Explaining the Rationale of Deep Learning Glaucoma Decisions with Adversarial Examples.

PURPOSE: To illustrate what is inside the so-called black box of deep learning models (DLMs) so that clinicians can have greater confidence in the conclusions of artificial intelligence by evaluating adversarial explanation on its ability to explain the rationale of DLM decisions for glaucoma and glaucoma-related findings. Adversarial explanation generates adversarial examples (AEs), or images that have been changed to gain or lose pathologic characteristic-specific traits, to explain the DLM's rationale. DESIGN: Evaluation of explanation methods for DLMs. PARTICIPANTS: Health screening participants (n = 1653) at the Seoul National University Hospital Health Promotion Center, Seoul, Republic of Korea. METHODS: We trained DLMs for referable glaucoma (RG), increased cup-to-disc ratio (ICDR), disc rim narrowing (DRN), and retinal nerve fiber layer defect (RNFLD) using 6430 retinal fundus images. Surveys consisting of explanations using AE and gradient-weighted class activation mapping (GradCAM), a conventional heatmap-based explanation method, were generated for 400 pathologic and healthy patient eyes. For each method, board-trained glaucoma specialists rated location explainability, the ability to pinpoint decision-relevant areas in the image, and rationale explainability, the ability to inform the user on the model's reasoning for the decision based on pathologic features. Scores were compared by paired Wilcoxon signed-rank test. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUC), sensitivities, and specificities of DLMs; visualization of clinical pathologic changes of AEs; and survey scores for locational and rationale explainability. RESULTS: The AUCs were 0.90, 0.99, 0.95, and 0.79 and sensitivities were 0.79, 1.00, 0.82, and 0.55 at 0.90 specificity for RG, ICDR, DRN, and RNFLD DLMs, respectively. Generated AEs showed valid clinical feature changes, and survey results for location explainability were 3.94 ± 1.33 and 2.55 ± 1.24 using AEs and GradCAMs, respectively, of a possible maximum score of 5 points. The scores for rationale explainability were 3.97 ± 1.31 and 2.10 ± 1.25 for AEs and GradCAM, respectively. Adversarial example provided significantly better explainability than GradCAM. CONCLUSIONS: Adversarial explanation increased the explainability over GradCAM, a conventional heatmap-based explanation method. Adversarial explanation may help medical professionals understand more clearly the rationale of DLMs when using them for clinical decisions.

Distinct gating mechanism of SOC channel involving STIM-Orai coupling and an intramolecular interaction of Orai in Caenorhabditis elegans.

Store-operated calcium entry (SOCE), an important mechanism of Ca2+ signaling in a wide range of cell types, is mediated by stromal interaction molecule (STIM), which senses the depletion of endoplasmic reticulum Ca2+ stores and binds and activates Orai channels in the plasma membrane. This inside-out mechanism of Ca2+ signaling raises an interesting question about the evolution of SOCE: How did these two proteins existing in different cellular compartments evolve to interact with each other? We investigated the gating mechanism of Caenorhabditis elegans Orai channels. Our analysis revealed a mechanism of Orai gating by STIM binding to the intracellular 2-3 loop of Orai in C. elegans that is radically different from Orai gating by STIM binding to the N and C termini of Orai in mammals. In addition, we found that the conserved hydrophobic amino acids in the 2-3 loop of Orai1 are important for the oligomerization and gating of channels and are regulated via an intramolecular interaction mechanism mediated by the N and C termini of Orai1. This study identifies a previously unknown SOCE mechanism in C. elegans and suggests that, while the STIM-Orai interaction is conserved between invertebrates and mammals, the gating mechanism for Orai channels differs considerably.

Exercise-induced recovery of plasma lipids perturbed by ageing with nanoflow UHPLC-ESI-MS/MS.

