Outgrowing the Predicament? National Identity and Seoul’s Dokdo Policy

Patrick Flamm 인하대학교 국제관계연구소 2015 Pacific Focus Vol.30 No.2

The Dokdo/Takeshima dispute between the ROK and Japan remains the single biggest obstacle to an improvement of South Korean–Japanese relations. The issue forces South Korean foreign policy actors to constantly maneuver between engagement with Japan out of strategic interests and confrontation because of the islets’ symbolic value for Korean national identity. Still, the scholarly debate has failed to comprehensively grasp the constitution of Dokdo as a political issue, while reducing it to “irrational emotions” that unnecessarily hinder urgent bilateral cooperation. Further, there prevails a one-dimensional and fixed understanding of Korean identity as largely post-colonial, without acknowledging the recent research on an increasingly internationalized Korean self-understanding. In taking a constructivist, discourse analytical approach, I am able to provide a sound assessment of the various active identity narratives relevant to Seoul’s Dokdo policy, while considering the odds for political change.

Safety and Efficacy of Elbasvir/Grazoprevir in Hepatitis C Virus (HCV) GT1-and GT4 infected Participants 65 Years and Older

( Steven L. Flamm ),( Cheng-yuan Peng ),( Oren Shibolet ),( Ronald Nahass ),( Peggy Hwang ),( Eliav Barr ),( Michael Robertson ),( Barbara Haber ),( Eungeol Sim ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Safety and efficacy of HCV therapy in older individuals is of growing importance as the population with HCV infection ages. The objectives of this study were to compare the safety and efficacy of elbasvir (EBR)/grazoprevir (GZR) in participants aged ≥65 and <65 years. Methods: Safety and efficacy data from participants with HCV genotype (GT)1 or 4 infection receiving EBR (50 mg/day)/GZR (100 mg/day) for 12 weeks in 12 clinical trials were pooled and analyzed according to age (≥65 years vs <65 years). Sustained virologic response (SVR) 12 was defined as HCV RNA <lower limit of quantification 12 weeks after end of treatment (COBAS ® AmpliPrep/COBAS® Taqman® v2.0). Results: In participants aged ≥65 years (n=339), mean age was 70 years (range, 65-82) versus 49 years (range, 18-64) in those <65 years (n=2139). Demographic parameters in participants aged ≥65 years versus <65 years were noncirrhotic (85% vs 83%), treatment-naive (72% vs 85%), HCV GT1 infection (99% vs 95%), male (44% vs 61%), and white (26% vs 59%), black (12% vs 13%), and Asian (61% vs. 26%) race, respectively. SVR12 rates were 323/339 (95.3%) and 2041/2139 (95.4%) in participants with HCV GT1 or 4 infection aged ≥65 and < 65 years, respectively (Table). Rates of serious adverse events (SAEs), discontinuations due to adverse events (AEs), drug-related SAEs, and deaths were similar in both age groups (Table). AEs (occurring in >5% of either age group) in participants aged ≥ 65 versus <65 years were headache (7.1% vs 13.0%), fatigue (6.8% vs 11.3%), nasopharyngitis (6.5% vs 4.9%), nausea (4.1% vs 7.2%), and diarrhea (3.5% vs 5.8%), respectively. Conclusions: The efficacy of EBR/GZR for 12 weeks was similar in participants aged ≥65 years versus those <65 years. Treatment was well tolerated in both age groups, with low rates of SAEs, discontinuations due to AEs, drug-related SAEs, and deaths.

향상된 Beam Shaping 적용시킨 극초단 레이저 펄스에 의한 퍼커션 드릴링 프로세스 스케일링

D. Grossmann,D. Flamm,J. Hellstern,M. Sailer,M. Kumkar 한국레이저가공학회 2020 Laser Solutions Vol.23 No.5

Rising South Korea: A Minor Player or a Regional Power?

