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BACKGROUND: The potential for residential greenness to improve cardiovascular health through both physical and psychological mechanisms is well recognized. However, evidence from rapidly urbanizing developing countries and cohort-based causal inference approaches, remains limited. We aim to examine the effect of residential greenness and time to cardiovascular mortality in South China. METHODS: We utilized data from a community-based population survey involving 748,209 participants at baseline from 2009 to 2015, followed up until 2020. Residential greenness exposure was assessed by the annual Normalized Difference Vegetation Index (NDVI) in the 500 m radius of each participant's residence. We used time-varying proportional hazard Cox models coupled with inverse probability weighting to fit marginal structural models and obtain hazard ratios (HRs) for cardiovascular disease (CVD) mortality after adjusting for confounders. Multiple effect modifiers on both additive and multiplicative scales were further explored. RESULTS: A total of 15,139 CVD-related deaths were identified during a median of 7.9 years of follow-up. A protective effect was found between higher greenness exposure and reduced CVD mortality, with a 9.3 % lower rate of total CVD mortality (HR 0.907, 95 % CI 0.859-0.957) based on a 0.1 increase in annual average NDVI. Demographic (age, marital status) and lifestyle factors (smoking, drinking status) were found to modify the association between residential greenness and CVD mortality (all P interaction values < 0.05 or 95 %CI for RERI excluded the value 0). Notably, this effect was more pronounced among older adults, married, and individuals having healthier lifestyles, indicating a greater benefit from greenness for these subgroups. CONCLUSIONS: Our findings support a causal link between increased residential greenness exposure and a reduced risk of CVD mortality in South China with marked heterogenous effects, which has public health implications for cultivating greener urban environments to mitigate the impact of CVD within the context of rapid urbanization.

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Enfermedades Cardiovasculares , Estilo de Vida , Humanos , Enfermedades Cardiovasculares/mortalidad , China/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Estudios de Cohortes , Anciano , Adulto , Características de la Residencia , Factores de Riesgo , Modelos de Riesgos Proporcionales

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Background: The protective effectiveness provided by naturally acquired immunity against SARS-CoV-2 reinfection remain controversial. Objective: To systematically evaluate the protective effect of natural immunity against subsequent SARS-CoV-2 infection with different variants. Methods: We searched for related studies published in seven databases before March 5, 2023. Eligible studies included in the analysis reported the risk of subsequent infection for groups with or without a prior SARS-CoV-2 infection. The primary outcome was the overall pooled incidence rate ratio (IRR) of SARS-CoV-2 reinfection/infection between the two groups. We also focused on the protective effectiveness of natural immunity against reinfection/infection with different SARS-CoV-2 variants. We used a random-effects model to pool the data, and obtained the bias-adjusted results using the trim-and-fill method. Meta-regression and subgroup analyses were conducted to explore the sources of heterogeneity. Sensitivity analysis was performed by excluding included studies one by one to evaluate the stability of the results. Results: We identified 40 eligible articles including more than 20 million individuals without the history of SARS-CoV-2 vaccination. The bias-adjusted efficacy of naturally acquired antibodies against reinfection was estimated at 65% (pooled IRR = 0.35, 95% CI = 0.26-0.47), with higher efficacy against symptomatic COVID-19 cases (pooled IRR = 0.15, 95% CI = 0.08-0.26) than asymptomatic infection (pooled IRR = 0.40, 95% CI = 0.29-0.54). Meta-regression revealed that SARS-CoV-2 variant was a statistically significant effect modifier, which explaining 46.40% of the variation in IRRs. For different SARS-CoV-2 variant, the pooled IRRs for the Alpha (pooled IRR = 0.11, 95% CI = 0.06-0.19), Delta (pooled IRR = 0.19, 95% CI = 0.15-0.24) and Omicron (pooled IRR = 0.61, 95% CI = 0.42-0.87) variant were higher and higher. In other subgroup analyses, the pooled IRRs of SARS-CoV-2 infection were statistically various in different countries, publication year and the inclusion end time of population, with a significant difference (p = 0.02, p < 0.010 and p < 0.010), respectively. The risk of subsequent infection in the seropositive population appeared to increase slowly over time. Despite the heterogeneity in included studies, sensitivity analyses showed stable results. Conclusion: Previous SARS-CoV-2 infection provides protection against pre-omicron reinfection, but less against omicron. Ongoing viral mutation requires attention and prevention strategies, such as vaccine catch-up, in conjunction with multiple factors.

