Absolute risk from double nested case-control designs: cause-specific proportional hazards models with and without augmented estimating equations.

We estimate relative hazards and absolute risks (or cumulative incidence or crude risk) under cause-specific proportional hazards models for competing risks from double nested case-control (DNCC) data. In the DNCC design, controls are time-matched not only to cases from the cause of primary interest, but also to cases from competing risks (the phase-two sample). Complete covariate data are available in the phase-two sample, but other cohort members only have information on survival outcomes and some covariates. Design-weighted estimators use inverse sampling probabilities computed from Samuelsen-type calculations for DNCC. To take advantage of additional information available on all cohort members, we augment the estimating equations with a term that is unbiased for zero but improves the efficiency of estimates from the cause-specific proportional hazards model. We establish the asymptotic properties of the proposed estimators, including the estimator of absolute risk, and derive consistent variance estimators. We show that augmented design-weighted estimators are more efficient than design-weighted estimators. Through simulations, we show that the proposed asymptotic methods yield nominal operating characteristics in practical sample sizes. We illustrate the methods using prostate cancer mortality data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Study of the National Cancer Institute.

Dental Students' Satisfaction With Web-Based Learning During the Initial Phase of the COVID-19 Pandemic: Mixed Methods Study.

BACKGROUND: The COVID-19 pandemic has precipitated an accelerated shift in education, moving from traditional learning to web-based learning. This transition introduced a notable transactional distance (TD) between the instructors and learners. Although disease control and staff and students' safety are the top priorities during a pandemic, the successful delivery of education is equally crucial. However, the ramifications of this swift transition are particularly critical in the context of dental education. Dental education is inherently practice oriented, necessitating hands-on training and manual skills development, which poses unique challenges to distance learning approaches. OBJECTIVE: This study aims to examine dental students' web-based learning satisfaction and experience of TD, investigate the predictors of web-based learning satisfaction, and explore the perceptions of students about the advantages and disadvantages of web-based learning. METHODS: This study explored the factors associated with web-based learning satisfaction using TD theory during the transition to web-based education. Psychological factors that could influence satisfaction were adapted from the health belief model. We conducted a cross-sectional web-based survey of 345 dental students from 2 institutions in South Korea who were enrolled in the spring semester of 2020. Data were collected between July 8 and September 14, 2020. Qualitative analysis was used to examine responses to open-ended questions concerning perceptions of web-based learning. RESULTS: A multivariate hierarchical linear regression model was used to analyze the effects of student characteristics, TD, and psychological factors (ie, perceived risk of infection and efficacy belief of web-based learning) on web-based learning satisfaction. The average score for web-based learning satisfaction was 3.62 (SD 0.84), just above the midpoint of the possible range (1-5). Self-regulated learning (ß=0.08; P=.046), learner-instructor interaction (ß=0.08; P=.03), and learner-content interaction (ß=0.64; P<.001) were associated with higher levels of satisfaction. Moreover, a significant association was revealed between high efficacy beliefs in web-based learning (ß=0.20; P<.001) and satisfaction. Although the learning structure (synchronous vs asynchronous) did not exhibit a significant association with satisfaction, the qualitative analysis results revealed that each structure possesses distinct strengths and weaknesses. The students in synchronous learning (79/345, 22.9%) recognized heightened autonomy in the "learning environment" (19/79, 24%); however, technical issues (28/79, 35%) and reduced concentration (15/79, 19%) were identified as downsides. Conversely, the students in asynchronous settings (266/345, 77.1%) emphasized unlimited access to learning content (74/266, 27.8%) and the flexibility of "learning in preferred time" (69/266, 25.9%). Nevertheless, challenges, such as self-management difficulties (66/266, 24.8%) and limited interactions (55/266, 20.7%), were evident. CONCLUSIONS: The findings suggest that efforts to minimize TD, facilitating self-regulated learning and interaction among students and instructors, are critical for achieving web-based learning satisfaction. Moreover, establishing a common understanding among students regarding the necessity and efficacy of web-based learning during epidemics could enhance their satisfaction.

A Single-Arm, Open-Label Phase II Study of ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma.

