Hypnotic effect of AR-001 through adenosine A1 receptor.

Insomnia is one of the most common sleep disorders, affecting 10-15% of the global population. Because classical remedies used to treat insomnia have various side effects, new therapeutics for insomnia are attracting attention. In the present study, we found that N2-Ethyl-N4-(furan-2-ylmethyl) quinazoline-2,4-diamine (AR-001) has adenosine A1 receptor agonistic activity and exhibits hypnotic efficacy by decreasing sleep onset latency and increasing total sleep time in a pentobarbital-induced sleep model. This hypnotic effect of AR-001 was significantly inhibited by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). As a result of immunohistochemistry, AR-001 was shown to increase neural activity in the sleep-promoting region, ventrolateral preoptic nucleus (VLPO), and decrease neural activity in the wake-promoting region, basal forebrain (BF), and lateral hypothalamus (LH), and that these effects of AR-001 were significantly inhibited by DPCPX treatment. In addition, AR-001 increased adenosine A1 receptor mRNA levels in the hypothalamus. In conclusion, this study suggests that AR-001 has a hypnotic effect, at least partially, through adenosine A1 receptor and may have therapeutic potential for insomnia.

The Effect of 3-Dimensional-Printed Sequential Dual Drug-Releasing Patch on the Capsule Formation Around the Silicone Implant in a Rat Model.

BACKGROUND: Implant-based breast reconstruction is associated with increased risk of early infection and late-stage capsular contracture. OBJECTIVES: We evaluated the feasibility of a dual drug-releasing patch that enabled the controlled delivery of antibiotics and immunosuppressants in a temporally and spatially appropriate manner to the implant site. METHODS: The efficacy of a dual drug-releasing patch, which was 3-dimensional-printed (3D-printed) with tissue-derived biomaterial ink, was evaluated in rats with silicone implants. The groups included implant only (n = 10); implant plus bacterial inoculation (n = 14); implant, bacterial inoculation, and patch loaded with gentamycin placed on the ventral side of the implant (n = 10), and implant, bacterial inoculation, and patch loaded with gentamycin and triamcinolone acetonide (n = 9). Histologic and immunohistochemical analyses were performed 8 weeks after implantation. RESULTS: The 2 drugs were sequentially released from the dual drug-releasing patch and exhibited different release profiles. Compared to the animals with bacterial inoculation, those with the antibiotic-only and the dual drug-releasing patch exhibited thinner capsules and lower myofibroblast activity and inflammation, indicating better tissue integration and less foreign body response. These effects were more pronounced with the dual drug-releasing patch than with the antibiotic-only patch. CONCLUSIONS: The 3D-printed dual drug-releasing patch effectively reduced inflammation and capsule formation in a rat model of silicone breast reconstruction. The beneficial effect of the dual drug-releasing patch was better than that of the antibiotic-only patch, indicating its therapeutic potential as a novel approach to preventing capsular contracture while reducing concerns of systemic side effects.

Effect of bacterial resistant zwitterionic derivative incorporation on the physical properties of resin-modified glass ionomer luting cement.

Biofilms induce microbial-mediated surface roughening and deterioration of cement. In this study, zwitterionic derivatives (ZD) of sulfobetaine methacrylate (SBMA) and 2-methacryloyloxyethyl phosphorylcholine, were added in concentrations of 0, 1, and 3% to three different types of commercially available resin-modified glass ionomer cement (RMGIC) (RMC-I: RelyX Luting 2, RMC-II: Nexus RMGI, and RMC-III: GC FujiCEM 2). The unmodified RMGICs served as the control group for comparison. The resistance of Streptococcus mutans to ZD-modified RMGIC was evaluated with a monoculture biofilm assay. The following physical properties of the ZD-modified RMGIC were assessed: wettability, film thickness, flexural strength, elastic modulus, shear bond strength, and failure mode. The ZD-modified RMGIC significantly inhibited biofilm formation, with at least a 30% reduction compared to the control group. The addition of ZD improved the wettability of RMGIC; however, only 3% of the SBMA group was statistically different (P < 0.05). The film thickness increased in proportion to the increasing ZD concentrations; there was no statistical difference within the RMC-I (P > 0.05). The experimental groups' flexural strength, elastic modulus, and shear bond strength showed an insignificant decrease from the control group; there was no statistical difference within the RMC-I (P > 0.05). The mode of failure differed slightly in each group, but all groups showed dominance in the adhesive and mixed failure. Thus, the addition of 1 wt.% ZD in RMGIC favorably enhanced the resistance to Streptococcus mutans without any tangible loss in flexural and shear bond strength.

