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Layered structure of sialoliths compared with tonsilloliths and antroliths
No full textObjectives: The aim of this study was to perform a comparative analysis of the ultrastructural and chemical composition of sialoliths, tonsilloliths, and antroliths and to describe their growth pattern. Materials and Methods: We obtained 19 specimens from 18 patients and classified the specimens into three groups: sialolith (A), tonsillolith (B), and antrolith (C). The peripheral, middle, and core regions of the specimens were examined in detail by histology, micro-computed tomography (micro-CT), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy, and transmission electron microscopy (TEM). Results: In the micro-CT, group A showed alternating radiodense and radiolucent layers, while group B had a homogeneous structure. Group C specimens revealed a compact homogeneous structure. Histopathologically, group A showed a laminated, teardrop-shaped, globular structure. Group B demonstrated degrees of immature calcification of organic and inorganic materials. In group C, the lesion was not encapsulated and showed a homogeneous lamellar bone structure. SEM revealed that group A showed distinct three layers: a peripheral multilayer zone, intermediate compact zone, and the central nidus area; groups B and C did not show these layers. The main elemental components of sialoliths were O, C, Ca, N, Cu, P, Zn, Si, Zr, F, Na, and Mg. In group B, a small amount of Fe was found in the peripheral region. Group C had a shorter component list: Ca, C, O, P, F, N, Si, Na, and Mg. TEM analysis of group A showed globular structures undergoing intra-vesicular calcification. In group B, bacteria were present in the middle layer. In the outer layer of the group C antrolith, an osteoblastic rimming was observed. Conclusion: Sialoliths had distinct three layers: a peripheral multilayer zone, an intermediate compact zone and the central nidus area, while the tonsillolith and antrolith specimens lacked distinct layers and a core.Y
Potential Antioxidant and Anti-Inflammatory Properties of Polyphenolic Compounds from Cirsium japonicum Extract
No full textCirsium japonicum is a medicinal plant that has been used due to its beneficial properties. However, extensive information regarding its therapeutic potential is scarce in the scientific literature. The antioxidant and anti-inflammatory potential of polyphenols derived from the Cirsium japonicum extracts (CJE) was systematically analyzed. High-performance liquid chromatography (HPLC) with mass spectrometry (MS) was used to examine the compounds in CJE. A total of six peaks of polyphenol compounds were identified in the extract, and their MS data were also confirmed. These bioactive compounds were subjected to ultrafiltration with LC analysis to assess their potential for targeting cyclooxygenase-2 (COX2) and DPPH. The outcomes showed which primary compounds had the highest affinity for binding both COX2 and DPPH. This suggests that components that showed excellent binding ability to DPPH and COX2 can be considered significant active substances. Additionally, in vitro analysis of CJE was carried out in macrophage cells after inducing inflammation with lipopolysaccharide (LPS). As a result, it downregulated the expression of two critical pro-inflammatory cytokines, COX2 and inducible nitric oxide synthase (iNOS). In addition, we found a solid binding ability through the molecular docking analysis of the selected compounds with inflammatory mediators. In conclusion, we identified polyphenolic compounds in CJE extract and confirmed their potential antioxidant and anti-inflammatory effects. These results may provide primary data for the application of CJE in the food and pharmaceutical industries with further analysis.Y
Foreign residents and local public expenditure: evidence from South Korea
No full textWith rapid globalization and the growth of immigration, countries worldwide have become multicultural societies and are experiencing social changes. Several studies have focused on the impact of foreign residents on society, particularly from a public finance perspective. The current study examines how foreign residents affect local budget expenditure in South Korea, which is currently facing a historically low fertility rate and the aging phenomenon. The employment permit system, which is a government-ordained system that allocates quotas for foreign employees by region and year, was adopted in the instrumental variable estimation to identify a causal linkage between foreign workers and local budget expenditure. We found that government spending decreases as the proportion of foreign residents among