BACKGROUND: ONC201 is a small molecule that can cause nonapoptotic cell death through loss of mitochondrial function. Results from the phase I/II trials of ONC201 in patients with refractory solid tumors demonstrated tumor responses and prolonged stable disease in some patients. METHODS: This single-arm, open-label, phase II clinical trial evaluated the efficacy of ONC201 at the recommended phase II dose (RP2D) in patients with recurrent or refractory metastatic breast or endometrial cancer. Fresh tissue biopsies and blood were collected at baseline and at cycle 2 day 2 for correlative studies. RESULTS: Twenty-two patients were enrolled; 10 patients with endometrial cancer, 7 patients with hormone receptor-positive breast cancer, and 5 patients with triple-negative breast cancer. The overall response rate was 0%, and the clinical benefit rate, defined by complete response (CR) + partial response (PR) + stable disease (SD), was 27% (n = 3/11). All patients experienced an adverse event (AE), which was primarily low grade. Grade 3 AEs occurred in 4 patients; no grade 4 AEs occurred. Tumor biopsies did not show that ONC201 consistently induced mitochondrial damage or alterations in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the TRAIL death receptors. ONC201 treatment caused alterations in peripheral immune cell subsets. CONCLUSION: ONC201 monotherapy did not induce objective responses in recurrent or refractory metastatic breast or endometrial cancer at the RP2D dose of 625 mg weekly but had an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03394027).

LiBis: an ultrasensitive alignment augmentation for low-input bisulfite sequencing.

The cell-free DNA (cfDNA) methylation profile in liquid biopsy has been utilized to diagnose early-stage disease and estimate therapy response. However, typical clinical procedures are capable of purifying only very small amounts of cfDNA. Whole-genome bisulfite sequencing (WGBS) is the gold standard for measuring DNA methylation; however, WGBS using small amounts of fragmented DNA introduces a critical challenge for data analysis, namely a low-mapping ratio. The resulting low sequencing depth and low coverage of CpG sites genome-wide is a bottleneck for the clinical application of cfDNA-based WGBS assays. We developed LiBis (Low-input Bisulfite Sequencing), a novel method for low-input WGBS data alignment. By dynamically clipping initially unmapped reads and remapping clipped fragments, we judiciously rescued those reads and uniquely aligned them to the genome. By substantially increasing the mapping ratio by up to 88%, LiBis dramatically improved the number of informative CpGs and the precision in quantifying the methylation status of individual CpG sites. LiBis significantly improved the cost efficiency of low-input WGBS experiments by dynamically removing contamination introduced by random priming. The high sensitivity and cost effectiveness afforded by LiBis for low-input samples will allow the discovery of genetic and epigenetic features suitable for downstream analysis and biomarker identification using liquid biopsy.

Ten-Eleven Translocation Ablation Impairs Cardiac Differentiation of Mouse Embryonic Stem Cells.

Ten-eleven Translocation (TET) dioxygenases mediated DNA methylation oxidation plays an important role in regulating the embryonic stem cells (ESCs) differentiation. Herein, we utilized a CRISPR/Cas9 based genome editing method to generate single, double, and triple Tet-deficient mouse ESCs (mESCs) and differentiated these cells toward cardiac progenitors. By using emerald green fluorescent protein (GFP; emGFP) expression under the control of Nkx2.5 promoter as marker for cardiac progenitor cells, we discovered that Tet1 and Tet2 depletion significantly impaired mESC-to-cardiac progenitor differentiation. Single-cell RNA-seq analysis further revealed that Tet deletion resulted in the accumulation of mesoderm progenitors to hamper cardiac differentiation. Re-expression of the Tet1 catalytic domain (Tet1CD) rescued the differentiation defect in Tet-triple knockout mESCs. Dead Cas9 (dCas9)-Tet1CD mediated loci-specific epigenome editing at the Hand1 loci validated the direct involvement of Tet-mediated epigenetic modifications in transcriptional regulation during cardiac differentiation. Our study establishes that Tet-mediated epigenetic remodeling is essential for maintaining proper transcriptional outputs to safeguard mESC-to-cardiac progenitor differentiation.

Efficacy and exploratory biomarker analysis of entinostat plus exemestane in advanced or recurrent breast cancer: phase II randomized controlled trial.

