592 research outputs found
Correlation of dynamic membrane fluctuations in red blood cells with diabetes mellitus and cardiovascular risks
No full textThe rheological and physiological properties of red blood cells (RBCs) are affected by many factors in the vascular environment. Among them, membrane fluctuations (MFs), particularly dynamic fluctuations in RBC cell membrane thickness (RBC-MFs), are likely to be altered by the level of glycation of haemoglobin in patients with diabetes mellitus (DM). We investigated the associations of RBC-MFs with physiological variables associated with DM and cardiovascular diseases (CVDs). Forty-one healthy control subjects and 59 patients with DM were enrolled. Five-microliter samples of blood were collected and diluted 400 times. To measure the RBC-MFs, holotomography was used, which non-invasively and precisely analyses the optical characteristics of RBCs. Associations between the RBC-MFs and biochemical parameters related to glucose homeostasis and lipid profiles were investigated. Independent associations of the RBC-MFs with the presence of CVDs were also analysed. RBC-MFs were lower in patients with DM than in healthy participants (61.64 +/- 7.49 nm vs 70.65 +/- 6.65 nm, P=1.4x10(-8)). RBC-MFs correlated modestly with glycated haemoglobin level (rho=-0.47) and weakly with age (rho=-0.36), duration of diabetes (rho=-0.36), fasting plasma glucose level (rho=-0.37), and the 10-year Framingham risk score (rho=-0.38) (all P<0.05). Low RBC-MFs were independently associated with the presence of CVDs after adjusting for CVD risk factors. The weak but significant associations of RBC-MFs with cardiometabolic risk factors and CVDs suggest that such deformity of circulating RBCs may be a useful marker of vascular complications of DM.
Bayesian probabilistic damage detection of a reinforced-concrete bridge column
No full textA Bayesian probabilistic approach for damage detection has been proposed for the continuous monitoring of civil structures (Sohn H, Law KH. Bayesian probabilistic approach for structure damage detection. Earthquake Engineering and Structural Dynamics 1997; 26: 1259-1281). This paper describes the application of the Bayesian approach to predict the location of plastic hinge deformation using the experimental data obtained from the vibration tests of a reinforced-concrete bridge column. The column was statically pushed incrementally with lateral displacements until a plastic hinge is fully formed at the bottom portion of the column. Vibration tests were performed at different damage stages. The proposed damage detection method was able to locate the damaged region using a simplified analytical model and the modal parameters estimated from the vibration tests, although (1) only the first bending and first torsional modes were estimated from the experimental test data, (2) the locations where the accelerations were measured did not coincide with the degrees of freedom of the analytical model, and (3) there existed discrepancies between the undamaged test structure and the analytical model. The Bayesian framework was able to systematically update the damage probabilities when new test data became available. Better diagnosis was obtained by employing multiple data sets than just by using each test data set separately. Copyright (C) 2000 John Wiley & Sons, Ltd.The "rst author wishes to express his sincere thanks to Professor Gerard C. Pardoen and his students at the
University of California at Irvine for providing an opportunity to observe the bridge column test. Also, the
authors are indebted to Dr Charles R. Farrar and Dr Scott W. Doebling of the Los Alamos National
Laboratory for providing the vibration test data. This research was partially sponsored by the National
Science Foundation under Grant No. CMS-95261-2
Troca ou produção? Uma introdução crítica à proposta teórica de Alfred Sohn-Rethel
No full textThis paper explores and analyzes the critique of the modern-traditional epistemology of the philosopher Alfred Sohn-Rethel, focusing on the categories of "social synthesis" and "real abstraction" that the author postulated in his magnum opus Manual Work and Intellectual Work (2001) . Sohn-Rethel\u27s perspective seeks to critically adapt Marx\u27s materialist conception of history to the analysis of the emergence of the fundamental categories of scientific knowledge, as formulated in European modernity. However, the author\u27s emphasis on exchange over production ends up being inconsistent with basic postulates derived from the critique of political economy formulated by Marx in Capital. Thus, from the review of Marx\u27s categories and taking into account the position of other authors, the research emphasizes the limitations derived from the