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1.  Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype 
The Journal of Clinical Investigation  null;126(10):3868-3878.
Reducing expression of the fetal hemoglobin (HbF) repressor BCL11A leads to a simultaneous increase in γ-globin expression and reduction in β-globin expression. Thus, there is interest in targeting BCL11A as a treatment for β-hemoglobinopathies, including sickle cell disease (SCD) and β-thalassemia. Here, we found that using optimized shRNAs embedded within an miRNA (shRNAmiR) architecture to achieve ubiquitous knockdown of BCL11A profoundly impaired long-term engraftment of both human and mouse hematopoietic stem cells (HSCs) despite a reduction in nonspecific cellular toxicities. BCL11A knockdown was associated with a substantial increase in S/G2-phase human HSCs after engraftment into immunodeficient (NSG) mice, a phenotype that is associated with HSC exhaustion. Lineage-specific, shRNAmiR-mediated suppression of BCL11A in erythroid cells led to stable long-term engraftment of gene-modified cells. Transduced primary normal or SCD human HSCs expressing the lineage-specific BCL11A shRNAmiR gave rise to erythroid cells with up to 90% reduction of BCL11A protein. These erythrocytes demonstrated 60%–70% γ-chain expression (vs. < 10% for negative control) and a corresponding increase in HbF. Transplantation of gene-modified murine HSCs from Berkeley sickle cell mice led to a substantial improvement of sickle-associated hemolytic anemia and reticulocytosis, key pathophysiological biomarkers of SCD. These data form the basis for a clinical trial application for treating sickle cell disease.
PMCID: PMC5096824  PMID: 27599293
2.  Does Periacetabular Osteotomy Have Depth-related Effects on the Articular Cartilage of the Hip? 
Osteoarthritis may result from abnormal mechanics leading to biochemically mediated degradation of cartilage. In a dysplastic hip, the periacetabular osteotomy (PAO) is designed to normalize the mechanics and our initial analysis suggests that it may also alter the cartilage biochemical composition. Articular cartilage structure and biology vary with the depth from the articular surface including the concentration of glycosaminoglycans (GAG), which are the charge macromolecules that are rapidly turned over and are lost in early osteoarthritis. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) enables noninvasive measurement of cartilage GAG content. The dGEMRIC index represents an indirect measure of GAG concentration with lower values indicating less GAG content. GAG content can normally vary with mechanical loading; however, progressive loss of GAG is associated with osteoarthritis. By looking at the changes in amounts of GAG in response to a PAO at different depths of cartilage, we may gain further insights into the types of biologic events that are occurring in the joint after a PAO.
We (1) measured the GAG content in the superficial and deep zones for the entire joint before and after PAO; and (2) investigated if the changes in the superficial and deep zone GAG content after PAO varied with different locations within the joint.
This prospective study included 37 hips in 37 patients (mean age 26 ± 9 years) who were treated with periacetabular osteotomy for symptomatic acetabular dysplasia and had preoperative and 1-year follow up dGEMRIC scans. Twenty-eight of the 37 also had 2-year scans. Patients were eligible if they had symptomatic acetabular dysplasia with lateral center-edge angle < 20° and no or minimal osteoarthritis. The change in dGEMRIC after surgery was assessed in the superficial and deep cartilage zones at five acetabular radial planes.
The mean ± SD dGEMRIC index in the superficial zone fell from 480 ± 137 msec preoperatively to 409 ± 119 msec at Year 1 (95% confidence interval [CI], −87 to −54; p < 0.001) and recovered to 451 ± 115 msec at Year 2 (95% CI, 34–65; p < 0.001), suggesting that there is a transient event that causes the biologically sensitive superficial layer to lose GAG. In the deep acetabular cartilage zone, dGEMRIC index fell from 527 ± 148 msec preoperatively to 468 ± 143 msec at Year 1 (95% CI, −66 to −30; p < 0.001) and recovered to 494 ± 125 msec at Year 2 (95% CI, 5–32; p = 0.008). When each acetabular radial plane was looked at separately, the change from before surgery to 1 year after was confined to zones around the superior part of the joint. The only significant change from 1 to 2 years was an increase in the superficial layer of the superior zone (1 year 374 ± 123 msec, 2 year 453 ± 117 msec, p < 0.006).
This study suggests that PAO may alter the GAG content of the articular cartilage with a greater effect on the superficial zone compared with the deeper acetabular cartilage zone, especially at the superior aspect of the joint. Some surgeons have observed that surgery itself can be a stressor that can accelerate joint degeneration. Perhaps the decrease in dGEMRIC index seen in the superficial layer may be a catabolic response to postsurgical inflammation given that some recovery was seen at 2 years. The decrease in dGEMRIC index in the deep layer seen mainly near the superior part of the joint is persistent and may represent a response of articular cartilage to normalization of increased mechanical load seen in this region after osteotomy, which may be a normal response to alteration in loading.
Clinical Relevance
This study looks at the biochemical changes in the articular cartilage before and after a PAO for dysplastic hips using MRI in a similar manner to using histological methods to study alterations in articular cartilage with mechanical loading. Although PAO alters alignment and orientation of the acetabulum, its effects on cartilage biology are not clear. dGEMRIC provides a noninvasive method of assessing these effects.
PMCID: PMC4626520  PMID: 26329795
3.  Understanding and Treating the Snapping Hip 
Snapping hip, or coxa saltans is a palpable or auditory snapping with movement of the hip joint. Extra-articular snapping is divided into external and internal types, and is caused laterally by the iliotibial band and anteriorly by the iliopsoas tendon. Snapping of the iliopsoas usually requires contraction of the hip flexors and may be difficult to distinguish from intra-articualar coxa saltans. Ultrasound can be a useful modality to dynamically detect tendon translation during hip movement to support the diagnosis of extra-articular snapping. Coxa saltans is typically treated with conservative measures including anti-inflammatories, stretching and avoidance of inciting activities. Recalcitrant cases are treated with surgery to lengthen the iliopsoas or iliotibial band.