BACKGROUND: We aimed to confirm the efficacy and safety of the oral histone deacetylase inhibitor entinostat in Japanese patients with hormone receptor-positive advanced/recurrent breast cancer and to explore potential biomarkers. METHODS: This phase II, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov; NCT03291886) was conducted at 28 Japanese sites (September 2017-July 2020; interim analysis cutoff: April 2019). Patients with progression/relapse following non-steroidal aromatase inhibitors were randomized 1:1 to entinostat (5 mg/week) or placebo, plus exemestane (25 mg/day). Primary endpoint was progression-free survival; secondary endpoints included overall survival and safety. Exploratory biomarker outcomes included lysine acetylation, immune cell profiles, estrogen receptor 1 mutations and plasma chemokines. RESULTS: Of 133 randomized patients, 131 (65 entinostat, 66 placebo) who received study drug were analyzed. Median (95% confidence interval) progression-free survival was 5.8 (3.2-7.8) months for entinostat and 3.3 (3.1-5.8) months for placebo (hazard ratio [95% confidence interval]: 0.75 [0.50 - 1.14]; P = 0.189). Median overall survival was not reached in either group. Entinostat tended to prolong progression-free survival in patients aged ≥65 years, not endocrine resistant, or with estrogen receptor 1 Y537S mutation. Candidate biomarkers of efficacy (progression-free survival) included lysine acetylation in CD3+ cells, plasma interferon gamma-induced protein 10, dendritic cell CD86 expression, and CD4+ cell expression of human leukocyte antigen-DR and inducible T-cell co-stimulator. Safety was similar to non-Japanese populations; however, seven entinostat-treated patients (10.8%) had reversible lung injury. CONCLUSIONS: In Japanese patients, the safety of entinostat plus exemestane was acceptable and progression-free survival was prolonged, although not significantly. Exploratory analyses identified potential biomarkers, including lysine acetylation, of efficacy.

Comparing the Effect of Declarative vs. Procedural Knowledge on Health Behavior Moderated by Outrage Factors.

Knowledge's effect on behavioral responses in a health crisis has been a point of inquiry in many empirical studies that obtained significant findings. However, a variety of knowledge types has been considered in these studies rarely. This study compared the effect of declarative vs. procedural knowledge on behavioral responses to the COVID-19 pandemic. In addition, we examined whether outrage factors, which refer to perceived risk characteristics that are likely to elicit emotional responses, can moderate cognitive knowledge's effect. Data were collected with a survey conducted five months after the first COVID-19 case was confirmed in South Korea. A total of 1,000 respondents completed questions on the two types of knowledge, risk perception, and health behaviors in the pandemic crisis, and three different outrage factors. The results showed that procedural knowledge on how-to-do something was associated significantly with the health behaviors in the crisis, while the declarative knowledge that involves knowing that "something is the case" was not. Further, the outrage factors moderated knowledge's effect in such a way that procedural knowledge's influence on health behaviors diminished when the respondents perceived that the pandemic was uncontrollable. On the other hand, procedural knowledge's effect increased when the outrage factor of fairness was heightened. The implications are discussed in the context of studies of knowledge's effect and the outrage factors' moderation.

The Outrage Effect of Personal Stake, Effect on Children, Dread, and Controllability on COVID-19 Risk Perception Moderated by Media Use.

Public response to the COVID-19 pandemic provides a unique opportunity to study how lay people's risk perception involves their emotive responses. We investigated how outrage factors as emotional responses to risk influence levels of risk perception in the context of the pandemic disease. Furthermore, how media use influences the perception of outrage factors is also examined. A nationwide online survey (n = 1,000) was conducted in South Korea. The survey results indicated that pandemic risk perception was connected to the generic intensity of perceived outrage factors as measured by averaging the perception of multiple outrage factors. Individual outrage factors such as personal stake, effect on children, dread, and controllability directly influenced risk perception regarding COVID-19. When the intensity of media use was considered, individuals with heavy media use perceived outrage factors more intensely than those who used media less frequently. Media use also moderated the outrage effect of catastrophic potential and moral nature on the perception of risk associated with the pandemic disease. For heavy media users, the outrage effect of moral nature was increased, while that of catastrophic potential decreased. The implications of the outrage effect on the pandemic disease risk perception are addressed. Finally, we discuss the meaning of heavy media users' varying levels of vulnerability to outrage effect by moral nature and catastrophic potential.

