Investigating effective methods of clinical pharmacy training on oncology for community pharmacists: An observational study.

INTRODUCTION: Kitasato University Hospital offers a training course for community pharmacists that focus on advanced pharmacy management care in outpatient cancer chemotherapy. The objective of this training program is to facilitate the transition from general to oncology certification for community pharmacists with limited experience in outpatient oncology to support the acquisition of an oncology specialty. AIM: To evaluate the relationship between the changes in awareness, knowledge, and self-assessment that advanced pharmacy management care traineeship in an outpatient oncology unit for community pharmacists brings to trainees and the duration of training. METHODS: A quantitative text analysis was conducted of the daily training reports of six community pharmacists who had participated previously in the training course and had received in-service training in oncology for at least 30 days. The pre- and post-training results of the knowledge tests and self-assessments of confidence, understanding, and performance were compared. This study was approved by the Research Ethics Committee of Kitasato Institute Hospital in October 2019 (Study No. 19044). RESULTS: The terms Prescription, Recommendation were extracted from the daily report after the 21st day of oncology in-service training. Furthermore, factors such as knowledge of cancer pharmacotherapy, confidence in patient education regarding the side effects of chemotherapy, and understanding of the work of pharmacists in outpatient cancer chemotherapy significantly increased at the end of the training. CONCLUSIONS: Community pharmacists with limited experience in outpatient oncology could improve their knowledge, understanding, and awareness of outpatient oncology patient care through 30 days of in-service oncology training in a hospital setting. The issues that emerged included training pharmacists to send follow-up documents on the patients' side effects and medication status as well as developing the literature search environment in community pharmacies.

Population Pharmacokinetic-Pharmacodynamic Target Attainment Analysis of Flomoxef in the Serum and Liver Tissue of Patients Undergoing Hepatic Resection.

The purpose of this study was to investigate the population pharmacokinetics of prophylactic flomoxef based on serum and liver tissue concentrations and to demonstrate a pharmacodynamic target concentration in the serum and liver tissue exceeding the MIC in order to design an effective dosing regimen. Serum samples (n = 210) and liver tissue samples (n = 29) from 43 individuals were analyzed using a nonlinear mixed-effects model. The pharmacodynamics index target value was regarded as the probability of maintaining flomoxef serum trough and liver tissue concentrations exceeding the MIC90 values, 0.5 mg/L and 1.0 mg/L, for Escherichia coli and methicillin-susceptible Staphylococcus aureus, respectively. The final population pharmacokinetic model was a two-compartment model with linear elimination. Creatinine clearance (CLCR) was identified as a significant covariate influencing total clearance when CLCR was less than 60 mL/min. The probability of achieving concentrations in the serum and liver tissue exceeding the MIC90 for E. coli or methicillin-susceptible S. aureus for a 1 g bolus dose was above 90% at 2 h after the initial dose. Our findings suggest that population pharmacokinetic parameters are helpful for evaluating flomoxef pharmacokinetics and determining intraoperative flomoxef redosing intervals.

The change rate in serum nitric oxide may affect lenvatinib therapy in hepatocellular carcinoma.

