Tumor acidification and GSH depletion by bimetallic composite nanoparticles for enhanced chemodynamic therapy of TNBC.

Chemodynamic therapy (CDT) based on intracellular Fenton reaction to produce highly cytotoxic reactive oxygen species (ROS) has played an essential role in tumor therapy. However, this therapy still needs to be improved by weakly acidic pH and over-expression of glutathione (GSH) in tumor microenvironment (TEM), which hinders its future application. Herein, we reported a multifunctional bimetallic composite nanoparticle MnO2@GA-Fe@CAI based on a metal polyphenol network (MPN) structure, which could reduce intracellular pH and endogenous GSH by remodeling tumor microenvironment to improve Fenton activity. MnO2 nanoparticles were prepared first and MnO2@GA-Fe nanoparticles with Fe3+ as central ion and gallic acid (GA) as surface ligands were prepared by the chelation reaction. Then, carbonic anhydrase inhibitor (CAI) was coupled with GA to form MnO2@GA-Fe@CAI. The properties of the bimetallic composite nanoparticles were studied, and the results showed that CAI could reduce intracellular pH. At the same time, MnO2 could deplete intracellular GSH and produce Mn2+ via redox reactions, which re-established the TME with low pH and GSH. In addition, GA reduced Fe3+ to Fe2+. Mn2+ and Fe2+ catalyzed the endogenous H2O2 to produce high-lever ROS to kill tumor cells. Compared with MnO2, MnO2@GA-Fe@CAI could reduce the tumor weight and volume for the xenograft MDA-MB-231 tumor-bearing mice and the final tumor inhibition rate of 58.09 ± 5.77%, showing the improved therapeutic effect as well as the biological safety. Therefore, this study achieved the high-efficiency CDT effect catalyzed by bimetallic through reshaping the tumor microenvironment.

Comparison of immune checkpoint inhibitors related to pulmonary adverse events: a retrospective analysis of clinical studies and network meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed tumor treatment. However, the risk of pulmonary adverse events (PAEs) associated with ICI combination therapy is still unclear. We aimed to provide a PAE overview and risk ordering of ICIs used in tumor treatment. METHODS: We searched the databases of PubMed, PsycINFO, Embase, Cochrane Library, CINAHL, Web of Science, Scopus, and clinical trial websites during January 2011-April 2023 to identify phase II and III randomized clinical trials (RCTs) and single-arm clinical trials wherein at least one treatment arm received ICIs (e.g., ICI monotherapy, a combination of two ICIs, or ICIs in combination with conventional cancer therapy). We reported the results of PAEs. Additionally, we compared risks of PAEs between different drug classes using a Bayesian network meta-analysis. RESULTS: Among 143 RCTs and 24 single-arm trials, the incidence of all-grade and grade 3-4 PAEs were highest with programmed death L1 (PD-L1) plus cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and plus chemotherapy and anti-PD1 plus anti-CTLA4, the lowest with targeted therapy drug plus chemotherapy and anti-PD1 plus anti-PDL1. Anti-PD1 plus anti-CTLA4 and plus chemotherapy was the intervention with the highest risk for all-grade and 3-4 grade PAEs, and the intervention with the lowest risk was chemotherapy and anti-PD1 plus anti-PDL1. In terms of all-grade PAEs, chemotherapy was safer than ICI monotherapy. Except for the anti-PD1 plus anti-PDL1 regimen, no significant difference in the risk of grade 3-4 PAEs was detected between dual-ICIs and single-ICIs. Furthermore, the risk of PAEs associated with nivolumab, pembrolizumab, and atezolizumab may be dose dependent. CONCLUSIONS: In the single-drug regimen, anti-PD1 caused the greatest incidence of PAEs. The risk of PAEs was higher with all single-ICIs than with chemotherapy. However, no significant difference in the risk of PAEs was detected between single-ICIs. In the combined regimen, anti-PD1 plus anti-CTLA4 and plus chemotherapy showed the greatest risk of PAEs, but there were no significant differences in risk between dual-ICIs and single-ICIs.

Public acceptance of COVID-19 control measures and associated factors during Omicron-dominant period in China: a cross-sectional survey.

