Protein Corona-Mediated Inhibition of Nanozyme Activity: Impact of Protein Shape.

During biomedical applications, nanozymes, exhibiting enzyme-like characteristics, inevitably come into contact with biological fluids in living systems, leading to the formation of a protein corona on their surface. Although it is acknowledged that molecular adsorption can influence the catalytic activity of nanozymes, there is a dearth of understanding regarding the impact of the protein corona on nanozyme activity and its determinant factors. In order to address this gap, we employed the AuNR@Pt@PDDAC [PDDAC, poly(diallyldimethylammonium chloride)] nanorod (NR) as a model nanozyme with multiple activities, including peroxidase, oxidase, and catalase-mimetic activities, to investigate the inhibitory effects of the protein corona on the catalytic activity. After the identification of major components in the plasma protein corona on the NR, we observed that spherical proteins and fibrous proteins induced distinct inhibitory effects on the catalytic activity of nanozymes. To elucidate the underlying mechanism, we uncovered that the adsorbed proteins assembled on the surface of the nanozymes, forming protein networks (PNs). Notably, the PNs derived from fibrous proteins exhibited a screen mesh-like structure with smaller pore sizes compared to those formed by spherical proteins. This structural disparity resulted in a reduced efficiency for the permeation of substrate molecules, leading to a more robust inhibition in activity. These findings underscore the significance of the protein shape as a crucial factor influencing nanozyme activity. This revelation provides valuable insights for the rational design and application of nanozymes in the biomedical fields.

Prognostic value of neutrophil-to-lymphocyte ratio dynamics in patients with septic acute kidney injury: a cohort study.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a prognostic marker for various diseases, but whether NLR dynamics (ΔNLR) is related to mortality and disease severity in patients with septic acute kidney injury (AKI) has not been determined. METHODS: Between August 2013 and August 2021, septic AKI patients at our center were retrospectively enrolled. ΔNLR was defined as the difference between the NLR at septic AKI diagnosis and at hospital admission. The relationship between the ΔNLR and mortality was evaluated by Kaplan-Meier curves, Cox proportional hazards, and cubic spline analyses. The prediction values were compared by area under the receiver-operating characteristic curve (AUROC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses. RESULTS: Of the 413 participants, the mean age was 63 ± 17 years, and 134 were female (32.4%). According to the median value, patients in the high-ΔNLR group had significantly greater 90-d mortality (74.4% vs. 46.6%, p < 0.001). After adjustment for potential confounders, high ΔNLR remained an independent predictor of 90-d mortality (HR = 2.80; 95% CI = 1.74-4.49, p < 0.001). Furthermore, ΔNLR had the highest AUROC for 90-d mortality (0.685) among the various biomarkers and exhibited an improved NRI (0.314) and IDI (0.027) when incorporated with PCT and CRP. For secondary outcomes, patients with high ΔNLR had increased risk of 30-d mortality (p = 0.004), need for renal replacement therapy (p = 0.011), and developing stage-3 AKI (p = 0.040) according to the adjusted models. CONCLUSIONS: High ΔNLR is independently associated with increased risk of patient mortality and adverse outcomes. ΔNLR might be utilized to facilitate risk stratification and optimize septic AKI management.

Modular Weaving DNAzyme in Skeleton of DNA Nanocages for Photoactivatable Catalytic Activity Regulation.

DNAzymes exhibit tremendous application potentials in the field of biosensing and gene regulation due to its unique catalytic function. However, spatiotemporally controlled regulation of DNAzyme activity remains a daunting challenge, which may cause nonspecific signal leakage or gene silencing of the catalytic systems. Here, we report a photochemical approach via modular weaving active DNAzyme into the skeleton of tetrahedral DNA nanocages (TDN) for light-triggered on-demand liberation of DNAzyme and thus conditional control of gene regulation activity. We demonstrate that the direct encoding of DNAzyme in TDN could improve the biostability of DNAzyme and ensure the delivery efficiency, comparing with the conventional surface anchoring strategy. Furthermore, the molecular weaving of the DNA nanostructures allows remote control of DNAzyme-mediated gene regulation with high spatiotemporal precision of light. In addition, we demonstrate that the approach is applicable for controlled regulation of the gene editing functions of other functional nucleic acids.

Octadecyl Gallate and Lipid-Modified MnSe2 Nanoparticles Enhance Radiosensitivity in Esophageal Squamous Cell Carcinoma and Promote Radioprotection in Normal Tissues.