Sohn-Rethel proposal when analyzing the social forms of knowledge.El presente artículo explora y analiza la crítica a la epistemología moderna-tradicional del filósofo Alfred Sohn-Rethel centrándose en las categorías de “síntesis social” y “abstracción real” que el autor postuló en su obra magna Trabajo manual y trabajo intelectual (2001). La perspectiva de Sohn-Rethel busca adecuar críticamente la concepción materialista de la historia de Marx al análisis de la emergencia de las categorías fundamentales del conocimiento científico, tal y como se formularon en la modernidad europea. Sin embargo, el énfasis que el autor sostiene del intercambio por encima de la producción termina por ser incongruente con postulados básicos derivados de la crítica de la economía política formulada por Marx en El Capital. Así, a partir de la revisión de las categorías de Marx y tomando en cuenta la posición de otros autores, la investigación enfatiza en los limitantes derivados de la propuesta de Sohn-Rethel al analizar las formas sociales del conocimiento.Este artigo explora e analisa a crítica à epistemologia moderno-tradicional do filósofo Alfred Sohn-Rethel, com foco nas categorias de "síntese social" e "abstração real" que o autor postulou em sua magnum opus Trabalho Manual e Trabalho Intelectual (2001). ). A perspectiva de Sohn-Rethel procura adaptar criticamente a concepção materialista da história de Marx à análise da emergência das categorias fundamentais do conhecimento científico, tal como formuladas na modernidade europeia. No entanto, a ênfase do autor na troca sobre a produção acaba sendo inconsistente com os postulados básicos derivados da crítica da economia política formulada por Marx em O Capital. Assim, a partir da revisão das categorias de Marx e levando em conta a posição de outros autores, a pesquisa enfatiza as limitações derivadas da proposta de Sohn-Rethel ao analisar as formas sociais de conhecimento
Application of time reversal guided waves to field bridge testing for baseline free damage diagnosis
No full textThis research is partially supported by Pennsylvania Infrastructure Technology Alliance (PITA) Program and Pennsylvania Department of Transportation (PennDOT). The first author would like to acknowledge the graduate fellowship program from Samsung Lee Kun Hee Scholarship Foundation in Seoul, Korea. The authors would like to thank Paul Majoris and James Johnson for granting access to the Buffalo Creek Bridge site. The authors also would like to thank Profs. David W. Greve and Irving J. Oppenheim for providing invaluable comments and making the scaled girder specimen available for our study
Development of Dual PZT Transducers for Reference-Free Crack Detection in Thin Plate Structures
No full textA new Lamb-wave-based nondestructive testing (NDT) technique, which does not rely on previously stored baseline data, is developed for crack monitoring in plate structures. Commonly, the presence of damage is identified by comparing "current data" measured from a potentially damaged stage of a structure with "baseline data" previously obtained at the intact condition of the structure. In practice, structural defects typically take place long after collection of the baseline data, and the baseline data can be also affected by external loading, temperature variations, and changing boundary conditions. To eliminate the dependence on the baseline data comparison, the authors previously developed a reference-free NDT technique using 2 pairs of collocated lead zirconate titanate (PZT) transducers placed on both sides of a plate. This reference-free technique is further advanced in the present study by the necessity of attaching transducers only on a single surface of a structure for certain applications such as aircraft. To achieve this goal, a new design of PZT transducers called dual PZT transducers is proposed. Crack formation creates Lamb wave mode conversion due to a sudden thickness change of the structure. This crack appearance is instantly detected from the measured Lamb wave signals using the dual PZT transducers. This study also suggests a reference-free statistical approach that enables damage classification using only the currently measured data set. Numerical simulations and experiments were conducted using an aluminum plate with uniform thickness and fundamental Lamb waves modes to demonstrate the applicability of the proposed technique to reference-free crack detection.This research is supported by the Radiation Technology Program under
Korea Science and Engineering Foundation (KOSEF) and the Ministry
of Science and Technology (M20703000015-07N0300-01510) and
Korea Research Foundation Grant funded by the Korean Government
(MOEHRD, Basic Research Promotion Fund) (KRF-2007-331-D00462).
