Serial Short-Term Outcomes of Very-Low-Birth-Weight Infants in the Korean Neonatal Network From 2013 to 2020.

BACKGROUND: We aimed to determine the current survival rate and short-term outcomes of very-low-birth-weight infants (VLBWIs) in Korea, as well as whether the survival rate and short-term outcomes have improved over time since 2013, which was when the Korean Neonatal Network (KNN) was launched. METHODS: This study used data from the annual reports of the KNN from 2013 to 2020. A total of 16,351 VLBWIs born at gestational age (GA) ≥ 22 weeks between January 1, 2013, and December 31, 2020, and who were registered in the KNN were enrolled. Serial outcomes were analyzed according to era (2013-14, 2015-16, 2017-18, and 2019-20). RESULTS: More mothers delivered by cesarean section, had diabetes or hypertension during their pregnancy, and received antenatal steroids when analyzed by era. Fewer infants were intubated at birth and had air leaks when analyzed by era. The overall survival rate of VLBWIs between 2013 and 2020 was 87%. The rate of respiratory distress syndrome was 77% and that of bronchopulmonary dysplasia was 32% between 2013 and 2020. The rates of intraventricular hemorrhage (grade ≥ 3), periventricular leukomalacia, and sepsis decreased over time. The survival rate of infants with a GA of 26 weeks has improved serially according to era. CONCLUSION: Since the launch of the KNN in 2013, the survival rates of infants with GA 26 weeks and short-term outcomes have improved, which implies a quality improvement in antenatal and delivery room care. Further studies on the long-term neurodevelopmental outcomes of these KNN registrants are warranted.

Serial Long-Term Growth and Neurodevelopment of Very-Low-Birth-Weight Infants: 2022 Update on the Korean Neonatal Network.

BACKGROUND: We aimed to evaluate the long-term growth and neurodevelopmental outcomes of very-low-birth-weight infants (VLBWIs, birth weight < 1,500 g) born between 2013, the establishment of the Korean Neonatal Network (KNN), and 2018, both at 18-24 months of corrected age and three years of age, using a nationwide large cohort, and to evaluate whether these outcomes have improved over time since 2013. METHODS: This study used data from the annual reports of the KNN for 18-24 months of corrected age (follow-up 1) and three years of age (follow-up 2). Follow-up 1 data were collected from 10,065 eligible VLBWIs born between January 1, 2013, and December 31, 2018. Follow-up 2 data were collected from 8,156 eligible VLBWIs born between January 1, 2013, and December 31, 2017. RESULTS: The overall follow-up rates of VLBWIs at follow-ups 1 and 2 were 74.6% (7,512/10,065) and 57.7% (4,702/8,156), respectively. The overall mortality rate between discharge from the neonatal intensive care unit and follow-up 1 was 1% (104/10,065). The overall mortality rate between follow-ups 1 and 2 was 0.049% (4/8,156). Growth restrictions decreased over time, especially weight growth restrictions, which significantly decreased according to era (17% in infants born in 2013-2014 and 13% in infants born in 2017-2018). Fewer infants were re-hospitalized and required rehabilitative support according to era at follow-up 1. More infants had language developmental delays and required language support according to era, both at follow-ups 1 and 2. The incidence of cerebral palsy has significantly decreased over time, from 6% in infants born in 2013-2014 to 4% in infants born in 2017-2018 at follow-up 1, and from 8% in infants born in 2013-2014 to 5% in infants born in 2017 at follow-up 2. CONCLUSION: Long-term outcomes of VLBWIs regarding weight growth and cerebral palsy, the most common motor disability in childhood, have improved serially according to era since 2013. However, the rate of infants with language delays requiring language support has increased according to era. Further studies are required on the increased trends of language delay and language support while improving motor outcomes.

Predictors of Early and Late Unplanned Intensive Care Unit Readmission: A Retrospective Cohort Study.