Radiotherapy, a widely used therapeutic strategy for esophageal squamous cell carcinoma (ESCC), is always limited by radioresistance of tumor tissues and side-effects on normal tissues. Herein, a signature based on four core genes of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, is developed to predict prognosis and assess immune cell infiltration, indicating that the cGAS-STING pathway and radiotherapy efficacy are closely intertwined in ESCC. A novel lipid-modified manganese diselenide nanoparticle (MnSe2 -lipid) with extraordinarily uniform sphere morphology and tumor microenvironment (TME) responsiveness is developed to simultaneously overcome radioresistance and reduce side-effects of radiation. The uniform MnSe2 encapsulated lipid effectively achieves tumor accumulation. Octadecyl gallate on surface of MnSe2 forming pH-responsive metal-phenolic covalent realizes rapid degradation in TME. The released Mn2+ promotes radiosensitivity by generating reactive oxygen species induced by Fenton-like reaction and activating cGAS-STING pathway. Spontaneously, selenium strengthens immune response by promoting secretion of cytokines and increasing white blood cells, and performs antioxidant activity to reduce side-effects of radiotherapy. Overall, this multifunctional remedy which is responsive to TME is capable of providing radiosensitivity by cGAS-STING pathway-mediated immunostimulation and chemodynamic therapy, and radioprotection of normal tissues, is highlighted here to optimize ESCC treatment.

Immunogenicity and safety of a SARS-CoV-2 mRNA vaccine (SYS6006) in healthy Chinese participants: A randomized, observer-blinded, placebo-controlled phase 2 clinical trial.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine enables quick upgrade of antigen sequence to combat emerging new variants. In an observer-blinded, randomized, placebo-controlled phase 2 trial, immunologically naïve 300 adults and 150 older participants were enrolled and randomized (1:1:1) to receive two doses of 20 µg or 30 µg of a SARS-CoV-2 mRNA vaccine (SYS6006) or placebo. Adverse events (AEs) were recorded through 30 days after the second dose. Live virus neutralizing antibody (Nab), S1 protein-specific binding antibody (S1-IgG) and cellular immunity were tested. Results showed that robust wild-type Nab response was elicited with geometric mean titers of 91.3 and 84.9 in the adults, and 74.0 and 115.9 in the elders, 14 days following the second dose (Day 35) in the 20-µg and 30-µg groups, respectively. All seroconverted for wild-type Nab except two participants. Nab against Omicron BA.5 was mild. Robust wild-type S1-IgG response was induced with geometric mean concentrations of 2751.0 and 3142.2 BAU/mL in adults, and 2474.1 and 2993.5 BAU/mL in elders at Day 35 in the 20-µg and 30-µg groups, respectively. S1-IgG against Omicron BA.2 was induced. Cellular immunity was elicited, particularly in enzyme-linked immunospot assay. The most frequent AEs were injection-site pain and fever. Most reported AEs were grade 1 or grade 2. The AE incidences were similar following the first dose and second dose. No vaccination-associated serious AE was reported. In conclusion, two-dose vaccination with SYS6006 demonstrated good safety, tolerability and immunogenicity in immunologically naïve healthy participants aged 18 years or more.

Stents migration into right atrium from severely calcified superior vena cava in a hemodialysis patient.

Vascular calcification is common among hemodialysis patients. In this report, we presented a case of superior vena cava (SVC) stent migration during endovascular angioplasty in a 50-year-old female hemodialysis patient with severe SVC calcification. The stent migration was refractory to the deployment of a second anchor stent, which shortly resulted in pericardium tamponade and was successfully rescued by emergent thoracotomy. The potential role of vascular calcification as a risk factor to stent migration was discussed. Patients with severe vascular calcification receiving endovascular angioplasty might need a careful risk screening for stent migration.

LncRNA HOTTIP as a diagnostic biomarker for acute respiratory distress syndrome in patients with sepsis and to predict the short-term clinical outcome: a case-control study.

