The 25-kDa linear polyethylenimine exerts specific antiviral activity against pseudorabies virus through interferencing its adsorption via electrostatic interaction.

Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease, which is responsible for enormous economic losses to the global pig industry. Although vaccination has been used to prevent PRV infection, the effectiveness of vaccines has been greatly diminished with the emergence of PRV variants. Therefore, there is an urgent need to develop anti-PRV drugs. Polyethylenimine (PEI) is a cationic polymer and has a wide range of antibacterial and antiviral activities. This study found that a low dose of 1 µg/mL of the 25-kDa linear PEI had significantly specific anti-PRV activity, which became more intense with increasing concentrations. Mechanistic studies revealed that the viral adsorption stage was the major target of PEI without affecting viral entry, replication stages, and direct inactivation effects. Subsequently, we found that cationic polymers PEI and Polybrene interfered with the interaction between viral proteins and cell surface receptors through electrostatic interaction to exert the antiviral function. In conclusion, cationic polymers such as PEI can be a category of options for defense against PRV. Understanding the anti-PRV mechanism also deepens host-virus interactions and reveals new drug targets for anti-PRV.IMPORTANCEPolyethylenimine (PEI) is a cationic polymer that plays an essential role in the host immune response against microbial infections. However, the specific mechanisms of PEI in interfering with pseudorabies virus (PRV) infection remain unclear. Here, we found that 25-kDa linear PEI exerted mechanisms of antiviral activity and the target of its antiviral activity was mainly in the viral adsorption stage. Correspondingly, the study demonstrated that PEI interfered with the virus adsorption stage by electrostatic adsorption. In addition, we found that cationic polymers are a promising novel agent for controlling PRV, and its antiviral mechanism may provide a strategy for the development of antiviral drugs.

Factors Associated with First-Time HIV Testing Among MSM via Secondary Distribution of HIV Self-test Kits in Zhuhai, China.

HIV self-testing (HIVST) is an effective method to expand HIV testing coverage worldwide. We analyze the results of HIVST and sexual behaviors of first-time testers among Men who have sex with men (MSM) who participated in a secondary distribution of HIVST kits. A total of 589 participants were recruited, including 173 first-time testers and 416 non-first-time testers. The first-time testers were mainly of Han ethnicity (aOR 1.88, 95% CI 1.10, 3.24), more likely to be HIV positive (aOR 7.18, 95% CI 2.37, 21.72), and had higher income (aOR 2.01, 95% CI 1.10, 3.69). Both groups were less likely to have anal sex with male partners (χ2: 146.24, P < 0.01), (χ2: 582.72, P < 0.01) or have sex with female partners (χ2: 19.01, P < 0.01), (χ2: 35.74, P < 0.01) after HIVST. We should expand HIVST among MSM and other key populations to identify first-time testers.

EXPRESS:The efficacy and safety of brentuximab vedotin for peripheral T-cell lymphoma: A systemic review and meta-analysis.

Peripheral T-cell lymphoma (PTCL) is an extensive class of heterogeneous diseases with dismal outcomes. Brentuximab vedotin (BV) is an antibody‒drug conjugate (ADC) comprising CD30-directed antibody. This review aimed to evaluate the efficacy and safety of BV for treating PTCL. We searched the PubMed, Embase, Cochrane Library and Web of Science databases for studies evaluating the efficacy of BV alone or in combination with other drugs for treating PTCL. The primary outcome measures included objective response rate (ORR), complete remission (CR), progression-free survival (PFS) and overall survival (OS). The secondary outcomes included 5-year OS, 5-year PFS and adverse events. 22 studies involving 1137 patients were included. These studies reported the use patterns of BV, ORR, CR, PFS, OS, and adverse events. The pooled ORR and CR rate were 68% (95% CI: 59%-75%) and 43% (95% CI: 34%-53%). For survival outcomes, the longest median PFS was 8.3 months, and the longest median OS was 26.3 months. The most common adverse event was peripheral neuropathy and neutropenia. The analysis suggested that BV alone or in combination with other drugs improved the response and survival rates in PTCL patients and was associated with tolerable adverse effects.

Low-Dose Treatment with Epirubicin, a Novel Histone Deacetylase 1 Inhibitor, Exerts Anti-leukemic Effects by Inducing Ferroptosis.

