1.Clinicopathological Correlations of Neurodegenerative Diseases in the National Brain Biobank of Korea
Young Hee JUNG ; Jun Pyo KIM ; Hee Jin KIM ; Hyemin JANG ; Hyun Jeong HAN ; Young Ho KOH ; Duk L. NA ; Yeon-Lim SUH ; Gi Yeong HUH ; Jae-Kyung WON ; Seong-Ik KIM ; Ji-Young CHOI ; Sang Won SEO ; Sung-Hye PARK ; Eun-Joo KIM
Journal of Clinical Neurology 2025;21(3):190-200
Background:
and Purpose The National Brain Biobank of Korea (NBBK) is a brain bank consortium supported by the Korea Disease Control and Prevention Agency and the Korea National Institute of Health, and was launched in 2015 to support research into neurodegenerative disease dementia (NDD). This study aimed to introduce the NBBK and describes clinicopathological correlations based on analyses of data collected from the NBBK.
Methods:
Four hospital-based brain banks have been established in South Korea: Samsung Medical Center Brain Bank (SMCBB), Seoul National University Hospital Brain Bank (SNUHBB), Pusan National University Hospital Brain Bank (PNUHBB), and Myongji Hospital Brain Bank (MJHBB). Clinical and pathological data were collected from these brain banks using standardized protocols. The prevalence rates of clinical and pathological diagnoses were analyzed in order to characterize the clinicopathological correlations.
Results:
Between August 2016 and December 2023, 185 brain specimens were collected and pathologically evaluated (SNUHBB: 117; PNUHBB: 27; SMCBB: 34; MJHBB: 7). The age at consent was 70.8±12.6 years, and the age at autopsy was 71.7±12.4 years. The four-most-common clinical diagnoses were Alzheimer’s disease (AD) dementia (20.0%), idiopathic Parkinson’s disease (15.1%), unspecified dementia (11.9%), and cognitively unimpaired (CU) (11.4%).Most cases of unspecified dementia had a pathological diagnosis of central nervous system (CNS) vasculopathy (31.8%) or AD (31.8%). Remarkably, only 14.2% of CU cases had normal pathological findings. The three-most-common pathological diagnoses were AD (26.5%), CNS vasculopathy (14.1%), and Lewy body disease (13.5%).
Conclusions
These clinical and neuropathological findings provide a deeper understanding of the mechanisms underlying NDD in South Korea.
2.Clinicopathological Correlations of Neurodegenerative Diseases in the National Brain Biobank of Korea
Young Hee JUNG ; Jun Pyo KIM ; Hee Jin KIM ; Hyemin JANG ; Hyun Jeong HAN ; Young Ho KOH ; Duk L. NA ; Yeon-Lim SUH ; Gi Yeong HUH ; Jae-Kyung WON ; Seong-Ik KIM ; Ji-Young CHOI ; Sang Won SEO ; Sung-Hye PARK ; Eun-Joo KIM
Journal of Clinical Neurology 2025;21(3):190-200
Background:
and Purpose The National Brain Biobank of Korea (NBBK) is a brain bank consortium supported by the Korea Disease Control and Prevention Agency and the Korea National Institute of Health, and was launched in 2015 to support research into neurodegenerative disease dementia (NDD). This study aimed to introduce the NBBK and describes clinicopathological correlations based on analyses of data collected from the NBBK.
Methods:
Four hospital-based brain banks have been established in South Korea: Samsung Medical Center Brain Bank (SMCBB), Seoul National University Hospital Brain Bank (SNUHBB), Pusan National University Hospital Brain Bank (PNUHBB), and Myongji Hospital Brain Bank (MJHBB). Clinical and pathological data were collected from these brain banks using standardized protocols. The prevalence rates of clinical and pathological diagnoses were analyzed in order to characterize the clinicopathological correlations.
Results:
Between August 2016 and December 2023, 185 brain specimens were collected and pathologically evaluated (SNUHBB: 117; PNUHBB: 27; SMCBB: 34; MJHBB: 7). The age at consent was 70.8±12.6 years, and the age at autopsy was 71.7±12.4 years. The four-most-common clinical diagnoses were Alzheimer’s disease (AD) dementia (20.0%), idiopathic Parkinson’s disease (15.1%), unspecified dementia (11.9%), and cognitively unimpaired (CU) (11.4%).Most cases of unspecified dementia had a pathological diagnosis of central nervous system (CNS) vasculopathy (31.8%) or AD (31.8%). Remarkably, only 14.2% of CU cases had normal pathological findings. The three-most-common pathological diagnoses were AD (26.5%), CNS vasculopathy (14.1%), and Lewy body disease (13.5%).