Daily physical exercise is an essential part of life and is required for remaining healthy; it enhances therapeutic efficacy in the elderly and prevents age-related diseases associated with lipid profile alterations, such as cardiovascular disease, diabetes mellitus, and dementia. To more efficiently analyse the lipid profiles and unveil the effect of exercise in aged mice, we optimized our study by examining the effects of using ionization modifiers in the mobile phase and in-source fragmentation of lysophospholipids on the simultaneous analysis of fatty acids (FAs) including hydroxyl fatty acids, glycerophospholipids, sphingolipids, and glycerolipids using nanoflow ultrahigh performance liquid chromatography-electrospray ionization-tandem mass spectrometry. We applied the optimization to investigate the lipidomic plasma alterations in young (7 weeks old) and aged (84 weeks old) mice (C57BL/6) subjected to treadmill exercise. Of the 390 identified lipid species, 159 were quantified to investigate ageing-related lipid species responsive to physical exercise. In particular, circulating lysophosphatidylcholine and lysophosphatidylethanolamine levels showed a significant decrease, and lysophosphatidic acid showed a simultaneous increase with ageing. The saturated FA (16:0 and 18:0) increased with ageing while the unsaturated FA 22:6 decreased. Dihydroxy fatty acid (18:1_2OH) showed an exercise-induced recovery against ageing. It is notable that the levels of five triacylglycerol species significantly increased by as much as threefold with ageing, but their levels largely recovered to those observed in the young mice after exercise. These findings can help understand the influence of ageing on lipid perturbation and the role of physical exercise on lipidomic recovery in response to ageing-associated loss of physical status. Graphical abstract.

Sentinel node navigation surgery using near-infrared indocyanine green fluorescence in early gastric cancer.

BACKGROUND: The aim of this study was to evaluate the feasibility of indocyanine green (ICG) fluorescent method for sentinel lymph node detection in early gastric cancer. METHODS: Between December 2012 and December 2014, 28 cases of pilot examination were performed at Seoul National University Bundang Hospital. Advanced version of multispectral fluorescence organoscope was used to identify sentinel node by quantitative estimation of ICG fluorescent signal intensity. Sensitivity, specificity, false positive value were analyzed and compared with dual tracer method. RESULTS: A total of 443 lymph nodes in 28 cases were examined and 184 sentinel nodes (41.5%) were identified by dual tracer method. The sensitivity using near-infrared ICG method was 98.9%. The specificity was 76.0% and false positive rate was 25.4% compared with dual tracer method. The adequate threshold for sentinel node detection was considered as 10% of maximum signal intensity. CONCLUSION: New near-infrared ICG fluorescent method could be a promising protocol for sentinel node navigation surgery in early gastric cancer.

Multispectral autofluorescence imaging for detection of cervical lesions: A preclinical study.

AIM: The aim of this study was to develop a novel optical imaging system for detecting protoporphyrin IX (PpIX) autofluorescence, to prove that PpIX autofluorescence is as useful as 5-aminolevulinic acid (5-ALA)-induced fluorescence for detecting and localizing cervical cancer, and to monitor the change in PpIX autofluorescence or induced PpIX fluorescence before, during, and after photodynamic therapy (PDT). METHODS: TC-1 cells - highly tumorigenic cells immortalized using human papillomavirus type 16 proteins E6 and E7 - were subcutaneously grafted into the thighs of nude mice. The suspected tumor tissues were visualized using autofluorescence imaging and induced fluorescence imaging under 5-ALA administration. When the 5-ALA-induced PpIX was sufficiently accumulated in tumor tissues, PDT was performed using a 635-nm laser. We observed the change in fluorescence intensity during PDT. For 3 weeks after PDT, we monitored tumor remission by using white-light imaging and fluorescence imaging. RESULTS: The transplanted cells were visualized by PpIX autofluorescence, which was induced by heme synthesis. After 5-ALA administration, PpIX could be targeted by using PDT, which decreased PpIX autofluorescence. Photobleaching is useful for monitoring PDT dosimetry and for determining the photodynamic response to therapy. CONCLUSION: PpIX autofluorescence clearly differentiated the tumor from adjacent normal tissues. The results of PpIX autofluorescence imaging and 5-ALA-induced fluorescence imaging were identical. PpIX autofluorescence imaging is a simple and cost-effective cervical cancer screening method that could be performed during or after PDT to ensure effective treatment or remission as a change in fluorescence intensity can be observed in real time without a blinding effect.

