Cost-effectiveness of early vs delayed use of abemaciclib combination therapy for patients with high-risk hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer.

BACKGROUND: Abemaciclib was newly approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) high-risk early breast cancer (EBC). Clinical guidelines recommended abemaciclib as the first-line treatment for HR+/ HER2- EBC (early use) or HR+/ HER2- metastatic breast cancer (MBC) (delayed use). OBJECTIVE: To compare the cost-effectiveness of early vs delayed use of abemaciclib for treatment of HR+/HER2- high-risk EBC. Early use was defined as combined abemaciclib and endocrine therapy as first-line therapy for EBC, followed by treatment with fulvestrant for MBC. Delayed use was defined as endocrine therapy for EBC, followed by combined abemaciclib and fulvestrant therapy for MBC. METHODS: A 5-state model was developed to estimate lifetime costs, life-years (LYs), and quality-adjusted life-years (QALYs) of hypothetical patients with HR+/ HER2- EBC from a third-party US payer's perspective. Key clinical and safety data were derived from the monarchE and MONARCH 2 clinical trials. Costs, utilities, and disutility values of adverse events were obtained from the literature. We calculated the incremental cost-effectiveness ratio (ICER) of early vs delayed abemaciclib use and compared it with a willingness-to-pay (WTP) threshold of $100,000 per LY or QALY. Deterministic and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the base-case model. RESULTS: Base-case analysis showed early use yielded 21.08 LYs and 17.93 QALYs for $586,213 and delayed use yielded 11.14 LYs and 9.38 QALYs for $157,576. The ICER of early vs delayed use was $43,136/LY and $50,104/QALY, which was cost-effective at the WTP threshold of $100,000. The PSA result indicated that a 94.6% likelihood of early use (vs delayed use) was cost-effective at the WTP threshold of $100,000 per QALY. CONCLUSIONS: This study suggests that giving abemaciclib in the early stage rather than waiting until patients develop metastatic disease (current standard of care in MBC) is a cost-effective strategy.

Health and wellbeing of staff working at higher education institutions globally during the post-COVID-19 pandemic period: evidence from a cross-sectional study.

BACKGROUND: The ongoing global crisis of Higher Education (HE) institutions during the post-COVID-19 pandemic period has increased the likelihood of enduring psychological stressors for staff. This study aimed to identify factors associated with job insecurity, burnout, psychological distress and coping amongst staff working at HE institutions globally. METHODS: An anonymous cross-sectional study was conducted in 2023 with staff at HE institutions across 16 countries. Job insecurity was measured using the Job Insecurity Scale (JIS), burnout using the Perceived Burnout measure question, psychological distress using the Kessler Psychological Distress Scale (K10), and coping using the Brief Resilient Coping Scale. Multivariable logistic regression with a stepwise variable selection method was used to identify associations. RESULTS: A total of 2,353 staff participated; the mean age (± SD) was 43(± 10) years and 61% were females. Most staff (85%) did not feel job insecurity, one-third (29%) perceived burnout in their jobs, more than two-thirds (73%) experienced moderate to very high levels of psychological distress, and more than half (58%) exhibited medium to high resilient coping. Perceived job insecurity was associated with staff working part-time [Adjusted Odds Ratio 1.53 (95% Confidence Intervals 1.15-2.02)], having an academic appointment [2.45 (1.78-3.27)], having multiple co-morbidities [1.86 (1.41-2.48)], perceived burnout [1.99 (1.54-2.56)] and moderate to very high level of psychological distress [1.68 (1.18-2.39)]. Perceived burnout was associated with being female [1.35 (1.12-1.63)], having multiple co-morbidities [1.53 (1.20-1.97)], perceived job insecurity [1.99 (1.55-2.57)], and moderate to very high levels of psychological distress [3.23 (2.42-4.30)]. Staff with multiple co-morbidities [1.46 (1.11-1.92)], mental health issues [2.73 (1.79-4.15)], perceived job insecurity [1.61 (1.13-2.30)], and perceived burnout [3.22 (2.41-4.31)] were associated with moderate to very high levels of psychological distress. Staff who perceived their mental health as good to excellent [3.36 (2.69-4.19)] were more likely to have medium to high resilient coping. CONCLUSIONS: Factors identified in this study should be considered in reviewing and updating current support strategies for staff at HE institutions across all countries to reduce stress and burnout and improve wellbeing.