PURPOSE: Intensive care unit (ICU) readmission is considered one of the major quality indicators of critical care. Reducing ICU readmission can improve patients' outcomes and optimize health resources, but there are limited data on the predictors of unplanned ICU readmission. This study aimed to identify the risk factors associated with unplanned ICU readmission within 48 hr (early) and after 48 hr (late) from ICU discharge. DESIGN: Retrospective cohort study. METHODS: Data were collected from patients' electronic medical records in a 24-bed medical ICU at a tertiary academic medical center in Busan, South Korea. Among all the patients admitted to the medical ICU (n = 1,033) between January 2015 and December 2017, 739 eligible patients were analyzed. A multivariable multinomial logistic regression model was conducted to identify predictors of ICU readmission. FINDINGS: Out of the 739 patients analyzed, 66 (8.9%) were readmitted to the medical ICU: 13 (1.8%) as early readmission and 53 (7.1%) as late readmission. Two significant predictors were identified for early readmission: ICU admission from the ward (odds ratio [OR] = 4.14; 95% confidence interval [CI] 1.25, 13.67) and mechanical ventilation support >14 days (OR = 13.25; 95% CI 1.78, 98.89). For late ICU admission, there were four risk factors: ICU admission from the ward (OR = 2.69; 95% CI 1.44, 5.05), tracheostomy placement (OR = 3.58; 95% CI 1.49, 8.59), mechanical ventilation support >14 days (OR = 4.77; 95% CI 1.67, 13.63), and continuous renal replacement therapy (OR = 4.57; 95% CI 2.42, 8.63). CONCLUSIONS: To prevent unplanned ICU readmission in patients at high risk, it is necessary to investigate further the role of clinical judgment and communication within the ICU clinical team and institutional-level support regarding ICU readmission events. CLINICAL RELEVANCE: Both ICU nurses and nurses in post-ICU settings should be aware of the potential risk factors associated with early and late ICU readmission. Predictors and readmission strategies may be different for early and late readmissions. Prospective multicenter studies are needed to examine how these factors influence post-ICU outcomes.

Some thoughts on the QR method for analytical similarity evaluation.

As indicated in a recent published draft guidance on comparative analytical assessment, the United States (US) Food and Drug Administration (FDA) seems to suggest the use of quality range (QR) method for analytical similarity evaluation. It is a concern that the use of QR method for analytical similarity evaluation could potentially approve biological products which are not deemed biosimilar to the reference biological products. In this article, the limitations and potential risk for the use of the QR method for analytical similarity evaluation are discussed. Alternatively, two modified versions of the QR method, which are referred to as effect size (ES) mQR and plausibility interval (PI) mQR methods are suggested. The performance and statistical properties of the mQR methods are evaluated via extensive clinical trial simulation under various scenarios. The results indicate that the modified versions of the QR method not only overcome the limitations of the QR method for analytical similarity evaluation, but also can potentially help in detecting reference product changes during manufacturing process.

Genotype-based enrichment study design for minimizing the sample size in bioequivalence studies using tolterodine and CYP2D6 genotype
.

OBJECTIVE: The objective of this study was to explore a pharmacogenomic information-based enrichment study design for reducing the sample size in bioequivalence (BE) studies using tolterodine and CYP2D6 genotypes. MATERIALS AND METHODS: A BE study of tolterodine was performed in a randomized, open-label, 2×2 cross-over design. A two one-sided test (TOST) was executed for pharmacokinetic (PK) parameters of tolterodine, and their geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were estimated. The coefficient of variation (CV) was calculated for each cytochrome P450 (CYP) 2D6 genotype group, and the sample size required to meet the power of an equivalence test was estimated, based on TOST in genotype stratified groups as well as in a conventional group. Replicated simulation datasets of PK parameters for each genotype group were generated using bootstrap resampling technique. RESULTS: The CVs of PK parameters in the conventional dataset were much greater than those in the genotype-based stratified groups. While up to 70 subjects were required for statistical power based on the CV of the area under the concentration-time curve (AUCt) observed in the conventional dataset, only 26 - 44 subjects in extensive metabolizers (EMs) and poor metabolizers (PMs), respectively, were required for the CYP2D6 genotype groups. The 90% CIs for GMR in all simulated datasets appeared to meet the BE criterion (0.8 - 1.25). CONCLUSION: This exploration demonstrated that a drug-metabolizing enzyme genotype-based enrichment strategy can be implemented to minimize the sample size in BE studies of drugs that have high PK variability due to polymorphic metabolizing enzyme(s).