PMCID: PMC4961351  PMID: 26524554
5.  Differential Benefit of Statin in Secondary Prevention of Acute Myocardial Infarction according to the Level of Triglyceride and High Density Lipoprotein Cholesterol 
Korean Circulation Journal  2016;46(3):324-334.
Background and Objectives
The differential benefit of statin according to the state of dyslipidemia has been sparsely investigated. We sought to address the efficacy of statin in secondary prevention of myocardial infarction (MI) according to the level of triglyceride and high density lipoprotein cholesterol (HDL-C) on admission.
Subjects and Methods
Acute MI patients (24653) were enrolled and the total patients were divided according to level of triglyceride and HDL-C on admission: group A (HDL-C≥40 mg/dL and triglyceride<150 mg/dL; n=11819), group B (HDL-C≥40 mg/dL and triglyceride≥150 mg/dL; n=3329), group C (HDL-C<40 mg/dL and triglyceride<150 mg/dL; n=6062), and group D (HDL-C<40 mg/dL & triglyceride≥150 mg/dL; n=3443). We evaluated the differential efficacy of statin according to the presence or absence of component of dyslipidemia. The primary end points were major adverse cardiac events (MACE) for 2 years.
Statin therapy significantly reduced the risk of MACE in group A (hazard ratio=0.676; 95% confidence interval: 0.582-0.785; p<0.001). However, the efficacy of statin was not prominent in groups B, C, or D. In a propensity-matched population, the result was similar. In particular, the benefit of statin in group A was different compared with group D (interaction p=0.042)
The benefit of statin in patients with MI was different according to the presence or absence of dyslipidemia. In particular, because of the insufficient benefit of statin in patients with MI and dyslipidemia, a different lipid-lowering strategy is necessary in these patients.
PMCID: PMC4891597  PMID: 27275169
Statin; Acute myocardial infarction; Triglyceride; High-density lipoprotein cholesterol; Prognosis
6.  Feasibility of a Randomized Clinical Trial for Treatment of Femoroacetabular Impingement of the Hip 
Orthopaedic Journal of Sports Medicine  2015;3(7):2325967115592844.
Symptomatic femoroacetabular impingement (FAI) is currently corrected by surgery. However, it is possible that nonsurgical treatment could resolve symptomatic FAI in some patients; thus, uncertainty about the necessity of surgical treatment exists. The current equipoise concerning FAI treatment presents an opportunity to conduct a randomized controlled trial (RCT) of surgical and nonsurgical treatment options. Given the unique challenge of adequate patient enrollment in RCTs, it is important that a preliminary study is done to appraise the feasibility of conducting an RCT.
To estimate enrollment rates of a planned future RCT to compare surgical and nonsurgical treatments for symptomatic FAI and to identify factors associated with patients’ willingness to participate in the randomized trial.
Study Design:
Cross-sectional study; Level of evidence, 4.
Patients diagnosed with FAI at 2 orthopaedic centers were presented with a hypothetical randomized trial comparing 2 treatment options for FAI. All patients completed forms providing information regarding their willingness to participate and treatment preferences.
A total of 75 patients participated in the study: 53 and 22 from 2 centers, respectively. Twenty-eight percent indicated absolute willingness to participate in the trial, 40% were probably willing or unsure, and 32% were definitely not willing; 18.7% had a strong preference for surgery while 2.7% strongly preferred nonsurgical treatment. The majority (78.6%) had no strong preference for either treatment arm. There were correlations between treatment preferences and willingness to participate. Patients with a strong treatment preference and/or a preference for surgery were less likely to be willing to participate.
The study findings suggest that sufficient patient accrual for a randomized trial of FAI treatment is currently feasible while equipoise still exists among patients and surgeons.
PMCID: PMC4622329  PMID: 26673688
femoroacetabular impingement (FAI); randomized clinical trial; feasibility study; surgical treatment; nonsurgical treatment
7.  How Do Acetabular Version and Femoral Head Coverage Change With Skeletal Maturity? 
Normal changes in acetabular version over the course of skeletal development have not been well characterized. Knowledge of normal version development is important because acetabular retroversion has been implicated in several pathologic hip processes.
The purpose of this study was to characterize the orientation of the acetabulum by measuring (1) acetabular version and (2) acetabular sector angles in pediatric patients during development. We also sought to determine whether these parameters vary by sex in the developing child.
We evaluated CT images of 200 hips in 100 asymptomatic pediatric patients (45 boys, 55 girls; mean age, 13.5 years; range, 9–18 years) stratified by the status of the triradiate physis and sex. We determined the acetabular anteversion angle at various levels in the axial plane as well as acetabular sector angles at five radial planes around the acetabulum.
For both genders, anteversion angle was greater for the closed physis group throughout all levels (p < 0.001) and both open and closed physis groups were more anteverted as the cut moved caudally away from the acetabular roof (p < 0.001). At the center of the femoral head, the mean anteversion angle (± SD) in girls was 15° ± 3° in the open group and 19° ± 5° in the closed group (p < 0.001). In boys, the mean anteversion angle increased from 14° ± 4° in the open group to 19° ± 4° in the closed group (p = 0.003). In the superior, posterosuperior, and posterior planes, the acetabular sector angles were greater in the closed compared with the open physis group for both boys and girls with the largest increase occurring in the male posterosuperior plane (approximately 20°) (all p < 0.05).
This study demonstrates that acetabular anteversion and acetabular sector angles in both male and female subjects increase with skeletal maturity as a result of growth of the posterior wall. This suggests that radiographic appearance of acetabular retroversion may not be attributable to overgrowth of the anterior wall but rather insufficient growth of the posterior wall, which has clinical treatment implications for pincer-type impingement.