BACKGROUND: Lenvatinib is appropriate for reducing the production of nitric oxide (NO) and facilitating as block angiogenesis. However, to our knowledge, there are no data that support the correlation between NO and clinical response in patients who received lenvatinib therapy for HCC. Therefore, we investigated the correlation between the change rate of NO levels and clinical responses including adverse events (AEs) after lenvatinib therapy for unresectable hepatocellular carcinoma (HCC). METHODS: This study was conducted using previously collected data from another study. We enrolled 70 patients who received lenvatinib for advanced or unresectable HCC. NO was measured by converting nitrate (NO3-) to nitrite (NO2-) with nitrate reductase, followed by quantitation of NO2- based on Griess reagent. To determine whether lenvatinib influences NO in unresectable HCC, we evaluated the influence of the change rate of NO from baseline after administration of lenvatinib on maximal therapeutic response and SAE. RESULTS: After lenvatinib administration, a change rate in the NO from 0.27 to 4.16 was observed. There was no difference between the clinical response to lenvatinib and the change rate of NO (p = 0.632). However, the change rate of NO was significantly lower in patients with AEs than in those without AEs (p = 0.030). When a reduction in NO rate of < 0.8 was defined as a clinically significant reduction of NO (CSRN), the CSRN group had significantly worse progression-free survival (PFS) and overall survival (OS) than the non-CSRN group (p = 0.029 and p = 0.005, respectively). CONCLUSION: Decreased NO levels were associated with the occurrence of AEs and worse prognosis after lenvatinib administration. Change rate in serum NO can be used as predictive markers in patients receiving lenvatinib therapy for HCC.

Serum concentration of oral midazolam as pediatric preanesthetic medication and factors related to the sedation level.

BACKGROUND: Preanesthetic medication is important to eliminate surgical anxiety in pediatric patients and facilitate their smooth transfer to the operating room. Midazolam is the most commonly used preanesthetic medication. However, it has been reported that the sedative effect varies from patient to patient. In this study, the pharmacokinetics of midazolam were examined, and the aim was to assess the factors affecting the quality of sedation. METHODS: The participants were children ranging in age from 6 months to 8 years scheduled for surgery. Midazolam 0.5 mg/kg was administered orally 30 min before entering the operating room, and the sedation level was evaluated at the time of mask application. Blood was collected after slow induction, and the serum concentration of midazolam was measured using high-performance liquid chromatography. RESULTS: A total of 98 patients were registered. There was no difference in serum concentrations between the effective sedation group and the ineffective sedation group (48.0 vs. 49.1 ng/mL), regardless of the effect of midazolam. Percentages of ineffective sedation by age (0 to 7 years) were 66.6%, 60%, 33.3%, 11.1%, 0%, 0%, 12.5%, and 0%, respectively. On multivariate logistic regression analysis, siblings (OR = 3.9, CI: 1.1-14.0, p = .03) and age (OR = 3.2, CI:1.2-8.5, p = .02) were related to an insufficient sedative effect. CONCLUSION: The serum concentration of oral midazolam reached effective levels even in patients in whom the sedative effect was inadequate. It is important to manage the perioperative period with appropriate concurrent premedication taking into account patient age and social background characteristics. CLINICAL TRIAL REGISTRATION: Clinical trial registry: UMIN R000052504.

Evaluation of a carbapenem antimicrobial stewardship program and clinical outcomes in a Japanese hospital.

INTRODUCTION: Microorganisms can evolve and become resistant to antimicrobials, and this is known as antimicrobial resistance (AMR). Inappropriate use of antibiotics contributes to AMR, and antimicrobial stewardship programs have been developed to mitigate AMR. The Appropriate Use of Carbapenems Program was implemented in March 2019 in a university hospital and its effect was evaluated. METHODS: We conducted a prospective audit and feedback on carbapenems at the time of prescription daily. Additionally, we compared a monthly survey of the total days of therapy (DOTs) per 1000 patient-days for carbapenems, piperacillin/tazobactam, and fluoroquinolones. The susceptibility of Pseudomonas aeruginosa to meropenem, piperacillin/tazobactam, and levofloxacin was tested before (January 2018 to February 2019) and after (March 2019 to December 2020) the intervention. RESULTS: The monthly median DOTs of carbapenem usage decreased after the intervention; carbapenem use immediately declined during the intervention period. The monthly median DOTs of piperacillin/tazobactam and fluoroquinolones also decreased and continued to decline significantly after the intervention. Susceptibility of P. aeruginosa to meropenem, piperacillin/tazobactam, and levofloxacin did not change significantly during the study. CONCLUSION: The implementation of the Appropriate Use of Carbapenems Program was effective in reducing the use of broad-spectrum antibiotics and maintaining the antibiotic susceptibility of P. aeruginosa.