OBJECTIVES: This study aims to evaluate the public acceptance of coronavirus disease 2019 (COVID-19) control measures during the Omicron-dominant period and its associated factors. METHODS: A cross-sectional design was conducted and 1391 study participants were openly recruited to participate in the questionnaire survey. Logistic regression model was performed to assess the association between the public acceptance and potential factors more specifically. RESULTS: By August 26, 2022, 58.9% of the study participants were less acceptive of the control measures while 41.1% expressed higher acceptance. Factors associated with lower acceptance included young age, such as < 18 (OR = 8.251, 95% CI: 2.009 to 33.889) and 18-29 (OR = 2.349, 95% CI: 1.564 to 3.529), and household per capita monthly income lower than 5000 yuan (OR = 1.512, 95% CI: 1.085 to 2.105). Furthermore, individuals who perceived that the case fatality rate (CFR) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was very low (OR = 6.010, 95% CI: 2.475 to 14.595) and that the restrictions could be eased once the CFR dropped to 2-3 times of the influenza (OR = 2.792, 95% CI: 1.939 to 4.023) showed greater oppositional attitudes. Likewise, respondents who were dissatisfied with control measures (OR = 9.639, 95% CI: 4.425 to 20.998) or preferred fully relaxation as soon as possible (OR = 13.571, 95% CI: 7.751 to 23.758) had even lower acceptability. By contrast, rural residents (OR = 0.683, 95% CI: 0.473 to 0.987), students (OR = 0.510, 95% CI: 0.276 to 0.941), public (OR = 0.417, 95% CI: 0.240 to 0.727) and private (OR = 0.562, 95% CI: 0.320 to 0.986) employees, and vaccinated participants (OR = 0.393, 95% CI: 0.204 to 0.756) were more compliant with control measures. CONCLUSION: More than half of the Chinese public were less supportive of COVID-19 control measures during Omicron-dominant period, which varied based on their different demographic characteristics, cognition and overall attitude towards SARS-CoV-2 infection. Control measures that struck a balance between public safety and individual freedom would be more acceptable during the pandemic.

Elimination of intracellular Ca2+ overload by BAPTA­AM liposome nanoparticles: A promising treatment for acute pancreatitis.

Calcium overload, a notable instigator of acute pancreatitis (AP), induces oxidative stress and an inflammatory cascade, subsequently activating both endogenous and exogenous apoptotic pathways. However, there is currently lack of available pharmaceutical interventions to alleviate AP by addressing calcium overload. In the present study, the potential clinical application of liposome nanoparticles (LNs) loaded with 1,2­bis(2­aminophenoxy)ethane­N,N,N',N'­tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA­AM), a cell­permeant calcium chelator, was investigated as a therapeutic approach for the management of AP. To establish the experimental models in vitro, AR42J cells were exposed to high glucose/sodium oleate (HGO) to induce necrosis, and in vivo, intra­ductal taurocholate (TC) infusion was used to induce AP. The findings of the present study indicated that the use of BAPTA­AM­loaded LN (BLN) effectively and rapidly eliminated excessive Ca2+ and reactive oxygen species, suppressed mononuclear macrophage activation and the release of inflammatory cytokines, and mitigated pancreatic acinar cell apoptosis and necrosis induced by HGO. Furthermore, the systemic administration of BLN demonstrated promising therapeutic potential in the rat model of AP. Notably, BLN significantly enhanced the survival rates of rats subjected to the TC challenge, increasing from 37.5 to 75%. This improvement was attributed to the restoration of pancreatic function, as indicated by improved blood biochemistry indices and alleviation of pancreatic lesions. The potential therapeutic efficacy of BLN in rescuing patients with AP is likely attributed to its capacity to inhibit oxidative stress, prevent premature activation of zymogens and downregulate the expression of TNF­α, IL­6 and cathepsin B. Thus, BLN demonstrated promising value as a novel therapeutic approach for promptly alleviating the burden of intracellular Ca2+ overload in patients with AP.

Development and validation of a nomogram for predicting immune-related pneumonitis after sintilimab treatment.