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COVID-19 , Reinfección , SARS-CoV-2 , Humanos , COVID-19/prevención & control , COVID-19/epidemiología , COVID-19/inmunología , SARS-CoV-2/inmunología , Inmunidad Innata

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Background: Disease prediction models often use statistical methods or machine learning, both with their own corresponding application scenarios, raising the risk of errors when used alone. Integrating machine learning into statistical methods may yield robust prediction models. This systematic review aims to comprehensively assess current development of global disease prediction integration models. Methods: PubMed, EMbase, Web of Science, CNKI, VIP, WanFang, and SinoMed databases were searched to collect studies on prediction models integrating machine learning into statistical methods from database inception to 2023 May 1. Information including basic characteristics of studies, integrating approaches, application scenarios, modeling details, and model performance was extracted. Results: A total of 20 eligible studies in English and 1 in Chinese were included. Five studies concentrated on diagnostic models, while 16 studies concentrated on predicting disease occurrence or prognosis. Integrating strategies of classification models included majority voting, weighted voting, stacking, and model selection (when statistical methods and machine learning disagreed). Regression models adopted strategies including simple statistics, weighted statistics, and stacking. AUROC of integration models surpassed 0.75 and performed better than statistical methods and machine learning in most studies. Stacking was used for situations with >100 predictors and needed relatively larger amount of training data. Conclusion: Research on integrating machine learning into statistical methods in prediction models remains limited, but some studies have exhibited great potential that integration models outperform single models. This study provides insights for the selection of integration methods for different scenarios. Future research could emphasize on the improvement and validation of integrating strategies.

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BACKGROUND: The performance evaluation of the Centers for Disease Control and Prevention (CDC) is crucial for enhancing the quality of public health services. With the ongoing reform of the CDC system in China, the existing performance evaluation system faces challenges. This study used the Delphi method to develop a new performance evaluation system for China's provincial, city, and county-level CDC. METHODS: Following the "Structure-Process-Outcome" model, assessment indicators were systematically collected. Indicators were modified and screened through two Delphi rounds based on CDC responsibilities, health development, and national policies. Twenty-four experts provided ratings and recommendations, and the research team evaluated questionnaire reliability, expert positivity, expert authority, and opinion consistency. RESULTS: The preliminary index system identified through the literature review and pre-survey included 11 primary, 30 secondary, and 64 tertiary indicators. After the first round of consultation, two secondary indicators and 11 tertiary indicators were removed and 22 tertiary indicators were added. After the second round of consultation, three secondary indicators and 11 tertiary indicators were removed and three tertiary indicators were added, at which point the p-value of the test for Kendall's coefficient of concordance W was < 0.001 and the coefficient of variation was within acceptable limits (< 0.25), so the consultation was concluded. The final index system included 11 primary, 25 secondary, and 67 tertiary indicators. CONCLUSIONS: This study responded to the CDC system reform by developing a comprehensive performance evaluation index system for provincial, city, and county-level CDC in China. The index system is both scientifically grounded and practical, serving as an effective tool for promoting the high-quality work of CDC organizations.