Reliability and validity of the Korean version of the Scale for the Assessment of Thought, Language, and Communication.

BACKGROUND: Our study aimed to assess the inter-rater and test-retest reliability, as well as concurrent and convergent validity, of the Korean version of the Scale for the Assessment of Thought, Language, and Communication (TLC scale). METHODS: The factor solutions and psychometric properties of the Korean version of the TLC scale were evaluated among 167 schizophrenia inpatients (study subjects) at two sites in South Korea. Using Pearson's correlation, the concurrent and convergent validities of each of the factor solutions were represented by the correlations with the scores on the Clinical Language Disorder Rating Scale, Brief Psychiatric Rating Scale, Young Mania Rating Scale, and Calgary Depression Scale. Using receiver operating characteristics curves, the optimal cut-off score for the Korean version of the TLC scale to distinguish between study subjects with and without disorganized speech, was identified. RESULTS: The results showed that the Korean version of the TLC scale has a three-factor solution: fluent disorganization, speech emptiness, and speech peculiarity. In addition, the interrater reliability of the Korean version of the TLC scale was moderately good (intraclass correlation coefficient = 0.51) and its test-retest reliability was very good (Pearson's correlation coefficient = 0.94). For detecting the current presence of disorganized speech, the optimal cut-off total score on the TLC scale was proposed to be 8 points (sensitivity = 88.1%; specificity = 82.9%). LIMITATIONS: Psychometric tools covering cognitive functions were not used in our study. CONCLUSIONS: The Korean version of the TLC scale is a promising psychometric method for examining formal thought disorder (FTD) and disorganized speech in schizophrenia patients.

Progressive decrease of N-acetylaspartate to total creatine ratio in the pregenual anterior cingulate cortex in patients with major depressive disorder: longitudinal 1H-MR spectroscopy study.

BACKGROUND: Longitudinal metabolic changes of total choline (tCho), creatine+phosphocreatine (total creatine, tCr), and N-acetylaspartate (NAA) in the pregenual anterior cingulate cortex (pACC) of patients with major depressive disorder (MDD) have not been well evaluated. PURPOSE: To evaluate the longitudinal changes of the metabolic levels of tCho, tCr, and NAA in the pACC of MDD patients and normal controls with the use of Single-voxel (1)HMRS. MATERIAL AND METHODS: Single-voxel (1)HMRS was acquired in the pACC of 21 female patients with MDD and 26 age- and gender-matched controls. Follow-up scans were acquired in 10 patients with MDD and 15 controls after 9-10 months from baseline scans. Absolute concentrations of tCho, tCr, and NAA, and the ratios of NAA/tCr and tCho/tCr were calculated and compared between and within groups. RESULTS: The patient group showed slightly improved clinical symptoms, as measured by Beck's Depression Inventory (P=0.035), after treatment with antidepressants. Comparison of baseline scans between the groups showed no differences in any of the absolute metabolite concentrations or ratios. The NAA/tCr ratio in the pACC of patients with MDD showed a significant decrease in the follow-up scan (P=0.032), and the NAA/tCr ratio of the baseline scan showed logarithmic negative association with illness duration (P=0.024). CONCLUSION: A progressive decrease in the NAA/tCr ratio in the pACC of patients with MDD was demonstrated and the decrease in this ratio was at the highest rate in the early period after illness onset. These findings indicate the neuronal degeneration and dysfunction of the pACC, and the importance of early clinical intervention in female patients with MDD.

Incidence and Risk Factors of Osteonecrosis of the Femoral Head after Cephalomedullary Nailing for Pertrochanteric Fractures: Observational Single-Center Study.

