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Epithelial ovarian cancer (EOC) is the seventh most common cancer among women worldwide. The 5-year survival rate for women with EOC is only 30%-50%, which is largely due to the typically late diagnosis of this condition. EOC is difficult to detect in its early stage because of its asymptomatic nature. Recently, near-infrared fluorescent (NIRF) imaging has been developed as a potential tool for detecting EOC at the molecular level. In this study, a NIRF-sensitive probe was designed to detect matrix metalloproteinase (MMP) activity in ovarian cancer cells. A cyanine fluorochrome was conjugated to the amino terminus of a peptide substrate with enzymatic specificity for MMP-3. To analyze the novel MMP-3 probe, an in vivo EOC model was established by subcutaneously implanting SKOV3 cells, a serous-type EOC cell line, in mice. This novel MMP-3-sensitive probe specifically reacted with only the active MMP-3 enzyme, resulting in a significantly enhanced NIRF emission intensity. Histological analysis demonstrated that MMP-3 expression and activity were enhanced in the stromal cells surrounding the ovarian cancer cells. These studies establish a molecular imaging reporter for diagnosing early-stage EOC. Additional studies are required to confirm the early-stage activity of MMP-3 in EOC and its diagnostic and prognostic significance.

[This corrects the article DOI: 10.1371/journal.pone.0192047.].

Long-term nicotine-derived nitrosamine ketone (NNK) and arecoline exposure promotes carcinogenesis and head and neck squamous cell carcinoma (HNSCC) progression, although most associated data on the two were analyzed individually. The molecular mechanisms underlying tumor progression associated with the synergistic effects of NNK and arecoline remain unclear. We treated SCC-25 and FaDu cells with NNK and arecoline (separately or in combination) for 3 months. Comparative analysis was performed to investigate the mechanism underlying the acquisition of properties related to tumor promotion, including stemness, anti-apoptosis, and resistance to HNSCC therapeutics. Long-term exposure to NNK and arecoline resulted in an increase in cancer stem cell properties, anti-apoptosis, and the resistance to cisplatin in HNSCC. We detected abundant epidermal growth factor receptor (EGFR) expression in HNSCC cells after combined treatment with NNK and arecoline. EGFR was pivotal in inducing tumor promotion and anti-apoptosis in cancer cells by inducing pAKT and NFκB. Combined treatment with NNK and arecoline synergistically facilitated tumor aggressiveness via EGFR-AKT signaling. Targeting EGFR-AKT signaling may be a feasible strategy for treating HNSCC.

The rapid emergence and global dissemination of SARS-CoV-2 that causes COVID-19 continues to cause an unprecedented global health burden resulting in nearly 7 million deaths. While multiple vaccine countermeasures have been approved for emergency use, additional treatments are still needed due to sluggish vaccine rollout, vaccine hesitancy, and inefficient vaccine-mediated protection. Immunoadjuvant compounds delivered intranasally can guide non-specific innate immune responses during the critical early stages of viral replication, reducing morbidity and mortality. N-dihydrogalactochitosan (GC) is a novel mucoadhesive immunostimulatory polymer of β-0-4-linked N-acetylglucosamine that is solubilized by the conjugation of galactose glycans with current applications as a cancer immunotherapeutic. We tested GC as a potential countermeasure for COVID-19. GC was well-tolerated and did not produce histopathologic lesions in the mouse lung. GC administered intranasally before and after SARS-CoV-2 exposure diminished morbidity and mortality in humanized ACE2 receptor expressing mice by up to 75% and reduced infectious virus levels in the upper airway. Fluorescent labeling of GC shows that it is confined to the lumen or superficial mucosa of the nasal cavity, without involvement of adjacent or deeper tissues. Our findings demonstrate a new application for soluble immunoadjuvants such as GC for preventing disease associated with SARS-CoV-2 and may be particularly attractive to persons who are needle-averse.

Renalase is a secreted flavoprotein with anti-inflammatory and pro-cell survival properties. COVID-19 is associated with disordered inflammation and apoptosis. We hypothesized that blood renalase levels would correspond to severe COVID-19 and survival. In this retrospective cohort study, clinicopathologic data and blood samples were collected from hospitalized COVID-19 subjects (March-June 2020) at a single institution tertiary hospital. Plasma renalase and cytokine levels were measured and clinical data abstracted from health records. Of 3,450 COVID-19 patients, 458 patients were enrolled. Patients were excluded if