Conclusions
These clinical and neuropathological findings provide a deeper understanding of the mechanisms underlying NDD in South Korea.
3.Clinicopathological Correlations of Neurodegenerative Diseases in the National Brain Biobank of Korea
Young Hee JUNG ; Jun Pyo KIM ; Hee Jin KIM ; Hyemin JANG ; Hyun Jeong HAN ; Young Ho KOH ; Duk L. NA ; Yeon-Lim SUH ; Gi Yeong HUH ; Jae-Kyung WON ; Seong-Ik KIM ; Ji-Young CHOI ; Sang Won SEO ; Sung-Hye PARK ; Eun-Joo KIM
Journal of Clinical Neurology 2025;21(3):190-200
Background:
and Purpose The National Brain Biobank of Korea (NBBK) is a brain bank consortium supported by the Korea Disease Control and Prevention Agency and the Korea National Institute of Health, and was launched in 2015 to support research into neurodegenerative disease dementia (NDD). This study aimed to introduce the NBBK and describes clinicopathological correlations based on analyses of data collected from the NBBK.
Methods:
Four hospital-based brain banks have been established in South Korea: Samsung Medical Center Brain Bank (SMCBB), Seoul National University Hospital Brain Bank (SNUHBB), Pusan National University Hospital Brain Bank (PNUHBB), and Myongji Hospital Brain Bank (MJHBB). Clinical and pathological data were collected from these brain banks using standardized protocols. The prevalence rates of clinical and pathological diagnoses were analyzed in order to characterize the clinicopathological correlations.
Results:
Between August 2016 and December 2023, 185 brain specimens were collected and pathologically evaluated (SNUHBB: 117; PNUHBB: 27; SMCBB: 34; MJHBB: 7). The age at consent was 70.8±12.6 years, and the age at autopsy was 71.7±12.4 years. The four-most-common clinical diagnoses were Alzheimer’s disease (AD) dementia (20.0%), idiopathic Parkinson’s disease (15.1%), unspecified dementia (11.9%), and cognitively unimpaired (CU) (11.4%).Most cases of unspecified dementia had a pathological diagnosis of central nervous system (CNS) vasculopathy (31.8%) or AD (31.8%). Remarkably, only 14.2% of CU cases had normal pathological findings. The three-most-common pathological diagnoses were AD (26.5%), CNS vasculopathy (14.1%), and Lewy body disease (13.5%).
Conclusions
These clinical and neuropathological findings provide a deeper understanding of the mechanisms underlying NDD in South Korea.
4.Clinical Features and Long-term Prognosis of Crohn’s Disease in Korea: Results from the Prospective CONNECT Study
Seung Wook HONG ; Byong Duk YE ; Jae Hee CHEON ; Ji Hyun LEE ; Ja Seol KOO ; Byung Ik JANG ; Kang-Moon LEE ; You Sun KIM ; Tae Oh KIM ; Jong Pil IM ; Geun Am SONG ; Sung-Ae JUNG ; Hyun Soo KIM ; Dong Il PARK ; Hyun-Soo KIM ; Kyu Chan HUH ; Young-Ho KIM ; Jae Myung CHA ; Geom Seog SEO ; Chang Hwan CHOI ; Hyun Joo SONG ; Gwang Ho BAIK ; Ji Won KIM ; Sung Jae SHIN ; Young Sook PARK ; Chang Kyun LEE ; Jun LEE ; Sung Hee JUNG ; Yunho JUNG ; Sung Chul PARK ; Young-Eun JOO ; Yoon Tae JEEN ; Dong Soo HAN ; Suk-Kyun YANG ; Hyo Jong KIM ; Won Ho KIM ; Joo Sung KIM
Gut and Liver 2022;16(6):907-920
Background/Aims:
The prospective Crohn’s Disease Clinical Network and Cohort Study is a nationwide multicenter cohort study of patients with Crohn’s disease (CD) in Korea, aiming to prospectively investigate the clinical features and long-term prognosis associated with CD.
