Pelvic congestion syndrome analysis through quantitative 2-dimensional phase-contrast magnetic resonance imaging: A promising vision from an observational cohort study.

BACKGROUND: To examine the application of quantitative 2-dimensional phase-contrast magnetic resonance imaging (2D PC-MRI) for treating patients with pelvic congestion syndrome (PCS). MATERIALS AND METHODS: We conducted a retrospective cross-sectional analysis by using quantitative 2D PC-MRI data enrolled between April 2017 and Sep 2023. In addition, 32 healthy female controls (HCs) were included. RESULTS: Most patients with PCS presented with chronic pelvic pain and more than half had extra-pelvic venous symptoms (80/81, 98% and 45/81, 56%, respectively). Quantitative 2D PC-MRI analyzed the 81 patients with PCS, 239 patients without PCS, and 32 HCs. The patients with PCS had higher stroke volume (SV), absolute SV (ASV), and mean flux (MF) in the calf region (interstitial pixel shift) than did the HCs. In the left gonadal vein, the patients with PCS had higher SV, backward flow volume (BFV), ASV, and MF and lower forward flow volume (FFV), stroke distance (SD), and mean velocity (MV) than did the HCs. However, the patients with PCS had lower SV, FFV, MF, SD, and MV in the great saphenous veins. Quantitative 2D PC-MRI analysis revealed that the PCS group had higher SV, FFV, BFV, ASV, and MF in the calf region than did the non-PCS group. The variables that most strongly differentiated the patients with PCS from the HCs were SV in the great saphenous veins, SD in the great saphenous veins and left gonadal vein, and MV in the great saphenous veins and left gonadal vein. Caudal flow in the left gonadal vein was identified in half of the patients with PCS (39/81, 48.1%); 14 of them received embolization for left gonadal vein. CONCLUSIONS: In additional to providing an objective 3-dimensional morphology of the pelvic veins and extra-pelvic leaks, quantitative 2D PC-MRI analysis reveals distinct hemodynamic profiles between patients with PCS, those without PCS, and HCs, especially in the gonadal veins and regional perfusion of the calves.

Preserving a qubit during state-destroying operations on an adjacent qubit at a few micrometers distance.

Protecting qubits from accidental measurements is essential for controlled quantum operations, especially during state-destroying measurements or resets on adjacent qubits, in protocols like quantum error correction. Current methods to preserve atomic qubits against such disturbances waste coherence time, extra qubits, and introduce additional errors. We demonstrate the feasibility of in-situ state-reset and state-measurement of trapped ions, achieving  >99.9% fidelity in preserving an 'asset' ion-qubit while a neighboring 'process' qubit is reset, and  >99.6% preservation fidelity while applying a detection beam for 11 µs on the same neighbor at a distance of 6 µm. This is achieved through precise wavefront control of addressing optical beams and using a single ion as both a quantum sensor for optical aberrations and an intensity probe with  >50 dB dynamic range. Our demonstrations advance quantum processors, enhancing speed and capabilities for tasks like quantum simulations of dissipation and measurement-driven phases, and implementing error correction.

Cretaceous crown male ant reveals the rise of modern lineages.

Most described Mesozoic ants belong to stem groups that existed only during the Cretaceous period. Previously, the earliest known crown ants were dated to the Turonian (Late Cretaceous, ca. 94-90 million years ago (Ma)) deposits found in the USA, Kazakhstan, and Botswana. However, the recent discovery of an alate male ant in Kachin amber from the earliest Cenomanian (ca. 99 Ma), representing a new genus and species, Antiquiformica alata, revises the narrative on ant diversification. Antiquiformica can be distinctly differentiated from all known male stem ants by its geniculate antennae with elongated scape, extending far beyond the occipital margin of the head and half the length of the funiculus, as well as its partly reduced forewing venation. Furthermore, the combination of a one-segmented waist with a well-developed node, elongated scape extending beyond the occipital margin, and reduced forewing venation, particularly the completely reduced m-cu and rs-m crossveins and absence of rm and mcu closed cells, firmly places the fossil within the extant subfamily Formicinae. Fourier transform infrared spectroscopy (FTIR) confirmed that the amber containing Antiquiformica alata originated from the Kachin mines in Myanmar. This discovery significantly revises our understanding of the early evolution of Formicinae. The presence of Antiquiformica in Cenomanian amber indicates that the subfamily Formicinae emerged at least by the start of the Late Cretaceous, with crown ants likely originating earlier during the earliest Cretaceous or possibly the Late Jurassic, although paleontological evidence is lacking to support the latter hypothesis.

Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin Attenuates Sorafenib-Induced Myocardial Inflammation and Toxicity.

Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium-glucose co-transporter-2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib-treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28-day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib-induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT-dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib-treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib-promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib-stimulated proinflammatory signaling (TNF-α/IL-1ß/IL-6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib-promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding.

Global mortality of chronic liver diseases attributable to Hepatitis B virus and Hepatitis C virus infections from 1990 to 2019 and projections to 2030.

BACKGROUND: The burden of chronic liver disease (CLD) deaths attributable to the hepatitis B virus (HBV) and hepatitis C virus (HCV) remains unknown. Further research is required to elucidate the extent of this burden in the eventual elimination of these diseases. METHODS: Data on liver cancer, cirrhosis, and other CLD among 204 countries and territories between 1990 and 2019 was extracted from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) published in 2019. The Bayesian age-period-cohort model was used to analyze the temporal trend and predict the disease burden by 2030. RESULTS: The number of HCV-related CLD deaths surpassed that of CLD deaths caused by HBV in 2019 (536833 deaths versus 523003 deaths) and is expected to be maintained until 2030 (689124 deaths versus 628824 deaths). East Asia had the highest burden of chronic HBV and HCV infections during the study period. In 2019, the largest age-standardized death rates (ASDR) of CLD deaths caused by HBV and HCV were mainly observed in Western Sub-Saharan Africa (18.75%) and Eastern Sub-Saharan Africa (16.42%), respectively. South Asia and East Asia are predicted to have the highest number of CLD deaths related to HCV and HBV by 2030. Eastern Europe and South Asia show the largest expected increase in disease burden caused by HCV or HBV between 2019 and 2030. No GBD region is projected to achieve the WHO target of a 65% reduction in mortality from chronic HBV and HCV infections by 2030. CONCLUSIONS: Although the mortality of CLD caused by HBV and HCV decreased in the last three decades (from 1990 to 2019), the number of deaths will continue to increase until 2030. Therefore, governments and international organizations need to strengthen the effectiveness of vaccines, screening, and treatment, especially in potential emerging hotspot regions.

A Causal Regulation Modeling Algorithm for Temporal Events with Application to Escherichia coli's Aerobic to Anaerobic Transition.

Time-series experiments are crucial for understanding the transient and dynamic nature of biological phenomena. These experiments, leveraging advanced classification and clustering algorithms, allow for a deep dive into the cellular processes. However, while these approaches effectively identify patterns and trends within data, they often need to improve in elucidating the causal mechanisms behind these changes. Building on this foundation, our study introduces a novel algorithm for temporal causal signaling modeling, integrating established knowledge networks with sequential gene expression data to elucidate signal transduction pathways over time. Focusing on Escherichia coli's (E. coli) aerobic to anaerobic transition (AAT), this research marks a significant leap in understanding the organism's metabolic shifts. By applying our algorithm to a comprehensive E. coli regulatory network and a time-series microarray dataset, we constructed the cross-time point core signaling and regulatory processes of E. coli's AAT. Through gene expression analysis, we validated the primary regulatory interactions governing this process. We identified a novel regulatory scheme wherein environmentally responsive genes, soxR and oxyR, activate fur, modulating the nitrogen metabolism regulators fnr and nac. This regulatory cascade controls the stress regulators ompR and lrhA, ultimately affecting the cell motility gene flhD, unveiling a novel regulatory axis that elucidates the complex regulatory dynamics during the AAT process. Our approach, merging empirical data with prior knowledge, represents a significant advance in modeling cellular signaling processes, offering a deeper understanding of microbial physiology and its applications in biotechnology.

Evaluation of next-generation sequencing for measurable residual disease monitoring in three major fusion transcript subtypes of B-precursor acute lymphoblastic leukaemia.

