국내 다기관에서 조사한 지역사회획득 메티실린내성 황색포도알균의 빈도와 임상적 특성

송진수,최평균,송경호,조재현,김성한,방지환,이창섭,박경화,박경운,신수,최희정,김의석,김동민,이미숙,박완범,김남중,오명돈,김의종,김홍빈,최강원 대한감염학회 2006 감염과 화학요법 Vol.38 No.6

목적 : 최근 전세계적으로 지역사회획득 메티실린내성 황색포도알균(community-associated methicillin-resistant Staphylococcus aureus, CA-MRSA)의 보고가 증가하고 있다. 하지만, 우리나라에서는 CA-MRSA 감염증에 대한 증례보고만 있을 뿐 아직까지 체계적인 연구결과가 없는 실정이다. 저자들은 국내에서 CA-MRSA의 빈도, 감염증의 임상적 양상, 분리된 균주의 항균제내성 양상을 조사하였다. 재료 및 방법 : 2005년 1월부터 2005년 6월까지 7개 병원에서 MRSA가 분리된 환자의 명단을 파악한 후 의무기록지와 건강보험심사평가원의 자료를 검토하였다. 외래나 응급실에서 혹은 입원 후 72시간 이내에 균주가 분리되고 MRSA 획득과 관련된 위험인자가 없는 경우 CA-MRSA로 정의하였으며, 분리된 균주의 임상적 의미에 따라 원인병원체(pathogen), 집락화(colonizer), 미결정(undetermined)으로 분류하였다. Penicillin과 oxacillin을 제외하고 3개 이상의 다른 계열 항균제에 내성이면 다제내성으로 정의하였다. 결과 : 연구기간동안 총 3,251주의 황색포도알균이 분리되었으며, 이 중 MRSA는 1,900주(58.4%)였다. MRSA 가운데 CA-MRSA는 114주(6.0%) 였으며, 이들이 분리된 부위는 귀(62주), 비뇨기계(14주), 피부 및 연부조직(11주), 호흡기계(10주), 혈액(3주) 등이었다. CA-MRSA 균주 가운데 집락균은 22주, 원인병원체는 22주였으며, 나머지 균주에 대해서는 그 임상적 의미를 결정할 수 없었다. 항균제 감수성 검사를 시행한 73균주 중 47주(64.4%)는 다제내성이었다. CA-MRSA 감염증 22예 중 피부 및 연부조직 감염(9예)과 중이염/외이도염(9예)이 가장 흔하였다. 침습적 감염증(invasive infection)은 4명(원발성 균혈증 3예, 감염성 관절염 1예)에서 확인되었지만, CA-MRSA 감염증으로 사망한 환자는 없었다. 결론 : 병원내 감염증에서는 MRSA가 심각한 문제이지만, 아직까지 지역사회 감염증에서 CA-MRSA는 흔하지 않았다. Background : Methicillin-resistant Staphylococcus aureus (MRSA) infection has emerged in patients who do not have the established risk factors. In Korea, little is known about the epidemiology and clinical features of community-associated MRSA (CA-MRSA). Material and Methods : Clinical microbiology laboratory databases of 7 hospitals were reviewed to identify the patients from whom MRSA was isolated during the period of January to July 2005. Only one isolate per patient was enrolled. In order to identify the risk factors of MRSA acquisition, the medical records and the Health Insurance Review Agency databases were reviewed. CA-MRSA was defined as MRSA isolated from patient without established risk factors. We analyzed patient demographics, underlying medical conditions, characteristics of infection, and antimicrobial susceptibility profiles. Results : Of total 3,251 S. aureus isolates, 1900 (58.4%) were MRSAs. Of the MRSA isolates, 114 (6.0%) were CA-MRSA. Of 114 CA-MRSA isolates, 22 (19.3%) were colonizers, 22 (19.3%) were pathogens, and the clinical significance of remaining 70 (61.4%) could not be determined. Median age of the 22 patients with CA-MRSA disease was 47 years. Nine patients had skin and soft tissue infections, 9 ear infections, 3 bacteremia, 1 septic arthritis. Seven patients had underlying medical disease. None died of the CA-MRSA infections. Of the 73 isolates of CA-MRSA, 47 (64.4%) were resistant to more than 3 classes of antibiotics besides β-lactams. Conclusion : Although MRSA is highly prevalent among hospital-associated S. aureus infection, CA-MRSA infections are not common.