BACKGROUND: Immune-related pneumonitis is a rare and potentially fatal adverse event associated with sintilimab. We aimed to develop and validate a nomogram for predicting the risk of immune-related pneumonitis in patients treated with sintilimab. METHODS: The least absolute shrinkage and selection operator (LASSO) regression was used to determine risk factors. Multivariable logistic regression was used to establish a prediction model. Its clinical validity was evaluated using calibration, discrimination, decision, and clinical impact curves. Internal validation was performed against the validation set and complete dataset. RESULTS: The study included 632 patients; 59 were diagnosed with immune-related pneumonitis. LASSO regression analysis identified that the risk factors for immune-related pneumonitis were pulmonary metastases (odds ratio [OR], 4.015; 95% confidence interval [CI]: 1.725-9.340) and metastases at >3 sites (OR, 2.687; 95% CI: 1.151-6.269). The use of combined antibiotics (OR, 0.247; 95% CI: 0.083-0.738) and proton pump inhibitors (OR, 0.420; 95% CI: 0.211-0.837) were protective factors. The decision and clinical impact curves showed that the nomogram had clinical value for patients treated with sintilimab. CONCLUSIONS: We have developed and validated a practical nomogram model of sintilimab-associated immune-related pneumonitis, which provides clinical value for determining the risk of immune-related pneumonitis and facilitating the safe administration of sintilimab therapy.

Effects of vertical integration on the healthcare system in China: a systematic review and meta-analysis.

Vertical integration is one possible way to improve the performance of a healthcare system; however, its effects are inconsistent, and there is a lack of evidence from undeveloped nations. This study aims to systematically review the evidence regarding effects of vertical integration on healthcare systems in China. We searched PubMed, Embase, Cochrane Library, Web of Science, ProQuest Health & Medicine Collection, China Knowledge Resource Integrated Database and Wanfang databases from April 2009 (initiation of new healthcare reform) to May 2021 for randomized controlled trials (RCTs), controlled before and after (CBA) trials, cohort studies and interrupted time series (ITS) trials. Vertical integration in the included studies must involve both primary health institutions and secondary or tertiary hospitals. After screening 3109 records, we ultimately analysed 47 studies, including 27 CBA trials, 18 RCTs and 2 ITS trials. The narrative synthesis shows that all but three studies indicated that vertical integration improved efficiency (utilization and cost of health services), quality of public health services and medical services, health provider-centred outcomes (knowledge and skill) and patient-centred outcomes (patients' clinical outcomes, behaviour and satisfaction). Despite the heterogeneity of vertical integration interventions across different studies, the meta-analysis reveals that it lowered diastolic blood pressure (mean difference (MD) -8.41, 95% confidence interval (CI) -15.18 to -1.65) and systolic blood pressure (MD-5.83, 95% CI -9.25 to -2.40) among hypertension patients, and it lowered HbA1c levels (MD -1.95, 95% CI -2.69 to -1.21), fasting blood glucose levels (MD -1.02, 95% CI -1.53 to -0.50) and 2-hour postprandial blood glucose levels (MD -1.78, 95% CI -2.67 to -0.89). The treatment compliance behaviour was improved for hypertension participants (risk ratio (RR) 1.08, 95% CI 1.04-1.13) and for diabetes patients (RR 1.32, 95% CI 1.08-1.61). Vertical integration in China can improve efficiency, quality of care, health provider-centred outcomes and patient-centred outcomes, but high-quality original studies are highly needed.

Pulmonary Toxicity Associated with Immune Checkpoint Inhibitors-Based Therapy: Current Perspectives and Future Directions.

Immune checkpoint inhibitors (ICIs) have shown efficacy in tumor therapy. However, the risk of pulmonary toxicity from ICI-based treatment regimens remains unknown. We searched multiple databases and clinical trial websites from January 2015 to December 2021 and summarized the pulmonary toxicity profile and risk ranking of ICI-based treatments in cancer patients. We included a Phase III randomized clinical trial (RCT) in which the treatment group received at least one ICI and experienced pulmonary adverse events (PAEs). Our study, which included 104 RCTs, found the highest incidence of grades 1-2 and 3-5 treatment-associated PAEs (Tr-PAEs) in programmed death 1 (PD-1)+ chemotherapy and PD-1+ cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), respectively. The first incidence rates of grades 1-2 and 3-5 immune-mediated PAEs (Im-PAEs) were PD1+CTLA-4+ chemotherapy and PD-L1 + CTLA4, respectively. Cytotoxic T lymphocyte-associated antigen 4 + chemotherapy regimen and PD-L1+ targeted therapy drug (TTD)+ chemotherapy regimen had the highest risk of developing grades 1-2 and 3-5 Tr-PAEs. Programmed death-L1+ CTLA-4 has a higher risk of grade 3-5 Tr-PAEs than PD-L1. The risk of grade 1-2 pulmonary toxicity was significantly different in the high-dose and low-dose groups of nivolumab and atezolizumab. Nivolumab and atezolizumab induced dose-dependent grade 1-2 pulmonary toxicity. Among single-agent regimens, PD-1 showed the greatest grade 1-2 pulmonary toxicity. Programmed death-L1+ TTD+ chemotherapy showed the greatest grade 3-5 pulmonary toxicity in combination therapy. PD-L1+ TTD+ chemotherapy was associated with a higher risk of grade 3-5 Tr-PAEs and a lower risk of Im-PAEs. We recommend a targeted approach to managing PAE.

