Search

Background Attention deficit-hyperactivity disorder (ADHD) is related to depressive disorder, and adolescents with both present poor outcomes. However, evidence for the safety of concomitantly using a methylphenidate (MPH) and a selective serotonin reuptake inhibitor (SSRI) among adolescent ADHD patients is limited, a literature gap aimed to address through this investigation. Methods We conducted a new-user cohort study using a nationwide claims database in South Korea. We identified a study population as adolescents who were diagnosed both ADHD and depressive disorder. MPH-only users were compared with patients who prescribed both a SSRI and a MPH. Fluoxetine and escitalopram users were also compared to find a preferable treatment option. Thirteen outcomes including neuropsychiatric, gastrointestinal, and other events were assessed, taking respiratory tract infection as a negative control outcome. We matched the study groups using a propensity score and used the Cox proportional hazard model to calculate the hazard ratio. Subgroup and sensitivity analyses were conducted in various epidemiologic settings. Results The risks of all the outcomes between the MPH-only and SSRI groups were not significantly different. Regarding SSRI ingredients, the risk of tic disorder was significantly lower in the fluoxetine group than the escitalopram group [HR 0.43 (0.25–0.71)]. However, there was no significant difference in other outcomes between the fluoxetine and escitalopram groups. Conclusion The concomitant use of MPHs and SSRIs showed generally safe profiles in adolescent ADHD patients with depression. Most of the differences between fluoxetine and escitalopram, except those concerning tic disorder, were not significant.

Background Although the morbidity and mortality of cardiovascular diseases (CVD) are rising in young women, the risk factors of CVD among Korean pre-menopausal women have not been intensively investigated. Aims To determine how age at menarche and other female reproductive factors are associated with the risk of CVD in pre-menopausal women. Methods and results A total of 1 088 992 pre-menopausal women who participated in health screening in 2009 were included. The study outcomes were myocardial infarction (MI) and ischaemic stroke. Cox proportional hazards regression analysis was conducted with adjustment of traditional CVD risk factors and reproductive factors. Results Mean age was 43.8 ± 5.3 years (98.9%, < 55 years), 3.5% were current smokers, and 1.2% were heavy drinkers. During a mean follow-up of 8.3years [9 032 685.9 person-years (PY)], there were 10 876 CVD events (1.0 per 1000 PY).With later menarche, the risk of CVD increased; ≤12 years [adjusted hazard ratio (HR) 1.04, 95% confidence interval 0.93–1.16], 13 years (reference), 14 years (1.06, 0.98–1.14), 15 years (1.15, 1.07–1.24), 16 years (1.23, 1.14–1.34), and ≥17 years (1.33, 1.24–1.44). Compared with non-users, oral contraceptives (OC) users (≥1 year) had an increased risk of CVD (1.11, 1.01–1.22) (P for trend = 0.007). Conclusions Later menarche than the mean age at menarche (13 years old) and the use of OC (≥1 year) were associated with a higher risk of CVD, after adjusting for traditional cardiovascular risk factors. This study suggests that female reproductive factors could be unique risk factors for CVD in pre-menopausal women.

ObjectiveThere is little evidence for finding optimal antipsychotic treatment for schizophrenia, especially in paediatrics. To evaluate the performance and clinical benefit of several prediction methods for 1-year treatment continuation of antipsychotics.Design and SettingsPopulation-based prognostic study conducting using the nationwide claims database in Korea.Participants5109 patients aged 2–18 years who initiated antipsychotic treatment with risperidone/aripiprazole for schizophrenia between 2010 and 2017 were identified.Main outcome measuresWe used the conventional logistic regression (LR) and common six machine-learning methods (least absolute shrinkage and selection operator, ridge, elstic net, randomforest, gradient boosting machine, and superlearner) to derive predictive models for treatment continuation of antipsychotics. The performance of models was assessed using the Brier score (BS), area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC). The clinical benefit of applying these models was also evaluated by comparing the treatment continuation rate between patients who received the recommended medication by models and patients who did not.ResultsThe gradient boosting machine showed the best performance in predicting treatment continuation for risperidone (BS, 0.121; AUROC, 0.686; AUPRC, 0.269). Among aripiprazole models, GBM for BS (0.114), SuperLearner for AUROC (0.688) and random forest for AUPRC (0.317) showed the best performance. Although LR showed lower performance than machine learnings, the difference was negligible. Patients who received recommended medication by these models showed a 1.2–1.5 times higher treatment continuation rate than those who did not.ConclusionsAll prediction models showed similar performance in predicting the treatment continuation of antipsychotics. Application of prediction models might be helpful for evidence-based decision-making in antipsychotic treatment.