Long-term outcomes of unicompartmental knee arthroplasty in patients requiring high flexion: an average 10-year follow-up study.

INTRODUCTION: To evaluate the long-term survival of unicompartmental knee arthroplasty (UKA) in the Asian population and assess differences in clinical outcomes between mobile- and fixed-bearing UKA. MATERIALS AND METHODS: Among 111 cases of UKA that were performed by 1 surgeon from January 2002 to December 2009, we retrospectively reviewed 96 cases (36 mobile-bearing, 62 fixed-bearing) for this study. We examined cause of revision or failure, type of reoperation/revision, and duration from the surgery date to the revision upon reviewing the medical record. Survival analysis was conducted using the Kaplan-Meier method. Functional outcomes were evaluated based on range of motion and patient-reported outcome (PRO) measures (Knee Injury and Osteoarthritis Outcome Score) for cases with at least 8 years of follow-up (average, 10.2 years). RESULTS: Overall, the 10-year survival was 88% [95% confidence interval (CI) 0.81-0.95], and the estimated mean survival time was 13.4 years (95% CI 12.5-14.2). In a comparison of survival between the mobile- and fixed-bearing groups, the former had a 10-year survival of 85% (95% CI, 0.72-0.97) and an estimated mean survival time of 13.5 years (95% CI 12.2-14.7) and the latter had a 10-year survival of 90% (95% CI 0.82-0.99) and an estimated mean survival time of 13.4 years (95% CI 12.3-14.4). Thus, there was no significant difference in survival between the two groups (log-rank test, p = 0.718). In addition, no significant difference in functional outcomes was observed between the two groups (p > 0.05 for all). CONCLUSIONS: UKA performed in the Asian population showed a relatively good functional outcome and survival rate at an average 10-year follow-up. No difference in survival and PROs was observed according to the bearing type. Although the present study demonstrated a good survival rate, similar to that in other Western studies, further studies investigating the impact of the Asian lifestyle on the long-term survival of UKA is necessary.

Pharmacodynamic effects of voglibose administered alone, administered with metformin, and administered with metformin in a fixed-dose combination in healthy Korean subjects
.

OBJECTIVE: This study aimed at exploring the effects of metformin on the pharmacodynamics of voglibose, while investigating the pharmacodynamics between a fixed-dose combination (FDC) of voglibose/metformin and coadministered doses of voglibose and metformin tablets in healthy Korean subjects. MATERIALS AND METHODS: A randomized, open-label, 2×3×3 crossover study with a 9-day washout period was conducted in 30 healthy subjects. All subjects received orally administered voglibose alone, individual voglibose and metformin tablets, or FDC 3 times daily for 5 days. Oral sucrose was administered on day -1 (pretreatment) and at 10 minutes after the morning dose of the study drug on day 5 of each period. Plasma glucose and serum insulin were measured over the course of 2 hours following sucrose loading. RESULTS: 21 subjects completed the study. The geometric mean ratios (GMR) of ΔCmax and the AUC of glucose for voglibose plus metformin vs. voglibose alone were 0.995 (90% CI, 0.800 - 1.237) and 0.969 (90% CI, 0.949 - 0.990), respectively; the GMRs for individual tablets vs. FDC were 1.118 (90% CI, 0.930 - 1.344) and 1.010 (90% CI, 0.974 - 1.048), respectively. A relatively smaller number of subjects experienced adverse events when receiving voglibose alone compared to those administered FDC or metformin and voglibose. There were no significant differences in adverse events between individual voglibose and metformin tablets and FDC. CONCLUSION: Coadministered metformin did not have statistically or clinically significant effects on the pharmacodynamics of voglibose in healthy subjects. Glucose levels following sucrose loading seem not to be clinically different between FDC and individual tablets of voglibose and metformin.
.

A quantitative analysis method for comitant exotropia using video-oculography with alternate cover.