the total population increases, and this impact is particularly noticeable in social welfare spending. The results of a battery of robustness tests support these findings. Furthermore, the findings varied depending on the heterogeneities within regions and political regimes. Additionally, we found suggestive evidence that foreign workers are one of the main factors that contribute to the results, causing local governments to spend more money on non-productive areas such as administrative expenses. Overall, the results show that a sharp inflow of foreign residents may be a risk factor in terms of the quantity and quality of local budget expenditure in South Korea, suggesting that immigration policies should be operated effectively to secure the fiscal soundness and sustainability of local finance.N
Single atom catalysts for water electrolysis: from catalyst-coated substrate to catalyst-coated membrane
No full textGreen hydrogen production through water electrolysis is considered the next-generation technology capable of industrial-scale hydrogen production to achieve carbon neutrality. The core of constructing a water electrolyzer lies in designing the membrane electrode assembly (MEA) with optimal integration of the membrane, electrocatalysts, and gas diffusion layer. Among the two representative MEA fabrication methods, catalyst-coated substrates (CCS) and catalyst-coated membranes (CCM), CCM shows great promise due to its catalyst layer/membrane interface contact and scalability. The key factor in the CCM method is the effective application of the powdered catalyst onto the membrane. In this respect, the utilization of single-atom catalysts (SACs) has emerged as a noteworthy focus due to their unprecedented catalytic activity resulting from unique electronic/atomic configurations and high atomic utilization efficiency. Incorporating SACs into CCM–MEA has the potential to be a cutting-edge water electrolysis technology. However, it is still in its infancy due to the instability of the components (SACs, membranes, ionomers, supports) and degradation during the SACs–CCM–MEA fabrication and cell operation. Herein, we outline the representative fabrication method of MEA and provide a comprehensive analysis of SACs applicable to MEA. Then, we discuss the advantages of SACs–CCM–MEA and the challenges for industrial hydrogen production. Finally, this review concludes with future perspectives on the development of single-atom catalyst-coated membranes and the expected achievements.N
Averaged switch model of single‑ended primary inductor converter in discontinuous conduction mode
No full textThis paper proposes a new averaged switch model for pulse-width modulated (PWM) single-ended primary-inductor converter (SEPIC) operating in discontinuous conduction mode (DCM). The equivalent series resistance (ESR) of each energy component is considered to achieve a more precise model. The model, which is modification of the conventional averaging equation, accurately reflects both the remaining current and the actual charge on each capacitor in DCM. The proposed model utilizes a new duty ratio constraint and predicts better than previous models at high frequencies. The dependent sources of the switch components are derived from the modified averaged equation, and an implementation of the model in LTspice XVII is provided to facilitate the frequency response analysis. The frequency response of a prototype SEPIC in DCM, with an input voltage of 5 V, an output voltage of 13.5 V, and a switching frequency of 100 kHz, was experimentally measured to verify the proposed model. Simulation and experimental results demonstrate that the proposed averaged switch model solves the discrepancies at high frequencies, which was a limitation of previous models.N
Comprehensive molecular characterization of TFE3-rearranged renal cell carcinoma
No full textTFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC. Understanding the unique traits of a rare kidney cancer type, TFE3-rearranged renal cell carcinoma, is important due to its poor response to usual treatments. This study explores the genetic and metabolic makeup of tRCC, comparing it with clear cell RCC and normal kidney cells. Using a mix of cell culture, whole exome sequencing, and various molecular analyses, the team conducted an experiment to reveal the unique genetic and metabolic profiles of tRCC. The researchers conclude that targeting the metabolic changes in tRCC, specifically through inhibiting PPARGC1A-mediated mitochondrial respiration, offers a new treatment approach. This approach marks a significant step in understanding and potentially treating tRCC. The implications of this study could lead to more effective treatments for patients with this challenging cancer type, emphasizing the importance of metabolic pathways in cancer therapy.This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.Y