Although numerous epidemiological studies revealed an association between ambient fine particulate matter (PM2.5) exposure and Alzheimers disease (AD), the PM2.5-induced neuron toxicity and associated mechanisms were not fully elucidated. The present study assessed brain toxicity in 6-month-old female triple-transgenic AD (3xTg-AD) mice following subchronic exposure to PM2.5 via an inhalation system. The treated mice were whole-bodily and continuously exposed to real-world PM2.5 for 3 months, while the control mice inhaled filtered air. Changes in cognitive and motor functions were evaluated using the Morris Water Maze and rotarod tests. Magnetic resonance imaging analysis was used to record gross brain volume alterations, and tissue staining with hematoxylin and eosin, Nissl, and immunohistochemistry methods were used to monitor pathological changes in microstructures after PM2.5 exposure. The levels of AD-related hallmarks and the oxidative stress biomarker malondialdehyde (MDA) were assessed using Western blot analysis and liquid chromatography-mass spectrometry, respectively. Our results showed that subchronic exposure to environmental levels of PM2.5 induced obvious neuronal loss in the cortex of exposed mice, but without significant impairment of cognitive and motor function. Increased levels of phosphorylated-tau and MDA were also observed in olfactory bulb or hippocampus after PM2.5 exposure, but no amyloid pathology was detected, as reported in previous studies. These results revealed that a relatively lower level of PM2.5 subchronic exposure from the environmental atmosphere still induced certain neurodegenerative changes in the brains of AD mice, especially in the olfactory bulb, entorhinal cortex and hippocampus, which is consistent with the nasal entry and spreading route for PM exposure. Systemic factors may also contribute to the neuronal toxicity. The effects of PM2.5 after a more prolonged exposure period are needed to establish a more comprehensive picture of the PM2.5-mediated development of AD.

Background: Recently, there have been conflicting results reporting an increased risk of AR or MR associated with oral fluoroquinolones (FQs).This study investigated whether the use of FQs increases the risk of mitral regurgitation (MR) or aortic regurgitation (AR). Methods: A retrospective cohort study was conducted by using the Taiwan National Health Insurance research database. A unidirectional case-crossover design without selecting controls from an external population was adopted in this study. A total of 26,650 adult patients with new onset of AR or MR between January 1, 2000, and December 31, 2012, were identified. The risk of outcomes was compared between the hazard period and one of the randomly selected referent periods of the same individuals. Results: Before exclusion of pneumonia diagnosed within 2 months before the index date, patients who took FQs had a significantly greater risk of AR or MR (adjusted odds ratio [aOR] 1.51, 95% confidence interval [CI] 1.30–1.77), any AR (combined AR and MR) (aOR 1.50, 95% CI 1.10–2.04), and any MR (combined AR and MR) (aOR 1.37, 95% CI 1.16–1.62). After exclusion of pneumonia, FQs exposure remained significantly associated with a greater risk of MR (aOR 1.38, 95% CI 1.17–1.62) and any MR (aOR 1.25, 95% CI 1.05–1.48). Conclusions: The findings suggested that patients treated with FQs could be warned about the potential risk for MR even after considering the possibility of protopathic bias. Reducing unnecessary FQs prescriptions may be considered to reduce the risk of valvular heart disease. [ABSTRACT FROM AUTHOR]

OBJECTIVES:To develop, demonstrate and evaluate an automated deep learning method for multiple cardiovascular structure segmentation. BACKGROUND:Segmentation of cardiovascular images is resource-intensive. We design an automated deep learning method for the segmentation of multiple structures from Coronary Computed Tomography Angiography (CCTA) images. METHODS:Images from a multicenter registry of patients that underwent clinically-indicated CCTA were used. The proximal ascending and descending aorta (PAA, DA), superior and inferior vena cavae (SVC, IVC), pulmonary artery (PA), coronary sinus (CS), right ventricular wall (RVW) and left atrial wall (LAW) were annotated as ground truth. The U-net-derived deep learning model was trained, validated and tested in a 70:20:10 split. RESULTS:The dataset comprised 206 patients, with 5.130 billion pixels. Mean age was 59.9 ± 9.4 yrs., and was 42.7% female. An overall median Dice score of 0.820 (0.782, 0.843) was achieved. Median Dice scores for PAA, DA, SVC, IVC, PA, CS, RVW and LAW were 0.969 (0.979, 0.988), 0.953 (0.955, 0.983), 0.937 (0.934, 0.965), 0.903 (0.897, 0.948), 0.775 (0.724, 0.925), 0.720 (0.642, 0.809), 0.685 (0.631, 0.761) and 0.625 (0.596, 0.749) respectively. Apart from the CS, there were no significant differences in performance between sexes or age groups. CONCLUSIONS:An automated deep learning model demonstrated segmentation of multiple cardiovascular structures from CCTA images with reasonable overall accuracy when evaluated on a pixel level.

Introduction: Visceral metastasis is an important predictor for poor outcomes in prostate cancer, however, the prognostic significance surrounding the specific sites of visceral metastasis remains unclear. The aim of this study was to evaluate the impact of different visceral metastatic sites on survival in patients with prostate cancer. Methods: We identified patients with metastatic prostate cancer between January 1, 2010 and December 31, 2023 using the TriNetX database. Patients were divided into 4 cohorts according to their specific metastatic sites: lung metastases, brain metastases, liver metastases, and bone metastases. Survival analysis was calculated using the Kaplan-Meier method and Cox regression models. Results: In total, 59,875 patients diagnosed with metastatic prostate cancer were identified, with 39,495 (65.2%) having bone metastases, 7,573 (12.5%) lung metastases, 5,240 (8.7%) brain metastases, and 7,567 (12.5%) liver metastases. The median overall survival was 44.4 months for patients with bone metastases, 31.9 months for lung metastases, 9.6 months for brain metastases, and 10 months for liver metastases. Lung metastases were associated with an improved survival when compared with liver and brain metastases. For patients with two visceral metastatic sites or concomitant bone metastases, liver metastases were related to worse outcomes. Asian patients experienced better OS than Caucasian and African American patients in visceral metastatic prostate cancer. Conclusion: Patients with lung metastases experienced better survival outcomes in prostate cancer with only one visceral metastatic site. Liver metastases were associated with worse outcomes when there were two visceral metastatic sites combined or concomitant bone metastases. Asian patients displayed improved survival rates when compared with both Caucasian and African American patients in visceral metastatic prostate cancer. [ABSTRACT FROM AUTHOR]