Level of Evidence
Level IV diagnostic study.
PMCID: PMC4353546  PMID: 25344405
8.  Angiotensin II type 1 receptor blockers as a first choice in patients with acute myocardial infarction 
Angiotensin II type 1 receptor blockers (ARBs) have not been adequately evaluated in patients without left ventricular (LV) dysfunction or heart failure after acute myocardial infarction (AMI).
Between November 2005 and January 2008, 6,781 patients who were not receiving angiotensin-converting enzyme inhibitors (ACEIs) or ARBs were selected from the Korean AMI Registry. The primary endpoints were 12-month major adverse cardiac events (MACEs) including death and recurrent AMI.
Seventy percent of the patients were Killip class 1 and had a LV ejection fraction ≥ 40%. The prescription rate of ARBs was 12.2%. For each patient, a propensity score, indicating the likelihood of using ARBs during hospitalization or at discharge, was calculated using a non-parsimonious multivariable logistic regression model, and was used to match the patients 1:4, yielding 715 ARB users versus 2,860 ACEI users. The effect of ARBs on in-hospital mortality and 12-month MACE occurrence was assessed using matched logistic and Cox regression models. Compared with ACEIs, ARBs significantly reduced in-hospital mortality(1.3% vs. 3.3%; hazard ratio [HR], 0.379; 95% confidence interval [CI], 0.190 to0.756; p = 0.006) and 12-month MACE occurrence (4.6% vs. 6.9%; HR, 0.661; 95% CI, 0.457 to 0.956; p = 0.028). However, the benefit of ARBs on 12-month mortality compared with ACEIs was marginal (4.3% vs. 6.2%; HR, 0.684; 95% CI, 0.467 to 1.002; p = 0.051).
Our results suggest that ARBs are not inferior to, and may actually be better than ACEIs in Korean patients with AMI.
PMCID: PMC4773713  PMID: 26701233
Angiotensin-converting enzyme inhibitors; Angiotensin II type 1 receptor blockers; Myocardial infarction; Mortality; Secondary prevention
9.  Temporal trends and in-hospital outcomes of primary percutaneous coronary intervention in nonagenarians with ST-segment elevation myocardial infarction 
Data regarding the outcomes of primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) in nonagenarians are very limited. The aim of the present study was to evaluate the temporal trends and in-hospital outcomes of primary PCI in nonagenarian STEMI patients.
We retrospectively reviewed data from the Korea Acute Myocardial Infarction Registry (KAMIR) from November 2005 to January 2008, and from the Korea Working Group on Myocardial Infarction (KorMI) from February 2008 to May 2010.
During this period, the proportion of nonagenarians among STEMI patients more than doubled (0.59% in KAMIR vs. 1.35% in KorMI), and the rate of use of primary PCI also increased (from 62.5% in KAMIR to 81.0% in KorMI). We identified 84 eligible study patients for which the overall in-hospital mortality rate was 21.4% (25.0% in KAMIR vs. 20.3% in KorMI, p = 0.919). Multivariate analysis identified two independent predictors of in-hospital mortality, namely a final Thrombolysis in Myocardial Infarction (TIMI) flow < 3 (odds ratio [OR], 13.7; 95% confidence interval [CI], 3.2 to 59.0; p < 0.001) and cardiogenic shock during hospitalization (OR, 6.7; 95% CI, 1.5 to 30.3; p = 0.013).
The number of nonagenarian STEMI patients who have undergone primary PCI has increased. Although a final TIMI flow < 3 and cardiogenic shock are independent predictors of in-hospital mortality, primary PCI can be performed with a high success rate and an acceptable in-hospital mortality rate.
PMCID: PMC4642011  PMID: 26552457
In-hospital outcomes; Aged, 90 and over; Myocardial infarction; Percutaneous coronary intervention
10.  Five-year clinical outcomes of drug-eluting stents according to on-label and off-label use 
To compare the clinical outcomes of ‘on-label’ and ‘off-label’ drug-eluting stents (DESs) over a 5-year follow-up period.
A total of 929 patients that underwent percutaneous coronary intervention with DESs were enrolled. Patients were divided into two groups according to on-label (n = 449) and off-label (n = 480) indications. Off-label use was defined as implantation of DESs for acute myocardial infarction (MI), very small vessel, a long stenotic lesion, chronic total occlusion, a bifurcation lesion, an ostial lesion, left main coronary artery disease, multivessel disease, a saphenous vein graft lesion, and a lesion with thrombus. Endpoints were composite of major adverse cardiac events (MACEs), which included all-cause death, ischemic-driven target vessel revascularization (Id-TVR), MI, and stent thrombosis (ST). Clinical outcomes in the two groups were compared for up to 5 years postimplantation.
At 1 year postimplantation, the off-label group had higher incidences of total MACEs (8.2% vs. 3.7%, p = 0.005), Id-TVR (5.0% vs. 1.6%, p = 0.004), and ST (1.7% vs. 0.3%, p = 0.042), and at 5 years postimplantation, the off-label group continued to have higher incidences of total MACEs (17.5% vs. 9.4%, p < 0.001), Id-TVR (13.1% vs. 5.8%, p = 0.024), and ST (2.1% vs. 0.3%, p = 0.021). Multivessel disease and diabetes were found to be independent risk factors of MACE in patients with an off-label indication.
Patients treated with an on-label DES had better long-term clinical outcomes than those treated with an off-label DES.
PMCID: PMC4939495  PMID: 27017384
Off-label use; Drug-eluting stent; Outcome assessment (health care)
11.  Comparison of Femoral Neck Stress Fractures in Pediatric versus Young Adult Athletes 
Orthopaedic Journal of Sports Medicine  2016;4(7 suppl4):2325967116S00179.