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Técnica Delphi , Agencias Gubernamentales , Indicadores de Calidad de la Atención de Salud , China , Consenso , Agencias Gubernamentales/normas

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BACKGROUND: Spicy food consumption has been reported to be inversely associated with mortality from multiple diseases. However, the effect of spicy food intake on the incidence of vascular diseases in the Chinese population remains unclear. This study was conducted to explore this association. METHODS: This study was performed using the large-scale China Kadoorie Biobank (CKB) prospective cohort of 486,335 participants. The primary outcomes were vascular disease, ischemic heart disease (IHD), major coronary events (MCEs), cerebrovascular disease, stroke, and non-stroke cerebrovascular disease. A Cox proportional hazards regression model was used to assess the association between spicy food consumption and incident vascular diseases. Subgroup analysis was also performed to evaluate the heterogeneity of the association between spicy food consumption and the risk of vascular disease stratified by several basic characteristics. In addition, the joint effects of spicy food consumption and the healthy lifestyle score on the risk of vascular disease were also evaluated, and sensitivity analyses were performed to assess the reliability of the association results. RESULTS: During a median follow-up time of 12.1 years, a total of 136,125 patients with vascular disease, 46,689 patients with IHD, 10,097 patients with MCEs, 80,114 patients with cerebrovascular disease, 56,726 patients with stroke, and 40,098 patients with non-stroke cerebrovascular disease were identified. Participants who consumed spicy food 1-2 days/week (hazard ratio [HR] = 0.95, 95% confidence interval [95% CI] = [0.93, 0.97], P <0.001), 3-5 days/week (HR = 0.96, 95% CI = [0.94, 0.99], P = 0.003), and 6-7 days/week (HR = 0.97, 95% CI = [0.95, 0.99], P = 0.002) had a significantly lower risk of vascular disease than those who consumed spicy food less than once a week (Ptrend <0.001), especially in those who were younger and living in rural areas. Notably, the disease-based subgroup analysis indicated that the inverse associations remained in IHD (Ptrend = 0.011) and MCEs (Ptrend = 0.002) risk. Intriguingly, there was an interaction effect between spicy food consumption and the healthy lifestyle score on the risk of IHD (Pinteraction = 0.037). CONCLUSIONS: Our findings support an inverse association between spicy food consumption and vascular disease in the Chinese population, which may provide additional dietary guidance for the prevention of vascular diseases.

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Background: Platelets play a critical role in hemostasis and inflammatory diseases. Low platelet count and activity have been reported to be associated with unfavorable prognosis. This study aims to explore the relationship between dynamics in platelet count and in-hospital morality among septic patients and to provide real-time updates on mortality risk to achieve dynamic prediction. Methods: We conducted a multi-cohort, retrospective, observational study that encompasses data on septic patients in the eICU Collaborative Research Database (eICU-CRD) and the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The joint latent class model (JLCM) was utilized to identify heterogenous platelet count trajectories over time among septic patients. We assessed the association between different trajectory patterns and 28-day in-hospital mortality using a piecewise Cox hazard model within each trajectory. We evaluated the performance of our dynamic prediction model through area under the receiver operating characteristic curve, concordance index (C-index), accuracy, sensitivity, and specificity calculated at predefined time points. Results: Four subgroups of platelet count trajectories were identified that correspond to distinct in-hospital mortality risk. Including platelet count did not significantly enhance prediction accuracy at early stages (day 1 C-indexDynamic  vs C-indexWeibull: 0.713 vs 0.714). However, our model showed superior performance to the static survival model over time (day 14 C-indexDynamic  vs C-indexWeibull: 0.644 vs 0.617). Conclusions: For septic patients in an intensive care unit, the rapid decline in platelet counts is a critical prognostic factor, and serial platelet measures are associated with prognosis.