The use of next-generation sequencing (NGS) for monitoring measurable residual disease (MRD) in acute lymphoblastic leukaemia (ALL) has been gaining traction. This study aimed to investigate the utility of NGS in MRD monitoring for the three major fusion transcript (FT) subtypes of B-precursor ALL (B-ALL). The MRD results for 104 bone marrow samples from 56 patients were analysed through NGS and real time quantitative reverse transcription PCR (RT-qPCR) for the three major FTs: BCR::ABL1, TCF3::PBX1, and ETV6::RUNX1. To validate the NGS approach, NGS-MRD was initially compared with allele-specific oligonucleotide-qPCR-MRD, and the coefficient of determination was good (R2=0.8158). A subsequent comparison of NGS-MRD with FT-MRD yielded a good coefficient of determination (R2=0.7690), but the coefficient varied by subtype. Specifically, the R2 was excellent for TCF3::PBX1 ALL (R2=0.9157), good for ETV6::RUNX1 ALL (R2=0.8606), and subpar for BCR::ABL1 ALL (R2=0.5763). The overall concordance between the two methods was 83.7%, and an excellent concordance rate of 95.8% was achieved for TCF3::PBX1 ALL. Major discordance, which was defined as a >1 log difference between discordant NGS-MRD and FT-MRD, occurred in 6.7% of the samples, with all but one sample being BCR::ABL1 ALL. Among the four non-transplanted patients with BCR::ABL1-MRD (+)/NGS-MRD (-), three did not relapse after long-term follow-up. Our finding indicates that NGS-MRD has a better prognostic impact than RT-qPCR-MRD in ETV6::RUNX1 and BCR::ABL1 ALL, whereas in TCF3::PBX1 ALL, both methods exhibit comparable efficacy.

In silico identification of a novel Cdc2-like kinase 2 (CLK2) inhibitor in triple negative breast cancer.

Dysregulation of RNA splicing processes is intricately linked to tumorigenesis in various cancers, especially breast cancer. Cdc2-like kinase 2 (CLK2), an oncogenic RNA-splicing kinase pivotal in breast cancer, plays a significant role, particularly in the context of triple-negative breast cancer (TNBC), a subtype marked by substantial medical challenges due to its low survival rates. In this study, we employed a structure-based virtual screening (SBVS) method to identify potential CLK2 inhibitors with novel chemical structures for treating TNBC. Compound 670551 emerged as a novel CLK2 inhibitor with a 50% inhibitory concentration (IC50) value of 619.7 nM. Importantly, Compound 670551 exhibited high selectivity for CLK2 over other protein kinases. Functionally, this compound significantly reduced the survival and proliferation of TNBC cells. Results from a cell-based assay demonstrated that this inhibitor led to a decrease in RNA splicing proteins, such as SRSF4 and SRSF6, resulting in cell apoptosis. In summary, we identified a novel CLK2 inhibitor as a promising potential treatment for TNBC therapy.

An ensemble machine learning model generates a focused screening library for the identification of CDK8 inhibitors.

The identification of an effective inhibitor is an important starting step in drug development. Unfortunately, many issues such as the characterization of protein binding sites, the screening library, materials for assays, etc., make drug screening a difficult proposition. As the size of screening libraries increases, more resources will be inefficiently consumed. Thus, new strategies are needed to preprocess and focus a screening library towards a targeted protein. Herein, we report an ensemble machine learning (ML) model to generate a CDK8-focused screening library. The ensemble model consists of six different algorithms optimized for CDK8 inhibitor classification. The models were trained using a CDK8-specific fragment library along with molecules containing CDK8 activity. The optimized ensemble model processed a commercial library containing 1.6 million molecules. This resulted in a CDK8-focused screening library containing 1,672 molecules, a reduction of more than 99.90%. The CDK8-focused library was then subjected to molecular docking, and 25 candidate compounds were selected. Enzymatic assays confirmed six CDK8 inhibitors, with one compound producing an IC50 value of ≤100 nM. Analysis of the ensemble ML model reveals the role of the CDK8 fragment library during training. Structural analysis of molecules reveals the hit compounds to be structurally novel CDK8 inhibitors. Together, the results highlight a pipeline for curating a focused library for a specific protein target, such as CDK8.

