Tracking cognitive trajectories in older survivors of COVID-19 up to 2.5 years post-infection.

Emerging evidence suggests that neurological and other post-acute sequelae of COVID-19 can persist beyond or develop following SARS-CoV-2 infection. However, the long-term trajectories of cognitive change after a COVID-19 infection remain unclear. Here we investigated cognitive changes over a period of 2.5 years among 1,245 individuals aged 60 years or older who survived infection with the original SARS-CoV-2 strain in Wuhan, China, and 358 uninfected spouses. We show that the overall incidence of cognitive impairment among older COVID-19 survivors was 19.1% at 2.5 years after infection and hospitalization, evaluated using the Telephone Interview for Cognitive Status-40. Cognitive decline primarily manifested in individuals with severe COVID-19 during the initial year of infection, after which the rate of decline decelerated. Severe COVID-19, cognitive impairment at 6 months and hypertension were associated with long-term cognitive decline. These findings reveal the long-term cognitive trajectory of the disease and underscore the importance of post-infection cognitive care for COVID-19 survivors.

Preparation of MPN@Zein-PpIX Membrane and Its Antibacterial Properties.

For antibacterial purposes, a photothermal and photodynamic antibacterial membrane was prepared through electrospinning. We used zein as the substrate and introduced Protoporphyrin IX (PpIX) into the protein structure. Then, we used electrospinning technology to weave the modified zein into a fiber structure. We finally introduced a metallic polyphenol network (MPN) coating on the fiber surface to form the final membrane: MPN@Zein-PpIX. Then, we investigated the photothermal and photodynamic properties of the membrane and assessed its antibacterial activity with in vitro agar plate counting methods. The MPN@Zein-PpIX membrane exhibited good singlet oxygen generation and excellent photothermal conversion. Additionally, it showed good antibacterial capacity in vitro, owing to the combination of photothermal and photodynamic properties. Our research provides a simple approach to prepare a multifunctional membrane with excellent antibacterial ability. We used the electrospinning technique to anchor PpIX onto zein to produce a fiber membrane (Zein-PpIX) that can be adhered in situ to improve the biocompatibility of PpIX, and the MPN makes the membrane surface more hydrophilic and more accessible to adhere to biological tissues. The MPN@Zein-PpIX membrane provided new ideas for combining PDT and PTT, and it had great potential for use in the antibacterial application field.

Photoresponsive heparin ionic complexes toward controllable therapeutic efficacy of anticoagulation.

Controllable heparin-release is of great importance and necessity for the precise anticoagulant regulation. Efforts have been made on designing heparin-releasing systems, while, it remains a great challenge for gaining the external-stimuli responsive heparin-release in either intravenous or catheter delivery. In this study, an azobenzene-containing ammonium surfactant is designed and synthesized for the fabrication of photoresponsive heparin ionic complexes through the electrostatic complexation with heparin. Under the assistance of photoinduced trans-cis isomerization of azobenzene, the obtained heparin materials perform reversible athermal phase transition between ordered crystalline and isotropic liquid state at room temperature. Compared to the ordered state, the formation of isotropic state can effectively improve the dissolving of heparin from ionic materials in aqueous condition, which realizes the photo-modulation on the concentration of free heparin molecules. With good biocompatibility, such a heparin-releasing system addresses photoresponsive anticoagulation in both in vitro and in vivo biological studies, confirming its great potential clinical values. This work provides a new designing strategy for gaining anticoagulant regulation by light, also opening new opportunities for the development of photoresponsive drugs and biomedical materials based on biomolecules.

High-performance self-cascade nanoreactors for combined ferroptosis, photothermal therapy, and starving therapy.