BACKGROUND: The purpose of this study was to evaluate the efficacy of a quantitative analysis method for comitant exotropia using video-oculography (VOG) with alternate cover. METHODS: Thirty-four subjects with comitant exotropia were included. Two independent ophthalmologists measured the angle of ocular deviation using the alternate prism cover test (APCT). The video files and data of changes in ocular deviation during the alternate cover test were obtained using VOG. To verify the accuracy of VOG, the value obtained using VOG and the angle of a rotating model eye were compared, and a new linear equation was subsequently derived using these data. The calculated values obtained using VOG were compared with those obtained using the APCT. RESULTS: Rotation of the model eye and the values obtained using VOG demonstrated excellent positive correlation (R = 1.000; p < 0.001). A simple linear regression model was obtained: rotation of the model eye = 0.978 × value obtained using VOG for a model eye - 0.549. The 95% limit of agreement for inter-observer variability was ±4.63 prism diopters (PD) for APCT and that for test-retest variability was ±3.56 PD for the VOG test. The results of APCT and calculated VOG test demonstrated a strong positive correlation. Bland-Altman plots revealed no overall tendency for the calculated values obtained from VOG to differ from those obtained using APCT. CONCLUSIONS: VOG with alternate cover is a non-invasive and accurate tool for quantitatively measuring and recording ocular deviation. In particular, it is independent of the proficiency of the examiner and, can therefore, be useful in the absence of skilled personnel. TRIAL REGISTRATION: ClinicalTrial.gov, NCT03119311 , Date of registration: 04/17/2017, Date of enrolment of the first participant to the trial: 04/25/2017.

Radiologic Factors Affecting Ankle Pain Before and After Total Knee Arthroplasty for the Varus Osteoarthritic Knee.

The aim of the present study was to evaluate the radiologic factors related to ankle pain before and after total knee arthroplasty (TKA) among patients with a varus osteoarthritic knee. Fifty-five patients (65 ankles) with a varus osteoarthritic knee who had undergone TKA and were followed up for >24 months were enrolled. For clinical assessment, the visual analog scale for pain and the American Orthopaedic Foot and Ankle Society ankle-hindfoot scale were used. For radiologic assessment, the mechanical axis deviation angle, talar tilt, tibial anterior surface angle, distal medial clear space, medial tibiotalar joint space, frontal tibial ground angle, and hindfoot alignment view angle were measured. The patients with ankle pain before TKA (11 ankles) had a larger hindfoot alignment view angle (9.2° ± 2.6°) than that of patients without ankle pain before TKA (54 ankles; 5.5° ± 4.8°; p = .007). The patients with newly developed ankle pain or experienced an aggravation of existing pain after TKA (8 ankles) had a significantly larger degree of residual varus (5.1° ± 2.1°) than did the patients without ankle pain before and after TKA or those with ankle pain before surgery. However, the severity of the pain was not different during the follow-up period (52 ankles; 1.6° ± 2.5°; p = .001). The results of the present study showed that residual varus deformity was associated with ankle pain after TKA. Surgeons should perform evaluations of the ankles of patients who complain of pain before and after TKA and should give careful attention to the correction of alignment during TKA.

The pharmacokinetic and pharmacodynamic interaction of clopidogrel and cilostazol in relation to CYP2C19 and CYP3A5 genotypes.