Predicting the cryotolerance of boar sperm through antioxidant stress.

High sperm cryotolerance is crucial to the successful cryopreservation of boar sperm. Evaluating the cryotolerance of boar sperm by using a rapid and convenient technique can enhance the commercial viability of these sperm. This study investigated the correlation between sperm parameters for three sample subsets-fresh sperm, sperm with H2O2-induced oxidative damage (hereinafter referred to as H2O2-induced sperm), and frozen-thawed sperm-to identify the potential of these correlations to predict cryotolerance. A total of 64 sperm samples were obtained from 64 Duroc boars. The sperm parameters of the three subsets, where the frozen-thawed sperm were analysed at 30 or 180 min after thawing, were determined, and the coefficients of correlation between these parameters were calculated. The results indicated that H2O2-induced oxidative stress resulted in decreases in various sperm parameters-including total motility (TM), viability (VIA), mitochondrial membrane potential (MMP), and live sperm with MMP (LMP)-but increased their coefficients of variation. Receiver operating characteristic (ROC) curve analysis revealed that the kinematic parameters of the H2O2-induced sperm effectively predicted those of the frozen-thawed boar sperm at 30 min after thawing; the corresponding area under the ROC curve (AUC) was 0.8667 for TM and 0.8733 for progressive motility in the H2O2-induced sperm. For measurement at 180 min after thawing, the sperm membrane and mitochondrial parameters of the H2O2-induced sperm effectively predicted the LMP of the frozen-thawed boar sperm; the corresponding AUC was 0.8489 for VIA, 0.8289 for MMP, and 0.8444 for LMP. To our knowledge, this is the first study to directly establish a strong correlation between post-thaw boar sperm quality and H2O2-induced oxidative stress before freezing. Our proposed technique can serve as a valuable reference for the development of practical applications aimed at enhancing techniques for cryopreserving boar sperm.

The effect of progressive exercise prescription for group exercise guidance for Taiwan seniors and Integrated Care for old People: Post-event movement observation.

Purpose: This study is aimed at the seniors of the "2022 Taiwan Senior Citizens Fitness Club Subsidy Plan" with a sample. Method: The doctor will diagnose and confirm whether the physical condition suits participation. Then, the professional sports instructor will design and arrange a progressive fitness enhancement group course suitable for the Senior person's physical fitness, conducted four times a week, every 2 h, for three months of group course training. Afterward, four group course instructors analyzed the motor ability of the three periods through a video, divided into 21 evaluation indicators. The data collection will be from January to May 2023. In addition, the Integrated Care for Old People (ICOPE) was used to assess the situation. Result: The results showed that all indexes were significantly better than those in week one at week 6. All indexes at week 12 were significantly better than those in week one and week 6 (p < .001), and the benefit of all indicators was the largest (Cohen's d: 2.79-5.11), the reliability of the scores of each index ICC (0.73-0.94). Conclusion: Progressive and multifaceted guidance on how to safely and effectively enhance the physical activity of senior citizens may be the most suitable method. Through progressive energy enhancement, the participants' physical activity and cognitive function can be improved, especially the overall rhythm of the music, which can be combined with high and low impact, dynamic and static balance control, agility, flexibility, and extensibility to achieve the benefits of health promotion.

Using Virtual Reality in a Rehabilitation Program for Patients With Breast Cancer: Phenomenological Study.