Tryptanthrin inhibits tumor angiogenesis via Notch/Dll4 signaling pathway in zebrafish.

Background: Anti-angiogenic pathways are important for inhibiting tumor growth and migration. Tryptanthrin has anticancer properties in vivo but its anti-angiogenesis activities and associated mechanisms remain unclear. Methods: The effects of tryptanthrin were investigated in vivo using fluorescent labeling of blood vessels in zebrafish. Fluorescence quantitation was conducted to analyze the level of delta-like ligand 4 (Dll4) gene expression. Transcriptome sequencing and quantitative polymerase chain reaction (qPCR) analyses were performed to explore the molecular mechanisms of anti-tumor angiogenesis. Results: Significant anti-tumor effects were observed in all 48-hpf (hours post-fertilization) zebrafish treated with tryptanthrin (P<0.05). The 6-hpf zebrafish were cultured to 48 and 72 hpf following tryptanthrin treatment. It was found that compared with the control groups, the fluorescence area and the number of complete internode vessels reduced significantly following treatment with medium and high concentrations of tryptanthrin (P<0.05). The relative expression of Dll4 in the 48-hpf zebrafish was significantly inhibited only in the high concentration group (P<0.05). qPCR analysis revealed that the levels of Krt18b, desma, Tnnt2c, and Krt4 gene expression were significantly up-regulated in zebrafish following Dll4 overexpression. After Dll4 knockdown, the level of desma and Tnnt2c gene expression was significantly up-regulated. Conclusions: Tryptanthrin can inhibit tumor growth in vivo in a concentration-dependent manner by down-regulating Dll4 protein expression, and at the same time up-regulating the level of desma and Tnnt2c gene expression.

Development and Validation of a Clinical Risk Score to Predict Immune-mediated Liver Injury Caused by Sintilimab: Assessed for Causality Using Updated RUCAM.

Background and Aims: Immune-mediated liver injury is a fatal side effect of sintilimab. This study aimed to shed light on the associated risk factors and characteristics of this adverse event. Methods: The clinical records of 772 patients treated with sintilimab were retrospectively reviewed to investigate risk factors associated with sintilimab immune-related hepatotoxicity, as well as its incidence and outcome. The Roussel Uclaf Causality Assessment Method was used to identify cases of sintilimab-induced hepatotoxicity. Furthermore, logistic regressions were performed to compare the clinical and bloodwork characteristics of patients with and without immune-mediated liver injury caused by checkpoint inhibitors. Results: Of the 585 patients included in the study, 71 (12.1%) developed liver injury during sintilimab use. The median RUCAM score with interquartile range was 7 (6, 8). Hypoproteinemia, dyslipidemia, and the presence of thyroid peroxidase antibodies were risk factors for sintilimab-related hepatotoxicity. A nomogram model was constructed for sintilimab-induced immune-mediated liver injury based on these risk factors, which had a C-index value of 0.713 and a good calibration curve. When applied to patients with grade ≥3 and ≥4 sintilimab-induced immune-mediated liver injury, it achieved C-index values of 0.752 and 0.811, respectively. The nomogram model also showed a good prediction potential in patients ≥65 years and males. Six of the patients with sintilimab-related hepatotoxicity showed improved liver function upon treatment with steroids. Conclusions: This study demonstrated that hypoproteinemia, dyslipidemia, and the presence of thyroid peroxidase antibodies were clinically feasible prognostic biomarkers to predict liver injury in patients treated with sintilimab.

Predictors of referral behaviour and intention amongst physicians in a medical consortium based on the theory of planned behaviour: a cross-sectional study in China.