Pancreatic islet transplantation is a promising strategy for the treatment of type I diabetes. High-mobility group box-1 (HMGB1), highly expressed in islet cells, is a potent immune stimulator in immune rejection. Heme oxygenase-1 (HO1) gene therapy can modulate the release of HMGB1 by altering intracellular molecules for successful cell transplantation. After delivery of the heme oxygenase-1 (HO1) gene to islet cells using an adeno-associated viral vector (AAV), it was evaluated the changes in cytoplasmic Ca

Orally absorbable gold nanoparticles (AuNP) having cancer ablation therapy is strongly demanded to treat glioblastoma multiforme (GBM) for patients with its highest incidence rate. Here, we develop a milk protein lactoferrin-conjugated AuNP for its oral absorption and targeting to the GBM through the interaction between lactoferrin (Lf) and lactoferrin receptor (LfR) that is highly expressed in the intestine, blood-brain barrier and GBM. For stability and long circulation of AuNP, glutathione and polyethylene glycol (PEG) is introduced, which is called to Lf-PEG-AuNP. When Lf-PEG-AuNP are orally administered to orthotopic GBM-bearing mice, 11-fold and 8-fold higher concentrations of AuNP are measured in bloodstreams and GBM in the brain, respectively, compared with unconjugated-AuNP. Therefore, orally administered Lf-PEG-AuNP exhibit an outstanding temperature rise in GBM by irradiating laser and significantly reduce tumor volume. Collectively, we suggest that the Lf-PEG-AuNP can fundamentally target GBM in the brain through oral absorption, and that its efficient photothermal therapy is possible., Graphical abstract Graphical abstract text: Lf-PEG-AuNP has strong absorption capacity at the GI tract and efficient accumulation on the GBM due to LfR-mediated transport. Therefore, external 532 nm NIR laser irradiation on the specific GBM region, resulted about 60 °C heat generation. The successful PTT treatment of Lf-PEG-AuNP, decreased GBM volume by 80% and the apoptosis and necrosis were observed at the treated site.Image 1, Highlights • Glioblastoma multiforme is notoriously malignant, especially in the elderly. • Oral formulation of therapeutic drugs reduce stress during administration. • Milk protein Lactoferrin (Lf) enables oral absorption and GBM targeting of drug. • Lf receptor-mediated transportation of Lf-shelled gold nanoparticle was verified. • Photothermal therapy of gold nanoparticle targeting GBM confers therapeutic effect.