Background: The objective of this study was to investigate the incidence of osteonecrosis of the femoral head (ONFH) after cephalomedullary nailing in elderly patients with pertrochanteric fractures and to analyze the risk factors related to ONFH. Methods: A total of 689 consecutive patients with cephalomedullary nailing for pertrochanteric fractures at our hospital were recruited. Of these, 368 patients who met the inclusion criteria were finally enrolled. ONFH after cephalomedullary nailing was identified by reviewing patients' electronic charts and serial radiographs. The ONFH group was then compared with the non-ONFH group. Results: ONFH was identified in 9 of 368 patients (2.4%). The time to diagnosis of ONFH averaged 23.8 months (range, 5-54 months) after index surgery. The mean age, body mass index, and bone mineral density (T-score in femur neck) were 84.1 ± 7.1 years, 23.7 ± 3.6 kg/m2, and -3.1 ± 0.7 kg/m2, respectively. The times from injury to surgery, from admission to surgery, and operation time averaged 4.2 ± 2.7 days, 3.6 ± 2.6 days, and 87.2 ± 30.0 minutes, respectively. Among 9 patients, 3 underwent conversion arthroplasty. The ONFH group had advanced age (p = 0.029), more basicervical fracture components (p = 0.002), and inadequate reduction (p = 0.045) compared to the non-ONFH group. On multivariate analysis, advanced age (odds ratio [OR], 1.61;, p = 0.022), basicervical fracture components (OR, 24.58; p = 0.001), and inadequate reduction (OR, 4.11; p = 0.039) were identified as risk factors of ONFH. Conclusions: Although ONFH is relatively rare after cephalomedullary nailing for pertrochanteric fractures in elderly patients, its risk may increase with advanced age, basicervical fracture components, and inadequate reduction. Therefore, in patients with these risk factors, meticulous and longer follow-up is needed even after bone union.

Study of operation dynamics for crystal temperature measurement in a diode end-pumped monolithic Yb:YAG laser.

A temperature measurement scheme was proposed in a diode end-pumped thin monolithic Yb:YAG laser by analyzing the red-shifting behaviors of each lasing peak. The amount of peak shift was measured on the basis of the threshold lasing spectrum by using a chopped pump beam. In order to determine the effective scale factor, the ratio between the peak shift and the temperature rise, the dynamics of the spectral shift, the output beam profile, and the output power were investigated. The effective scale factor was determined to be about 0.0114 nm/°C in the case of the crystal sandwiched by copper bocks with a hole, wherein the plane stress approximation is valid. On the other hand, the effective scale factor significantly decreased in the case of the crystal sandwiched by sapphire plates.

Plasma homocysteine level and hepatic sulfur amino acid metabolism in mice fed a high-fat diet.

PURPOSE: Obesity, a feature of metabolic syndrome, is a risk factor for cardiovascular disease, and elevated plasma homocysteine is associated with increased cardiovascular risk. However, little published information is available concerning the effect of obesity on homocysteine metabolism. METHODS: Hepatic homocysteine metabolism was determined in male C57BL/6 mice fed a high-fat diet for 12 weeks. RESULTS: High-fat diet increased plasma homocysteine but decreased hepatic homocysteine levels. Hepatic S-adenosylhomocysteine hydrolase levels were down-regulated in the obese mice, which was in part responsible for the decrease in hepatic S-adenosylmethionine/S-adenosylhomocysteine, which served as an index of transmethylation potential. Despite the decrease in hepatic cysteine, hepatic taurine synthesis was activated via up-regulation of cysteine dioxygenase. Hepatic levels of methionine adenosyltransferase I/III, methionine synthase, methylene tetrahydrofolate reductase, and gamma-glutamylcysteine ligase catalytic subunit were unchanged. Obese mice showed elevated betaine-homocysteine methyltransferase and decreased cystathionine beta-synthase activities, although the quantities of these enzymes were unchanged. CONCLUSION: This study suggests that plasma homocysteine level is increased in obesity-associated hepatic steatosis, possibly as a result of increased hepatic homocysteine efflux along with an altered sulfur amino acid metabolism.

