Purpose: To evaluate 24-month outcomes of anti-vascular endothelial growth factor (VEGF) treatment in polypoidal choroidal vasculopathy (PCV). Methods: Retrospective review of medical records was performed for 34 patients (34 eyes) who were diagnosed with PCV. The best-corrected visual acuity (BCVA) was measured before the injection and at 6, 12, and 24 months after the first injection. The value measured before treatment was compared with those measured after treatment. Results: The patients received mean 6.5 ± 2.1 intravitreal anti-VEGF injections during the 24-month follow-up period. The logarithm of minimal angle of resolution (logMAR) BCVA before the injection and at 6, 12, and 24 months after the first injections were 0.57 ± 0.32, 0.43 ± 0.29, 0.46 ± 0.33, and 0.62 ± 0.39, respectively. The BCVA was significantly improved at 6 and 12 months (p = 0.001 and p = 0.037, respectively). However, there was no significant difference between BCVA before the injection and 24 months (p = 1.000) after the first injection. At the 24-month follow-up, stable (< 2 logMAR lines of change) or improved (≥ 2 logMAR lines of improvement) BCVA was noted in 13 (38.2%) and 10 eyes (29.4%), respectively. Conclusions Anti-VEGF therapy was beneficial in maintaining long-term visual acuity in PCV. However, significant improvement in visual acuity was not noted.

Differentiated thyroid cancer demonstrates a wide range of clinical presentations, from very indolent cases to those with an aggressive prognosis. Therefore, diagnosing and treating each cancer appropriately based on its risk status is important. The Korean Thyroid Association (KTA) has provided and amended the clinical guidelines for thyroid cancer management since 2007. The main changes in this revised 2024 guideline include 1) individualization of surgical extent according to pathological tests and clinical findings, 2) application of active surveillance in low-risk papillary thyroid microcarcinoma, 3) indications for minimally invasive surgery, 4) adoption of World Health Organization pathological diagnostic criteria and definition of terminology in Korean, 5) update on literature evidence of recurrence risk for initial risk stratification, 6) addition of the role of molecular testing, 7) addition of definition of initial risk stratification and targeting thyroid stimulating hormone (TSH) concentrations according to ongoing risk stratification (ORS), 8) addition of treatment of perioperative hypoparathyroidism, 9) update on systemic chemotherapy, and 10) addition of treatment for pediatric patients with thyroid cancer.

Purpose: To evaluate the proportion of bevacizumab and the reason for its usage in wet age-related macular degeneration (AMD). Methods: Retrospective analysis of medical records was performed for 1,541 patients who received ranibizumab, aflibercept, or bevacizumab injection to treat wet AMD. The proportion of bevacizumab among the entire set of injections was identified. The reason for selecting bevacizumab was additionally identified. Results: During the study period, a total of 2,929 anti-vascular endothelial growth factor (anti-VEGF) injections were performed; 2,236 (76.3%) were ranibizumab or aflibercept injections and 693 (23.7%) were bevacizumab injections. The most common reason for bevacizumab usage was ‘having a 0.1 or worse best-corrected visual acuity or being unable to assure reimbursement due to the development of extensive scarring or geographic atrophy’ (297 bevacizumab injections, 42.9%). The second most common reason was ‘the inability to assure reimbursement such as extrafoveal choroidal neovascularization (CNV) or early CNV without definite fluid in the foveal region’ (201 bevacizumab injections, 29.0%). Conclusions Bevacizumab was used in 23.7% of the anti-VEGF injections to treat wet AMD. When analyzing patients’ treatment burden and financial impact, the results of the present study may provide useful information. Further multi-center studies are required to evaluate more precisely the usage of anti-VEGF drugs.

