Death, cardiac event and acute liver injury of bedaquiline and delamanid in patients with multidrug resistant tuberculosis : a nationwide cohort study

Kim, Juhwan Sungkyunkwan University 2022 국내박사

Background: Bedaquiline and delamanid are newly approved drugs indicated for multidrug resistant tuberculosis (MDR-TB), yet there is a paucity of their safety data beyond experimental setting. Bedaquiline carries a black box warning of increased risk of death compared to the placebo arm, and there is a need to establish the magnitudes of additive QT interval prolonging effect and hepatotoxicity of bedaquiline and delamanid. This study aimed to assess the risk of all-cause death, long QT-related cardiac event, and acute liver injury among MDR-TB patient treated with bedaquiline or delamanid in South Korea. Methods: Individuals aged 18 years or older diagnosed with pulmonary MDR-TB and received at least 4 second-line anti-TB drugs were identified in the South Korea national health insurance system database between 2016 and 2019. Bedaquiline and delamanid groups included those who initiated treatment with bedaquiline- or delamanid-containing regimen, respectively. Comparator group included those who received a standard regimen that included aminoglycosides and/or fluoroquinolones and other second-line anti-TB drugs. Study follow-up began on the day after treatment initiation. Primary outcome was all-cause mortality at 12- and 24-months, and secondary outcomes were long QT-related cardiac event and acute liver injury assessed until the earliest date of discontinuation of index drugs, death or end of study period (December 31st, 2020). I computed stabilized inverse probability of treatment weighting (sIPTW) based on propensity score for receiving bedaquiline or delamanid by fitting a multivariate logistic regression model using the baseline characteristics measured prior or on the date of MDR-TB diagnosis. Then, I estimated sIPTW hazard ratios (HR) with 95% confidence interval (CI) for bedaquiline and delamanid, compared with standard regimen group, adjusted for the baseline characteristics. Results: Among 1,998 MDR-TB patients, 315 (15.8%) and 292 (14.6%) received bedaquiline and delamanid, respectively, and all baseline characteristics were balanced after applying sIPTW. Primary analysis showed non-significant mortality risk reduction in both bedaquiline (sIPTW-adjusted HR 0.73 [95% CI: 0.42-1.27] at 