Brain volumetry in Parkinson's disease with and without dementia: where are the differences?

BACKGROUND: Cognitive dysfunction is well documented in Parkinson's disease (PD). However, association between regional brain volume change and cognitive decline of PD is uncertain. PURPOSE: To compare regional brain volume difference between PD without dementia (PDND) and PD with dementia (PDD). MATERIAL AND METHODS: We enrolled 16 normal controls (mean ± SD: 69.5 ± 6.31) and 32 sex-, age-matched patients with PD (16 PDND and 16 PDD patients with Hoehn & Yahr stage II or III). Cognitive function was assessed using mini-mental status examination (MMSE). Intracranial volume (ICV) and the hippocampal volumes were manually measured using magnetic resonance imaging (MRI). Regional gray/white matter volume changes were analyzed using voxel-based morphometry. RESULTS: Age, ICV, volume of gray matter volume (GMV), white matter, and hippocampi did not differ among the three groups. The regional GMV of PDD was significantly decreased in the areas of right middle frontal gyrus, short insular gyri, superior temporal gyri; both precuneus compared to PDND (uncorrected P < 0.001). In the partial correlation analysis (controlled for age, sex, ICV), regional GMV of PD was positively correlated with MMSE score in the areas of short insular gyri, right circular insular sulcus, right calcarine sulcus, left superior temporal gyrus (planum porale), and left inferior precentral sulcus (uncorrected P < 0.001). CONCLUSION: We suggest that the volume loss of hippocampus may not be a finding in developing of PDD while variation of the regional volume of the frontal, insular cortex, superior temporal gyri, and precuneus lobes may be a phenomenon of PDD.

Clonazepam quiets tinnitus: a randomised crossover study with Ginkgo biloba.

OBJECTIVE: To assess the effect of Ginkgo biloba and clonazepam, a γ-aminobutyric acid (GABA)-receptor agonist, upon tinnitus. METHODS: This was an open-label, randomised, crossover study. 27 men and 11 women (aged 16-80 (mean 58)) with tinnitus for more than 2 months were enrolled. Participants were randomised to either clonazepam or G biloba for the first 3 weeks. For the next 2 weeks of washout no medication was taken. For the final 3 weeks, subjects were given the other drug. The initial dose of clonazepam and G biloba was one tablet daily (clonazepam 0.5 mg; G biloba 40 mg). Subjects were instructed to increase the dose by one tablet every 3 days to a maximum of four tablets daily until they perceived a satisfactory decrease in tinnitus loudness or intolerable side effects. Tinnitus was assessed with pitch and loudness matching, tinnitus handicap inventory, and visual analogue scales of loudness, duration and annoyance. RESULTS: Comparing before and after each drug, clonazepam significantly improved tinnitus loudness (74% of subjects), duration (63%), annoyance (79%), and tinnitus handicap inventory score (61%), whereas the G biloba showed no significant differences on any of these measures. CONCLUSION: Clonazepam is effective in treating tinnitus; G biloba is ineffective.

Expression of hepatic and ovarian cytochrome P450 during estrous cycle in rats.

It is known that gender differences in drug metabolism are largely attributed to changes in sex and growth hormones. Serum concentrations of estradiol, progesterone, prolactin, follicle-stimulating hormone, and luteinizing hormone change markedly during the human menstrual cycle and the rat estrous cycle. However, little information is available regarding the effects of the human menstrual cycle or the rat estrous cycle on expression and activity of cytochrome P450 (CYP) isoforms. The present study was carried out to determine the expression and activity of CYP-dependent drug-metabolizing enzymes in the liver and ovary during the estrous cycle. The expression and activity of microsomal CYP isoforms (CYP1A1, CYP1A2, CYP1B1, CYP2B1, CYP2C11, CYP2C12, CYP2E1, CYP3A1, CYP3A2, and CYP4A), cytochrome b(5) and NADPH-dependent CYP reductase in the liver and ovary were measured in female rats in diestrus and proestrus. Our results indicated that hepatic and ovarian expression and activity of CYP isoforms, cytochrome b(5), and NADPH-dependent CYP reductase were not different between diestrus and proestrus, although serum estradiol concentration and uterus weight were markedly increased in the proestrus phase. These results suggest that the cytochrome P450-dependent system is not sensitive to changes in the estrous cycle, and further studies are warranted to determine the effects of the estrous cycle on in vivo metabolism of xenobiotics.