Any opinions, findings, and conclusions or recommendations expressed
in this material are those of the author(s) and do not necessarily reflect
the views of the funding agencies
Breath analyzer for personalized monitoring of exercise-induced metabolic fat burning
No full text© 2022Obesity increases the risk of chronic diseases, such as type 2 diabetes mellitus, dyslipidemia, and cardiovascular diseases. Simple anthropometric measurements have time limitations in reflecting short-term weight and body fat changes. Thus, for detecting, losing or maintaining weight in short term, it is desirable to develop portable/compact devices to monitor exercise-induced fat burn in real time. Exhaled breath acetone and blood-borne β-hydroxybutyric acid (BOHB) are both correlated biomarkers of the metabolic fat burning process that takes place in the liver, predominantly post-exercise. Here, we have fabricated a compact breath analyzer for convenient, noninvasive and personalized estimation of fat burning in real time in a highly automated manner. The analyzer collects end-tidal breath in a standardized, user-friendly manner and it is equipped with an array of four low-power MEMS sensors for enhanced accuracy; this device presents a combination of required and desirable design features in modern portable/compact breath analyzers. We analyzed the exhaled breath (with our analyzer) and the blood samples (for BOHB) in 20 participants after exercise; we estimated the values of BOHB, as indication of the fat burn, resulting in Pearson coefficient r between the actual and predicted BOHB of 0.8. The estimation uses the responses from the sensor array in our analyzer and demographic and anthropometric information from the participants as inputs to a machine learning algorithm. The system and approach herein may help guide regular exercise for weight loss and its maintenance based on individuals own metabolic changes.N
Identification of novel variants associated with tacrolimus concentrations in kidney transplant patients by next generation sequencing
No full text학위논문 (박사)-- 서울대학교 대학원 : 약학대학 약학과, 2019. 2. 오정미.1. 서론
타크로리무스는 면역억제제로서 대부분의 고형장기 이식 환자에서 널리 쓰이고 있으나 치료 영역이 좁고 개인간 약동학적 변동이 커 개인맞춤 요법을 필요로 하고 있다. 체중 기준으로 투약을 시작하고 최저 약물농도측정(therapeutic dose monitoring, TDM)을 통해 용량을 조절함으로써 부작용을 최소화하고 이식편 거부반응을 줄이고 있다.
투여 초기부터 약물농도를 조절하기 위해 타크로리무스 약동학에 영향을 미치는 인자에 대한 연구가 다양하게 시행되었고, 병용약물, 유전형, 식이요법 및 화학적 랩 검사가 보고되었다. 유전형으로 CYP3A5 rs776746 단일염기다형성은(single nucleotide polymorphism, SNP), 인트론 3 (6986 A>G, CYP3A5*3) 위치의 대립형질(allele), 이상 전령 리보핵산(messenger ribonucleic acid, mRNA) 스플라이싱을 통해 CYP3A5 효소의 발현을 조절함으로써 주요하게 약물 대사에 영향을 미친다. 본 유전형은 영향력이 크지만, 현재 40-50%만의 변이를 설명하므로 다른 유전형의 역할에 대한 연구들이 진행되었다. CYP3A4, POR, NR1I2, 그리고 SUMO4가 보고되었으나 여전히 타크로리무스의 약동학적 다양성에 대한 설명이 충족되고 있지 않다.
유전체 분석 기술이 발전함에 따라 광범위 유전체 연구와 차세대 염기서열분석(next generation sequencing, NGS)를 통해 잠재적인 새로운 SNP을 발굴하게 되었다. 따라서 본 기술을 통해 타크로리무스와 연관된 새로운 약동학 관련 유전자를 발견할 것으로 기대된다. 본 연구에서는 신장이식 환자에서 타크로리무스에 영향을 미치는 새로운 유전형을 알아내고자 하였다.