Timing of re-dosing based on population pharmacokinetic-pharmacodynamics target attainment analysis of cefmetazole in subjects undergoing lower gastrointestinal surgery.

INTRODUCTION: This study was conducted to evaluate the population pharmacokinetics of prophylactic cefmetazole sodium (CMZ) based on the serum concentrations and establish a pharmacodynamics target concentration exceeding the minimum inhibitory concentration (MIC) to design the re-dosing interval. METHODS: Serum (n = 362) samples from 107 individuals were analyzed using a nonlinear mixed-effects model. The pharmacodynamics index obtained was regarded as the probability of maintaining CMZ serum trough exceeding the minimal inhibitory concentration (MIC) of 2 mg/L. This MIC was chosen to account for methicillin-susceptible Staphylococcus aureus (MSSA), E. coli, and Klebsiella pneumoniae RESULTS: The final population pharmacokinetic model was a two-compartment model with linear elimination. Creatinine clearance and body weight were identified as significant covariates influencing the central clearance and volume of distribution in the central compartment. The probability of achieving serum concentrations exceeding the MIC90 for MSSA, E. coli, and Klebsiella pneumoniae for a 1 g dose with a 10 min intravenous infusion was above 90% except for good renal function (CLcr â‰§ 95 mL/min) at 2 h after the initial dose. For patients with good renal function (CLcr â‰§ 95 mL/min), a CMZ of 2 g re-dosing interval seemed necessary to meet the achievement probability. In patients with impaired renal function (CLcr ≤20 mL/min), the probability of achievement exceeded 90% even when the dosing interval was extended to 8 h. CONCLUSIONS: We evaluated re-dosing intervals based on the population pharmacokinetics. Re-dosing intervals should be determined based on renal function.

Population Pharmacokinetic and Pharmacodynamic Target Attainment Analysis of Cefazolin in the Serum and Hip Joint Capsule of Patients Undergoing Total Hip Arthroplasty.

The objectives of this study were to evaluate the population pharmacokinetics of prophylactic cefazolin (CFZ) from its serum and hip joint capsule concentrations in patients undergoing total hip arthroplasty and to establish the pharmacodynamic target concentration exceeding the MIC for designing an effective dosing regimen for serum and the hip joint capsule. We analyzed 249 serum samples and 125 hip joint capsule samples from 125 individuals using a nonlinear mixed-effects model. The pharmacodynamic index target value obtained from our results indicates the probability of maintaining CFZ trough and hip joint capsule concentrations exceeding the MIC of 1 mg/liter to account for methicillin-susceptible S. aureus (MSSA). We estimated the population pharmacokinetics using a two-compartment model. The estimated population pharmacokinetic parameters were as follows: clearance (CL) (liters/h) = 1.46 × (creatinine clearance [CLcr] [ml/min]/77)0.891, volume of distribution of the central compartment (Vc) (liters) = 7.5, central-hip joint capsule compartment clearance (Q) (liters/h) = 3.38, and volume of distribution in the hip joint capsule compartment (VJC) (liters) = 36.1. The probability of achieving concentrations exceeding the MIC90 for MSSA was approximately 100% for serum and 100% for the hip joint capsule at 3 h after the initial dose. Our findings suggest that population-based parameters are useful for evaluating CFZ pharmacokinetics and that individual dosages should be determined based on the dosage regimen that achieves and maintains adequate tissue CFZ concentration.

Pharmacokinetic Analysis, Analgesic Effects, and Adverse Effects of Tapentadol in Cancer Patients with Pain.