Cross-sectional association of physical activity levels with risks of sarcopenia among older Taiwanese adults.

OBJECTIVES: The updated World Health Organization 2020 guidelines strongly recommend an optimal physical activity level of 150-300 min/week for older adults. However, few studies have examined the relationship between different levels of physical activity and sarcopenia. Therefore, the purpose of this study was to investigate the cross-sectional associations between overall physical activity levels, gender, intensity, and the risk of sarcopenia among older Taiwanese adults. METHODS: A nationwide cross-sectional telephone survey of older adults (≥ 65 years) was conducted in Taiwan from October 2019 to January 2020. Participants were interviewed to collect self-reported data on their level of physical activity (measured by the Taiwanese version of the IPAQ-SF), sarcopenia risk (measured by the SARC-F questionnaire), and sociodemographics. RESULTS: A total of 1068 older adults were surveyed. Compared with the optimal physical activity level recommendations in the WHO guidelines and after adjusting for potential confounders and proposing an association independent of sedentary behavior, older adults with insufficient physical activity levels (< 150 min/week) were more likely to have a higher risk of sarcopenia (OR: 3.24; CI: 1.67-6.27), whereas older adults who exceeded physical activity guidelines (> 300 min/week) were more likely to have a lower risk of sarcopenia (OR: 0.39; CI: 0.20-0.78). Maintaining moderate-intensity physical activity is essential for older adults, as physical activity that exceeds the guidelines can significantly lower the risk of sarcopenia; meanwhile, insufficient physical activity can greatly increase it. Also, there seems to be a similar association between sarcopenia risk across different physical activity levels in vigorous-intensity physical activities in older adults. However, due to the small number of sarcopenia-risk participants who met or exceeded vigorous-intensity physical activity levels, further comparisons between different vigorous-intensity physical activity levels did not show significant differences in sarcopenia risk. Additionally, insufficient physical activity was found to be an important risk factor for sarcopenia in both genders, while physical activity that exceeded the guidelines prevented sarcopenia in females. CONCLUSIONS: The findings of this study highlight the potential dose-response relationship related to physical activity. The 2020 WHO guidelines provide the public with minimum recommendations for physical activity. However, exceeding these recommended levels appears to be more effective in preventing sarcopenia in older adults and may offer even greater health benefits. Future research should further explore whether exceeding these guidelines could result in additional health benefits.

Relationship between Sociodemographic and Health-Related Factors and Sedentary Time in Middle-Aged and Older Adults in Taiwan.

Background and Objectives: This study aimed to investigate the associations between sociodemographic and health-related factors and sedentary time in middle-aged and older Taiwanese adults. Materials and Methods: A total of 1031 participants (460 men, 571 women; mean age 65.0 years ± 7.8 years; range 55 to 93 years) were randomly recruited from the National Computer Assessment Telephone Interview, Taiwan, in 2013. Sedentary time, TV viewing, physical activity, and sociodemographic factors were assessed through questionnaires. Body mass index was self-reported and calculated to evaluate obesity. In 2023, the associations between sedentary time and sociodemographic and health-related factors were analyzed using Pearson's correlation, cross tabulation, and logistic regression and were stratified by gender. Results: Over 47% of participants reported spending more than 2 h watching TV, and more than 33% reported engaging in over 6 h of total sedentary activities. Men and women with insufficient physical activity had a higher probability of prolonged sedentary time than their physically active counterparts (p = 0.032 for men, p = 0.024 for women). Both men and women who spent more than 2 h watching TV daily were more likely to have high sedentary time compared to those with shorter TV viewing durations (both p < 0.001). Highly educated and unmarried women exhibited a higher likelihood of prolonged sedentary time than their less educated and married counterparts (p = 0.021 and p = 0.01, respectively). Conclusions: Sedentary time showed significant and positive associations with both insufficient physical activity and prolonged TV viewing in both genders. Additionally, significant associations were observed between sedentary time and high education and unmarried status in women. These findings emphasize the importance of implementing gender-specific approaches in future interventions and policy initiatives aimed at reducing sedentary behavior among middle-aged and older adults.