Blood culture-free ultra-rapid antimicrobial susceptibility testing
No full textTreatment assessment and patient outcome for sepsis depend predominantly on the timely administration of appropriate antibiotics1-3. However, the clinical protocols used to stratify and select patient-specific optimal therapy are extremely slow4. In particular, the major hurdle in performing rapid antimicrobial susceptibility testing (AST) remains in the lengthy blood culture procedure, which has long been considered unavoidable due to the limited number of pathogens present in the patient's blood. Here we describe an ultra-rapid AST method that bypasses the need for traditional blood culture, thereby demonstrating potential to reduce the turnaround time of reporting drug susceptibility profiles by more than 40-60 h compared with hospital AST workflows. Introducing a synthetic beta-2-glycoprotein I peptide, a broad range of microbial pathogens are selectively recovered from whole blood, subjected to species identification or instantly proliferated and phenotypically evaluated for various drug conditions using a low-inoculum AST chip. The platform was clinically evaluated by the enrolment of 190 hospitalized patients suspected of having infection, achieving 100% match in species identification. Among the eight positive cases, six clinical isolates were retrospectively tested for AST showing an overall categorical agreement of 94.90% with an average theoretical turnaround time of 13 +/- 2.53 h starting from initial blood processing. An ultra-rapid antimicrobial susceptibility testing method is introduced that bypasses the need for traditional blood culture, demonstrating the potential to significantly reduce the turnaround time of reporting drug susceptibility profiles.N
Insights from Li and Zn systems for advancing Mg and Ca metal batteries
No full textThe inherent limitations of lithium (Li)-ion batteries have sparked interest in exploring alternative technologies, especially those relying on metallic anodes: monovalent Li and divalent zinc (Zn), magnesium (Mg), and calcium (Ca) metals. In particular, Mg and Ca metal batteries offer significant advantages based on the natural abundance of their raw materials and high energy-storage capabilities resulting from the bivalency of the carrier ions. Yet, these battery systems are far from commercialization, and the lack of reliable electrolytes constitutes a primary concern. The formation of ion-insulating passivation layers on these metallic anodes and their inferior desolvation kinetics have long been recognized as formidable hurdles in the way of optimizing the electrolyte composition. These impediments call for innovative strategies in electrolyte engineering and an extensive analysis of the resulting solid-electrolyte-interphase (SEI) layer. In this review, we introduce recent pioneering studies of divalent Mg and Ca metal batteries that have been concerned with these issues. This review particularly focuses on drawing an analogy with Li and Zn metal batteries in terms of the relative advancement and by benchmarking against the strategies developed for these analogous systems. The areas of interest include a fundamental understanding of the thermodynamics and evolution of the morphology of metallic anodes, a correlation between the electrolyte and SEI compositions, state-of-the-art electrolyte strategies to realize reversible (de)plating of Mg and Ca, and new perspectives on the SEI properties and their relevance to corrosion and the calendar life. We finally encourage researchers in the community to delve into these emerging areas by linking with successful stories in the analogous systems, but identifying distinct aspects of Mg and Ca batteries that still require attention. This review presents the progress and future direction of Mg and Ca metal batteries with a focus on electrolyte and solid-electrolyte-interphase engineering, by drawing lessons from the more extensively researched Li and Zn metal batteries.N
A Population PK Study