Despite the great potential of starving therapy caused by nanoreactor based on glucose oxidase (GOX) in tumor therapy, efficiency and uncontrolled reaction rates in vivo lead to inevitable toxicity to normal tissues, which seriously hindering their clinical conversion. Herein, a cascade nanoreactor (GOX/Mn/MPDA) was constructed by coating mesoporous polydopamine nanoparticles (MPDA) with MnO2 shell and then depositing GOX into honeycomb-shaped manganese oxide nanostructures to achieve a combination of ferroptosis, photothermal therapy and starving therapy. Upon uptake of nanodrugs to cancer cells, the MnO2 shell would deplete glutathione (GSH) and produce Mn2+, while a large amount of H2O2 generated from the catalytic oxidation of glucose by GOX would accelerate the Fenton-like reaction mediated by Mn2+, producing high toxic •OH. More importantly, the cascade reaction between GOX and MnO2 would be further strengthened by localized hyperthermia caused by irradiated by near-infrared laser (NIR), inducing significant anti-tumor effects in vitro and in vivo. Regarding the effectiveness of tumor treatment in vivo, the tumor inhibition rate achieved an impressive 64.33%. This study provided a new strategy for anti-tumor therapeutic by designing a photothermal-enhanced cascade catalytic nanoreactor.

Self-Reported Neurological Symptoms Two Years After Hospital Discharge Among COVID-19 Survivors.

Background: The acute stage of COVID-19 often presents with neurological manifestations. Objective: This study aims to investigate the long-term neurological effects on survivors. Methods: This study recruited 1,546 COVID-19 survivors from Wuhan, including 1,119 nonsevere cases and 427 severe survivors. Participants were interviewed two years after discharge to report their neurological symptoms. The neurological symptoms of COVID-19 were compared between survivors of severe and nonsevere COVID-19. Results: Among the 1,546 COVID-19 survivors, 44.24% discovered at least one neurological symptom. The most prevalent self-reported symptom was fatigue (28.33%), memory deficit (13.26%), attention deficit (9.96%), myalgia (8.34%), dizziness (3.82%), and headache (2.52%). Severe cases had higher incidences of fatigue, myalgia, memory deficit, attention deficit than nonsevere cases. Older age, severe COVID-19, and comorbidity burden were associated with long-term neurological symptoms. Conclusion: Neurological symptoms are common among COVID-19 survivors, especially in severe cases.

Combined chemo and photo therapy of programmable prodrug carriers to overcome delivery barriers against nasopharyngeal carcinoma.

Indocyanine green (ICG) has been employed in medical diagnostics due to its superior photophysical characteristics. However, these advantages are offset by its quick body clearance and inferior photo-stability. In this work, programmable prodrug carriers for chemotherapy/PDT/PTT against nasopharyngeal carcinoma (NPC) were created in order to increase photo-stability and get around biochemical hurdles. The programmable prodrug carriers (PEG-PLA@DIT-PAMAM) that proactively penetrated deeply into NPC tumors and produced the deep phototherapy and selective drug release under laser irradiation was created by dendrimer-DOX/ICG/TPP (DIT-PAMAM) and PEGylated poly (α-lipoic acid) (PLA) copolymer. Long circulation times and minimal toxicity to mammalian cells are two benefits of PEG-coated carriers. The overexpressed GSH on the tumor cell or vascular endothelial cell of the NPC disintegrated the PEG-g-PLA chains and released the DIT-PAMAM nanoparticles after the carriers had reached the NPC tumor periphery. Small, positively charged DIT-PAMAM nanoparticles may penetrate tumors effectively and remain inside tumor for an extended period of time. In addition, the induced ROS cleaved the thioketal linkers for both DOX and nanoparticles and product hyperthermia (PTT) to kill cancer cells under laser irradiation, facilitating faster diffusion of nanoparticles and more effective tumor penetration with a programmable publication of DOX. The programmable prodrug carries showed high photo-stability high photo-stability, which enabled very effective PDT, PTT, and tumor-specific DOX release. With the goal of combining the effects of chemotherapy, PDT, and PTT against NPC, this research showed the great efficacy of programmable prodrug carriers.

Alginate based photothermal cryogels boost ferrous-supply for enhanced antibacterial chemodynamic therapy and accelerated wound healing.

