New Isocoumarins from An Endophytic Fungal Strain Diaporthe arengae M2 and Their Antibacterial Activities.

Four new isocoumarin derivatives 12-O-acetyl-isocitreoisocoumarinol (1), (+)-(10R)-O-acetyl-diaportinol (2-a), (-)-(10S)-O-acetyl-diaportinol (2-b), peyroisocoumarin E (3) and new stereoconfigurations of three isocoumarin derivatives desmethyldichlorodiaportinol A (4), threo-monochlorodiaportinol A (5-a), erytheo-monochlorodiaportinol A (5-b), together with nine known ones (6-14), were separated from the rice fermentation of endophytic fungus Diaporthe arengae M2 isolated from Camellia oleifera. The structures of new compounds were determined by extensive spectroscopic analyses including nuclear magnetic resonance (NMR) and high resolution electrospray ionization mass spectroscopy (HR-ESI-MS). Compounds 4, 7, 8, 12, 13 exhibited definite inhibition against five strains of bacteria with the MIC values range from 16 µg/mL to 64 µg/mL.

Neutralizing Chimeric Anti-F1 Monoclonal Antibody against Yersinia pestis Infection.

Drug-resistant Yersinia pestis (Y. pestis) poses a threat to the use of antibiotics to treat Y. pestis infections. Passive immunization with neutralizing monoclonal antibodies (mAbs) is one approach to the treatment of infectious diseases. In this study, a murine single-chain fragment variable (scFv) phage antibody library targeting the F1 antigen was constructed and screened. Therapeutic intravenous injection of 400 µg chimeric mAb S1 through tail veins provided complete protection against Y. pestis (strain: 91001) challenge in a pneumonic plague mouse model. Timely antibody treatment eliminated the bacteria and reduced lung inflammation. Our data suggest that chimeric mAb S1 is a candidate treatment for Y. pestis infection that warrants further study.

Robot-assisted therapy in stratified intervention: a randomized controlled trial on poststroke motor recovery.

Objective: To compare the effects of robot-assisted therapy with conventional therapy for accelerating stratified intervention in poststroke patients with upper limb dysfunction. Background: For stroke survivors, recovery of upper extremity function remains a major challenge in rehabilitation. Literature has suggested that the rate of recovery may improve if treatments can be individualized to their clinical profiles. However, there still lack clinical evidence on how to create treatment tailored to individual patients. Robot-assisted Therapy (RT) provides a straightforward approach to adjustment of the assistance-resistance continuum for individual patients. In early Brunnstrom stages of recovery, patients benefit from assistance training, whereas in later stages the training is favored with resistance. Therefore, RT may enhance Conventional Therapy (CT) but the use of RT in stratified intervention has not been investigated. This study evaluated the possible benefit of adopting RT following a protocol of upper-limb training, which was stratified with the Brunnstrom stage of each individual. Methods: This study was a single-blinded randomized controlled trial. A total of 53 patients with stroke were recruited and randomized into 2 groups (CT, n = 27, 3 dropped out and RT, n = 26, 2 dropped out). Both groups were trained once per day, 5 days per week for 4 weeks. The CT group received 30 min of conventional therapy; the RT group received 30 min of upper limb robot-assisted training. Patients were assessed at the beginning, week-2, and week-4 of the treatment. The outcome measures included the Fugl-Meyer Assessment Upper-Extremity (FMA-UE) and the Modified Barthel Index (MBI). Results: Across the 4-week intervention, participants in the RT group recovered 1.979 points of FMA-UE per week, compared to 1.198 points per week in the CT group (t94 = 3.333, p < 0.01); the recovery rate was 0.781 points/week higher in the RT group than in the CT group. Moreover, the recovery of FMA-UE was faster in proximal joints (t94 = 3.199, p < 0.01), and for patients in Brunnstrom Stage III (t34 = 2.526, p < 0.05). The improvements in MBI were not significantly different between RT and CT. Conclusion: Robot-assisted therapy showed initial evidence for the acceleration of post-stroke recovery of motor function in the upper limb. Initial observations suggested that patients in Brunnstrom recovery stage III might benefit the most from the stratified intervention assisted by robotics. Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=61834, Identifier [ChiCTR2000039010]. Registered 13 March 2020.