BACKGROUND: The present research aims to investigate the clinical diagnostic value of LncRNA HOXA distal transcript antisense RNA (HOTTIP) in acute respiratory distress syndrome (ARDS) of sepsis and its predictive significance for mortality. METHODS: One hundred eighteenth patients with sepsis and 96 healthy individuals were enrolled. RT-qPCR to examine HOTTIP levels. The incidence of ARDS and death was recorded. The diagnostic significance of HOTTIP in sepsis ARDS was examined using ROC and logistic regression analysis. The correlation between HOTTIP and disease severity was evaluated using Pearson's coefficients. Kaplan-Meier analysis and COX regression were employed to examine the predictive significance of mortality. Validation of HOTTIP target miRNA by dual-luciferase assay. RESULTS: HOTTIP was persistently up-regulated in patients with ARDS sepsis than in patients without ARDS patients (P < 0.05). HOTTIP was a risk factor for the development of ARDS, which could be diagnosed in ARDS patients from non-ARDS patients (AUC = 0.847). Both the SOFA score (r = 0.6793) and the APACHE II score (r = 0.6384) were positively correlated with the HOTTIP levels. Furthermore, serum HOTTIP was an independent predictor of short-term mortality (HR = 4.813. 95%CI: 1.471-15.750, P = 0.009) and noticeably predicted the occurrence of short-term death (log rank = 0.020). miR-574-5p, a target miRNA for HOTTIP, was reduced in patients with sepsis ARDS and negatively correlated with HOTTIP. CONCLUSIONS: The presence of HOTTIP serves as a diagnostic biomarker for the occurrence of ARDS, exhibits correlation with disease severity, and provides predictive value of short-term mortality in sepsis patients. HOTTIP may be involved in ARDS progression by targeting miR-574-5p.

Optic Nerve Sheath Diameter Sonography for the Diagnosis of Intracranial Hypertension in Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

OBJECTIVES: Timely diagnosis and management of elevated intracranial pressure (ICP) in patients with traumatic brain injury (TBI) can significantly reduce mortality rates. Ultrasound examination of the optic nerve sheath diameter (ONSD) is considered a potential, noninvasive, and effective method for assessing ICP. We conducted a systematic review and meta-analysis of ONSD ultrasound detection and invasive ICP monitoring methods to compare and evaluate the diagnostic accuracy of ONSD ultrasound detection methods for intracranial hypertension (IH) in patients with TBI. METHODS: We searched the Web of Science, PubMed, and Embase databases to assess the diagnostic accuracy of ONSD sonography for predicting increased ICP. The 2 authors independently extracted the collected data. Simultaneously, the QUADAS-2 tool was used to evaluate the bias risk of each study and conducted random-effects meta-analyses for the accuracy and specificity of diagnosis, and calculated pooled estimates. RESULTS: Ten studies with 512 patients were included. The diagnostic accuracy of ONSD sonography for IH was revealed as a pooled sensitivity of 0.85 (95% confidence interval [CI], 0.79-0.89) and specificity of 0.88 (95% CI, 0.80-0.93), compared with the invasive ICP monitoring standard for patients with TBI. CONCLUSIONS: ONSD sonography may be a useful method for predicting increased ICP in adult patients with TBI. Further clinical studies are required to confirm the diagnostic value of ONSD sonography.

The dynamic role of platelets in cancer progression and their therapeutic implications.

Systemic antiplatelet treatment represents a promising option to improve the therapeutic outcomes and therapeutic efficacy of chemotherapy and immunotherapy due to the critical contribution of platelets to tumour progression. However, until recently, targeting platelets as a cancer therapeutic has been hampered by the elevated risk of haemorrhagic and thrombocytopenic (low platelet count) complications owing to the lack of specificity for tumour-associated platelets. Recent work has advanced our understanding of the molecular mechanisms responsible for the contribution of platelets to tumour progression and metastasis. This has led to the identification of the biological changes in platelets in the presence of tumours, the complex interactions between platelets and tumour cells during tumour progression, and the effects of platelets on antitumour therapeutic response. In this Review, we present a detailed picture of the dynamic roles of platelets in tumour development and progression as well as their use in diagnosis, prognosis and monitoring response to therapy. We also provide our view on how to overcome challenges faced by the development of precise antiplatelet strategies for safe and efficient clinical cancer therapy.

Serum total protein-to-albumin ratio predicts risk of death in septic acute kidney injury patients: A cohort study.