AIM: The primary objective of the present study was to evaluate the pharmacokinetic and pharmacodynamic interactions between clopidogrel and cilostazol in relation to the CYP2C19 and CYP3A5 genotypes. METHODS: In a randomized, three-way crossover study, 27 healthy subjects were administered clopidogrel (300 mg), cilostazol (100 mg) or clopidogrel + cilostazol orally. Plasma concentrations of clopidogrel, cilostazol and their active metabolites (clopidogrel thiol metabolite, 3,4-dehydrocilostazol and 4″-trans-hydroxycilostazol), and adenosine diphosphate-induced platelet aggregation were measured for pharmacokinetic and pharmacodynamic assessment. RESULTS: The area under the plasma concentration-time curve (AUC) of the active thiol metabolite of clopidogrel was highest in the CYP2C19 extensive metabolizers (EM) and lowest in the poor metabolizers (PM). Cilostazol decreased the thiol metabolite AUC by 29% in the CYP3A5*1/*3 genotype [geometric mean ratio (GMR) 0.71; 90% confidence interval (CI) 0.58, 0.86; P = 0.020] but not in the CYP3A5*3/*3 genotype (GMR 0.93; 90% CI 0.80, 1.10; P = 0.446). Known effects of the CYP2C19 and CYP3A5 genotypes on the exposure of cilostazol and its metabolites were observed but there was no significant difference in the AUC of cilostazol and 3,4-dehydrocilostazol between cilostazol and clopidogrel + cilostazol. The inhibition of platelet aggregation from 4 h to 24 h (IPA4-24 ) following the administration of clopidogrel alone was highest in the CYP2C19 EM genotype and lowest in the CYP2C19 PM genotype (59.05 ± 18.95 vs. 36.74 ± 13.26, P = 0.023). However, the IPA of the CYP2C19 PM following co-administration of clopidogrel and cilostazol was comparable with that of the CYP2C19 EM and intermediate metabolizers (IM) only in CYP3A5*3/*3 subjects. CONCLUSIONS: The additive antiplatelet effect of cilostazol plus clopidogrel is maximized in subjects with both the CYP2C19 PM and CYP3A5*3/*3 genotypes because of a lack of change of clopidogrel thiol metabolite exposure in CYP3A5*3/*3 as well as the highest cilostazol IPA in CYP2C19 PM and CYP3A5*3/*3 subjects.

Age at menarche in Korean adolescents: trends and influencing factors.

BACKGROUND: An increased incidence of central precocious puberty has been recently reported in South Korea, which suggests an ongoing downward trend in pubertal development in the Korean population. We aimed to verify the trend in age at menarche in young Korean women during the last decade and associated factors. METHODS: We analyzed a population-based sample of 3409 Korean girls, aged 10-18 years, using data from the Korean National Health and Nutrition Examination Surveys (KNHANES) II (2001), III (2005), IV (2007-2009), and V (2010 and 2011). Average age at menarche was studied using the Kaplan-Meier survival method and predictors were analyzed using Cox proportional hazards model. The percentage of subjects who had experienced menarche at each age level was compared by using the Cochran-Armitage test. RESULTS: Overall mean age at menarche was 12.7 years. The percentage of subjects who experienced menarche before the age of 12 years was 21.4 % in 2001 but increased to 34.6 % in 2010/2011 (p < 0.01). In addition, the percentage of girls who experienced menarche before the age of 14 years increased from 76 % in 2001 to 92 % in 2010/2011 (p < 0.005). Adolescents whose mothers who had experienced early menarche (HR 1.48, 95 % CI [1.22-1.80]), and adolescents who were overweight (HR 1.24, 95 % CI [1.04-1.49]) were more likely to have experienced menarche. Additionally, underweight adolescents (HR 0.27, 95 % CI [0.12-0.60]) and adolescents who had a mother having late menarche (HR 0.68, 95 % CI [0.59-0.79]) were expected to have late menarche. None of the socioeconomic factors assessed in our study showed an association with age at menarche. CONCLUSIONS: A downward trend in age at menarche was defined in Korean adolescents during the last decade. Furthermore, influences of genetic and nutritional parameters on individual variance in age at menarche were defined.

Pharmacokinetic study of metformin to compare voglibose/metformin fixed-dose combination with coadministered voglibose and metformin.

The aim of this study was to compare the pharmacokinetic characteristics of metformin between a fixed-dose combination (FDC) of voglibose/metformin and coadministered individual voglibose and metformin tablets in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 7-day wash-out period was conducted. Plasma samples were collected for up to 24 hours and were analyzed for metformin using a validated liquid chromatography tandem mass-spectrometry (LC/MS). A noncompartmental method was used to calculate the pharmacokinetic parameters. Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. In total, 28 subjects completed the study. The geometric mean ratio (GMR) and the 90% confidence interval (CIs) of Cmax and AUC0-t of metformin were 102.4 (94.5-111.0) and 107.1 (100.1-114.7), respectively. In total, 7 adverse drug reactions occurred in 4 subjects during the study; of these, 3 cases were from 3 subjects in the test treatment group, and 4 cases were from 3 subjects in the reference treatment group. All adverse drug reactions had been reported previously, and all subjects recovered fully without any sequelae. In conclusion, the pharmacokinetic profiles of metformin in two different study treatments, a voglibose/metformin FDC vs. the coadministration of the individual formulations, met the regulatory criteria for bioequivalence in healthy Korean subjects under fasting conditions. There was no significant difference in safety profiles between the two treatments.