The relevance of motor sequence and visual perception skills in learning Chinese handwriting.

This study explored visual perception skills and the ability to write according to standard stroke order and their links to the learning of Chinese handwriting. Thirty-seven children (aged 6-8) (15 boys and 22 girls) participated in a handwriting test and visual perception evaluation (Test of Visual Perceptual Skills-3rd Edition, TVPS-3). A computerized system was used to evaluate the stroke order accuracy, legibility, and automation of stroke movements. The stroke order accuracy was found to positively correlate with the scores of TVPS-3 (r = .498, p < .05) and to significantly correlate with handwriting legibility (r = .435, p < .05) as well as the automation of stroke movements (r = .494, p < .01). This study revealed that visual perception skill is related to stroke order accuracy and provides directions to assist students who encounter difficulties in learning Chinese handwriting.

PRMT-7/PRMT7 activates HLH-30/TFEB to guard plasma membrane integrity compromised by bacterial pore-forming toxins.

Bacterial pore-forming toxins (PFTs) that disrupt host plasma membrane integrity (PMI) significantly contribute to the virulence of various pathogens. However, how host cells protect PMI in response to PFT perforation in vivo remains obscure. Previously, we demonstrated that the HLH-30/TFEB-dependent intrinsic cellular defense (INCED) is elicited by PFT to maintain PMI in Caenorhabditis elegans intestinal epithelium. Yet, the molecular mechanism for the full activation of HLH-30/TFEB by PFT remains elusive. Here, we reveal that PRMT-7 (protein arginine methyltransferase-7) is indispensable to the nuclear transactivation of HLH-30 elicited by PFTs. We demonstrate that PRMT-7 participates in the methylation of HLH-30 on its RAG complex binding domain to facilitate its nuclear localization and activation. Moreover, we showed that PRMT7 is evolutionarily conserved to regulate TFEB cellular localization and repair plasma damage caused by PFTs in human intestinal cells. Together, our observations not only unveil a novel PRMT-7/PRMT7-dependent post-translational regulation of HLH-30/TFEB but also shed insight on the evolutionarily conserved mechanism of the INCED against PFT in metazoans.

A structural equation model for cyber academic dishonesty in higher education: Evidence from Taiwan.

With the continued spread of the rise of online teaching, and the massive use of 3C products (computer, communication, and consumer electronics), the cases of academic plagiarism or using others' works as own works caused by inappropriate use of the Internet are occurring all the time. However, very little research has been conducted on the cyber ethical climate in relation to cyber academic dishonesty. This study investigates the structural relationship between cyber ethical climate, cyber self-efficacy, cyber ethical attitude and cyber academic dishonesty, among university and graduate students, and develops a multiple mediation model. A total of 812 university and graduate students from 32 universities in Taiwan completed the online questionnaire. The results of the study show that the multiple mediation model is valid and find that the cyber ethical climate creates a favorable context for organizing members to demonstrate cyber ethical behavior, demonstrating the importance of mutual influence on cyber academic dishonesty between the cyber ethical climate created by teachers and the cyber ethical climate of class peers. Based on these results, we deeply examine the practical implications and make specific recommendations to improve the cyber ethical behavior of university and graduate students.

Nanoscaled biphasic calcium phosphate modulates osteogenesis and attenuates LPS-induced inflammation.