2. 연구방법
본 연구는 단일 기관 후향적 관찰 연구로 수행되었다. 2007년부터 2014년까지 서울대병원에서 신장이식을 새로 받은 18세 이상 성인 중 타크로리무스(Prograf®) 포함한 면역억제 삼중요법을 받는 환자가 포함되었다. 다장기 이식 또는 이식적 탈감작 요법을 받은 환자는 제외되었다. IRB 승인을 받아 총 147명 환자가 모집되어 75명은 발굴군, 72명은 재현군으로 분류되었다.
타크로리무스는 0.075 mg/kg 1일 2회로 이식전 시작하여 TDM에 따라, 이식후 1개월째 10-12 ng/mL, 3개월째 8-10 ng/mL, 6개월째 6-8 ng/mL, 이후 4-6 ng/mL로 용량이 조절되었다. 타크로리무스 농도는 액체크로마토그래피 질량분석법으로 측정되었다. 혈중 최정 농도는 1-3일, 4-7일, 8-14일, 15-28일, 1-3개월, 4-6개월, 7-12개월의 평균값으로 계산되었고 총 콜레스테롤, 적혈구, 총 빌리루빈, 알부민, 크레아티닌과 같은 임상변수 정보가 수집되었다.
대상환자의 혈액은 전향적으로 수집되어 QuickGene DNA kit로 유전적 데옥시리보핵산(genomic deoxyribonucleic acid, gDNA)를 추출하였다. Sure Select Human All Exon kit V5 + UTRs (Agilent) 키트를 통해 gDNA 표적부위를 캡쳐하여 증폭시켰다. Bioanalyzer를 통해 상태 검사후 Ion PI chip에 로딩하여 Ion Proton로 시퀀싱하였다. Torrent Mapping Alignment Program ver4.0.6으로 매핑하여 Torrent Variant Caller plugin ver4.4.3.3으로 서열을 호출하였다. 소수형질빈도(minor allele frequency, MAF)는 SNVrap을 통해 주석을 달았다. 차세대염기서열분석의 염기서열은 Sanger sequencing으로 검증하였다. 타크로리무스 영향 유전형 중 표적부위에 포함되지 않은 ABCB1, ABCC2, ABCG2, CYP3A4, CYP3A5, NR1I2, POR, PPARA, PPARD, SLCO1B3 그리고 SUMO4 유전자의 19개 변이는 SNaPshot 또는 SNPtype assay로 별도로 분석하였다.
용량 보정 농도(C/D)는 타크로리무스 혈중 최저농도를 1일 투여용량으로 나눈 값으로 계산되었다. 상관분석을 위해 log 변환시켰고, ANOVA 선형 회귀분석을 부가모델(addivite model)로 매 시점 분석되었다. 거짓발견비율(false positive rate, FDR)로 보정하여 p<0.05를 유의한 것으로 판단하였다. 확인된 유전변이는 Hardy-Weinberg 평형 관계를 평가하였다. 선형혼합모형(linear mixed model, LMM) 분석을 통해 매 시점 유전형과 임상변수에 대한 관계를 보았다. Haploview 프로그램을 통해 일배체병(haplotype)과 연관 불평형(linkage disequilibrium, LD)이 측정되었다.
3. 연구결과
모집된 환자는 발굴군과 재현군에서 인구학적 특성의 유의한 차이를 보이지 않았다. 차세대 염기서열 분석은 평균 측정(depth)이 57.78x (41.09-105.5)이었고, 표적부위에서 20x 이상 측정된 비율은 87.87% (77.87-96.09)이었다. 총 293,531개 변이가 확인되었다. 발굴군의 2,900개의 C/D 값과 변이 간 상관분석 결과 chromosome 3의 NR1I2, chromosome 7의 PTCD1, CPSF4, ZNF789, ZKSCAN5, FAM200A, ZSCAN25, CYP3A5, CYP3A7, 그리고 CYP3A4가 확인되었다. FDR 보정 결과 총 16개 변이가 전기간 의미가 있었고 CYP3A7 rs2257401의 C>G 변이가 3일째 가장 영향이 컸다(전기간 p = 1.74 x10-7 and p = 0.0138).