Pharmacokinetic comparison of amlodipine adipate/valsartan fixed-dose combination with amlodipine besylate/valsartan fixed-dose combination in healthy volunteers.

The aim of this study was to compare pharmacokinetic characteristics of fixed-dose combination (FDC) of two different salt form of amlodipine, amlodipine adipate/valsartan and amlodipine besylate/ valsartan, in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 14-day wash-out period was conducted. Plasma samples were collected for up to 144 hours for amlodipine and 24 hours for valsartan. Plasma concentrations of amlodipine and valsartan were analyzed using a validated ultra-performance liquid chromatography tandem mass-spectrometry. A non-compartmental method was used to calculate pharmacokinetic parameters. Vital signs and adverse events were monitored and physical examinations, laboratory tests, and electrocardiograms were conducted to evaluate safety. 44 subjects completed the study. The 90% CIs for the geometric mean ratio of Cmax and the AUC0-t were 93.5 - 100.4% and 93.2 - 98.3% for amlodipine, and 92.1 - 121.3% and 94.1 - 115.2% for valsartan, respectively. 17 adverse events occurred in 15 subjects during the study; 5 and 7 adverse drug reactions from the 5 and 6 subjects were considered to probably be related to the test and reference treatments respectively. All adverse drug reactions were in line with those known for the reference drug. All subjects recovered fully with no sequelae. A FDC of amlodipine adipate/valsartan and amlodipine besylate/valsartan combination tablets met the regulatory criteria for bioequivalence. In addition, no significant difference was observed in the safety assessments between two treatments. Thus, the newly developed FDC of amlodipine adipate/valsartan seems to be interchangeable with amlodipine besylate valsartan combination.

The Effect of Hinge Position on Posterior Tibial Slope in Medial Open-Wedge High Tibial Osteotomy.

PURPOSE: To evaluate whether hinge position affects the change in posterior tibial slope in medial open-wedge high tibial osteotomy (HTO). METHODS: We retrospectively evaluated 19 knees from 17 patients who underwent medial open-wedge HTO by 3-dimensional computed tomography scan before and after surgery. A 3-dimensional image model was constructed by applying reverse-engineering software to the computed tomography DICOM (Digital Imaging and Communications in Medicine) files. The hinge axis (i.e., the position of the hinge compared with the anteroposterior axis on an axial view), posterior tibial slope, medial-proximal tibial angle, and gap ratio (i.e., the ratio of anterior gap to posterior gap in the opened wedge) were measured. RESULTS: The mean hinge axis was 4.92° ± 3.86°. Posterior tibial slope increased from 7.29° ± 2.56° preoperatively to 10.48° ± 3.01° postoperatively (P = .001). The mean medial-proximal tibial angle was 85.96° ± 1.97° preoperatively and 93.13° ± 3.17° postoperatively (P = .001). The mean gap ratio was 62.48% ± 7.26%. Linear regression analysis determined that the hinge axis (P = .0001) was a significant factor changing posterior tibial slope. CONCLUSIONS: Hinge position affected the change in posterior tibial slope in medial open-wedge HTO; in particular, a posterolateral hinge position led to an increase in posterior tibial slope. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Radiographic diagnosis of occult distal fibular avulsion fracture in children with acute lateral ankle sprain.

BACKGROUND: Skeletally immature children with ankle sprain are presumed to have distal fibula fracture than ligamentous injury. The purpose of this study is to determine the incidence of associated occult avulsion fracture in children with lateral ankle sprain and the efficacy of identifying fractures using anterior talofibular ligament view. METHODS: Patients who were diagnosed with distal fibular fracture in the initial ankle anteroposterior, lateral, and mortise were excluded and 78 patients (below 16 y of age) who had been initially diagnosed as ankle sprain were included. The initial and 4 weeks' follow-up ankle series and additional anterior talofibular ligament view suggested by Haraguchi were evaluated. RESULTS: Twenty patients were diagnosed with occult distal fibular avulsion fracture. Ten patients were diagnosed in anterior talofibular ligament view and others were diagnosed in the follow-up radiography. Displacement was highest on the anterior talofibular ligament view. CONCLUSIONS: This study found 20 (26%) of 78 ankle sprain show occult avulsion fracture in the anterior talofibular ligament view or follow-up radiography. The anterior talofibular ligament view is an appropriate radiologic view for the diagnosis of distal fibular avulsion fracture. LEVEL OF EVIDENCE: Level IV--diagnostic study.