Micron-scale structure biphasic calcium phosphate (BCP) materials have demonstrated promising clinical outcomes in the field of bone tissue repair. However, research on biphasic calcium phosphate materials at the nanoscale level remains limited. In this study, we synthesize granular-shaped biphasic calcium phosphate nanomaterials with multiple desirable characteristics, including negatively charged surfaces, non-cytotoxicity, and the capability to penetrate cells, using a nanogrinding dispersion process with a polymeric carboxylic acid as the dispersant. Our results reveal that treating human osteoblasts with 0.5 µg/mL biphasic calcium phosphate nanomaterials results in a marked increase in alkaline phosphatase (ALP) activity and the upregulation of osteogenesis-related genes. Furthermore, these biphasic calcium phosphate nanomaterials exhibit immunomodulatory properties. Treatment of THP-1-derived macrophages with BCP nanomaterials decreases the expression of various inflammatory genes. Biphasic calcium phosphate nanomaterials also mitigate the elevated inflammatory gene expression and protein production triggered by lipopolysaccharide (LPS) exposure in THP-1-derived macrophages. Notably, we observe that biphasic calcium phosphate nanomaterials have the capacity to reverse the detrimental effects of LPS-stimulated macrophage-conditioned medium on osteoblastic activity and mineralization. These findings underscore the potential utility of biphasic calcium phosphate nanomaterials in clinical settings for the repair and regeneration of bone tissue. In conclusion, this study highlights the material properties and positive effects of biphasic calcium phosphate nanomaterials on osteogenesis and immune regulation, opening a promising avenue for further research on inflammatory osteolysis in patients undergoing clinical surgery.

Ganciclovir as a potential treatment for glioma: a systematic review and meta-analysis.

BACKGROUND: Glioma is a challenging malignant tumor with a low survival rate and no effective treatment. Recently, ganciclovir, an antiviral drug, combined with gene therapy and its own antiviral ability, has been proposed as a potential treatment for glioma. However, there are differences in the results of various clinical trials. In this study, we conducted a systematic review and meta-analysis to evaluate the efficacy of ganciclovir in treating glioma. METHODS: We searched databases such as PubMed, EMBASE, and Cochrane Library before March 30, 2023. The search terms included glioma, ganciclovir, valganciclovir and treatment. Calculated 1, 2 and 4-year survival rate by risk difference (RD), and overall survival (OS) by odds ratio (OR). RESULTS: Five randomized controlled trials (RCTs) with a total of 606 high-grade glioma patients were included. The results showed that ganciclovir can improve 2-yeaer (RD = 0.179, 95% CI 0.012-0.346, P = 0.036) and 4-year survival rate (RD = 0.185, 95% CI 0.069-0.3, P = 0.002) and OS (OR 2.393, 95% CI 1.212-4.728, P = 0.012) compared with the control group. CONCLUSIONS: This meta-analysis showed that ganciclovir significantly improved the prognosis of glioma patients. Therefore, we suggest that more cases of ganciclovir as a glioma treatment can be conducted, or a large clinical trial can be designed.

Association between first-line antidepressant use and risk of dementia in older adults: a retrospective cohort study.

BACKGROUND: Prior studies suggested that antidepressant use is associated with an increased risk of dementia compared to no use, which is subject to confounding by indication. We aimed to compare the dementia risk among older adults with depression receiving first-line antidepressants (i.e., SSRI/SNRI) versus psychotherapy, which is also considered the first-line therapy for depression. METHODS: This retrospective cohort study was conducted using the US Medical Expenditure Panel Survey from 2010 to 2019. We included adults aged ≥ 50 years diagnosed with depression who initiated SSRI/SNRI or psychotherapy. We excluded patients with a dementia diagnosis before the first record of SSRI/SNRI use or psychotherapy. The exposure was the patient's receipt of SSRI/SNRI (identified from self-report questionnaires) or psychotherapy (identified from the Outpatient Visits or Office-Based Medical Provider Visits files). The outcome was a new diagnosis of dementia within 2 years (i.e., survey panel period) identified using ICD-9/ICD-10 codes from the Medical Conditions file. Using a multivariable logistic regression model, we reported adjusted odds ratios (aORs) with 95% confidence intervals (CIs). We also conducted subgroup analyses by patient sex, age group, race/ethnicity, severity of depression, combined use of other non-SSRI/SNRI antidepressants, and presence of underlying cognitive impairment. RESULTS: Among 2,710 eligible patients (mean age = 61 ± 8, female = 69%, White = 84%), 89% used SSRIs/SNRIs, and 11% received psychotherapy. The SSRI/SNRI users had a higher crude incidence of dementia than the psychotherapy group (16.4% vs. 11.8%), with an aOR of 1.36 (95% CI = 1.06-1.74). Subgroup analyses yielded similar findings as the main analyses, except no significant association for patients who were aged < 65 years (1.23, 95% CI = 0.93-1.62), male (1.34, 95% CI = 0.95-1.90), Black (0.76, 95% CI = 0.48-1.19), had a higher PHQ-2 (1.39, 95% CI = 0.90-2.15), and had underlying cognitive impairment (1.06, 95% CI = 0.80-1.42). CONCLUSIONS: Our findings suggested that older adults with depression receiving SSRIs/SNRIs were associated with an increased dementia risk compared to those receiving psychotherapy.