CD19-targeted chimeric antigen receptor (CAR) T cell therapies have driven a paradigm shift in the treatment of relapsed/refractory B-cell malignancies. However, >50% of CD19-CAR-T-treated patients experience progressive disease mainly due to antigen escape and low persistence. Clinical prognosis is heavily influenced by CAR-T cell function and systemic cytokine toxicities. Furthermore, it remains a challenge to efficiently, cost-effectively, and consistently manufacture clinically relevant numbers of virally engineered CAR-T cells. Using a highly efficient piggyBac transposon-based vector, Quantum pBac™ (qPB), we developed a virus-free cell-engineering system for development and production of multiplex CAR-T therapies. Here, we demonstrate in vitro and in vivo that consistent, robust and functional CD20/CD19 dual-targeted CAR-T stem cell memory (CAR-TSCM) cells can be efficiently produced for clinical application using qPB™. In particular, we showed that qPB™-manufactured CAR-T cells from cancer patients expanded efficiently, rapidly eradicated tumors, and can be safely controlled via an iCasp9 suicide gene-inducing drug. Therefore, the simplicity of manufacturing multiplex CAR-T cells using the qPB™ system has the potential to improve efficacy and broaden the accessibility of CAR-T therapies. [ABSTRACT FROM AUTHOR]

Background: The lean soft tissue mass (LSTM) of the limbs is approximately 63% of total skeletal muscle mass. For athletes, measurement of limb LSTM is the basis for rapid estimation of skeletal muscle mass. This study aimed to establish the estimation equation of LSTM in Asian athletes using bioelectrical impedance analysis (BIA). Methods: A total of 198 athletes (121 males, 77 females; mean age 22.04 ± 5.57 years) from different sports in Taiwan were enrolled. A modeling group (MG) of 2/3 (n = 132) of subjects and a validation group (VG) of 1/3 (n = 68) were randomly assigned. Using the InBody S-10, resistance and reactance were measured at 50 kHz from the right palm to the right sole while the participant was in the supine position. Predictor variables were height (h), weight (W), age, Sex, Xc, resistance index (RI; RI = h2 / R). LSTM of arms and legs measured by dual-energy X-ray absorptiometry (DXA) was the response variable. Multivariate stepwise regression analysis method was used to establish BIA estimation equations as ArmsLSTMBIA-Asian and LegsLSTMBIA-Asian. Estimation equations performance was confirmed by cross-validation. Results: Estimation equation "ArmsLSTMBIA-Asian = 0.096 h2/R– 1.132 Sex + 0.030 Weight + 0.022 Xc– 0.022 h + 0.905, r2 = 0.855, SEE = 0.757 kg, n = 132" and "LegsLSTMBIA Asian = 0.197h2/R" + 0.120 h– 1.242 Sex + 0.055 Weight– 0.052 Age + 0.033 Xc –16.136, r2 = 0.916, SEE = 1.431 kg, n = 132" were obtained from MG. Using DXA measurement results of VG for correlation analysis and Limit of Agreement (LOA) of Bland-Altman Plot, ArmsLST is 0.924, -1.53 to 1.43 kg, and LegsLST is 0.957, -2.68 to 2.90 kg. Conclusion: The established single-frequency BIA hand-to-foot (whole body) estimation equation quickly and accurately estimates LSTM of the arms and legs of Asian athletes. [ABSTRACT FROM AUTHOR]

