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.

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.

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.

Time series study on the effects of daily average temperature on the mortality from respiratory diseases and circulatory diseases: a case study in Mianyang City.

BACKGROUND: Climate change caused by environmental pollution is the most important one of many environmental health hazards currently faced by human beings. In particular, the extreme temperature is an important risk factor for death from respiratory and circulatory diseases. This study aims to explore the meteorological-health effect and find out the vulnerable individuals of extreme temperature events in a less developed city in western China. METHOD: We collected the meteorological data and data of death caused by respiratory and circulatory diseases in Mianyang City from 2013 to 2019. The nonlinear distributed lag model and the generalized additive models were combined to study the influence of daily average temperature (DAT) on mortality from respiratory and circulatory diseases in different genders, ages. RESULTS: The exposure-response curves between DAT and mortality from respiratory and circulatory diseases presented a nonlinear characteristic of the "V" type. Cumulative Relative Risk of 30 days (CRR30) of deaths from respiratory diseases with 4.48 (2.98, 6.73) was higher than that from circulatory diseases with 2.77 (1.96, 3.92) at extremely low temperature, while there was no obvious difference at extremely high temperature. The health effects of low temperatures on the respiratory system of people of all ages and genders were persistent, while that of high temperatures were acute and short-term. The circulatory systems of people aged < 65 years were more susceptible to acute effects of cold temperatures, while the effects were delayed in females and people aged ≥65 years. CONCLUSION: Both low and high temperatures increased the risk of mortality from respiratory and circulatory diseases. Cold effects seemed to last longer than heat did.

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.

Effects of sodium-glucose cotransporter type 2 inhibitors on cardiovascular, renal, and safety outcomes in patients with cardiovascular disease: a meta-analysis of randomized controlled trials.

BACKGROUND: Controlled studies and observational studies have shown that sodium-glucose cotransporter type 2 inhibitors (SGLT-2i) are beneficial for the survival of patients with heart failure (HF). However, it is unclear whether SGLT-2i can provide benefit in patients with other cardiovascular diseases. Here, we conducted a systematic review and meta-analysis to determine the outcomes of cardiovascular, renal, and safety outcomes of SGLT-2i administration in patients with cardiovascular diseases. METHODS: We searched PubMed, EMBASE, Cochrane Library, Web of Science databases, and ClinicalTrials.gov databases for randomised controlled trials written in English from inception until November 1, 2020. Two reviewers independently identified randomised controlled trials comparing the effects of SGLT-2i in patients with cardiovascular disease with or without diabetes. Primary outcomes were cardiovascular outcomes and renal outcomes. Secondary outcomes were safety outcomes, including adverse endocrine outcomes and adverse infection outcomes. The effects of SGLT-2i were evaluated using RevMan5.3 software. The Cochrane risk of bias tool was used to assess study quality. RESULTS: We identified 10 randomised controlled trials (25,108 patients in the SGLT-2i group and 18,574 patients in the placebo group). Meta-analysis revealed that SGLT-2i treatment significantly reduced all-cause mortality, cardiovascular mortality, and hospitalisation for heart failure (HHF) in patients with cardiovascular disease (all-cause mortality relative risk [RR]: 0.86; 95% confidence interval [CI] 0.81-0.91; P < 0.00001; I2 = 0%; cardiovascular mortality RR: 0.85; 95% CI 0.79-0.92; P < 0.0001; I2 = 26%; HHF RR: 0.69; 95% CI 0.64-0.81; P < 0.00001; I2 = 0%). In patients with HF, mortality and HHF after SGLT-2i treatment for HF with reduced ejection fraction were significantly reduced, whereas HF with preserved ejection fraction did not differ compared with placebo treatment. Moreover, SGLT-2i induced a lower incidence of renal damage and myocardial infarction than the placebo group; however, the risk of infection, amputation, volume depletion, and diabetic ketoacidosis was higher. CONCLUSIONS: SGLT-2i had significant clinical effects on cardiovascular outcomes and significantly influenced acute kidney injury. The effects of SGLT-2i on cardiovascular disease were independent of diabetic status. Sotagliflozin could have advantages over other SGLT-2i in lowering HHF.

Recombinant Expression of Thrombolytic Agent Reteplase in Marine Microalga Tetraselmis subcordiformis (Chlorodendrales, Chlorophyta).

Tetraselmis subcordiformis, a unicellular marine green alga, is used widely in aquaculture as an initial feeding for fish, bivalve mollusks, penaeid shrimp larvae, and rotifers because of its rich content of amino acids and fatty acids. A stable nuclear transformation system using the herbicide phosphinothricin (PPT) as a selective reagent was established previously. In this research, the recombinant expression in T. subcordiformis was investigated by particle bombardment with the rt-PA gene that encodes the recombinant human tissue-type plasminogen activator (Reteplase), which is a thrombolytic agent for acute myocardial infarction treatment. Transgenic algal strains were selected by their resistance to PPT, and expression of rt-PA was validated by PCR, Southern blotting, and Western blotting, and bioactivity of rt-PA was confirmed by the fibrin agarose plate assay for bioactivity. The results showed that rt-PA was integrated into the genome of T. subcordiformis, and the expression product was bioactive, indicating proper post-transcriptional modification of rt-PA in T. subcordiformis. This report contributes to efforts that take advantage of marine microalgae as cell factories to prepare recombinant drugs and in establishing a characteristic pathway of oral administration in aquaculture.