OBJECTIVE: Sepsis is the leading cause of acute kidney injury (AKI). Increasing evidence shows that serum total protein-to-albumin ratio (TAR) could serve as an inflammation- and nutrition-based prognostic marker in various diseases. The purpose of this study was to assess the prognostic value of TAR in predicting the clinical outcomes of septic AKI patients. METHODS: We retrospectively enrolled septic AKI patients between August 2015 and August 2022 at West China Hospital of Sichuan University. Patients admitted between August 2015 and August 2021 were defined as the original cohort. The primary outcomes were 30-day and 90-day all-cause mortality of septic AKI patients. The secondary outcomes were septic shock, transfer to the intensive care unit, mechanical ventilation, requirement for renal replacement therapy, and stage 3 AKI. The utility of TAR was further verified in a validation cohort of septic AKI patients admitted between September 2021 and August 2022. RESULTS: In the original cohort, a total of 309 eligible patients with a median age of 58 years were enrolled, of which 70.2 % were males. In multivariate Cox analysis, after adjustments for age, sex, and other confounding factors, higher TAR at admission was associated with an increased risk of 30-day and 90-day all-cause mortality in septic AKI patients (HR 1.91, 95 % CI 1.18-3.09, P = 0.008; HR 1.54, 95 % CI 1.01-2.34, P = 0.043, respectively). Subgroup analysis revealed no significant interactions in most strata. TAR at AKI diagnosis or discharge was not significantly related to 30-day (P = 0.120 and 0.153, respectively) or 90-day mortality (P = 0.147 and 0.124, respectively). We found no relationship between baseline TAR and septic shock, transfer to the intensive care unit, mechanical ventilation, requirement for renal replacement therapy, or stage 3 AKI (all P > 0.05). In the validation cohort of 81 septic AKI patients, TAR at admission remained a significant prognosticator for 30-day and 90-day mortality (HR 4.367, 95 % CI 1.20-15.87, P = 0.025; HR 4.237, 95 % CI 1.59-11.27, P = 0.004). CONCLUSIONS: TAR at admission is an independent risk factor for 30-day and 90-day mortality in septic AKI patients and could be used as a convenient and economic septic AKI prognostic indicator.

Key elements and checklist of shared decision-making conversation on life-sustaining treatment in emergency: a multispecialty study from China.

BACKGROUND: Shared decision-making (SDM) has broad application in emergencies. Most published studies have focused on SDM for a certain disease or expert opinions on future research gaps without revealing the full picture or detailed guidance for clinical practice. This study is to investigate the optimal application of SDM to guide life-sustaining treatment (LST) in emergencies. METHODS: This study was a prospective two-round Delphi consensus-seeking survey among multiple stakeholders at the China Consortium of Elite Teaching Hospitals for Residency Education. Participants were identified based on their expertise in medicine, law, administration, medical education, or patient advocacy. All individual items and questions in the questionnaire were scored using a 5-point Likert scale, with responses ranging from "very unimportant" (a score of 1) to "extremely important" (a score of 5). The percentages of the responses that had scores of 4-5 on the 5-point Likert scale were calculated. A Kendall's W coefficient was calculated to evaluate the consensus of experts. RESULTS: A two-level framework consisting of 4 domains and 22 items as well as a ready-to-use checklist for the informed consent process for LST was established. An acceptable Kendall's W coefficient was achieved. CONCLUSION: A consensus-based framework supporting SDM during LST in an emergency department can inform the implementation of guidelines for clinical interventions, research studies, medical education, and policy initiatives.

Sarcoidosis or Tuberculosis: Should Corticosteroids Be Used?

Sarcoidosis shows high similarity with tuberculosis in clinical manifestations and imaging features. It is rarely reported whether sarcoidosis patients with suspected latent tuberculosis can be treated safely with immunosuppressive therapy. We reported on a 54-year-old man who presented with enlarged lymph nodes persisting for decades, accompanied by renal impairment and refractory hypercalcemia. The patient was diagnosed with sarcoidosis and suspected latent tuberculosis (as suggested by a positive tuberculin test and tuberculosis interferon-gamma release assays) and received prednisone under follow-up. The patient showed significant amelioration in hypercalcemia and shrinkage of lymph nodes, without evidence of developing active tuberculosis. For sarcoidosis patients with suspected latent tuberculosis, immunosuppressive agents can be utilized safely based on close monitoring. Further efforts are required to reveal whether sarcoidosis and tuberculosis can trigger similar immune responses and what the clinical implications are.

Massive Hemorrhage Following Acupuncture Treatment in a Neurofibromatosis Type 1 Patient.

Neurofibromatosis type 1 (NF1) is a genetic disorder involving multiple organs. Vascular involvement is a rare complication among NF1 patients. We report a case of a 59-year-old female NF1 patient who presented with a massive hematoma over the scapular area after undergoing acupuncture treatment. Contrast-enhanced CT and MRI demonstrated a slightly hyperdense mass measuring 24.2 × 10.3 cm in size, and multiple enlarged and tortuous malformed vessels were seen arising from the left subclavian artery. Arterial embolization and subsequent surgical mass resection were successfully performed. This case indicates that minor injuries such as acupuncture-related ones could cause severe hemorrhage in patients with vascular malformation related to NF1. Endovascular angiography and embolization proved to be effective in localizing the culprit vessel and stopping active bleeding in our patient.

Recent advances in nanoantibiotics against multidrug-resistant bacteria.