Urine Cytology Rarely Escalates Clinical Management in the Surveillance of Non-muscle-Invasive Bladder Cancer.

INTRODUCTION: The use of urine cytology in the surveillance of non-muscle invasive bladder cancer (NMIBC) is widely variable in clinical practice. We studied the impact of surveillance urine cytology on clinical decision making during NMIBC surveillance. METHODS: A retrospective chart review was conducted on patients surveilled for clinical NMIBC from 2013 to 2020 with at least one follow-up cytology result after diagnosis. Patients were classified into risk categories according to American Urological Association (AUA) NMIBC guidelines. Data were obtained regarding tumor recurrence pathology and the frequency and findings of surveillance cystoscopies and urine cytologies. Positive (suspicious, malignant) and negative (atypical or negative for malignant cells) cytology results were correlated with cystoscopy and pathology findings when obtained within 3 months of the cytology specimen to determine if cytology impacted plan of care. RESULTS: Two hundred fourteen patients with NMIBC were followed for a median of 34 months, with 1045 urine cytologies collectively obtained over the surveillance period. There were no positive urine cytologies among patients with low-risk NMIBC; therefore, cytology did not change management in this cohort. The potential for cytology to escalate management for patients of any risk group (ie, positive cytology in the absence of positive cystoscopy or pathology findings) occurred in 30 (2.9%) cases. However, clinical decision making was only altered in 4 cases (0.4% of all cytologies). CONCLUSIONS: Less than 1% of urine cytology specimens collected during NMIBC surveillance impacted clinical management, none of whom had low-risk disease. The use of urine cytology for surveillance of low-risk NMIBC should continue to be strongly discouraged, as it did not change management in any such cases.

Relationship between Androgen Deprivation Therapy and Normal-Tension Glaucoma in Patients with Prostate Cancer: A Nationwide Cohort Study.

PURPOSE: This study assessed the relationship between newly developed normal-tension glaucoma (NTG) and androgen deprivation therapy (ADT) in patients with prostate cancer. MATERIALS AND METHODS: A retrospective population-based cohort study was performed. During the period between 2008 and 2017, a total of 218203 prostate cancer patients were identified in a nationwide claims database in the Republic of Korea. The final analysis included 170874 patients (42909 in the ADT group, 127965 in the control group) after applying the inclusion and exclusion criteria. The incidences of NTG according to ADT duration were compared with controls. Exact matching was conducted to adjust comorbidities between cohorts. Cox proportional hazard regression models were performed after controlling for latent confounding factors, and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of NTG according to ADT were obtained. RESULTS: In the matched cohort, the ADT group was associated with a significantly reduced risk of NTG in multivariable analysis compared to the control group. The risk of NTG decreased in patients who underwent ADT for less than 2 years (HR=0.824; 95% CI, 0.682-0.995; p=0.0440) and in those using ADT over 2 years (HR=0.796; 95% CI, 0.678-0.934; p=0.0051), compared to the controls. CONCLUSION: Medical castrations for patients with prostate cancer results in a lower incidence of newly diagnosed NTG compared to no ADT. These findings suggest that testosterone may be involved in the pathogenesis of NTG.

A microphysiological model of human trophoblast invasion during implantation.

Successful establishment of pregnancy requires adhesion of an embryo to the endometrium and subsequent invasion into the maternal tissue. Abnormalities in this critical process of implantation and placentation lead to many pregnancy complications. Here we present a microenigneered system to model a complex sequence of orchestrated multicellular events that plays an essential role in early pregnancy. Our implantation-on-a-chip is capable of reconstructing the three-dimensional structural organization of the maternal-fetal interface to model the invasion of specialized fetal extravillous trophoblasts into the maternal uterus. Using primary human cells isolated from clinical specimens, we demonstrate in vivo-like directional migration of extravillous trophoblasts towards a microengineered maternal vessel and their interactions with the endothelium necessary for vascular remodeling. Through parametric variation of the cellular microenvironment and proteomic analysis of microengineered tissues, we show the important role of decidualized stromal cells as a regulator of extravillous trophoblast migration. Furthermore, our study reveals previously unknown effects of pre-implantation maternal immune cells on extravillous trophoblast invasion. This work represents a significant advance in our ability to model early human pregnancy, and may enable the development of advanced in vitro platforms for basic and clinical research of human reproduction.