Differences in cognitive function and daily living skills between early- and late-stage schizophrenia.

OBJECTIVES: Cognitive dysfunction is a core feature of schizophrenia; deficits often manifest prior to diagnosis and persist throughout the course of the illness. This study was performed to assess the difference in cognitive function and daily living skills between the early- and late-stage schizophrenia. METHODS: Fifty-five clinically stable patients with schizophrenia were recruited (25 with < 5-year and 30 with > 5-year disease durations). We evaluated subjects' clinical states, cognitive function, and psychosocial factors. The Korean versions of MATRICS Consensus Cognitive Battery and UCSD Performance-based Skills Assessment were used for evaluating cognitive function and daily living skills. Chi-square, Wilcoxon rank sum, and t-tests were used to analyze the data. RESULTS: The two groups did not differ for most demographic variables. No significant differences between groups were found for clinical symptoms, psychosocial factors, or non-social cognitive domains. However, the early-stage group had higher social cognition domain scores than the late-stage group (p = 0.01). Early-stage patients scored significantly higher than those in the late-stage group did in the communication and comprehension/planning domains (p = 0.037 and 0.027, respectively), and total score (p = 0.003) of the Performance-based Skills Assessment. CONCLUSIONS: We observed significant differences between patients with early- and late-stage illness with regard to social cognition and performance-based skills.

The effect of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of cilostazol and its active metabolites in healthy Korean subjects.

AIMS: The primary objective of this study was to evaluate the effects of Ginkgo biloba extracts (GBE) on the pharmacokinetics of cilostazol and its metabolites. The secondary objective was to assess the effect of GBE on the pharmacodynamics of cilostazol. METHODS: A randomized, double-blind, two-way crossover study was conducted with 34 healthy Korean subjects. All subjects were given an oral dose of cilostazol (100 mg) plus GBE (80 mg) or cilostazol (100 mg) plus placebo twice daily for 7 days. Plasma concentrations of cilostazol and its active metabolites (3,4-dehydrocilostazol and 4'-trans-hydroxycilostazol) were measured using liquid chromatography-tandem mass spectroscopy on day 7 for pharmacokinetic assessment. The adenosine diphosphate-induced platelet aggregation and bleeding time were measured at baseline and on day 7 for pharmacodynamic assessment. RESULTS: The geometric mean ratios of area under the concentration-time curve for dosing interval for cilostazol plus GBE vs. cilostazol plus placebo were 0.96 (90% confidence interval, 0.89-1.03; P = 0.20) for cilostazol, 0.96 (90% confidence interval, 0.90-1.02; P = 0.30) for 3,4-dehydrocilostazol and 0.98 (90% confidence interval, 0.93-1.03; P = 0.47) for 4'-trans-hydroxycilostazol. The change of aggregation after administration of cilostazol plus GBE seemed to be 1.31 times higher compared with cilostazol plus placebo, without statistical significance (P = 0.20). There were no significant changes in bleeding times and adverse drug reactions between the treatments. CONCLUSIONS: Co-administration of GBE showed no statistically significant effects on the pharmacokinetics of cilostazol in healthy subjects. A large cohort study with long-term follow-up may be needed to evaluate the possible pharmacodynamic interaction between cilostazol and GBE, given that there was a remarkable, but not statistically significant, increase in inhibition of platelet aggregation.

Comparison of the axillary venous approach and subclavian venous approach for efficacy of permanent pacemaker implantation. 8-Year follow-up results.