In this study, we conducted a pharmacokinetic analysis of tapentadol (TP) in Japanese patients with cancer pain and identified covariates influencing pharmacokinetic parameters. In addition, the analgesic effects and adverse effects of TP were investigated. Data were collected from in-patients with cancer pain who had been administered TP as an extended-release formula. The median (range) estimated clearance (CL/F) and distribution volume (Vd/F) of TP were 86.7 (31.3-213.7) L/h and 1288 (189-6736) L, respectively. There was a strong negative correlation between CL/F and age, Child-Pugh score, and albumin-bilirubin (ALBI) score. The subjects were further divided into two groups according to the factors highly correlated with CL/F. The CL/F of patients in the Child-Pugh B group was 0.46-times that of patients in the Child-Pugh A group. In addition, the CL/F of patients with an ALBI score > -2.40 was 0.56-times that of patients with ALBI scores ≤-2.40, and both differences were statistically significant (p < 0.05). The mean intensity of pain over 24 h was investigated daily from before starting TP for the first 7 d of the treatment. TP reduced pain in six of nine patients; the mean pain visual analogue scale score decreased significantly from 59.2 mm before administration to 42.5 mm at days 5-7. Overall, the Child-Pugh and ALBI scores significantly affected the clearance of TP, which was reduced in patients with impaired liver function. These results suggest that TP is an opioid with a sufficient analgesic effect for cancer patients.

Investigating the risk of bone fractures in elderly patients with type 2 diabetes mellitus: a retrospective study.

BACKGROUND: Elderly patients with type 2 diabetes mellitus (T2DM) experience fractures more frequently than elderly individuals without diabetes. Fractures requiring hospitalization greatly affect quality of life, and although elderly patients with T2DM have several risk factors associated with fractures, only a few studies have evaluated these in detail in the Asian population. We conducted a retrospective study of elderly patients with T2DM for evaluating factors associated with fracture risk. METHODS: We conducted a retrospective study using electronic medical records (EMR) of patients aged ≥65 years with T2DM who were admitted to a public general medical institute in central Tokyo, Japan. We evaluated factors associated with fractures necessitating hospitalization in elderly patients with T2DM characteristics and hypoglycemic agent use. Factors associated with fracture risk were identified using multivariable logistic regression analysis. RESULTS: A total of 2,112 elderly patients (age ≥ 65 years) with T2DM were analyzed. Among them, 69 (3.3%) patients had been hospitalized for fractures. Factors associated with fractures were female sex (OR, 3.46), eGFR < 60 ml / min / 1.73 m2 (OR, 0.55), and thiazolidine use (OR, 4.28). Further, a separate analysis based on sex revealed that the use of thiazolidines was significantly associated with fracture risk in both sexes. CONCLUSIONS: In elderly patients with T2DM, the key factor associated with fractures was the use of thiazolidines in both males and females. In this study, the use of thiazolidines was newly identified as a factor which increased the risk of fractures requiring hospitalization in elderly males. The study findings should be considered when hypoglycemic agents are selected for treating elderly patients with T2DM. Information bias, selection bias, and the effect of concomitant drugs may be the underlying reasons for why eGFR < 60 mL / min / 1.73 m2 reduced the fracture risk. However, details are unknown, and additional investigations are needed.

[Clinical Effects of Opioid Switching to Tapentadol - Retrospective Analysis of Efficacy and Adverse Effects].

The objective of our study was to evaluate the efficacy and adverse effects of opioid switching to tapentadol(TP). It was a retrospective survey carried out at the Kitasato University Hospital outpatient clinic between September 2014 and May 2016. We evaluated pain intensity using the visual analogue scale and the occurrence of adverse effects before switching, at the first evaluation after switching, and during the steady state of TP administration. We included 10 patients; of these, 3 patients discontinued TP owing to uncontrolled pain. The conversion ratio of the previously administered opioids to TP was 1.17 at the time of the first evaluation after switching and 1.42 during the steady state. The mean(±SD)pain intensity was 4.2±2.2 before opioid switching and 4.6±2.2 at the time of the first evaluation after switching. The mean(±SD)pain intensity in the 7 patients excluding the 3 patients who discontinued TP was 4.3±2.0 before opioid switching and 2.7±1.9 during the steady state. Somnolence improved in 5 patients and constipation improved in 2 patients when a stable dose was achieved. Opioid switching to TP was appropriately accomplished using the conversion ratio. Furthermore, pain, sleepiness, and constipation improved following successful titration. These data suggest that TP can be useful in the treatment of cancer pain, in addition to the currently used opioid preparations.