일렬 자가조혈모세포이식을 받은 다발성 골수종 환자에서 발생한 뇌 톡소포자충증 1례

김계형,송경호,전재현,박완범,박상원,김홍빈,김남중,김인호,오명돈 대한감염학회 2010 감염과 화학요법 Vol.42 No.3

Toxoplasmosis is a rare but fatal complication in hematopoietic stem cell transplant recipients, usually associated with allogeneic hematopoietic stem cell transplantation (HSCT). We report a case of cerebral toxoplasmosis in a patient with multiple myeloma, following tandem autologous stem cell transplantation. A 55-year-old Korean male presented with weakness in both legs that had progressed to both arms. A magnetic resonance imaging scan of the brain revealed multiple, variablesized ring-enhancing lesions with surrounding edema in the cerebral hemispheres and brain stem. Stereotactic biopsy revealed bradyzoites of Toxoplasma gondii in the brain tissue. The patient received trimethoprim-sulfamethoxazole, followed by pyrimethamine and sulfadiazine, accompanying treatment for progressive multiple myeloma. Cerebral toxoplasmosis should be considered as one of the differential diagnoses in patients with neurologic signs following autologous HSCT.

Mycobacterium mageritense에 의한 당뇨병성 족부 감염증 1예

김충종,김낙현,김문석,김계형,전재현,박문석,박경운,박완범,박상원,김홍빈,김남중,오명돈,최강원 대한감염학회 2008 감염과 화학요법 Vol.40 No.6

Diabetic foot infection is one of the important complications in patients with advanced diabetes mellitus. Limb threatening infections such as osteomyelitis, abscess, and necrotizing fasciitis are frequently accompanied by the disease. Non-tuberculous mycobacterium (NTM) is a rare causative organism of diabetic foot infection. Thus, if one is not suspicious or meticulous, infection due to NTM will be easily overlooked and this will result in delayed diagnose and treat. Therefore, it is necessary to consider NTM as the causative organism if the wound does not respond to the conventional antibiotic treatment and the culture from the adequately obtained specimen reveals atypical acid-fast bacilli. We present a case of diabetic foot infection with osteomyelitis and abscess due to Mycobacterium mageritense, one of the rapid growing mycobacteria, that was successfully treated with surgical debridement and appropriate antibiotic treatment.

반복적인 부비동염으로 내원한 Good 증후군 1예

송경호,김계형,김충종,박경운,전상훈,김홍빈,김남중,오명돈,최강원 대한감염학회 2007 감염과 화학요법 Vol.39 No.5

Good 증후군은 흉선종과 면역결핍이 동반되는 질환으로, B세포의 감소로 인한 범저감마글로불린혈증과 CD4^(+)T세포의 감소로 인한 세포성 면역저하가 동시에 나타나는 것을 특징으로 한다. 본 증례는 18개월 전부터 발생한 반복적인 부비동염을 주소로 내원한 43세 남자 환자로, 내원 1년 전 흉선종절제수술을 시행받았으며, 면역학적 검사상 범저감마글로불린혈증과 T세포의 감소 등의 이상 소견이 발견되었다. 정주 면역글로불린과 경험적 항생제(amoxicillin/clavulanic acid) 사용 후 부비동염이 호전되었으며, 예방접종과 정기적인 면역글로불린 투여 후 특이 합병증없이 경과 관찰 중이다. Good's syndrome is the association of thymoma with immunodeficiency, characterized by hypogammaglobulinemia, B-cell lymphopenia and variably defects in cellular immunity with CD4^(+) T-cell lymphopenia and an inverted CD4^(+):CD8^(+) T-cell ratio. We report a 43-year-old male patient who presented with a 18-month history of productive cough and postnasal drip. One year ago, he underwent the operation for resection of a thymoma. Despite of appropriate management, sinusitis relapsed multiple times. He was found to have hypogammaglobulinemia with nearly absent B cells(4/μL). The CD4^(+) T-cell count was 554/μL with an inverted CD4^(+):CD8^(+) T-cell ratio of 0.6. His symptoms and signs improved with antibiotic treatment and monthly administration of intravenous immunoglobulin (IVIG, 400 mg/kg).