David Shin,Patrick Flamm 인하대학교 국제관계연구소 2013 Pacific Focus Vol.28 No.3

South Korea’s rising status in regional and global affairs has received significant attention in recent years. In academic, media, and policy debates,though, South Korea is usually regarded as a mere middle power that, due to its geopolitical situation, has only limited leeway in its foreign policy choices. Accordingly, it must constantly maneuver between its larger neighbors:China, Japan, and Russia. However, this perspective negates the fact that the same geopolitical constraints also apply to other states in the region. Thus no country can easily project its power onto others. We use the concept of “regional power” as a template for investigating South Korea’s rising stature in regional and global politics, and argue that Seoul appears quite capable of keeping up with other assumed regional powers. Hence, we not only provide a novel account of South Korea’s foreign policy options but also go beyond current approaches by asking about the (undetermined) possibilities that exist for Seoul’s regional relations

Pseudomonas aeruginosa MdaB and WrbA are Water-soluble Two-electron Quinone Oxidoreductases with the Potential to Defend against Oxidative Stress

Laura K Green,Anne C La Flamme,David F Ackerley 한국미생물학회 2014 The journal of microbiology Vol.52 No.9

Water-soluble quinone oxidoreductases capable of reducingquinone substrates via a concerted two-electron mechanismhave been implicated in bacterial antioxidant defence. Twoelectrontransfer avoids formation of dangerously reactivesemi-quinone intermediates, moreover previous work inPseudomonas putida indicated a direct protective effect forthe quinols generated by an over-expressed oxidoreductase. Here, the Pseudomonas aeruginosa orthologs of five quinoneoxidoreductases – MdaB, ChrR, WrbA, NfsB, and NQO1 –were tested for their possible role in defending P. aeruginosaagainst H2O2 challenge. In in vitro assays, each enzyme wasshown to reduce quinone substrates with only minimal semiquinoneformation. However, when each was individuallyover-expressed in P. aeruginosa no overt H2O2-protectivephenotype was observed. It was shown that this was due toa masking effect of the P. aeruginosa catalase, KatA; in a katAmutant, H2O2 challenged strains over-expressing the WrbAand MdaB orthologs grew significantly better than the emptyplasmid control. A growth advantage was also observed forH2O2 challenged P. putida strains over-expressing P. aeruginosawrbA, mdaB or katA. Despite not conferring a growthadvantage to wild type P. aeruginosa, it is possible that thesequinone oxidoreductases defend against H2O2 toxicity atlower concentrations.

HCV, Alcoholic : PE-136 ; Sustained virologic response (SVR) in prior peginterferon/ribavirin (PR) treatment failures after retreatment with boceprevir (BOC) + PR: The PROVIDE study interim results

( Jp Bronowicki ),( M Davis ),( S Flamm ),( S Gordon ),( E Lawitz ),( E Yoshida ),( J Galati ),( V Luketic ),( J Mccone ),( I Jacobson ),( P Marcellin ),( A Muir1 ),( F Poordad ),( Ld Pedicone ),( W D 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