We aimed to explore whether the imaging of antiporter system x(C)(−) of immune cells with (4S)-4-(3-(18)F-fluoropropyl)-l-glutamate ((18)F-FSPG) PET can assess inflammatory bowel disease (IBD) activity in murine models and patients (NCT03546868). Methods: (18)F-FSPG PET imaging was performed to assess IBD activity in mice with dextran sulfate sodium-induced and adoptive T-cell transfer–induced IBD and a cohort of 20 patients at a tertiary care center in South Korea. Immunohistochemical analysis of system x(C)(−) and cell surface markers was also studied. Results: Mice with experimental IBD showed increased intestinal (18)F-FSPG uptake and xCT expression in cells positive (+) for CD11c, F4/80, and CD3 in the lamina propria, increases positively associated with clinical and pathologic disease activity. (18)F-FSPG PET studies in patients, most of whom were clinically in remission or had mildly active IBD, showed that PET imaging was sufficiently accurate in diagnosing endoscopically active IBD and remission in patients and bowel segments. (18)F-FSPG PET correctly identified all 9 patients with superficial or deep ulcers. Quantitative intestinal (18)F-FSPG uptake was strongly associated with endoscopic indices of IBD activity. The number of CD68(+)xCT(+) and CD3(+)xCT(+) cells in 22 bowel segments from patients with ulcerative colitis and the number of CD68(+)xCT(+) cells in 7 bowel segments from patients with Crohn disease showed a significant positive association with endoscopic indices of IBD activity. Conclusion: The assessment of system x(C)(−) in immune cells may provide diagnostic information on the immune responses responsible for chronic active inflammation in IBD. (18)F-FSPG PET imaging of system x(C)(−) activity may noninvasively assess the IBD activity.

Summary Objectives Previous studies of the relationships between female reproductive factors and osteoarthritis (OA) have shown conflicting results. In this study, we aimed to explore the relationships between reproductive factors and joint replacement arthroplasty of the knee (TKRA) and hip (THRA) in a large nationwide population-based cohort of postmenopausal Korean women. Methods We included 1,134,680 subjects who participated in national health examinations in 2009 in the study. The study outcomes were incident THRA or TKRA due to severe hip or knee OA. The relationships between reproductive factors and THRA or TKRA were evaluated using a multivariable-adjusted proportional hazards model. Results During a mean follow-up duration of 8.2 years, 1,610 incident THRA cases and 60,670 incident TKRA cases were observed. Later age at menarche, longer breastfeeding, HRT and OC use were associated with increased risk of TKRA for severe knee OA, while later age at menopause and longer reproductive span were associated with decreased risk. With regard to THRA for severe hip OA, later menarche, longer breastfeeding, HRT more than 5 years, and OC use more than 1 year were associated with higher risk. The associations between reproductive factors and severe OA were more pronounced in underweight and younger subjects. Conclusion We found that shorter estrogen exposure was associated with higher risk of TKRA due to severe knee OA, and such associations were more pronounced in underweight and younger subjects. The association between shorter estrogen exposure and THRA was not robust.

Background To assess the association between the reproductive factors of age at menarche, age at menopause, and reproductive span and the incidence of myocardial infarction (MI) and ischemic stroke (IS). Methods We used a population-based retrospective cohort study from the National Health Insurance Service database of Korea including a total of 1,224,547 postmenopausal women. Associations between age at menarche (≤ 12, 13–14 [reference], 15, 16, and ≥ 17 years), age at menopause ( Results During a median follow-up of 8.4 years, 25,181 MI and 38,996 IS cases were identified. Late menarche (≥ 16 years), early menopause (≤ 50 years), and short reproductive span (≤ 36 years) were linearly associated with a 6%, 12–40%, and 12–32% higher risk of MI, respectively. Meanwhile, a U-shaped association between age at menarche and risk of IS was found, with a 16% higher risk in early menarche (≤ 12 years) and a 7–9% higher risk in late menarche (≥ 16 years). Short reproductive span was linearly associated with an increased risk of MI, whereas both shorter and longer reproductive spans were associated with an increased risk of IS. Conclusions This study demonstrated different patterns of association between age at menarche and incidence of MI and IS: a linear association for MI versus a U-shaped association for IS. Female reproductive factors in addition to traditional cardiovascular risk factors should be considered when assessing overall cardiovascular risk in postmenopausal women.

