1.Post‑transplant cyclophosphamide plus anti‑thymocyte globulin decreased serum IL‑6 levels when compared with post‑transplant cyclophosphamide alone after haploidentical hematopoietic stem cell transplantation
Jeong Suk KOH ; Myung‑Won LEE ; Thi Thuy Duong PHAM ; Bu Yeon HEO ; Suyoung CHOI ; Sang‑Woo LEE ; Wonhyoung SEO ; Sora KANG ; Seul Bi LEE ; Chul Hee KIM ; Hyewon RYU ; Hyuk Soo EUN ; Hyo‑Jin LEE ; Hwan‑Jung YUN ; Deog‑Yeon JO ; Ik‑Chan SONG
Blood Research 2025;60():5-
Background:
Post-transplantation cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are common pro‑ phylactic strategies for graft-versus-host disease (GVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Interleukin (IL)-6 is a surrogate marker for cytokine release syndrome (CRS) and acute GVHD.Method The clinical outcomes and complications of haplo-HSCT with PTCy plus ATG versus PTCy monotherapy were compared according to serum IL-6 levels at Chungnam National University Hospital (Daejeon, South Korea) from Jan‑ uary 2019 to February 2023.
Results:
Forty patients who underwent haplo-HSCT were analyzed. A significant difference in IL-6 levels was observed between the PTCy plus ATG and PTCy alone groups (7.47 ± 10.55 vs. 117.65 ± 127.67; p = 0.003). More patients in the PTCy plus ATG group had a CRS grade of 0 than in the PTCy alone group (p < 0.001). Serum IL-6 levels were associated with grades II–IV acute GVHD (r = 0.547, p < 0.001). The cumulative incidence (CI) of grades II–IV acute GVHD was significantly higher in the PTCy alone group (67.9% vs. 4.8%; p < 0.001). No significant difference in the CI for chronic GVHD was detected between the PTCy plus ATG and PTCy alone groups (72.1% vs. 82.0%; p = 0.730). The CI of 1-year non-relapse mortality was significantly higher in the PTCy alone group than in the PTCy plus ATG group (42.2% vs. 15.9%; p = 0.022). The 1-year overall survival (OS) was significantly better in the PTCy plus ATG group (75.9% vs. 35.3%; p = 0.011). The 1-year GVHD-free, relapse-free survival rate was 29.4% in the PTCy alone group and 54.0% in the PTCy plus ATG group (p = 0.038).
Conclusion
Serum IL-6 levels were higher in the PTCy alone group than in the PTCy plus ATG group. The addition of ATG before stem cell infusion affected IL-6 levels and reduced the incidences of CRS and grade II–IV acute GVHD in haplo-HSCT patients. This study suggests that PTCy plus ATG as GVHD prophylaxis in haplo-HSCT is beneficial in terms of clinical outcomes and complications of HSCT.
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.Post‑transplant cyclophosphamide plus anti‑thymocyte globulin decreased serum IL‑6 levels when compared with post‑transplant cyclophosphamide alone after haploidentical hematopoietic stem cell transplantation
Jeong Suk KOH ; Myung‑Won LEE ; Thi Thuy Duong PHAM ; Bu Yeon HEO ; Suyoung CHOI ; Sang‑Woo LEE ; Wonhyoung SEO ; Sora KANG ; Seul Bi LEE ; Chul Hee KIM ; Hyewon RYU ; Hyuk Soo EUN ; Hyo‑Jin LEE ; Hwan‑Jung YUN ; Deog‑Yeon JO ; Ik‑Chan SONG
Blood Research 2025;60():5-
Background:
Post-transplantation cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are common pro‑ phylactic strategies for graft-versus-host disease (GVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Interleukin (IL)-6 is a surrogate marker for cytokine release syndrome (CRS) and acute GVHD.Method The clinical outcomes and complications of haplo-HSCT with PTCy plus ATG versus PTCy monotherapy were compared according to serum IL-6 levels at Chungnam National University Hospital (Daejeon, South Korea) from Jan‑ uary 2019 to February 2023.