AIMS: Leukemia is hematopoietic stem cell malignant tumor with poor outcomes. Histone deacetylase 1 (HDAC1) is highly expressed in leukemia and current HDAC1 inhibitors have clinical limitations in leukemia therapy. Therefore, novel HDAC1 inhibitor is imperative to being found and its mechanism needs to be further explored. MATERIALS AND METHODS: Novel HDAC1 inhibitors were discovered through drug virtual screening. CCK-8, EdU and soft agar assay were used to assess the anti-leukemic effect of the candidate HDAC1 inhibitor. ROS, lipid peroxidation, intracellular Fe2+ and LIP assay were employed to verify cell ferroptosis. Additionally, a xenograft model was performed to explore the efficacy and safety of candidate HDAC1 inhibitor in vivo. RESULTS: HDAC1 might be a promising therapeutic target for leukemia and Epirubicin (Epi) could be used as a potential HDAC1 inhibitor. Low-dose Epi exhibited good anti-leukemic effects by inhibiting cell proliferation, DNA synthesis and colony formation. Low-dose Epi could induce ferroptosis by triggering lipid peroxidation, which was better than that treated with current HDAC1 inhibitors Chidamide or Vorinostat, ROS generation and Fe2+ overload in leukemia cells. Mechanistically, low-dose Epi induced ferroptosis by targeting amino acid metabolism and iron metabolism. Similar results were found in a xenograft model in NOG mice with a good safety profile. CONCLUSION: Our study demonstrated that Epi might be used as a HDAC1 inhibitor. Low-dose Epi could inhibit tumor progression by inducing cell ferroptosis in vitro and in vivo. Thus, Epi administration with lower concentration may be much more favorable and safer in the treatment with leukemia.

Incidence and spontaneous clearance of gonorrhea and chlamydia infections among men who have sex with men: a prospective cohort study in Zhuhai, China.

Background: Men who have sex with men (MSM) face significant risks of Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (NG) infection. Nevertheless, only limited studies have looked into the site-specific infection and clearance of CT/NG. In order to prevent transmission, it is essential to understand the underlying factors that drive infection and spontaneous clearance. Methods: A 12-week cohort study examined the association between CT/NG infection, self-clearance, and sexual behaviors among MSM. The Willingness Service recruited participants who completed weekly questionnaires and provided urine, throat, and rectal swab samples. Results: The study involved 151 men, in which 51 (33.8%) were diagnosed with CT/NG infection during the study period. HIV (OR = 11.31), kissing (OR = 1.59), receptive oral sex (OR = 36.64), and insertive anal sex (OR = 19.73) constituted significant risk factors. 100% condom use (OR = 5.78) and antibiotic (OR = 7.53) were more likely to cause spontaneous clearance. Discussion: MSM may engage in riskier sexual behaviors due to insufficient knowledge and awareness of STI prevention, leading to increased susceptibility to NG/CT. It is crucial to concentrate on enhancing health education for MSM. Conclusion: This study found that the rectum was the most prevalent site of CT/NG and sexual behavior can influence the infection. Additionally, the appropriate use of antibiotics and consistent condom use may contribute to clear spontaneously.

Dually Crosslinked Copper-Poly(tannic acid) Nanoparticles with Microenvironment-Responsiveness for Infected Wound Treatment.

Reducing the burden of death due to wound infection is an urgent global public health priority. Metal-phenolic networks (MPNs) have received widespread attention in antimicrobial infections due to their facile synthesis process, excellent biocompatibility, and antimicrobial properties brought about by polyphenols and metal ions. However, typical therapeutic MPNs show rapid release of metal ions due to their poor solution stability, impeding long-acting efficacy in multiple wound healing stages. To address these issues, copper-poly (tannic acid) nanoparticles (Cu-PTA NPs): robust (dually crosslinked), microenvironment-responsive, antibacterial, antioxidative, and anti-inflammatory are prepared, which hierarchically modulate the infected wound healing process. Covalently polymerized via phenol-formaldehyde condensation and crosslinked with bioactive Cu2+ , reactive polyphenols are preserved, and Cu2+ is efficiently entrapped in the PTA scaffold. The proposed strategy relieves the systemic toxicity, and only high reactive oxygen species (ROS)level as stimuli can "turn on" the catalytic activity of Cu2+ to implement antibacterial therapy specifically in an infected wound. Systematic tissue regeneration assessment on the infected full-thickness skin wounds of rats demonstrates enhanced wound healing rate. Cu-PTA NPs enables the direct application in infected wound and exertion of long-acting healing efficacy. This synergetic therapy strategy will pave the way for more complicated infections and inflammatory diseases.

Prediction models for depression risk among older adults: systematic review and critical appraisal.

