Liquid-liquid phase separation-related genes associated with prognosis, tumor microenvironment characteristics, and tumor cell features in bladder cancer.

OBJECTIVE: This study aimed to explore the Liquid-liquid phase separation (LLPS)-related genes associated with the prognosis of bladder cancer (BCa) and assess the potential application of LLPS-related prognostic signature for predicting prognosis in BCa patients. METHODS: Clinical information and transcriptome data of BCa patients were extracted from the Cancer Genome Atlas-BLCA (TCGA-BLCA) database and the GSE13507 database. Furthermore, 108 BCa patients who received treatment at our institution were subjected to a retrospective analysis. The least absolute shrinkage and selection operator (LASSO) analysis was performed to develop an LLPS-related prognostic signature for BCa. The CCK8, wound healing and Transwell assays were performed. RESULTS: Based on 62 differentially expressed LLPS-related genes (DELRGs), three DELRGs were screened by LASSO analysis including kallikrein-related peptidase 5 (KLK5), monoacylglycerol O-acyltransferase 2 (MOGAT2) and S100 calcium-binding protein A7 (S100A7). Based on three DELRGs, a novel LLPS-related prognostic signature was constructed for individualized prognosis assessment. Kaplan-Meier curve analyses showed that LLPS-related prognostic signature was significantly correlated with overall survival (OS) of BCa. ROC analyses demonstrated the LLPS-related prognostic signature performed well in predicting the prognosis of BCa patients in the training group (the area under the curve (AUC) = 0.733), which was externally verified in the validation cohort 1 (AUC = 0.794) and validation cohort 2 (AUC = 0.766). Further experiments demonstrated that inhibiting KLK5 could affect the proliferation, migration, and invasion of BCa cells. CONCLUSIONS: In this study, a novel LLPS-related prognostic signature was successfully developed and validated, demonstrating strong performance in predicting the prognosis of BCa patients.

Causal association between mitochondrial function and psychiatric disorders: Insights from a bidirectional two-sample Mendelian randomization study.

BACKGROUND: Previous observational studies have suggested that there appears to be a close association between mitochondrial function and psychiatric disorders, but whether a causal role exists remains unclear. METHODS: We extracted genetic instruments for 67 mitochondrial-related proteins and 10 psychiatric disorders from publicly available genome-wide association studies, and employed five distinct MR methods and false discovery rate correction to detect causal associations between them. Additionally, we conducted a series of sensitivity tests and additional model analysis to ensure the robustness of the results. For potential causal associations, we further performed reverse MR analyses to assess the impact of reverse causality. RESULTS: We identified a total of 2 significant causal associations and 24 suggestive causal associations. Specifically, Phenylalanine-tRNA ligase was found to increase the risk of Alzheimer's disease, while Mitochondrial glutamate carrier 2 decreased the risk of autism spectrum disorder. Furthermore, there was no evidence of significant pleiotropy, heterogeneity, or reverse causality. LIMITATIONS: This study was limited to individuals of European ancestry, and the conclusions drawn are merely revelatory. CONCLUSION: This study provides novel insights into the relationship between mitochondria and psychiatric disorders, as well as the pathogenesis and treatment strategies for psychiatric disorders.

Characterization of TBP and TAFs in Mungbean (Vigna radiata L.) and Their Potential Involvement in Abiotic Stress Response.