Versatile Effects of GABA Oolong Tea on Improvements in Diastolic Blood Pressure, Alpha Brain Waves, and Quality of Life.

Emerging evidence has demonstrated that using a new manufacturing technology to produce γ-aminobutyric acid (GABA)-fortified oolong (GO) tea could relieve human stress and exert versatile physiological benefits. The purpose of this human study was to investigate the therapeutic effects of daily GO tea consumption on improvements in blood pressure, relaxation-related brain waves, and quality of life (QOL) over a period of 28 consecutive days. Total polyphenols, major catechins, and free amino acids were analyzed via an HPLC assay. Changes in heart rate, blood pressure, α brain waves (index of relaxation), and the eight-item QOL score were investigated on days 0, 7, 14, 21, and 28. The chemical analysis results showed that GO tea contained the most abundant amino acids and GABA, contributing to the relaxation activity. Among all study participants, the daily consumption of GO tea could reduce systolic blood pressure on day 21 and diastolic blood pressure on day 28 (p < 0.05 for both). For participants with pre-hypertension, GO tea could effectively reduce heart rate and systolic and diastolic blood pressure on day 28 (p < 0.05). At the end of the study, incremental changes in alpha brain waves and QOL scores were also demonstrated (p < 0.05 for both). This study suggests that GO tea might potentially serve as a natural source for alternative therapy to improve blood pressure, stress relief, and QOL.

Association between first-line antidepressant use and risk of dementia in older adults: a retrospective cohort study.

Background: Prior studies suggested that antidepressant use is associated with an increased risk of dementia compared to no use, which is subject to confounding by indication. We aimed to compare the dementia risk among older adults with depression receiving first-line antidepressants (i.e., SSRI/SNRI) versus psychotherapy, which is also considered the first-line therapy for depression. Methods: This retrospective cohort study was conducted using the US Medical Expenditure Panel Survey from 2010 to 2019. We included adults aged ≥50 years diagnosed with depression who initiated SSRI/SNRI or psychotherapy. We excluded patients with a dementia diagnosis before the first record of SSRI/SNRI use or psychotherapy. The exposure was the patient's receipt of SSRI/SNRI (identified from self-report questionnaires) or psychotherapy (identified from the Outpatient Visits or Office-Based Medical Provider Visits files). The outcome was a new diagnosis of dementia within 2 years (i.e., survey panel period) identified using ICD-9/ICD-10 codes from the Medical Conditions file. Using a multivariable logistic regression model, we reported adjusted odds ratios (aORs) with 95% confidence intervals (CIs). We also conducted subgroup analyses by patient sex, age group, race, severity of depression, combined use of other non-SSRI/SNRI antidepressants, and presence of underlying cognitive impairment. Results: Among 2,710 eligible patients (mean age= 61±8, female=69%, white=84%), 89% used SSRIs/SNRIs, and 11% received psychotherapy. The SSRI/SNRI users had a higher crude incidence of dementia than the psychotherapy group (16.1% vs. 12.7%), with an aOR of 1.39 (95% CI=1.21-1.59). Subgroup analyses yielded similar findings as the main analyses, except no significant association for patients who were black (0.75, 95% CI=0.55-1.02), had a higher PHQ-2 (1.08, 95% CI=0.82-1.41), had concomitant non-SSRI/SNRI antidepressants (0.75, 95% CI=0.34-1.66), and had underlying cognitive impairment (0.84, 95% CI=0.66-1.05). Conclusions: Our findings suggested that older adults with depression receiving SSRIs/SNRIs were associated with an increased dementia risk compared to those receiving psychotherapy.