Get PDF학위논문(박사) -- 서울대학교대학원 : 의과대학 의학과, 2024. 2. 이상건.Purpose: Pregabalin (PGB) is a high-affinity ligand for the α2δ subunit of voltage-dependent calcium channel blocker. It is commonly used as an add-on therapy for focal-onset epilepsy and is known for its simple pharmacokinetic profile. The factors that affect the adverse events (AEs), the types of anticonvulsants that form a better combination, and the relationship between concentration and AEs need to be better understood. It is thus indispensable to develop an appropriate pharmacokinetic (PK) model for PGB polytherapy and inspect it from various perspectives. Therefore, this study aimed to investigate the factors that could affect AEs by considering both the pharmacokinetic and non- pharmacokinetic aspects of PGB in polytherapy. Methods: We obtained 193 samples from 149 epilepsy patients who had received multiple doses of PGB among 2963 patients in the Epilepsy Registry Cohort of Seoul National University Hospital from February 2011 to January 2014. We designated 968 patients as the control group who did not take PGB and had available demographic information. The population PK modeling of PGB was performed using Monolix 2021R2 software with the stochastic approximation expectation-maximization (SAEM) algorithm for parameter estimation. Owing to data sparsity from patients, we used a preliminary structural model from a previous study with dense PK data from 41 healthy volunteers. We built the final model by integrating it with patient data. A two-compartment model adequately described the PGB concentration profile with a first- order absorption model and proportional residual error. In addition, we explored the relationships between AEs, seizure control, and PK variables. We determined the factors that affected AEs among PK variables and performed a multivariable analysis to identify the factors that influenced the occurrence of dizziness. We also calculated the cut-off level of Cmax for dizziness status using Youdens' index. We investigated the AEs according to the type of CoASM and ranked them. Furthermore, we compared the rates of AEs due to PGB with other ASMs using propensity score matching (PSM). Results: Per the final PK model, the apparent clearance (CL) and volume of distribution (V/F) of the central and peripheral parts were estimated to be 4.11 L/h, 21.44 L, and 18.83 L, respectively. The PK variables of the AE groups did not differ significantly when comparing the simple means. However, in stratified analysis, the Cmax of patients with dizziness was significantly higher. It was verified through a multivariable analysis that the factors were contributing to dizziness. The cut-off value of Cmax for the occurrence of dizziness was 6.571 mg/L (sensitivity 0.709, specificity 0.667). However, in the group of any adverse effects, the seizure-free patients had a higher rate of AEs, which was statistically significant. The concentration fluctuation was smaller in the seizure-free group. The CoASM analysis revealed that PGB combination with clobazam (CLO) and zonisamide (ZNS) significantly contributed to somnolence. We investigated the AEs and seizure-free status and ranked the ASMs that exhibited favorable outcomes when combined with PGB. Considering all AEs, the top four ASMs that exhibited the most favorable outcome when combined with PGB were oxcarbazepine (OXC), levetiracetam (LEV), lamotrigine (LTG), and topiramate (TPM) in order. As a result of PSM, PGB had higher occurrence rates of somnolence and dizziness compared to those associated with other ASMs, consistent with previous studies. Conclusion: We developed a population PK model using sparse sampling data from patients with partial-onset epilepsy who underwent polytherapy, which reflects the real-world data. Polytherapy containing PGB was reviewed from various aspects; it presented a better combination of PGB and several previously unknown characteristics of PGB were revealed. We suggested a cut- off value to minimize the concentration-related AEs. This provides reference data for clinicians to select the appropriate ASM with PGB and compare PGB with other ASMs.배경: 프레가발린(PGB)은 전압 의존성 칼슘 채널 차단제인 α2δ 부분 유닛에 대한 고친화 리간드이다. 이는 주로 부분 발작에 대한 부가 치료로 사용되며 단순한 약동학적 특성을 보이는 것이 알려져 있다. 그러나 다른 항경련제와의 병용 시 부작용에 대한 연구는 거의 없다. 또한 부작용에 영향을 미치는 요인, 더 나은 조합을 이루는 항경련제의 종류, 농도와 부작용의 관계 등에 대한 연구도 없다. 본 연구에서는 PGB의 인구 약동학(PK) 모델을 구축하고, PGB 농도와 부작용의 상관관계를 평가하고, PGB 부작용에 영향을 미치는 요인들을 분석하였다. 또한 PGB와 병용되는 항경련제의 종류에 따른 부작용의 차이를 비교하여, 임상적으로 유용한 정보를 제공하고자 하였다.
대상 및 방법: 우리는 2011년 2월부터 2014년 1월까지 서울대학교병원 뇌전증 코호트로 등록된 코호트에서 2963명의 환자 중, PGB를 복용한 간질 환자 149명으로부터 193개의 표본을 얻었다. PGB를 복용하지 않은 환자 중 968명을 대조군으로 지정하였다. PGB의 인구 약동학 모델링은 매개 변수 추정을 위해 SAEM 알고리즘을 사용하는 Monolix 2021R2 소프트웨어를 사용하여 수행하였다. 환자로부터 얻은 농도 정보가 모델 구축하기에 충분하지 않았으므로, 건강한 자원자 41명으로부터 밀도 있는 약동학 데이터를 가진 이전 연구의 예비 구조 모델을 사용하였다. 이후 환자 데이터와 통합하여 최종 모델을 구축하였다. 일차 흡수 모델과 비례 잔여 오차(proportional residual error)를 가진 이중 구획 모델은 PGB 농도 프로파일을 적절하게 설명하였다. 또한 부작용, 발작 조절, 및 약동학 변수 사이의 관계를 탐색하였다. 부작용에 영향을 미치는 PK 변수를 결정하고, 어지럼증의 발생에 영향을 미치는 요인을 확인하기 위해 다변량 분석을 수행하였다. 또한 Youden's index를 사용하여 어지럼증 상태에 대한 Cmax의 임계값을 계산하였다 우리는 CoASM의 종류에 따른 부작용을 조사하고 순위를 매겼다. 이에 더하여 성향 점수 매칭(propensity score matching)을 사용하여 PGB와 다른 ASM들의 부작용 발생률을 비교하였다.