Uncontrolled hemorrhage is a main cause of pre-hospital death. Given the importance of hemostatic wound dressings in pre-hospital emergency treatment, novel composite materials are required for fast hemostasis, synergistic bacterial ablation with negligible resistance and wound healing acceleration. Herein, multifunctional SCTF cryogels were fabricated by the simultaneous cross-linking of sodium alginate (SA) and tannic acid (TA) with Fe3+ ions. As a result, the prepared SCTF cryogels consisted of Fe3+/TA-based metal phenolic networks (MPNs) and Fe3+/SA-based 3D skeleton for collagen (CA). MPNs endowed the cryogels with photothermal effect, photothermal-enhanced Fenton activity and pH/photothermal dual-responsive release property of TA and Fe2+, which were beneficial for the antibacterial capacity. Due to the intrinsic high porosity, in vitro and in vivo assays demonstrated that SCTF cryogels possessed good hemostatic capacity. Moreover, the synergistic photothermal therapy (PTT), chemodynamic therapy (CDT) and pH/photothermal responsive chemo-therapy dramatically enhanced the bactericidal efficacy of SCTF cryogels both in vitro and in vivo. Eventually, their outstanding healing-accelerating effects were confirmed via animal experiments, which were attributed to the presence of CA and TA. Therefore, the developed composite materials could offer new strategy on exploiting multifunctional wound dressing for clinical applications in the future.

α-Fe2O3 based nanotherapeutics for near-infrared/dihydroartemisinin dual-augmented chemodynamic antibacterial therapy.

Due to the negligible bacterial resistance, chemodynamic therapy (CDT) is a promising treatment for bacterial infection. However, it is severely impeded by the constant body temperature, shortage of Fe(Ⅱ) ions and insufficient H2O2 level in infected tissue. To enhance the therapeutic efficiency of CDT, improved strategies are urgently needed to tackle these problems. Herein, we exploited an infection microenvironment-responsive nanotherapeutics for near-infrared (NIR)/dihydroartemisinin (DHA) dual-augmented antibacterial CDT. The convenient encapsulation of DHA-loaded α-Fe2O3 nanorods with metal-polyphenol networks (MPN) led to the generation of an antibacterial nanoagent Fe2O3@DHA@MPN (FDM). Afterwards, its photothermal and peroxidase-like activities were intensively studied. Furthermore, the bactericidal efficacy of FDM was evaluated through both in vitro and in vivo antibacterial assays. Firstly, FDM showed both satisfactory photothermal and NIR/DHA dual-augmented peroxidase-like activities. Besides, it exhibited a pH-responsive release behavior of both Fe(Ⅱ) ions and DHA. Moreover, it presented tannic acid-mediated bacterial adhesion effect. In vitro experiments demonstrated that FDM could achieve a satisfactory efficiency against both planktonic bacteria and biofilms. In vivo assays illustrated both the extraordinary synergistic antibacterial effect and efficient anti-inflammatory ability of FDM. The outcomes indicated that the exploited antibacterial agent could offer new insight on developing intelligent nanotherapeutics for clinical use in the future. STATEMENT OF SIGNIFICANCE: The antibacterial efficiency of chemodynamic therapy (CDT) is seriously limited by the constant body temperature, shortage of Fe(Ⅱ) ions and insufficient H2O2 level at the mildly acidic inflammatory microenvironment. To address these issues, we have developed a pH-responsive nanoagent (Fe2O3@DHA@MPN) for near-infrared (NIR)/dihydroartemisinin (DHA) dual-augmented CDT. Through the NIR-induced photothermal effect of exterior Fe(Ⅲ)/tannic acid complex, the increased local temperature led to a photothermal enhanced CDT. Besides, a continuous supply of Fe(Ⅱ) ions could be achieved by tannic acid-mediated Fe(Ⅲ) reduction. Moreover, DHA was adopted as a substitute for H2O2 to initiate DHA-mediated CDT. Both in vitro and in vivo assays demonstrated its outstanding bactericidal efficiency. Therefore, the developed nanotherapeutics could be a promising candidate for clinical trials.

Alginate-based aerogels as wound dressings for efficient bacterial capture and enhanced antibacterial photodynamic therapy.