To compare the demographics, metabolic bone health, radiologic features, treatment approaches and recurrence rates of pediatric versus young adult athletes with femoral neck stress fractures.
A retrospective review was performed on all patients <45 years-old who were diagnosed with a femoral neck stress fracture at a single tertiary-care referral center from 2003-2015. Patients who had undergone previous hip surgery or had primary bone disorders/lesions were excluded. Variables analyzed included demographics, presenting symptoms, metabolic bone health (laboratory results, Dexa scores, menstrual history, eating disorder history), imaging, treatment approach and clinical course.
Forty-nine patients (mean age 21.4 years, range 5-44, 78% females) met study inclusion criteria, including 28 pediatric patients (mean age 14.4 years, range 5-19 years, 71% females) and 21 young adults (mean age 30.8 years, range 20-44 years, 86% females). A higher percentage of females was seen with each increasing decade of age, with 50% of pediatric patients under 11 years-old being male. Mean BMI was lower (p=0.04) in the pediatric group (20.6 kg/m2 +/-3.42) than the adult group (21.8 kg/m2 +/-2.04). Pain was the presenting complaint in all patients, with pain localized to the groin in 80% of cases. Participation in running sports was higher for the young adult cohort (86%) than the pediatric cohort (50%), while multiple sports were played more by pediatric patients (29%) than young adults (5%). History of previous acute fractures (2%) and previous stress fractures (14%) was identical between groups. Delayed menarche was recorded in 6% of pediatric patients, and menstrual irregularity was reported in 29% and 33% of pediatric and adult females, respectively. The base of the femoral neck was most common location for fracture in both pediatric (67%) and adult (81%) groups, while transcervical fractures were more likely to occur in pediatric (29%) than adult patients (6%). More significant treatment interventions were pursued in the pediatric group (spica casting: n=2, operative screw fixation, n=4) than the adult group, all of whom demonstrated healing with activity modification, with varying degrees of weight bearing protection and medical optimization of metabolic bone health. There was no difference in the mean time to healing (13.3 weeks), or in the mean time to return to sports (Peds: 16wks, Adults: 13wks) between groups. There was a significant correlation between time to RTS and the extent of the femoral neck edema (p=0.048).
Pediatric caregivers should be aware of femoral neck stress fractures in young athletes, an entity historically described almost exclusively in adults. Stress fractures in pediatric and adolescent patients are more likely to occur higher on the neck than adult patients, and both sexes in children may be affected to a greater degree than in adult counterparts, in whom females are affected much more commonly. Groin pain and participation in running sports are common in both groups, while multi-sport pediatric athlete patients may be more likely to be affected than in the adult population. More significant treatment interventions may be warranted in children. To avoid the catastrophic sequella of a displaced femoral neck fracture, proactive diagnostic workup and consideration of interventions such as spica casting or surgical screw fixation should be exercised given concerns related to non-compliance in this population.
PMCID: PMC4968246
12.  The Prognostic Value of the Left Ventricular Ejection Fraction Is Dependent upon the Severity of Mitral Regurgitation in Patients with Acute Myocardial Infarction 
Journal of Korean Medical Science  2015;30(7):903-910.
The prognostic value of the left ventricle ejection fraction (LVEF) after acute myocardial infarction (AMI) has been questioned even though it is an accurate marker of left ventricle (LV) systolic dysfunction. This study aimed to examine the prognostic impact of LVEF in patients with AMI with or without high-grade mitral regurgitation (MR). A total of 15,097 patients with AMI who received echocardiography were registered in the Korean Acute Myocardial Infarction Registry (KAMIR) between January 2005 and July 2011. Patients with low-grade MR (grades 0-2) and high-grade MR (grades 3-4) were divided into the following two sub-groups according to LVEF: LVEF ≤ 40% (n = 2,422 and 197, respectively) and LVEF > 40% (n = 12,252 and 226, respectively). The primary endpoints were major adverse cardiac events (MACE), cardiac death, and all-cause death during the first year after registration. Independent predictors of mortality in the multivariate analysis in AMI patients with low-grade MR were age ≥ 75 yr, Killip class ≥ III, N-terminal pro-B-type natriuretic peptide > 4,000 pg/mL, high-sensitivity C-reactive protein ≥ 2.59 mg/L, LVEF ≤ 40%, estimated glomerular filtration rate (eGFR), and percutaneous coronary intervention (PCI). However, PCI was an independent predictor in AMI patients with high-grade MR. No differences in primary endpoints between AMI patients with high-grade MR (grades 3-4) and EF ≤ 40% or EF > 40% were noted. MR is a predictor of a poor outcome regardless of ejection fraction. LVEF is an inadequate method to evaluate contractile function of the ischemic heart in the face of significant MR.
PMCID: PMC4479944  PMID: 26130953
Mitral Regurgitation; Acute Myocardial Infarction; Left Ventricular Ejection Fraction
13.  Three-dimensional hip cartilage quality assessment of morphology and dGEMRIC by planar maps and automated segmentation 
The quantitative interpretation of hip cartilage MRI has been limited by the difficulty of identifying and delineating the cartilage in a 3D dataset, thereby reducing its routine usage. In this paper a solution is suggested by unfolding the cartilage to planar 2D maps on which both morphology and biochemical degeneration patterns can be investigated across the entire hip joint.
Morphological TrueFISP and biochemical dGEMRIC hip images were acquired isotropically for 15 symptomatic subjects with mild or no radiographic osteoarthritis. A multi-template based label fusion technique was used to automatically segment the cartilage tissue, followed by a geometric projection algorithm to generate the planar maps. The segmentation performance was investigated through a leave-one-out study, for two different fusion methods and as a function of the number of utilized templates.