Purpose: A cross-sectional study was conducted to investigate the feasibility of implementing routine collection of the Euro-Qol 5 dimensions (EQ-5D) questionnaire, to inform drug and health technology reimbursement decision making. Methods: Women with breast cancer were recruited during scheduled clinic visits to an academic cancer centre. EQ-5D-5L was self-administered using electronic tablets. Diagnostic and treatment data were abstracted from patient charts. Feasibility was assessed primarily by the proportion of patients who fully completed EQ-5D-5L and by their willingness to complete the instrument at each clinic visit. Results: 588 women were approached for study participation, 341 were enrolled. Fully completed EQ-5D-5L questionnaires were obtained in 323 participants (95% of participants, 95% CI 92–97%). Median time for EQ-5D-5L completion was 1.5 minutes (range:0.35 to 14.7). Mean age of participants was 58 years old. Most women who completed EQ-5D were White, born outside Canada and presented a high education level; one-quarter had metastatic disease. Most participants reported "No problems" in all EQ-5D-5L dimensions. Mean EQ-5D-5L index and mean EQ-5D-5L VAS values for all participants were respectively 0.83 (SD 0.13) and 75.7 (SD 17.45), with patients with metastatic disease scoring the lowest values. Seventy-eight percent of participants were willing to complete EQ-5D-5L at each clinic visit; lower Charlson comorbidity index and higher education level were predictors of willingness to continue to answer EQ-5D-5L. Conclusions: Tablet-based collection of EQ-5D-5L in the context of routine clinical practice proved to be feasible. However, many patients declined study participation or reported being in full health, raising concerns about whether this method of collecting EQ-5D adequately represents the health status of all breast cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the IOP-lowering efficacy and safety of latanoprostene bunod (LBN) ophthalmic solution 0.024% (Vyzulta®), the first topical nitric oxide-donating prostaglandin analog (PGA), in clinical practice. Materials and methods: A retrospective medical chart review from July 2021 to July 2023 of patients with open-angle glaucoma receiving LBN with at least 1 year follow–up was conducted. All included patients received LBN 0.024% as a replacement for a PGA, with examinations at 1-, 3-, 6-and 12-months follow-up. Main outcome measures were IOP, retinal nerve fiber layer thickness, visual fields before/after LBN use and adverse effects. Subgroup analysis with glaucoma types and PGA use were performed for additional IOP reduction after LBN use. Results: Among 78 included patients, 47 patients (81 eyes), 60% with open-angle glaucoma (OAG) remained on LBN throughout 12-month follow-up. Baseline IOP was 18.2±4.2 mm Hg, and Prostaglandin analog (PGA)-IOP was 14.4 ± 3.0 mm Hg (21% mean IOP reduction). After switched to LBN, mean additional IOP reduction was 1.0 mm Hg at month 1, and the greatest reduction was 1.6 mm Hg (8.8% additional mean IOP reduction) at month 12 (P<0.0001). Subgroup analysis (NTG, 73%) showed that mean additional IOP reduction at month 12 was 1.3±2.0 mm Hg in NTG group and 2.1±3.2 mm Hg in POAG group (7.7% vs. 8.7% additional IOP reduction rates, P = 0.23). Subgroup analysis of PGA use at month 12 was 1.8±2.3 mm Hg in tafluoprost group and 0.5±1.7 mm Hg in travoprost group (9.5% vs.2.6% additional IOP reduction rates, P = 0.02). Tolerable ocular adverse effects included irritation (n = 16, 19.8%), mild conjunctival hyperemia (n = 11, 13.6%), dark circles (n = 4, 4.9%) and blurred vision (n = 2, 2.5%). There were no significant visual field and retinal nerve fiber layer thickness changes after 12 months of treatment with LBN 0.024%. Conclusions: Although high intolerable adverse effects including conjunctival hyperemia and eye irritation happened in the first month, remaining sixty percent of patients exhibited statistically significant additional IOP reductions in the replacement of other PGAs during 12 months of clinical use of LBN 0.024%. [ABSTRACT FROM AUTHOR]

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease that causes dysfunction of salivation and harmful oral conditions. The association between periodontal disease (PD) and pSS with or without geniquin therapy remains controversial. This study evaluated the association between geniquin therapy and the risk of subsequent development of PD in pSS patients. From Taiwan's National Health Insurance Research Database, we selected a control cohort of 106,818 pSS patients, followed up from 2000 to 2015, matched (1:4) by age and index year with 427,272 non-pSS patients. We also analyzed 15,149 pSS patients receiving geniquin therapy (cohort 1) and 91,669 pSS patients not receiving geniquin therapy (cohort 2). After adjusting for confounding factors, multivariate Cox proportional hazards regression analysis was used to compare the risk of PD over the 15-year follow-up. In the control cohort, 11,941 (11.2%) pSS patients developed PD compared to 39,797 (9.3%) non-pSS patients. In cohorts 1 and 2, 1,914 (12.6%) pSS patients receiving geniquin therapy and 10,027 (10.9%) pSS patients not receiving geniquin therapy developed PD. The adjusted hazard ratio (HR) for subsequent PD in pSS patients was 1.165 (95% confidence interval [CI] = 1.147–1.195, p < 0.001) and in pSS patients receiving geniquin therapy was 1.608 (95% CI = 1.526–1.702, p < 0.001). The adjusted HR for PD treatment was 1.843. Patients diagnosed with pSS showed an increased risk of developing subsequent PD and receiving PD treatment than patients without pSS, while pSS patients receiving geniquin therapy showed even higher risks. [ABSTRACT FROM AUTHOR]

There is limited research about how groups solve collective action problems in uncertain environments, especially if groups are confronted with unknown unknowns. We aim to develop a more comprehensive view of the characteristics that allow both groups and individuals to navigate such issues more effectively. In this article, we present the results of a new online experiment where individuals make decisions of whether to contribute to the group or pursue self-interest in an environment with high uncertainty, including unknown unknowns. The behavioral game, Port of Mars is framed as a first-generation habitat on Mars where participants have to make decisions on how much to invest in the shared infrastructure to maintain system health and how much to invest in personal goals. Participants can chat during the game, and take surveys before and after the game in order to measure personality attributes and observations from the game. Initial results suggest that a higher average social value orientation and more communication are the key factors that explain why some groups are more successful than others in surviving Port of Mars. Neither other attributes of players nor the group's communication content explain the observed differences between groups. [ABSTRACT FROM AUTHOR]