The development of novel wound dressings, such as aerogels, with rapid hemostasis and bactericidal capacities for pre-hospital care is necessary. To prevent the occurrence of bacterial resistance, antibacterial photodynamic therapy (aPDT) with broad-spectrum antibacterial ability and negligible bacterial resistance has been intensively studied. However, photosensitizers often suffer from poor water solubility, short singlet oxygen (1O2) half-life and restricted 1O2 diffusion distance. Herein, sodium alginate was covalently modified by photosensitizers and phenylboronic acid, and cross-linked by Ca(II) ions to generate SA@TPAPP@PBA aerogel after lyophilization as an antibacterial photodynamic wound dressing. Afterwards, its photodynamic and bacterial capture activities were intensively evaluated. Furthermore, its hemostasis and bactericidal efficiency against Staphylococcus aureus were assessed via in vitro and in vivo assays. First, chemical immobilization of photosensitizers led to an enhancement of its solubility. Moreover, it showed an excellent hemostasis capacity. Due to the formation of reversible covalent bonds between phenylboronic acid and diol groups on bacterial cell surface, the aerogel could capture S. aureus tightly and dramatically enhance aPDT. To sum up, the prepared aerogel illustrated excellent hemostasis capacity and antibacterial ability against S. aureus. Therefore, they have great potential to be utilized as wound dressing in clinical trials.

A Patient With Focal Myositis and Primary Cutaneous Diffuse Large B-Cell Lymphoma: A Case Report.

We report a rare case of a 92-year-old male, with a history of statin/ezetimibe intake, complained of pain and swelling of left forearm. The patient was diagnosed with focal myositis at first. Symptoms aggravated after 2 months of immunomodulatory therapy, and accompanied with protrusion lesion at left elbow. Biopsy of the protrusion lesion turned out to be primary cutaneous diffuse large B-cell lymphoma.

Tumor suppressor role of sFRP­4 in hepatocellular carcinoma via the Wnt/ß­catenin signaling pathway.

Hepatocellular carcinoma (HCC) is a malignant tumor located in the liver. Secreted frizzled­related protein 4 (sFRP­4) is associated with cancer occurrence, but the relationship between sFRP­4 and HCC is not completely understood. The present study aimed to investigate the role and mechanism underlying sFRP­4 in HCC. sFRP­4 mRNA expression levels were determined via reverse transcription­quantitative PCR and immunohistochemistry. The Cell Counting Kit­8 assay was performed to evaluate HCCLM3 and Huh7 cell viability. Moreover, HCCLM3 and Huh7 cell proliferation were assessed using the BrdU ELISA assay kit, and cell apoptosis was measured via flow cytometry. Western blotting was conducted to measure ß­catenin and GSK­3ß protein expression levels. The results demonstrated that sFRP­4 expression was significantly downregulated in HCC tissues and cells compared with adjacent healthy tissues and MIHA cells, respectively. Moreover, the results indicated that compared with the control group, sFRP­4 overexpression inhibited HCC cell viability and proliferation, and accelerated HCC cell apoptosis. Furthermore, the results suggested that sFRP­4 inhibited the Wnt/ß­catenin signaling pathway by upregulating GSK­3ß expression and downregulating ß­catenin expression, thus restraining the malignant behavior of HCC cells. In conclusion, the present study indicated that sFRP­4 served a tumor suppressor role in HCC cells by restraining the Wnt/ß­catenin signaling pathway.

Evolution and mutations of hepatitis B virus quasispecies in genotype B and C during vertical transmission.

Evolution patterns of HBV QS between genotype B and C during vertical transmission are not well understood. In this study, we enrolled 10 HBV infected mother-infant pairs (four pairs with genotype B, four pairs with genotype C, and two with co-infection) without anti-viral therapy. Serum HBV DNA of mothers and infants were sequenced, HBV QS complexity and diversity were analyzed, polymorphisms and mutation sites were recorded, and phylogenetic trees were performed. Our result showed that the QS complexities in P (amino acid), C/PreC (amino acid), and PreS1 (nucleotide) gene were significantly higher in mothers than in infants in pairs with genotype C (P < 0.05), however, full-length and other genes showed non-significant differences (P > 0.05). Unlike genotype C, QS complexity of P gene (nucleotide) was significantly higher in infants than in mothers (P < 0.05) in pairs with genotype B, similarly, QS complexities of full-length and other genes (except Pre S2) were also higher in infants than in mothers but without significant differences (P > 0.05). QS diversities of full-length and most genes in genotype B were comparable between mothers and their infants (P > 0.05), in pairs with genotype C, dS of P, X, RT genes, genetic distance of Pre S1 gene (amino acid) and dN of Pre S1 gene were significant higher in mothers than in infants (P < 0.05). Several HBV mutations correlated with immune escape, e antigen loss and drug resistance were observed in infants. The results indicated that differences of HBV QS evolution patterns between genotype B and C during vertical transmission might contribute to distinct prognosis.