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BACKGROUND: This multicenter, double-blinded, randomized controlled trial (RCT) aims to assess the impact of an artificial intelligence (AI)-based model on the efficacy of intracranial aneurysm detection in CT angiography (CTA) and its influence on patients' short-term and long-term outcomes. METHODS: Study design: Prospective, multicenter, double-blinded RCT. SETTINGS: The model was designed for the automatic detection of intracranial aneurysms from original CTA images. PARTICIPANTS: Adult inpatients and outpatients who are scheduled for head CTA scanning. Randomization groups: (1) Experimental Group: Head CTA interpreted by radiologists with the assistance of the True-AI-integrated intracranial aneurysm diagnosis strategy (True-AI arm). (2) Control Group: Head CTA interpreted by radiologists with the assistance of the Sham-AI-integrated intracranial aneurysm diagnosis strategy (Sham-AI arm). RANDOMIZATION: Block randomization, stratified by center, gender, and age group. PRIMARY OUTCOMES: Coprimary outcomes of superiority in patient-level sensitivity and noninferiority in specificity for the True-AI arm to the Sham-AI arm in intracranial aneurysms. SECONDARY OUTCOMES: Diagnostic performance for other intracranial lesions, detection rates, workload of CTA interpretation, resource utilization, treatment-related clinical events, aneurysm-related events, quality of life, and cost-effectiveness analysis. BLINDING: Study participants and participating radiologists will be blinded to the intervention. SAMPLE SIZE: Based on our pilot study, the patient-level sensitivity is assumed to be 0.65 for the Sham-AI arm and 0.75 for the True-AI arm, with specificities of 0.90 and 0.88, respectively. The prevalence of intracranial aneurysms for patients undergoing head CTA in the hospital is approximately 12%. To establish superiority in sensitivity and noninferiority in specificity with a margin of 5% using a one-sided α = 0.025 to ensure that the power of coprimary endpoint testing reached 0.80 and a 5% attrition rate, the sample size was determined to be 6450 in a 1:1 allocation to True-AI or Sham-AI arm. DISCUSSION: The study will determine the precise impact of the AI system on the detection performance for intracranial aneurysms in a double-blinded design and following the real-world effects on patients' short-term and long-term outcomes. TRIAL REGISTRATION: This trial has been registered with the NIH, U.S. National Library of Medicine at ClinicalTrials.gov, ID: NCT06118840 . Registered 11 November 2023.

Asunto(s)

Inteligencia Artificial , Angiografía por Tomografía Computarizada , Aneurisma Intracraneal , Humanos , Aneurisma Intracraneal/diagnóstico por imagen , Método Doble Ciego , Estudios Prospectivos , Valor Predictivo de las Pruebas , Estudios Multicéntricos como Asunto , Angiografía Cerebral/métodos , Masculino , Femenino , Factores de Tiempo , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto

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AIMS: A recent guideline presented by the ESC Congress in 2022 had indicated a novel therapy targeted at pulmonary artery hypertension, known as pulmonary artery denervation (PADN), which get inspired from a laboratorial trial that could lowering the pulmonary artery pressure through the intervention on the animals. Our aim is to conduct a network meta-analysis to compare the efficacy and safety of PADN from six aspects with the current conventional therapies. METHODS AND RESULTS: According to the PRISMA guidance, databases including Ovid, ClinicalTrials.gov, Medline, Embase, and PubMed were searched from inception to 22 August 2023, along with a full assessment of the previous five meta-analyses. Data were extracted and curated for Bayesian network meta-analysis. The primary outcome was the change in the 6-min walking distance (6MWD) from baseline with a secondary outcome called change in mean pulmonary artery pressure (mPAP) from baseline. The four safety outcomes included risk of clinical worsening, hospitalization, mortality and severe adverse events (SAEs). The comparison is structured on a contrast model based on 65 randomized controlled trials (RCTs) on PADN and the other conventional mainstream drugs. PADN had a better effect in improving 6MWD than Placebo (-77.76 m, 95% CI: -102.04 to -54.34 m), Macitentan (-65.32 m, 95% CI: -95.34 to -36.1 m), Bosentan (-64.5 m, 95% CI: -94.7 to -35.07 m), Iloprost (-62.66 m, 95% CI: -99.48 to -27.13 m), Oxygen (-62.42 m, 95% CI: -100.01 to -25.78 m), Treprostinil (-62.01 m, 95% CI: -89.04 to -35.61 m), Riociguat (-60.59 m, 95% CI: -86.11 to -35.98 m), Selexipag (-47.2 m, 95% CI: -85.61 to -10.19 m), Sildenafil (-44.92 m, 95% CI: -74.43 to -16.15 m), or Sitaxsentan (-39.53 m, 95% CI: -78.99 to -0.76 m). PADN had a better antihypertensive effect than placebo and showed statistical significant lower risks to induce clinical worsening and re-hospitalization than treprostinil, riociguat, and placebo groups. No statistically significant difference in risk of mortality and severe adverse events was observed between PADN versus the other interventions. CONCLUSIONS: Compared with 16 types of conventional therapies and Placebo, PADN has advantage over nine single therapies and Placebo in improving 6MWD and appears to be better than two types of dual-drug combined therapies while with no statistical significance. PADN shows a favourable antihypertensive effect on mPAP and has a lower risk to trigger clinical worsening or hospitalization, while its risk on mortality and severe adverse events is still inconclusive.