Introduction: To promote patients' referral across healthcare institutions and integrated care delivery, we identified predictors of physicians' behaviour and intention to refer patients in a county medical consortium in China on the basis of the theory of planned behaviour (TPB). Methods: This census-based cross-sectional study was conducted in Yangxi Hospital Group (YHG). All physicians in county hospitals and township health centres were invited to participate. Structural equation modelling was employed to analyse the relationships between referral intention and behaviour and other TPB variables in the group of whole participants and in sub-groups. Results: In total, 330 physicians participated in this study. One-third of participants were general practitioners, and half of them were from county hospitals. Referral behaviour of females (χ2 = 20.372, p < 0.001), who had lower education levels (χ2 = 17.859, p = 0.001), lower professional title (χ2 = 14.963, p = 0.005), and lower monthly salary (χ2 = 33.753, p < 0.001) were less frequent than the others. Among them, 116 (35.2%), 108 (32.7%), and 106 (32.1%) respondents reported that they had never referred patients, had referred patients 1-9 times, and had referred patients over 10 times during the past 3 months, respectively. The mean score of referral intention was 4.23/5 (SD = 0.71). In the model with all participants, a stronger referral intention (ß = 0.218, 95% CI = 0.080-0.356) was associated with more frequent referral behaviour. The subjective norm (ß = 0.703, 95% CI = 0.590-0.817) was the strongest predictor of physicians' referral intention, followed by perceived behavioural control (ß = 0.234, 95% CI = 0.090-0.378). Mediated by referral intention, subjective norms (ß = 0.153, p < 0.01) and perceived behavioural control (ß = 0.190, p < 0.01) had significant indirect effects on physicians' referral behaviour. The model with participants in county hospitals showed similar results to the model with all participants. Meanwhile, in the model with participants in township health centres, there were no significant associations between referral behaviour and other TPB constructs. Conclusion: Physicians' referral behaviour was influenced by intention, subjective norms, and perceived behavioural control in Chinese county hospitals.

Preparation and Hemostatic Effect of Micro-Nanograded Porous Particles Doped with Dopamine-Based Water-Triggered Intelligent Composite Adhesives.

The wet environment of water or tissue in bleeding wounds poses significant challenges to the adhesion performance of existing hemostatic adhesives. An intelligent composite adhesive prepared by doping starch-based silicate micro-nanograded porous particles (MBC@CMS) with dopamine-hyperbranched polymers (HPD, 7800 Mw) synthesized by the Michael addition reaction could be triggered by water to form a glue (MBC@CMS-HPD). The results indicated that MBC@CMS-HPD could still have adhesion properties under running water washing and water immersion and could effectively seal the water outlet. The results of the glue-forming mechanism showed that MBC@CMS-HPD had better wettability than water, which could eliminate water molecules at the wet adhesive surface. When contacted with water, the agglomeration of the HPD hydrophobic chain increases the exposure of the catechol group, and the relative atomic mass of the N element on the surface increases from 2.8 to 4.8%. The adhesion of MBC@CMS-HPD was enhanced and stable. MBC@CMS-HPD showed significant hemostasis effects in five injury bleeding models of Sprague-Dawley (SD) rats and New Zealand rabbits. Especially in the fatal femoral artery bleeding model of New Zealand rabbits, MBC@CMS-HPD reduced the amount of bleeding by 75% and shortened the bleeding time by 78% compared with the a-cyanoacrylate adhesives. The results of the coagulation mechanism showed that compared with HPD, MBC@CMS-HPD could activate both endogenous and exogenous coagulation pathways. Among them, after contact with blood, HPD formed a gel to close the blood outlet, and MBC@CMS entered the wound to activate the internal and external coagulation pathways. In addition, HPD and MBC@CMS had good histocompatibility and degradability, which has the potential to be applied to different wounds.

Photocatalytic Ag/AgBr-MBG for Rapid Antibacterial and Wound Repair.

In daily life and during surgery, the skin, as the outermost organ of the human body, is easily damaged to form wounds. If the wound was infected by the bacteria, especially the drug-resistant bacteria such as methicillin-resistant staphylococcus aureus (MRSA), it was difficult to recover. Therefore, it was important to develop the safe antimicrobial strategy to inhibit bacterial growth in the wound site, in particular, to overcome the problem of bacterial drug resistance. Here, the Ag/AgBr-loaded mesoporous bioactive glass (Ag/AgBr-MBG) was prepared, which had excellent photocatalytic properties under simulated daylight for rapid antibacterial activity within 15 min by generating reactive oxygen species (ROS). Meanwhile, the killing rate of Ag/AgBr-MBG against MRSA was 99.19% within 15 min, which further reduced the generation of drug-resistant bacteria. In addition, Ag/AgBr-MBG particles could disrupt bacterial cell membranes, showing the broad-spectrum antibacterial properties and promoting tissue regeneration and infected wound healing. Ag/AgBr-MBG particles might have potential applications as a light-driven antimicrobial agent in the field of biomaterials.