Analysis of the Incidence and Risk Factors of Postoperative Delirium in Patients With Degenerative Cervical Myelopathy.

OBJECTIVE: The purpose of this study is to analyze various risk factors that can cause postoperative delirium (POD) in degenerative cervical myelopathy (DCM) patients, which may affect normal recovery and outcomes after surgery, and to help deal with them in advance and to take a medical approach. METHODS: A total of 148 patients aged 60 years or older who underwent laminoplasty or anterior cervical discectomy and fusion (ACDF) for DCM from 2008 to 2015 were included in this study. Incidence and multiple risk factors for development of POD were analyzed. RESULTS: POD occurred in 24 patients (16.2%). Among the 148 patients, 78 received laminoplasty, of whom 19 patients (24%) experienced delirium; the other 70 patients underwent ACDF, of whom 5 patients (7.1%) experienced delirium. History of Parkinson disease (odds ratio [OR], 178.242; p = 0.015), potassium level (OR, 3.764; p = 0.031), and surgical approach of laminoplasty over ACDF (OR, 8.538; p = 0.008) were found to be significant risk factors in a multivariate analysis. Age (OR, 1.056; p = 0.04) and potassium level (OR, 3.217; p = 0.04) were significant risk factors in the laminoplasty group. CONCLUSION: The findings of this study suggest that the incidence and risk factors for POD may vary in patients with DCM. It is necessary to understand multiple factors that affect the development of POD.

Simultaneous reduction and fixation using an anatomical suprapectineal quadrilateral surface plate through modified Stoppa approach in superomedially displaced acetabular fractures.

Treatment of superomedially displaced acetabular fractures including a quadrilateral surface (QLS) is challenging. We present a surgical technique using an anatomical suprapectineal QLS plate through the modified Stoppa approach and report the availability of this plate to treat this fracture type along with the surgical outcomes. Sixteen consecutive patients (14 men and 2 women) who underwent surgical treatment using an anatomical suprapectineal QLS plate through a modified Stoppa approach for superomedially displaced acetabular fractures between June 2018 and June 2020, were enrolled retrospectively. These fractures included 11 both-column fractures and 5 anterior-column and posterior hemitransverse fractures, which were confirmed on preoperative 3-dimensional computed tomography. Surgical outcomes were clinically assessed using the Postel Merle d'Aubigné (PMA) score and visual analog scale (VAS) score at the final follow-up, and radiological evaluations were performed immediately after the operation and at the final follow-up. For comparative analysis, 23 patients who underwent internal fixation with the conventional reconstruction plate through modified ilioinguinal approach between February 2010 and May 2018, were selected. This control group was composed of 18 both-column fractures and 5 anterior-column and posterior hemitransverse fractures. The follow-up period was at least 1 year in all patients. The mean operation time and blood loss was 109 min, and 853 ml, respectively, whereas 236 min, and 1843 ml in control group. Anatomical reduction was achieved in 14 (87.5%) patients, while imperfect reduction was achieved in the remaining 2 patients. At the final follow-up, radiographic grades were excellent, fair, and poor in 14 patients (87.5%), one, and one, respectively. The mean PMA score was 16.1 (range 13-18) and the mean VAS score was 1.0 (range 0-3). No secondary reduction loss or implant loosening was observed. However, 2 patients underwent conversion to total hip arthroplasty (THA) due to post-traumatic arthritis and subsequent joint pain. No other complications were observed. In the comparative analysis, radiological outcome showed a significant relationship with the conversion to THA (p = 0.013). Shorter operation time and less blood loss were significantly observed in the QLS plate fixation group through the modified Stoppa approach compared with the conventional reconstruction plate fixation group through modified ilioinguinal approach (p < 0.001, respectively). Simultaneous reduction and fixation using an anatomical suprapectineal QLS plate through the modified Stoppa approach may be a viable technique in superomedially displaced acetabular fractures along with shorter operation time and less blood loss.