결과: 최종 약동학 모델에서 겉보기 청소율(CL; appearance clearance) 중심부 및 말초 분포량(Vc/F: central part distribution, Vp/F: peripheral part distribution)이 각각 4.11 L/h, 21.44 L, 그리고 18.83 L로 추정되었다. 부작용 그룹의 PK 변수는 단순 평균 비교시 유의한 차이가 없었다. 그러나 층화 분석에서 어지럼증이 있는 환자의 Cmax가 유의하게 높았다. 다변량 분석을 통해 이 요인이 어지럼증에 기여하는 것을 확인하였다. 어지럼증 발생에 대한 Cmax의 임계값은 6.571 mg/L(민감도 0.709, 특이도 0.667)이었다. 농도 변동은 발작이 검사 전 3개월간 뇌전증 발작이 없었던 그룹에서 더 작게 나왔다.
CoASM 분석에서 클로바잠(CLO)과 조니사마이드(ZNS)가 PGB 와 같이 사용할 경우 졸음을 유발함을 보였으며, 이는 통계적으로 유의하였다. 모든 부작용을 고려할 때, PGB와 결합했을 때 가장 유리한 결과를 보인 상위 네 가지 ASM은 순서대로 옥사카르바제핀(OXC), 레베티라세탐(LEV), 라모트리진(LTG), 그리고 토피라메이트(TPM)였다. PGB 와 다른 항경련제들을 비교하였을 때, PGB는 졸음과 어지러움의 발생률이 높았으며 이는 기존 연구와 일치하였다. 이에 더하여 저자들은 PGB가 클로바잠(CLO)보다 졸음 기여도가 높다는 것을 발견하였다.
결론: 이 연구는 뇌전증 환자로부터 희소한 샘플링 데이터를 사용하여 새로운 인구 약동학 모델을 개발하였다. 어지럼증과 Cmax 와의 관계를 밝히고, cut-off value 를 제시하였다. 약물 조합에 따른 부작용을 분석하여 더 우수한 조합과 졸림 및 어지러움을 유발하는 조합을 제시하였다. 또한 농도의 변동이 seizure free 여부에 미치는 영향을 정량적으로 확인하여, 임상적으로 필요시 복용 횟수를 조절할 것을 제안하였다. 이 연구는 임상 의사들이 PGB와 함께 사용할 적절한 약물을 선택하는 데 도움을 주고, PGB 부가요법으로 선택함에 있어 참고 자료로서 활용 가치가 있을 것이다.Chapter 1. Introduction 8
Chapter 2. Methods 9
2.1 Patient enrollment and study design
2.2 Determination of PGB concentration
2.3 Population PK model development and evaluation
2.4 Statistics
2.5 Ranking favorable ASM for combination with PGB
Chapter 3. Results 19
3.1 Patient characteristics
3.2 Population PK analysis
3.3 AEs of pregabalin
3.4 Association of AEs of pregabalin with dose and concentration
3.5 The correlation between AEs of pregabalin by CoASM
3.6 PGB vs. other ASMs: using propensity score matching
Chapter 4. Discussion 26
4.1 Comparison of pre-existing population PK model
4.2 Potential factors influencing AEs
4.3 PGB and other CoASM: optimal combination
4.4 Comparison with other ASMs: AE of PGB in polytherapy
4.5 Limitations
Chapter 5. Conclusions . 36
Tables 37
Figures 86
Supplementay Material . 99
Bibliography . 102
Abstract in Korean 106박