Background: Patients in the PR control arms of BOC Phase 2/3 studies who did not achieve SVR could enroll in PROVIDE and receive BOC+PR. This interim analysis examines the preliminary efficacy and safety of BOC+PR in patients who failed prior treatment with PR. Methods: BOC (800 mg TID with food) was given with P 1.5 mcg/kg/week and weight-based R (600-1400 mg/day) BID for up to 44 weeks. If >2 weeks had elapsed since end of treatment in the previous study, PR was given for 4 weeks before adding BOC. Protocol specified analyses include patients who received at least one dose of BOC. Denominators for on-treatment response include patients who reached the specific time point or discontinued. The denominators for SVR include all patients who reached end of follow-up, discontinued, or were treatment failures. Results: Characteristics of 168 enrolled patients were: 67% male, 84% Caucasian, mean age 52 years, mean BMI 27.9 kg/m2, 77% high viral load (>800,000 IU/mL; mean log10 6.26); 10% cirrhotic; 61% subtype 1a. Table shows the proportion of BOC treated patients with undetectable HCV RNA at tested time points. SVR was achieved in 40% of prior null responders (<2 log10 decline in HCV RNA at TW12 in prior study) and 68% of prior partial responders/relapsers; 78% (38/49) of prior null responders and 24% (26/107) of prior partial responders/ relapsers had <1 log10 decline in HCV RNA after the PR lead in. Overall SVR was 47% in patients with <1 log10 decline with lower SVR rates in prior null responders (36%) vs. prior partial responders/relapsers (65%). 68% of patients with >1 log decline achieved SVR (55% prior null responders; 70% prior partial responders/relapsers). Seven percent of patients discontinued due to AEs, while 48% experienced anemia, 34% dysgeusia and 22% neutropenia. Conclusions: BOC+PR achieved high SVR rates regardless of prior response to PR. The degree of interferon responsiveness after PR lead in correlates with prior response and can help predict SVR for prior null responders. The safety profile is comparable to that previously reported for BOC+PR.

HCV : PE-136 ; Sustained virologic response (SVR) in prior peginterferon/ribavirin (PR) treatment failures after retreatment with boceprevir (BOC) + PR: The PROVIDE study interim results

( Jp Bronowicki ),( M Davis ),( S Flamm ),( S Gordon ),( E Lawitz ),( E Yoshida ),( J Galati ),( V Luketic ),( J Mccone ),( Jacobson ),( P Marcellin ),( A Muir ),( F Poordad ),( Ld Pedicone ),( W Deng 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1

Background: Patients in the PR control arms of BOC Phase 2/3 studies who did not achieve SVR could enroll in PROVIDE and receive BOC+PR. This interim analysis examines the preliminary efficacy and safety of BOC+PR in patients who failed prior treatment with PR. Methods: BOC (800 mg TID with food) was given with P 1.5 mcg/kg/week and weight-based R (600-1400 mg/day) BID for up to 44 weeks. If >2 weeks had elapsed since end of treatment in the previous study, PR was given for 4 weeks before adding BOC. Protocol specified analyses include patients who received at least one dose of BOC. Denominators for on-treatment response include patients who reached the specific time point or discontinued. The denominators for SVR include all patients who reached end of follow-up, discontinued, or were treatment failures. Results: Characteristics of 168 enrolled patients were: 67% male, 84% Caucasian, mean age 52 years, mean BMI 27.9 kg/m2, 77% high viral load (>800,000 IU/mL; mean log10 6.26); 10% cirrhotic; 61% subtype 1a. Table shows the proportion of BOC treated patients with undetectable HCV RNA at tested time points. SVR was achieved in 40% of prior null responders (<2 log10 decline in HCV RNA at TW12 in prior study) and 68% of prior partial responders/relapsers; 78% (38/49) of prior null responders and 24% (26/107) of prior partial responders/ relapsers had <1 log10 decline in HCV RNA after the PR lead in. Overall SVR was 47% in patients with <1 log10 decline with lower SVR rates in prior null responders (36%) vs. prior partial responders/relapsers (65%). 68% of patients with >1 log decline achieved SVR (55% prior null responders; 70% prior partial responders/relapsers). Seven percent of patients discontinued due to AEs, while 48% experienced anemia, 34% dysgeusia and 22% neutropenia. Conclusions: BOC+PR achieved high SVR rates regardless of prior response to PR. The degree of interferon responsiveness after PR lead in correlates with prior response and can help predict SVR for prior null responders. The safety profile is comparable to that previously reported for BOC+PR.