자발성 세균성 복막염을 일으킨 그람음성간균의 3세대 세팔로스포린 내성률 변화

방지환,송경호,박주경,박완범,김성한,김홍빈,김남중,오명돈,김의종,이효석,최강원 대한감염학회 2007 감염과 화학요법 Vol.39 No.3

The third generation cephalosporin is widely used in treatment of spontaneous bacterial peritonitis (SBP). Resistance to the third generation cephalosporin was associated with poor outcome in patients with SBP. Thus it is necessary to know the changes in resistance rate. We planned to investigate retrospectively on resistance rate of the third generation cephalosporin of gram negative bacteria isolated in patients with SBP, who visited Seoul National University Hospital between 1998 and 2006. The Clinical and Laboratory Standards Institute guidelines were applied for antibiotic susceptibility test. A total of 269 consecutive episodes of clinically and microbiologically proven SBP was identified during the study period and 209 cases were caused by gram negative organisms. Among 209 isolates, 22 (10.5%) showed resistance to the third generation cephalosporin. The prevalence of resistance was decreasing during the study period (P=0.014).

무릎운동훈련들이 안쪽빗넓은근과 가쪽넓은근의 수축 개시시간에 미치는 효과

김명진,김지원,이재온,박경희,신화경 한국전문물리치료학회 2001 한국전문물리치료학회지 Vol.8 No.2

The purpose of this study was to investigate the effect of knee exercises on the onset times of vastus medialis oblique muscle (VMO) and vastus lateralis muscle (VL) and in healthy subjects. Fifteen subjects (7 men, 8 women) in a mean age of 25.4 years participated in the study. Electromyographic (EMG) signals were recorded from the VMO and VL under four exercises. Knee exercises consisted of open kinematic terminal knee extension, straight leg raising, isometric hip adduction exercise, and closed kinematic terminal knee extension. No significant differences were found in the onset times of EMG activities of VMO and VL in the four exercises. There were also no significant differences among the exercises. These results coincided with previous studies that found no difference between onset of VMO and VL. However, it is difficult to say that there is no difference between onset of VMO and VL in healthy subjects. To confirm this results, further researches that follow same onset determination metod and exercises are needed. Not only is the study of onset time of muscle needed, but also the studies of the amount of activation and the rate of increase of muscle activation are needed.

