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Computing an element of the Clarke subdifferential of a function represented by a program is an important problem in modern non-smooth optimization. Existing algorithms either are computationally inefficient in the sense that the computational cost depends on the input dimension or can only cover simple programs such as polynomial functions with branches. In this work, we show that a generalization of the latter algorithm can efficiently compute an element of the Clarke subdifferential for programs consisting of analytic functions and linear branches, which can represent various non-smooth functions such as max, absolute values, and piecewise analytic functions with linear boundaries, as well as any program consisting of these functions such as neural networks with non-smooth activation functions. Our algorithm first finds a sequence of branches used for computing the function value at a random perturbation of the input; then, it returns an element of the Clarke subdifferential by running the backward pass of the reverse-mode automatic differentiation following those branches. The computational cost of our algorithm is at most that of the function evaluation multiplied by some constant independent of the input dimension n, if a program consists of piecewise analytic functions defined by linear branches, whose arities and maximum depths of branches are independent of n.

Introduction While studies have extensively examined the clinical and pharmacokinetic correlates of drug-drug interactions (DDIs) with antiretroviral therapy (ART), less is known about DDIs from the perspective of people living with HIV (PLHIV). Among an international sample of PLHIV, we examined experiences, concerns and challenges regarding DDIs. Methods Data came from an international, web-based survey that was conducted among adult PLHIV aged ≥18 years who were receiving ART during 2019 (Positive Perspectives Wave 2, n=2389). Data were analyzed using descriptive statistics and with a special focus on the Asian region comprising participants from China, Taiwan, Japan, and South Korea (n=230). Multivariable analyses were performed using pooled data from all 2389 participants. Statistical significance was at p

The base deficit (B), international normalized ratio (I), and Glasgow coma scale (GCS) (BIG) score is useful in predicting mortality in pediatric trauma patients; however, studies on the use of BIG score in adult patients with trauma are sparse. In addition, studies on the correlation between the BIG score and massive transfusion (MT) have not yet been conducted. This study aimed to evaluate the predictive value of BIG score for mortality and the need for MT in adult trauma patients. This retrospective study used data collected between 2016 and 2020 at our hospital’s trauma center and registry. The predictive value of BIG score was compared with that of the Injury Severity Score (ISS) and Revised Trauma Score (RTS). Logistic regression analysis was carried out to assess whether BIG score was an independent risk factor. Receiver operating characteristic (ROC) curve analysis was performed, and predictive values were evaluated by measuring the area under the ROC curve (AUROC). In total, 5,605 patients were included in this study. In logistic regression analysis, BIG score was independently associated with in-hospital mortality (odds ratio (OR): 1.1859; 95% confidence interval (CI): 1.1636–1.2086) and MT (OR: 1.0802; 95% CI: 1.0609–1.0999). The AUROCs of BIG score for in-hospital mortality and MT were 0.852 (0.842–0.861) and 0.848 (0.838–0.857), respectively. Contrastingly, the AUROCs of ISS and RTS for in-hospital mortality were 0.795 (0.784–0.805) and 0.859 (0.850–0.868), respectively. Moreover, AUROCs of ISS and RTS for MT were 0.812 (0.802–0.822) and 0.838 (0.828–0.848), respectively. The predictive value of BIG score for mortality and MT was significantly higher than that of the ISS. The BIG score also showed a better AUROC for predicting in-hospital mortality compared with RTS. In conclusion, the BIG score is a useful indicator for predicting mortality and the need for MT in adult trauma patients.

For beyond fifth-generation (5G) and future wireless communications, spatial consistency that represents the correlation between propagation channel characteristics in close proximity has become one of the major issues in channel modeling to describe channels more realistically in emerging scenarios such as device-to-device (D2D). In this paper, we propose a novel path loss model based on multi-dimensional Gaussian process regression (GPR) that gives spatial consistency to channels in propagation environment by predicting local shadow fading while fitting large-scale path loss from measured data. The proposed model has a special structure consisting of a radial mean function and a local shadow fading term. In contrast to the log-distance path loss model and other regression-based approaches, the special structure of the proposed model provides good spatial consistency. Moreover, since the proposed model is based on GPR, it provides the uncertainty of the predicted path loss. We validate the performance of the proposed model in terms of prediction accuracy with the measurement datasets from two different indoor environments. Our experiments show that the proposed model predicts better than the log-distance path loss model, especially when spatial correlation gets more significant. The proposed model can be also used to simulate path loss in a general environment after training the measurement data.