Hepatic Dipeptidyl Peptidase-4 Controls Pharmacokinetics of Vildagliptin In Vivo.

The main route of elimination of vildagliptin, which is an inhibitor of dipeptidyl peptidase-4 (DPP-4), in humans is cyano group hydrolysis to produce a carboxylic acid metabolite M20.7. Our in vitro study previously demonstrated that DPP-4 itself greatly contributed to the hydrolysis of vildagliptin in mouse, rat, and human livers. To investigate whether hepatic DPP-4 contributes to the hydrolysis of vildagliptin in vivo, in the present study, we conducted in vivo pharmacokinetics studies of vildagliptin in mice coadministered with vildagliptin and sitagliptin, which is another DPP-4 inhibitor, and also in streptozotocin (STZ)-induced diabetic mice. The area under the plasma concentration-time curve (AUC) value of M20.7 in mice coadministered with vildagliptin and sitagliptin was significantly lower than that in mice administered vildagliptin alone (P < 0.01). Although plasma DPP-4 expression level was increased 1.9-fold, hepatic DPP-4 activity was decreased in STZ-induced diabetic mice. The AUC values of M20.7 in STZ-induced diabetic mice were lower than those in control mice (P < 0.01). Additionally, the AUC values of M20.7 significantly positively correlated with hepatic DPP-4 activities in the individual mice (Rs = 0.943, P < 0.05). These findings indicated that DPP-4 greatly contributed to the hydrolysis of vildagliptin in vivo and that not plasma, but hepatic DPP-4 controlled pharmacokinetics of vildagliptin. Furthermore, enzyme assays of 23 individual human liver samples showed that there was a 3.6-fold interindividual variability in vildagliptin-hydrolyzing activities. Predetermination of the interindividual variability of hepatic vildagliptin-hydrolyzing activity might be useful for the prediction of blood vildagliptin concentrations in vivo.

Delayed de-induction of CYP2C9 compared to CYP3A after discontinuation of rifampicin: Report of two cases
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OBJECTIVE: Timely dose reduction of concomitant medications is important after withdrawal of rifampicin, a CYP inducer. However, little is known about the differences in the time course of deinduction for various CYP isoforms. To clarify the time courses of deinduction of CYP2C9 and -CYP3A activities after rifampicin withdrawal, we monitored these enzyme activities in 2 patients over time after discontinuing rifampicin. MATERIALS AND METHODS: Two patients (aged 70 and 80 years) received warfarin and rifampicin for anticoagulation and antituberculosis therapy, respectively. Warfarin doses were increased due to rifampicin-induced CYP activity. Upon completion of antituberculosis therapy, rifampicin was discontinued and warfarin doses were titrated downward according to prothrombin time. We monitored CYP2C9 and CYP3A activities over their clinical courses by measuring the metabolic clearance of S-warfarin to S-7-hydroxywarfarin and that of cortisol to 6ß-hydroxycortisol, respectively. RESULTS: In both patients, the time courses of CYP2C9 deinduction appeared to be delayed compared to CYP3A. CONCLUSION: Our findings suggest that a uniform dose reduction protocol for drugs metabolized by different CYP isoforms may be unsafe after rifampicin withdrawal.
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Comprehensive analysis of the Co-structures of dipeptidyl peptidase IV and its inhibitor.