Purpose: To evaluate the proportion of bevacizumab and the reason for its usage in wet age-related macular degeneration (AMD). Methods: Retrospective analysis of medical records was performed for 1,541 patients who received ranibizumab, aflibercept, or bevacizumab injection to treat wet AMD. The proportion of bevacizumab among the entire set of injections was identified. The reason for selecting bevacizumab was additionally identified. Results: During the study period, a total of 2,929 anti-vascular endothelial growth factor (anti-VEGF) injections were performed; 2,236 (76.3%) were ranibizumab or aflibercept injections and 693 (23.7%) were bevacizumab injections. The most common reason for bevacizumab usage was ‘having a 0.1 or worse best-corrected visual acuity or being unable to assure reimbursement due to the development of extensive scarring or geographic atrophy’ (297 bevacizumab injections, 42.9%). The second most common reason was ‘the inability to assure reimbursement such as extrafoveal choroidal neovascularization (CNV) or early CNV without definite fluid in the foveal region’ (201 bevacizumab injections, 29.0%). Conclusions Bevacizumab was used in 23.7% of the anti-VEGF injections to treat wet AMD. When analyzing patients’ treatment burden and financial impact, the results of the present study may provide useful information. Further multi-center studies are required to evaluate more precisely the usage of anti-VEGF drugs.

Ischemic stroke results from arterial occlusion and can cause irreversible brain injury. A non-human primate (NHP) model of ischemic stroke was previously developed to investigate its pathophysiology and for efficacy testing of therapeutic candidates; however, fine motor impairment remains to be well-characterized. We evaluated hand motor function in a cynomolgus monkey model of ischemic stroke. Endovascular transient middle cerebral artery occlusion (MCAO) with an angiographic microcatheter induced cerebral infarction. In vivo magnetic resonance imaging mapped and measured the ischemia-induced infarct lesion. In vivo diffusion tensor imaging (DTI) of the stroke lesion to assess the neuroplastic changes and fiber tractography demonstrated three-dimensional patterns in the corticospinal tract 12 weeks after MCAO. The hand dexterity task (HDT) was used to evaluate fine motor movement of upper extremity digits. The HDT was modified for a home cage-based training system, instead of conventional chair restraint training. The lesion was localized in the middle cerebral artery territory, including the sensorimotor cortex. Maximum infarct volume was exhibited over the first week after MCAO, which progressively inhibited ischemic core expansion, manifested by enhanced functional recovery of the affected hand over 12 weeks after MCAO. The total performance time decreased with increasing success rate for both hands on the HDT. Compensatory strategies and retrieval failure improved in the chronic phase after stroke. Our findings demonstrate the recovery of fine motor skill after stroke, and outline the behavioral characteristics and features of functional disorder of NHP stroke model, providing a basis for assessing hand motor function after stroke.

The function of microglia/macrophages after ischemic stroke is poorly understood. This study examines the role of microglia/macrophages in the focal infarct area after transient middle cerebral artery occlusion (MCAO) in rhesus monkeys. We measured infarct volume and neurological function by magnetic resonance imaging (MRI) and non-human primate stroke scale (NHPSS), respectively, to assess temporal changes following MCAO. Activated phagocytic microglia/macrophages were examined by immunohistochemistry in post-mortem brains (n=6 MCAO, n=2 controls) at 3 and 24 hours (acute stage), 2 and 4 weeks (subacute stage), and 4, and 20 months (chronic stage) following MCAO. We found that the infarct volume progressively decreased between 1 and 4 weeks following MCAO, in parallel with the neurological recovery. Greater presence of cluster of differentiation 68 (CD68)-expressing microglia/macrophages was detected in the infarct lesion in the subacute and chronic stage, compared to the acute stage. Surprisingly, 98~99% of transforming growth factor beta (TGFβ) was found colocalized with CD68-expressing cells. CD68-expressing microglia/macrophages, rather than CD206⁺ cells, may exert anti-inflammatory effects by secreting TGFβ after the subacute stage of ischemic stroke. CD68⁺ microglia/macrophages can therefore be used as a potential therapeutic target.
Brain ; Haplorhini ; Immunohistochemistry ; Infarction, Middle Cerebral Artery ; Inflammation ; Macaca mulatta ; Magnetic Resonance Imaging ; Microglia ; Middle Cerebral Artery ; Primates ; Stroke ; Transforming Growth Factor beta