Claudin-18.2 (CLDN18.2) is specifically expressed in pancreatic precancerous lesions and pancreatic ductal adenocarcinoma (PDAC). We assessed the clinical characteristics of patients with CLDN18.2-overexpressing pancreatic cancer to identify patients who might benefit from CLDN18-targeted treatment. A total of 130 patients with surgically resected PDAC were investigated for the immunohistochemical expression of claudin-18 (CLDN18). The CLDN18 staining intensities (0–3+) and relative proportion of positive tumor cells were analyzed by two independent raters. Tumors positive for CLDN18 expression were defined as ≥80% of tumor cells with 2+ or 3+ staining intensity in a CLDN18 immunohistochemical assay. Positive CLDN18 expression was present in 41/130 (31.5%) surgically resected PDACs and the relative proportion of positive tumor cells and the staining intensity were directly correlated (p < 0.001). Positive CLDN18 expression was significantly associated with well-differentiated tumors (p < 0.001) and less regional node involvement (p = 0.045). The positive CLDN18-expressing group showed no statistical difference in median overall survival (17.4 months vs. 20.6 months, p = 0.770) compared to the negative CLDN18-expressing group. Distant nodal metastasis was more frequent in the positive CLDN18-expressing group (p = 0.011). CLDN18 is frequently expressed in PDAC, and high CLDN18-expressing PDACs showed some different clinicopathologic characteristics. High CLDN18 expression was not associated with prognosis in patients with surgically resected PDAC.

Purpose: To compare the efficacy and tolerability of mirabegron and solifenacin in pediatric patients with idiopathic overactive bladder (OAB) and to identify factors affecting OAB symptom improvement after treatment. Materials and Methods: We retrospectively reviewed 103 patients (5–15 years old) who visited our hospital with OAB symptoms between July 2017 and March 2019. All participants had received solifenacin or mirabegron. Those who had secondary OAB or who did not complete the frequency-volume chart either before or after treatment were excluded. The age-adjusted bladder capacity ratio was used to evaluate bladder capacity. Efficacy was assessed on the basis of patient reports and changes in the frequency-volume chart, and ≥90% reduction was regarded as “responding to medication.” Tolerability was assessed by obtaining reports from patients about the adverse effects of the drug. Results: After the exclusion of 58 patients, 45 patients (29 in solifenacin-group and 16 in mirabegron-group) were included in the primary analysis. The age-adjusted bladder capacity ratio increased from 0.71 to 0.96 (p

Chronic kidney disease (CKD) is a strong risk factor for cardiovascular disease. An electrocardiogram (ECG) is a basic test for screening cardiovascular disease. However, the impact of ECG abnormalities on cardiovascular prognosis in patients with CKD is largely unknown. A total of 2442 patients with CKD (stages 3–5) who underwent ECG between 2013 and 2015 were selected from the electronic health record database of the Korea University Anam Hospital. ECG abnormalities were defined using the Minnesota classification. The five-year major adverse cerebrocardiovascular event (MACCE), the composite of death, myocardial infarction (MI), and stroke were analyzed. The five-year incidences for MACCE were 27.7%, 20.8%, and 17.2% in patients with no, minor, and major ECG abnormality (p < 0.01). Kaplan–Meier curves also showed the highest incidence of MI, death, and MACCE in patients with major ECG abnormality. Multivariable Cox regression analysis revealed age, sex, diabetes, CKD stage, hsCRP, antipsychotic use, and major ECG abnormality as independent risk predictors for MACCE (adjusted HR of major ECG abnormality: 1.39, 95% CI: 1.09–1.76, p < 01). Among the detailed ECG diagnoses, sinus tachycardia, myocardial ischemia, atrial premature complex, and right axis deviation were proposed as important ECG diagnoses. The accuracy of cardiovascular risk stratification was improved when the ECG results were added to the conventional SCORE model (net reclassification index 0.07). ECG helps to predict future cerebrocardiovascular events in CKD patients. ECG diagnosis can be useful for cardiovascular risk evaluation in CKD patients when applied in addition to the conventional risk stratification model.

Abstract Background Androgen receptor (AR)-targeted treatments improve the survival of castration-resistant prostate cancer (CRPC) patients; however, secondary resistance to these agents ultimately occurs in virtually all patients. Therefore, alternative therapeutic targets are urgently needed. Since growing evidence demonstrates that WNT/β-catenin signaling plays an important role in CRPC, the antitumor activity and mechanism of action of CWP232291, a small molecule β-catenin inhibitor, were investigated in prostate cancer. Methods We assessed the antitumor activity of CWP232291 in prostate cancer cell lines and primary cells derived from CRPC patients. The effect of CWP232291 on apoptotic cell death, endoplasmic reticulum (ER) stress, cell viability, and WNT/β-catenin signaling was evaluated by flow cytometry, western blotting, luciferase reporter assay, and fluorescence microscopy. Antitumor efficacy was assessed in two CRPC xenograft mouse models. Results CWP232291 induced ER stress, resulting in upregulation of the proapoptotic protein CHOP and activation of caspase-3-dependent apoptosis. In addition, CWP232291 suppressed the expression of β-catenin by affecting WNT-dependent transcriptional activity, and downregulated AR and its splice variants in prostate cancer cells. Antitumor activity was observed in prostate cancer cells in vitro and ex vivo, and antitumor efficacy was observed in vivo. Conclusions Beyond providing preclinical evidence of therapeutic efficacy for the novel small molecule β-catenin inhibitor CWP232291 in CRPC, our results show that inducing ER stress and targeting WNT/β-catenin signaling may be a novel strategy against CRPC.