The TATA-box binding protein (TBP) and TBP-associated factors (TAFs) constitute the transcription factor IID (TFIID), a crucial component of RNA polymerase II, essential for transcription initiation and regulation. Several TFIID subunits are shared with the Spt-Ada-Gcn5-acetyltransferase (SAGA) coactivator complex. Recent research has revealed the roles of TBP and TAFs in organogenesis and stress adaptation. In this study, we identified 1 TBP and 21 putative TAFs in the mungbean genome, among which VrTAF5, VrTAF6, VrTAF8, VrTAF9, VrTAF14, and VrTAF15 have paralogous genes. Their potential involvement in abiotic stress responses was also investigated here, including high salinity, water deficit, heat, and cold. The findings indicated that distinct genes exerted predominant influences in the response to different abiotic stresses through potentially unique mechanisms. Specifically, under salt stress, VrTBP, VrTAF2, and VrTAF15-1 were strongly induced, while VrTAF10, VrTAF11, and VrTAF13 acted as negative regulators. In the case of water-deficit stress, it was likely that VrTAF1, VrTAF2, VrTAF5-2, VrTAF9, and VrTAF15-1 were primarily involved. Additionally, in response to changes in ambient temperature, it was possible that genes such as VrTAF5-1, VrTAF6-1, VrTAF9-2, VrTAF10, VrTAF13, VrTAF14b-2, and VrTAF15-1 might play a dominant role. This comprehensive exploration of VrTBP and VrTAFs can offer a new perspective on understanding plant stress responses and provide valuable insights into breeding improvement.

Nuciferine analogs block voltage-gated sodium, calcium and potassium channels to regulate the action potential and treat arrhythmia.

Dysfunction of the Nav1.5, Cav1.2, and Kv channels could interfere with the AP and result in arrhythmias and even heart failure. We herein present a novel library of nuciferine analogs that target ion channels for the treatment of arrhythmias. Patch clamp measurements of ventricular myocytes revealed that 6a dramatically blocked both the INa and ICa without altering the currentvoltage relationship (including the activation potential and peak potential), accelerated the inactivation of Nav and Cav channels and delayed the resurrection of these channels after inactivation. Additionally, 6a significantly decreased the APA and RMP without affecting the APD30 or APD50. The IC50 values of 6a against Nav1.5 and Cav1.2 were 4.98 µM and 4.62 µM, respectively. Furthermore, 6a (10 µM) blocked IKs, IK1, and Ito with values of 17.01 %±2.54 %, 9.09 %±2.78 %, and 11.15 %±3.52 %, respectively. Surprisingly, 6a weakly inhibited hERG channels, suggesting a low risk of proarrhythmia. The cytotoxicity evaluation of 6a with the H9c2 cell line indicated that this compound was noncytotoxic. In vivo studies suggested that these novel nuciferine analogs could shorten the time of arrhythmia continuum induced by BaCl2 and normalize the HR, QRS, QT and QTc interval and the R wave amplitude. Moreover, 6a dose-dependently affected aconitine-induced arrhythmias and notably improved the cumulative dosage of aconitine required to evoke VP, VT, VF and CA in rats with aconitine-induced arrhythmia. In conclusion, nuciferine analogs could be promising ion channel blockers that could be further developed into antiarrhythmic agents.

Dual Caregiving and Mental Health Among Long-Term Care Nursing Assistants: The Moderating Role of Social Support.

AIM: To investigate the association of long-term care nursing assistants' dual caregiving roles with mental health and to determine whether social support moderates this relationship. DESIGN: A cross-sectional survey. METHODS: We surveyed 962 certified long-term care nursing assistants working in long-term care and medical facilities across Taiwan from October 2022 to July 2023. 'Dual caregiving roles' denote the fulfilment of caregiving duties both at work and within families. Mental health was evaluated using the 5-item Brief Symptom Rating Scale. Logistic regression analysis was utilized to investigate the association of dual caregiving roles and psychological job demands with poor mental health. Moreover, we explored whether family, colleague, and supervisor support moderated the association between dual caregiving roles and poor mental health. RESULTS: Among long-term care nursing assistants, 15% had dual caregiving responsibilities. Individuals with both dual caregiving roles and high psychological job demands faced the highest risk of poor mental health compared to those without dual caregiving roles and low psychological job demands. Having dual caregiving roles was associated with poor mental health compared to workers without such roles. Additionally, support from family, colleagues, and supervisors mitigates the association between caregivers' dual caregiving roles and poor mental health. CONCLUSION: A substantial proportion of long-term care nursing assistants had dual caregiving roles, leading to an additional mental health burden when combined with high psychological job demands. High social support attenuated this association. IMPLICATIONS FOR THE PROFESSION: Long-term care nursing assistants with dual caregiving roles had poorer mental health outcomes. Yet, support from family, colleagues, and supervisors mitigated these effects. These results emphasize the importance of enhancing social support to protect the mental well-being of long-term care nursing assistants managing both formal and informal caregiving duties. REPORTING METHOD: This study adheres to the STROBE guideline of reporting. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.

Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.

BACKGROUND: Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. METHODS: We quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022, based on calendar-time proportional hazards models and matching approaches. RESULTS: We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR 1.66; 95% CI 1.07, 2.59; p = 0.02) after the first dose. CONCLUSIONS: Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.

Caffeinated chewing gum improves the batting and pitching performance of female softball players: a randomized crossover study.

BACKGROUND: The purpose of this study was to investigate the effects of caffeinated chewing gum on female softball pitching and hitting performance in trained female softball fielders and pitchers. METHODS: Twenty-four trained female softball players (10 pitchers and 14 fielders) were divided into a caffeine chewing gum trial (CAF) or a placebo trial (PLA) in a single-blind, randomized, crossover experimental design. Two pieces of gum containing 100 mg of caffeine (CAF) or without caffeine (PLA) were chewed for 10 minutes and then spit out, followed by a 15-minute warm-up. The physical tests included grip strength and countermovement jump (CMJ). The softball-specific tests included pitching or hitting. The two trials were separated by seven days. RESULTS: The CAF trial had significantly higher grip strength than the PAL trial in fielder (P=0.032, Cohen's d=0.29) and pitcher (P=0.016, Cohen's d=0.33). The height of CMJ in fielders was significantly higher in the CAF trial than in the PLA trial (P=0.015, Cohen's d=0.65) but not in pitchers (P=0.596, Cohen's d=0.15). The fielder's average and maximum batting exit speeds were significantly higher in the CAF trial than in the PLA trial (P<0.05). The average and max fastball speeds of the CAF trial were significantly higher than that of the PLA trial in pitchers (P<0.05). CONCLUSIONS: The study showed that chewing gum containing two pieces of gum containing 100 mg of caffeine effectively improved female softball fielder's batting performance and pitcher's pitching performance.

In situ modification of foaming bacterial cellulose with chitosan and its application to active food packaging.

Owing to a lack of specific biological functions, bacterial cellulose (BC) has been restricted in its application to the field of active packaging. In this study, we developed antimicrobial packaging materials using foaming BC (FBC) with chitosan (CS) and applied it to the preservation of chilled sea bass. The material property analysis demonstrated that 1.5 % CS/FBC maintained a high water content of 91 %, a swelling ratio of 75.6 %, great stress of 1.61 MPa, and great strain of 1.87 %. CS incorporation into FBC also decreased its crystallinity from 73.39 % to 69.3 %. Meanwhile, 1.5 % CS/FBC also provided great antimicrobial ability against Escherichia coli and Staphylococcus aureus by approximately 2 log colony-forming units/mL inhibition utilizing contact-killing. Results of the preservation assessment indicated that 1.5 % CS/FBC efficiently inhibited Shewanella putrefaciens growth, reduced total volatile basic nitrogen release, and slightly inhibited lipid oxidation. Based on the above results, CS/FBC is an ecofriendly biomaterial produced from a microorganism that possesses high absorbency and strong antibacterial properties, making it suitable for development as antibacterial active packaging.

Magnetic conjugated microporous polymer for rapid extraction and sensitive analysis of environmental endocrine disruptors in environmental waters and dairy products.