Methods:
Patients diagnosed with CD between January 2009 and September 2019 were prospectively enrolled. They were divided into two cohorts according to the year of diagnosis: cohort 1 (diagnosed between 2009 and 2011) versus cohort 2 (between 2012 and 2019).
Results:
A total of 1,175 patients were included, and the median follow-up duration was 68 months (interquartile range, 39.0 to 91.0 months). The treatment-free durations for thiopurines (p<0.001) and anti-tumor necrosis factor agents (p=0.018) of cohort 2 were shorter than those of cohort 1. Among 887 patients with B1 behavior at diagnosis, 149 patients (16.8%) progressed to either B2 or B3 behavior during follow-up. Early use of thiopurine was associated with a reduced risk of behavioral progression (adjusted hazard ratio [aHR], 0.69; 95% confidence interval [CI], 0.50 to 0.90), and family history of inflammatory bowel disease was associated with an increased risk of behavioral progression (aHR, 2.29; 95% CI, 1.16 to 4.50). One hundred forty-one patients (12.0%) underwent intestinal resection, and the intestinal resection-free survival time was significantly longer in cohort 2 than in cohort 1 (p=0.003). The early use of thiopurines (aHR, 0.35;95% CI, 0.23 to 0.51) was independently associated with a reduced risk of intestinal resection.
Conclusions
The prognosis of CD in Korea appears to have improved over time, as evidenced by the decreasing intestinal resection rate. Early use of thiopurines was associated with an improved prognosis represented by a reduced risk of intestinal resection.
5.Clinical Course of Hepatitis B Viral Infection in Patients Undergoing Anti-Tumor Necrosis Factor α Therapy for Inflammatory Bowel Disease
Ji Min LEE ; Shu-Chen WEI ; Kang-Moon LEE ; Byong Duk YE ; Ren MAO ; Hyun-Soo KIM ; Soo Jung PARK ; Sang Hyoung PARK ; Eun Hye OH ; Jong Pil IM ; Byung Ik JANG ; Dae Bum KIM ; Ken TAKEUCHI
Gut and Liver 2022;16(3):396-403
Background/Aims:
Little is known about the clinical course of hepatitis B virus (HBV)-infected patients undergoing anti-tumor necrosis factor α (TNF-α) therapy for inflammatory bowel disease (IBD). We aimed to investigate the clinical course of HBV infection and IBD and to analyze liver dysfunction risks in patients undergoing anti-TNF-α therapy.
Methods:
This retrospective multinational study involved multiple centers in Korea, China, Tai-wan, and Japan. We enrolled IBD patients with chronic or resolved HBV infection, who received anti-TNF-α therapy. The patients’ medical records were reviewed, and data were collected using a web-based case report form.
Results:
Overall, 191 patients (77 ulcerative colitis and 114 Crohn’s disease) were included, 28.3% of whom received prophylactic antivirals. During a median follow-up duration of 32.4 months, 7.3% of patients experienced liver dysfunction due to HBV reactivation. Among patients with chronic HBV infection, the proportion experiencing liver dysfunction was significantly higher in the non-prophylaxis group (26% vs 8%, p=0.02). Liver dysfunction occurred in one patient with resolved HBV infection. Antiviral prophylaxis was independently associated with an 84% reduction in liver dysfunction risk in patients with chronic HBV infection (odds ratio, 0.16; 95% confidence interval, 0.04 to 0.66; p=0.01). The clinical course of IBD was not associated with liver dysfunction or the administration of antiviral prophylaxis.
Conclusions
Liver dysfunction due to HBV reactivation can occur in HBV-infected IBD patients treated with anti-TNF-α agents. Careful monitoring is needed in these patients, and antivirals should be administered, especially to those with chronic HBV infection.