OBJECTIVE: To provide an overview of prediction models for the risk of major depressive disorder (MDD) among older adults. METHODS: We conducted a systematic review combined with a meta-analysis and critical appraisal of published studies on existing geriatric depression risk models. RESULTS: The systematic search screened 23,378 titles and abstracts; 14 studies including 20 prediction models were included. A total of 16 predictors were selected in the final model at least twice. Age, physical health, and cognitive function were the most common predictors. Only one model was externally validated, two models were presented with a complete equation, and five models examined the calibration. We found substantial heterogeneity in predictor and outcome definitions across models; important methodological information was often missing. All models were rated at high or unclear risk of bias, primarily due to methodological limitations. The pooled C-statistics of 12 prediction models was 0.83 (95%CI=0.77-0.89). CONCLUSION: The usefulness of all models remains unclear due to several methodological limitations. Future studies should focus on methodological quality and external validation of depression risk prediction models.

High Genetic Diversity of HIV-1 and Active Transmission Clusters among Male-to-Male Sexual Contacts (MMSCs) in Zhuhai, China.

Monitoring genetic diversity and recent HIV infections (RHIs) is critical for understanding HIV epidemiology. Here, we report HIV-1 genetic diversity and RHIs in blood samples from 190 HIV-positive MMSCs in Zhuhai, China. MMSCs with newly reported HIV were enrolled from January 2020 to June 2022. A nested PCR was performed to amplify the HIV polymerase gene fragments at HXB2 positions 2604-3606. We constructed genetic transmission network at both 0.5% and 1.5% distance thresholds using the Tamura-Nei93 model. RHIs were identified using a recent infection testing algorithm (RITA) combining limiting antigen avidity enzyme immunoassay (LAg-EIA) assay with clinical data. The results revealed that 19.5% (37/190) were RHIs and 48.4% (92/190) were CRF07_BC. Two clusters were identified at a 0.5% distance threshold. Among them, one was infected with CRF07_BC for the long term, and the other was infected with CRF55_01B recently. We identified a total of 15 clusters at a 1.5% distance threshold. Among them, nine were infected with CRF07_BC subtype, and RHIs were found in 38.8% (19/49) distributed in eight genetic clusters. We identified a large active transmission cluster (n = 10) infected with a genetic variant, CRF79_0107. The multivariable logistic regression model showed that clusters were more likely to be RHIs (adjusted OR: 3.64, 95% CI: 1.51~9.01). The RHI algorithm can help to identify recent or ongoing transmission clusters where the prevention tools are mostly needed. Prompt public health measures are needed to contain the further spread of active transmission clusters.

Combined Self-Assembled iRGD Polymersomes for Effective Targeted siRNA Anti-Tumor Therapy.

Introduction: iRGD is usually used as a motif to modify siRNA-nanodelivery vectors to improve tumor-targeting and penetration. However, most of the modifications are realized by covalent conjugation, which normally requires complex preparation processes possibly with low conjugation efficiency and yield, and might lower its bioactivity. To avoid this, here, we presented an alternative physical method to decorate iRGD on nanopolymersomes via facile self-assembly in water. Methods: siVEGF was chosen as a siRNA model, and lipopolysaccharide-amine nanopolymersomes (NPs), an efficient cytosolic delivery vector developed by our group, was used as an original vector. By successively incubating siVEGF with NPs, followed by adding iRGD, a siVEGF-loaded NPs functionalized with iRGD (siRNA/iRGD-NPs) was obtained. The properties of iRGD-NPs or siRNA/iRGD-NPs were evaluated in vitro and in vivo. Results: iRGD is efficiently introduced onto NPs with different amounts, which can be precisely controlled by the feeding ratio. The introduced iRGD keeps tumor-targeting and -penetrating bioactivity, which endows iRGD-NPs with ~100% of tumor-cell uptake and excellent tumor spheroid-penetration, and thus iRGD-NPs can efficiently deliver siVEGF to significantly inhibit angiogenesis in zebrafish and tumor growth in nude mice bearing breast cancer without obvious toxicity. Conclusion: This study provides a facile physical method to decorate nanodelivery vectors with iRGD for effective targeted siRNA anti-tumor therapy.

Comparison between HIV self-testing and facility-based HIV testing approach on HIV early detection among men who have sex with men: A cross-sectional study.