Implementation of a Skull-Conformal Phased Array for Transcranial Focused Ultrasound Therapy.

OBJECTIVE: To implement a skull-conformal phased array for ultrasound-guided transcranial focused ultrasound therapy with improved patient comfort. METHODS: Using patient-specific computed tomography and MRI neuroimaging data, tightly-conforming helmet scaffolds were designed computationally. The helmet scaffolds were designed to hold reusable transducer modules at near-normal incidence in an optimal configuration for the treatment location(s) of interest. Numerical simulations of trans-skull ultrasound propagation were performed to evaluate different conformal array designs and to compare with hemispherical arrays similar to those employed clinically. A 4096-element phased array was constructed by 3D printing a helmet scaffold optimised for an ex vivo human skullcap, and its performance was evaluated via benchtop and in vivo experiments. RESULTS: Acoustic field measurements confirmed the system's ability to focus through human skull bone using simulation-based transcranial aberration corrections. Preliminary in vivo testing demonstrated safe trans-human skull blood-brain barrier (BBB) opening in rodents. CONCLUSION: Patient-specific conformal ultrasound phased arrays appear to be a feasible and safe approach for conducting transcranial BBB opening procedures. SIGNIFICANCE: Skull-conformal phased arrays stand to improve patient comfort and have the potential to accelerate the adoption of transcranial FUS therapy by improving access to the technology.

Age-related changes in hepatic expression and activity of cytochrome P450 in male rats.

Age-related changes in hepatic expression and activity of cytochrome P450 (CYP) were investigated in male rats aged 3 (weanling), 12 (young), 26 (adult), and 104 (old) weeks. Levels of microsomal protein, total CYP, and cytochrome b(5) increased fully after puberty. CYP1A1 was detected only in 3-week-old rats, and CYP1A2, CYP2B1, and CYP2E1 were maximally expressed at 3 weeks but decreased at 12 and 26 weeks. CYP2C11 and CYP3A2 increased markedly after puberty and decreased with aging. Ethoxyresorufin-O-deethylase, methoxyresorufin-O-demethylase, pentoxyresorufin-O-depenthylase, and p-nitrophenol hydroxylase activities were at their highest in 3-week-old rats, and midazolam hydroxylase activity was at a maximum in 12-week-old rats but decreased with aging. The present results show that increasing age caused significant alterations in hepatic expression/activity of CYP isoforms in an isoform-specific manner. These results suggest that age-related changes in hepatic CYP isoforms may be an important factor for deciding the efficacy and safety of xenobiotics.

Development of an Improved Menopausal Symptom-Alleviating Licorice (Glycyrrhiza uralensis) by Biotransformation Using Monascus albidulus.

Licorice (Glycyrrhiza uralensis) contains several compounds that have been reported to alleviate menopausal symptoms via interacting with estrogen receptors (ERs). The compounds exist mainly in the form of glycosides, which exhibit low bioavailability and function. To bioconvert liquiritin and isoliquiritin, the major estrogenic compounds, to the corresponding deglycosylated liquiritigenin and isoliquiritigenin, respectively, licorice was fermented with Monascus, which has been demonstrated to deglycosylate other substances. The contents of liquiritigenin and isoliquiritigenin in Monascus-fermented licorice increased by 10.46-fold (from 38.03 µM to 379.75 µM) and 12.50-fold (from 5.53 µM to 69.14 µM), respectively, compared with their contents in non-fermented licorice. Monascus-fermented licorice exhibited 82.5% of the ERß binding activity of that observed in the positive control (17 ß-estradiol), whereas the non-fermented licorice exhibited 54.1% of the binding activity in an in vivo ER binding assay. The increase in the ERß binding activity was associated with increases in liquiritigenin and isoliquiritigenin contents. Liquiritigenin acts as a selective ligand for ERß, which alleviates menopausal symptoms with fewer side effects, such as heart disease and hypertension, compared with a ligand for ERα. In addition, Monascus-fermented licorice contained 731 mg/kg of monacolin K, one of the metabolites produced by Monascus that reduces serum cholesterol. Therefore, Monascus-fermented licorice is a promising material for the prevention and treatment of menopausal syndrome with fewer side effects.