Inhibiting glycosphingolipids alleviates cardiac hypertrophy by reducing reactive oxygen species and restoring autophagic homeostasis.

Introduction: Cardiac hypertrophy is a compensatory stress response produced by a variety of factors, and pathologic hypertrophy can lead to irreversible, severe cardiac disease. Glycosphingolipids (GSLs) are vital constituents of cells, and changes in their content and composition are important factors causing mitochondrial dysfunction in diabetic cardiomyopathy; however, the relationship between GSLs expression and cardiac hypertrophy and specific mechanisms associated with it are not clear. Methods: Here, using male C57BL/6 mice, we performed aortic arch reduction surgery to establish an animal model of pressure overload cardiac hypertrophy. In addition, phenylephrine was used in vitro to induce H9c2 cells and neonatal rat left ventricular myocytes (NRVMs) to establish a cellular hypertrophy model. Results: Mass spectrometry revealed that the composition of GSLs was altered in pressure overload-induced hypertrophied mouse hearts and in stimulated hypertrophied cardiomyocyte cell lines. Specifically, in both cases, the proportion of endogenous lactosylceramide (LacCer) was significantly higher than in controls. Inhibition of GSL synthesis with Genz-123346 in NRVMs reduced cell hypertrophy, as well as fibrosis and apoptosis. By Western blotting, we detected decreased intracellular expression of Sirt3 and elevated phosphorylation of JNK after phenylephrine stimulation, but this was reversed in cells pretreated with Genz-123346. Additionally, increased protein expression of FoxO3a and Parkin, along with a decreased LC3-II/I protein ratio in phenylephrine-stimulated cells (compared with unstimulated cells), indicated that the mitochondrial autophagy process was disrupted; again, pretreatment with Genz-123346 reversed that. Discussion: Our results revealed that changes in GSLs in cardiomyocytes, especially an increase of LacCer, may be a factor causing cellular hypertrophy, which can be alleviated by inhibition of GSLs synthesis. A possible mechanism is that GSLs inhibition increases the expression of Sirt3 protein, scavenges intracellular reactive oxygen species, and restores mitochondrial autophagy homeostasis, thereby lessening cardiomyocyte hypertrophy. In all, these results provide a new perspective for developing drugs for cardiac hypertrophy.

Response of soybean Cd to soil Cd and pH and its associated health risk in a high geological background area in Guizhou Province, Southwest China.

This study comprehensively examined the accumulation of cadmium (Cd) in soybeans grown in low- and high-Cd soils around the high geological background areas in Guizhou province. The aim was to analyze the relationship between soybean Cd and soil pH and soil Cd, alongside assessing the potential carcinogenic and non-carcinogenic risks associated with Cd in soybeans. Cd content of soybeans cultivated in the high-Cd area (0.430 mg/kg) was significantly higher than that in low-Cd areas (0.156 mg/kg) (P < 0.05). Biological concentration factors (BCFs) of soybean for Cd in low- and high-Cd areas were 0.282 and 0.314, respectively, with no significant differences (P > 0.05). Multiple linear regression results indicated that soil pH was a determining factor for Cd accumulation in soybeans in both areas. Furthermore, soil pH and soil Cd could accurately predict Cd accumulation in soybeans according to the neural network model. These findings suggest that regulating soil pH could reduce Cd accumulation in soybeans in areas with high geological background. In both areas, there was no significant non-carcinogenic risk for the adult population (HQ value < 1) through soybean consumption. However, according to the Monte Carlo model, the percentage of Cd in soybeans exceeding the acceptable range (CR value > 1.00 × 10 -04) in areas was 99.18%, indicating an unacceptable carcinogenic risk for the adult population. Our discussion revealed that reducing the soybean intake and increasing soil pH did not effectively lower the carcinogenic risk of Cd in soybeans to an acceptable range (CR value ≤ 1.00 × 10 -04). These findings necessitate further exploration of alternative remediation strategies to ensure the safe production of soybeans, such as screening for low-Cd accumulation soybean varieties and implementing the combined remediation strategies.

Mortality salience and helping behavior amidst public crisis: cross-sectional evidence during COVID-19.