The effects of menopausal hormone therapy (MHT) on non-alcoholic fatty liver disease (NAFLD) were compared based on the route of estrogen administration. The study included 368 postmenopausal women who received MHT for 12 months. Patients were divided into transdermal (n = 75) and oral (n = 293) groups based on the estrogen route. Changes in the prevalence of NAFLD were compared between the two groups before and after 12 months of MHT. In addition, differences in the progression of NAFLD after MHT based on the dose of estrogen and type of progestogen were evaluated in the oral group. After MHT, the prevalence of NAFLD decreased from 24–17.3% in the transdermal group but increased from 25.3–29.4% in the oral group. Little or no change was found in clinical characteristics and laboratory tests in the transdermal group during MHT. However, serum levels of total cholesterol and low-density lipoprotein cholesterol decreased and triglycerides and high-density lipoprotein cholesterol increased significantly in the oral group. Furthermore, changes in the prevalence of NAFLD were not significantly different based on the dose of estrogen or type of progestogen. Our findings indicate that transdermal estrogen can be beneficial in terms of NAFLD progression.

Background High-mobility group box-1 (HMGB1) released from the tumor microenvironment plays a pivotal role in the tumor progression. HMGB1 serves as a damaged-associated molecular pattern (DAMP) that induces tumor angiogenesis and its development. Glycyrrhizin (GL) is an effective intracellular antagonist of tumor released HMGB1, but its pharmacokinetics (PK) and delivery to tumor site is deficient. To address this shortcoming, we developed lactoferrin-glycyrrhizin (Lf-GL) conjugate. Methods Biomolecular interaction between Lf-GL and HMGB1 was evaluated by surface plasmon resonance (SPR) binding affinity assay. Inhibition of tumor angiogenesis and development by Lf-GL attenuating HMGB1 action in the tumor microenvironment was comprehensively evaluated through in vitro, ex vivo, and in vivo. Pharmacokinetic study and anti-tumor effects of Lf-GL were investigated in orthotopic glioblastoma mice model. Results Lf-GL interacts with lactoferrin receptor (LfR) expressed on BBB and GBM, therefore, efficiently inhibits HMGB1 in both the cytoplasmic and extracellular regions of tumors. Regarding the tumor microenvironment, Lf-GL inhibits angiogenesis and tumor growth by blocking HMGB1 released from necrotic tumors and preventing recruitment of vascular endothelial cells. In addition, Lf-GL improved the PK properties of GL approximately 10-fold in the GBM mouse model and reduced tumor growth by 32%. Concurrently, various biomarkers for tumor were radically diminished. Conclusion Collectively, our study demonstrates a close association between HMGB1 and tumor progression, suggesting Lf-GL as a potential strategy for coping with DAMP-related tumor microenvironment.

BACKGROUND Mood disorder has emerged as a serious concern for public health, especially, bipolar disorder has a less favorable prognosis than depression. Although prompt recognition of depression conversion to bipolar disorder is needed, early prediction is challenging due to overlapping symptoms. Recently, there are attempts to develop the prediction model using federated learning. Federated learning in medical fields is a method for training multi-institutional machine learning models without patient-level data sharing. OBJECTIVE This study aimed to develop and validate a federated, differentially private multi-institutional bipolar transition prediction model. METHODS This retrospective study enrolled patients diagnosed with a first depressive episode at five tertiary hospitals in South Korea. We developed model for predicting bipolar transition using data from four institutions, 17,631 patients. Also, we used data from 4,541 patients for external validation from one institution. We created standardized pipelines to extract large-scale clinical features from four institutions without any code modification. Further, we performed feature selection in a federated environment for computational efficiency and applied differential privacy to gradient updates. The study performed feature selection in a federated environment and applied differential privacy to gradient updates. We compared the federated and four local models developed with each hospital data on internal and external validation datasets. RESULTS In the internal dataset, 279 out of 17,631 patients showed bipolar disorder transition. In the external dataset, 60 out of 4,541 patients showed bipolar disorder transition. The average performance of the federated model in the internal test (area under the curve [AUC]: 0.726) and external validation (AUC: 0.719) datasets was higher than other locally developed models (AUC: 0.642-0.707 and AUC: 0.642-0.699, respectively). CONCLUSIONS This study developed and validated a differentially private federated model using distributed multi-institutional psychiatric data with standardized pipelines in a real-world environment. The federated model performed better than models using local data only.