2017년 2학기 ‘부산의 하루’ 수강생 설문조사의 분석

김대래, 박명선, 태경호 신라대학교 부산학연구센터 2018 부산연구 Vol.16 No.1

2017년도 부산학강좌를 수강한 부산출신 학생 122명을 분석하였다. 학생들의 종교는 무교가 60.7%이고 불교가 21.3%, 개신교 8.2% 그리고 가톨릭 9%의 비중을 보였다. 아빠의 고향은 59%가 부산, 경남이 29.5%로 부산과 경남을 합하면 88.5%로 절대적인 비중을 점하였다. 대구경 북은 6.5%, 호남제주는 4.9%였다. 엄마의 고향은 부산 54.1%, 경남 22.1%로 부산과 경남이 76.2%로 역시 압도적 비중을 점하고 있지만 아빠의 고향에 비해서는 집중도가 낮았다. 대구경북 은 6.5%, 호남제주는 7.4%였다. 부산에서 경기가 있는 프로야구를 얼마나 관람하였는가에 대한 설문에는 33.6%가 ‘한 번도 보 지 않았다’고 답하였고 1번이 22.1%, 2번이 11.5%로 1-2회가 33.6%로 한 번도 보지 않은 학생 의 비율과 정확히 같았다. 해외여행의 횟수는 한 번도 해외에 가보지 않은 학생이 30.3%, 1번이 28.7%, 2번이 14.8%였다. 부산국제영화제에 참가한 횟수에 대해서는 61.5%가 참여한 경험이 없 다고 하였는데, 이들은 2017년도 부산국제영화제에 참여할 의사가 있는지에 대한 설문에서도 ‘생 각해 보지 않았다’거나 ‘참여의사가 없다’고 하였다. 즐겨 마시는 음료에 대한 설문에서는 커피가 26.2%로 가장 많았고 그 다음은 19.7%의 콜라였다. 이어 14.8%의 스포츠음료, 13.9%의 과일주 스, 12.3%의 사이다가 뒤를 이었다. 부산의 대표음식에 대한 설문에는 돼지국밥 36.2%, 어묵 20.9%, 밀면 13.6%, 씨앗호떡 6.7%, 파전 4%의 순으로 나타났다. 의외였던 것은 생선회가 전혀 중요하게 인식되고 있지 않았고 씨앗 호떡이 4번째로 올라온 점이다. 외지에서 온 친구에게 안내해주고 싶은 곳을 고르는 설문에서는 광안리 21.8%, 해운대 12.5%, 서면 6.5%, 센텀시티 5.4%, 국제영화제 5%, 광안대교(순환대교) 4.4% 순이었다. 사투리 사용여부를 물어본 결과 그냥 편하게 쓴다는 응답이 87.7%로 대다수가 그냥 부산말을 일상에 쓰고 있었다. 부산에서 새로 생겼으면 하는 설문에는 공원 11.3%, 번지점 프 10%, 연극공간 6.1%, 익스트림경기장 6.1%, 미술관 5.4%, 돔 야구장 5.3%, 오페라하우스 5.2%, 도서관 5.2% 순으로 나타났다. 대형쇼핑몰이 인근에 들어오면 지역발전에 도움이 될 것인 가에 대한 설문에는 절반을 약간 넘는 52.5%가 ‘그렇다’고 응답하였다. 부산사람들이 ‘휴지를 잘 버리는지’에 대한 설문에 대해서는 의견들이 매우 다양하게 나타났는 데, ‘휴지를 잘 버린다’는 쪽의 응답이 좀 더 많았다. ‘새치기를 잘 한다’는 설문에도 ‘그렇지 않다’ 는 응답이 다소 많았다. ‘자리양보를 잘한다’는 설문에는 대체로 긍정적이었다. ‘길을 물으면 잘 가르켜주는가’에 대한 설문에는 ‘그렇다’는 응답이 다수였다. ‘승강기에서 잘 기다려준다’는 설문에 는 ‘그렇다’는 응답이 우세하였다. ‘난폭운전을하지않는다’는 설문에는 ‘그렇지않다’는 응답이 다수를 이루었다. ‘전혀그렇지않다’는 응답도 16.4%나 되어 학생들은 부산의 운전질서에 관해 매우 부정적인 생각을 가지고 있었다. ‘운전할 때 양보운전을 잘한다’는 설문에는 ‘그렇지않다’는 응답이 더 많았다. ‘교통신호를 잘 안지 킨다’는 설문에 대한 응답도 ‘잘 안지킨다’는 쪽의 응답이 좀 더 많았다. 전체적으로 교통질서와 관련하여 학생들은 부정적인 인식이 좀 더 강하였다. ‘거리는 깨끗한가’에 대한 설문에는 ‘그렇지 않다’는 답변이 더 많았다. ‘하천물은 맑은가’에 대한 설문도 부정적인 응답이 우세하였다. ‘청소를 잘한다’는 설문에 대해서도 부정적인 응답이 많았다. ‘길거리가깨끗한가’라는 설문과 거의 응답이 같은 것으로 나와 청소를 잘 하지 않아 길거리가 깨끗하지 않다는 생각을 하고 있는 것으로 보인 다. We analyzed responses from 122 students originally from Busan enrolled in the Busan Studies class. 60.7% of students reported being non-religious; 21.3% were Buddhists; 8.2% were Protestants; and 9% were atholics. The hometowns of the students’ fathers varied: Busan (59% of the students) and Gyeongnam province (29.5%) together accounted for 88.5% of respondents, outstripping Daegu/Gyeongbuk province (6.5%) and Honam/Jeju (4.9%). Their mothers' hometowns were also predominantly Busan (54.1%) and Gyeongnam province (22.1%), totaling 76.2%, though this proportion was lower than that of the hometowns of the students’ fathers. Daegu/Gyeongbuk and Honam/Jeju accounted for 6.5% and 7.4% of the mothers’ hometowns respectively. In response to the question "how many times have you watched professional baseball games?", 33.6% of the respondents answered that they had never watched a game. 22.1% answered that they had watched once, and 11.5% twice, making the proportion of students who had watched games either once or twice 33.6%, the exact same proportion as the percentage of students who had never watched one. Regarding the number of overseas trips respondents had taken, 30.3% answered that they had never traveled abroad; 28.7% had travelled once and 14.8% twice. 61.5% of the students surveyed answered that they had never participated in the Busan International Film Festival (BIFF) and that they had not thought about participating or had not wished to participate in the BIFF in 2017. As for favorite beverages, coffee ranked first (26.2%), cola ranked second (19.7%), followed by sports drinks (14.8%), fruit juices (13.9%), and sprite (12.3%). When asked what kind of food represented Busan best, students chose pork and rice soup the most (36.2%), followed by fish cake (20.9%), wheat noodles (13.6%), mixed-seed sweet pancake (ranking a surprisingly high 6.7%), and scallion pancake (4%). An interesting finding was that students did not think of raw fish as a typically Busan dish. In response to the question of where students would take their friends from other regions to show them the city, the results are as follows: Gwanganli (21.8%), Haeundae (12.5%), Seomyun (6.5%), Centum City (5.4%), Busan International Film Festival (5%) and Gwangan Bridge (4.4%). Regarding the Bus an dialect, 87.7% of the students surveyed said that they use it comfortably and without any hesitation in their daily lives. The amenities that students would like to see in Busan in the future were public parks (11.3%), bungee jumping (10%), theaters (6.1%), extreme sports parks (6.1%), museums (5.4%), indoor baseball parks (5.3%), opera houses (5.2%) and libraries (5.2%). 52.5% of the students surveyed answered that a large shopping mall would help develop their neighborhood. While students’ responses varied on the question of whether Busan people litter, a majority thought littering was less pervasive. A majority of students also believed that people in Busan did not generally cut in line. Responses were found to be generally positive regarding Busan people offering their seats to others, giving others directions and waiting for people to get off first in the elevator. Most students think that people in Busan drive recklessly, with 16.4% “strongly” believing so. More students indicated disagreeing with the statement that ‘people yield when driving.’ There were also more responses of ‘agree’ to the statement that ‘people do not follow traffic rules.’ Overall, students did not believe that people in Busan obey the rules of the road. A majority of students also did not believe that Busan’s streets are clean. The question on whether river water is clean was also dominated by negative responses. Also, the students did not believe that Busan city-goers cleaned up well after themselves. Given that the responses to the previous question were very similar to the question about street cleanliness, it is found that the students believed that the streets are dirty because they are not cleaned well.