SOX4 is a pivotal regulator of tumorigenesis in differentiated thyroid cancer.

The SOX family consists of about 20 transcription factors involved in embryonic development, reprogramming, and cell fate determination. In this study, we demonstrated that SOX4 was significantly upregulated in differentiated thyroid cancer. Immunohistochemical analysis revealed that high SOX4 expression was associated with papillary histology, extrathyroidal extension, lymph node metastasis, and advanced disease stage. Patients whose tumors exhibited high SOX4 expression had a shorter recurrence-free survival, though significance was lost in multivariate Cox regression analysis. SOX4 silencing in thyroid cancer cells slowed cell growth, attenuated clonogenicity, and suppressed anoikis resistance. Additionally, SOX4 knockdown impeded xenograft tumor growth in nude mice. Knockdown of SOX4 expression was accompanied by reduced phosphorylation of AKT and ERK. Furthermore, CRABP2 expression correlated with SOX4 expression, and SOX4 silencing decreased CRABP2 expression and its downstream effectors such as integrin ß1 and ß4. These results indicate that SOX4 has both prognostic and therapeutic implications in differentiated thyroid cancer, and targeting SOX4 may modulate tumorigenic processes in the thyroid.

Time-course analysis of frontal gene expression profiles in the rat model of posttraumatic stress disorder and a comparison with the conditioned fear model.

Posttraumatic stress disorder (PTSD) is a complex disorder that involves physiological, emotional, and cognitive dysregulation that may occur after exposure to a life-threatening event. In contrast with the condition of learned fear with resilience to extinction, abnormal fear with impaired fear extinction and exaggeration are considered crucial factors for the pathological development of PTSD. The prefrontal cortex (mPFC) is considered a critical region of top-down control in fear regulation, which involves the modulation of fear expression and extinction. The pathological course of PTSD is usually chronic and persistent; a number of studies have indicated temporal progression in gene expression and phenotypes may be involved in PTSD pathology. In the current study, we use a well-established modified single-prolonged stress (SPS&FS) rat model to feature PTSD-like phenotypes and compared it with a footshock fear conditioning model (FS model); we collected the frontal tissue after extreme stress exposure or fear conditioning and extracted RNA for transcriptome-level gene sequencing. We compared the genetic profiling of the mPFC at early (<2 h after solely FS or SPS&FS exposure) and late (7 days after solely FS or SPS&FS exposure) stages in these two models. First, we identified temporal differences in the expressional patterns between these two models and found pathways such as protein synthesis factor eukaryotic initiation factor 2 (EIF2), transcription factor NF-E2-related factor 2 (NRF2)-mediated oxidative stress response, and acute phase responding signaling enriched in the early stage in both models with significant p-values. Furthermore, in the late stage, the sirtuin signaling pathway was enriched in both models; other pathways such as STAT3, cAMP, lipid metabolism, Gα signaling, and increased fear were especially enriched in the late stage of the SPS&FS model. However, pathways such as VDR/RXR, GP6, and PPAR signaling were activated significantly in the FS model's late stage. Last, the network analysis revealed the temporal dynamics of psychological disorder, the endocrine system, and also genes related to increased fear in the two models. This study could help elucidate the genetic temporal alteration and stage-specific pathways in these two models, as well as a better understanding of the transcriptome-level differences between them.

Essence of the Giant Reduction of Power Density in Osmotic Energy Conversion in Porous Membranes: Importance of Testing Area.

Harvesting osmotic energy through nanofluidic devices with diverse materials has received considerable attention in recent years. Often, a small testing area on a membrane was chosen to assess its power performance by calculating power density as output power per effective area. Since the choice of this testing area is arbitrary, and it is usually quite small, the result obtained can be too optimistic. There is a need to come up with a common standard so that the performance of a device/membrane can be assessed reasonably. In this study, we systematically investigate the power density as a function of testing area in nanoporous anodic-aluminum-oxide membranes. Through changing the aperture size of substrates, we clearly show that the obtained power density decreases drastically with increasing testing area. For instance, the power density acquired from the testing area of µm2-scale can be five orders of magnitude larger than that from the pristine membrane of cm2-scale. We also advance simulations by building a 3D model to simulate osmotic-driven ion transport in the multichannel system. The result of modeling agrees with our experimental observation that the power density decreases with increasing number of channels, and the ionic concentration profile reveals that the concentration polarization becomes serious as the number of channels increases. Our result highlights the importance of effective area on testing the power performance in nanofluidic devices.