Purpose: Various factors such as blood velocity, turbulent flow,and intimal injury are the most basic elements in free tissue transfers. However, how blood flow is reestablished, maintained, and changed after vascular anastomosis has rarely been studied.Methods: A 54-year-old male sustained an unreplantable severe crushing injury to his right hand. The middle finger was transferred to the thumb as an ectopic replantation using an anastomosis between the radial and digital arteries. However, secondary reconstruction for the first web space defect was inevitable and an anteromedial thigh free flap procedure was performed 2 months later using the previously anastomosed vessels. During the procedures, we noted morphologic changes in the microvessels and tried to explain those phenomena by applying the principles of hemodynamics.Results: Due to the discrepancy in vascular size between the radial and digital arteries, the velocity of the blood flow in the post-anastomotic site, which was the digital artery, must have been increased by Poiseuille’s law. Supposing that the velocity through the post-anastomotic site of the digital artery was increased, the pressure exerted by that flow decreased, resulting in more shrinkage of the vessel lumen of the digital artery by Bernoulli’s principle. Pascal’s law could also be applied in confined spaces with a static flow; where there is a constant pressure, as the radius of the post-anastomotic digital artery diminishes, the tension within the digital artery’s wall also simultaneously decreases. By Laplace’s law, the post-anastomotic digital artery’s wall thickens as less tension is exerted on the wall.Conclusion: Understanding these simple flow mechanics will enable microsurgeons to better avoid the risk factors causing thrombosis, which is related to flap failure.

To evaluate the association between female reproductive factors and the incidence of exudative age-related macular degeneration (AMD).A total of 1,297,388 postmenopausal women over 50 years of age who participated in both national health screening and cancer screening in 2009 were identified using the Korea National Health Insurance System database. Data on female reproductive factors were collected using a self-administered questionnaire. Patients were followed up until 2018, and the incident cases of exudative AMD were identified. The hazard ratios and 95% confidence intervals for exudative AMD were estimated using the multivariable-adjusted Cox proportional hazard model.During a mean follow-up of 7.27 years, 4,086 patients were newly diagnosed with exudative AMD. The hazard ratio (95% confidence intervals) for exudative AMD was 1.14 (1.01-1.31) for a reproductive period ≥40 years compared with a reproductive period30 years, 1.72 (1.48-2.00) for patients with ≥5 years of hormone replacement therapy, and 1.29 (1.09-1.52) for those with 2 to 5 years of hormone replacement therapy compared with those who never underwent hormone replacement therapy.Female reproductive factors were associated with the risk of exudative AMD. Greater lifetime exposure to endogenous and exogenous estrogen was associated with a higher incidence of exudative AMD.

Objectives This study identified the association between excessive exposure to screen media and behavioral and emotional problems in elementary school students. Methods A total of 331 parents of children aged 7-10 years were recruited from "The Kids Cohort for Understanding of Internet Addiction Risk Factors in Early Childhood (K-CURE)" study. Children's demographics, household media ownership, screen time, and behavioral/emotional problems were assessed using a parental questionnaire. Children's behavior/emotional problems were measured using the Korean version the of Child Behavior Checklist (K-CBCL) score. Results The total K-CBCL score in the screen overuse group was 51.18±9.55, significantly higher than 47.28±10.09 in the control group (t=2.14, p=0.05). For each subscale, the externalization score (51.65±10.14, 48.33±8.97, respectively; t=2.02, p

1.0 µm near-infrared (NIR) is considered unsuitable as an imaging and analytical signal in biological environments owing to the strong absorption of water at around the regions. Conversely, the 1.0 µm NIR can be converted to heat and used as a local water-molecular heating strategy for photothermal therapy of biological tissues. Herein, we designed a Nd-Yb co-doped nanomaterial (water-heating nanoparticles (NPs)) as a strong 1.0 µm emissive NP to target the absorption band of water. Furthermore, introducing Tm ions into the water-heating NPs improved the NIR lifetime, and it was developed as an NIR imaging-guided water-heating probe (water-heating NIR NPs). In the glioblastoma multiforme (GBM) mouse model, tumor-targeted water-heating NIR NPs reduced the tumor volume by 78.9% in the presence of high-resolution intracranial NIR long-lifetime imaging. Hence, water-heating NIR NPs can be used as a novel nanomaterial for imaging and photothermal ablation in deep-tissue-bearing tumor therapy.