Dentists' attitudes toward patient-centered care and its predictors: a cross-sectional study in South Korea.

BACKGROUND: Patient-centered care (PCC) has been one of medical practice's most frequently discussed principles. However, attitudes toward PCC among dentists remain underexplored. This study focuses on examining dentists' patient-centered attitudes and investigating their predictors. METHODS: The Patient-Practitioner Orientation Scale which consists of Sharing and Caring subscales was used to assess patient-centered attitudes. The statistical analysis included 217 dentists from South Korea. Hierarchical linear regression analysis was performed to examine the predictors such as sociodemographic aspects, academic factors, work-related factors, and empathy. RESULTS: A patient-centered attitude of Caring subscale (M = 4.29, SD = 0.56) emerged, but the provider-centered attitude was higher in Sharing subscale (M = 3.40, SD = 0.48). Work year, academic track, and empathy were associated significantly with an overall caring aspect of patient-centered attitude, while the gender effect remained insignificant. Empathy had a critical and significant impact on the patient-centered attitude. CONCLUSIONS: Efforts to enhance patient-centeredness in Sharing are needed; post-graduate education and transition to a more patient-centered health system are recommended. Moreover, empathy still matters as it was found to be a significant predictor of patient-centered attitudes. The findings of this study support the need for efforts to enhance patient-centered attitudes among dentists, which will help generate discussion on improving the curriculum of post-graduate education and health system reform.

Competing risks predictions with different time scales under the additive risk model.

In the analysis for competing risks data, regression modeling of the cause-specific hazard functions has been usually conducted using the same time scale for all event types. However, when the true time scale is different for each event type, it would be appropriate to specify regression models for the cause-specific hazards on different time scales for different event types. Often, the proportional hazards model has been used for regression modeling of the cause-specific hazard functions. However, the proportionality assumption may not be appropriate in practice. In this article, we consider the additive risk model as an alternative to the proportional hazards model. We propose predictions of the cumulative incidence functions under the cause-specific additive risk models employing different time scales for different event types. We establish the consistency and asymptotic normality of the predicted cumulative incidence functions under the cause-specific additive risk models specified on different time scales using empirical processes and derive consistent variance estimators of the predicted cumulative incidence functions. Through simulation studies, we show that the proposed prediction methods perform well. We illustrate the methods using stage III breast cancer data obtained from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute.

Asymmetric Hsp90 N domain SUMOylation recruits Aha1 and ATP-competitive inhibitors.

The stability and activity of numerous signaling proteins in both normal and cancer cells depends on the dimeric molecular chaperone heat shock protein 90 (Hsp90). Hsp90's function is coupled to ATP binding and hydrolysis and requires a series of conformational changes that are regulated by cochaperones and numerous posttranslational modifications (PTMs). SUMOylation is one of the least-understood Hsp90 PTMs. Here, we show that asymmetric SUMOylation of a conserved lysine residue in the N domain of both yeast (K178) and human (K191) Hsp90 facilitates both recruitment of the adenosine triphosphatase (ATPase)-activating cochaperone Aha1 and, unexpectedly, the binding of Hsp90 inhibitors, suggesting that these drugs associate preferentially with Hsp90 proteins that are actively engaged in the chaperone cycle. Importantly, cellular transformation is accompanied by elevated steady-state N domain SUMOylation, and increased Hsp90 SUMOylation sensitizes yeast and mammalian cells to Hsp90 inhibitors, providing a mechanism to explain the sensitivity of cancer cells to these drugs.

Direct and Indirect Associations of Media Use With COVID-19 Vaccine Hesitancy in South Korea: Cross-sectional Web-Based Survey.