Background: Surgery is an essential treatment for early-stage breast cancer. However, various side effects of breast cancer surgery, such as arm dysfunction and lymphedema, remain causes for concern. Rehabilitation exercises to prevent such side effects should be initiated within 24 hours after surgery. Virtual reality (VR) can assist the process of rehabilitation; however, the feasibility of applying VR for rehabilitation must be explored, in addition to experiences of this application. Objective: This study explored patients' attitudes toward and experiences of using VR for their rehabilitation to determine the feasibility of such VR use and to identify potential barriers. Methods: A phenomenological qualitative study was conducted from September to December 2021. A total of 18 patients with breast cancer who had undergone surgical treatment were interviewed using open-ended questions. The Colaizzi 7-step procedure for phenomenological analysis was used for data analysis. To ensure high study reliability, this study followed previously reported quality criteria for trustworthiness. Results: Three themes were identified: (1) VR was powerful in facilitating rehabilitation, (2) early and repetitive upper limb movements were an advantage of VR rehabilitation, and (3) extensive VR use had challenges to be overcome. Most of the interviewed patients reported positive experiences of using VR for rehabilitation. Specifically, VR helped these patients identify appropriate motion and angle limits while exercising; in other words, knowledge gained through VR can play a key role in the rehabilitation process. In addition, the patients reported that the use of VR provided them company, similar to when a physiotherapist is present. Finally, the gamified nature of the VR system seemed to make VR-based rehabilitation more engaging than traditional rehabilitation, particularly with respect to early rehabilitation; however, the high cost of VR equipment made VR-based rehabilitation difficult to implement at home. Conclusions: The interviewed patients with breast cancer had positive experiences in using VR for rehabilitation. The high cost of both VR equipment and software development presents a challenge for applying VR-based rehabilitation.

Refining risk stratification in paediatric B-acute lymphoblastic leukaemia: Combining IKZF1plus and Day 15 MRD positivity.

This study investigates the potential utility of IKZF1 deletion as an additional high-risk marker for paediatric acute lymphoblastic leukaemia (ALL). The prognostic impact of IKZF1 status, in conjunction with minimal/measurable residual disease (MRD), was evaluated within the MRD-guided TPOG-ALL-2013 protocol using 412 newly diagnosed B-ALL patients aged 1-18. IKZF1 status was determined using multiplex ligation-dependent probe amplification. IKZF1 deletions, when co-occurring with CDKN2A, CDKN2B, PAX5 or PAR1 region deletions in the absence of ERG deletions, were termed IKZF1plus. Both IKZF1 deletion (14.6%) and IKZF1plus (7.8%) independently predicted poorer outcomes in B-ALL. IKZF1plus was observed in 4.1% of Philadelphia-negative ALL, with a significantly lower 5-year event-free survival (53.9%) compared to IKZF1 deletion alone (83.8%) and wild-type IKZF1 (91.3%) (p < 0.0001). Among patients with Day 15 MRD ≥0.01%, provisional high-risk patients with IKZF1plus exhibited the worst outcomes in event-free survival (42.0%), relapse-free survival (48.0%) and overall survival (72.7%) compared to other groups (p < 0.0001). Integration of IKZF1plus and positive Day 15 MRD identified a subgroup of Philadelphia-negative B-ALL with a 50% risk of relapse. This study highlights the importance of assessing IKZF1plus alongside Day 15 MRD positivity to identify patients at increased risk of adverse outcomes, potentially minimizing overtreatment.

Learning through connections: clinical participation and interpersonal relationships in longitudinal integrated clerkships and traditional block rotations in Taiwan.

BACKGROUND: Longitudinal integrated clerkships (LICs) and traditional block rotations (TBRs) employ different designs that provide various learning experiences for students. In this study, we explored students' clinical participation and interpersonal interactions in LICs and TBRs at 2 metropolitan hospitals in Taiwan. METHODS: In April 2018, we enrolled 15 LIC and 29 TBR students. We conducted a cross-sectional survey which required the students to outline a typical daily schedule during their internal medicine rotations and draw an ecomap of the clinical team members. With the patient in the center as a reference, the size of each circle in an ecomap indicated the importance of the member; the distances and number of connecting lines between two circles represented the relationship and frequency of interaction, respectively, between the corresponding members. We analyzed the results and compared the responses of the LIC and TBR students. RESULTS: The LIC students spent more time on direct patient care and in the outpatient clinic/operation room, whereas the TBR students participated more in educational activities and in observation behind their seniors. In the ecomap analysis, the LIC students had a closer relationship with attending physicians and had better interactions with patients and preceptors than did the TBR students. Conversely, the TBR students felt closer to and interacted more frequently with interns and residents. CONCLUSIONS: The LIC students had more opportunities to care for patients directly and engaged in interactions with patients and attending physicians more frequently than did the TBR students. TRIAL REGISTRATION: Ethical approval for the study was obtained from the Institutional Review Board of Tri-Service General Hospital (TSGHIRB 2-106-05-018).