BACKGROUND: We comprehensively analyzed X-ray cocrystal structures of dipeptidyl peptidase IV (DPP-4) and its inhibitor to clarify whether DPP-4 alters its general or partial structure according to the inhibitor used and whether DPP-4 has a common rule for inhibitor binding. RESULTS: All the main and side chains in the inhibitor binding area were minimally altered, except for a few side chains, despite binding to inhibitors of various shapes. Some residues (Arg125, Glu205, Glu206, Tyr662 and Asn710) in the area had binding modes to fix a specific atom of inhibitor to a particular spatial position in DPP-4. We found two specific water molecules that were common to 92 DPP-4 structures. The two water molecules were close to many inhibitors, and seemed to play two roles: maintaining the orientation of the Glu205 and Glu206 side chains through a network via the water molecules, and arranging the inhibitor appropriately at the S2 subsite. CONCLUSIONS: Our study based on high-quality resources may provide a necessary minimum consensus to help in the discovery of a novel DPP-4 inhibitor that is commercially useful.

Dipeptidyl peptidase-4 greatly contributes to the hydrolysis of vildagliptin in human liver.

The major metabolic pathway of vildagliptin in mice, rats, dogs, and humans is hydrolysis at the cyano group to produce a carboxylic acid metabolite M20.7 (LAY151), whereas the major metabolic enzyme of vildagliptin has not been identified. In the present study, we determined the contribution rate of dipeptidyl peptidase-4 (DPP-4) to the hydrolysis of vildagliptin in the liver. We performed hydrolysis assay of the cyano group of vildagliptin using mouse, rat, and human liver samples. Additionally, DPP-4 activities in each liver sample were assessed by DPP-4 activity assay using the synthetic substrate H-glycyl-prolyl-7-amino-4-methylcoumarin (Gly-Pro-AMC). M20.7 formation rates in liver microsomes were higher than those in liver cytosol. M20.7 formation rate was significantly positively correlated with the DPP-4 activity using Gly-Pro-AMC in liver samples (r = 0.917, P < 0.01). The formation of M20.7 in mouse, rat, and human liver S9 fraction was inhibited by sitagliptin, a selective DPP-4 inhibitor. These findings indicate that DPP-4 is greatly involved in vildagliptin hydrolysis in the liver. Additionally, we established stable single expression systems of human DPP-4 and its R623Q mutant, which is the nonsynonymous single-nucleotide polymorphism of human DPP-4, in human embryonic kidney 293 (HEK293) cells to investigate the effect of R623Q mutant on vildagliptin-hydrolyzing activity. M20.7 formation rate in HEK293 cells expressing human DPP-4 was significantly higher than that in control HEK293 cells. Interestingly, R623Q mutation resulted in a decrease of the vildagliptin-hydrolyzing activity. Our findings might be useful for the prediction of interindividual variability in vildagliptin pharmacokinetics.

Acquired resistance to gemcitabine and cross-resistance in human pancreatic cancer clones.

The efficacy of gemcitabine (GEM), a standard treatment agent for pancreatic cancer, is insufficient because of primary or acquired resistance to this drug. Patients with tumors intrinsically sensitive to GEM gradually acquire resistance and require a shift to second agents, which are associated with the risk of cross-resistance. However, whether cross-resistance is actually present has long been disputed. Using six GEM-resistant and four highly GEM-resistant clones derived from the pancreatic cancer cell line BxPC-3, we determined the resistance of each clone and parent cell line to GEM and four anticancer agents (5-FU, CDDP, CPT-11, and DTX). The GEM-resistant clones had different resistances to GEM and other agents, and did not develop a specific pattern of cross-resistance. This result shows that tumor cells are heterogeneous. However, all highly GEM-resistant clones presented overexpression of ribonucleotide reductase subunit M1 (RRM1), a target enzyme for metabolized GEM, and showed cross-resistance with 5-FU. The expression level of RRM1 was high; therefore, resistance to GEM was high. We showed that a tumor cell acquired resistance to GEM, and cross-resistance developed in one clone. These results suggest that only cells with certain mechanisms for high-level resistance to GEM survive against selective pressure applied by highly concentrated GEM. RRM1 may be one of the few factors that can induce high resistance to GEM and a suitable therapeutic target for GEM-resistant pancreatic cancer.