Piperine and Its Metabolite's Pharmacology in Neurodegenerative and Neurological Diseases.

Piperine (PIP) is an active alkaloid of black and long peppers. An increasing amount of evidence is suggesting that PIP and its metabolite's could be a potential therapeutic to intervene different disease conditions including chronic inflammation, cardiac and hepatic diseases, neurodegenerative diseases, and cancer. In addition, the omnipresence of PIP in food and beverages made this compound an important investigational material. It has now become essential to understand PIP pharmacology and toxicology to determine its merits and demerits, especially its effect on the central nervous system (CNS). Although several earlier reports documented that PIP has poor pharmacokinetic properties, such as absorption, bioavailability, and blood-brain barrier permeability. However, its interaction with metabolic enzyme cytochrome P450 superfamily and competitive hydrophobic interaction at Monoamine oxide B (MAO-B) active site have made PIP both a xenobiotics bioenhancer and a potential MAO-B inhibitor. Moreover, recent advancements in pharmaceutical technology have overcome several of PIP's limitations, including bioavailability and blood-brain barrier permeability, even at low doses. Contrarily, the structure activity relationship (SAR) study of PIP suggesting that its several metabolites are reactive and plausibly responsible for acute toxicity or have pharmacological potentiality. Considering the importance of PIP and its metabolites as an emerging drug target, this study aims to combine the current knowledge of PIP pharmacology and biochemistry with neurodegenerative and neurological disease therapy.

Clinical application of protein-enhanced diet using mealworms in patients undergoing hepato-pancreato-biliary surgery.

OBJECTIVE: Patients with or without cancers who undergo major gastrointestinal surgery experience malnutrition owing to their catabolic status during the postoperative period. In this study, we evaluated the effect of the clinical application of protein-enhanced diet using mealworms in patients who underwent hepato-pancreato-biliary surgeries. METHODS: This study was designed as a prospective, two-armed, and double-blinded phase III study. The target number of enrolled patients was 216, and the patients were randomized on a 1:1 basis, either to the trial group (consuming mealworms) or to the control group (consuming grain powder). The primary endpoint was to examine the changes in body composition, including phase angle. For secondary outcomes, the activities of immune cells were evaluated using the patients' blood samples. RESULTS: No difference in the demographic characteristics of patients was observed. The ratio of the actual protein intake to the recommended daily intake in the trial group was significantly higher than that in the control group (110.03% vs. 98.80%, P = 0.023). In the data on body composition measured by InBody S-10 (Biospace, Seoul, South Korea), the ratios in body cell mass, fat free mass, muscle mass, and phase angle at the study endpoint compared with those at admission showed no statistically significant difference between the two groups. Immune cell analyses suggested that cytotoxic T cells in the trial group had higher activity than in the study group (1.192 vs. 0.974, P = 0.028). CONCLUSIONS: In this study, protein-enhanced diet using mealworms clinically improved the activity of immune cells. However, it did not significantly improve the patients' nutritional status after they experienced hepato-pancreato-biliary surgeries.

Androgen Deprivation Therapy in Patients with Prostate Cancer is Associated with the Risk of Subsequent Alzheimer's Disease but Not with Vascular Dementia.

PURPOSE: We aimed to investigate the association between androgen deprivation therapy (ADT) and the risk of dementia according to subtypes of dementia in men with prostate cancer. MATERIALS AND METHODS: We performed a nationwide population-based cohort study using the nationwide claims database in Korea. A total of 195,308 men with newly diagnosed prostate cancer were identified between January 2008 and December 2017, and 132,700 men were selected for analysis after applying inclusion and exclusion criteria. The patients were divided into ADT and non-ADT groups. To adjust for imbalances in relevant comorbidities between the groups, exact matching was performed. Study events included newly developed Alzheimer's disease, vascular dementia, and overall dementia. Cox proportional hazard regression models were used. RESULTS: After exact matching, 44,854 men with prostate cancer were selected for the main analysis. In age-adjusted Cox regression analysis, the ADT group was significantly associated with increased risks for overall dementia (hazard ratio [HR], 1.070; 95% confidence interval [CI], 1.009-1.134; p=0.0232) and Alzheimer's disease (HR, 1.086; 95% CI, 1.018-1.160; p=0.0127), compared to the non-ADT group. No difference in vascular dementia risk was observed between the two groups (HR, 0.990; 95% CI, 0.870-1.126; p=0.8792). CONCLUSIONS: The risk of overall dementia increased in men who received ADT. According to dementia subtypes, ADT was associated with an increased risk of Alzheimer's disease, but not with vascular dementia.

