against Pancreatic Ductal Adenocarcinoma in Mice.

Engineered vaccinia virus serves as an oncolytic virus for cancer virotherapy. We evaluated the oncolytic characteristics of VGF- and O1-deleted recombinant mitogen-activated protein kinase (MAPK)-dependent vaccinia virus (MDRVV). We found that compared with viruses with the deletion of either gene alone, MDRVV is more attenuated in normal cells and can replicate in cancer cells that exhibit constitutive ERK1/2 activation in the MAPK pathway. We armed MDRVV with a bifunctional fusion gene encoding cytosine deaminase and uracil phosphoribosyltransferase (CD/UPRT), which converts 5-fluorocytosine (5-FC) into chemotherapeutic agents, and evaluated its oncolytic activity alone or in combination with 5-FC in human pancreatic cancer cell lines, tumor mouse models of peritoneal dissemination and liver metastasis, and ex vivo-infected live pancreatic cancer patient-derived tissues. CD/UPRT-armed MDRVV alone could efficiently eliminate pancreatic cancers, and its antitumor effects were partially enhanced in combination with 5-FC in vitro and in vivo. Moreover, the replication of MDRVV was detected in tumor cells of patient-derived, surgically resected tissues, which showed enlarged nuclei and high expression of pERK1/2 and Ki-67, and not in stromal cells. Our findings suggest that systemic injections of CD/UPRT-armed MDRVV alone or in combination with 5-FC are promising therapeutic strategies for pancreatic ductal adenocarcinoma.

Tranexamic ACid during PancereaticoDuodenectomy (TAC-PD): study protocol for a multicentre randomised, blind, placebo-controlled trial.

INTRODUCTION: Pancreaticoduodenectomy (PD) is a major gastroenterological surgery that results in a substantial amount of blood loss. Several studies have demonstrated that major blood loss during PD is associated with both short-term and long-term poor outcomes. Administration of perioperative tranexamic acid (TXA) has been reported to reduce intraoperative blood loss in various surgeries, including cardiovascular surgery and orthopaedic surgery. Nevertheless, the effect of perioperative TXA use in patients undergoing PD has not been investigated. This study aims to investigate the effect of TXA on blood loss during PD. METHODS AND ANALYSIS: A multicentre (six hospitals), randomised, blind (patient-blinded, surgeon-blinded, anaesthesiologist-blinded, monitor-blinded), placebo-controlled trial of TXA during PD was started in September 2019. Patients undergoing PD for biliary, duodenal or pancreatic diseases are randomly assigned to the TXA or placebo group. The stratification factors are the institutions and preoperative clinical diagnosis. Before skin incision, the participants in TXA group are administrated 1 g TXA as a loading infusion followed by a maintenance infusion of 125 mg/hour TXA until the end of surgery or 8 hours from the incision. Participants in the placebo group are administrated the same volume of saline that is indistinguishable from the TXA. The primary outcome is blood loss during PD. The secondary outcomes are intraoperative and postoperative (up to day 2) blood transfusions, operation time, anaesthesia time, postoperative laboratory variables, length of hospital stay, in-hospital and 90-day mortality and postoperative complications occurring within 28 days of surgery or requiring readmission. To date, 115 patients of a planned 220 have been enrolled in the study. ETHICS AND DISSEMINATION: This protocol was approved by the Nagoya University Clinical Research Review Board and is registered with Japan Registry of Clinical Trials on 15 August 2019. The results of this trial will be disseminated through peer-reviewed journals. TRIAL REGISTRATION NUMBER: jRCTs041190062.

Impact of initial coagulation and fibrinolytic markers on mortality in patients with severe blunt trauma: a multicentre retrospective observational study.