BACKGROUND: Long-term data on lead complication rates are limited for both the axillary and subclavian venous approaches for permanent pacemaker implantation. METHODS AND RESULTS: We conducted a single-center, retrospective, nonrandomized comparison. We reviewed the patients who had consented to receiving a permanent pacemaker implant. A superficial landmark or radiographic contrast guiding was used for the axillary venous approach, whereas conventional landmarks were used for the subclavian venous approach. From January 1992 to December 2005, we analyzed 1,161 permanent pacemaker leads in 655 patients [subclavian venous approach (group I: 338 patients, 542 leads) and axillary venous approach (group II: 317 patients, 619 leads)]. Baseline characteristics of the patients did not differ. However, DDD-pacemakers and atrial leads were used more often in group II than in group I (94% vs. 62% and 49% vs. 40%, P<0.01). During the 8-year follow-up, lead complication rates were lower in group II (17 leads, 3%) than in group I (31 leads, 6%) (P=0.03), and group II had a better complication-free survival curve than group I with a 49% relative risk reduction in lead complication rates (hazard ratio =0.51; 95% confidence interval, 0.27-0.94; P=0.03). CONCLUSIONS: The axillary venous approach for permanent pacemaker implantation has better long-term efficacy and lower lead complication rates than the subclavian venous approach.

Effects of interval between age at first pregnancy and age at diagnosis on breast cancer survival according to menopausal status: a register-based study in Korea.

BACKGROUND: The influence of parity and time interval between age at first pregnancy (AFP) and age at diagnosis on breast cancer survival is not established in the same way as their influence on breast cancer risk. We aimed to investigate the association of time interval or parity with prognosis in pre- and postmenopausal women in Korea. METHODS: We conducted a retrospective study of 29,167 women with breast cancer through the Korean Breast Cancer Registry from 1993-2009. Information on reproductive factors, including breastfeeding, AFP, and parity were collected from a routine questionnaire. Conditional logistic regression was used to estimate the associations between menopausal status and overall mortality (OM) and breast-cancer-specific mortality (BCSM), adjusting for treatment and stage. RESULTS: High parity (≥5) increased the hazard ratios (HR) of BCSM (HR = 1.33, 95% confidence interval (CI): 0.83-2.11, p < 0.001) and OM (HR = 1.20, 95% CI: 0.85-1.68.73, p < 0.001) in premenopausal and postmenopausal women (BCSM, HR: 1.62, 95% CI: 0.93-2.82, p < 0.001; OM, HR = 1.58, 95% CI: 1.14-2.21, p <0.001). A longer time interval between age at breast cancer diagnosis and AFP reduced the HRs of BCSM (HR = 0.97, 95% CI: 0.96-0.98, p = 0.001) and OM (HR = 0.98, 95% CI: 0.97-0.98, p < 0.001) in premenopausal women, but had an adverse effect on the HR of OM (HR = 1.03, 95% CI: 1.02-1.03, p < 0.001) in postmenopausal women. CONCLUSIONS: High parity (≥5) was associated with poor breast cancer prognosis in both pre- and postmenopausal women. The time intervals between reproductive events had different effects on breast cancer outcomes depending on menopausal status.

Effect of voglibose on the pharmacokinetics of metformin in healthy Korean subjects.

OBJECTIVE: The objective of this study was to evaluate the effects of voglibose on the pharmacokinetics of metformin. METHODS: A randomized, open-label, two-way crossover study with a 7-day washout period was conducted. All subjects were given an oral dose of metformin with or without voglibose 3 x daily for 7 days. Plasma concentrations of metformin on day 7 were measured using high performance liquid chromatography (HPLC) with UV detection for pharmacokinetic assessment Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. RESULTS: 22 subjects completed the study. The geometric mean ratios for C(ss,max) of metformin (metformin plus voglibose vs. metformin only) were 0.98 (90% CI, 0.92 - 1.05; p > 0.05) and for AUC-τ, the ratio was 0.99 (90% CI, 0.92 - 1.06; p > 0.05). There were no significant differences in adverse drug reactions between metformin with and without voglibose. However, the incidence of adverse events was higher in period 1 than in period 2 (16 cases vs. 1 case, p < 0.001). CONCLUSIONS: Co-administration of metformin and voglibose had no statistically or clinically significant effects on the pharmacokinetics of metformin in healthy subjects. The pharmacodynamic interaction study to evaluate the effect of metformin on the pharmacodynamics of voglibose is in progress.