Risk of cardiovascular intervention after androgen deprivation therapy in prostate cancer patients with a prior history of ischemic cardiovascular and cerebrovascular disease: A nationwide population-based cohort study.

BACKGROUND: Androgen deprivation therapy for prostate cancer is known to increase the risk of cardiovascular disease, but there is controversy regarding the cardiovascular risk in patients with preexisting cardiovascular disease. This study assessed the risk of cardiovascular intervention after androgen deprivation therapy in patients with a history of cardiovascular disease, cerebrovascular disease, and cardiovascular intervention. MATERIALS AND METHODS: Between 2008 and 2017, 195,308 men with newly diagnosed prostate cancer were identified from the nationwide claims database in South Korea. Among them, 49,090 men with a history of ischemic cardiovascular and cerebrovascular diseases were analyzed. The patients were divided into the androgen deprivation therapy (n = 14,092) and non-androgen deprivation therapy (n = 34,988) groups. The primary outcome was cardiovascular interventions (percutaneous transluminal angioplasty and coronary bypass surgery). Cox proportional hazard regression models were used to estimate the adjusted hazard ratios and 95% confidence intervals of the events. RESULTS: After balancing the covariates with 1:1 exact matching, the two groups had 10,514 subjects each. Multivariable analysis demonstrated that androgen deprivation therapy was not significantly associated with an increased risk of cardiovascular interventions (hazard ratio, 1.060; 95% confidence interval, 0.923-1.217; P = 0.4104), regardless of the duration of therapy. A history of cardiovascular intervention, diabetes mellitus, antithrombotic medication use, and cardiovascular events significantly increased the risk of cardiovascular intervention. CONCLUSIONS: Androgen deprivation therapy was not associated with cardiovascular intervention in patients with a previous history of cardiovascular disease, regardless of the duration of therapy. Therefore, the cardiovascular risk of androgen deprivation therapy should be reassessed in this population.

Variable effects of underlying diseases on the prognosis of patients with COVID-19.

Underlying diseases might be risk factors for poor prognosis in patients with coronavirus disease (COVID-19); however, we still do not know whether these diseases are independent factors affecting prognosis, which type of underlying diseases are risk factors, and which type of clinical outcomes are affected. We retrospectively reviewed cohort data from 7,590 de-identified patients with COVID-19 who were diagnosed using severe acute respiratory syndrome-coronavirus-2 RNA polymerase chain reaction test up to May 15, 2020. We used linked-medical claims data provided by the Health Insurance Review and Assessment Service in South Korea. Underlying diseases were identified using the diagnostic codes in the patients' files from January 1, 2019 to December 31, 2019. The total mortality rate was 3.0% in patients with COVID-19. After adjusting for age, sex, and concomitant chronic conditions, we found that congestive heart failure, chronic pulmonary diseases, diabetes without chronic complications, renal diseases, and malignancy were factors that significantly increased the cost of treatment. Cerebrovascular disease, chronic pulmonary disease, and paralysis were found to be independent factors significant in prolonging hospital stay. Diabetes with chronic complications was independently associated with intensive care unit admission. In addition, underlying congestive heart failure (odds ratio [OR], 1.724; P = 0.003), dementia (OR, 1.598; P = 0.012), diabetes with and without chronic complications (OR, 1.821; P = 0.002 and OR, 1.518; P = 0.022, respectively), renal disease (OR, 2.299; P = 0.002), and malignancy (OR, 1.529; P = 0.039) were significant factors associated with death, even after adjustments. Underlying diseases were significant independent factors of the poor prognosis in patients with COVID-19. The effects were variable according to the type of underlying disease and clinical outcome. Therefore, patients with COVID-19 with underlying diseases should be monitored more closely because they are more at risk of a poor prognosis.

Androgen-deprivation therapy and the risk of newly developed fractures in patients with prostate cancer: a nationwide cohort study in Korea.