6.Prediction of Early Recanalization after Intravenous Thrombolysis in Patients with Large-Vessel Occlusion
Young Dae KIM ; Hyo Suk NAM ; Joonsang YOO ; Hyungjong PARK ; Sung-Il SOHN ; Jeong-Ho HONG ; Byung Moon KIM ; Dong Joon KIM ; Oh Young BANG ; Woo-Keun SEO ; Jong-Won CHUNG ; Kyung-Yul LEE ; Yo Han JUNG ; Hye Sun LEE ; Seong Hwan AHN ; Dong Hoon SHIN ; Hye-Yeon CHOI ; Han-Jin CHO ; Jang-Hyun BAEK ; Gyu Sik KIM ; Kwon-Duk SEO ; Seo Hyun KIM ; Tae-Jin SONG ; Jinkwon KIM ; Sang Won HAN ; Joong Hyun PARK ; Sung Ik LEE ; JoonNyung HEO ; Jin Kyo CHOI ; Ji Hoe HEO ;
Journal of Stroke 2021;23(2):244-252
Background:
and Purpose We aimed to develop a model predicting early recanalization after intravenous tissue plasminogen activator (t-PA) treatment in large-vessel occlusion.
Methods:
Using data from two different multicenter prospective cohorts, we determined the factors associated with early recanalization immediately after t-PA in stroke patients with large-vessel occlusion, and developed and validated a prediction model for early recanalization. Clot volume was semiautomatically measured on thin-section computed tomography using software, and the degree of collaterals was determined using the Tan score. Follow-up angiographic studies were performed immediately after t-PA treatment to assess early recanalization.
Results:
Early recanalization, assessed 61.0±44.7 minutes after t-PA bolus, was achieved in 15.5% (15/97) in the derivation cohort and in 10.5% (8/76) in the validation cohort. Clot volume (odds ratio [OR], 0.979; 95% confidence interval [CI], 0.961 to 0.997; P=0.020) and good collaterals (OR, 6.129; 95% CI, 1.592 to 23.594; P=0.008) were significant factors associated with early recanalization. The area under the curve (AUC) of the model including clot volume was 0.819 (95% CI, 0.720 to 0.917) and 0.842 (95% CI, 0.746 to 0.938) in the derivation and validation cohorts, respectively. The AUC improved when good collaterals were added (derivation cohort: AUC, 0.876; 95% CI, 0.802 to 0.950; P=0.164; validation cohort: AUC, 0.949; 95% CI, 0.886 to 1.000; P=0.036). The integrated discrimination improvement also showed significantly improved prediction (0.097; 95% CI, 0.009 to 0.185; P=0.032).
Conclusions
The model using clot volume and collaterals predicted early recanalization after intravenous t-PA and had a high performance. This model may aid in determining the recanalization treatment strategy in stroke patients with large-vessel occlusion.
7.Prediction of Early Recanalization after Intravenous Thrombolysis in Patients with Large-Vessel Occlusion
Young Dae KIM ; Hyo Suk NAM ; Joonsang YOO ; Hyungjong PARK ; Sung-Il SOHN ; Jeong-Ho HONG ; Byung Moon KIM ; Dong Joon KIM ; Oh Young BANG ; Woo-Keun SEO ; Jong-Won CHUNG ; Kyung-Yul LEE ; Yo Han JUNG ; Hye Sun LEE ; Seong Hwan AHN ; Dong Hoon SHIN ; Hye-Yeon CHOI ; Han-Jin CHO ; Jang-Hyun BAEK ; Gyu Sik KIM ; Kwon-Duk SEO ; Seo Hyun KIM ; Tae-Jin SONG ; Jinkwon KIM ; Sang Won HAN ; Joong Hyun PARK ; Sung Ik LEE ; JoonNyung HEO ; Jin Kyo CHOI ; Ji Hoe HEO ;
Journal of Stroke 2021;23(2):244-252
Background:
and Purpose We aimed to develop a model predicting early recanalization after intravenous tissue plasminogen activator (t-PA) treatment in large-vessel occlusion.
Methods:
Using data from two different multicenter prospective cohorts, we determined the factors associated with early recanalization immediately after t-PA in stroke patients with large-vessel occlusion, and developed and validated a prediction model for early recanalization. Clot volume was semiautomatically measured on thin-section computed tomography using software, and the degree of collaterals was determined using the Tan score. Follow-up angiographic studies were performed immediately after t-PA treatment to assess early recanalization.