A Randomized, Controlled Trial of Sofosbuvir/Velpatasvir/Voxilaprevir or Sofosbuvir/Velpatasvir for 12 Weeks in DAA-Experienced Patients with GT1-6 HCV Infection: The POLARIS-4 Study

( Paul Kwo ),( Stefan Zeuzem ),( Steven L. Flamm ),( Myron Tong ),( John M Vierling ),( Stephen Pianko ),( Peter Buggisch ),( Victor de Lédinghen ),( Robert H. Hyland ),( Xiaoru Wu ),( Evguenia S. Sva 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: DAAs provide safe and highly efficacious therapies for HCV infection. However, the small proportion of patients who do not achieve a sustained virologic response with DAA-based regimens represent a population with an unmet medical need. Sofosbuvir(SOF) and velpatasvir(VEL) are pangenotypic inhibitors of the HCV NS5B and NS5A proteins, respectively, and voxilaprevir(VOX) is a pangenotypic HCV NS3/4A protease inhibitor. This study evaluates treatment with a SOF/VEL/VOX for 12weeks and a SOF/VEL for 12weeks as salvage regimens in DAA-experienced patients who had not previously received an NS5A inhibitor. Methods: Patients with genotypes 1-3 were randomized 1:1 to receive open-label SOF/VEL/VOX or SOF/VEL for 12weeks, stratified according to genotype and cirrhosis status. Patients of all other genotypes were assigned to receive SOF/VEL/VOX for 12weeks. DAA-experienced patients who previously were treated with an NS5A inhibitor or with only an NS3/4A protease inhibitor in combination with ribavirin and Peg-IFN were excluded. The primary endpoint evaluates the superiority of the SVR12 of each treatment to a prespecified goal of 85%. Results: Of the 333 patients who were randomized and treated, 77% were male, 19% had the IL28B CC genotype, 46% had compensated cirrhosis and 43% had genotype 1 infection. Most patients had prior DAA experience with either an NS5B inhibitor alone(73%) or an N5SB inhibitor and an NS3/4A protease inhibitor(25%); the most common prior treatment regimens were SOF with ribavirin ±Peg-IFN and SOF combined with simeprevir. Treatment was well tolerated.No SAE was assessed to be attributable to study drug. Overall, SVR12 was achieved in 97%(177/182) of patients treated with SOF/VEL/VOX and 90%(136/151) patients treated with SOF/VEL. SOF/VEL/VOX met the prespecified 85% SVR12 performance goal(p<0.001); SOF/VEL did not. Conclusions: SOF/VEL/VOX for 12 weeks provides a safe, well tolerated and effective retreatment options for patients who did not previously achieve SVR following treatment with non-NS5A inhibitor-containing DAA regimens.

The Safety and Tolerability of SOF/VEL/VOX for 8/12 Weeks in >1,000 Patients Treated in the POLARIS Studies: An Integrated Analysis