Telomerase reverse transcriptase and neurodegenerative diseases.

Neurodegenerative diseases (NDs) are chronic conditions that result in progressive damage to the nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). Age is a major risk factor for NDs. Telomere shortening is a biological marker of cellular aging, and telomerase reverse transcriptase (TERT) has been shown to slow down this process by maintaining telomere length. The blood-brain barrier (BBB) makes the brain a unique immune organ, and while the number of T cells present in the central nervous system is limited, they play an important role in NDs. Research suggests that NDs can be influenced by modulating peripheral T cell immune responses, and that TERT may play a significant role in T cell senescence and NDs. This review focuses on the current state of research on TERT in NDs and explores the potential connections between TERT, T cells, and NDs. Further studies on aging and telomeres may provide valuable insights for developing therapeutic strategies for age-related diseases.

Smart microneedle patches for wound healing and management.

The number of patients with non-healing wounds is generally increasing globally, placing a huge social and economic burden on every country. The complexity of the wound-healing process remains a major health challenge despite the numerous studies that have been reported on conventional wound dressings. Therefore, a therapeutic system that combines diagnostic and therapeutic modalities is essential to monitor wound-related biomarkers and facilitate wound healing in real time. Microneedles, as a multifunctional platform, are promising for transdermal diagnostics and drug delivery. Their advantages are mainly reflected in painless transdermal drug delivery, good biocompatibility, and ease of self-administration. In this work, we review recent advances in the use of microneedle patches for wound healing and monitoring. The paper first provides a brief overview of the skin structure and the wound healing process, and then discusses the current state of research and prospects for the development of wound-related biomarkers and their real-time monitoring based on microneedle sensors. It summarizes the current state of research based on the unique design of microneedle patches, including biomimetic, conductive, and environmentally responsive, to achieve wound healing. It further summarizes the prospects for the application of different microneedle-based drug delivery modalities and drug delivery substances for wound healing, due to their superior transdermal drug delivery advantages. It concludes with challenges and expectations for the use of smart microneedle patches for wound healing and management.

Hepatotoxicity of immune checkpoint inhibitors: What is Currently Known.

BACKGROUND: This systematic review and network meta-analysis aimed to provide a complete hepatotoxicity profile, hepatotoxicity spectrum, and safety ranking of immune checkpoint inhibitor drugs for cancer treatment. METHODS: PubMed, Embase, Scopus, CINAHL, Web of Science, psycINFO, Cochrane Library, and ClinicalTrials.gov. websites were searched, and a manual search of relevant reviews and trials up to January 1, 2022, was undertaken. Head-to-head III randomized controlled trials comparing any 2 or 3 of the following treatments or different doses of the same immune checkpoint inhibitor drug were included: programmed death 1 (PD-1), programmed death ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors and conventional therapy. We included 106 randomized trials (n=164,782) containing 17 treatment arms. RESULTS: The overall incidence of hepatotoxicity was 4.06%. The rate of fatal liver adverse events was 0.07%. The programmed death ligand 1 inhibitor+targeted therapy drug+chemotherapy group had the highest risk of treatment-related increases in all-grade alanine aminotransferase and aspartate aminotransferase levels, and the differences were significant. For immune-related hepatotoxicity, no significant difference was found between PD-1 and CTLA-4 inhibitors for all-grade hepatotoxicity; however, CTLA-4 inhibitors were associated with a higher risk of grade 3-5 hepatotoxicity than PD-1 inhibitors. CONCLUSIONS: The highest incidence of hepatotoxicity and fatality was observed with triple therapy. The overall incidence of hepatotoxicity was similar between different dual regimens. For immune checkpoint inhibitor monotherapy, the overall risk of immune-mediated hepatotoxicity related to CTLA-4 inhibitors did not differ significantly from that of PD-1 inhibitors. There was no direct relationship between the risk of liver injury and drug dose, whether monotherapy or combination therapy was used.

Chitosan and hyaluronic-based hydrogels could promote the infected wound healing.