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BACKGROUND: Following percutaneous coronary intervention with stent placement to treat acute coronary syndromes, international clinical guidelines generally recommend dual antiplatelet therapy with aspirin plus a P2Y12 receptor inhibitor for 12 months to prevent myocardial infarction and stent thrombosis. However, data on single antiplatelet therapy with a potent P2Y12 inhibitor earlier than 12 months after percutaneous coronary intervention for patients with an acute coronary syndrome are scarce. The aim of this trial was to assess whether the use of ticagrelor alone, compared with ticagrelor plus aspirin, could reduce the incidence of clinically relevant bleeding events without an accompanying increase in major adverse cardiovascular or cerebrovascular events (MACCE). METHODS: In this randomised, placebo-controlled, double-blind clinical trial, patients aged 18 years or older with an acute coronary syndrome who completed the IVUS-ACS study and who had no major ischaemic or bleeding events after 1-month treatment with dual antiplatelet therapy were randomly assigned to receive oral ticagrelor (90 mg twice daily) plus oral aspirin (100 mg once daily) or oral ticagrelor (90 mg twice daily) plus a matching oral placebo, beginning 1 month and ending at 12 months after percutaneous coronary intervention (11 months in total). Recruitment took place at 58 centres in China, Italy, Pakistan, and the UK. Patients were required to remain event-free for 1 month on dual antiplatelet therapy following percutaneous coronary intervention with contemporary drug-eluting stents. Randomisation was done using a web-based system, stratified by acute coronary syndrome type, diabetes, IVUS-ACS randomisation, and site, using dynamic minimisation. The primary superiority endpoint was clinically relevant bleeding (Bleeding Academic Research Consortium [known as BARC] types 2, 3, or 5). The primary non-inferiority endpoint was MACCE (defined as the composite of cardiac death, myocardial infarction, ischaemic stroke, definite stent thrombosis, or clinically driven target vessel revascularisation), with an expected event rate of 6·2% in the ticagrelor plus aspirin group and an absolute non-inferiority margin of 2·5 percentage points between 1 month and 12 months after percutaneous coronary intervention. The two co-primary endpoints were tested sequentially; the primary superiority endpoint had to be met for hypothesis testing of the MACCE outcome to proceed. All principal analyses were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03971500, and is completed. FINDINGS: Between Sept 21, 2019, and Oct 27, 2022, 3400 (97·0%) of the 3505 participants in the IVUS-ACS study were randomly assigned (1700 patients to ticagrelor plus aspirin and 1700 patients to ticagrelor plus placebo). 12-month follow-up was completed by 3399 (>99·9%) patients. Between month 1 and month 12 after percutaneous coronary intervention, clinically relevant bleeding occurred in 35 patients (2·1%) in the ticagrelor plus placebo group and in 78 patients (4·6%) in the ticagrelor plus aspirin group (hazard ratio [HR] 0·45 [95% CI 0·30 to 0·66]; p<0·0001). MACCE occurred in 61 patients (3·6%) in the ticagrelor plus placebo group and in 63 patients (3·7%) in the ticagrelor plus aspirin group (absolute difference -0·1% [95% CI -1·4% to 1·2%]; HR 0·98 [95% CI 0·69 to 1·39]; pnon-inferiority<0·0001, psuperiority=0·89). INTERPRETATION: In patients with an acute coronary syndrome who had percutaneous coronary intervention with contemporary drug-eluting stents and remained event-free for 1 month on dual antiplatelet therapy, treatment with ticagrelor alone between month 1 and month 12 after the intervention resulted in a lower rate of clinically relevant bleeding and a similar rate of MACCE compared with ticagrelor plus aspirin. Along with the results from previous studies, these findings show that most patients in this population can benefit from superior clinical outcomes with aspirin discontinuation and maintenance on ticagrelor monotherapy after 1 month of dual antiplatelet therapy. FUNDING: The Chinese Society of Cardiology, the National Natural Scientific Foundation of China, and the Jiangsu Provincial & Nanjing Municipal Clinical Trial Project. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

