Pharmacokinetic Study for Bridging Data Package

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Effects of pregnane X receptor (NR1I2) and CYP2B6 genetic polymorphisms on the induction of bupropion hydroxylation by rifampin.

We investigated genetic polymorphisms in the pregnane X receptor (NR1I2) in Korean individuals (n = 83) and the effects of NR1I2 genotypes on rifampin-mediated induction of bupropion hydroxylation. The pharmacokinetics of bupropion and hydroxybupropion were evaluated after an oral dose of bupropion (150 mg) administered before and after rifampin treatment for 7 days in 35 healthy subjects. The area under the time-concentration curve (AUC) ratio of hydroxybupropion to bupropion in CYP2B6*6 carriers was significantly lower than that in CYP2B6*6 noncarriers in both the basal and rifampin-induced states (p = 0.012). Among the CYP2B6*6 carriers (n = 13), the NR1I2 TGT (-25385T + g.7635G + g.8055T) carriers exhibited a significantly lower AUC ratio, representing the CYP2B6 hydroxylation activity, compared with the TGT noncarriers, in the induced state (11.9 versus 20.3, p = 0.045). The percent difference in the AUC ratio between the basal and induced states was also significantly different (212% versus 58.8%, p = 0.006). However, no significant difference was observed among the NR1I2 TGT genotypes for the CYP2B6*6 noncarriers (n = 22). In conclusion, it is suggested the NR1I2 TGT genotype decreases the bupropion hydroxylation induced by treatment with rifampin, particularly in CYP2B6*6 carriers.ope