The relationship between molybdenum and kidney-related disease outcomes, including hyperuricemia, is not well investigated. This study aims to determine whether molybdenum and its antioxidative property are associated with systemic inflammation and kidney-related disease parameters including hyperuricemia. Urinary molybdenum's epidemiological relationship to hyperuricemia and kidney-disease related outcomes was evaluated in 15,370 adult participants in the National Health and Nutrition Examination Survey (NHANES) collected between 1999 and 2016. Individuals' urinary molybdenum levels were corrected to their urinary creatinine concentrations. The association between urinary molybdenum-to-creatinine ratio and kidney-disease related outcomes were assessed by multivariable linear and logistic regression analyses, adjusting for covariates including age, sex, ethnicity, diabetes mellitus, hypertension, body mass index, and estimated glomerular filtration rate. Antimony and tungsten were used as control trace metals. Experimentally, HK-2 cell was used to assess molybdenum's antioxidative properties. HK-2 cells were challenged with H2O2-induced oxidative stress. Oxidative stress was measured using a fluorescent microplate assay for reactive oxygen species (ROS) and antioxidation levels were assessed by measuring the expression of manganese superoxide dismutase. In the adult NHANES population, urinary molybdenum-to-creatinine ratio was significantly associated with decreased serum uric acid (β, -0.119; 95% CI, -0.148 to -0.090) concentrations, and decreased prevalence of hyperuricemia (OR, 0.73; 95% CI, 0.64–0.83) and gout (OR, 0.71; 95% CI, 0.52–0.94). Higher urinary molybdenum levels were associated with lower levels of systemic oxidative stress (gamma-glutamyltransferase levels; β, -0.052; 95% CI, -0.067 to -0.037) and inflammation (C-reactive protein levels; β, -0.184; 95% CI, -0.220 to -0.148). In HK-2 cells under H2O2-induced oxidative stress, molybdenum upregulated manganese superoxide dismutase expression and decreased oxidative stress. Urinary molybdenum levels are associated with decreased prevalence of hyperuricemia and gout in adult population. Molybdenum's antioxidative properties might have acted as an important mechanism for the reduction of systemic inflammation, ROS, and uric acid levels. [ABSTRACT FROM AUTHOR]

Objectives: Parents of children diagnosed with severe-to-profound sensorineural hearing loss may experience a range of emotions owing to a lack of knowledge and experience in dealing with such children. However, most audiology clinics only attend to children with deaf and hard of hearing (DHH) and not their parents. Thus, parents' emotional and support needs are frequently excluded from the intervention sessions, making their own needs invisible. This study aimed to identify academic and clinical instruments used for assessing parental emotional status (PES) and ecological support systems (ESS) in early intervention and determine the factors affecting PES and ESS among parents of DHH children undergoing cochlear implantation. Materials and methods: This scoping review followed the rigorous methodological framework; searched Medline (via OVID and EMBSCO), Scopus, and Web of Science; and selected studies relevant to validated instruments used to evaluate the PES and ESS among parents of DHH children below 6 years old. Before selecting and reviewing relevant articles, two reviewers independently assessed article titles and abstracts from the data sources. Two reviewers verified half of the first reviewer's extracted data. Results: Overall, 3060 articles were retrieved from the database search, and 139 were selected for full-text review following title and abstract reviews. Ultimately, this study included 22 articles. Among them, 23 and 12 validated instruments, most of which are generic measures, were used for assessing PES and ESS, respectively. Three condition-specific instruments were identified and designed to be administered following cochlear implantation surgery. Conclusions: This study revealed that healthcare professionals who interact with parents of DHH children lack the necessary instruments, particularly for parents of children undergoing cochlear implantation surgery. Therefore, it is necessary to develop condition-specific instruments for parents who consider cochlear implantation for their children. [ABSTRACT FROM AUTHOR]

Deubiquitinating enzymes (DUBs) play a pivotal role in regulating the antiviral immune response by targeting members of the RLR signaling pathway. As a pivotal member of the RLR pathway, TRAF3 is essential for activating the MAVS/TBK-1/IRF3 signaling pathway in response to viral infection. Despite its importance, the function of DUBs in the TRAF3-mediated antiviral response is poorly understood. Ubiquitin-specific protease 26 (USP26) regulates the RLR signaling pathway to modulate the antiviral immune response. The results demonstrate that EV71 infection upregulates the expression of USP26. Knockdown of USP26 significantly enhances EV71-induced expression of IFN-β and downstream interferon-stimulated genes (ISGs). Deficiency of USP26 not only inhibits EV71 replication but also weakens the host's resistance to EV71 infection. USP26 physically interacts with TRAF3 and reduces the K63-linked polyubiquitination of TRAF3, thereby promoting pIRF3-mediated antiviral signaling. USP26 physically interacts with TRAF3 and reduces the K63-linked polyubiquitination of TRAF3, thereby promoting pIRF3-mediated antiviral signaling. Conversely, knockdown of USP26 leads to an increase in the K63-linked polyubiquitination of TRAF3. These findings unequivocally establish the essential role of USP26 in RLR signaling and significantly contribute to the understanding of deubiquitination-mediated regulation of innate antiviral responses. [ABSTRACT FROM AUTHOR]