BACKGROUND: Environmental endocrine disruptors (EEDs) are a class of new pollutants that are diffusely used in the medical industry and animal husbandry. In view of toxicity concerns, elevated levels of EEDs in the environment and food, which cause potential harm to human beings and ecosystems, must be monitored. Determination of EEDs contaminants to ensure environment and food safety has became a major concern worldwide, it is also a challenging task because of their trace level and probable matrices interference. Thus, developing rapid adsorption and efficient analysis methods for EEDs is apparently necessary. RESULTS: A magnetic conjugated micro-porous polymer (Fe3O4@TbDt) was designed and synthesized, which was endowed with large specific surface area, rich functional groups and magnetic responsiveness. The material showed high extraction efficiency for EEDs via magnetic solid-phase extraction (MSPE). The quantum chemistry calculations showed the adsorption mechanism of Fe3O4@TbDt on EEDs mainly included electrostatic interactions, van der waals forces (N-H … π interaction, C-H … π interaction), and multiple hydrogen bonds. Finally, a trace analysis method for nine EEDs was established combined with HPLC-MS/MS under optimized MSPE conditions. The method showed a good linearity (R2 ≥ 0.996), low limits of detection (0.25-5.1 ng L-1), high precision (RSD of 1.1-8.2 %, n = 6). The applicability of this method was investigated by analyzing four water samples and two dairy products, and satisfactory recovery rates (82.1-100.7 %) were obtained. The proposed method showed the potential for the analysis of EEDs residues in food and environmental samples. SIGNIFICANCE: The developed MSPE method based on conjugated micro-porous polymers (CMPs) is simple, green, and efficient compared to existing techniques. The application of CMPs provides a new idea for preparing versatile sample pre-treatment materials. What's more, this work has certain reference value for addressing of EEDs residues in the environment and food.

Novel metabolic and lipidomic biomarkers of sarcopenia.

BACKGROUND: The pathophysiology of sarcopenia is complex and multifactorial and has not been fully elucidated. The impact of resistance training and nutritional support (RTNS) on metabolomics and lipodomics in older adults with sarcopenia remains uncertain. This study aimed to explore potential biomarkers of sarcopenia and clinical indicators of RTNS in older sarcopenic adults. METHODS: Older individuals diagnosed with sarcopenia through routine health checkups at a community hospital were recruited for a 12-week randomized controlled trial focusing on RTNS. Plasma metabolomic and lipidomic profiles of 45 patients with sarcopenia and 47 matched controls were analysed using 1H-nuclear magnetic resonance (1H-NMR) and liquid chromatography-mass spectrometer (LC-MS). RESULTS: At baseline, the patient and control groups had similar age, sex, and height distribution. The patient group had significantly lower weight, BMI, grip strength, gait speed, skeletal muscle index, lean mass of both the upper and lower limbs, and lower limb bone mass. There was a significant difference in 12 metabolites between the control and patient groups. They are isoleucine (patient/control fold change [FC] = 0.86 ± 0.04, P = 0.0005), carnitine (FC = 1.05 ± 0.01, P = 0.0110), 1-methylhistamine/3-methylhistamine (FC = 1.24 ± 0.14, P = 0.0039), creatinine (FC = 0.71 ± 0.04, P < 0.0001), carnosine (FC = 0.71 ± 0.04, P = 0.0007), ureidopropionic acid (FC = 0.61 ± 0.10, P = 0.0107), uric acid (FC = 0.88 ± 0.03, P = 0.0083), PC (18:2/20:0) (FC = 0.69 ± 0.03, P = 0.0010), PC (20:2/18:0) (FC = 0.70 ± 0.06, P = 0.0014), PC (18:1/20:1) (FC = 0.74 ± 0.05, P = 0.0015), PI 32:1 (FC = 4.72 ± 0.17, P = 0.0006), and PI 34:3 (FC = 1.88 ± 0.13, P = 0.0003). Among them, carnitine, 1-methylhistamine/3-methylhistamine, creatinine, ureidopropionic acid, uric acid, PI 32:1, and PI 34:3 were first identified. Notably, PI 32:1 had highest diagnostic accuracy (0.938) for sarcopenia. 1-Methylhistamine/3-methylhistamine, carnosine, PC (18:2/20:0), PI 32:1, and PI 34:3 levels were not different from the control group after RTNS. These metabolites are involved in amino acid metabolism, lipid metabolism, and the PI3K-AKT/mTOR signalling pathway through the ingenuity pathway analysis. CONCLUSIONS: These findings provide information on metabolic changes, lipid perturbations, and the role of RTNS in patients with sarcopenia. They reveal new insights into its pathological mechanisms and potential therapies.