낸드 플래시 기반 저장장치의 수명 향상을 위한 계층 교차 최적화 기법

학위논문 (박사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2016. 2. 김지홍.Replacing HDDs with NAND flash-based storage devices (SSDs) has been one of the major challenges in modern computing systems especially in regards to better performance and higher mobility. Although uninterrupted semiconductor process scaling and multi-leveling techniques lower the price of SSDs to the comparable level of HDDs, the decreasing lifetime of NAND flash memory, as a side effect of recent advanced device technologies, is emerging as one of the major barriers to the wide adoption of SSDs in high-performance computing systems. In this dissertation, we propose new cross-layer optimization techniques to extend the lifetime (in particular, endurance) of NAND flash memory. Our techniques are motivated by our key observation that erasing a NAND block with a lower voltage or at a slower speed can significantly improve NAND endurance. However, using a lower voltage in erase operations causes adverse side effects on other NAND characteristics such as write performance and retention capability. The main goal of the proposed techniques is to improve NAND endurance without affecting the other NAND requirements. We first present Dynamic Erase Voltage and Time Scaling (DeVTS), a unified framework to enable a system software to exploit the tradeoff relationship between the endurance and erase voltages/times of NAND flash memory. DeVTS includes erase voltage/time scaling and write capability tuning, each of which brings a different impact on the endurance, performance, and retention capabilities of NAND flash memory. Second, we propose a lifetime improvement technique which takes advantage of idle times between write requests when erasing a NAND block with a slower speed or when writing data to a NAND block erased with a lower voltage. We have implemented a DeVTS-enabled FTL, called dvsFTL, which optimally adjusts the erase voltage/time and write performance of NAND devices in an automatic fashion. Our experimental results show that dvsFTL can improve NAND endurance by 62%, on average, over DeVTS-unaware FTL with a negligible decrease in the overall write performance. Third, we suggest a comprehensive lifetime improvement technique which exploits variations of the retention requirements as well as the performance requirement of SSDs when writing data to a NAND block erased with a lower voltage. We have implemented dvsFTL+, an extended version of dvsFTL, which fully utilizes DeVTS by accurately predicting the write performance and retention requirements during run times. Our experimental results show that dvsFTL+ can further improve NAND endurance by more than 50% over dvsFTL while preserving all the NAND requirements. Lastly, we present a reliability management technique which prevents retention failure problems when aggressive retention-capability tuning techniques are employed in real environments. Our measurement results show that the proposed technique can recover corrupted data from retention failures up to 23 times faster over existing data recovery techniques. Furthermore, it can successfully recover severely retention-failed data, such as ones experienced 8 times longer retention times than the retention-time specification, that were not recoverable with the existing technique. Based on the evaluation studies for the developed lifetime improvement techniques, we verified that the cross-layer optimization approach has a significant impact on extending the lifetime of NAND flash-based storage devices. We expect that our proposed techniques can positively contribute to not only the wide adoption of NAND flash memory in datacenter environments but also the gradual acceleration of using flash as main memory.Chapter 1 Introduction 1 1.1 Motivation 1 1.2 Dissertation Goals 3 1.3 Contributions 4 1.4 Dissertation Structure 5 Chapter 2 Background 7 2.1 Threshold Voltage Window of NAND Flash Memory 7 2.2 NAND Program Operation 10 2.3 Related Work 11 2.3.1 System-Level SSD Lifetime Improvement Techniques 12 2.3.2 Device-Level Endurance-Enhancing Technique 15 2.3.3 Cross-Layer Optimization Techniques Exploiting NAND Tradeoffs 17 Chapter 3 Dynamic Erase Voltage and Time Scaling 20 3.1 Erase Voltage and Time Scaling 22 3.1.1 Motivation 22 3.1.2 Erase Voltage Scaling 23 3.1.3 Erase Time Scaling 26 3.2 Write Capability Tuning 28 3.2.1 Write Performance Tuning 29 3.2.2 Retention Capability Tuning 30 3.2.3 Disturbance Resistance Tuning 33 3.3 NAND Endurance Model 34 Chapter 4 Lifetime Improvement Technique Using Write-Performance Tuning 39 4.1 Design and Implementation of dvsFTL 40 4.1.1 Overview 40 4.1.2 Write-Speed Mode Selection 41 4.1.3 Erase Voltage Mode Selection 44 4.1.4 Erase Speed Mode Selection 46 4.1.5 DeVTS-wPT Aware FTL Modules 47 4.2 Experimental Results 50 4.2.1 Experimental Settings 50 4.2.2 Workload Characteristics 53 4.2.3 Endurance Gain Analysis 54 4.2.4 Overall Write Throughput Analysis 56 4.2.5 Detailed Analysis 58 Chapter 5 Lifetime Improvement Technique Using Retention-Capability Tuning 60 5.1 Design and Implementation of dvsFTL+ 62 5.1.1 Overview 62 5.1.2 Retention Requirement Prediction 64 5.1.3 Maximization of Endurance Benefit 66 5.1.4 Minimization of Reclaim Overhead 68 5.2 Experimental Results 69 5.2.1 Experimental Settings 69 5.2.2 Workload Characteristics 70 5.2.3 Endurance Gain Analysis 72 5.2.4 NAND Requirements Analysis 73 5.2.5 Detailed Analysis of Retention-Time Predictor 76 5.2.6 Detailed Analysis of Endurance Gain 83 Chapter 6 Reliability Management Technique for NAND Flash Memory 87 6.1 Overview 89 6.2 Motivation 91 6.2.1 Limitations of the Existing Retention-Error Management Policy 91 6.2.2 Limitations of the Existing Retention-Failure Recovery Technique 92 6.3 Retention Error Recovery Technique 95 6.3.1 Charge Movement Model 95 6.3.2 A Selective Error-Correction Procedure 99 6.3.3 Implementation 100 6.4 Experimental Results 103 Chapter 7 Conclusions 108 7.1 Summary and Conclusions 108 7.2 Future Work 110 7.2.1 Lifetime Improvement Technique Exploiting The Other NAND Tradeoffs 110 7.2.2 Development of Extended Techniques for DRAM-Flash Hybrid Main Memory Systems 111 7.2.3 Development of Specialized SSDs 112 Bibliography 114 초 록 122Docto

Surveillance versus Adjuvant Treatment with Chemotherapy or Radiotherapy for Stage I Seminoma: A Systematic Review and Meta-Analysis According to EAU COVID-19 Recommendations

Background and Objectives: During the coronavirus disease 2019 (COVID-19) outbreak, the European Association of Urology (EAU) Guidelines Office Rapid Reaction Group (GORRG) recommended that patients with clinical stage I (CSI) seminoma be offered active surveillance (AS). This meta-analysis aimed to evaluate the efficacy of AS versus adjuvant treatment with chemotherapy or radiotherapy for improving the overall survival (OS) of CSI seminoma patients. Materials and Methods: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PubMed/Medline, EMBASE, and Cochrane Library databases were searched. The primary outcome was 5-year OS, and the secondary outcome was the 5-year relapse-free survival (RFS). The outcomes were analyzed as odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 14 studies were included. Overall, the quality scores were relatively high, and little publication bias was noted. In terms of the 5-year OS, 7 studies were analyzed; there was no significant difference between AS and adjuvant treatment (OR, 0.99; 95% CI, 0.41-2.39; p = 0.97). In terms of 5-year RFS, 12 studies were analyzed. Adjuvant treatment reduced the risk of 5-year recurrence by 85% compared with AS (OR, 0.15; 95% CI, 0.08-0.26; p < 0.001). Conclusions: In terms of the OS in CSI seminoma patients, no intergroup difference was noted, so it is reasonable to offer AS, as recommended by the EAU GORRG until the end of the COVID-19 pandemic. However, since there is a large intergroup difference in the recurrence rate, further research on the long-term (>5 years) outcomes is warranted.ope