Purpose: The authors performed this study to investigate the risk factors for predicting stent failure and to evaluate its impact on prognosis. Materials and Methods: Between January 2002 and March 2017, we retrospectively reviewed 117 consecutive patients who underwent retrograde ureteral stenting and exchanging at least once every 3 months for malignant ureteral obstruction. The patients were classified according to their pre-stenting chronic kidney disease (CKD) stage. The factors affecting stent failure were analyzed using a logistic regression model. Overall survival (OS) was estimated, and the prognostic significance of each variable was estimated using Cox proportional-hazards regression modeling. Results: Before stenting, 91 patients were CKD stages 1–3 and 26 patients were CKD stages 4–5. These two groups differed significantly only in pre-stenting estimated glomerular filtration rate (eGFR), bilateral obstruction, and pre-stenting pyuria. Among the 117 patients, stent failure occurred in 30 patients (25.6%), and there were no differences between the groups. Pre-stenting pyuria and post-stenting complications were significant predictors of stent failure. There were 79 deaths in total, including 56 in the CKD stages 1–3 group and 23 in the CKD stages 4–5 group. In the multivariate analysis predicting patient OS, pre-stenting eGFR and post-stenting disease progression were significant factors. Conclusions: Internal ureteral stenting was effective for maintaining renal function in malignant ureteral obstruction. However, it did not restore renal function, which is related to the prognosis of the patients. Therefore, to improve patients' renal function and prognosis, patients who require stenting must be quickly recognized and treated.

This study was conducted to investigate the developmental characteristics of adipocytes and to identify selectively white and brown adipocytes through Fourier transform infrared (FTIR) spectroscopy. For the developmental characterization of adipocytes, cells and conditioned media of white and brown adipocytes were respectively collected and analyzed. A higher amide I/amide II ratio was observed in the conditioned medium of brown adipocyte than in that of white adipocyte, indicating differences in secretory protein profiles. In contrast, an amide I/amide II ratio was higher in white adipocytes than in brown adipocytes, and mature adipocytes have higher lipid amounts than pre-adipocytes. Lipid acyl chain length was the longest in white adipocytes. These differences suggested that FTIR spectroscopy can be used to characterize developmental stages and/or types of adipocytes. To identify the possibility of selectively classifying adipose-derived stem cells, FTIR spectroscopy spectra were obtained in cells before/after white/brown adipocyte differentiation using FTIR spectroscopy and then analyzed by the principal component analysis method. All data indicated that the discrimination between adipocytes was possible in the analysis of the infrared spectroscopy spectrum by the principal component analysis technique. This study suggested the possibility of FTIR spectroscopy as a new type of cell sorting system without tagging.

Purpose: We investigated the effects of holmium laser enucleation of the prostate (HoLEP) in patients with a small prostate (≤30 mL) in whom medical treatment was ineffective. Materials and Methods: Data from 132 patients who underwent HoLEP by a single surgeon between 2012 and 2015 were retrospectively analyzed. All patients received benign prostatic hyperplasia medication for at least 6 months before surgery. The patients were divided into 2 groups according to prostate size: group 1, ≤30 mL (n=30); and group 2, ＞30 mL (n=102). Clinical characteristics and the International Prostate Symptom Score (IPSS), including quality of life (QoL), peak urinary flow rate (Qmax), and postvoid residual urine (PVR), before surgery and 3 months postoperatively, were compared between the 2 groups. Results: In group 1, the IPSS, QoL, and PVR significantly decreased and the Qmax significantly increased 3 months after surgery. The voiding subscore also significantly decreased 3 months after surgery (p＜0.001), but the storage subscore was not significantly different (p=0.055). In group 2, hemoglobin, the IPSS, QoL, and PVR significantly decreased and the Qmax significantly increased 3 months after surgery. In these patients, both the storage subscore and voiding subscore significantly decreased after surgery (both p＜0.001). There were no significant differences between the groups in hemoglobin, IPSS, QoL, Qmax, and PVR either before or 3 months after surgery. Conclusions: When other medical treatments are ineffective, HoLEP is an effective intervention for patients with a small prostate.