Chromosome 7의 haplotype 분석 결과 CPSF1 rs883403와 rs1043466, ZNF789 rs6962772, FAM200A rs10238965, 그리고 ZSCAN25 rs1859690가 한 블록, ZSCAN25 rs3735453, CYP3A5 rs15524와 rs776746, CYP3A7 rs10211, rs12360와 rs2257401, 그리고 CYP3A4 rs12333983가 각각 블록을 형성하였다.
재현군에서는 2,940개의 타크로리무스 농도가 수집되었고, 1인당 34(27-77)회 측정되었다. 발굴군에서 유의하게 측정된 변이 CYP3A5 rs15524와 rs776746, CYP3A7 rs10211, rs12360와 rs2257401, 그리고 CYP3A4 rs12333983와 rs2242480가 분석되었다. 모든 변이가 유의하게 C/D에 영향을 미침이 확인되었다. ZNF789 rs6962772, FAM200A rs10238965, 그리고 CYP3A7 rs10211와 rs12360의 SNP이 동일함이 보여 향후 분석에서 제외되었다. LD 정도는 각각 CYP3A7 rs2257401와 CYP3A5 rs776746 (r2 = 0.79)가 높고, CYP3A4 rs2242480와 CYP3A5 rs776746 (r2 = 0.50)가 중등도이었다. 이에 이배체형(diplotype) 빈도를 확인하여 CYP3A5 rs15524와 rs776746, CYP3A7 rs10211와 rs2257401, 그리고 CYP3A4 rs12333983로 CAGCA-CAGCA, TGAGT-TGAGT 및 그 외 서열은 각 9.3%, 45.3%, 44.2%이었고 TGAGT-TGAGT는 타크로리무스 C/D를 강하게 증가시켰다.
모든 환자군을 합쳐 LMM 분석을 한결과 최종적으로 CYP3A7 rs2257401 유전형과 나이, 알부민, 적혈구용적율, 크레아티닌이 최종 포함되었다. CYP3A7 rs2257401 변이의 영향을 확인하고자 CYP3A5 발현자와 비발현자로 구분하여 각 유전형과 C/D의 영향을 확인한 결과 CYP3A5 발현군에서도 CYP3A7 rs2257401 변이가 타크로리무스의 C/D에 유의하게 영향을 미침을 확인하였다.
4. 결론
본 연구는 CYP3A7 유전형이 타크로리무스 C/D의 개인차에 강하게 연관됨을 입증하였다. 따라서, CYP3A7 rs2257401 다형성이 신이식 환자에서 최적화된 개인 맞춤 타크로리무스 용량과 용법을 제시하는데 활용될 것으로 기대된다.Although tacrolimus have been studied widely for variation of its pharmacokinetics (PK), there is currently no consensus on the best individualized dosing method of tacrolimus. The purpose of this study was to identify genotypes associated with tacrolimus dose-adjusted trough concentration (C/D) in Korean kidney transplant recipients using whole-exome sequencing (WES).
A total of 147 patients administering tacrolimus in seventy-five of the discovery set and seventy-two of replication set. Data was collected retrospectively from 80 kidney transplant recipients treated with tacrolimus for the first year. Tacrolimus trough concentrations measured by LC-MS/MS were collected. Average tacrolimus C/D were calculated and log transformed for PK parameters (logC/D) in each period. The genomes of the patients in the discovery set were sequenced using WES. Known tacrolimus pharmacokinetics related intron variants were genotyped. Genetic variants associated with logC/D were analyzed by ANOVA and adjusted by false discovery rate. Haplotype was tested with the variants in same chromosome by Haploview software. Linear mixed effect model was constructed with clinical variables and identified variants in R ver3.4.4.