Importance: The COVID-19 pandemic has led to 775 million documented cases and over 7 million deaths worldwide as of March 2024 and is an ongoing health crisis. To limit viral spread within households and in the community, public health officials have recommended self-isolation, self-quarantine of exposed household contacts, and mask use. Yet, risk of household transmission (HHT) may be underestimated due to low frequency of sampling, and risk factors for HHT are not well understood. Objectives: To estimate the secondary attack rate of SARS-CoV-2 within households and to define the risk factors for new infections in household members who are in close contact with the index case. Design, setting, and participants: In this prospective cohort study, from March 2020—December 2021 we enrolled 60 households with index cases who tested positive for SARS-CoV-2. All household contacts and index cases were tested daily for SARS-CoV-2 via reverse transcription polymerase chain reaction (RT-PCR) using self-collected anterior nares specimens. Households were followed until all study participants in the household tested negative for SARS-CoV-2 for seven consecutive days. We collected sex, age, race/ethnicity, comorbidities, and relationship to index case for secondary contacts, household level characteristics including primary income, household density, and square feet per person on property. We compared the sociodemographic variables between COVID-19 positive and negative household members and between households where secondary transmission did and did not occur. Main outcomes and measures: Daily anterior nares swabs were tested for SARS-CoV-2 using RT-PCR, in order to assess duration of nasal shedding of SARS-CoV-2, as well as risk of transmission to secondary household contacts. Results: Of the 163 participants in this study, 84 (51.5%) were women; median age (IQR) was 36.0 (17.0–54.0) years of age; 78 (47.8%) were white and 48 (29.5%) were Hispanic/LatinX. Of the fifty households with household contacts, at least one secondary case occurred in twenty-six households (52.0%) and forty-five household contacts (43.7%) were infected. Secondary attack rate was lowest among children of index cases (6/23, 26.1%). Modified Poisson regression identified that the risk of transmission to household contacts increases significantly with age (Risk ratio for each increase in years of age = 1.01, 95% CI = 1.00–1.02). Mixed effects regression models identified that participants with chronic diseases, such as asthma, diabetes, cancer, or cardiac disease, had higher Cts at baseline when compared to participants without chronic diseases (6.62, 95% CI: 1.46–11.77, p = 0.02) and show a slower rate of increase in Ct over time (-0.43, 95% CI: -0.77 to -0.09, p = 0.02) Conclusions and relevance: This study suggests that HHT represents a key source of community-based infection of SARS-CoV-2. Allocation of resources for contact investigations and prevention interventions should focus on the individuals at highest risk of infection in households, especially those with higher density homes. [ABSTRACT FROM AUTHOR]

Abnormal speech prosody has been widely reported in individuals with autism. Many studies on children and adults with autism spectrum disorder speaking a non-tonal language showed deficits in using prosodic cues to mark focus. However, focus marking by autistic children speaking a tonal language is rarely examined. Cantonese-speaking children may face additional difficulties because tonal languages require them to use prosodic cues to achieve multiple functions simultaneously such as lexical contrasting and focus marking. This study bridges this research gap by acoustically evaluating the use of Cantonese speech prosody to mark information structure by Cantonese-speaking children with and without autism spectrum disorder. We designed speech production tasks to elicit natural broad and narrow focus production among these children in sentences with different tone combinations. Acoustic correlates of prosodic focus marking like f0, duration and intensity of each syllable were analyzed to examine the effect of participant group, focus condition and lexical tones. Our results showed differences in focus marking patterns between Cantonese-speaking children with and without autism spectrum disorder. The autistic children not only showed insufficient on-focus expansion in terms of f0 range and duration when marking focus, but also produced less distinctive tone shapes in general. There was no evidence that the prosodic complexity (i.e. sentences with single tones or combinations of tones) significantly affected focus marking in these autistic children and their typically-developing (TD) peers. [ABSTRACT FROM AUTHOR]