BACKGROUND: Acute coagulopathy is a well-known predictor of poor outcomes in patients with severe trauma. However, using coagulation and fibrinolytic markers, how one can best predict mortality to find out potential candidates for treatment of coagulopathy remains unclear. This study aimed to determine preferential markers and their optimal cut-off values for mortality prediction. METHODS: We conducted a retrospective observational study of patients with severe blunt trauma (injury severity score ≥ 16) transferred directly from the scene to emergency departments at two trauma centres in Japan from January 2013 to December 2015. We investigated the impact and optimal cut-off values of initial coagulation (platelet counts, fibrinogen and prothrombin time-international normalised ratio) and a fibrinolytic marker (D-dimer) on 28-day mortality via classification and regression tree (CART) analysis. Multivariate logistic regression analysis confirmed the importance of these markers. Receiver operating characteristic curve analyses were used to examine the prediction accuracy for mortality. RESULTS: Totally 666 patients with severe blunt trauma were analysed. CART analysis revealed that the initial discriminator was fibrinogen (cut-off, 130 mg/dL) and the second discriminator was D-dimer (cut-off, 110 µg/mL in the lower fibrinogen subgroup; 118 µg/mL in the higher fibrinogen subgroup). The 28-day mortality was 90.0% (lower fibrinogen, higher D-dimer), 27.8% (lower fibrinogen, lower D-dimer), 27.7% (higher fibrinogen, higher D-dimer) and 3.4% (higher fibrinogen, lower D-dimer). Multivariate logistic regression demonstrated that fibrinogen levels < 130 mg/dL (adjusted odds ratio [aOR], 9.55; 95% confidence interval [CI], 4.50-22.60) and D-dimer ≥110 µg/mL (aOR, 5.89; 95% CI, 2.78-12.70) were independently associated with 28-day mortality after adjusting for probability of survival by the trauma and injury severity score (TRISS Ps). Compared with the TRISS Ps alone (0.900; 95% CI, 0.870-0.931), TRISS Ps with fibrinogen and D-dimer yielded a significantly higher area under the curve (0.942; 95% CI, 0.920-0.964; p < 0.001). CONCLUSIONS: Fibrinogen and D-dimer were the principal markers for stratification of mortality in patients with severe blunt trauma. These markers could function as therapeutic targets because they were significant predictors of mortality, independent from severity of injury.

Improvement of the skin penetration of hydrophobic drugs by polymeric micelles.

Polymeric micelles, which form through the self-assembly of poly(ethylene glycol)-poly(amino acid) block copolymers, are systemic nanocarriers in targeted cancer therapy. These micelles can encapsulate therapeutic compounds, such as lipophilic substances, charged compounds, and metal complexes, that have characteristics of increased solubility, sustained release, and improved tissue distribution. However, few studies have been conducted on the local distribution of polymeric micelles. Thus, we evaluated the skin penetration pattern of hydrophobic drugs in polymeric micelles. We revealed that improved water solubility by the encapsulation of the hydrophobic drugs indomethacin and resveratrol in polymeric micelles significantly increased the amount of drugs penetrating into the skin. Moreover, polymeric micelles did not enhance the permeability of drugs. Furthermore, although the polymers remained on or in the stratum corneum, the encapsulated drugs gradually moved deeper into the skin. These results indicate that encapsulated hydrophobic drugs in polymeric micelles can penetrate the living cell layer of the skin without bringing about unexpected side effects associated with other ingredients in the formulation. Thus, polymeric micelles for encapsulating hydrophobic drugs can be used for skin applications.

Construction of mouse 129/Ola BAC library for targeting experiments using E14 embryonic stem cells.

Gene targeting is a powerful method of specifically modifying genes of interest. It has been most consistently successful in the 129 mouse strain, because the embryonic stem (ES) cells of 129 mice are relatively easy to culture. In gene-targeting experiments, the use of ES cell-derived genomic clones as a source of homology arms is desirable, because the genetic variation among mouse strains results in a reduced frequency of homologous recombination. In this study, we generated an arrayed mouse 129/Ola BAC library derived from E14.1 ES cells, one of the frequently used ES cell lines. More than 135,000 BAC clones with a mean insert size of 110 kb were isolated. This library is estimated to represent a 5.5-fold mouse genome coverage. The BAC clones can be screened within 2 days by PCR. Considering that all 8 loci so far examined are contained in this BAC library, we believe it will be a useful resource for gene targeting studies using E14 ES cells as well as for genome analysis.