12-month and 0.90 [0.57-1.43] at 24-month) and delamanid groups (0.77 [0.38-1.55] at 12-month and 0.89 [0.50-1.60] at 24-month). sIPTW-adjusted HRs of long QT-related cardiac events and acute liver injury were 1.41 (0.57-3.48) and 1.76 (1.31-2.36) for bedaquiline, and 2.10 (0.95-4.67) and 1.14 (0.81-1.61) for delamanid, respectively. Conclusions: My study addresses the limited data on comparative safety of bedaquiline and delamanid, supporting their use in MDR-TB treatment. Null association between bedaquiline and all-cause death reaffirms its safety and refutes the current black box warning. The risk of serious adverse events with bedaquiline and delamanid warrant further investigation due to limited number of outcomes observed in the study population. 베다퀼린과 델라마니드는 2012년과 2013년 다제내성 결핵 치료를 위해 임상허가를 받은 의약품으로써, 임상시험을 통해 객담배양 음전률 촉진의 효능을 입증 받은 바 있다. 하지만, 임상시험 대상 외 일반인구집단에서의 두 의약품에 대한 안전성 정보는 부족한 실정이다. 베다퀼린은 임상 2상 시험에서 위약군 대비 높은 사망률을 보여 미국 FDA에서 약물에 대한 심각한 약물유해반응 또는 주의사항에 대해 경고하는 Black Box Warning이 발표된 바 있으며, 또한 베다퀼린과 델라마니드 복용에 따른 QT간격 연장 및 급성 간독성 이상반응에 대한 위험성을 확립할 필요가 있다. 따라서 본 연구에서는 국내 보건의료 빅데이터를 활용한 다제내성 결핵 코호트를 구축하여 베다퀼린과 델라마니드의 안전성을 평가하고자 하였다. 전 국민을 포함하는 건강보험공단 건강보험청구자료를 활용하여 후향적 코호트 연구를 수행하였으며, 연구 대상자는 2016년부터 2019년 사이 다제내성 폐결핵을 진단받은 18세 이상 환자로 정의하였다. 베다퀼린 또는 델라마니드를 포함하는 다제내성 결핵 치료요법을 받은 환자를 베다퀼린 또는 델라마니드군으로 정의하였으며, 두 약제를 포함하지 않는 치료요법을 받은 환자를 표준치료군으로 정의하였다. 치료요법을 시작한 날로부터 추적관찰을 시작하였으며, 1차 결과변수는 모든 원인으로 인한 사망으로 정의하였고, 2차 결과변수는 약제 복용기간 내 QT연장으로 인한 심실 부정맥과 급성 간독성 이상반응으로 정의하였다. 신약 복용군과 표준요법군의 비교성을 확보하고 잠재적 교란요인을 통제하기 위하여, 성향점수를 활용한 표준화 역확률가중치(stabilized inverse probability of treatment weight; sIPTW) 방법을 적용하였다. 콕스 비례-위험 모형을 활용하여 각 결과변수에 대한 위험률(hazard ratio; HR)과 그에 따른 95% 신뢰구간(confidence interval; CI)를 산출하였다. 총 1,998명의 다제내성 결핵환자 중, 315명(15.8%)과 292명(14.6%)이 각각 베다퀼린과 델라마니드를 포함하는 치료요법을 받았으며, sIPTW방법을 적용 후 치료군 간의 기본특성이 균형을 이뤘다. 치료 시작 후 12개월 및 24개월 시점에서 베다퀼린 치료요법은 통계적으로 유의하지 않은 사망 위험 감소 효과를 보였으며, (sIPTW-adjusted HR 0.73 [95% CI: 0.42-1.27] 및 0.90 [0.57-1.43]), 델라마니드 치료요법도 비슷한 결과를 보였다(0.77 [0.38-1.55] 및 0.89 [0.50-1.60]). QT 연장으로 인한 심실 부정맥의 위험률은 베다퀼린 치료군에서 1.41 (0.57-3.48), 델라마니드 치료군에서 2.10 (0.95-4.67)로 나타났다. 급성 간독성의 위험률은 베다퀼린 치료군에서 1.76 (1.31-2.36), 델라마니드 치료군에서 1.14 (0.81-1.61)로 나타났다. 본 연구를 통해서 일반인구집단에서 베다퀼린과 델라마니드의 안전성에 대한 실제임상근거를 생성하였다. 베다퀼린 치료요법은 다제내성 결핵 환자에서 사망 위험을 증가시키지 않았으며, 이는 현재 미국 FDA Black Box Warning을 반박하는 근거로 활용할 수 있다. 두 약제 복용에 따른 심실 부정맥 및 급성 간독성 위험에 대해서는 더 많은 연구대상자를 확보하여 위험성 평가 연구 수행이 필요하다.