Background: As a real mortality salience, a public crisis would have a major impact on individual minds, behaviors, and lifestyles. COVID-19 provides us with a stark real-world example to understand these implications. Previous research has revealed that some individuals become more willing to help the infected at the risk of their own lives, while others become more self-centered and indifferent during COVID-19. To explain this paradoxical phenomenon, our study used two rival mediators in the relationship between mortality salience and helping behavior during COVID-19: death anxiety and death reflection. Methods: A cross-sectional survey was conducted among Chinese college students (N = 684) during the pandemic. We used a parallel mediation model to explore the mediating roles of death anxiety and death reflection in the relationship between mortality salience and helping behavior during COVID-19. Results: The results of our study indicate two key findings. First, mortality salience is negatively related to helping behavior during COVID-19 via death anxiety. This suggests that individuals with higher levels of mortality salience experienced increased death anxiety, which in turn led to a decrease in helping behavior. Second, mortality salience is positively related to helping behavior during COVID-19 via death reflection. This indicates that individuals with higher levels of mortality salience engaged in deeper reflection on death, which subsequently resulted in an increase in helping behavior. Conclusion: Our study provides valuable insights into the complex relationship between mortality salience and helping behaviors in the time of public crisis, and can help lead to more positive attitudes toward public crisis events such as COVID-19.

Temperature-Dependent Oxidation Behavior of Silicon Carbide Surface: Reactive Molecular Dynamics Simulations.

The high-temperature oxidation mechanism of silicon carbide (SiC) is crucial for designing thermal protection systems in aircraft. This study explored the oxidative chemical reaction processes and mechanism on SiC surface and interfaces within the temperature range of 300-2300 K by using reactive molecular dynamics simulation. The oxygen impact on the silica (SiOx) growth of the SiC surface was analyzed, which shows a progressive increase of silica thickness. The simulation results indicated that the oxidation process of SiC was a typical passive oxidation mechanism. With the environmental temperature rising and oxygen impact, the increase of oxidation thickness on the SiC surface undergoes three oxidizing reaction processes: little chemical adsorption of oxygen molecules on the initial surface, rapid oxidation of silicon and carbon, and dramatic oxidation of the interface between the oxidation layer and SiC. Additionally, this work studied the mechanism of oxidation thickness growth and chemical diffusion of oxygen. The oxidation rate is weakened according to the oxygen atom diffusion barrier effect of silica repulsion. Moreover, the kinetic parameters were statistically calculated by fitting the growth of Si-O bonds and their reaction rate constants. Subsequently, the activation energy and pre-exponential factors were derived by using the Arrhenius equation to model the chemical reaction kinetics of the thermal oxidation process. The chemical reaction behaviors of the two stages could be concluded as follows: (i) in stage I, the initial oxidation is reaction rate limiting; (ii) in stage II, SiC oxidation is limited by both the oxidation reaction rate and the oxygen diffusion coefficient of the oxidation layer. The activation energy of stage II increased compared with stage I due to the oxygen atoms diffusion barrier between the oxidation layers. This study on the oxidation and ablation mechanism of the SiC surface at the atomic scale would provide insight into understanding thermal oxidation behavior and the design of ceramic materials.

Childhood maltreatment and aggressive behavior among college students: a serial mediation model of authenticity and alexithymia.

Introduction: Aggressive behavior among college students is a concerning issue that not only affects the mental health and personal development of those involved but also poses a threat to societal stability. Existing literature has consistently demonstrated a positive correlation between childhood maltreatment and aggressive behavior. However, the specific mechanisms through which childhood maltreatment leads to aggressive behavior remain unclear. This study aims to explore the impact of childhood maltreatment on aggressive behavior among college students and to examine the mediating roles of authenticity and alexithymia in this relationship. Methods: To investigate these relationships, we conducted an online survey among 1,148 Chinese college students. Participants completed the Childhood Trauma Questionnaire-Short Form (CTQ-SF), Authenticity Scale, Toronto Alexithymia Scale (TAS-20), and 12-item Aggression Questionnaire (12-AQ). These instruments allowed us to measure the variables of interest and to analyze the potential mediating effects of authenticity and alexithymia. Results: The findings of our study indicate that both authenticity and alexithymia mediate the positive relationship between childhood maltreatment and aggressive behavior. Specifically, the mediating effect of authenticity was 0.04 (95% CI [0.01, 0.06]), while that of alexithymia was 0.10 (95% CI [0.07, 0.13]). Moreover, we observed a chain-mediating effect involving both authenticity and alexithymia, with a chain-mediating effect of 0.03 (95% CI [0.02, 0.05]). Conclusions: This study demonstrates that childhood maltreatment can positively predict aggressive behavior in college students, and this relationship is mediated individually and sequentially by authenticity and alexithymia. Our findings contribute valuable insights to the existing research on aggressive behavior and provide a theoretical framework for developing interventions aimed at reducing aggressive behaviors among college students.