Comparison of Surgical Outcomes between Single-Use and Reusable Flexible Ureteroscopes for Renal Stone Management: A Systematic Review and Meta-Analysis

Background and Objectives: Disposable flexible ureteroscopes have been widely used because of their cost-effectiveness and higher sterility potential compared with reusable flexible ureteroscopes. This study aimed to compare the surgical outcomes and complication rates in patients who undergo reusable or disposable flexible ureteroscopic stone surgeries (fURS) for urinary stone disease. Materials and Methods: A systematic review and meta-analysis were conducted under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. This systematic review was registered with PROSPERO (CRD42022331291). Clinical trials comparing reusable and disposable fURS for stone disease were found from PubMed, EMBASE, Cochrane Library, and the Web of Science up to March 2022. Participants were patients with upper urinary tract stones; the interventions were reusable or disposable fURS. Outcomes, including stone-free rate, operation time, length of hospital stay, and complication rate, were compared for analysis. Results: Overall, 111 studies were identified, but after removing duplicate studies, 75 studies remained. Thirty-two of these studies were excluded. Of the 43 screened studies, 11 met the eligibility criteria. There was no difference in the stone-free rate (SFR) between disposable and reusable fURS (p = 0.14; OR = 1.36; 95% CI, 0.9 to 2.04). For operation time, no difference was identified between reusable and disposable fURS groups (p = 0.12; MD = -5.31; 95% CI, -12.08 to 1.46). For hospital stay, there was also no difference between the two groups (p = 0.61; MD = -0.03; 95% CI, -0.17 to 0.10). There was no significant difference in complication rate between the two groups (p = 0.85; OR = 0.95; 95% CI, 0.56 to 1.61). Conclusions: There were no differences in the SFR, operation time, length of hospital stay, and complication rate between reusable and disposable fURS. Disposable fURS may be a comparable alternative to reusable fURS.ope

A New Parameter for Calcium Oxalate Stones: Impact of Linear Calculus Density on Non-Contrast Computed Tomography

Background and Objectives: Non-contrast computed tomography (NCCT) is widely used to evaluate urolithiasis. The NCCT attenuation, measured in Hounsfield units (HU), has been evaluated to predict stone characteristics. We propose a novel parameter, linear calculus density (LCD), and analyze variables from NCCT imaging to predict calcium oxalate (CaOx) stones, which are common and challenging to fragment. Materials and Methods: We retrospectively reviewed the medical records of patients with urolithiasis between 2014 and 2017. Among those, 790 patients were included. Based on the NCCT pre-treatment, the maximal stone length (MSL), mean stone density (MSD), and stone heterogeneity index (SHI) were obtained. In addition, the variation coefficient of stone density (VCSD = SHI/MSD × 100) and linear calculus density (LCD = VCSD/MSL) were calculated. In accordance with the stone analysis, the patients were divided into two groups (CaOx and non-CaOx groups). The logistic regression model and receiver operating characteristic (ROC) curve were used for predictive modeling. Results: In the CaOx group, the SHI, VCSD, and LCD were more significant than in the non-CaOx group (all p < 0.001). SHI (OR 1.002, 95% CI 1.001-1.004, p < 0.001), VCSD (OR 1.028, 95% CI 1.016-1.041, p < 0.001), and LCD (OR 1.352, 95% CI 1.270-1.444, p < 0.001) were significant independent factors for CaOx stones in the logistic regression models. The areas under the ROC curve for predicting CaOx stones were 0.586 for SHI, 0.66 for VCSD, and 0.739 for LCD, with a cut-point of 2.25. Conclusions: LCD can be a useful new parameter to provide additional information to help discriminate CaOx stones before treatment.ope