Early- and late-phase changes of brain activity and early-phase neuromodulation in the posttraumatic stress disorder rat model.

Posttraumatic stress disorder (PTSD) is a complex syndrome that may occur after life-threatening events. Fear memory abnormalities may play vital roles in the pathogenesis of PTSD. Previous work has found that fear memories are not rigid; the retrieval of fear memories may change over time. Furthermore, prior studies suggest that theta wave (4 Hz) activity is highly correlated with fear expression in an animal model. However, the relationship between pathological fear memory and potential brain wave features in PTSD remains largely uncharacterized. Here, we hypothesized that after traumatic stress exposure, the longitudinal dynamics of abnormal fears in PTSD animal models could be reflected by the measurement of local field potentials (LFPs). Using a well-established modified single-prolonged stress and footshock (SPS & FS) PTSD rat model, animals were restrained for 2 h and subsequently subjected to 20 min of forced swimming, then exposed to diethyl ether until they lost consciousness and placed in a conditioning chamber for fear conditioning. To characterize the temporal changes, we characterized freezing behavior brain wave features during the conditioning chamber re-exposure in the early (10 and 30 min; 2, 4, and 6 h) and late (day 1, 3, 7, and 14) phases after traumatic stress exposure. Our results indicate that SPS & FS rats showed co-morbid PTSD phenotypes including significantly higher levels of anxiety-, depression-, and anhedonia-like behaviors, and impaired fear extinction. Delta wave (0.5-4 Hz) suppression in the medial prefrontal cortex, amygdala, and ventral hippocampus occurred 10 and 30 min after traumatic stress, followed by continuous delta wave activity from 2 h to day 14, correlating with fear levels. tDCS reduced delta activity and alleviated PTSD-like phenotypes in the SPS & FS group. In this study, profiling abnormal fears with brain wave correlates may improve our understanding of time-dependent pathological fear memory retrieval in PTSD and facilitate the development of effective intervention strategies.

Apoptotic Cell-Derived CD14(+) Microparticles Promote the Phagocytic Activity of Neutrophilic Precursor Cells in the Phagocytosis of Apoptotic Cells.

Membranous CD14 is crucial in the phagocytic activity of neutrophils. However, the role of CD14(+) microparticles (MPs) derived from apoptotic neutrophils (apo-MP) during the phagocytic process is not clear. All trans-retinoic acid (ATRA) induces acute promyelocytic leukemic NB4 cells along granulocytic differentiation. In this study, we investigated the role of CD14(+)apo-MP in the cell-cell interaction during the phagocytic process of apoptotic cells by viable ATRA-NB4 cells. We firstly demonstrate that CD14 expression and phagocytic activity of NB4 cells were upregulated simultaneously after ATRA treatment in a time-dependent manner, and both were significantly enhanced via concurrent lipopolysaccharide treatment. The phagocytic activity of ATRA-NB4 cells and lipopolysaccharide-treated ATRA-NB4 cells were both significantly attenuated by pre-treating cells with an antibody specific to either CD14 or TLR4. Further flow cytometric analysis demonstrates that apoptotic ATRA-NB4 cells release CD14(+)apo-MP in an idarubicin dosage-dependent manner. Both CD14 expression and the phagocytic activity of viable ATRA-NB4 cells were significantly enhanced after incubation with apo-MP harvested from apoptotic ATRA-NB4 cells, and the apo-MP-enhanced phagocytic activity was significantly attenuated by pre-treating apo-MP with an anti-CD14 antibody before incubation with viable cells. We conclude that CD14(+)apo-MP derived from apoptotic ATRA-NB4 cells promotes the phagocytic activity of viable ATRA-NB4 cells in engulfing apoptotic cells.