To explore the application efficacy and significance of deep learning in anesthesia management for gastrointestinal tumors (GITs) surgery, 80 elderly patients with GITs who underwent surgical intervention at our institution between January and September 2021 were enrolled. According to the preoperative anesthesia management methodology, patients were rolled into a control (Ctrl) group (using 10 mg dexamethasone 1–2 hours before surgery) and an experimental (Exp) group (using a deep learning-based anesthesia monitoring system on the basis of the Ctrl group), with 40 cases in each group. A comprehensive comparative analysis was performed between the two cohorts, encompassing postoperative cognitive evaluations, Montreal Cognitive Assessment (MoCA) scores, gastrointestinal functionality, serum biomarkers (including interleukin (IL)-6, C-reactive protein (CRP), and cortisol levels), length of hospitalization, incidence of complications, and other pertinent metrics. The findings demonstrated that anesthesia monitoring facilitated by deep learning algorithms effectively assessed the anesthesia state of patients. Compared to the Ctrl group, patients in the Exp group showed significant differences in cognitive assessments (word recall, number connection, number coding) (P<0.05). Additionally, the Exp group exhibited a notably increased MoCA score (25.3±2.4), significantly shorter time to first flatus postoperatively (35.8±13.7 hours), markedly reduced postoperative pain scores, significantly shortened time to tolerate a liquid diet postoperatively (19.6±5.2 hours), accelerated recovery of serum-related indicators, and a significantly decreased mean length of hospital stay (11.4±3.2 days) compared to the Ctrl group. In summary, administering dexamethasone under the anesthesia management of GITs surgery based on gradient boosting decision tree (GBDT) and pharmacokinetics pharmacodynamics (PKPD) models can promote patient recovery, reduce the incidence of postoperative cognitive impairment (POCD), and improve patient prognosis. [ABSTRACT FROM AUTHOR]

The challenges of the COVID-19 pandemic have highlighted an increasing clinical demand for safe and effective treatment options against an overzealous immune defence response, also known as the "cytokine storm". Andrographolide is a naturally derived bioactive compound with promising anti-inflammatory activity in many clinical studies. However, its cytokine-inhibiting activity, in direct comparison to commonly used nonsteroidal anti-inflammatory drugs (NSAIDs), has not been extensively investigated in existing literature. The anti-inflammatory activities of andrographolide and common NSAIDs, such as diclofenac, aspirin, paracetamol and ibuprofen were measured on lipopolysaccharide (LPS) and interferon-γ induced RAW264.7 cells. The levels of PGE2, nitric oxide (NO), TNF-α & LPS-induced release of pro-inflammatory cytokines on differentiated human macrophage THP-1 cells were measured against increasing concentrations of andrographolide and aforementioned NSAIDs. The associated mechanistic pathway was examined on NFκB using flow cytometry on the human endothelial-leukocyte adhesion molecule (ELAM9) (E-selectin) transfected RAW264.7 cells with green fluorescent protein (GFP). Andrographolide exhibited broad and potent anti-inflammatory and cytokine-inhibiting activity in both cell lines by inhibiting the release of IL-6, TNF-α and IFN-γ, which are known to play a key role in the etiology of cytokine storm and the pathogenesis of inflammation. In comparison, the tested NSAIDs demonstrated weak or no activity against proinflammatory mediators except for PGE2, where the activity of andrographolide (IC50 = 8.8 μM, 95% CI = 7.4 to 10.4 μM) was comparable to that of paracetamol (IC50 = 7.73 μM, 95% CI = 6.14 to 9.73 μM). The anti-inflammatory action of andrographolide was associated with its potent downregulation of NFκB. The wide-spectrum anti-inflammatory activity of andrographolide demonstrates its therapeutic potential against cytokine storms as an alternative to NSAIDs. [ABSTRACT FROM AUTHOR]

Background: This pilot study aimed to investigate medication nonadherence among Taiwanese patients with diabetes, hypertension, and hyperlipidemia using the Chinese version of the Two-Part Medication Nonadherence Scale (C-TPMNS) and the National Health Insurance (NHI) Medicloud system. The study revealed insights into the factors contributing to nonadherence and the implications for improving patient adherence to medications for chronic conditions. However, the small sample size limits the generalizability of the findings. Additionally, the study identified the need for further research with larger and more diverse samples to validate the preliminary findings. Methods: The study conducted surveys individuals in central Taiwan who received three-high medications and those who returned expired medications from chain pharmacies. A structured questionnaire including the C-TPMNS was administered, and additional data on medical history and HbA1c, LDL, and blood pressure levels were collected from the NHI Medicloud system. Data analysis was performed using multiple ordered logistic regression and Wald test methods. Setting interpretation cutoff point to determine medication nonadherence. Results: The study found that 25.8% of participants were non-adherent to prescribed medications. Non-adherent individuals had significantly higher systolic blood pressure (SBP ≥ 140 mmHg) than adherent participants. Non-adherence was also associated with factors such as lower education, single status, living alone, abnormal glucose postprandial concentration, and triglyceride levels. The C-TPMNS demonstrated good reliability (Cronbach's alpha = 0.816) and validity (area under the ROC curve = 0.72). Conclusion: The study highlighted the complexity of medication nonadherence with diverse determinants and emphasized the importance of tailored interventions. The findings underscored the need for region-specific research to comprehensively address medication nonadherence, especially focusing on adherence to medications for hypertension, hyperlipidemia, and diabetes. The study also identified the need for larger, more diverse studies to validate and expand upon the initial findings and emphasized the importance of pharmacist interventions and patient empowerment in managing chronic conditions and improving overall health outcomes. [ABSTRACT FROM AUTHOR]