Risk factors of cervical central lymph node metastasis in stage T1a unifocal papillary thyroid carcinoma.

To investigate the correlation of cervical central lymph node metastasis (CLNM) in stage T1a unifocal papillary thyroid carcinoma (PTC) with the clinicopathological characteristics, ultrasonography features and the number of lymph node dissection, and to analyze the risk factors of CLNM. Data from 493 unifocal PTC patients (T1a) who underwent partial or total thyroidectomy and pCLND at the Guizhou Provincial People's Hospital were collected and retrospectively analyzed. They were divided into two groups in accordance with cervical CLNM or not. Their information, including clinical characteristics, ultrasound (US) features, pathological results, and other characteristics of the groups, was analyzed and compared using univariate and multivariate logistic regression analyses. A total of 493 patients were eligible in this study. Among them, 33.7% (166/493) of PTC patients had cervical CLNM, and 66.3% (327/493) did not. The two groups were compared using a univariate analyses, and there were no significant differences between the two groups in age, maximum tumor size, tumor location, aspect ratio, boundary, morphology, echogenicity, BRAFV600E and HT (P > 0.05), and there were significant differences between gender, capsule contact, microcalcifications, rich vascularity, and number of lymph node dissection (P < 0.05). A multivariate logistic regression analyses was performed to further clarify the correlation of these indices. However, only male (OR = 1.770, P = 0.009), microcalcifications (OR = 1.791, P = 0.004), capsule contact (OR = 1.857, P = 0.01), and number of lymph node dissection (OR = 2.274, P < 0.001) were independent predictors of cervical CLNM. In conclusion, four independent predictors of cervical CLNM, including male, microcalcifications, capsule contact, and number of lymph node dissection, were screened out. Therefore, a comprehensive assessment of these risk factors should be conducted when designing individualized treatment regimens for PTC patients.

A preliminary study of artificial intelligence to recognize tessellated fundus in visual function screening of 7-14 year old students.

BACKGROUND: To evaluate the accuracy of artificial intelligence (AI)-based technology in recognizing tessellated fundus in students aged 7-14 years. METHODS: A retrospective study was conducted to collect consecutive fundus photographs for visual function screening of students aged 7-14 years old in Haikou City from June 2018 to May 2019, and 1907 cases were included in the study. Among them, 949 cases were male and 958cases were female. The results were manually analyzed by two attending ophthalmologists to ensure the accuracy of the results. In case of discrepancies between the results analyzed by the two methods, the manual results were used as the standard. To assess the sensitivity and specificity of AI in recognizing tessellated fundus, a Kappa consistency test was performed comparing the results of manual recognition with those of AI recognition. RESULTS: Among 1907 cases, 1782 cases, or 93.4%, were completely consistent with the recognition results of manual and AI; 125 cases, or 6.6%, were analyzed with differences. The diagnostic rates of manual and AI for tessellated fundus were 26.1% and 26.4%, respectively. The sensitivity, specificity and area of the ROC curve (AUC) of AI for recognizing tessellated fundus in students aged 7-14 years were 88.0%, 95.4% and 0.917, respectively. The results of test showed that that the manual and AI identification results were highly consistent (κ = 0.831, P = 0.000). CONCLUSION: AI analysis has high specificity and sensitivity for tessellated fundus identification in students aged 7-14 years, and it is feasible to apply artificial intelligence to visual function screening in students aged 7-14 years.

Feasibility of augmented reality using dental arch-based registration applied to navigation in mandibular distraction osteogenesis: a phantom experiment.