Performance of several simple, noninvasive models for assessing significant liver fibrosis in patients with chronic hepatitis B.

AIM: To compare the performance of several simple, noninvasive models comprising various serum markers in diagnosing significant liver fibrosis in the same sample of patients with chronic hepatitis B (CHB) with the same judgment standard. METHODS: A total of 308 patients with CHB who had undergone liver biopsy, laboratory tests, and liver stiffness measurement (LSM) at the Southwest Hospital, Chongqing, China between March 2010 and April 2014 were retrospectively studied. Receiver operating characteristic (ROC) curves and area under ROC curves (AUROCs) were used to analyze the results of the models, which incorporated age-platelet (PLT) index (API model), aspartate transaminase (AST) to alanine aminotransferase (ALT) ratio (AAR model), AST to PLT ratio index (APRI model), γ-glutamyl transpeptidase (GGT) to PLT ratio index (GPRI model), GGT-PLT-albumin index (S index model), age-AST-PLT-ALT index (FIB-4 model), and age-AST-PLT-ALT-international normalized ratio index (Fibro-Q model). RESULTS: The AUROCs of the S index, GPRI, FIB-4, APRI, API, Fibro-Q, AAR, and LSM for predicting significant liver fibrosis were 0.726 (P<0.001), 0.726 (P<0.001), 0.621 (P=0.001), 0.619 (P=0.001), 0.580 (P=0.033), 0.569 (P=0.066), 0.495 (P=0.886), and 0.757 (P<0.001), respectively. The S index and GPRI had the highest correlation with histopathological scores (r=0.373, P<0.001; r=0.372, P<0.001, respectively) and LSM values (r=0.516, P<0.001; r=0.513, P<0.001, respectively). When LSM was combined with S index and GPRI, the AUROCs were 0.753 (P<0.001) and 0.746 (P<0.001), respectively. CONCLUSION: S index and GPRI had the best diagnostic performance for significant liver fibrosis and were robust predictors of significant liver fibrosis in patients with CHB for whom transient elastography was unavailable.

sFRP-4, a potential novel serum marker for chronic hepatitis B-related hepatocellular carcinoma.

BACKGROUND: The current methods used for diagnosing hepatocellular carcinoma (HCC) are unsatisfactory. Here, we assessed the serum levels of secreted frizzled related protein 4 (sFRP-4) for diagnosing HCC in patients infected with chronic hepatitis B (CHB). METHODS: In 272 patients with CHB enrolled, 142 were patients with HCC. Thirty-three healthy subjects were recruited as healthy controls. The CHB patients were assigned to a test group or a validation group based on the time of enrollment. Human antibody arrays were used to screen 15 patients (8 CHB-related HCC patients, 7 CHB patients) for serum markers. Four markers and one candidate marker were assessed in the test group and validation group, respectively. RESULTS: Human antibody assays indicated that the serum levels of sFRP-4 in HCC patients were significantly higher than those in CHB patients (P<0.05). Additionally, serum sFRP-4 levels were significantly higher in the HCC patients than those in the non-HCC patients in both test group (79.7 vs 41.3 ng/mL; P<0.001) and validation group (89.0 vs 39.0 ng/mL; P<0.001). Areas under the Receiver Operating Characteristic curves (AUCs) for alpha-fetoprotein (AFP) and sFRP-4 were similar in both test group and validation group. In the test group, the combination of sFRP-4 (a sensitivity of 94.4%, a specificity of 60.5% at 46.4 ng/mL) and AFP (a sensitivity of 75.0%, a specificity of 87.2% at 11.3 ng/mL) showed better performance for diagnosing HCC (a sensitivity of 79.2% and a specificity of 95.3%). The AUC for combined sFRP-4 and AFP increased to 0.941 (95% CI: 0.908-0.975), and similar results were seen in the validation group. CONCLUSION: sFRP-4 is a candidate serum marker for diagnosing HCC in CHB patients, and the combination of sFRP-4 with AFP may improve the diagnostic accuracy of HCC.