(A)study on the asymmetrical factorical experiments

Ju Hwan, Kim 동국대대학원 1982 국내석사

Reservoir Characterization of the Horn River Shale in British Columbia, Canada : Integration of Core, Well log and Seismic data

Woo, Ju Hwan 충북대학교 2018 국내박사

The geoscience-based reservoir characterization essentially identifies lithofacies in a different scale based on diverse data such as core, well logs and seismic profiles. The Horn River shale represents about 25.7% (11.1Tcf) of the remaining recoverable raw gas reserves in British Columbia, Canada. The Horn River shale consists of the Muskwa, Otter Park and Evie shales that are underlain by the Keg River carbonates and overlain by the Fort Simpson shales. This study focuses on the stratigraphic and sedimentological features of 162m long borehole in the Horn River shale. Six lithofacies are identified: faintly laminated siliceous mudstone (FLSM), homogeneous siliceous mudstone (HSM), laminated siliceous mudstone (LSM), laminated mixed mudstone (LMM), argillaceous mudstone (AM), and calcareous mudstone (CM). The FLSM and HSM are the most dominant facies of the Evie and Muskwa shales. These facies have high silica and organic contents. In order to establish a quantitative relationship between the core lithology and wireline logs, electrofacies are derived from wireline log data through the pattern recognition method. Prediction of electrofacies in shale succession with core is based on the comparison of results from various supervised methods (MRGC, ANN, and SVM). SVM and ANN methods are important to better understand the complex relationships between core lithofacies and well logs. However, these algorithms have limitations when they are applied to non-cored wells, so the MRGC algorithm was selected to propagate the electrofacies. To build up the seismic-scale facies models, the stochastic methods are appropriate, particularly in case of insufficient electrofacies data. In order to enhance the accuracy and applicability of these methods, this study applies trend data for sequential indicator simulation modeling. The trend data is four equally weighted seismic attributes: density and gamma ray inversion, envelope, and spectral decomposition volume. The 3D model of lithofacies provides lateral facies distribution, and it is useful to visualize porosity, permeability and brittleness of shale succession. The physical, biological and chemical observations in various scales can be integrated within the sequence stratigraphic framework. It is the main procedure of sequence stratigraphic interpretation to recognize key stratal surfaces and stratal stacking patterns. The Th / U ratios against the spectral uranium curve represent a proxy record of sea level change that influences the depositional regime and the accumulation of organic matter. In the shale succession, the T-R sequence bounding surfaces can be recognized from analyses of vertical trends such as lithofacies, spectral gamma-ray, and TOC. The sequence stratigraphic analysis of a vertical succession of variable lithofacies provides geological framework to figure out the sediment type, redox condition, and possible reservoir potential. This study demonstrates that the integration of lithofacies, TOC, spectral gamma ray ratio, and geochemical data is useful for estimating the variation of lithology, detrital flux, redox conditions, and organic matter accumulation in the Horn River shale. The Horn River shales can be divided into six 4th order T-R sequence that are grouped into two 3rd order T-R sequences of a few millions of years.

A study on long-term reliability of Parylene-C coated neural electrode using in-vitro accelerated life test

Kim, Ju Hwan 서울시립대학교 일반대학원 2020 국내석사

Neural electrode has been widely used for research and medical applications and getting more attention due to their expanding utilities for understanding our nervous system. Parylene-C has been widely used as a flexible and biocompatible insulation material for implantable neural electrode because of its good moisture barrier properties, low gas permeability, and high dielectric property. However, the long-term reliability of Parylene-C as the encapsulation layer of neural electrode has not been systemically studied yet. In this paper, we investigated the long-term reliability of Parylene-C coated gold-channel neural electrode. The Parylene-C coated neural electrode was immersed in phosphate buffered saline (PBS) at an elevated temperature to perform an accelerated lifetime test. The electrochemical characteristic data were obtained and analyzed to evaluate the long-term reliability of Parylene-C coated neural electrode. Characteristic change over time was observed and mechanism of failure was investigated. Initial test showed rapid degradation of the characteristics due to humidity penetration. In order to reduce the degradation a flexible printed circuit board (FPCB) was used, and the lifetime of electrode was increased. It was demonstrated that the failure of electrode occurred by not just breakdown of metal-polymer heterojunction but humidity penetration into the PCB-pad site. 신경 전극은 연구 및 임상의료 용도로 널리 사용되고 있으며 특히 신경계에 대한 연구에서 유용하게 쓰여 더욱 주목을 받는 소자이다. Parylene-C는 수분의 침습을 막는 특성을 가지고 있고 가스 투과율이 낮으며 유전율이 높아 인체에 삽입할 수 있는 유연하고 생체에 적합한 신경전극의 재료로 쓰이고 있다. 그러나 신경전극을 보호하는 유전층으로서 Parylene-C의 장기적인 신뢰성은 아직 체계적으로 연구되지 않았다. 본 논문에서는 Parylene-C가 코팅된 AU 채널 신경 전극의 장기 신뢰도를 조사하였다. 이를 위해 Parylene-C가 코팅된 신경 전극을 높은 온도에서 인산염 완충 식염수(PBS)에 담가 가속 수명 시험을 수행하였고 실험 결과를 통해 전기화학 특성 데이터를 입수하고 분석하여 Parylene-C 기반 신경 전극의 장기 신뢰도를 평가하였다. 실험이 진행될수록 전기적 특성이 변화하는 것을 관찰할 수 있었고 또한 특성이 변화하고 전극의 특성이 열화 되는 메커니즘을 조사할 수 있었다. 초기 실험에서는 습기의 침투로 인해 전극이 급격하게 열화 되는 것을 확인할 수 있었다. 이러한 열화를 막기 위해 FPCB를 도입하였고 이를 통해 전극의 수명이 늘어난 것을 확인하였다. 또한 실험결과를 통해서 금속-폴리머 접합의 파괴뿐만 아니라 PCB-전극 패드 사이에 침습이 일어나 전극의 수명이 감소하는 것을 알 수 있었다.