Correction: Technology-Based Interventions in Oral Anticoagulation Management: Meta-Analysis of Randomized Controlled Trials.

[This corrects the article DOI: 10.2196/18386.].

Technology-Based Interventions in Oral Anticoagulation Management: Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: An increasing number of patients have received prophylactic or therapeutic oral anticoagulants (OACs) for thromboembolic complications of diseases. The use of OACs is associated with both clinical benefits and risks. Considering the challenges imposed by this class of drugs, as well as the enormous progress made in portable device technology, it is possible that technology-based interventions may improve clinical benefits for patients and optimize anticoagulation management. OBJECTIVE: This study was designed to comprehensively evaluate the role of technology-based interventions in the management of OACs. METHODS: We searched 6 databases-PubMed, EMBASE, Cochrane, Cumulative Index to Nursing and Allied Health Literature, Scopus, and PsycINFO-to retrieve relevant studies published as of November 1, 2019, to evaluate the effect of technology-based interventions on oral anticoagulation management. RevMan (version 5.3; Cochrane) software was used to evaluate and analyze clinical outcomes. The methodological quality of studies was assessed by the Cochrane risk of bias tool. RESULTS: A total of 15 randomized controlled trials (RCTs) were selected for analysis. They reported data for 2218 patients (1110 patients in the intervention groups and 1108 patients in the control groups). A meta-analysis was performed on the effectiveness and safety data reported in the RCTs. Technology-based interventions significantly improved the effectiveness of oral anticoagulation management (mean difference [MD]=6.07; 95% CI 0.84-11.30; I2=72%; P=.02). The safety of oral anticoagulation management was also improved, but the results were not statistically significant. Bleeding events were reduced (major bleeding events MD=1.02; 95% CI 0.78-1.32; I2=0%; P=.90; minor bleeding events MD=1.06, 95% CI 0.77-1.44; I2=41%; P=.73) and thromboembolism events were reduced (MD=0.71; 95% CI 0.49-1.01; I2=0%; P=.06). In general, patients were more satisfied with technology-based interventions, which could also improve their knowledge of anticoagulation management, improve their quality of life, and reduce mortality and hospitalization events. CONCLUSIONS: Using technology to manage OACs can improve the effectiveness and safety of oral anticoagulation management, result in higher patient satisfaction, and allow greater understanding of anticoagulation.

Synergistic effects of HSE and LTR elements from hsp70 gene promoter of Ulva prolifera (Ulvophyceae, Chlorophyta) upon temperature induction1.

Besides heat stress, the 70 kDa heat shock proteins (HSP70s) have been shown to respond to cold stress. However, the involved cis-acting elements remain unknown. The hsp70 gene from the green macroalga Ulva prolifera (Uphsp70) has been cloned, from which one heat shock element HSE and one low-temperature-responsive element LTR were found in the promoter. Using the established transient expression system and quantitative GUS assay, a series of element deletion experiments were performed to determine the functions of HSE and LTR in response to temperature stress. The results showed that under cold stress, both HSE and LTR were indispensable, since deletion leads to complete loss of promoter activity. Under heat stress, although the HSE could respond independently, coexistence with LTR was essential for high induced activity of the Uphsp70 promoter. Therefore, synergistic effects exist between HSE and LTR elements in response to temperature stress in Ulva, and extensive bioinformatics analysis showed that the mechanism is widespread in algae and plants, since LTR coexists widely with HSE in the promoter region of hsp70. Our findings provide important supplements to the knowledge of algal and plant HSP70s response to temperature stress. We speculated that for algal domestication and artificial breeding, HSE and LTR elements might serve as potential molecular targets to temperature acclimation.

Decision fractional fast Fourier transform Doppler compensation in underwater acoustic orthogonal frequency division multiplexing.

A method of compensating for Doppler distortions of underwater acoustic channels for orthogonal frequency division multiplexing (OFDM) signals is proposed. This method is based on symbol rebuilding. OFDM symbol rebuilding is performed after fractional fast Fourier transform (F-FFT) processing. A stochastic gradient-type adaptive algorithm is designed to learn the combiner weights for detection. Synthetic data and experimental data from a recent mobile acoustic communication experiment are used to demonstrate the performance of the proposed method, which represents a significant improvement over the F-FFT detection technique.

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.

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.

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.

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.

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.

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.

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.

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.

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.