BACKGROUND: The battle against the 2019 novel coronavirus (COVID-19) has not concluded. Despite the availability of vaccines, the high prevalence of vaccine hesitancy represents a significant challenge to public health, and raising vaccine acceptance among the public is critical. Although media has become an increasingly popular source of COVID-19 vaccine-related information, the question of whether and how media use is related to the public's vaccine hesitancy warrants exploration. OBJECTIVE: This study aimed to (1) examine the level of COVID-19 vaccine hesitancy, (2) identify factors associated with COVID-19 vaccine hesitancy, and (3) explore the direct and indirect relationship between media use and vaccine hesitancy through psychological factors. METHODS: A month before COVID-19 vaccination was initiated in South Korea, we conducted a cross-sectional web-based survey over 6 days (January 20-25, 2021). This study included 1016 participants, and a logit model for regression analyzed associations between sociodemographic factors, health-related factors, psychological factors, and media use toward one's COVID-19 vaccine hesitancy. Additionally, we conducted a path analysis to examine the indirect effects of media use on vaccine hesitancy by using psychological factors (ie, perceived risk of COVID-19 infection, perceived benefits, and perceived barriers of COVID-19 vaccination). RESULTS: Among the participants (N=1016), 53.3% (541/1016) hesitated to take the COVID-19 vaccine, while 46.7% (475/1016) agreed to accept the vaccine. Of the sociodemographic factors, female gender (odds ratio [OR] 1.967, 95% CI 1.36-2.86; P<.001), age in 50s (OR 0.47, 95% CI 0.23-0.96; P=.004), and age over 60s (OR 0.49, 95% CI 0.24-0.99; P=.04) were significant individual predictors of COVID-19 vaccine hesitancy. Perceived susceptibility of infection (OR 0.69, 95% CI 0.52-0.91; P=.01) and perceived benefits of vaccination (OR 0.69, 95% CI 0.52-0.91; P=.01) were associated with lower vaccine hesitancy. Perceived barriers of vaccination (OR 1.63, 95% CI 1.29-2.07; P<.001) and lower trust in government (OR 0.72, 95% CI 0.53-0.98; P=.04) were related to vaccine hesitancy. The use of offline and online media as sources for the perceived benefits of vaccination was associated with vaccine hesitancy, resulting in lower vaccine hesitancy. Moreover, perceived susceptibility of the disease and perceived barriers of vaccination mediated the association between social media use and vaccine hesitancy. CONCLUSIONS: Our findings revealed a considerable level of COVID-19 vaccine hesitancy in South Korea. Gender-based and generation-based public health policies and communication are recommended. Efforts to lower the perceived risk of vaccine side effects and heighten perceived benefits of the vaccine are required. Although the use of media has a positive and negative effect on the population's vaccine hesitancy, efforts should be made to disseminate reliable and timely information on media while confronting misinformation or disinformation for successive implementation of vaccine programs during pandemics.

Analysis on Students' Career Preparation in One Korean Medical School: Based on the Relationship and Trend Between Career Maturity and Specialty Indecision.

BACKGROUND: For medical school students, specialty choice after graduation significantly impacts their future doctor life. Several Korean medical schools have made efforts to prepare career development programs. However, career support programs based on the systematic analysis of medical school students' first to the final year are still lacking. Therefore, this study aims to analyze the students' career preparation of one medical school in Korea using the Career Maturity Inventory (CMI) and Specialty Indecision Scale (SIS) and to explore the relationship between CMI and SIS variables. METHODS: From December 2020 to July 2021, we conducted an online survey of 600 students in years 1 to 4 at Seoul National University College of Medicine. We analyzed the differences between the years of the students through one-way analysis of variance of the CMI and SIS and the relationship between the two instruments by correlation analysis and multiple regression analysis. RESULTS: A total of 198 students completed the survey. The average scores of the CMI variables tended to increase as the year of study went up, and the confidence score of the 1st year students was significantly lower than that of the 2nd and 4th year students. Although there was almost no consistent decrease by year in the SIS variables, 3rd and 4th year students showed significantly lower readiness scores than 1st year students. Additionally, we found that the CMI variables mostly had a negative effect on the SIS variables. CONCLUSION: There is an increasing tendency for career maturity by year of study in Korean medical school students. However, looking at the SIS results, the career concerns vary among the students. Therefore, medical schools can effectively use the SIS to identify the career concerns of students.