Studies on the redox regulation of Bcl-2-transfected L929 cells

Cheon, Hwan Ju 연세대학교 2002 국내석사

종양괴사인자에 대한 bcl-2의 방어기작을 규명하기 위해서 L929 세포에 bcl-2 유전자를 넣어 bcl-2 영구발현 L929 세포주들을 확립하였다. 종양괴사인자와 actinomycin D에 대해서 bcl-2 발현 L929 세포주들간에 다른 방어정도를 나타냈다. 다른 방어 정도를 나타내는 bcl-2 발현 L929 세포주들 중 두 세포주를 선택하여 R1과 R2라고 명명하고 종양괴사인자에 대해 다른 방어정도가 다르게 나타나는 원인을 규명하고자 하였다. 종양괴사인자 처리시 R1과 R2는 L929 세포에 비해서 증가된 방어효과를 보였다. 반면에 종양괴사인자와 actinomycin D를 함께 처리하였을 경우 R1은 여전히 방어효과를 나타냈으나, R2의 경우는 오히려 L929 보다도 약하게 나타났다. 종양괴사인자 처리시 R1과 R2 의 NF-κB의 활성이 증가되었고 , L929 세포에서는 NF-κB의 활성이 나타나지 않았다. 종양괴사인자 처리시 R1의 AP-1 활성은 L929 세포보다 감소되었고 종양괴사인자와 actinomycin D를 함께 처리하였을 경우 R1의 AP-1 활성은 L929 세포에 비해서 감소하였으나 R2의 활성은 오히려 증가하였다. 활성산소 역시 종양괴사 처리시엔 R1의 활성산소생성량이 L929 세포에 비해서 감소되었고 종양괴사인자와 actinomycin D 처리시 R1의 활성산소생성량은 L929 세포보다 감소하였으나 R2의 활성은 증가하였다. 이상의 실험결과로부터, 종양괴사인자의 신호전달기전에서 AP-1과 NF-κB의 활성 사이의 균형은 bcl-2 발현 L929 세포주들의 방어기전에 주요요인으로 작용하는 것으로 결론지을 수 있다. 또한, AP-1과 NF-κB의 활성은 ROS의 생성량과 상관관계가 있으며 이들에 의해서 조절받는 것을 알 수 있다. Caspase가 bcl-2 발현 L929 세포주들의 방어기전에 관여하는지의 여부를 알기 위해서 caspase의 inhibitor인 zVAD-fmk를 처리한 결과, 세포사멸을 일으키는 caspase의 억제와 상관없이 각 세포주들의 세포사멸이 증가한다. 이로 미루어 보아서, csapase는 bcl-2 발현 L929 세포주들의 방어기전의 차이에 관여하지 않음을 알 수 있다. To investigate the protection mechanism of Bcl-2 against tumor necrosis factor(TNF)-mediated cell death, the Bcl-2 gene was transfected into the L929 cells and stably expressed. Two kinds of clones having different sensitivity against TNF and actinomycin D treatment have been isolated, and named R1 and R2. Upon treatment with TNF, R1 and R2 were more resistant than control L929 cells against TNF cytotoxicity. In case of TNF plus actinomycin D treatment, R1 was resistant against TNF cytotoxicity, whereas R2 became more sensitive than control L929 cells. Furthermore, R1 and R2 showed higher NF-κB activities than control L929 cells. AP-1 activity and ROS formation of R1 were suppressed upon TNF treatment. In case of TNF plus actinomycin D treatment, R2 showed a remarkable increase of AP-1 activity and ROS formation and they were much higher than that of control L929 cells. These data suggest that the balance between NF-κB and AP-1 may play an important role in the TNF sensitivity in Bcl-2 transfected L929 cells and regulated by ROS. Pan-caspase inhibitor zVAD-fmk could block cytotoxicity in neither R1 nor R2 cell. These results implicate that redox regulation of the TNF sensitivity in Bcl-2-transfected L929 cell was not through caspase cascade but through counteraction between NF-κB and AP-1 signaling pathway.