For each of the generated planar maps, various patterns could be seen, indicating areas of healthy and degenerated cartilage. Dice coefficients for cartilage segmentation varied from 0.76 with four templates to 0.82 with 14 templates. Regional analysis suggests even higher segmentation performance in the superior half of the cartilage.
The proposed technique is the first of its kind to provide planar maps that enable straightforward quantitative assessment of hip cartilage morphology and dGEMRIC values. This technique may have important clinical applications for patient selection for hip preservation surgery, as well as for epidemiological studies of cartilage degeneration patterns. It is also shown that 10-15 templates are sufficient for accurate segmentation in this application.
PMCID: PMC4404159  PMID: 25278060
Osteoarthritis; hip; dGEMRIC; MRI; segmentation; label fusion
14.  Differential Clinical Implications of High-Degree Atrioventricular Block Complicating ST-Segment Elevation Myocardial Infarction according to the Location of Infarction in the Era of Primary Percutaneous Coronary Intervention 
Korean Circulation Journal  2016;46(3):315-323.
Background and Objectives
The clinical implication of high-degree (second- and third-degree) atrioventricular block (HAVB) complicating ST-segment elevation myocardial infarction (STEMI) is ripe for investigation in this era of primary percutaneous coronary intervention (PCI). We sought to address the incidence, predictors and prognosis of HAVB according to the location of infarct in STEMI patients treated with primary PCI.
Subjects and Methods
A total of 16536 STEMI patients (anterior infarction: n=9354, inferior infarction: n=7692) treated with primary PCI were enrolled from a multicenter registry. We compared in-hospital mortality between patients with HAVB and those without HAVB with anterior or inferior infarction, separately. Multivariate analyses were performed to unearth predictors of HAVB and to identify whether HAVB is independently associated with in-hospital mortality.
STEMI patients with HAVB showed higher in-hospital mortality than those without HAVB in both anterior (hazard ratio [HR]=9.821, 95% confidence interval [CI]: 4.946-19.503, p<0.001) and inferior infarction (HR=2.819, 95% CI: 2.076-3.827, p<0.001). In multivariate analyses, HAVB was associated with increased in-hospital mortality in anterior myocardial infarction (HR=19.264, 95% CI: 5.804-63.936, p<0.001). However, HAVB in inferior infarction was not an independent predictor of increased in-hospital mortality (HR=1.014, 95% CI: 0.547-1.985, p=0.901).
In this era of primary PCI, the prognostic impact of HAVB is different according to the location of infarction. Because of recent improvements in reperfusion strategy, the negative prognostic impact of HAVB in inferior STEMI is no longer prominent.
PMCID: PMC4891596  PMID: 27275168
Atrioventricular block; Myocardial infarction; Primary percutaneous coronary intervention; In-hospital mortality
15.  The alpha angle as a predictor of contralateral slipped capital femoral epiphysis 
Contralateral hip involvement in slipped capital femoral epiphysis (SCFE) is common. Femoral head−neck asphericity, as measured by an elevated alpha angle, has not previously been assessed with respect to SCFE risk. Our aim was to assess the utility of the alpha angle in predicting contralateral SCFE.
We retrospectively reviewed 168 patients (94 males) managed surgically for unilateral SCFE between 2001 and 2013 who had a minimum of 18 months follow-up. The alpha angle, the posterior sloping angle (PSA), and the modified Oxford score were recorded for every patient at the time of initial SCFE presentation. Follow-up clinical records and radiographs were assessed to determine the presence of absence of contralateral SCFE.
Forty-five patients (27 %) developed a contralateral SCFE. Patients who developed a contralateral SCFE had a significantly higher alpha angle (51° vs 45°, p < 0.001) than patients who did not develop a contralateral SCFE. There was no significant difference in PSA or modified Oxford score (both p > 0.10) between patients who developed a contralateral SCFE and those who did not. Using a proposed alpha angle of 50.5° as a threshold for prophylactic fixation, 26 (58 %) of the 45 cases of contralateral SCFE in our study would have been prevented and 18 (15 %) of 123 patients would have undergone fixation unnecessarily.
We found the alpha angle to positively correlate with contralateral SCFE risk. Patients with significantly elevated alpha angles may be at greater risk of contralateral SCFE and benefit from further investigation or prophylactic hip fixation.
PMCID: PMC4909647  PMID: 27052742
Slipped capital femoral epiphysis; Alpha angle; Hip; Fixation
16.  Does Previous Pelvic Osteotomy Compromise the Results of Periacetabular Osteotomy Surgery? 
As the Bernese periacetabular osteotomy (PAO) has grown in popularity, specific indications and the results in patients treated for those indications need to be evaluated. Currently, although many patients undergo PAO after having had prior pelvic osteotomy, there is limited information regarding the efficacy of the PAO in these patients.
The purpose of this study was to compare the (1) early pain, function, activity, and quality of life outcomes; (2) radiographic correction; and (3) major complications and failures between patients who underwent PAO after prior pelvic reconstruction versus those who had a PAO without prior surgery.
Between February 2008 and January 2012, 39 patients underwent PAO after prior pelvic osteotomy at one of 11 centers and were entered into a collaborative multicenter database. Of those, 34 (87%) were available for followup at a mean of 2.5 years (range 1–5 years). This group was compared with a matched group of 78 subjects, of whom 71 (91%) were available for followup at a similar interval. We compared clinical outcomes including UCLA activity score, SF-12, and Hip Disability and Osteoarthritis Outcome Score (HOOS); radiographic measures—anterior and lateral center-edge angle and acetabular inclination (AI)—and reoperations, major complications, and conversions to total hip arthroplasty.