Association between treatment of hepatitis C virus and risk of cardiovascular disease among insured patients with the virus in the United States.

PURPOSE: Hepatitis C virus (HCV) infection has been associated with increased risk of cardiovascular disease (CVD). It is unclear whether HCV treatment affects risk of CVD among patients infected with HCV. We assessed the incidence and risk of CVD among insured patients with HCV infection and evaluated if HCV treatment was associated with reduced CVD risk. METHODS: This retrospective cohort study used MarketScan Commercial and Medicare Supplement databases. Patients newly diagnosed with HCV (vs. patients without HCV) between January 2008 and August 2015 were categorized by treatment (none, insufficient, or minimum effective) based on receipt and duration of anti-HCV treatments. After propensity score matching, time-dependent Cox proportional hazards models were used to compare CVD risk between patients with HCV versus without and between patients with HCV by treatment type and duration. RESULTS: HCV was associated with 13% increased risk of developing CVD overall (adjusted hazard ratio [aHR] 95% CI 1.26-1.35) and with 13% (aHR 1.07-1,18), 9% (aHR 1.03-1.15), and 32% (aHR 1.24-1.40) significantly increased risks of developing coronary artery disease, cerebrovascular disease, and peripheral vascular disease, respectively. Among patients with HCV, compared with no treatment, receipt of minimum effective treatment was associated with 24% decreased risk of CVD, and receipt of insufficient treatment was associated with 14% decreased risk of CVD. CONCLUSIONS: Individuals chronically infected with HCV had a higher incidence of CVD. Among patients with HCV, receipt of antiviral treatment for HCV was associated with decreased risk of CVD.

Characterization of Mammary Tumors Arising from MMTV-PyVT Transgenic Mice.

Among genetically engineered mouse models of breast cancer, MMTV-PyVT is a mouse strain in which the oncogenic polyoma virus middle T antigen is driven by the mouse mammary tumor virus promoter. The aim of the present study was to perform morphologic and genetic analyses of mammary tumors arising from MMTV-PyVT mice. To this end, mammary tumors were obtained at 6, 9, 12, and 16 weeks of age for histology and whole-mount analyses. We conducted whole-exome sequencing to identify constitutional and tumor-specific mutations, and genetic variants were identified using the GRCm38/mm10 mouse reference genome. Using hematoxylin and eosin analysis and whole-mount carmine alum staining, we demonstrated the progressive proliferation and invasion of mammary tumors. Frameshift insertions/deletions (indels) were noted in the Muc4. Mammary tumors showed small indels and nonsynonymous single-nucleotide variants but no somatic structural alterations or copy number variations. In summary, we validated MMTV-PyVT transgenic mice as a multistage model for mammary carcinoma development and progression. Our characterization may be used as a reference for guidance in future research.

Direct mass spectrometric imaging of document handwriting with laser desorption ionization and post ultraviolet photodissociation.

Handwriting represents personal education and physical or psychological states. This work describes a chemical imaging technique for document evaluation that combines laser desorption ionization with post ultraviolet photo-induced dissociation (LDI-UVPD) in mass spectrometry. Taken the advantages of chromophores in ink dyes, handwriting papers were subjected to direct laser desorption ionization without additional matrix materials. It is a surface-sensitive analytical method that uses a low intensity pulsed laser at 355 nm to remove chemical components from very outermost surfaces of overlapped handwritings. Meanwhile, the transfer of photoelectrons to those compounds leads to the ionization and the formation of radical anions. The gentle evaporation and ionization property enable the dissection of chronological orders. Paper documents maintain intact without extensive damages after laser irradiation. The evolving plume resulting from the irradiation of the 355 nm laser is fired by the second ultraviolet laser at 266 nm that is in parallel to the sample surface. In contrast to collision activated dissociation in tandem MS/MS, such post ultraviolet photodissociation generates much more different fragment ions through electron-directed specific cleavages of chemical bonds. LDI-UVPD can not only provide graphic representation of chemical components but also reveal hidden dynamic features such as alterations, pressures and aging.