( Michael Manns ),( Edward J. Gane ),( Bernard E. Willems ),( Stuart K. Roberts ),( Steven Flamm ),( Marc Bourlière ),( Tarik Asselah ),( Laurent Alric ),( Sunjin Hwang ),( Robert H. Hyland ),( Luisa 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: The once-daily fixed-dose combination tablet of sofosbuvir/ velpatasvir/voxilaprevir (SOF/VEL/VOX) was evaluated for the treatment of genotype 1-6 HCV patients with and without compensated cirrhosis. Treatment was for 12 weeks for DAA-experienced patients (POLARIS-1 and POLARIS-4) and for 8 weeks for DAA-naive patients (POLARIS-2 and POLARIS-3). This analysis describes the safety of these 4 Phase 3 studies. Methods: Treatment-emergent adverse events (AEs) and laboratory abnormalities were assessed in patients who received SOF/VEL/VOX or placebo for 12 weeks(POLARIS-1), SOF/VEL/VOX or SOF/VEL for 12 weeks(POLARIS-4), or SOF/VEL/VOX for 8 weeks or SOF/VEL for 12 weeks(POLARIS-2 and POLARIS-3). SAEs and deaths were followed until post-treatment Week 24. Results: 1056 patients were treated with SOF/VEL/VOX for 8 (n=611) or 12 (n=445) weeks, 700 received SOF/VEL for 12 weeks, and 152 received placebo. 38% had compensated cirrhosis, 28% had a BMI ≥30 kg/m2, 36% were female, and 12% were ≥65 years old. Two deaths were reported, one illicit drug overdose and one attributed to hypertension, neither were related to treatment. SAEs and discontinuations were more frequent in the placebo group and occurred with similar frequency in the other groups; none were related to study treatment. Headache, fatigue, nausea, and diarrhea were the most common AEs. Mild diarrhea and nausea occurred more frequently in the SOF/VEL/VOX groups. Overall, 5.1 - 6.6% of patients who received SOF/VEL/VOX or SOF/VEL had Grade 3 or 4 laboratory abnormalities. Among patients receiving VOX, one patient each had a Grade 3 elevation in ALT and bilirubin. Conclusions: SOF/VEL/VOX for 8 or 12 weeks in the POLARIS studies was well tolerated with a low frequency of Grade 3 or 4 AEs, SAEs, and AEs leading to discontinuation. The frequency of AEs in the SOF/VEL/VOX groups was similar to SOF/VEL and placebo groups, with higher rates of mild diarrhea and nausea compared to SOF/VEL.

Impact of Treatment Duration and Addition of Ribavirin on Real-World Effectiveness of Elbasvir/Grazoprevir: Retrospective Analyses from the Trio Network

( Eungeol Sim ),( Chizoba Nwankwo ),( Bruce Bacon ),( Michael P. Curry ),( Douglas T. Dieterich ),( Steven L. Flamm ),( Kris V. Kowdley ),( Scott Milligan ),( Naoky C. Tsai ),( Zobair M. Younossi ),( 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Lengthening treatment with elbasvir/grazoprevir (EBR/ GZR) to 16 weeks and/or adding ribavirin (RBV) is recommended for select patients with HCV GT1 infection. However, realworld data (J Hepatol 2017;66:S295) suggest that utilization of this regimen is low. This study examined the use of 12- and 16- week EBR/GZR ±RBV regimens in different patient subgroups. Methods: Data were collected from providers and specialty pharmacies through Trio Health’s disease management program. Patients (n=442) with HCV GT1 infection who initiated EBR/GZR therapy between Jan 28, 2016 (FDA approval) to Dec 31, 2016 were included. Results: 401 (91%) patients received EBR/GZR for 12 weeks, 12 (3%) received EBR/GZR+RBV for 12 weeks, 11 (2%) received EBR/GZR for 16 weeks, and 18 (4%) received EBR/GZR+RBV for 16 weeks. Possible baseline NS5A resistance was identified in 13/285 patients with GT1a infection: 3 (23%) received EBR/ GZR for 12 weeks, 1 (8%) received EBR/GZR+RBV for 12 weeks, 2 (15%) received EBR/GZR for 16 weeks, and 7 (54%) received EBR/GZR+RBV for 16 weeks. Across all patients, the +RBV subgroup had a higher proportion of treatment-experienced patients (43%, 13/30) than the -RBV group (17%, 69/412); and the 16-week subgroup had a higher proportion of GT1A subtype (93%, 27/29) than the 12-week group (62%, 258/413). Other characteristics including gender, age, baseline viral load, and cirrhosis were similar between regimens and between groups defined by RBV addition or therapy duration. SVR12 results at time of abstract submission were available for 262/442 patients. Overall per protocol (PP) SVR12 was 97% (253/262). Across GT1 subgroups (defined by subtype, prior treatment experience, and fibrosis) that received EBR/GZR for 12 weeks without RBV, the PP SVR12 was ≥94% (TABLE). Conclusions: In real-world practice, EBR/GZR was highly effective, with the majority of patients treated for 12 weeks without RBV. Full SVR12 data will be presented at the conference.