Columnar Organization of Nonalternant Fluorinated Dehydrobenzannulenes.

Two new partially fluorinated dehydrobenzannulenes have been prepared by inter- and intramolecular oxidative homocoupling of diyne precursors. These systems contain fluorinated and nonfluorinated arene rings in a non-alternant arrangement. Both macrocycles are roughly planar and organize into extended columns in the solid state. The assembly of these columns is mediated by the combination of dispersion interactions, slipped [π···π] stacking interactions of the perfluorinated rings with each other, and their association with the nonfluorinated rings in the molecules of the neighboring macrocycles. These results suggest that partial fluorination of dehydrobenzannulenes can serve as a versatile motif for their assembly into columnar superstructures.

Ajuga taiwanensis Extract Promotes Wound-healing via Activation of PDGFR/MAPK Pathway.

Chronic and prolonged wounds are a serious public problem that may severely affect the quality of life and result in psychological pressure. Fibroblasts play a crucial role in the wound process and in skin pathology. Herbal drugs have long been used for wound care worldwide. Ajuga taiwanensis (Lamiaceae) is a folk medicine for antipyretics, anti-inflammation, and reducing swelling in Taiwan. This study aimed to investigate the effect of A. taiwanensis in wound healing and the underlying mechanisms. Under human dermal fibroblast (HDF) wound-healing activity-guided fractionation, we found that a sub-fraction (AT-M) of A. taiwanensis extract (AT) and the major ingredients significantly promoted wound healing and decreased IL-1ß and - 6 expressions on HDFs. Furthermore, the fraction of AT-M enhanced wound healing on C57BL/6 mouse skins, increased PDGFR expressions, and activated the PDGFR/MAPK pathway. Taken together, A. taiwanensis extracts promote wound healing by the PDGFR pathway and lead to enhanced cell spreading and motility, thereby having a possible beneficial effect on wound healing.

Laser-induced optical breakdown is a prior strategy for acquired melanin-increased disorder in dermal layer.

This brief report discusses the challenges in treating dermal melanosis and the limitations of current laser treatments due to inadequate tissue penetration and potential side effects. It introduces laser-induced optical breakdown (LIOB) as a novel therapeutic approach using a picosecond laser with a diffractive lens array (DLA) to target dermal pigmentation effectively. LIOB induces multiphoton ionization, leading to melanin clearance through phagocytosis and apoptotic cell removal, while also promoting dermal remodeling and collagen synthesis. We present a case of successful treatment of dermal pigmentation in a 55-year-old woman using 755 nm-picosecond alexandrite laser therapy, demonstrating significant improvement without recurrence. The findings suggest that LIOB offers a promising solution for acquired dermal hypermelanosis by addressing both diffuse and localized pigmentation effectively, leading to skin rejuvenation with minimal downtime and high patient satisfaction.

Clinical outcomes of hydrofiber foam dressing in the treatment of abrasion wounds: A retrospective study.

Mopeds are a popular mode of transportation in Taiwan, yet collision accidents often lead to abrasion requiring medical attention. While hydrofiber foam dressing (HFD) have proven to help control exudates, reduce the frequency of dressing changes, and preserve more viable tissue, there is currently no established clinical guideline for the treatment of abrasion wounds with dressings. Therefore, the aim of this study was to investigate the clinical outcomes of abrasions treated with hydrofiber foam dressings. A total of 127 patients treated with HFDs between June 2018 and January 2021 were included in this study. Abrasions were categorized into 3 grades: grade I (n = 0) involving the epidermal layer, grade II (n = 89) involving the dermal layer, and grade III (n = 38) involving subcutaneous layer, bone or tendon. Statistical analysis showed that there was a significant difference in healing time (P < 0.001) and the number of outpatient department (OPD) visits (P = 0.013) between grade II and grade III. However, there was no significant difference in the number of dressing pieces used. This study offers a clinical reference for the use of hydrofiber foam dressings in treating different grades of abrasion wounds caused by moped accidents.