Trend Analysis of Inpatient Medical Adverse Events in Taiwan (2014-2020): Findings From Taiwan Patient Safety Reporting System.

OBJECTIVES: Medical adverse event (MAE) reporting and management are essential for patient safety campaigns. An epidemiological assessment of MAE trends is crucial for understanding the effectiveness of patient safety improvement efforts. This study analyzed the trends of inpatient MAEs, focusing on MAE incidence and harm severity. METHODS: Longitudinal secondary data (over 2014-2020) on MAEs reported by 18 hospitals were retrieved from the Taiwan Patient-safety Reporting system. The numbers and incidence rates (per 1000 inpatient days) of reported MAEs were calculated. The harm severity levels of six major MAE categories were analyzed. Trend and generalized estimating equation analyses were conducted to investigate changes in MAE patterns. RESULTS: Trend analyses revealed significant decreasing trends in the number (4763-3107 per year; Jonckheere-Terpstra test = -1.952, P = 0.05) and incidence rates (0.92-0.62 per 1000 inpatient days; ß = -0.5017, P = 0.00) of harmful MAEs over 7-year study period. Among the most frequently reported MAEs, tube-related events exhibited the most significant decreasing trend (28%-23.8%; Jonckheere-Terpstra test = -2.854, P = 0.00). The reported numbers, incidence rates, and severity of falls and tube-related events dropped significantly. CONCLUSIONS: By analyzing representative longitudinal MAE data, this study demonstrated the effectiveness of nationwide patient safety improvement campaigns in Taiwan. Our data reveal significant reductions in the reported numbers, incidence rates, and severity of several major MAEs. Specifically, our data indicate significant reductions in the incidence and severity of tube-related events, which can be beneficial for patient safety improvement efforts.

Early enteral nutrition in patients with out-of-hospital cardiac arrest under target temperature management was associated with a lower 7-day bacteremia rate: A post-hoc analysis of a retrospective cohort study.

INTRODUCTION: Early enteral nutrition (EN) is a nutritional strategy for reducing the incidence of in-hospital infections. However, the benefits of early EN, under targeted temperature management (TTM) in patients with out-of-hospital cardiac arrest (OHCA), remain unclear. We aimed to evaluate the effect of early EN on the infective complications of OHCA patients who underwent TTM. METHODS: We retrospectively searched the clinical databases of two adult emergency tertiary referral hospitals in southern Taiwan and identified patients admitted for OHCA who underwent TTM between 2017 and 2022. The 85 enrolled patients were divided into two groups based on timing: early EN (EN within 48 h of admission) and delayed EN (EN > 48 h after admission). Clinical outcomes of 7-day infective complications between the two groups were analyzed. RESULTS: Early EN was provided to 57 (67 %) of 85 patients and delayed EN was provided to the remaining 28 (33 %) patients. No significant differences in baseline patient characteristics were observed between the two groups. In addition, no differences in clinical outcomes were observed, except that the early EN group had a lower 7-day bacteremia rate (5.3 % vs. 26.9 %, p = 0.013). Gram-negative bacteria were the major pathogen among the 7-day infective complications. CONCLUSION: In OHCA patients treated with TTM, early EN was associated with a lower 7-day bacteremia rate. Furthermore, the application of early EN in this population was well tolerated without significant adverse events.

Low-dose imiquimod induces melanogenesis in melanoma cells through an ROS-mediated pathway.