Results:
Forty patients who underwent haplo-HSCT were analyzed. A significant difference in IL-6 levels was observed between the PTCy plus ATG and PTCy alone groups (7.47 ± 10.55 vs. 117.65 ± 127.67; p = 0.003). More patients in the PTCy plus ATG group had a CRS grade of 0 than in the PTCy alone group (p < 0.001). Serum IL-6 levels were associated with grades II–IV acute GVHD (r = 0.547, p < 0.001). The cumulative incidence (CI) of grades II–IV acute GVHD was significantly higher in the PTCy alone group (67.9% vs. 4.8%; p < 0.001). No significant difference in the CI for chronic GVHD was detected between the PTCy plus ATG and PTCy alone groups (72.1% vs. 82.0%; p = 0.730). The CI of 1-year non-relapse mortality was significantly higher in the PTCy alone group than in the PTCy plus ATG group (42.2% vs. 15.9%; p = 0.022). The 1-year overall survival (OS) was significantly better in the PTCy plus ATG group (75.9% vs. 35.3%; p = 0.011). The 1-year GVHD-free, relapse-free survival rate was 29.4% in the PTCy alone group and 54.0% in the PTCy plus ATG group (p = 0.038).
Conclusion
Serum IL-6 levels were higher in the PTCy alone group than in the PTCy plus ATG group. The addition of ATG before stem cell infusion affected IL-6 levels and reduced the incidences of CRS and grade II–IV acute GVHD in haplo-HSCT patients. This study suggests that PTCy plus ATG as GVHD prophylaxis in haplo-HSCT is beneficial in terms of clinical outcomes and complications of HSCT.
4.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.
5.Post‑transplant cyclophosphamide plus anti‑thymocyte globulin decreased serum IL‑6 levels when compared with post‑transplant cyclophosphamide alone after haploidentical hematopoietic stem cell transplantation
Jeong Suk KOH ; Myung‑Won LEE ; Thi Thuy Duong PHAM ; Bu Yeon HEO ; Suyoung CHOI ; Sang‑Woo LEE ; Wonhyoung SEO ; Sora KANG ; Seul Bi LEE ; Chul Hee KIM ; Hyewon RYU ; Hyuk Soo EUN ; Hyo‑Jin LEE ; Hwan‑Jung YUN ; Deog‑Yeon JO ; Ik‑Chan SONG
Blood Research 2025;60():5-
Background:
Post-transplantation cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are common pro‑ phylactic strategies for graft-versus-host disease (GVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Interleukin (IL)-6 is a surrogate marker for cytokine release syndrome (CRS) and acute GVHD.Method The clinical outcomes and complications of haplo-HSCT with PTCy plus ATG versus PTCy monotherapy were compared according to serum IL-6 levels at Chungnam National University Hospital (Daejeon, South Korea) from Jan‑ uary 2019 to February 2023.
Results:
Forty patients who underwent haplo-HSCT were analyzed. A significant difference in IL-6 levels was observed between the PTCy plus ATG and PTCy alone groups (7.47 ± 10.55 vs. 117.65 ± 127.67; p = 0.003). More patients in the PTCy plus ATG group had a CRS grade of 0 than in the PTCy alone group (p < 0.001). Serum IL-6 levels were associated with grades II–IV acute GVHD (r = 0.547, p < 0.001). The cumulative incidence (CI) of grades II–IV acute GVHD was significantly higher in the PTCy alone group (67.9% vs. 4.8%; p < 0.001). No significant difference in the CI for chronic GVHD was detected between the PTCy plus ATG and PTCy alone groups (72.1% vs. 82.0%; p = 0.730). The CI of 1-year non-relapse mortality was significantly higher in the PTCy alone group than in the PTCy plus ATG group (42.2% vs. 15.9%; p = 0.022). The 1-year overall survival (OS) was significantly better in the PTCy plus ATG group (75.9% vs. 35.3%; p = 0.011). The 1-year GVHD-free, relapse-free survival rate was 29.4% in the PTCy alone group and 54.0% in the PTCy plus ATG group (p = 0.038).
Conclusion
Serum IL-6 levels were higher in the PTCy alone group than in the PTCy plus ATG group. The addition of ATG before stem cell infusion affected IL-6 levels and reduced the incidences of CRS and grade II–IV acute GVHD in haplo-HSCT patients. This study suggests that PTCy plus ATG as GVHD prophylaxis in haplo-HSCT is beneficial in terms of clinical outcomes and complications of HSCT.