Ten genes, NR1I2 on chromosome 3 and CYP3A7, CYP3A5, CYP3A4, PTCD1, CPSF4, ZNF789, ZKSCAN5, FAM200A, ZSCAN25 and on chromosome 7, were identified. Among the 16 identified variants, CYP3A7 rs2257401 was found to be the most significant variant among the periods (between p = 1.74 x10-7 and p = 0.0138). Haplotype was tested with the 13 variants in chromosome 7 showing two linkage disequilibrium blocks. One block included CYP3A5 variants with CYP3A4 and CYP3A7 variants. CYP family diplotype also showed significant difference in each group. Further, CYP3A7 rs2257401 genotype variant showed a significant difference in tacrolimus C/D for those expressing CYP3A5 showing its own effect. The linear mixed effect model was used to account for effect of variants and clinical factors. In linear mixed effect model, age, serum albumin, creatinine, hematocrit and CYP3A7 rs2257401 was included.
The results suggest that CYP3A7 rs2257401 may serve as a significant genetic marker for tacrolimus pharmacokinetics in kidney transplantation.Chapter 1.Introduction 12
1.1. 신장이식 환자에서 면역억제제의 사용 . 12
1.1.1. 신장이식. 12
1.1.2. 면역억제제. 13
1.1.3. 타크로리무스 . 13
1.2. 타크로리무스의 약동학적 다양성 15
1.2.1. 타크로리무스의 약동학 . 15
1.2.2. 타크로리무스 약동학과 연관된 임상변수 18
1.2.3. 타크로리무스 약동학과 연관된 유전형 바이오마커 . 19
1.2.4. 타크로리무스 약동학과 연관된 유전자 바이오마커 . 23
1.2.5. 타크로리무스 약동학과 연관된 병용약물 24
1.3. 차세대염기서열 분석. 25
1.3.1. 차세대염기서열분석의 발전 25
1.3.2. 전장엑솜분석 . 26
1.3.3. 비해독부위분석 및 인트론 분석 26
1.3.4. 생물정보학 분석 27
1.4. 선형혼합모형과 악동학 모델 28
1.5. 연구 목적 . 29
Chapter 2.Methods 30
2.1. 연구디자인 및 연구집단. 30
2.2. 면역억제제 요법 33
2.3. 타크로리무스 약동학과 연관된 유전형 분석 34
2.3.1. 타크로리무스 약동학 파라미터의 산출 . 34
2.3.2. 임상변수 자료 수집 34
2.3.3. 검체 수집 및 데옥시리보핵산 추출. 35
2.3.4. 차세대염기서열 분석. 35
2.3.5. 기보고된 유전형 분석. 36
2.3.6. 생물정보학 분석 43
2.3.7. 시퀀싱 변이 호출 검증 . 43
2.3.8. 연관 분석 . 44
2.4. 타크로리무스 약동학과 연관된 유전형 검증 46
2.4.1. 유전형 분석 및 자료 수집 . 46
2.4.2. 통계 분석 . 46
2.5. 선형혼합모형 분석 47
2.5.1. 기본 모형 . 47
2.5.2. 임상변수 모형 및 유전형 모형 47
2.6. 기타 통계 분석 48
Chapter 3.Results 49
3.1. 인구학적 특성 49
3.2. 시퀀싱 분석 결과 51
3.3. 타크로리무스 약동학과 연관된 유전형의 분석 53
3.4. 타크로리무스 약동학과 일배체형의 상관관계 63
3.5. 재현군에서 타크로리무스 약동학에 대한 유전형의 영향 검증. 67
3.6. CYP3A5 발현군에서의 CYP3A7 rs2257401의 효과 71
3.7. 기본 모형 . 73
3.8. 임상변수 선형혼합모형의 구축 73
3.9. 최종 선형혼합모형 78
Chapter 4.Discussion 83
4.1. 결론 89
참고문헌 . 90
Abstract 103Docto
Continuous fatigue crack monitoring without baseline data
No full textIn order to overcome the susceptibility of conventional non-destructive testing (NDT) techniques to operational and environmental variations, a new damage detection technique that does not require direct comparison with baseline data was previously developed by the authors for detecting a crack in a plate structure. This reference-free technique employs two pairs of collocated lead zirconate titanate transducers (PZTs) placed on both sides of the plate to generate and measure Lamb waves. Then, the existence of mode conversion due to the crack is identified from the Lamb wave signals instantly measured by PZTs. In this study, the effectiveness of the proposed technique is tested using a steel girder specimen. A cyclic loading is applied to the girder resulting in fatigue cracks, and the proposed technique detects the appearance of fatigue damage solely based on the measured Lamb waves at the present stage. Experimental results are presented to demonstrate the applicability of the proposed technique to fatigue crack monitoring, and issues related to PZT installation are discussed.This research is supported by the Radiation Technology
Program under Korea Science and Engineering Foundation
(KOSEF) and the Ministry of Science and Technology
(M20703000015-07N0300-01510) andKorea Research
Foundation Grant funded by the Korean Government
(MOEHRD, Basic Research Promotion Fund)
(KRF-2007-331-D00462). Any opinions, findings and
conclusions or recommendations expressed in this material