Evaluation of the efficacy and safety of changes in antiretroviral regimens for HIV-infected patients.

PURPOSE: Antiretroviral therapy is now available for HIV-infected patients, and so-called highly active antiretroviral therapy (HAART) now makes it possible to strongly suppress viral proliferation and restore immunity. However, the development of new drugs and regimens for HAART is still in progress, with the aim of overcoming a number of associated problems. For this purpose, changes in the prescribed anti-HIV drugs are often made. In the present study, we attempted to clarify the actual effects of such treatment modifications in patients who had been started on HAART. METHODS: We retrospectively investigated HIV-infected patients who had been started on HAART at Kitasato University Hospital between April 1997 and March 2013. The patients' backgrounds, characteristics and laboratory data were established from the hospital medical records. RESULTS: The total follow-up time was 447.3 person-years. The patients remained on their initial regimen for a median period of 2040 days, and 39 patients took a second regimen for a median of 2714 days. There was no treatment failure due to regimen change. The reason for the regimen change was adverse effects in 49 cases, poor adherence/virological failure in 4, immunological failure in 3, patient request in 2, and proposals made by health care workers, or for simplification, in 11. The number of patients who required regimen change due to renal dysfunction showed a gradual increase. The number of times anti-HIV drugs were taken per day was not altered when the regimen changed, being mainly once or twice a day. CONCLUSION: In the present study, there were no instances of treatment failure due to regimen change. Through appropriate regimen change, it is possible to avoid serious adverse effects, and to improve patient adherence. Further adverse effects associated with long-term antiretroviral therapy, and reduction of adherence through medication fatigue should be considered. Drug selection and regimen change should be considered in relation to long-term prognosis.

Efficacy of the bleeding risk scoring system for optimal prophylactic anticoagulation therapy of venous thromboembolism in trauma patients: a single-center, retrospective, observational cohort study.

BACKGROUND: We developed a bleeding risk scoring system (BRSS) using prophylactic anticoagulation therapy to comprehensively assess the risk of venous thromboembolism (VTE) in trauma patients. This study evaluated the usefulness of this system in trauma patients, with a focus on minimizing the rate of bleeding events associated with prophylactic anticoagulation therapy. METHODS: We retrospectively evaluated the efficacy of BRSS in trauma patients who received prophylactic anticoagulation therapy for VTE at the Kitasato University Hospital Emergency and Critical Care Center between April 1, 2015, and August 31, 2020. To compare the incidence of bleeding events, patients were divided into two groups: one group using the BRSS (BRSS group) and another group not using the BRSS (non-BRSS group). RESULTS: A total of 94 patients were enrolled in this study, with 70 and 24 patients assigned to the non-BRSS and BRSS groups, respectively. The major bleeding event rates were not significantly different between the two groups (BRSS group, 4.2%; non-BRSS group, 5.7%; p = 1.000). However, minor bleeding events were significantly reduced in the BRSS group (4.2% vs.27.1%; p = 0.020). Multivariate logistic regression analysis showed that BRSS was not an independent influencing factor of major bleeding events (odds ratio, 0.660; 95% confidence interval: 0.067-6.47; p = 0.721). Multivariate logistic regression analysis showed that BRSS was an independent influencing factor of minor bleeding events (odds ratio, 0.119; 95% confidence interval: 0.015-0.97; p = 0.047). The incidence of VTE did not differ significantly between groups (BRSS group, 4.2%; non-BRSS group, 8.6%; p = 0.674). CONCLUSIONS: BRSS may be a useful tool for reducing the incidence of minor bleeding events during the initial prophylactic anticoagulation therapy in trauma patients. There are several limitations of this study that need to be addressed in future research.