6.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.
7.Exercise improves muscle mitochondrial dysfunction-associated lipid profile under circadian rhythm disturbance
Yu GU ; Dong-Hun SEONG ; Wenduo LIU ; Zilin WANG ; Yong Whi JEONG ; Jae-Cheol KIM ; Dae Ryong KANG ; Rose Ji Eun LEE ; Jin-Ho KOH ; Sang Hyun KIM
The Korean Journal of Physiology and Pharmacology 2024;28(6):515-526
We investigated whether endurance exercise training (EXT) ameliorates circadian rhythm (CR)-induced risk factors by improving skeletal muscle (SKM) mitochondrial biogenesis, reducing oxidative stress, and modulating apoptotic protein expression. We distinguished between regular and shift workers using the National Health and Nutrition Examination Survey (NHANES) and investigated the health problems caused by shift work (CR disturbance) and the potential therapeutic effects of exercise. In our animal study, 36 rats underwent 12 weeks of CR disturbance, divided into regular and irregular CR groups. These groups were further split into EXT (n = 12) and sedentary (n = 12) for an additional 8 weeks. We analyzed SKM tissue to understand the molecular changes induced by CR and EXT. NHANES data were analyzed using SAS 9.4 and Prism 8 software, while experimental animal data were analyzed using Prism 8 software. The statistical procedures used in each experiment are indicated in the figure legends. Our studies showed that CR disturbance increases dyslipidemia, alters circadian clock proteins (BMAL1, PER2), raises apoptotic protein levels, and reduces mitochondrial biogenesis in SKM. EXT improved LDL-C and HDLC levels without affecting muscle BMAL1 expression. It also enhanced mitochondrial biogenesis (AMPK, PGC-1α, Tfam, NADH-UO, COX-I), antioxidant levels (Catalase, SOD1, SOD2), and apoptotic protein (p53, Bax/Bcl2) expression or activity in SKM. We demonstrated that shift work-induced CR disturbance leads to dyslipidemia, diminished mitochondrial biogenesis, and reduced antioxidant capacity in SKM. However, EXT can counteract dyslipidemia under CR disturbance, potentially lowering the risk of cardiovascular disorders.
8.Study Design and Protocol for a Randomized Controlled Trial to Assess Long-Term Efficacy and Safety of a Triple Combination of Ezetimibe, Fenofibrate, and Moderate-Intensity Statin in Patients with Type 2 Diabetes and Modifiable Cardiovascular Risk Factors (ENSEMBLE)
Nam Hoon KIM ; Juneyoung LEE ; Suk CHON ; Jae Myung YU ; In-Kyung JEONG ; Soo LIM ; Won Jun KIM ; Keeho SONG ; Ho Chan CHO ; Hea Min YU ; Kyoung-Ah KIM ; Sang Soo KIM ; Soon Hee LEE ; Chong Hwa KIM ; Soo Heon KWAK ; Yong‐ho LEE ; Choon Hee CHUNG ; Sihoon LEE ; Heung Yong JIN ; Jae Hyuk LEE ; Gwanpyo KOH ; Sang-Yong KIM ; Jaetaek KIM ; Ju Hee LEE ; Tae Nyun KIM ; Hyun Jeong JEON ; Ji Hyun LEE ; Jae-Han JEON ; Hye Jin YOO ; Hee Kyung KIM ; Hyeong-Kyu PARK ; Il Seong NAM-GOONG ; Seongbin HONG ; Chul Woo AHN ; Ji Hee YU ; Jong Heon PARK ; Keun-Gyu PARK ; Chan Ho PARK ; Kyong Hye JOUNG ; Ohk-Hyun RYU ; Keun Yong PARK ; Eun-Gyoung HONG ; Bong-Soo CHA ; Kyu Chang WON ; Yoon-Sok CHUNG ; Sin Gon KIM
Endocrinology and Metabolism 2024;39(5):722-731
Background:
Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined.
Methods:
This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months.
Conclusion
This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.