Background: To assess whether HIV self-testing (HIVST) has a better performance in identifying HIV-infected cases than the facility-based HIV testing (HIVFBT) approach. Methods: A cross-sectional study was conducted among men who have sex with men (MSM) by using an online questionnaire (including information on sociodemographic, sexual biography, and HIV testing history) and blood samples (for limiting antigen avidity enzyme immunoassay, gene subtype testing, and taking confirmed HIV test). MSM who were firstly identified as HIV positive through HIVST and HIVFBT were compared. Chi-square or Fisher's exact test was used to explore any association between both groups and their subgroups. Results: In total, 124 MSM HIV cases were identified from 2017 to 2021 in Zhuhai, China, including 60 identified through HIVST and 64 through HIVFBT. Participants in the HIVST group were younger (≤30 years, 76.7% vs. 46.9%), were better educated (>high school, 61.7% vs. 39.1%), and had higher viral load (≥1,000 copies/ml, 71.7% vs. 50.0%) than MSM cases identified through HIVFBT. The proportion of early HIV infection in the HIVST group was higher than in the HIVFBT group, identified using four recent infection testing algorithms (RITAs) (RITA 1, 46.7% vs. 25.0%; RITA 2, 43.3% vs. 20.3%; RITA 3, 30.0% vs. 14.1%; RITA 4, 26.7% vs. 10.9%; all p < 0.05). Conclusions: The study showed that HIVST has better HIV early detection among MSM and that recent HIV infection cases mainly occur in younger and better-educated MSM. Compared with HIVFBT, HIVST is more accessible to the most at-risk population on time and tends to identify the case early. Further implementation studies are needed to fill the knowledge gap on this medical service model among MSM and other target populations.

Association Between Low-Dose Aspirin and Uric Acid in the Elderly: An Observational Retrospective Cross-Sectional Study.

PURPOSE: Uric acid is an independent factor for arteriosclerotic cardiovascular disease (ASCVD). Although aspirin is one of the most widely used agent in patients with ASCVD, there were only a few studies focusing on the effects of low-dose aspirin on uric acid metabolism with controversial results. The present study aimed to investigate an association between low-dose aspirin treatment for more than one month and serum uric acid (SUA) with its urinary excretion in elderly patients. PATIENTS AND METHODS: This paper presents an observational retrospective cross-sectional study to determine the association between continuous daily taking low-dose aspirin (50-100mg) for more than one month and SUA with fraction excretion of uric acid (FEUA) in elderly patients. A total of 506 inpatients equal or over 60 in Department of Geriatrics of Peking University First Hospital were enrolled from 2017 to 2020. About 41.9% of them were taking aspirin for more than one month, while others were not taking this medicine. The correlation between aspirin use and SUA or FEUA was analyzed, and group-comparison was performed in different dosage groups of aspirin. RESULTS: After correcting confounding factors, there is no remarkable correlation between taking low-dose aspirin and SUA or FEUA, but a decreasing trend (coefficients=-4.946) of SUA in hyperuricemia patients with low-dose aspirin was observed despite no obvious difference (P=0.534). Whether SUA or FEUA has no significant difference between 50mg/d and 100mg/d aspirin subjects. CONCLUSION: SUA and urinary uric acid excretion are not associated with using of 50-100mg/d aspirin for more than one month in elderly patients with ASCVD or at risk.

Dopamine-assisted co-deposition of hydroxyapatite-functionalised nanoparticles of polydopamine on implant surfaces to promote osteogenesis in environments with high ROS levels.

Environments with high reactive oxygen species (ROS) levels, which are common in patients with diseases such as diabetes, periodontitis, and osteoporosis, impair the osseointegration of implants. To address this issue, by using a one-pot dopamine-assisted co-deposition method, we constructed a three-dimensional coating of hydroxyapatite-functionalised nanoparticles of polydopamine (HA/nPDAs) on implant surfaces, where polydopamine is designed to protect cells via scavenging excessive ROS and HA facilitates osteogenesis. First, nanoparticles of polydopamine (nPDAs) were prepared by self-polymerization and assembly of dopamine under alkaline conditions, and HA/nPDAs were obtained by incubating nPDAs in simulated body fluid (SBF) due to metal chelation and ionic interactions triggered by the catechol moieties of PDA. Thereafter, HA/nPDAs with thickness of ~4 µm were constructed on titanium surfaces by immersing titanium discs in a weak alkaline solution of HA/nPDAs and dopamine through interface interactions driven by catechol chemistry. The properties of coatings (e.g., thickness, composition, hydrophilia and morphology) can be controlled by preparation conditions such as mineralization time and reactant concentration. The coatings display efficient ROS-scavenging ability, promote cell proliferation, and upregulate the activity of alkaline phosphatase and the expression of osteogenesis-related genes in environments with high or normal ROS levels, demonstrating the great promise of such coatings for osseointegration promotion, especially in the state of high ROS in diseases. This study provides a facile, efficient, mild, and universal strategy in engineering functional surfaces on any substrates for diversified applications by simple variation of co-deposited components, through taking advantages of versatile catechol chemistry and nanoparticles with stereo structure and great specific surface area.