The work of the Holy Spirit in preaching : focusing on John Wesley and Karl Barth

Kwak, Ju-Hwan School of Theology at Claremont 1994 국내석사

Search for neutrino oscillations in line-e at lampf

Kang, Ju Hwan University of New Mexico 1987 국내박사

Intelligent systems for strategic power infrastructure defense

Jung, Ju-Hwan UMI Dissertation Services 2002 국내박사

Synthesis of structurally controlled noble metal nano- and micro-materials and their applications for colorimetric detection of biomolecules

오주환 Korea University 2017 국내박사

Nobel metal nanomaterials (NMNs) have been of significant interest owing to their shape-dependent electrical, optical, magnetic, and chemical properties. Particularly, NMNs comprised of gold or silver (or both) exhibit distinctive shape-dependent physical and chemical properties, which leads to myriad of research in NMNs with high anisotropy. One of the most frequently utilized method for synthesizing anisotropic NMNs is seed-mediated synthesis. In detail, highly monodispersed anisotropic NMNs can be obtained by introducing preformed nanoparticle seeds into a growth solution containing shape-directing agents, weak reductant, and metal precursor. This method also offers an ideal model system for the elucidation of mechanisms involved in the atomistic deposition and assembly process. We have been thoroughly investigated the growth of noble metal nanoparticle seeds and the characteristics of the resultant anisotropic nanostructures. Additionally, we also have investigated synthesis of gold microstructures in deep euteic solvent which is a kind of nascent green alternative for ionic liquid. Furthermore, the obtained NMNs are employed in colorimetric detection for various targets that are highly related with biological system including cancer gene, DNA binders and heavy metal ions after surface functionalization with DNA.

Nano-Characterization of Co-Cr-P-Pt Magnetic thin Films for Magnetic Recording

최주환 University of Massachusetts Lowell 1999 해외박사

In the present study, four sets of Co-Cr-P-Pt magnetic thin films were investigated in order to understand the effect of phosphorus and platinum on the alloy system. The main part of this study was to understand the effect of each element on the alloy and to investigate the microstructural features. The foremost feature, the compositional distribution in the Co-Cr-P-Pt thin films, was investigated as a function of phosphorus and platinum addition. The addition of 4-6 at. % P and 11-13 at. % Pt showed significant improvements in coercivity. This was caused by the segregation of Cr. Modulation of the other element was observed and had direct relationship with the segregation of Cr. The segregation of the non-magnetic phase caused an increase in coercivity. The average grain size, shape, physical separations, and crystallographic orientation relation were investigated. Phosphorus increased the in-plane orientation while decreasing the Co (002). Meanwhile, the addition of Pt decreased the in-plane orientation resulting in a random orientation that promoted magnetic isolation between grains. The changes in inplane orientation affected the noise characteristics. Transmission electron microscopy was used to examine the microstructures of a magnetic layer. Electron energy loss spectroscopy in conjunction with energy dispersive x-ray spectroscopy was also used.