Asunto(s)

Síndrome Coronario Agudo , Aspirina , Quimioterapia Combinada , Hemorragia , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria , Ticagrelor , Humanos , Ticagrelor/uso terapéutico , Aspirina/uso terapéutico , Aspirina/administración & dosificación , Intervención Coronaria Percutánea/métodos , Síndrome Coronario Agudo/terapia , Método Doble Ciego , Masculino , Femenino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/uso terapéutico , Anciano , Hemorragia/inducido químicamente , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Terapia Antiplaquetaria Doble/métodos , Resultado del Tratamiento

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BACKGROUND: Intravascular ultrasound-guided percutaneous coronary intervention has been shown to result in superior clinical outcomes compared with angiography-guided percutaneous coronary intervention. However, insufficient data are available concerning the advantages of intravascular ultrasound guidance for patients with an acute coronary syndrome. This trial aimed to investigate whether the use of intravascular ultrasound guidance, as compared with angiography guidance, improves the outcomes of percutaneous coronary intervention with contemporary drug-eluting stents in patients presenting with an acute coronary syndrome. METHODS: In this two-stage, multicentre, randomised trial, patients aged 18 years or older and presenting with an acute coronary syndrome at 58 centres in China, Italy, Pakistan, and the UK were randomly assigned to intravascular ultrasound-guided percutaneous coronary intervention or angiography-guided percutaneous coronary intervention. Patients, follow-up health-care providers, and assessors were masked to random assignment; however, staff in the catheterisation laboratory were not. The primary endpoint was target vessel failure, a composite of cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularisation at 1 year after randomisation. This trial is registered at ClinicalTrials.gov, NCT03971500, and is completed. FINDINGS: Between Aug 20, 2019 and Oct 27, 2022, 3505 patients with an acute coronary syndrome were randomly assigned to intravascular ultrasound-guided percutaneous coronary intervention (n=1753) or angiography-guided percutaneous coronary intervention (n=1752). 1-year follow-up was completed in 3504 (>99·9%) patients. The primary endpoint occurred in 70 patients in the intravascular ultrasound group and 128 patients in the angiography group (Kaplan-Meier rate 4·0% vs 7·3%; hazard ratio 0·55 [95% CI 0·41-0·74]; p=0·0001), driven by reductions in target vessel myocardial infarction or target vessel revascularisation. There were no significant differences in all-cause death or stent thrombosis between groups. Safety endpoints were also similar in the two groups. INTERPRETATION: In patients with an acute coronary syndrome, intravascular ultrasound-guided implantation of contemporary drug-eluting stents resulted in a lower 1-year rate of the composite outcome of cardiac death, target vessel myocardial infarction, or clinically driven revascularisation compared with angiography guidance alone. FUNDING: The Chinese Society of Cardiology, the National Natural Scientific Foundation of China, and Jiangsu Provincial & Nanjing Municipal Clinical Trial Project. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

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Síndrome Coronario Agudo , Angiografía Coronaria , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Ultrasonografía Intervencional , Humanos , Síndrome Coronario Agudo/terapia , Síndrome Coronario Agudo/diagnóstico por imagen , Síndrome Coronario Agudo/cirugía , Intervención Coronaria Percutánea/métodos , Ultrasonografía Intervencional/métodos , Femenino , Masculino , Persona de Mediana Edad , Angiografía Coronaria/métodos , Anciano , Resultado del Tratamiento , China