Factors Associated with Burnout among Healthcare Workers during an Outbreak of MERS.

OBJECTIVE: Although healthcare workers (HCWs) experienced significant stress during the 2015 outbreak of Middle East Respiratory Syndrome (MERS), the factors associated with this stress remain unknown. Thus, the present study assessed burnout among HCWs during the MERS outbreak to identify the influential factors involved in this process. METHODS: This study was a retrospective chart review of the psychological tests and questionnaires completed by 171 hospital employees from two general hospitals that treated MERS patients. The tests included the Oldenburg Burnout Inventory, Positive Resources Test, the questionnaires assessed exposure to the MERS outbreak event and perceptions about MERS. RESULTS: Of the 171 HCWs, 112 (65.5%) experienced disengagement and 136 (79.5%) suffered from exhaustion. Disengagement was associated with lower levels of purpose and hope, a higher perception of job risk, and exposure to the media. Exhaustion was associated with lower levels of purpose and hope, a higher perception of little control of the infection, a higher perception of job risk, prior experience related to infections, and being female. CONCLUSION: Our results revealed the risk and protective factors associated with burnout among HCWs during an outbreak of MERS. These findings should be considered when determining interventional strategies aimed at ameliorating burnout among HCWs.

Association of Cardiovascular Mortality and Deep Learning-Funduscopic Atherosclerosis Score derived from Retinal Fundus Images.

PURPOSE: The prediction of atherosclerosis using retinal fundus images and deep learning has not been shown possible. The purpose of this study was to develop a deep learning model which predicted atherosclerosis by using retinal fundus images and to verify its clinical implications by conducting a retrospective cohort analysis. DESIGN: Retrospective cohort study. METHODS: The database at the Health Promotion Center of Seoul National University Hospital (HPC-SNUH) was used. The deep learning model was trained using 15,408 images to predict carotid artery atherosclerosis, which was named the deep-learning funduscopic atherosclerosis score (DL-FAS). A retrospective cohort was constructed of participants 30-80 years old who had completed elective health examinations at HPC-SNUH. Using DL-FAS as the main exposure, participants were followed for the primary outcome of death due to CVD until Dec. 31, 2017. RESULTS: For predicting carotid artery atherosclerosis among subjects, the model achieved an area under receiver operating curve (AUROC) and area under the precision-recall curve (AUPRC), accuracy, sensitivity, specificity, positive and negative predictive values of 0.713, 0.569, 0.583, 0.891, 0.404, 0.465, and 0.865 respectively. The cohort consisted of 32,227 participants, 78 cardiovascular disease (CVD) deaths, and 7.6-year median follow-up visits. Those with DL-FAS greater than 0.66 had an increased risk of CVD deaths compared to those with DL-FAS <0.33 (hazard ratio: 8.33; 95% confidence interval [CI], 3.16-24.7). Risk association was significant among intermediate and high Framingham risk score (FRS) subgroups. The DL-FAS improved the concordance by 0.0266 (95% CI, 0.0043-0.0489) over the FRS-only model. The relative integrated discrimination index was 20.45% and net reclassification index was 29.5%. CONCLUSIONS: A deep learning model was developed which could predict atherosclerosis from retinal fundus images. The resulting DL-FAS was an independent predictor of CVD deaths when adjusted for FRS and added predictive value over FRS.