We evaluated the risk of osteoporosis and fractures associated with androgen deprivation therapy (ADT) use and duration in men with prostate cancer. From the nationwide claims database in South Korea, a total of 218,203 men with prostate cancer were identified between 2008 and 2017. After applying the inclusion and exclusion criteria, a total of 144,670 patients were included in the analysis. To adjust for comorbidities between cohorts, 1:1 propensity score matching was used. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of events associated with ADT, after controlling for potential confounding factors. In the matched cohort, there were differences in the incidence of newly developed osteoporosis (8.79% in the ADT group vs. 7.08% in the non-ADT group, p < 0.0001) and fractures (8.12% in the ADT group vs. 5.04% in the non-ADT group, p < 0.0001). Age-adjusted Cox regression analysis revealed that the ADT group had a significantly higher risk of osteoporosis (HR, 1.381; 95% CI, 1.305-1.461; p < 0.0001) and fractures (HR, 1.815; 95% CI, 1.703-1.935; p < 0.0001) compared to the non-ADT group. Furthermore, the risk of osteoporosis and fractures increased as the duration of ADT increased. The ADT was associated with an increased risk of osteoporosis and fractures in prostate cancer patients. Clinicians who administer ADT for patients with prostate cancer should always be mindful of the risk of osteoporosis and fracture, avoid unnecessary ADT, and perform regular bone health check-ups.

Factors Affecting Nursing Students' Practice of Medical Information Protection.

Infringement of personal medical information can lead to psychological, social, and economic damages; legal repercussions; information abuse; and invasion of patients' privacy. This study identified the effects of nursing students' ethical inclination, knowledge, and perception on their medical information protection practice. Participants were third- and fourth-year students of one nursing college in a city in South Korea. Participants' perception of the importance of medical information protection was correlated with their practice of medical information protection (r = 0.62, P < .001), and their ethical inclination toward idealism was correlated with perceived need to protect medical information (r = 0.18, P = .049). The perception of the need for medical information protection was a significant predictor of the practice of medical information protection (R2 = 0.39, P < .001). Findings suggested that nursing students' perception of medical information protection affected their practice of information protection. Therefore, measures to improve nursing students' perception of the importance of medical information protection might be useful to improve their practice of information protection in clinical settings. There is an urgent need to identify the barriers to the practice of medical information protection, and ongoing training on medical information protection should be included in nursing courses.

[Relationships among Non-Nursing Tasks, Nursing Care Left Undone, Nurse Outcomes and Medical Errors in Integrated Nursing Care Wards in Small and Medium-Sized General Hospitals].

PURPOSE: This study aimed to identify the degree of non-nursing tasks and nursing care left undone in integrated nursing care wards, and examine their relationships with nurses' burnout, job satisfaction, turnover intentions, and medical errors. METHODS: A cross-sectional questionnaire survey was conducted. Data were collected using self-report questionnaires from 346 nurses working in 20 wards of seven small and medium-sized general hospitals, and analyzed using multiple regression and multiple logistic regression analysis with the SPSS WIN 25.0 program. RESULTS: The mean score for non-nursing tasks was 7.32±1.71, and that for nursing care left undone was 4.42 ± 3.67. An increase in non-nursing tasks (ß = .12, p = .021) and nursing care left undone (ß = .18, p < .001) led to an increase in nurses' burnout (F = 6.26, p < .001). As nursing care left undone (ß = .13, p = .018) increased, their turnover intentions also (F = 3.96, p < .001) increased, and more medical errors occurred (odds ratio 1.08, 95% confidence interval 1.02~1.15). CONCLUSION: Non-nursing tasks and nursing care left undone are positively associated with nurses' burnout, turnover intentions, and the occurrence of medical errors. Therefore, it is important to reduce non-nursing tasks and nursing care left undone in order to deliver high quality nursing care and in turn increase patient safety.

Development of 3D Printed Bruch's Membrane-Mimetic Substance for the Maturation of Retinal Pigment Epithelial Cells.

Retinal pigment epithelium (RPE) is a monolayer of the pigmented cells that lies on the thin extracellular matrix called Bruch's membrane. This monolayer is the main component of the outer blood-retinal barrier (BRB), which plays a multifunctional role. Due to their crucial roles, the damage of this epithelium causes a wide range of diseases related to retinal degeneration including age-related macular degeneration, retinitis pigmentosa, and Stargardt disease. Unfortunately, there is presently no cure for these diseases. Clinically implantable RPE for humans is under development, and there is no practical examination platform for drug development. Here, we developed porcine Bruch's membrane-derived bioink (BM-ECM). Compared to conventional laminin, the RPE cells on BM-ECM showed enhanced functionality of RPE. Furthermore, we developed the Bruch's membrane-mimetic substrate (BMS) via the integration of BM-ECM and 3D printing technology, which revealed structure and extracellular matrix components similar to those of natural Bruch's membrane. The developed BMS facilitated the appropriate functions of RPE, including barrier and clearance functions, the secretion of anti-angiogenic growth factors, and enzyme formation for phototransduction. Moreover, it could be used as a basement frame for RPE transplantation. We established BMS using 3D printing technology to grow RPE cells with functions that could be used for an in vitro model and RPE transplantation.