OBJECTIVE: Distraction osteogenesis is a primary treatment for severe mandibular hypoplasia. Achieving the ideal mandible movement direction through precise distraction vector control is still a challenge in this surgery. Therefore, the aim of this study was to apply Optical See-Through (OST) Augmented Reality (AR) technology for intraoperative navigation during mandibular distractor installation and analyze the feasibility to evaluate the effectiveness of AR in a phantom experiment. METHODS: Phantom was made of 3D-printed mandibular models based on preoperative CT scans and dental arch scans of real patients. Ten sets of 3D-printed mandible models were included in this study, with each set consisting of two identical mandible models assigned to the AR group and free-hand group. 10 sets of mandibular distraction osteogenesis surgical plans were designed using software, and the same set of plans was shared between the AR and free-hand groups. Surgeons performed bilateral mandibular distraction osteogenesis tasks under the guidance of AR navigation, or the reference of the preoperative surgical plan displayed on the computer screen. The differences in angular errors of distraction vectors and the distance errors of distractor positions under the guidance of the two methods were analyzed and compared. RESULTS: 40 distractors were implanted in both groups, with 20 cases in each. In intra-group comparisons between the left and right sides, the AR group exhibited a three-dimensional spatial angle error of 1.88 (0.59, 2.48) on the left and 2.71 (1.33, 3.55) on the right, with P = 0.085, indicating no significant bias in guiding surgery on both sides of the mandible. In comparisons between the AR group and the traditional free-hand (FH) group, the average angle error was 1.94 (1.30, 2.93) in the AR group and 5.06 (3.61, 9.22) in the free-hand group, with P < 0.0001, resulting in a 61.6% improvement in accuracy. The average displacement error was 1.53 ± 0.54 mm in the AR group and 3.56 ± 1.89 mm in the free-hand group, with P < 0.0001, indicating a 57% improvement in accuracy. CONCLUSION: Augmented Reality technology for intraoperative navigation in mandibular distraction osteogenesis is accurate and feasible. A large randomized controlled trial with long-term follow-up is needed to confirm these findings. TRIAL REGISTRATION: The project has been registered with the Chinese Clinical Trial Registry, with registration number ChiCTR2300068417. Date of Registration: 17 February 2023.

Incidence rates of hepatocellular carcinoma based on risk stratification in steatotic liver disease for precision medicine: A real-world longitudinal nationwide study.

BACKGROUND: Detailed subgroup incidence rates for steatotic liver disease (SLD)-related hepatocellular carcinoma (HCC) are critical to inform practice and public health interventions but remain sparse. We aimed to fill in this gap. METHODS AND FINDINGS: In a retrospective cohort study of adults with SLD from the United States (US) Merative Marketscan Research Databases (1/2007 to 12/2021), we estimated HCC incidence stratified by sex, age, cirrhosis, diabetes mellitus (DM), and a combination of all these 4 factors. We excluded patients with significant alcohol use and chronic viral hepatitis. We analyzed data from 741,816 patients with SLD (mean age 51.5 ± 12.8 years, 46% male, 14.7% cirrhosis). During a 2,410,166 person-years (PY) follow-up, 1,740 patients developed HCC. The overall HCC incidence yielded 0.72 per 1,000 PY (95% confidence interval [CI, 0.68, 0.75]). The incidence was higher in males (0.95, 95% CI [0.89, 1.01]) compared to females (0.52, 95% CI [0.48, 0.56]) (p < 0.001). For those with cirrhosis, the incidence was significantly higher at 4.29 (95% CI [4.06, 4.51]) compared to those without cirrhosis (0.14, 95% CI [0.13, 0.16]) (p < 0.001). Additionally, the incidence was higher in patients with DM (1.19, 95% CI [1.12, 1.26]) compared to those without DM (0.41, 95% CI [0.38, 0.44]) (p < 0.001). Chronic kidney disease (CKD) was also associated with a higher HCC incidence of 2.20 (95% CI [2.00, 2.41]) compared to those without CKD (0.58, 95% CI [0.55, 0.62]) (p < 0.001). Similarly, individuals with cardiovascular disease (CVD) had a higher HCC incidence of 1.89 (95% CI [1.75, 2.03]) compared to those without CVD (0.51, 95% CI [0.48, 0.54]) (p < 0.001). Finally, the incidence of HCC was significantly higher in patients with non-liver cancer (3.90, 95% CI [3.67, 4.12]) compared to those without other cancers (0.29, 95% CI [0.26, 0.31]) (p < 0.001). On further stratification, HCC incidence incrementally rose by 10-year age intervals, male sex, cirrhosis, and DM, reaching 19.06 (95% CI [16.10, 22.01]) and 8.44 (95% CI [6.78, 10.10]) in males and females, respectively, but only 0.04 for non-diabetic, noncirrhotic aged <40 years patients in both sexes. The main limitation of this methodology is the potential misclassification of the International Classification of Diseases (ICD) codes inherent in claims database studies. CONCLUSIONS: This nationwide study provided robust granular estimates for SLD-related HCC incidence stratified by several key risk factors. In addition to cirrhosis, future surveillance strategies, prevention, public health initiatives, and future research models should also take into account the impact of sex, age, and DM.