시스템의 處理率 向上과 交錯 狀態 豫防에 관한 시뮬레이션 硏究

金明姬,朴美卿 梨花女子大學校 韓國生活科學硏究院 1989 韓國生活科學硏究院 論叢 Vol.43 No.-

본 연구는 87년 3월부터 6월 사이에 이화 여대의 VAX-11/780 시스템에서 발생하였던 심각한 시스템 정체 현상의 원인 분석과 이에 따른 해결 방안을 강구하고자 컴퓨터 시뮬레이션 방법에 따라 대상 시스템을 모델화한 후 당시 상황을 구현하여 이에 대한 실험을 수행하였다. 그 결과 소형 컴퓨터 시스템의 경우 하나의 교착 상태 발생으로도 시스템 정체를 일으킬 수 있으며, 특히 대상 시스템에서는 주기억 장치와 보조기억 장치 사이의 프로세스 진행과정에서 교착 상태가 발생하였음을 알아내었다. 또한 그 원인으로는 처리해야 할 작업량에 비해 주기억 장치의 용량이 부족한데 있었고, 당시의 작업 부하량에 맞는 최소 주기억 용량으로 그 크기를 확장함으로써 문제를 해결할 수 있었다. 그밖에 주기억 용량 확장에 따른 처리가능한 작업량 및 시스템의 처리율 향상을 예측할 수 있었다. VAX-11/780 at Ewha Womans University experienced a serious system blocking during the first semester of 1987. This paper describes a simulation model of the system, which we constructed to study the cause of the problem. Both the VAX-11/780 system behavior and workload were modeled. The analysis of the simulation indicates that the cause was the deadlock associated with the memory resources. This paper suggests a method which prevents the deadlock occurrence and hence avoids the system throughput degradation. Also, this paper describes the relation among memory size, workload and the system throughput in the target VAX system.