Risk factors for and prognosis of carboplatin-related hypersensitivity in patients with epithelial ovarian cancer.

PURPOSE: We aimed to identify the predictive risk factors for carboplatin-related hypersensitive reactions (HRs) and investigate their impact on survival outcomes in patients with epithelial ovarian cancer (EOC). METHODS: This retrospective study included 222 patients with EOC who received carboplatin infusion between July 2016 and November 2019. We compared the clinicopathologic characteristics and survival outcomes between carboplatin-related hypersensitivity and non-hypersensitivity groups. Hypersensitivity data were classified using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, categorizing grades from 1 to 5 as mild/moderate/severe/life-threatening/death. Multiple logistic regression analysis was used to analyze risk factors of HRs. The Cox proportional hazard regression model was used to determine the factors of being significantly associated with overall survival. RESULTS: Of the 222 patients, eight exhibited HRs (incidence rate, 3.6%). All HRs were of grade 3 or 4 (life-threatening). In all cases, a desensitization protocol was followed. Advanced stage (III or IV) (P = 0.022), previous history of carboplatin use (P < 0.001), and recurrent ovarian cancer (P = 0.001) were significantly associated with HR to carboplatin. Multivariate logistic analysis showed that a previous history of carboplatin was the only independent risk factor for carboplatin-related hypersensitivity (OR, 20.19; 95% CI 1.22 - 3034.10; P = 0.034). However, HR to carboplatin did not influence the overall survival (P = 0.526). CONCLUSION: In EOC patients, prior use of carboplatin was an independent risk factor for carboplatin-related HRs; HRs to carboplatin did not influence the overall survival. Clinicians should not underestimate the possibility risk of carboplatin HSRs when re-administrating carboplatin in EOC patients.

Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer.

BACKGROUND: Entinostat is an oral inhibitor of class I histone deacetylases intended for endocrine therapy-resistant patients with hormone receptor-positive (HR+) advanced or metastatic breast cancer (BC). We examined the safety, efficacy, and pharmacokinetics of entinostat monotherapy and combined entinostat/exemestane in Japanese patients. METHODS: This phase 1 study (3 + 3 dose-escalation design) enrolled postmenopausal women with advanced/metastatic HR+ BC previously treated with nonsteroidal aromatase inhibitors. Dose-limiting toxicities (DLTs) of entinostat monotherapy (3 mg/qw, 5 mg/qw, or 10 mg/q2w) and entinostat+exemestane (5 mg/qw + 25 mg/qd) were assessed. Pharmacokinetics, lysine acetylation (Ac-K), and T-cell activation markers were measured at multiple time points. RESULTS: Twelve patients were enrolled. No DLTs or grade 3-5 adverse events (AEs) occurred. Drug-related AEs (≥ 2 patients) during DLT observation were hypophosphatemia, nausea, and platelet count decreased. Six patients (50%) achieved stable disease (SD) for ≥ 6 months, including one treated for > 19 months. Median progression-free survival was 13.9 months (95% CI 1.9-not calculable); median overall survival was not reached. Area under the plasma concentration-time curve and Ac-K in peripheral blood CD19+ B cells increased dose-proportionally. The changing patterns of entinostat concentrations and Ac-K levels were well correlated. T-cell activation markers increased over time; CD69 increased more in patients with SD ≥ 6 months vs. SD < 6 months. CONCLUSIONS: Entinostat monotherapy and combined entinostat/exemestane were well tolerated in Japanese patients, with no additional safety concerns compared with previous reports. The correlation between pharmacokinetics and Ac-K in peripheral blood CD19+ B cells, and also T-cell activation markers, merits further investigation. TRIAL REGISTRATION: JAPIC Clinical Trial Information, JapicCTI-153066 . Registered 12 November 2015. ClinicalTrials.gov, NCT02623751 . Registered 8 December 2015.

Cabozantinib plus docetaxel and prednisone in metastatic castration-resistant prostate cancer.