Feasibility of Synthetic Computed Tomography Images Generated from Magnetic Resonance Imaging Scans Using Various Deep Learning Methods in the Planning of Radiation Therapy for Prostate Cancer.

We aimed to evaluate and compare the qualities of synthetic computed tomography (sCT) generated by various deep-learning methods in volumetric modulated arc therapy (VMAT) planning for prostate cancer. Simulation computed tomography (CT) and T2-weighted simulation magnetic resonance image from 113 patients were used in the sCT generation by three deep-learning approaches: generative adversarial network (GAN), cycle-consistent GAN (CycGAN), and reference-guided CycGAN (RgGAN), a new model which performed further adjustment of sCTs generated by CycGAN with available paired images. VMAT plans on the original simulation CT images were recalculated on the sCTs and the dosimetric differences were evaluated. For soft tissue, a significant difference in the mean Hounsfield unites (HUs) was observed between the original CT images and only sCTs from GAN (p = 0.03). The mean relative dose differences for planning target volumes or organs at risk were within 2% among the sCTs from the three deep-learning approaches. The differences in dosimetric parameters for D98% and D95% from original CT were lowest in sCT from RgGAN. In conclusion, HU conservation for soft tissue was poorest for GAN. There was the trend that sCT generated from the RgGAN showed best performance in dosimetric conservation D98% and D95% than sCTs from other methodologies.

Androgen deprivation therapy may reduce the risk of primary open-angle glaucoma in patients with prostate cancer: a nationwide population-based cohort study.

BACKGROUND: We evaluated the risk of developing primary open-angle glaucoma (POAG) according to androgen deprivation therapy (ADT) status in patients with prostate cancer. MATERIALS AND METHODS: From the nationwide claims database in South Korea, 218,203 men with prostate cancer were identified between 2008 and 2017. After applying the inclusion and exclusion criteria, a total of 170,701 patients (42,877 in the ADT and non-ADT groups and 127,824 in the non-ADT group) were included in the analysis. To adjust for comorbidities between cohorts, exact matching was performed. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of POAG associated with ADT after controlling for potential confounding factors. RESULTS: In the matched cohort, the ADT group had a lower proportion of newly developed POAG than the non-ADT group (2.10% vs. 2.88%, respectively; P < 0.0001). Multivariable analysis revealed that the ADT group had a significantly lower risk of POAG than the non-ADT group (HR, 0.808; 95% CI, 0.739-0.884; P < 0.0001). The risk of POAG was lower in patients who underwent ADT for less than 2 years (HR, 0.782; 95% CI, 0.690-0.886; P = 0.0001) and in those receiving ADT for over 2 years (HR, 0.825; 95% CI, 0.744-0.916; P = 0.0003) compared with the non-ADT group. CONCLUSIONS: The use of ADT was associated with a decreased risk of POAG in Korean patients with prostate cancer. Our findings suggest that testosterone may be involved in the pathophysiology of POAG, and this should be confirmed through further studies.

Does androgen-deprivation therapy increase the risk of ischemic cardiovascular and cerebrovascular diseases in patients with prostate cancer? A nationwide population-based cohort study.