스테로이드 치료 후 회복기의 규칙적인 운동이 쥐의 스테로이드 유발성 위축 뒷다리근에 미치는 영향

최명애,변영순,황애란,김희승,홍해숙,최스미,서화숙,이경숙,박미정,신기수,안경주,이윤경,임지회 대한기초간호자연과학회 2002 Journal of korean biological nursing science Vol.4 No.1

This study was conducted to determine whether low intensity regular exercise following steroid treatment could attenuate steroid-induced muscle atrophy. Thirty-eight Sprague-Dawley rats weighing 165~175g were divided into six groups;control group(C), dexamethasone administration group(D), sedentary after normal saline administration group(C+Se), exercise after normal saline administration group(C+Ex), sedentary group after dexamethasone administration(D+Se), exercise group after dexamethasone administration(D+Ex). Either dexamethasone(5mg/kg) or normal saline was injected for 7days accordingly. Exercise was started at 10m/min on the 10?grade treadmill and gradually increased up to 15m/min by the 7th day for 60minutes/day(20min×3). The data were analyzed by Kruskal-Wallis test and Mann-Whitney U test using the SPSS WIN 9.0 program. Body weight, muscle weight and myofibrillar protein content of both plantaris and gastrocnemius, Type I, II muscle fiber cross-sectional area of plantaris, and Type II muscle fiber cross-sectional area of gastrocnemis in D group were significantly lower than those of C group(p<.05) respectively. Hindlimb muscle weight, myofibrillar protein content of both plantaris and gastrocnemius, Type I muscle fiber cross-sectional area of soleus and Type I, II muscle fiber cross-sectional area of plantaris in D+Ex group tended to increase compared to those of D+Se group. Myofibrillar protein content of both plantaris and gastrocnemius, Type I muscle fiber cross-sectional area of plantaris in D+Ex group tended to increase compared to those of C+Se group. Based on these results, it is suggested that regular low-intensity exercise during recovery period after steroid treatment might facilitate the recovery from steroid-induced muscle atrophy.

Kiwi pectinesterase 저해제의 정제 및 특성

고은경,김명화,허원녕 목포대학교 자연자원개발연구소 1999 자연자원연구 Vol.2 No.-

Kiwi pectinesterase inhibitor(PEI)를 분리하기 위하여 CNBr-sepharose 4B에 orange pectinesterase(PE)를 공유결합으로 결합시켜 affinity chromatography용 수지를 제조하였다. 제조된 수지를 사용하여 PEI를 강력하게 선택적으로 결합시켜 pH 9.5의 높은 이온 강도를 갖는 용액으로 단일한 활성 peak로 용출·분리하였다. 분리된 kiwi PEI의 분자량은 12.5% SDS-PAGE 전기영동상에서 약 16.6 KDa 정도의 밀접한 이중 band로 나타났다. 분리된 PEI를 -25,℃ 5℃ 및 실온에서 30일 동안 보관·저장하였을 때 냉장, 냉동상태에서는 저해활성이 2주정도 경과시 25% 정도 감소하고 그 이후에는 큰 변화 없이 유지되었으나, 실온에서는 저해활성이 급격히 감소하여 저장 4주 정도에 거의 활성을 상실하였다. 이들의 활성특성을 조사해 본 결과 최적저해활성 pH는 7.5이고 최적저해반응 온도는 20℃였고, 70℃까지는 내열성을 지녔다. 또한 0.2M NaCl의 기질농도에서 최적저해 활성을 나타내었으며, kiwi PEI의 PE에 대한 저해작용은 noncompetitive inhibition인 것으로 나타났다. The resin for affinity chromatography was prepared to separate pectinesterase inhibitor(PEI) from ripened kiwi fruit(Actinidia chinensis) by CNBr-activated Sepharose 4B being covalently bound by orange petinesterse(PE). The affinity resin strongly and selectively bound PEI, which could be eluted in high yield as a single, homogeneous and sharp peak by pH 9.5 without loss of inhibitory activity. The separated PEI had maintained almost inhibitory activity at -25℃ and 5℃ during 30 days but lost it at room temperature in 4 weeks. The PEI possessed a molecular weight of 16.6 KDa, as estimated by 12.5% SDS-PAGE. The optimum pH, the optimum temperature, the thermostable range and NaCl concentration of substrate for PEI inhibitory activity appeared to be 7.5, 20℃, below 70℃ and 0.2 M respectively. The kind of inhibition on tomato pectinesterase was found to be noncompetitive, using citrus pectin as substrate.