Multidrug-resistant (MDR) bacteria-caused infections have been a major threat to human health. The abuse of conventional antibiotics accelerates the generation of MDR bacteria and makes the situation worse. The emergence of nanomaterials holds great promise for solving this tricky problem due to their multiple antibacterial mechanisms, tunable antibacterial spectra, and low probabilities of inducing drug resistance. In this review, we summarize the mechanism of the generation of drug resistance, and introduce the recently developed nanomaterials for dealing with MDR bacteria via various antibacterial mechanisms. Considering that biosafety and mass production are the major bottlenecks hurdling the commercialization of nanoantibiotics, we introduce the related development in these two aspects. We discuss urgent challenges in this field and future perspectives to promote the development and translation of nanoantibiotics as alternatives against MDR pathogens to traditional antibiotics-based approaches.

Efficacy of Jiao's scalp acupuncture in combination with Xiangshao granules on chronic tension-type headache with concomitant nonalcoholic fatty liver disease in climacteric women.

OBJECTIVE: This study aimed to assess the efficacy of Jiao's scalp acupuncture in combination with Xiangshao granules on chronic tension-type headache (CTTH) with concomitant nonalcoholic fatty liver disease (NAFLD) in climacteric women. METHODS: In this study, we enrolled 150 climacteric women with CTTH and concomitant NAFLD. The participants were divided into three groups based on the random number table: medication group, acupuncture group, and acupuncture-medication group. Treatment continued for 2 months. The efficacy of CTTH was assessed based on the visual analog scale/score (VAS). The influence on NAFLD was assessed based on body mass index (BMI), controlled attenuation parameter (CAP), and the ratio of hepatic-splenic computed tomography (CT) value. The Participant Health Questionnaire-9 (PHQ-9) score was compared among the three groups. RESULTS: A total of 123 participants completed the trial, including 37 participants in the medication group, 41 participants in the acupuncture group, and 45 participants in the acupuncture-medication group. Results are summarized hereinafter. (1) The total clinical efficiency rates of the medication group, acupuncture group, and acupuncture-medication group were 89.19% (33 of 37), 90.24% (37 of 41), and 95.65% (44 of 46), respectively. (2) Except for the BMI of the medication group ( P = 0.063), a significant difference in VAS, BMI, CAP, the ratio of hepatic-splenic CT value, and PHQ-9 score was found in the three groups ( P < 0.01). (3) There was a significant difference in VAS, BMI, CAP, and PHQ-9 among the three groups ( P < 0.01), with those in the acupuncture-medication group being superior. No difference in the ratio of hepatic-splenic CT value was found ( P = 0.440). (4) The efficacy differed significantly among the three groups ( χ2 = 8.130, P = 0.017), and it was significantly superior in the acupuncture-medication group ( P = 0.008, P = 0.013). CONCLUSIONS: Jiao's scalp acupuncture, in combination with Xiangshao granules, was superior in treating CTTH in climacteric women compared with either acupuncture or medication. Jiao's scalp acupuncture, in combination with Xiangshao granules, was superior in subsiding the negative moods in participants with CTTH and concomitant NAFLD.

Immunogenicity and safety of a new hexavalent rotavirus vaccine in Chinese infants: A randomized, double-blind, placebo-controlled phase 2 clinical trial.

Rotavirus remains a major cause of diarrhea among 5-y-old children, and vaccination is currently the most effective and economical measure. We conducted a randomized, double-blind, placebo-controlled phase II clinical trial designed to determine the dosage, immunogenicity, and safety profile of a novel hexavalent rotavirus vaccine. In total, 480 eligible healthy infants, who were 6-12 weeks of age at the time of randomization were randomly allocated (1:1:1) to receive 105.5 focus-forming unit (FFU) or 106.5FFU of vaccine or placebo on a 0, 28 and 56-d schedule. Blood samples were collected 28 d after the third dose to assess rotavirus immunoglobulin A (IgA) antibody levels. Adverse events (AEs) up to 28 d after each dose and serious adverse events (SAEs) up to 6 months after the third dose were recorded as safety measurements. The anti-rotavirus IgA seroconversion rate of the vaccine groups reached more than 70.00%, ranging from 74.63% to 76.87%. The postdose 3 (PD3) geometric mean concentrations (GMCs) of anti-rotavirus IgA among vaccine recipients ranged from 76.97 U/ml to 84.46 U/ml. At least one solicited AE was recorded in 114 infants (71.25%) in the high-dose vaccine group, 106 infants (66.25%) in the low-dose vaccine group and 104 infants (65.00%) in the placebo group. The most frequently solicited AE was fever. The novel oral hexavalent rotavirus vaccine was safe and immunogenic in infants support the conclusion to advance the candidate vaccine for phase 3 efficacy trials.