Prostate-specific membrane antigen (PSMA), overexpressed in prostate cancer, has become a popular target for radionuclide-based theranostic applications in the advanced stages of prostate cancer. We conducted a meta-analysis of the therapeutic effects of PSMA-targeting alpha therapy [225Ac-PSMA radioligand therapy (RLT)] in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: A systematic search was performed using the keywords "mCRPC," "225Ac-PSMA," and "alpha therapy". Therapeutic responses were analyzed as the pooled proportions of patients with more than 50% of prostate-specific antigen (PSA) decline and any PSA decline. Survival outcomes were analyzed by estimating summary survival curves for progression-free survival (PFS) and overall survival (OS). Adverse events were analyzed as the pooled proportions of patients with xerostomia and severe hematotoxicity (anemia, leukocytopenia, and thrombocytopenia). Results: Nine studies with 263 patients were included in our meta-analysis. The pooled proportions of patients with more than 50% of PSA decline and any PSA decline were 60.99% [95% confidence interval (CI) = 54.92-66.83%] and 83.57% (95% CI = 78.62-87.77%), respectively. The estimated mean PFS and mean OS were 9.15 months (95% CI = 6.69-11.03 months) and 11.77 months (95% CI = 9.51-13.49 months), respectively. The pooled proportions of patients with adverse events were 62.81% (95% CI = 39.34-83.46%) for xerostomia, 14.39% (95% CI = 7.76-22.63%) for anemia, 4.12% (95% CI = 0.97-9.31%) for leukocytopenia, and 7.18% (95% CI = 2.70-13.57%) for thrombocytopenia. Conclusion: In our study, around 61% of patients had more than 50% of PSA decline and 84% of patients had any PSA decline after 225Ac-PSMA RLT. The common adverse events in 225Ac-PSMA RLT were xerostomia in 63% of patients and severe hematotoxicity in 4-14% of patients.

Diabetes is a disease condition characterized by a prolonged, high blood glucose level, which may lead to devastating outcomes unless properly managed. Here, we introduce a simple camera-based optical monitoring system (OMS) utilizing the nanoparticle embedded contact lens that produces color changes matching the tear glucose level without any complicated electronic components. Additionally, we propose an image processing algorithm that automatically optimizes the measurement accuracy even in the presence of image blurring, possibly caused by breathing, subtle movements, and eye blinking. As a result, using in vivo mouse models and human tear samples we successfully demonstrated robust correlations across the glucose concentrations measured by three different independent techniques, validating the quantitative efficacy of the proposed OMS. For its methodological simplicity and accessibility, our findings strongly support that the innovation offered by the OMS and processing algorithm would greatly facilitate the glucose monitoring procedure and improve the overall welfare of diabetes patients.

Metals are indispensable for the activities of all living things, from single-celled organisms to higher organisms, including humans. Beyond their intrinsic quality as metal ions, metals help creatures to maintain requisite biological processes by forming coordination complexes with endogenous ligands that are broadly distributed in nature. These types of naturally occurring chelating reactions are found through the kingdoms of life, including bacteria, plants and animals. Mimicking these naturally occurring coordination complexes with intrinsic biocompatibility may offer an opportunity to develop nanomedicine toward clinical applications. Herein, we introduce representative examples of naturally occurring coordination complexes in a selection of model organisms and highlight such bio-inspired metal-chelating nanomaterials for theranostic applications.