BACKGROUND: Melanogenesis is the process of melanin maturation which not only protects skin from UV radiation but also plays an important role in antigenicity of melanomas. Imiquimod (IMQ) is a toll-like receptor 7 (TLR7) agonist that exhibits antiviral and anticancer activity. OBJECTIVE: To explore whether IMQ could induce melanogenesis in melanoma cells. METHODS: The mouse melanoma cell line B16F10, the mouse immortalized melanocyte Melan-A, and human melanoma cell lines MNT-1, C32 and A375 were utilized in this study. The pigmented level was observed by the centrifuged cell pellet. The intracellular and extracellular melanin levels were examined in the absorbance in NaOH-extracted cell lysate and cell-cultured medium, respectively. The expression of melanogenesis related proteins was examined by immunoblotting. The intracellular cyclic AMP amount was evaluated by the cAMP Glo assay kit. The activity of phosphodiesterase 4B (PDE4B) was investigated by CREB reporter assay with overexpressed PDE4B or not. RESULTS: We demonstrated that a low dose of IMQ could trigger melanogenesis in B16F10 cells. IMQ induced microphthalmia-associated transcription factor (MITF) nuclear translocation, upregulated the expression of melanogenesis-related proteins, increased tyrosinase (TYR) activity, and led to pigmentation in B16F10 cells. Next, we found that IMQ-induced melanogenesis was activated by excessive intracellular cAMP accumulation, which was regulated through IMQ-mediated PDE4B inhibition. Finally, IMQ-induced ROS production was found to be involved in melanogenesis by its control of PDE4B activity. CONCLUSIONS: Low dose of IMQ could activate melanogenesis through the ROS/PDE4B/PKA pathway in melanoma cells.

Identification of selective dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors and their effects on tau and microtubule.

The overexpression of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), commonly observed in neurodegenerative diseases like Alzheimer's disease (AD) and Down syndrome (DS), can induce the formation of neurofibrillary tangles (NFTs) and amyloid plaques. Hence, designing a selective DYRK1A inhibitor would result in a promising small molecule for treating neurodegenerative diseases. Developing selective inhibitors for DYRK1A has been a difficult challenge due to the highly preserved ATP-binding site of protein kinases. In this study, we employed a structure-based virtual screening (SBVS) campaign targeting DYRK1A from a database containing 1.6 million compounds. Enzymatic assays were utilized to verify inhibitory properties, confirming that Y020-3945 and Y020-3957 showed inhibitory activity towards DYRK1A. In particular, the compounds exhibited high selectivity for DYRK1A over a panel of 120 kinases, reduced the phosphorylation of tau, and reversed the tubulin polymerization for microtubule stability. Additionally, treatment with the compounds significantly reduced the secretion of inflammatory cytokines IL-6 and TNF-α activated by DYRK1A-assisted NFTs and Aß oligomers. These identified inhibitors possess promising therapeutic potential for conditions associated with DYRK1A in neurodegenerative diseases. The results showed that Y020-3945 and Y020-3957 demonstrated structural novelty compared to known DYRK1A inhibitors, making them a valuable addition to developing potential treatments for neurodegenerative diseases.

Early HIV diagnosis enhances quality-adjusted life expectancy of men who have sex with men living with HIV: A population-based cohort study in Taiwan.

BACKGROUND: Whether early HIV diagnosis is beneficial for HIV patients themselves remains uncertain, given the stigma and social discrimination associated with an HIV diagnosis. This study aimed to measure the impact of early HIV diagnosis on quality-adjusted life expectancy (QALE) in comparison with late HIV diagnosis, from real-world data in Taiwan under universal access to antiretroviral therapy (ART). METHODS: This population-based cohort study included 14,570 men who have sex with men (MSM) in the national HIV registry and a quasi-random sample (n = 127) of MSM patients to measure quality of life using the EQ-5D health utility instrument. We integrated quality of life data into the extrapolated cohort survival curve to estimate the QALE in patients with early versus late HIV diagnosis (≤30 days before AIDS diagnosis). Loss-of-QALE were estimated by comparing the cohort with age-, sex-, and calendar-year-matched referents simulated from vital statistics. Difference-in-differences was estimated to quantify the effect of early HIV diagnosis. RESULTS: Early HIV diagnosis is associated with a loss-of-life expectancy of 3.11 years, with an average health utility of 0.95, in contrast to those diagnosed late (loss-of-life expectancy 8.47 years, with an average health utility of 0.86). After integration of survival and life quality, early HIV diagnosis results in a reduction of loss-of-QALE by 8.28 quality-adjusted life years among MSM living with HIV. CONCLUSIONS: Under universal access to ART, early HIV diagnosis is highly beneficial for people living with HIV themselves, with a net gain of 8.28 healthy life years compared with those diagnosed late.