Although both groups reached clinical improvement in all categorical measures, the revision PAO group demonstrated greater pain (HOOS pain, study 74 versus 85, p = 0.03; 95% confidence interval [CI], 18.58 to −0.95) and less function (HOOS activities of daily living, study 80 versus 92, p = 0.002; 95% CI, 018.99–4.45) than the primary cohort. The revision cohort achieved a smaller average radiographic correction than in patients undergoing PAO without prior pelvic surgery. The mean correction in AI was less dramatic when directly comparing the revision and comparison groups (−12° to −17°, p < 0.001, SD 2.3–8.5). Although there was no difference in severe complications requiring further surgery, there were two conversions to hip arthroplasty (p = 0.109; 95% CI, 0.004–2.042) in the study group.
PAO performed after prior pelvic surgery is associated with improvements in pain, function, radiographic correction, and early complication rates, but the improvements observed at short-term followup were smaller and more variable than those seen in patients who had not undergone prior pelvic surgery. We recommend considering PAO for residual deformities after prior osteotomy to improve function and quality life but warning patients of potential ceiling effects with a second periacetabular surgery.
Level of Evidence
Level III, therapeutic study.
PMCID: PMC4353529  PMID: 25560959
17.  Periacetabular Osteotomy Restores the Typically Excessive Range of Motion in Dysplastic Hips With a Spherical Head 
Residual acetabular dysplasia is seen in combination with femoral pathomorphologies including an aspherical femoral head and valgus neck-shaft angle with high antetorsion. It is unclear how these femoral pathomorphologies affect range of motion (ROM) and impingement zones after periacetabular osteotomy.
(1) Does periacetabular osteotomy (PAO) restore the typically excessive ROM in dysplastic hips compared with normal hips; (2) how do impingement locations differ in dysplastic hips before and after PAO compared with normal hips; (3) does a concomitant cam-type morphology adversely affect internal rotation; and (4) does a concomitant varus-derotation intertrochanteric osteotomy (IO) affect external rotation?
Between January 1999 and March 2002, we performed 200 PAOs for dysplasia; of those, 27 hips (14%) met prespecified study inclusion criteria, including availability of a pre- and postoperative CT scan that included the hip and the distal femur. In general, we obtained those scans to evaluate the pre- and postoperative acetabular and femoral morphology, the degree of acetabular reorientation, and healing of the osteotomies. Three-dimensional surface models based on CT scans of 27 hips before and after PAO and 19 normal hips were created. Normal hips were obtained from a population of CT-based computer-assisted THAs using the contralateral hip after exclusion of symptomatic hips or hips with abnormal radiographic anatomy. Using validated and computerized methods, we then determined ROM (flexion/extension, internal- [IR]/external rotation [ER], adduction/abduction) and two motion patterns including the anterior (IR in flexion) and posterior (ER in extension) impingement tests. The computed impingement locations were assigned to anatomical locations of the pelvis and the femur. ROM was calculated separately for hips with (n = 13) and without (n = 14) a cam-type morphology and PAOs with (n = 9) and without (n = 18) a concomitant IO. A post hoc power analysis based on the primary research question with an alpha of 0.05 and a beta error of 0.20 revealed a minimal detectable difference of 4.6° of flexion.
After PAO, flexion, IR, and adduction/abduction did not differ from the nondysplastic control hips with the numbers available (p ranging from 0.061 to 0.867). Extension was decreased (19° ± 15°; range, −18° to 30° versus 28° ± 3°; range, 19°–30°; p = 0.017) and ER in 0° flexion was increased (25° ± 18°; range, −10° to 41° versus 38° ± 7°; range, 17°–41°; p = 0.002). Dysplastic hips had a higher prevalence of extraarticular impingement at the anteroinferior iliac spine compared with normal hips (48% [13 of 27 hips] versus 5% [one of 19 hips], p = 0.002). A PAO increased the prevalence of impingement for the femoral head from 30% (eight of 27 hips) preoperatively to 59% (16 of 27 hips) postoperatively (p = 0.027). IR in flexion was decreased in hips with a cam-type deformity compared with those with a spherical femoral head (p values from 0.002 to 0.047 for 95°–120° of flexion). A concomitant IO led to a normalization of ER in extension (eg, 37° ± 7° [range, 21°–41°] of ER in 0° of flexion in hips with concomitant IO compared with 38° ± 7° [range, 17°–41°] in nondysplastic control hips; p = 0.777).
Using computer simulation of hip ROM, we could show that the PAO has the potential to restore the typically excessive ROM in dysplastic hips. However, a PAO can increase the prevalence of secondary intraarticular impingement of the aspherical femoral head and extraarticular impingement of the anteroinferior iliac spines in flexion and internal rotation. A cam-type morphology can result in anterior impingement with restriction of IR. Additionally, a valgus hip with high antetorsion can result in posterior impingement with decreased ER in extension, which can be normalized with a varus derotation IO of the femur. However, indication of an additional IO needs to be weighed against its inherent morbidity and possible complications. The results are based on a limited number of hips with a pre- and postoperative CT scan after PAO. Future prospective studies are needed to verify the current results based on computer simulation and to test their clinical importance.
Level of Evidence
Level III, therapeutic study.
PMCID: PMC4353534  PMID: 25488403
18.  Effectiveness of Drug-Eluting Stents versus Bare-Metal Stents in Large Coronary Arteries in Patients with Acute Myocardial Infarction 
Journal of Korean Medical Science  2011;26(4):521-527.