The most important function of skin is to prevent biological dehydration and protect internal structures from the environment. When a wound becomes infected, the bacteria cause a sustained inflammatory response at the infected site, further delaying the healing process. Therefore, the search for better antibacterial strategies has become a topic of great concern. Therefore, the development of multifunctional hydrogels with antibacterial properties, ROS removal, and hemostasis is urgently required for promoting wound healing process. Chitosan is the only cationic natural polysaccharide with good biocompatibility, antibacterial and hemostatic ability. It is a candidate material to prepare hydrogel wound dressing. Hyaluronic acid (HA) is a natural biological macromolecule that belongs to a group of heteropolysaccharides known as non-sulfated glycosaminoglycans. It is a major component of the skin extracellular matrix (ECM) and is involved in inflammation, angiogenesis, and tissue regeneration. Here, the hydrogel was designed with the natural macromolecular of the gallic acid-grafted quaternized chitosan (GA-QCS) and oxidized hyaluronic acid (OHA) via Schiff base and/or Michael addition reaction. It was found that the GA-QCS/OHA hydrogel exhibited multifunctional capabilities with injectable, hemostasis, degradation, and release of medicines. In addiation, GA-QCS/OHA hydrogels exhibited remarkable antioxidant and migration promoting effects in vitro. And the mupirocin-loaded GA-QCS/OHA hydrogels had inhibitory effects on E. coli (Gram-negative bacterium) and S. aureus (Gram-positive bacterium) in vitro. A full-thickness skin of S. aureus infection mouse wound model was used to test the bioactive effect of the hydrogels and the accelerated wound healing was obtained due to the inhibiting the proinflammatory factor TNF-α and upregulating the vascularization factor CD31. This study proposed an effective strategy based on antioxidant, antibacterial, self-healing multifunctional hydrogel for wound healing under various infectious complications. This natural macromolecular hydrogel could act as an effective reactive oxygen species scavenger to promote the wound healing in the future.

General population preferences for cancer care in health systems of China: A discrete choice experiment.

BACKGROUND: The increasing incidence of cancer in China has posed considerable challenges for cancer care delivery systems. This study aimed to determine the general population's preferences for cancer care, to provide evidence for building a people-centered integrated cancer care system. METHODS: We conducted a discrete choice experiment that involved 1,200 participants in Shandong Province. Individuals were asked to choose between cancer care scenarios based on the type and level of hospitals, with various out-of-pocket costs, waiting time, and contact working in the hospitals. Individual preferences, willingness to pay, and uptake rate were estimated using a mixed-logit model. RESULTS: This study included 848 respondents (70.67%). Respondents preferred county hospitals with shorter hospitalization waiting times and contact working in hospitals. Compared to the reference levels, the three highest willingness to pay values were related to waiting time for hospitalization (¥97,857.69-¥145411.70-¥212,992.10/$14512.70-$21565.16-$31587.61), followed by the county-level hospital (¥32,545.13/$4826.58). The preferences of the different groups of respondents were diverse. Based on a county-level general hospital with contact in the hospital, 50% out-of-pocket costs and a waiting time of 15 days, the probability of seeking baseline care was 0.37. Reducing the waiting time from 15 to 7, 3, and 0 days, increases the probability of choosing a county-level hospital from 0.37 to 0.58, 0.64, and 0.70, respectively. CONCLUSIONS: This study suggests that there is a substantial interest in attending county-level hospitals and that reducing hospitalization waiting time is the most effective measure to increase the probability of seeking cancer care in county-level hospitals.

Patients' and Care Professionals' Evaluation of the Effect of a Hospital Group on Integrated Care in Chinese Urban Health Systems: A Propensity Score Matching and Difference-in-differences Regression Approach.