OBJECTIVE: To evaluate the safety and efficacy of cabozantinib combined with docetaxel. PATIENTS AND METHODS: This was a phase 1/2 multicentre study in patients with metastatic castration-resistant prostate cancer (mCRPC). Docetaxel (75 mg/m2 every 3 weeks with daily prednisone 10 mg) was combined with escalating doses of daily cabozantinib (20, 40 and 60 mg). Based on the results of the phase 1 study, the investigation was expanded into a randomized study of docetaxel with prednisone (hereafter 'docetaxel/prednisone') plus the maximum tolerated dose (MTD) of cabozantinib compared with docetaxel/prednisone alone. RESULTS: A total of 44 men with mCRPC were enrolled in this phase 1/2 trial. An MTD of 40 mg cabozantinib plus docetaxel/prednisone was determined. Dose-limiting toxicities were neutropenic fever and palmar-plantar erythrodysesthesia, and there was one death attributable to a thromboembolic event. In addition, grade 3 or 4 myelosuppression, hypophosphataemia and neuropathy were seen in three or more patients. In the phase 1 study, the median time to progression (TTP) and overall survival (OS) time were 13.6 and 16.3 months, respectively. In the phase 2 study, which was terminated early because of poor accrual, the median TTP and OS favoured the combination (n = 13) compared to docetaxel/prednisone alone (n = 12; 21.0 vs 6.6 months; P = 0.035 and 23.8 vs 15.6 months; P = 0.072, respectively). CONCLUSION: Despite the limited number of patients in this study, preliminary data suggest that cabozantinib can be safely added to docetaxel/prednisone with possible enhanced efficacy.

A phase 1 study of entinostat in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1513, Pediatric Early Phase-Clinical Trial Network (PEP-CTN).

BACKGROUND: Entinostat is an oral small molecule inhibitor of class I histone deacetylases (HDAC), which has not previously been evaluated in pediatrics. We conducted a phase I trial to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), toxicity profile, pharmacokinetics (PK), and pharmacodynamics (PD) of entinostat in children with relapsed or refractory solid tumors including central nervous system (CNS) malignancies. METHODS: A rolling six dose escalation design evaluated two dose levels. Entinostat oral tablet formulation was administered once per week, four doses per 28-day cycle. PK and PD studies were performed. RESULTS: Twenty-one eligible patients' median (range) age was 14 years (6-20). Six subjects were treated at 3 mg/m2 dose level and 15 were treated in 4 mg/m2 dose level. The study included patients with CNS tumors (n = 12), sarcomas (n = 6), or other solid tumors (n = 3). Eight patients were not fully evaluable for toxicity due to progression of disease prior to receiving the required percentage of protocol therapy. No cycle one dose-limiting toxicity (DLT) was observed at either dose level. A three-fold higher area under the curve (AUC) was achieved in our cohort compared to adults using a similar dosing schedule. The PD studies showed increase in acetylated lysine in peripheral blood leukocytes at both doses. CONCLUSIONS: Entinostat was well tolerated with no DLT observed. All patients experienced progression within the first two cycles, except one patient with ependymoma with stable disease. Based on PK and PD, the R2PD in pediatric patients with solid tumors is 4 mg/m2 orally administered once weekly.

Knowledge, attitudes, and practices (KAP) toward COVID-19: a cross-sectional study in South Korea.

BACKGROUND: The public must routinely practice precautionary behaviors to control the spread of COVID-19, as no vaccines and antiviral treatments are currently available. This paper examines the public's knowledge, attitudes, and practices (KAP) related to COVID-19 and their relationships and identified the pandemic's vulnerable populations to provide recommendations for behavioral interventions and policies. METHODS: Data collection took place over 3 days (June 26-29) via an online survey 5 months after the Korea Centers for Disease Control and Prevention (KCDC) confirmed the first COVID case in South Korea; 970 subjects were included in the statistical data analysis. RESULTS: Knowledge directly affected both attitudes (e.g., perceived risk and efficacy belief) and practices (e.g., personal hygiene practices and social distancing). Among the influencing factors of COVID-19 preventive behaviors, efficacy belief was the most influential and significant practice factor. It mediated the relationship between knowledge and all three preventive behaviors (wearing facial masks, practicing hand hygiene, and avoiding crowded places). The level of knowledge varied by sociodemographic characteristics. Females (ß = 0.06, p <  0.05) and individuals with higher levels of education (ß = 0.06, p <  0.05) demonstrated higher levels of knowledge. CONCLUSION: To increase precautionary behaviors among the public, health officials and policymakers must promote knowledge and efficacy belief. Future interventions and policies should also be developed in a 'person-centered' approach, targeting vulnerable subgroups, embracing them, and closing the gap of KAP toward COVID-19.