9.Exercise improves muscle mitochondrial dysfunction-associated lipid profile under circadian rhythm disturbance
Yu GU ; Dong-Hun SEONG ; Wenduo LIU ; Zilin WANG ; Yong Whi JEONG ; Jae-Cheol KIM ; Dae Ryong KANG ; Rose Ji Eun LEE ; Jin-Ho KOH ; Sang Hyun KIM
The Korean Journal of Physiology and Pharmacology 2024;28(6):515-526
We investigated whether endurance exercise training (EXT) ameliorates circadian rhythm (CR)-induced risk factors by improving skeletal muscle (SKM) mitochondrial biogenesis, reducing oxidative stress, and modulating apoptotic protein expression. We distinguished between regular and shift workers using the National Health and Nutrition Examination Survey (NHANES) and investigated the health problems caused by shift work (CR disturbance) and the potential therapeutic effects of exercise. In our animal study, 36 rats underwent 12 weeks of CR disturbance, divided into regular and irregular CR groups. These groups were further split into EXT (n = 12) and sedentary (n = 12) for an additional 8 weeks. We analyzed SKM tissue to understand the molecular changes induced by CR and EXT. NHANES data were analyzed using SAS 9.4 and Prism 8 software, while experimental animal data were analyzed using Prism 8 software. The statistical procedures used in each experiment are indicated in the figure legends. Our studies showed that CR disturbance increases dyslipidemia, alters circadian clock proteins (BMAL1, PER2), raises apoptotic protein levels, and reduces mitochondrial biogenesis in SKM. EXT improved LDL-C and HDLC levels without affecting muscle BMAL1 expression. It also enhanced mitochondrial biogenesis (AMPK, PGC-1α, Tfam, NADH-UO, COX-I), antioxidant levels (Catalase, SOD1, SOD2), and apoptotic protein (p53, Bax/Bcl2) expression or activity in SKM. We demonstrated that shift work-induced CR disturbance leads to dyslipidemia, diminished mitochondrial biogenesis, and reduced antioxidant capacity in SKM. However, EXT can counteract dyslipidemia under CR disturbance, potentially lowering the risk of cardiovascular disorders.
10.Exercise improves muscle mitochondrial dysfunction-associated lipid profile under circadian rhythm disturbance
Yu GU ; Dong-Hun SEONG ; Wenduo LIU ; Zilin WANG ; Yong Whi JEONG ; Jae-Cheol KIM ; Dae Ryong KANG ; Rose Ji Eun LEE ; Jin-Ho KOH ; Sang Hyun KIM
The Korean Journal of Physiology and Pharmacology 2024;28(6):515-526
We investigated whether endurance exercise training (EXT) ameliorates circadian rhythm (CR)-induced risk factors by improving skeletal muscle (SKM) mitochondrial biogenesis, reducing oxidative stress, and modulating apoptotic protein expression. We distinguished between regular and shift workers using the National Health and Nutrition Examination Survey (NHANES) and investigated the health problems caused by shift work (CR disturbance) and the potential therapeutic effects of exercise. In our animal study, 36 rats underwent 12 weeks of CR disturbance, divided into regular and irregular CR groups. These groups were further split into EXT (n = 12) and sedentary (n = 12) for an additional 8 weeks. We analyzed SKM tissue to understand the molecular changes induced by CR and EXT. NHANES data were analyzed using SAS 9.4 and Prism 8 software, while experimental animal data were analyzed using Prism 8 software. The statistical procedures used in each experiment are indicated in the figure legends. Our studies showed that CR disturbance increases dyslipidemia, alters circadian clock proteins (BMAL1, PER2), raises apoptotic protein levels, and reduces mitochondrial biogenesis in SKM. EXT improved LDL-C and HDLC levels without affecting muscle BMAL1 expression. It also enhanced mitochondrial biogenesis (AMPK, PGC-1α, Tfam, NADH-UO, COX-I), antioxidant levels (Catalase, SOD1, SOD2), and apoptotic protein (p53, Bax/Bcl2) expression or activity in SKM. We demonstrated that shift work-induced CR disturbance leads to dyslipidemia, diminished mitochondrial biogenesis, and reduced antioxidant capacity in SKM. However, EXT can counteract dyslipidemia under CR disturbance, potentially lowering the risk of cardiovascular disorders.

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