BACKGROUND: A hospital group is an organizational integration strategy that has recently been widely implemented in Chinese urban health systems to promote integrated care. This study aims to evaluate the effect of hospital group on integrated care from the perspectives of both patients and care professionals. METHODS: Two cross-sectional surveys were conducted in Shenzhen city of China, in June 2018 and July 2021. All thirty Community Health Stations (CHSs) in the hospital group were included in the intervention group, with 30 CHSs in the same district selected as the control group by simple random sampling. All care professionals within both the intervention and the control groups were invited to participate in the surveys. Twelve CHSs were selected from 30 CHSs in the intervention and the control groups by simple random sampling, and 20 patients with type 2 diabetes mellitus (T2DM) were selected from each of these selected CHSs to participate in the survey by systematic sampling. The Rainbow Model of Integrated Care-Measurement Tool (Chinese version) was used to assess integrated care. Propensity score matching and difference-in-differences regression (PSM-DID) were used to evaluate the effect of the hospital group on integrated care. RESULTS: After matching, 528 patients and 1896 care professionals were included in the DID analysis. Results from care professionals indicated that the hospital group significantly increased technical competence of the health system by 0.771 points, and cultural competence by 1.423 points. Results from patients indicated that the hospital group significantly decreased organizational integration of the health system by 0.649 points. CONCLUSION: The results suggests that the effect of the hospital group on integrated care over and above routine strategies for integrated care is limited. Therefore, it is necessary to pay attention to implementing professional, clinical and other integration strategies beyond establishing hospital groups, in urban Chinese health systems.

Reoxygenation Modulates the Adverse Effects of Hypoxia on Wound Repair.

Hypoxia is a major stressor and a prominent feature of pathological conditions, such as bacterial infections, inflammation, wounds, and cardiovascular defects. In this study, we investigated whether reoxygenation has a protective effect against hypoxia-induced acute injury and burn using the C57BL/6 mouse model. C57BL/6 mice were exposed to hypoxia and treated with both acute and burn injuries and were in hypoxia until wound healing. Next, C57BL/6 mice were exposed to hypoxia for three days and then transferred to normoxic conditions for reoxygenation until wound healing. Finally, skin wound tissue was collected to analyze healing-related markers, such as inflammation, vascularization, and collagen. Hypoxia significantly increased inflammatory cell infiltration and decreased vascular and collagen production, and reoxygenation notably attenuated hypoxia-induced infiltration of inflammatory cells, upregulation of pro-inflammatory cytokine levels (IL-6 and TNF-α) in the wound, and remission of inflammation in the wound. Immunofluorescence analysis showed that reoxygenation increased the expression of the angiogenic factor α-SMA and decreased ROS expression in burn tissues compared to hypoxia-treated animals. Moreover, further analysis by qPCR showed that reoxygenation could alleviate the expression of hypoxic-induced inflammatory markers (IL-6 and TNF), increase angiogenesis (SMA) and collagen synthesis (Col I), and thus promote wound healing. It is suggested that oxygen can be further evaluated in combination with oxygen-releasing materials as a supplementary therapy for patients with chronic hypoxic wounds.

Relationships between job satisfaction, organizational commitment, burnout and job performance of healthcare professionals in a district-level health care system of Shenzhen, China.

Background: Existing research indicates that job satisfaction has effects on job performance, but little evidence exists about the mechanism through which the satisfaction-performance association operates. This study aims to examine the effect of job satisfaction on job performance in a district-level health care system of China and to explore the effect mechanism mediated by organizational commitment and burnout. Methods: Cluster sampling was used in this study. All healthcare professionals in the Nanshan Medical Group, who were at work in the last 3 months and able to complete online questionnaire independently were invited to participate the anonymous online survey. Job satisfaction, organizational commitment, burnout and job performance were measured by tools, which have been validated in China. Descriptive statistics were used for the socio-demographic variables and the four job psychological variables. Pearson correlation coefficients was used to determine associations among each of the psychological variables. Linear regression was used to examine association between job performance and other three psychological variables. PROCESS macro was used to examine the mediation effects of organizational commitment and burnout on the association between job satisfaction and performance. Results: In total, 1,200 healthcare professionals completed the anonymous online survey. Job satisfaction, organizational commitment, and job performance were positively correlated with one another, with burnout negatively correlated with them. Linear regression revealed that demographic characteristics, job satisfaction, organizational commitment, and burnout explained 5, 6, 2, and 9% of the variance in job performance. Path analysis showed that the coefficient of the direct effect of job satisfaction on job performance was 0.18, the coefficients of the indirect effects of job satisfaction on job performance through organizational commitment and burnout were 0.17 and 0.37, respectively. The coefficients of the indirect effects of organizational commitment on job performance through burnout was -0.04, but it was not significant. Conclusion: It is promising to improve job performance of providers in Chinese healthcare systems by improving job satisfaction and reducing burnout. Tailored support policies for female healthcare professionals, appropriate incentive mechanisms and improving multidisciplinary healthcare delivery are potential to improve job performance of healthcare professionals in integrated healthcare systems.