Purpose: Microsurgical vasovasostomy is associated with high patency and pregnancy rates, but is difficult and requires significant effort and time to learn. Therefore, we assessed a simplified loupe-assisted vasovasostomy method using a Prolene stent. Materials and Methods: The medical records of 82 patients who underwent loupe-assisted vasovasostomy with a Prolene stent by a single surgeon between January 2004 and December 2015 were reviewed. The association between the vasal obstructive interval (VOI) and the success rate was evaluated. Results: The average age at the time of vasovasostomy was 39.8 years (range, 29∼57 years). The mean VOI was 6.6 years (range, 1∼19 years). The mean operation time was 87.0 minutes (range, 55.0∼140.0 minutes). The overall patency and natural pregnancy rates were 90.2% and 45.1%, respectively. The success rate decreased as time after vasectomy increased (odds ratio, 0.869; 95% confidence interval, 0.760∼0.993; p=0.039). The cases were divided into 2 groups according to the mean VOI: group A (＞7 years) and group B (≤7 years), with 31 cases (37.8%) and 51 cases (62.2%), respectively. The patency and pregnancy rates of group A were 80.6% and 51.6%, respectively, while those of group B were 96.1% and 41.2%, respectively. Conclusions: Loupe-assisted vasovasostomy using a Prolene stent is a safe and effective method.

Abstract The simultaneous occurrence of the structural and magnetic phase transitions observed in MnV2O4 is one clear example of strong interplay among the spin, orbital and lattice degrees of freedom. The structure of MnV2O4 is switched by the magnetic field and the linear magnetostriction is very high. The orbital order mediates the interaction between the spin and the lattice generating these phenomena. In this work, we present experimental evidence of an orbital order in MnV2O4 and its reorientation under a rotating magnetic field as obtained by nuclear magnetic resonance(NMR). The shift in the resonance frequency of the V NMR spectrum is symmetrical with respect to 45° as an external magnetic field of 7 T rotates from the c-axis to the b-axis, indicating that the initial easy axis flips to the orthogonal direction most parallel to the field direction. The spectrum of V3+ ions splits into four peaks with a maximum shift of 40 MHz. Our analysis revealed that this is the combined effect of the anisotropic hyperfine field due to an ordered orbital and the dipolar hyperfine field. Reorientation of the orbital order in response to an external magnetic field accompanies the macroscopically observed magnetostriction in MnV2O4.

In the original publication of this article [1], there are mistakes in Fig. 4d. The corrected Fig. 4 should be:

Purpose: The goal of this study was to investigate the association between hypercholesterolemia and the time required for progression to castration-resistant prostate cancer (CRPC) in patients who have undergone androgen deprivation therapy (ADT). Materials and Methods: Data from 154 patients with prostate cancer between 2005 and 2012 were reviewed retrospectively. ADT was employed as a treatment modality for these patients either due to multiple bone metastases at the time of diagnosis or due to old age in combination with other morbidities. Serum cholesterol levels and statin use were reviewed. We analyzed the factors associated with the development of CRPC after ADT treatment. The mean follow-up period was 34.8 months. Results: The mean age of the patients was 71.3 years old and their mean prostate-specific antigen level was 141.8±212.6 ng/mL. Their mean cholesterol level was 175.9±37.7 mg/dL, and 14 patients (9.1%) were statin users. CRPC developed in 44 patients (28.6%), and the mean duration from ADT treatment to CRPC was 24.1 months. In a multivariate analysis, hypercholesterolemia was associated with the development of CRPC (hazard ratio [HR]=1.017, p＜0.001), depending on clinical T stage (p=0.005) and the presence of bone metastasis (p＜0.001). A subanalysis showed that hypercholesterolemia was associated with the development of CRPC in patients with bone metastasis (HR=1.032, p＜0.001), but not in patients without bone metastasis. Conclusions: Hypercholesterolemia may be associated with the development of CRPC after ADT in patients with bone metastasis. Further studies with longer follow-up periods and larger samples are needed to validate this finding.

Urinary incontinence after robot-assisted radical prostatectomy (RARP) is one of the most bothersome complications affecting patients' daily lives. The efficacy of the bladder neck plication stitch technique in promoting an earlier return of continence was prospectively evaluated in 158 patients who underwent RARP for clinically localized prostate cancer by a single surgeon at our institute from March 2012 to January 2013. Patients were randomized 1:1 to undergo surgery with (n = 79) or without (n = 79) the bladder neck plication stitch, and their time to recovery from incontinence, defined as being pad free, was compared. Recovery from incontinence at 1, 3, and 6 months were observed in 22 (27.8%), 42 (53.2%), and 57 (72.2%) patients, respectively, treated with, and 23 (29.1%), 47 (59.5%), and 59 (74.7%) patients, respectively, treated without the bladder neck plication stitch, with no significant difference in time to recovery from incontinence between the two groups. Multivariate analysis showed that age, membranous urethral length and shape of the prostatic apex on magnetic resonance imaging were independent predictors of early recovery from urinary incontinence after RARP. The bladder neck plication stitch had no effect on time to recovery from postoperative urinary incontinence following RARP.