Effectiveness study of surface electromyography combined with spine 3D data system to evaluate scoliosis.

OBJECTIVE: To evaluate the clinical effectiveness of surface electromyography combined with a spine 3D data system. METHODS: 10 idiopathic scoliosis patients (age: 12.90±3.67 years, height: 155.90±20.07 cm, weight: 48.00±12.86 kg, 6 major thoracic lateral bends and 4 lumbar bends) who were selected to attend the outpatient clinic of Ruijin Rehabilitation Hospital, First diagnosed as scoliosis by imaging examination (EOS system), evaluation by using the surface electromyography monitoring system, the radiation-free 3D spine data acquisition and analysis system, the surface electromyography of the paravertebral muscles (root mean square value (RMS) of the resting standing and action position of the spine) and the Cobb angle of scoliosis were recorded. RESULTS: The RMS of the convex side was larger than that of the concave side in the two postures (P<0.05), and The RMS value of bilateral action position was significantly higher than that of rest position (P<0.05). There was no correlation between RMS ratio and Cobb angle in two positions of thoracic scoliosis (P>0.05). There was a significant correlation between the RMS ratio at rest position of lumbar scoliosis and Cobb angle. At rest, the RMS value of convex side was significantly correlated with the Cobb angle measured by the EOS system and the 3D data system (P<0.05, of which P<0.01). The Cobb angle measured by 3D data system and the EOS system was significantly correlated (P<0.01). CONCLUSION: Surface EMG can be used to evaluate the motor function of paravertebral muscles on both sides of scoliosis patients. The new 3D data system has high accuracy in evaluating scoliosis. The combination of the two can dynamically evaluate scoliosis, which is more clinically effective.

Fluorescence/colorimetric dual-signal sensor based on carbon dots and gold nanoparticles for visual quantification of Cr3.

A convenient and sensitive dual-signal visualization method is constructed for detection of trivalent chromium ions (Cr3+) based on fluorescent carbon dots (CDs) and glutathione-modified gold nanoparticles (GSH-Au NPs). The fluorescence of CDs can be quenched by GSH-Au NPs due to the inner filter effect. Cr3+ induces aggregation of GSH-Au NPs because of the coordination with GSH on the surface of Au NPs, leading to the red shift of surface plasmon resonance absorption of Au NPs that provides a "turn-on" fluorescence and colorimetric assay for Cr3+. The fluorescence/colorimetric dual signal detection shows high sensitivity for Cr3+ with wide detection linear ranges (0.5-70 µM for fluorescence detection and 2-50 µM for colorimetric detection) and low detection limits (0.31 µM for fluorescence detection and 0.30 µM for colorimetric detection). Besides, the method has high selectivity for Cr3+ and can be used for detection of Cr3+ in lake water and tap water samples, showing great potential for visual detection of environmental Cr3+.

Global prevalence and characteristics of infections and clinical outcomes in hospitalised patients with cirrhosis: a prospective cohort study for the CLEARED Consortium.