Objective: This study examines the association between changes in mental health before and during the COVID-19 pandemic and COVID-19 mortality across geographic areas and by race/ethnicity. Methods: A cross-sectional survey was conducted in Los Angeles County between April and May 2021. The study used the Patient Health Questionnaire-2 to assess major depression risk. Participants' home ZIP codes were classified into low, middle, and high COVID-19 mortality impacted areas (CMIA). Results: While there were existing mental health disparities due to differences in demographics and social determinants of health across CMIA in 2018, the pandemic exacerbated the disparities, especially for residents living in high CMIA. Non-White residents in high CMIA reported the largest deterioration in mental health. Differences in mental health by CMIA persisted after controlling for resident characteristics. Conclusions: Living in an area with higher COVID-19 mortality rates may have been associated with worse mental health, with Non-White residents reporting worse mental health outcomes in the high mortality area. Policy implications: It is crucial to advocate for greater mental health resources in high COVID-19 mortality areas especially for racial/ethnic minorities. [ABSTRACT FROM AUTHOR]

As most teleosts are unable to synthesize vitamin C, supplemental diets containing vitamin C diets play a crucial role in fish health. The aim of this study was to investigate the effect of dietary vitamin C on the intestinal enzyme activity and intestinal microbiota of silver pomfre (Pampus argenteus). Four experimental diets were supplemented with basic diets containing 300 mg of vitamin C/kg (group tjl3), 600 mg of vitamin C/kg (group tjl6), and 1200 mg of vitamin C/kg (group tjl12), as well as vitamin C-free supplemental basic diet (group tjl0), respectively. The four diets were fed to juvenile P. argenteus (average initial weight: 4.68 ± 0.93 g) for 6 weeks. The results showed that the activity of SOD (superoxide dismutase) and CAT (catalase) increased significantly while that of MDA (malondialdehyde) decreased significantly in group tjl3 compared to vitamin group tjl0. At the genus level, groups tjl0, tjl6, and tjl12 contained the same dominant microbial community, Stenotrophomonas, Photobacterium, and Vibrio, whereas group tjl3 was dominated by Stenotrophomonas, Delftia, and Bacteroides. Among the fish fed with a basic diet containing 300 mg of vitamin C/kg, the intestines exhibited a notable abundance of probiotic bacteria, including lactic acid bacteria (Lactobacillus) and Bacillus. The abundance of Aeromonas in groups tjl3 and tjl6 was lower than that of the vitamin C-free supplemental basic diet group, whereas Aeromonas was not detected in group tjl12. In addition, a causative agent of the disease outbreak in cultured P. argenteus, Photobacterium damselae subsp. Damselae (PDD) was the dominant microbiota community in groups tjl0, tjl6 and tjl12, whereas the abundance of PDD in group tjl3 was the lowest among the diets. Taken together, the diets supplied with vitamin C could influence the composition microbial community of P. argenteus. The low level of vitamin C (300 mg of vitamin C/kg per basic diet) supplementation could not only improve the antioxidant capacity but also resist the invasion of pathogenic bacteria. [ABSTRACT FROM AUTHOR]

Background and aim: Mild hypothermia in hepatic ischemia-reperfusion injury is increasingly being studied. This study aimed to conduct a systematic evaluation of the effectiveness of mild hypothermia in improving hepatic ischemia-reperfusion injury. Methods: We systematically searched CNKI, WanFang Data, PubMed, Embase, and Web of Science for original studies that used animal experiments to determine how mild hypothermia(32–34°C) pretreatment improves hepatic ischemia-reperfusion injury(in situ 70% liver IR model). The search period ranged from the inception of the databases to May 5, 2023. Two researchers independently filtered the literature, extracted the data, and assessed the risk of bias incorporated into the study. The meta-analysis was performed using RevMan 5.4.1 and Stata 15 software. Results: Eight randomized controlled trials (RCTs) involving a total of 117 rats/mice were included. The results showed that the ALT levels in the mild hypothermia pretreatment group were significantly lower than those in the normothermic control group [Standardized Mean Difference (SMD) = -5.94, 95% CI(-8.09, -3.78), P<0.001], and AST levels in the mild hypothermia pretreatment group were significantly lower than those in the normothermic control group [SMD = -4.45, 95% CI (-6.10, -2.78), P<0.001]. The hepatocyte apoptosis rate in the mild hypothermia pretreatment group was significantly lower than that in the normothermic control group [SMD = -6.86, 95% CI (-10.38, -3.33), P<0.001]. Hepatocyte pathology score in the mild hypothermia pretreatment group was significantly lower than that in the normothermic control group [SMD = -4.36, 95% CI (-5.78, -2.95), P<0.001]. There was no significant difference in MPO levels between the mild hypothermia preconditioning group and the normothermic control group [SMD = -4.83, 95% CI (-11.26, 1.60), P = 0.14]. SOD levels in the mild hypothermia preconditioning group were significantly higher than those in the normothermic control group [SMD = 3.21, 95% CI (1.27, 5.14), P = 0.001]. MDA levels in the mild hypothermia pretreatment group were significantly lower than those in the normothermic control group [SMD = -4.06, 95% CI (-7.06, -1.07) P = 0.008]. Conclusion: Mild hypothermia can attenuate hepatic ischemia-reperfusion injury, effectively reduce oxidative stress and inflammatory response, prevent hepatocyte apoptosis, and protect liver function. [ABSTRACT FROM AUTHOR]