Results:
Early recanalization, assessed 61.0±44.7 minutes after t-PA bolus, was achieved in 15.5% (15/97) in the derivation cohort and in 10.5% (8/76) in the validation cohort. Clot volume (odds ratio [OR], 0.979; 95% confidence interval [CI], 0.961 to 0.997; P=0.020) and good collaterals (OR, 6.129; 95% CI, 1.592 to 23.594; P=0.008) were significant factors associated with early recanalization. The area under the curve (AUC) of the model including clot volume was 0.819 (95% CI, 0.720 to 0.917) and 0.842 (95% CI, 0.746 to 0.938) in the derivation and validation cohorts, respectively. The AUC improved when good collaterals were added (derivation cohort: AUC, 0.876; 95% CI, 0.802 to 0.950; P=0.164; validation cohort: AUC, 0.949; 95% CI, 0.886 to 1.000; P=0.036). The integrated discrimination improvement also showed significantly improved prediction (0.097; 95% CI, 0.009 to 0.185; P=0.032).
Conclusions
The model using clot volume and collaterals predicted early recanalization after intravenous t-PA and had a high performance. This model may aid in determining the recanalization treatment strategy in stroke patients with large-vessel occlusion.
8.Diagnostic Yield and Clinical Impact of Video Capsule Endoscopy in Patients with Chronic Diarrhea: A Korean Multicenter CAPENTRY Study.
Hyun Joo SONG ; Jeong Seop MOON ; Seong Ran JEON ; Jin Oh KIM ; Jinsu KIM ; Dae Young CHEUNG ; Myung Gyu CHOI ; Yun Jeong LIM ; Ki Nam SHIM ; Byong Duk YE ; Jae Hee CHEON ; Cheol Hee PARK ; Hyun Soo KIM ; Ji Hyun KIM ; Dong Kyung CHANG ; Jae Hyuk DO ; Kyeong Ok KIM ; Byung Ik JANG ; Sung Jae SHIN
Gut and Liver 2017;11(2):253-260
BACKGROUND/AIMS: In some cases, chronic diarrhea is unexplained, and small bowel disorders may be one of the causes. The aim of this study was to assess the diagnostic yield and clinical impact of video capsule endoscopy (VCE) in patients with chronic diarrhea. METHODS: We retrospectively analyzed records from October 2002 to August 2013 in the VCE nationwide database registry (n=2,964). Ninety-one patients from 15 medical centers (60 males and 31 females; mean age, 47±19 years) were evaluated for VCE as a result of chronic diarrhea. RESULTS: The duration of chronic diarrhea was 8.3±14.7 months. The positive diagnostic yield of VCE was 42.9% (39/91). However, 15.4% (14/91) exhibited an inconsistent result, and 41.8% (38/91) were negative. Abnormal findings consistent with chronic diarrhea included erosions/aphthous ulcers (19.8%), ulcers (17.6%), mucosal erythema (3.3%), edema (1.1%), and luminal narrowing (1.1%). The most common diagnoses were functional diarrhea associated with irritable bowel syndrome in 37 patients (40.7%) and Crohn’s disease in 18 patients (19.8%). After VCE examination, the diagnosis was changed in 34.1% of the patients (31/91). Hematochezia (odds ratio [OR], 8.802; 95% confidence interval [CI], 2.126 to 36.441) and hypoalbuminemia (OR, 4.811; 95% CI, 1.241 to 18.655) are predictive factors of a positive diagnostic yield. CONCLUSIONS: VCE had a favorable diagnostic yield and clinical impact on the management of patients with chronic diarrhea.
Capsule Endoscopy*
;
Diagnosis
;
Diarrhea*
;
Edema
;
Erythema
;
Female
;
Gastrointestinal Hemorrhage
;
Humans
;
Hypoalbuminemia
;
Irritable Bowel Syndrome
;
Male
;
Phenobarbital
;
Retrospective Studies
;
Ulcer
9.Efficacy and Safety of Infliximab Therapy and Predictors of Response in Korean Patients with Crohn's Disease: A Nationwide, Multicenter Study.