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BACKGROUND: Parkinson's disease (PD) is a common central nervous system neurodegenerative disease. Neuroinflammation is one of the significant neuropathological hallmarks. As a traditional Chinese medicine, Safranal exerts anti-inflammatory effects in various diseases, however, whether it plays a similar effect on PD is still unclear. The study was to investigate the effects and mechanism of Safranal on PD. METHODS: The PD mouse model was established by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP firstly. Next, the degree of muscle stiffness, neuromuscular function, motor retardation and motor coordination ability were examined by observing and testing mouse movement behavior. Immunofluorescence staining was used to observe the expression of tyrosine hydroxylase (TH). The dopamine (DA) content of the striatum was detected by High-performance liquid chromatography (HPLC). The expression of TH and NLRP3 inflammasome-related markers NLRP3, IL-1ß, and Capase-1 were detected by Real-time Polymerase Chain Reaction (qRT-PCR) and western blotting (WB) respectively. RESULTS: Through behavioral testing, Parkinson's mouse showed a higher muscle stiffness and neuromuscular tension, a more motor retardation and activity disorders, together with a worse motor coordination compared with sham group. Simultaneously, DA content and TH expression in the striatum were decreased. However, after using Safranal treatment, the above pathological symptoms of Parkinson's mouse all improved compared with Safranal untreated group, the DA content and TH expression were also increased to varying degrees. Surprisingly, it observed a suppression of NLRP3 inflammation in the striatum of Parkinson's mouse. CONCLUSIONS: Safranal played a neuroprotective effect on the Parkinson's disease and its mechanism was related to the inhibition of NLRP3 inflammasome activation.

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Ciclohexenos , Modelos Animales de Enfermedad , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Fármacos Neuroprotectores , Enfermedad de Parkinson , Terpenos , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratones , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Terpenos/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Masculino , Ciclohexenos/farmacología , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Ratones Endogámicos C57BL , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Dopamina/metabolismo , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Interleucina-1beta/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Caspasa 1/metabolismo

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BACKGROUND: The mortality rate of acute respiratory distress syndrome (ARDS) increases with age (≥ 65 years old) in critically ill patients, and it is necessary to prevent mortality in elderly patients with ARDS in the intensive care unit (ICU). Among the potential risk factors, dynamic subphenotypes of respiratory rate (RR), heart rate (HR), and respiratory rate-oxygenation (ROX) and their associations with 28-day mortality have not been clearly explored. METHODS: Based on the eICU Collaborative Research Database (eICU-CRD), this study used a group-based trajectory model to identify longitudinal subphenotypes of RR, HR, and ROX during the first 72 h of ICU stays. A logistic model was used to evaluate the associations of trajectories with 28-day mortality considering the group with the lowest rate of mortality as a reference. Restricted cubic spline was used to quantify linear and nonlinear effects of static RR-related factors during the first 72 h of ICU stays on 28-day mortality. Receiver operating characteristic (ROC) curves were used to assess the prediction models with the Delong test. RESULTS: A total of 938 critically ill elderly patients with ARDS were involved with five and 5 trajectories of RR and HR, respectively. A total of 204 patients fit 4 ROX trajectories. In the subphenotypes of RR, when compared with group 4, the odds ratios (ORs) and 95% confidence intervals (CIs) of group 3 were 2.74 (1.48-5.07) (P = 0.001). Regarding the HR subphenotypes, in comparison to group 1, the ORs and 95% CIs were 2.20 (1.19-4.08) (P = 0.012) for group 2, 2.70 (1.40-5.23) (P = 0.003) for group 3, 2.16 (1.04-4.49) (P = 0.040) for group 5. Low last ROX had a higher mortality risk (P linear = 0.023, P nonlinear = 0.010). Trajectories of RR and HR improved the predictive ability for 28-day mortality (AUC increased by 2.5%, P = 0.020). CONCLUSIONS: For RR and HR, longitudinal subphenotypes are risk factors for 28-day mortality and have additional predictive enrichment, whereas the last ROX during the first 72 h of ICU stays is associated with 28-day mortality. These findings indicate that maintaining the health dynamic subphenotypes of RR and HR in the ICU and elevating static ROX after initial critical care may have potentially beneficial effects on prognosis in critically ill elderly patients with ARDS.