Silodosin versus Tamsulosin for Medical Expulsive Therapy of Ureteral Stones: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background and Objectives: This systematic review and meta-analysis of randomized controlled trials was performed to compare the therapeutic effects and safety profiles of silodosin and tamsulosin for medical expulsive therapy (MET) of ureteral stones. Materials and Methods: We searched PubMed, EMBASE, the Cochrane Library, and Web of Science to identify articles published before July 2022 that described randomized controlled trials comparing silodosin and tamsulosin for MET of ureteral stones. Endpoints were stone expulsion rate, stone expulsion time, and total complication rate. Results: In total, 14 studies were included in our analysis. The size of ureteral stones was &lt;1 cm. Compared with tamsulosin, silodosin resulted in a significantly higher stone expulsion rate (p &lt; 0.01, odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.91 to 3.06, I2 = 0%) and significantly shorter stone expulsion time (p &lt; 0.01, mean difference = -3.04, 95% CI = -4.46 to -1.63, I2 = 89%). The total complication rate did not significantly differ between silodosin and tamsulosin (p = 0.33, OR = 1.15, 95% CI = 0.87 to 1.52, I2 = 7%). Conclusions: Compared with tamsulosin, silodosin resulted in significantly better expulsion of ureteral stones &lt;1 cm. The total complication rate did not significantly differ between silodosin and tamsulosin. Thus, silodosin may be superior to tamsulosin for MET of ureter stones &lt;1 cm.ope

The Safety and the Pharmacokinetics and Pharmacodynamics of a Pegylated Interferon Alpha-2a Formulation, Dong-A's DA-3021

Background: Interferons (IFNs) are proteins made and released by lymphocytes in response to the presence of pathogens and used in the treatment of hepatitis B or C virus. The purpose of this study is to investigate the safety, pharmacokinetics and pharmacodynamics of a pegylated interferon alpha-2a formulation. Methods: This study was a randomized, open-label, 2-period, crossover design. Each group had 17 subjects who took $180\;{\mu}g$ of PEGASYS^® as a reference formulation and DA-3021 as a test formulation with a washout period of 21 days. Blood samples were obtained over 336 hours after the dose in each treatment period. Blood concentrations of interferon were analyzed using the enzyme-linked immunosorbent assay (ELISA). The primary pharmacokinetic parameters were Cmax and $AUC_{last}$. The pharmacodynamics were assessed by 2',5'-OAS (oligoadenylate synthetase) using a radioimmunoassay (RIA). The primary pharmacodynamic parameters were $E_{max}$ and $AUE_{last}$. Results: Thirty four healthy male volunteers participated in the study and completed both treatment periods. The 90% confidence intervals for the geometric mean ratios of the pharmacodynamic parameters (test : reference drug) were 0.95-1.09 for $AUE_{last}$ and 0.92-1.05 for $E_{max}$, lying within the bioequivalence range of 0.8-1.25, while the pharmacokinetics parameters were not included within the equivalence range. Most common adverse events were flu-like symptoms, with no serious adverse event reported. Conclusion: The results assessed by the bioequivalence criterion indicated that the pharmacodynamics of DA-3021 was equivalent to that of PEGASYS®.ope

Serum Cystatin C Is a Major Predictor of Vancomycin Clearance in a Population Pharmacokinetic Analysis of Patients with Normal Serum Creatinine Concentrations

We developed a population pharmacokinetic model of vancomycin by integrating the effects of cystatin C and other demographic factors in a large population of Korean patients with normal serum creatinine concentrations to elucidate the precise role of serum cystatin C concentrations in the prediction of vancomycin clearance. A population pharmacokinetic model of vancomycin was developed using NONMEM software from a total of 1,373 vancomycin concentration measurements in 678 patients whose serum creatinine concentrations were lower than 1.2 mg/dL. Covariate selection revealed that cystatin C was the most influential factor and had negative influence ((-0.78)) in the relationship. Total body weight, sex, age, and serum creatinine were also significantly correlated with the clearance. The estimated intersubject variabilities of clearance and volume of distribution were 24.7% and 25.1%, respectively. A 14-fold difference in predicted trough concentrations was observed according to only cystatin C concentrations in a population of simulated individuals with median demographic characteristics. The use of serum cystatin C as marker of vancomycin clearance for more accurate predictions of serum vancomycin concentrations could be useful, particularly among patients with normal serum creatinine concentrations.OAIID:oai:osos.snu.ac.kr:snu2013-01/102/0000050045/1SEQ:1PERF_CD:SNU2013-01EVAL_ITEM_CD:102USER_ID:0000050045ADJUST_YN:YEMP_ID:A078941DEPT_CD:801CITE_RATE:.993FILENAME:vancomycin cystatin c model_jkms 2013.pdfDEPT_NM:의학과EMAIL:[email protected]_YN:YCONFIRM:

Natural Gesture Recognition for Realistic Interaction in the Virtual Environment

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