BACKGROUND: Infections have a poor prognosis in inpatients with cirrhosis. We aimed to determine regional variations in infections and their association with clinical outcomes in a global cohort of inpatients with cirrhosis. METHODS: In this prospective cohort study initiated by the CLEARED Consortium, we enrolled adults (aged >18 years) with cirrhosis who were non-electively admitted to 98 hospitals from 26 countries or regions across six continents between Nov 5, 2021, and Dec 10, 2022. Data at admission, during hospitalisation, and for 30 days after discharge were collected through patient reports and chart reviews. Collected data included demographics; country and country income level per World Bank classifications (high-income countries [HICs], upper-middle-income countries [UMICs], and low-income or lower-middle-income countries [L-LMICs]); comorbidities; characteristics related to cirrhosis and the infections, including types, culture results, and drug resistance profile; antibiotic use; and disease course while hospitalised and for 30 days post-discharge. The primary outcome was in-hospital death or hospice referral in those with versus those without an admission infection (defined by the presence of infection on or within 48 h of admission). Multivariable log-binomial regression for in-hospital death or hospice referral was performed to identify risk factors. FINDINGS: Of 4550 patients screened, 4238 patients (mean age 56·1 years [SD 13·3]; 2711 [64·0%] male and 1527 [36·0%] female) with complete data were enrolled. 1351 (31·9%) had admission infections. A higher proportion of patients in L-LMICs had infections (318 [41·7%] of 762 vs 444 [58·3%] without infection) than in UMICs (588 [30·6%] of 1922 vs 1334 [69·4%]) or HICs (445 [28·6%] of 1554 vs 1109 [71·4%]). Patients with admission infections had worse severity of cirrhosis and were more likely to have had an infection or been hospitalised in the preceding 6 months. The most common specific infection types were spontaneous bacterial peritonitis (391 [28·9%] of 1351), pneumonia (233 [17·2%]), and urinary tract infections (193 [14·3%]). 549 (40·6%) patients were culture-positive for bacterial or fungal infections, with the lowest culture-positive rates in Africa and mainland China. Most of the isolated organisms were Gram-negative (345 [63%] of 549), then Gram-positive (157 [29%]), and then fungi or mixed (47 [9%]), with Escherichia coli, Klebsiella pneumoniae, and Enterococcus spp being the top three isolated pathogens. The overall rate of drug resistance was 40% (220 of 549 with positive cultures), being highest in UMICs. The most used empirical antimicrobials were third-generation cephalosporins (453 [37%] of 1241), followed by the broad-spectrum ß-lactams and ß-lactamase inhibitors (289 [23%]). De-escalation was observed in 62 (20%) of 304 patients who had their antibiotics changed. Patients with versus without admission infections had a higher rate of in-hospital death or hospice transfer (299 [22·1%] of 1351 vs 232 [8·0%] of 2887; p<0·0001), a result replicated in multivariable analysis (adjusted risk ratio 1·75 [95% CI 1·42-2·06]; p<0·0001). Older age, self-reported female gender, not being in a HIC, lactulose use, and higher MELD-Na score were also associated with in-hospital death or hospice transfer on multivariable analysis. INTERPRETATION: In the CLEARED Consortium cohort of inpatients with cirrhosis, the rates and types of infections, causative organisms, and culture-positivity varied substantially across regions, and infections were associated with a higher mortality risk. Culture positivity, which guides appropriate antibiotic use, was low. Taking a global perspective, considering regional variations in infections, drug resistance, and resources, could help to alleviate disparities in burden and outcomes. FUNDING: US Department of Veterans Affairs, the Richmond Institute for Veterans Research, the National Natural Science Foundation of China, Shanghai Rising-Star Program, the National Council for Scientific and Technological Development of Brazil, and Shanghai Municipal Key Clinical Specialty.

Dual osmotic controlled release platform for antibiotics to overcome antimicrobial-resistant infections and promote wound healing.

Methicillin-Resistant Staphylococcus aureus forming into biofilms can trigger chronic inflammation and disrupt skin wound healing processes. Prolonged and excessive use of antibiotics can expedite the development of resistance, primarily because of their limited ability to penetrate microbial membranes and biofilms, especially antibiotics with intracellular drug targets. Herein, we devise a strategy in which virus-inspired nanoparticles control the release of antibiotics through rapid penetration into both bacterial cells and biofilms, thereby combating antimicrobial-resistant infections and promoting skin wound healing. Lipid-based nanoparticles based on stearamine and cholesterol were designed to mimic viral highly ordered nanostructures. To mimic the arginine-rich fragments in viral protein transduction domains, the primary amines on the surface of the lipid-based nanoparticles were exchanged by guanidine segments. Levofloxacin, an antibiotic that inhibits DNA replication, was chosen as the model drug to be incorporated into nanoparticles. Hyaluronic acid was coated on the surface of nanoparticles acting as a capping agent to achieve bacterial-specific degradation and guanidine explosion in the bacterial microenvironment. Our virus-inspired nanoparticles displayed long-acting antibacterial effects and powerful biofilm elimination to overcome antimicrobial-resistant infections and promote skin wound healing. This work demonstrates the ability of virus-inspired nanoparticles to achieve a dual penetration of microbial cell membranes and biofilm structures to address antimicrobial-resistant infections and trigger skin wound healing.