Downregulation of Rad51 Expression and Activity Potentiates the Cytotoxic Effect of Osimertinib in Human Non-Small Cell Lung Cancer Cells.

INTRODUCTION: Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has shown significant clinical benefits in patients with EGFR-sensitizing mutations or the EGFR T790M mutation. The homologous recombination (HR) pathway is crucial for repairing DNA double-strand breaks (DSBs). Rad51 plays a central role in HR, facilitating the search for homology and promoting DNA strand exchange between homologous DNA molecules. Rad51 is overexpressed in numerous types of cancer cells. B02, a specific small molecule inhibitor of Rad51, inhibits the DNA strand exchange activity of Rad51. Previous studies have indicated that B02 disrupted Rad51 foci formation in response to DNA damage and inhibited DSBs repair in human cells and sensitized them to chemotherapeutic drugs in vitro and in vivo. However, the potential therapeutic effects of combining osimertinib with a Rad51 inhibitor are not well understood. The aim of this study was to elucidate whether the downregulation of Rad51 expression and activity can enhance the osimertinib-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells. METHODS: We used the MTS, trypan blue dye exclusion and colony-formation ability assay to determine whether osimertinib alone or in combination with B02 had cytotoxic effects on NSCLC cell lines. Real-time polymerase chain reaction was conducted to measure the amounts of Rad51 mRNA. The protein levels of phosphorylated AKT and Rad51 were determined by Western blot analysis. RESULTS: We found that osimertinib reduced Rad51 expression by inactivating AKT activity. Rad51 knockdown using small interfering RNA or AKT inactivation through the phosphatidylinositol 3-kinase inhibitor LY294002 or si-AKT RNA transfection enhanced the cytotoxic and growth inhibitory effects of osimertinib. In contrast, AKT-CA (a constitutively active form of AKT) vector-enforced expression could mitigate the cytotoxic and cell growth inhibitory effects of osimertinib. Furthermore, B02 significantly enhanced the cytotoxic and cell growth inhibitory effects of osimertinib in NSCLC cells. Compared to parental cells, the activation of AKT and Rad51 expression in osimertinib-resistant cells could not be significantly inhibited by osimertinib treatment. Moreover, the increased expression of Rad51 is associated with the resistance mechanism in osimertinib-resistant H1975 and A549 cells. CONCLUSION: Collectively, the downregulation of Rad51 expression and activity enhances the cytotoxic effect of osimertinib in human NSCLC cells.

Treatment pattern among patients with relapsed/refractory multiple myeloma (RRMM) who had received pomalidomide-based regimens in Taiwan.

BACKGROUND/PURPOSE: The treatment landscape of relapsed/refractory multiple myeloma (RRMM) is rapidly evolving in Taiwan. The present study aimed to assess the treatment patterns among RRMM patients in Taiwan. METHODS: This retrospective, chart review-based, non-interventional study collected data on RRMM patients (≥20 years old) receiving pomalidomide-based treatment between January 2017 and December 2020 across five sites in Taiwan. RESULTS: Median age of the study population was 65.6 years. Approximately 75% patients received a doublet regimen and 25% were on a triplet regimen. Disease progression was the most common cause for switching to pomalidomide-based treatments in doublet (71.2%) and triplet (58.3%) groups. Patients in doublet and triplet groups (>80%) received 4 mg pomalidomide as a starting dose. Overall response rate (ORR: 31.5% and 45.8%) and median progression-free survival (PFS: 4.7 and 6.8 months) were reported in the doublet and triplet regimen. Doublet regimen was discontinued mainly due to disease progression or death (78.1%); however, triplet regimen patients mainly terminated their treatment due to reimbursement limitations (29.2%). Healthcare resource utilization (HRU) was comparable between doublet and triplet groups. CONCLUSION: In Taiwan, half of RRMM patients received pomalidomide-based triplet regimens. Triplet regimens showed a trend towards better outcomes with longer PFS and higher response rates compared to doublets. Notably, the duration of triplet use is influenced by reimbursement limitations. This study provides insight into RRMM treatment patterns in Taiwan and the findings suggest that triplet regimens may be a better alternative than doublet regimens.