are those of the author(s) and do not necessarily reflect
the views of the funding agencies. The authors also
would like to thank Professors Kent A. Harris and Piervincenzo
Rizzo at University of Pittsburgh for designing
the steel girder specimen and conducting fatigue loading
tests
THE OFF-LABEL USE OF ATYPICAL ANTIPSYCHOTICS AND ITS IMPACT ON ATTENTION DEFICIT/HYPERACTIVITY DISORDER (ADHD)
No full textAtypical antipsychotics (AAPs) (also known as second-generation antipsychotics) are the US Food and Drug Administration (FDA) approved medications for schizophrenia, bipolar I disorder, depression and autism. Compared to the typical antipsychotics, AAPs were marketed as reducing adverse side effects such as extrapyramidal symptoms. This resulted in extensive use of AAPs for not only the FDA approved indications but also other conditions that are not approved. However, several post-marketing clinical trials evaluated the use of AAPs and reported serious adverse side effects, including metabolic syndrome, cardiovascular events, or death.
The extensive use of AAPs by pediatrics is an important policy problem that imposes serious concerns on public health and economy in the US. A large proportion of total pediatric AAP use is off-label in which the safety and effectiveness are not yet established. Moreover, among the off-label conditions for which AAPs were used, ADHD was the most common primary mental diagnosis.
From public health perspective, the risk of type II diabetes in pediatric AAP users was estimated. A retrospective cohort study was conducted and a twice higher risk of developing type II diabetes was estimated for AAP users compared to non-users in pediatrics.
From economic efficiency perspective, the cost-effectiveness of AAPs compared to other ADHD medications in pediatric ADHD patients was estimated. Among non-stimulant ADHD medication treatment strategies, AAPs resulted in the lower expected health outcome than other ADHD medications. Also, AAPs were not a favored choice with respect to cost-effectiveness. A comparative effectiveness study that compares resource utilization and costs between atypical antipsychotic (AAP) users and non-AAP users in ADHD revealed that AAP users were likely to visit a healthcare facility for outpatient and inpatient services more frequently than non-AAP users. Total health care costs were significantly higher for AAP users with additional costs of 2,784 (2012 dollars) during a year after initiating the AAP treatment
Molecular Decrowding by Tissue Expansion Allows Precise Determination of the Spatial Distribution of Synaptic Proteins at a Nanometer Scale by exTEM
No full textTo understand how the molecular machinery of synapsesworks, itis essential to determine an inventory of synaptic proteins at a subsynapticresolution. Nevertheless, synaptic proteins are difficult to localizebecause of the low expression levels and limited access to immunostainingepitopes. Here, we report on the exTEM (epitope-exposedby expansion-transmission electron microscopy) method that enables the imagingof synaptic proteins in situ. This method combinesTEM with nanoscale resolution and expandable tissue-hydrogel hybridsfor enhanced immunolabeling with better epitope accessibility viamolecular decrowding, allowing successful probing of the distributionof various synapse-organizing proteins. We propose that exTEM canbe employed for studying the mechanisms underlying the regulationof synaptic architecture and function by providing nanoscale moleculardistribution of synaptic proteins in situ. We alsoenvision that exTEM is widely applicable for investigating proteinnanostructures located in densely packed environments by immunostainingof commercially available antibodies at nanometer resolution.11Nsciescopu
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