This study compared clinical outcomes of drug-eluting stents (DES) versus bare-metal stents (BMS) in large coronary arteries in patients with acute myocardial infarction (MI). A total of 985 patients who underwent single-vessel percutaneous coronary intervention (PCI) in large coronary arteries (≥ 3.5 mm) in lesions < 25 mm were divided into DES group (n = 841) and BMS group (n = 144). Clinical outcomes during 12 months were compared. In-hospital outcome was similar between the groups. At six months, death/MI rate was not different. However, DES group had significantly lower rates of target-lesion revascularization (TLR) (1.7% vs 5.6%, P = 0.021), target-vessel revascularization (TVR) (2.2% vs 5.6%, P = 0.032), and total major adverse cardiac events (MACE) (3.4% vs 11.9%, P = 0.025). At 12 months, the rates of TLR and TVR remained lower in the DES group (2.5% vs 5.9%, P = 0.032 and 5.9% vs 3.1%, P = 0.041), but the rates of death/MI and total MACE were not statistically different. The use of DES in large vessels in the setting of acute MI is associated with lower need for repeat revascularization compared to BMS without compromising the overall safety over the course of one-year follow-up.
PMCID: PMC3069571  PMID: 21468259
Myocardial Infarction; Drug-Eluting Stents
19.  Comparative Study of Low Doses of Rosuvastatin and Atorvastatin on Lipid and Glycemic Control in Patients with Metabolic Syndrome and Hypercholesterolemia 
This multicenter, open-labeled, randomized trial was performed to compare the effects of rosuvastatin 10 mg and atorvastatin 10 mg on lipid and glycemic control in Korean patients with nondiabetic metabolic syndrome.
In total, 351 patients who met the modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for metabolic syndrome with low-density lipoprotein cholesterol (LDL-C) levels ≥ 130 mg/dL were randomized to receive either rosuvastatin 10 mg (n = 173) or atorvastatin 10 mg (n = 178) for over 6 weeks.
After 6 weeks of treatment, greater reductions in total cholesterol (- 35.94 ± 11.38 vs. - 30.07 ± 10.46%, p < 0.001), LDL-C (48.04 ± 14.45 vs. 39.52 ± 14.42%, p < 0.001), non-high-density lipoprotein cholesterol (- 42.93 ± 13.15 vs. - 35.52 ± 11.76%, p < 0.001), and apolipoprotein-B (- 38.7 ± 18.85 vs. - 32.57 ± 17.56%, p = 0.002) levels were observed in the rosuvastatin group as compared to the atorvastatin group. Overall, the percentage of patients attaining the NCEP ATP III goal was higher with rosuvastatin as compared to atorvastatin (87.64 vs. 69.88%, p < 0.001). Changes in glucose and insulin levels, and homeostasis model assessment of insulin resistance index were not significantly different between the two groups. The safety and tolerability of the two agents were similar.
Rosuvastatin 10 mg was more effective than atorvastatin 10 mg in achieving NCEP ATP III LDL-C goals in patients with nondiabetic metabolic syndrome, especially in those with lower NCEP ATP III target level goals.
PMCID: PMC2829413  PMID: 20195400
Metabolic syndrome X; Hypercholesterolemia; Rosuvastatin; Atorvastatin
20.  Characteristics, In-Hospital and Long-Term Clinical Outcomes of Nonagenarian Compared with Octogenarian Acute Myocardial Infarction Patients 
Journal of Korean Medical Science  2014;29(4):527-535.
We compared clinical characteristics, management, and clinical outcomes of nonagenarian acute myocardial infarction (AMI) patients (n=270, 92.3±2.3 yr old) with octogenarian AMI patients (n=2,145, 83.5±2.7 yr old) enrolled in Korean AMI Registry (KAMIR). Nonagenarians were less likely to have hypertension, diabetes and less likely to be prescribed with beta-blockers, statins, and glycoprotein IIb/IIIa inhibitors compared with octogenarians. Although percutaneous coronary intervention (PCI) was preferred in octogenarians than nonagenarians, the success rate of PCI between the two groups was comparable. In-hospital mortality, the composite of in-hospital adverse outcomes and one year mortality were higher in nonagenarians than in octogenarians. However, the composite of the one year major adverse cardiac events (MACEs) was comparable between the two groups without differences in MI or re-PCI rate. PCI improved 1-yr mortality (adjusted hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.36-0.69, P<0.001) and MACEs (adjusted HR, 0.47; 95% CI, 0.37-0.61, P<0.001) without significant complications both in nonagenarians and octogenarians. In conclusion, nonagenarians had similar 1-yr MACEs rates despite of higher in-hospital and 1-yr mortality compared with octogenarian AMI patients. PCI in nonagenarian AMI patients was associated to better 1-yr clinical outcomes.
Graphical Abstract
PMCID: PMC3991796  PMID: 24753700
Aged, Eighty and over; Myocardial Infarction; Percutaneous Coronary Intervention
21.  Can Radiographic Morphometric Parameters for the Hip Be Assessed on MRI? 
Although morphometric hip parameters measured on radiographs are valuable tools guiding diagnosis and therapy in patients with hip disorders, some clinicians use MRI for such measurements, although it is unclear whether the parameters assessed on MRI differ from those assessed on radiographs.
We asked whether the lateral center-edge angle (LCE), Tönnis angle, extrusion index, and anterior center-edge angle (ACE) are similar on MRI and radiography.
We retrospectively reviewed the imaging data of 103 hips from 103 patients: 46 with femoroacetabular impingement and 57 with hip dysplasia. We manually measured the LCE, Tönnis angle, extrusion index, and ACE from radiographs and MRI in all 103 hips. Four straight coronal (Ant-10 mm, Ant-5 mm, Center, and Post-5 mm), three straight sagittal (S-Med-5 mm, S-Center, S-Lat-5 mm), and three 25º oblique sagittal (OS-Med-5 mm, OS-Center, OS-Lat-5 mm) reformats were reconstructed from a three-dimensional isotropic morphologic MRI sequence. MRI measurements were compared against the gold standard radiographic measurements.
We found good agreement for the LCE angle, Tönnis angle, and extrusion index between radiographic and coronal slice MRI measurements. The mean differences between radiographic and MRI measurements were 5º or less or 5% or less (for the extrusion index) in all coronal MRI slices. However, the differences between ACE angles on sagittal MRI slices and radiographs ranged from 5° to 28º.