Association between primary biliary cholangitis with diabetes and cardiovascular diseases: A bidirectional multivariable Mendelian randomization study.

BACKGROUND AND AIMS: Primary biliary cholangitis (PBC) is an autoimmune disease often accompanied by multisystem damage. This study aimed to explore the causal association between genetically predicted PBC and diabetes, as well as multiple cardiovascular diseases (CVDs). METHODS: Genome-wide association studies (GWAS) summary data of PBC in 24,510 individuals of European ancestry from the European Association for the Study of the Liver was used to identify genetically predicted PBC. We conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to estimate the impacts of PBC on diabetes (N = 17,685 to 318,014) and 20 CVDs from the genetic consortium (N = 171,875 to 1,030,836). RESULTS: SVMR provided evidence that genetically predicted PBC is associated with an increased risk of type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), heart failure (HF), hypertension, atrial fibrillation (AF), stroke, ischemic stroke, and small-vessel ischemic stroke. Additionally, there was no evidence of a causal association between PBC and coronary atherosclerosis. In the MVMR analysis, PBC maintained independent effects on T1D, HF, MI, and small-vessel ischemic stroke in most models. CONCLUSION: Our findings revealed the causal effects of PBC on diabetes and 7 CVDs, and no causal relationship was detected between PBC and coronary atherosclerosis.

Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.

Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. Here, we quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022. We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR: 1.66; 95% CI: 1.07, 2.59; p = 0.02) after the first dose. Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.

Epinephelus coioides Sec3 promotes Singapore grouper iridovirus infection by negatively regulates immune response.

Exocyst, a protein complex, plays a crucial role in various cellular functions, including cell polarization, migration, invasion, cytokinesis, and autophagy. Sec3, known as Exoc1, is a key subunit of the Exocyst complex and can be involved in cell survival and apoptosis. In this study, two subtypes of Sec3 were isolated from Epinephelus coioides, an important marine fish in China. The role of E. coioides Sec3 was explored during Singapore grouper iridovirus (SGIV) infection, an important pathogen of marine fish which could induce 90 % mortality. E. coioides Sec3 sequences showed a high similarity with that from other species, indicating the presence of a conserved Sec3 superfamily domain. E. coioides Sec3 mRNA could be detected in all examined tissues, albeit at varying expression levels. SGIV infection could upregulate E. coioides Sec3 mRNA. Upregulated Sec3 significantly promoted SGIV-induced CPE, and the expressions of viral key genes. E. coioides Sec3 could inhibit the activation of NF-κB and AP-1, as well as SGIV-induced cell apoptosis. The results illustrated that E. coioides Sec3 promotes SGIV infection by regulating the innate immune response.

An observational study on imported COVID-19 cases in Hong Kong during mandatory on-arrival hotel quarantine.

Background: Hong Kong enforced stringent travel restrictions during the COVID-19 pandemic. Understanding the characteristics of imported COVID-19 cases is important for establishing evidence-based control measures. Methods: Retrospective cohort study summarising the characteristics of imported cases detected in Hong Kong between 13 November 2020 and 31 January 2022, when compulsory quarantine was implemented. Findings: A total of 2269 imported COVID-19 cases aged 0-85 years were identified, of which 48.6 % detected on arrival. A shorter median delay from arrival to isolation was observed in Delta and Omicron cases (3 days) than in ancestral strain and other variants cases (12 days; p < 0.001). Lower Ct values at isolation were observed in Omicron cases than in ancestral strain or other variants cases. No Omicron cases were detected beyond 14 days after arrival. Cases detected after 14 days of quarantine (n=58, 2.6 %) were more likely asymptomatic at isolation and had higher Ct value during isolation, some of them indicating re-positivity or post-arrival infections. Conclusions: Testing inbound travellers at arrival and during quarantine can detect imported cases early, but may not prevent all COVID-19 introductions into the community. Public health measures should be adapted in response to the emergence of SARS-CoV-2 variants based on evidence from ongoing surveillance.