Chang Hwan CHOI ; In Do SONG ; Young Ho KIM ; Ja Seol KOO ; You Sun KIM ; Joo Sung KIM ; Nayoung KIM ; Eun Soo KIM ; Jae Hak KIM ; Ji Won KIM ; Tae Oh KIM ; Hyun Soo KIM ; Hyo Jong KIM ; Young Sook PARK ; Dong Il PARK ; Soo Jung PARK ; Hyun Joo SONG ; Sung Jae SHIN ; Suk Kyun YANG ; Byong Duk YE ; Kang Moon LEE ; Bo In LEE ; Sun Young LEE ; Chang Kyun LEE ; Jong Pil IM ; Byung Ik JANG ; Tae Joo JEON ; Yu Kyung CHO ; Sae Kyung CHANG ; Seong Ran JEON ; Sung Ae JUNG ; Yoon Tae JEEN ; Jae Myung CHA ; Dong Soo HAN ; Won Ho KIM
Yonsei Medical Journal 2016;57(6):1376-1385
PURPOSE: Infliximab is currently used for the treatment of active Crohn's disease (CD). We aimed to assess the efficacy and safety of infliximab therapy and to determine the predictors of response in Korean patients with CD. MATERIALS AND METHODS: A total of 317 patients who received at least one infliximab infusion for active luminal CD (n=198) and fistulizing CD (n=86) or both (n=33) were reviewed retrospectively in 29 Korean referral centers. Clinical outcomes of induction and maintenance therapy with infliximab, predictors of response, and adverse events were evaluated. RESULTS: In patients with luminal CD, the rates of clinical response and remission at week 14 were 89.2% and 60.0%, respectively. Male gender and isolated colonic disease were associated with higher remission rates at week 14. In week-14 responders, the probabilities of sustained response and remission were 96.2% and 93.3% at week 30 and 88.0% and 77.0% at week 54, respectively. In patients with fistulizing CD, clinical response and remission were observed in 85.0% and 56.2% of patients, respectively, at week 14. In week-14 responders, the probabilities of sustained response and remission were 94.0% and 97.1%, respectively, at both week 30 and week 54. Thirty-nine patients (12.3%) experienced adverse events related to infliximab. Serious adverse events developed in 19 (6.0%) patients including seven cases of active pulmonary tuberculosis. CONCLUSION: Infliximab induction and maintenance therapy are effective and well tolerable in Korean patients with luminal and fistulizing CD. However, clinicians must be aware of the risk of rare yet critical adverse events.
Colonic Diseases
;
Crohn Disease*
;
Humans
;
Infliximab*
;
Male
;
Phenobarbital
;
Referral and Consultation
;
Retrospective Studies
;
Tuberculosis
;
Tuberculosis, Pulmonary
10.Indications for Detection, Completion, and Retention Rates of Small Bowel Capsule Endoscopy Based on the 10-Year Data from the Korean Capsule Endoscopy Registry.
Yun Jeong LIM ; Oh Young LEE ; Yoon Tae JEEN ; Chi Yeon LIM ; Dae Young CHEUNG ; Jae Hee CHEON ; Byong Duk YE ; Hyun Joo SONG ; Jin Su KIM ; Jae Hyuk DO ; Kwang Jae LEE ; Ki Nam SHIM ; Dong Kyung CHANG ; Cheol Hee PARK ; Byung Ik JANG ; Jeong Seop MOON ; Hoon Jai CHUN ; Myung Gyu CHOI ; Jin Oh KIM
Clinical Endoscopy 2015;48(5):399-404
BACKGROUND/AIMS: Capsule endoscopy (CE) is widely used. However, CE has limitations including incomplete examination, inadequate bowel preparation, and retention. The aim of this study was to estimate the indications for and detection, completion, and retention rates of small intestine CE based on the 10-year data from the Korean Capsule Endoscopy Registry. METHODS: Twenty-four hospitals participated in this study. Clinical information, such as reasons for CE, method and quality of bowel preparation, and incomplete examination and capsule retention rates, was collected and analyzed. RESULTS: A total of 2,914 CEs were registered. The most common reason for CE was obscure gastrointestinal bleeding (59%). Significant lesions were detected in 66% of cases. Positive CE diagnosis occurred in 63% of cases. The preparation method did not significantly affect the quality of bowel preparation for CE. The overall incomplete rate was 33%, and was high in the elderly and those with poor bowel preparation. Capsule retention was 3% and high in patients with small bowel tumors and Crohn's disease and in children under 10 years of age. CONCLUSIONS: CE is a valuable technique; while the overall detection rate is high, incompletion and retention rates are also relatively high. CE should be carefully considered in the elderly and children less than 10 years of age, as well as in patients with small bowel tumors and Crohn's disease.
Aged
;
Capsule Endoscopy*
;
Child
;
Crohn Disease
;
Diagnosis
;
Hemorrhage
;
Humans
;
Intestine, Small

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