Telbivudine prevents vertical transmission of hepatitis B virus from women with high viral loads: a prospective long-term study.

BACKGROUND & AIMS: Hepatitis B virus (HBV) infection is a leading cause of liver diseases. We investigated the efficacy and safety of telbivudine in preventing transmission of HBV from hepatitis B e antigen-positive pregnant women with high viral loads to their infants in an open-label study. METHODS: We performed a prospective study of 450 hepatitis B e antigen-positive pregnant women with HBV DNA levels greater than 10(6) IU/mL; 279 women received telbivudine (600 mg/d) during weeks 24 to 32 of gestation, and 171 women who were unwilling to take antiviral drugs participated as controls. All newborns were vaccinated with a recombinant HBV vaccine and hepatitis B immune globulin, according to a standard immunoprophylaxis procedure. Mother-to-child transmission of HBV was determined by detection of hepatitis B surface antigen and HBV DNA in the infant 6 months after birth. RESULTS: None of the infants whose mothers were given telbivudine tested positive for of hepatitis B surface antigen at 6 months, compared with 14.7% of infants in the control group (P = 5.317 × 10(-8)). Levels of HBV DNA also decreased among women given telbivudine; 40 of 172 (23.2%) women given telbivudine had undetectable HBV DNA levels before delivery, compared with none of the controls. A significantly higher proportion of women given telbivudine had undetectable levels of HBV DNA in cord blood (99.1%) than controls (61.5%; P = 1.195 × 10(-22)). No severe adverse events or complications were observed in women or infants. CONCLUSIONS: Telbivudine significantly reduces vertical transmission of HBV from pregnant women to their infants; it is safe and well tolerated by women and infants. Antiretroviral Pregnancy Registry Health Care Providers ID: 26592; Government number: Natural Science Foundation of China (NSFC) 30830090, 30972598; and Third Military Medical University Key Project for Clinical Research: 2012XLC05).

Expression pattern of serum cytokines in hepatitis B virus infected patients with persistently normal alanine aminotransferase levels.

PURPOSE: About 60-80 % of chronic hepatitis B virus (HBV) carriers are characterized with persistently normal alanine transaminase (ALT). Differences of cytokine expression are associated with the prognosis of HBV infection. We investigated the expression pattern of 30 cytokines associated with anti-HBV immunity in patients with normal ALT. METHODS: Four patient groups (immune tolerance, inactive hepatitis B surface antigen carriers, resolved hepatitis B, and control; 10 subjects per group) were assigned. Thirty cytokines, including IFN-γ, IL-1ß, IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-17C, IL-21, IL-22, IL-23p19, IL-28A, IL-29, CCL5, CCL16, CCL20, CCL22, CXCL9, CXCL10, CXCL11, TNFRSF8, TNFRSF18, IL-6R, gp130, and TGF-ß1, were measured using a human cytokine antibody array. Signal intensities were obtained by laser scanner. Protein-protein interactions were analyzed by STRING (Search Tool for the Retrieval of Interacting Genes/Proteins). RESULTS: Significant differences of signal intensities were observed for IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-12p40, IL-12p70, IL-15, IL-21, IL-23p19, IL-28A, and IL-29. The lowest intensity was in controls. Among three HBV infection groups, significant differences were observed in IL-2, IL-4, IL-12p70, IL-15, IL-21, IL-23p19, and IL-29. The highest intensity was in the inactive group. All cytokines with significant differences were involved JAK-STAT signaling that up-regulate FOXP3, SOCS3 and MX1. CONCLUSION: Differential expression of cytokines in JAK-STAT signaling is an important factor associated with prognosis of HBV infection. The elevation of γC cytokines, IL-12p70, IL-23p19, and IL-29 may promote spontaneous HBeAg seroconversion and HBV clearance.