LCE, Tönnis angle, and extrusion index can be measured on MRI with comparable results to radiography. The ACE angle on radiographs cannot be estimated reliably from MRI.
Clinical Relevance
MRI provides similar morphometric measurements as radiography for most hip parameters, except for the ACE angle.
PMCID: PMC3563814  PMID: 23100186
22.  Is the Damage of Cartilage a Global or Localized Phenomenon in Hip Dysplasia, Measured by dGEMRIC? 
The mechanism of damage in osteoarthritis is believed to be multifactorial where mechanical and biological factors are important in its initiation and progression. Hip dysplasia is a classic model of increased mechanical loading on cartilage attributable to insufficient acetabular coverage that leads to osteoarthritis. If the damage is all attributable to direct mechanical damage then one initially would expect only local, not global changes.
We hypothesize that in hip dysplasia although the elevated cumulative contact stresses are localized, the damage to cartilage is biologically mediated, therefore, biochemical changes will be global.
Thirty-two patients with symptomatic hip dysplasia were scanned using a 1.5-T MRI scanner. We used a high-resolution three-dimensional dGEMRIC technique to characterize the distribution of cartilage damage in dysplastic hips. High-resolution isotropic acquisition was reformatted around the femoral neck axis and the dGEMRIC index was calculated separately for femoral and acetabular cartilages. Joint space widths also were evaluated in each reformatted slice. Each hip was characterized by the presence or absence of joint migration and by Tönnis grade.
The global dGEMRIC index correlated with the dGEMRIC indices of individual regions with the highest correlations occurring in the anterosuperior to posterosuperior regions. The corresponding correlations for joint space width were uniformly lower, suggesting that tissue loss is a more local phenomenon. Higher Tönnis grades and hips with joint migration were associated with lower dGEMRIC indices.
The dGEMRIC index shows a global decrease, whereas tissue loss is more localized. This suggests that hip osteoarthritis in acetabular dysplasia is a biologically mediated event that affects the entire joint.
PMCID: PMC3528925  PMID: 23079789
23.  Concomitant Impact of High-Sensitivity C-Reactive Protein and Renal Dysfunction in Patients with Acute Myocardial Infarction 
Yonsei Medical Journal  2013;55(1):132-140.
The present study aimed to investigate the impact of high-sensitivity C-reactive protein (hs-CRP) and renal dysfunction on clinical outcomes in acute myocardial infarction (AMI) patients.
Materials and Methods
The study involved a retrospective cohort of 8332 patients admitted with AMI. The participants were divided into 4 groups according to the levels of estimated glomerular filtration rate (eGFR) and hs-CRP: group I, no renal dysfunction (eGFR ≥60 mL·min-1·1.73 m-2) with low hs-CRP (≤2.0 mg/dL); group II, no renal dysfunction with high hs-CRP; group III, renal dysfunction with low hs-CRP; and group IV, renal dysfunction with high hs-CRP. We compared major adverse cardiac events (MACE) over a 1-year follow-up period.
The 4 groups demonstrated a graded association with increased MACE rates (group I, 8.8%; group II, 13.8%; group III, 18.6%; group IV, 30.1%; p<0.001). In a Cox proportional hazards model, mortality at 12 months increased in groups II, III, and IV compared with group I [hazard ratio (HR) 2.038, 95% confidence interval (CI) 1.450-2.863, p<0.001; HR 3.003, 95% CI 2.269-3.974, p<0.001; HR 5.087, 95% CI 3.755-6.891, p<0.001].
High hs-CRP, especially in association with renal dysfunction, is related to the occurrence of composite MACE, and indicates poor prognosis in AMI patients.
PMCID: PMC3874927  PMID: 24339298
C-reactive protein; glomerular filtration rate; myocardial infarction
25.  Anterior Delayed Gadolinium-enhanced MRI of Cartilage Values Predict Joint Failure After Periacetabular Osteotomy 
Several available compositional MRIs seem to detect early osteoarthritis before radiographic appearance. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) has been most frequently used in clinical studies and reportedly predicts premature joint failure in patients undergoing Bernese periacetabular osteotomies (PAOs).
We asked, given regional variations in biochemical composition in dysplastic hips, whether the dGEMRIC index of the anterior joint would better predict premature joint failure after PAOs than the coronal dGEMRIC index as previously reported.
We retrospectively reviewed 43 hips in 41 patients who underwent Bernese PAO for hip dysplasia. Thirty-seven hips had preserved joints after PAOs and six were deemed premature failures based on pain, joint space narrowing, or subsequent THA. We used dGEMRIC to determine regional variations in biochemical composition. Preoperative demographic and clinical outcome score, radiographic measures of osteoarthritis and severity of dysplasia, and dGEMRIC indexes from different hip regions were analyzed in a multivariable regression analysis to determine the best predictor of premature joint failure. Minimum followup was 24 months (mean, 32 months; range, 24–46 months).
The two cohorts were similar in age and sex distribution. Severity of dysplasia was similar as measured by lateral center-edge, anterior center-edge, and Tönnis angles. Preoperative pain, joint space width, Tönnis grade, and coronal and sagittal dGEMRIC indexes differed between groups. The dGEMRIC index in the anterior weightbearing region of the hip was lower in the prematurely failed group and was the best predictor.
Success of PAO depends on the amount of preoperative osteoarthritis. These degenerative changes are seen most commonly in the anterior joint. The dGEMRIC index of the anterior joint may better predict premature joint failure than radiographic measures of hip osteoarthritis and coronal dGEMRIC index.
Level of Evidence
Level II, prognostic study. See Instructions for Authors for a complete description of levels of evidence.
PMCID: PMC3492640  PMID: 22907475

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