Burnout and peritraumatic distress of healthcare workers in the COVID-19 pandemic.

BACKGROUND: To evaluate the current status of emotional exhaustion and peritraumatic distress of healthcare workers (HCWs) in the COVID-19 pandemic, and identify factors associated with their mental health status. METHODS: An online survey involving 1068 of consented HCWs that included nurses, physicians, and public health officers was conducted in May 2020. Descriptive statistics and multivariate regression analyses were performed on the collected data. RESULTS: Although no significant difference in peritraumatic distress was observed among the surveyed HCWs, the workers' experience of emotional exhaustion varied according to work characteristics. Respondents who were female, older, living with a spouse, and/or full-time workers reported higher levels of emotional exhaustion. Public health officers and other medical personnel who did not have direct contact with confirmed patients and full-time workers had a higher level of peritraumatic distress. Forced involvement in work related to COVID-19, worry about stigma, worry about becoming infected, and perceived sufficiency of organizational support negatively predict emotional exhaustion and peritraumatic distress. CONCLUSIONS: Job-related and emotional stress of HCWs should not be neglected. Evidence-based interventions and supports are required to protect HCWs from mental illness and to promote mental health of those involved in the response to the COVID-19 pandemic.

Effects of COVID-19 Emergency Alert Text Messages on Practicing Preventive Behaviors: Cross-sectional Web-Based Survey in South Korea.

BACKGROUND: Sending emergency messages via mobile phone text messaging can be a promising communication tool to rapidly disseminate information and promote preventive behavior among the public during epidemic outbreaks. The battle to overcome COVID-19 is not yet over; thus, it is essential that the public practices preventive measures to prevent the spread of COVID-19. OBJECTIVE: This study aimed to investigate the effectiveness of reading and obtaining information via emergency alert SMS text messages and their effects on the individual's practice of preventive behaviors during the early stages of the COVID-19 outbreak in South Korea. METHODS: A cross-sectional web-based survey comprising 990 participants was conducted over 3 days (March 25-27, 2020). A multivariable logistic regression analysis revealed the sociodemographic factors that might influence the behavior of reading emergency alert text messages. A hierarchical linear regression model estimated the associations between reading emergency alert text messages for each precautionary behavior practiced against COVID-19. Additionally, the indirect effects of reading the text messages on each precautionary behavior via psychological factors (ie, perceived risk and response efficacy) were calculated. All data were weighted according to the 2019 Korea census data. RESULTS: Overall, 49.2% (487/990) of the participants reported that they always read emergency alert text messages and visited the linked website to obtain more information. Factors such as female sex (odds ratio [OR] 1.68, 95% CI 1.28-2.21) and older age (30-39 years: OR 2.02, 95% CI 1.25-3.28; 40-49 years: OR 2.84, 95% CI 1.80-4.47; 50-59 years: OR 3.19, 95% CI 2.01-5.06; 60 years and above: OR 3.12, 95% CI 2.00-4.86 versus 18-29 years) were identified to be associated with a higher frequency of reading the text messages. Participants who always read the text messages practiced wearing facial masks (ß=.074, P=.01) more frequently than those who did not. In terms of social distancing, participants who reported they always read the text messages avoided crowded places (ß=.078, P=.01) and canceled or postponed social gatherings (ß=.103, P<.001) more frequently than those who did not read the text messages. Furthermore, reading text messages directly and indirectly affected practicing precautionary behaviors, as the mediation effect of response efficacy between reading text messages and practicing preventive behaviors was significant. CONCLUSIONS: Our findings suggest that emergency alert text messages sent to individuals' mobile phones are timely and effective strategies for encouraging preventive behavior in public. Sending emergency alert text messages to provide the public with accurate and reliable information could be positively considered by the health authorities, which might reduce the negative impact of infodemics.