PURPOSE: We investigated whether ADT use was associated with the risk of ischemic cardiovascular diseases (CVD) and cerebrovascular diseases (CrVD) in a nationwide population-based cohort. METHODS: Claims data of the Health Insurance and Review Assessment system in South Korea were used. In total, 195,308 men with newly diagnosed prostate cancer between January 1, 2008 and December 31, 2017 were identified. After applying the exclusion criteria, 131,189 men were enrolled. The study cohort was divided into ADT and non-ADT groups. Study outcomes were newly developed CVD, cardiovascular intervention (CVI), and CrVD. To control for potential confounders, various cardiovascular risk factors were balanced between groups. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of events. RESULTS: Univariable analysis revealed that ADT was significantly associated with an increased risk of CVD and CrVD. Multivariable analysis did not reveal this association. In the propensity score matched cohort (n = 61,722), multivariable analysis demonstrated that ADT independently reduced the risk of CVD (HR 0.890; 95% CI 0.846-0.936; p < 0.0001), CVI (HR 0.873; 95% CI 0.770-0.991; p = 0.0352), and CrVD (HR 0.869; 95% CI 0.824-0.917; p < 0.0001). CVD risk was significantly decreased in patients using ADT for over 2 years. CVI and CrVD risks were significantly lower in men using ADT for over 3 years. CONCLUSION: This study demonstrated that ADT may reduce the risk of CVD, CVI, and CrVD, and ADT duration is associated with this risk reduction.

External Validation of the Long Short-Term Memory Artificial Neural Network-Based SCaP Survival Calculator for Prediction of Prostate Cancer Survival.

PURPOSE: Decision-making for treatment of newly diagnosed prostate cancer (PCa) is complex due to the multiple initial treatment modalities available. We aimed to externally validate the SCaP (Severance Study Group of Prostate Cancer) Survival Calculator that incorporates a long short-term memory artificial neural network (ANN) model to estimate survival outcomes of PCa according to initial treatment modality. MATERIALS AND METHODS: The validation cohort consisted of clinicopathological data of 4,415 patients diagnosed with biopsy-proven PCa between April 2005 and November 2018 at three institutions. Area under the curves (AUCs) and time-to-event calibration plots were utilized to determine the predictive accuracies of the SCaP Survival Calculator in terms of progression to castration-resistant PCa (CRPC)-free survival, cancer-specific survival (CSS), and overall survival (OS). RESULTS: Excellent discrimination was observed for CRPC-free survival, CSS, and OS outcomes, with AUCs of 0.962, 0.944, and 0.884 for 5-year outcomes and 0.959, 0.928, and 0.854 for 10-year outcomes, respectively. The AUC values were higher for all survival endpoints compared to those of the development cohort. Calibration plots showed that predicted probabilities of 5-year survival endpoints had concordance comparable to those of the observed frequencies. However, calibration performances declined for 10-year predictions with an overall underestimation. CONCLUSION: The SCaP Survival Calculator is a reliable and useful tool for determining the optimal initial treatment modality and for guiding survival predictions for patients with newly diagnosed PCa. Further modifications in the ANN model incorporating cases with more extended follow-up periods are warranted to improve the ANN model for long-term predictions.

2-Hydroxy-4-Methylbenzoic Anhydride Inhibits Neuroinflammation in Cellular and Experimental Animal Models of Parkinson's Disease.

Microglia-mediated neuroinflammation is one of the key mechanisms involved in acute brain injury and chronic neurodegeneration. This study investigated the inhibitory effects of 2-hydroxy-4-methylbenzoic anhydride (HMA), a novel synthetic derivative of HTB (3-hydroxy-4-trifluoromethylbenzoic acid) on neuroinflammation and underlying mechanisms in activated microglia in vitro and an in vivo mouse model of Parkinson's disease (PD). In vitro studies revealed that HMA significantly inhibited lipopolysaccharide (LPS)-stimulated excessive release of nitric oxide (NO) in a concentration dependent manner. In addition, HMA significantly suppressed both inducible NO synthase and cyclooxygenase-2 (COX-2) at the mRNA and protein levels in LPS-stimulated BV-2 microglia cells. Moreover, HMA significantly inhibited the proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in LPS-stimulated BV-2 microglial cells. Furthermore, mechanistic studies ensured that the potent anti-neuroinflammatory effects of HMA (0.1, 1.0, and 10 µM) were mediated by phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) in LPS-stimulated BV-2 cells. In vivo evaluations revealed that intraperitoneal administration of potent neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg, four times a 1 day) in mice resulted in activation of microglia in the brain in association with severe behavioral deficits as assessed using a pole test. However, prevention of microglial activation and attenuation of Parkinson's disease (PD)-like behavioral changes was obtained by oral administration of HMA (30 mg/kg) for 14 days. Considering the overall results, our study showed that HMA exhibited strong anti-neuroinflammatory effects at lower concentrations than its parent compound. Further work is warranted in other animal and genetic models of PD for evaluating the efficacy of HMA to develop a potential therapeutic agent in the treatment of microglia-mediated neuroinflammatory disorders, including PD.