Causal effects of female reproductive features on nonalcoholic fatty liver disease: A mendelian randomization study.

BACKGROUND AND AIMS: Epidemiological evidence on the associations between female reproductive features and nonalcoholic fatty liver disease (NAFLD) is conflicting. To explore their causalities, we conducted a Mendelian randomization (MR) study. METHODS: Summary-level data were obtained, and univariable MR was performed to explore the causalities between female reproductive features and NAFLD. And we performed multivariable MR and MR mediation analysis to explore the mediation effects of educational attainment (EA) and body mass index (BMI) for these associations. Sensitivity analyses were performed to evaluate pleiotropy and heterogeneity. RESULTS: There were causal effects of age at menarche (AAMA) (odds ratio [OR]: 0.817, 95% confidence interval [CI]: 0.736-0.907, per year-increase), age at first birth (AFB) (OR: 0.851, 95%CI: 0.791-0.926, per year-increase) and age at first sexual intercourse (AFS) (OR: 0.676, 95%CI: 0.511-0.896, per standard deviation-increase) on NAFLD risk. Besides, the causal effects were also observed on NAFLD phenotypes including liver fat content (LFC) and alanine aminotransferase (ALT). Further mediation analysis showed that BMI mediated partial proportion of effects of AAMA and AFS on NAFLD/ALT, AFB on NAFLD/LFC/ALT, while EA mediated partial proportion of effects of AFB on NAFLD/LFC/ALT, and AFS on NAFLD/ALT. CONCLUSIONS: This study provided convincing evidence that early AAMA, AFB, and AFS were risk factors for NAFLD. Reproductive health education, obesity management, and education spread might be the beneficial strategies for NAFLD prevention.

DGA ameliorates severe acute pancreatitis through modulating macrophage pyroptosis.

Severe acute pancreatitis (SAP) is an inflammatory disease with varying severity, ranging from mild local inflammation to severe systemic disease, with a high incidence rate and mortality. Current drug treatments are not ideal. Therefore, safer and more effective therapeutic drugs are urgently needed. 7α,14ß-dihydroxy-ent-kaur-17-dimethylamino-3,15-dione DGA, a diterpenoid compound derivatized from glaucocalyxin A, exhibits anti-inflammatory activity. In this study, we demonstrated the therapeutic potential of DGA against SAP and elucidated the underlying mechanisms. Treatment with DGA markedly (1) inhibited death of RAW264.7 and J774a.1 cells induced by Nigericin and lipopolysaccharide, (2) alleviated edema, acinar cell vacuolation, necrosis, and inflammatory cell infiltration of pancreatic tissue in mice, and (3) inhibited the activity of serum lipase and the secretion of inflammatory factor IL-1ß. DGA significantly reduced the protein expression of IL-1ß and NLRP3 and inhibited the phosphorylation of NF-κB. However, DGA exhibited no inhibitory effect on the expression of caspase-1, gasdermin D (GSDMD), NF-κB, TNF-α, or apoptosis-associated speck-like protein (ASC) and on the cleavage of caspase-1 or GSDMD. Molecular docking simulation confirmed that DGA can bind to TLR4 and IL-1 receptor. In conclusion, DGA may effectively alleviate the symptoms of SAP in mice and macrophages by inhibiting the binding of TLR4 and IL-1 receptor to their ligands; therefore, DGA is a promising drug candidate for the treatment of patients with SAP.

Persteroid, a new steroid from the marine-derived fungus Penicillium sp. ZYX-Z-143.

A new steroid named persteroid (1) and seven known compounds (2-8) were isolated from the marine-derived fungus Penicillium sp. ZYX-Z-143. The structure of 1 was determined by HRESIMS, NMR, and ECD calculations. Compound 1 showed inhibitory activity against protein tyrosine phosphatase 1B (PTP1B) with IC50 value of 46.31 ± 0.52 µM. Moreover, compound 1 potently suppressed nitric oxide (NO) production on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The cytotoxicity and antibacterial activity of all isolates were tested.