Effect of a combination of S-1 and gemcitabine on cell cycle regulation in pancreatic cancer cell lines.

In a previous study, we showed that a combination of an oral fluoropyrimidine anticancer agent (S-1) and gemcitabine (GEM) had synergistic effects on cell growth and cell cycle arrest in the pancreatic cancer cell line MIA PaCa-2. Therefore, we conducted further mechanistic studies using the pancreatic cancer cell lines MIA PaCa-2 and SUIT-2. The combined effect of S-1 and GEM in SUIT-2 cells was evaluated using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the effects of S-1, GEM and S-1 plus GEM on cell cycle regulation were assessed using flow cytometry. We also examined the expression of several cell cycle regulatory proteins in both MIA PaCa-2 and SUIT-2 cells by western blotting. Classical isobolographic analysis of the MTT assay results showed that the combination of S-1 and GEM had a synergistic effect in SUIT-2 cells, and flow cytometric analysis of the cell cycle showed that the combination of S-1 plus GEM induced S-phase arrest to a greater degree than did either S-1 or GEM alone. Also, the combination of S-1 and GEM resulted in the downregulation of cyclin D1 expression and upregulation of cyclin A, p21 and p27 expression levels. Treatment of MIA PaCa-2 and SUIT-2 cells with a combination of both drugs also led to the increased phosphorylation of checkpoint kinase 1. Combined treatment with S-1 and GEM resulted in more prolonged S-phase arrest than with either treatment alone. This difference is shown to be potentially due to the higher levels of phosphorylated checkpoint kinase 1 in pancreatic cancer cell lines treated with the two agents.

Acute kidney injury in Japanese type 2 diabetes patients receiving sodium-glucose cotransporter 2 inhibitors: A nationwide cohort study.

The present retrospective study aimed to identify factors associated with an increased risk of acute kidney injury in Japanese patients with type 2 diabetes treated with sodium-glucose cotransporter 2 inhibitors. We identified 171,622 patients with type 2 diabetes treated with sodium-glucose cotransporter 2 inhibitors; among them, 476 (0.3%) patients developed acute kidney injury. The hazard ratio for acute kidney injury occurrence risk was analyzed using a Cox proportional hazards model adjusted for patient characteristics at baseline and use of concomitant agents. In the adjusted model, patients who developed acute kidney injury were mostly men, aged ≥65 years, had lower body mass index, had a history of heart failure and used diuretics more frequently than those who did not. These findings suggest that associated clinical risk factors should be thoroughly evaluated before administering sodium-glucose cotransporter 2 inhibitors to minimize acute kidney injury onset.

Internal Validation of a Risk Scoring System for Venous Thromboembolism After Total hip or Knee Arthroplasty.

We developed a computerized clinical decision support system (CCDSS) for venous thromboembolism (VTE) risk assessment. We aimed to demonstrate its relevance and evaluate associations between risk level and VTE incidence in patients undergoing total hip/knee arthroplasty. In this case-control study, VTE was confirmed using ultrasonography/computed tomography angiography in 1098 adults at a tertiary care hospital over five years (2013-2018). Postoperative VTE incidence was classified into three risk levels (moderate, high, and highest). The overall VTE incidence was 11.7%, which increased with a risk level of 0%, 5.8%, and 12.8% in moderate-risk, high-risk, and highest-risk patients, respectively. Highest-risk patients were significantly more likely to develop VTE than high-risk patients (odds ratio [OR] 2.4; 95% confidence interval [CI] 1.2-5.5; p = 0.01). VTE development was more likely in patients with risk scores ≥4 relative to those with risk scores of 2-3 (OR 1.8; 95% CI 1.2-2.7; p = 0.003) and -1 to 1 (OR 3.3; 95% CI 1.6-7.7; p < 0.001). This study indicates that risk level and VTE incidence are associated; our scoring system appears useful for patients undergoing total hip/knee arthroplasty.