BACKGROUND: Carvedilol is commonly used to treat hypertension as a β- and α1-adrenoreceptor blocker, but it is metabolized by CYP2D6, and CYP2D6*10 allele is dominant in Asian population. The objective of this study was to assess the influence of CYP2D6 polymorphisms on the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of carvedilol in healthy Korean volunteers. METHODS: A PK/PD study for a single and multiple dosing of carvedilol were conducted. All volunteers in 3 genotypic groups received single oral dose of carvedilol 12.5 mg for 3 days, then 25 mg QD for 5 days, and 12.5 mg QD for another 3 days. PK parameters for carvedilol and its three metabolites were determined using non-compartmental analysis. For PD properties, blood pressure, heart rate, and the chronotropic dose 25 (CD25) value were obtained. RESULTS: The IM_2 group with two *10 alleles (intermediate metabolizers) exhibited lower clearance of carvedilol as well as higher area under the curve (AUC) for O-desmethyl carvedilol. The ratio of CD25 to baseline at multiple dosing was significantly higher in the combined IM group (IM_1 and IM_2) than in the EM group, however, the ratio of CD25 after single and multiple dosing and the other PD markers were not significantly different between the 3 genotypic groups compared with the baseline. CONCLUSION: These findings showed that CYP2D6 genotype influenced the PK characteristics of carvedilol and no differences in PD response were observed in Korean healthy volunteers. Registered at the ClinicalTrials.gov, NCT02286934.
Alleles ; Asian Continental Ancestry Group ; Blood Pressure ; Cytochrome P-450 CYP2D6* ; Genotype ; Healthy Volunteers ; Heart Rate ; Humans ; Hypertension ; Polymorphism, Genetic ; Volunteers*

In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p < 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials.
Chromatography, Liquid ; Drug-Related Side Effects and Adverse Reactions ; Incidence ; Mass Screening ; Mass Spectrometry ; Metabolomics ; Pharmacogenetics* ; Plasma ; Real-Time Polymerase Chain Reaction

BACKGROUND: Plate fixation is the most commonly used technique for the treatment of shaft fractures of both forearm bones (SFBFBs). However, all fractures are difficult to treat with plate fixation because of soft tissue injuries, fracture patterns, or the patient's condition. The purpose of this study is to compare the functional results of plate fixation only and combined plate and intramedullary (IM) nail fixation in SFBFBs. METHODS: Fifty-nine cases of SFBFBs that were surgically treated from June 2007 to July 2012 were retrospectively reviewed. In this study, 47 cases that were followed up for more than 12 months were included. All SFBFBs were divided into two groups according to the methods used for internal fixation: plate fixation only (group A) and combined plate and IM nail fixation (group B). The fixation methods were determined intraoperatively. Plate fixation was considered as the first option in all cases, but combined plate and IM nail fixation was selected as the second option if it was difficult to be fixed with plate only. Groups A and B comprised of 31 and 16 cases, respectively. The functional results were evaluated by the Grace and Eversmann rating system and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. RESULTS: In groups A and B, a radiologic union was achieved in 30/31 and 14/16 cases and average union time was 11.1 and 17.8 weeks, respectively. According to the Grace and Eversmann rating system, group A had excellent results in 15 cases, good in 14, acceptable in one, and unacceptable in one. Group B had excellent results in three cases, good in nine, acceptable in two, and unacceptable in two. The average DASH score was 7.1 points (range, 0 to 19.2 points) in group A and 15.1 points (range, 0 to 29.6 points) in group B. Three cases of nonunion with unacceptable results achieved a bony union by additional procedures and the functional results of these cases improved to good or excellent. CONCLUSIONS: The functional results and the average union time were superior in group A than in group B. However, we think that combined fixation is a useful method for SFBFBs that cannot be treated with plate fixation only.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Bone Nails/*statistics & numerical data ; Bone Plates/*statistics & numerical data ; Female ; Forearm/surgery ; Fracture Fixation, Intramedullary/adverse effects/*methods/*statistics & numerical data ; Humans ; Male ; Middle Aged ; Radius Fractures/epidemiology/*surgery ; Range of Motion, Articular/*physiology ; Retrospective Studies ; Treatment Outcome ; Ulna Fractures/epidemiology/*surgery ; Young Adult

Sirtuin 1 (SIRT1) is a mammalian NAD+-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-kappaB), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (alpha-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.
Acetylation ; Actins ; Animals ; Collagen ; Connective Tissue Growth Factor ; Diet ; Diet, High-Fat ; Fibrosis ; Glucose ; Inflammation* ; Insulin Resistance ; Liver ; Macrophages ; Metabolism ; Mice* ; NF-kappa B ; Obesity ; Sirtuin 1 ; Sterol Regulatory Element Binding Protein 1 ; Weight Gain