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Enfermedad Crítica , Síndrome de Dificultad Respiratoria , Humanos , Anciano , Síndrome de Dificultad Respiratoria/diagnóstico , Pulmón , Pronóstico , Signos Vitales , Estudios Retrospectivos

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BACKGROUND: China has a serious air pollution problem and a high prevalence of obesity. The interaction between the two and its impact on all-cause mortality is a public health issue of great concern. OBJECTIVES: This study aimed to investigate the association between long-term exposure to particulate matter with aerodynamic diameter ≤ 1 µm (PM1) and all-cause mortality, as well as the interaction effect of body mass index (BMI) in the association. METHODS: A total of 33,087 participants from 162 counties in 25 provinces in China were included, with annual average PM1 exposure being estimated based on the county address. The PM1-mortality relation was evaluated using the time-varying Cox proportional hazards models, with the dose-response relationship being fitted using the penalized splines. Besides, the potential interaction effect of BMI in the PM1-mortality relation was evaluated. RESULTS: The incidence of all-cause deaths was 76.99 per 10,000 person-years over a median of 8.2 years of follow-up. After controlling for potential confounders, the PM1-mortality relation was approximately J-shaped. The full-adjustment analysis observed the hazard ratio (HR) of all-cause mortality was 1.114 [95 % confidence interval (CI): 1.017-1.220] corresponding to a 10 µg/m3 rise in PM1 concentration. Further stratified analyses suggested the adverse effects of PM1 might be more pronounced among the underweight. DISCUSSION: Higher PM1 concentrations were associated with an increase in all-cause mortality. The BMI might further alter the relation, and the underweight population was the sensitive subgroup of the population that needed to be protected.

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Contaminantes Atmosféricos , Contaminación del Aire , Humanos , Índice de Masa Corporal , Estudios Prospectivos , Delgadez/inducido químicamente , Material Particulado/análisis , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , China/epidemiología , Estudios de Cohortes , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Exposición a Riesgos Ambientales/análisis

RESUMEN

The modification patterns of N6-methyladenosine (m6A) regulators and interacting genes are deeply involved in tumors. However, the effect of m6A modification patterns on human proteomics remains largely unknown. We evaluated the molecular characteristics and clinical relevance of m6A modification proteomics patterns among 1013 pan-cancer samples from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). More than half of the m6A proteins were expressed at higher levels in tumor tissues and presented oncogenic characteristics. Furthermore, we performed multi-omics analyses integrating with transcriptomics data of m6A regulators and interactive coding and non-coding RNAs and developed a m6A multi-omics signature to identify potential m6A modification target proteins across global proteomics. It was significantly associated with overall survival in nine cancer types, tumor mutation burden (P = 0.01), and immune checkpoints including PD-L1 (P = 4.9 × 10-8) and PD-1 (P < 0.01). We identified 51 novel proteins associated with the multi-omics signature (PFDR < 0.05). These proteins were functional through pathway enrichment analyses. The protein with the highest hit frequency was CHORDC1, which was significantly up-regulated in tumor tissues in nine cancer types. Its higher abundance was significantly associated with a poorer prognosis in seven cancer types. The identified m6A target proteins might provide infomation for the study of molecular mechanism of cancer.

Asunto(s)

Adenina/análogos & derivados , Multiómica , Neoplasias , Humanos , Proteómica , Neoplasias/genética

RESUMEN

BACKGROUND: Single-nucleotide polymorphisms linked with the rs1474868 T allele (MFN2 [mitofusin-2] T/T) in the human mitochondrial fusion protein MFN2 gene are associated with reduced platelet MFN2 RNA expression and platelet counts. This study investigates the impact of MFN2 on megakaryocyte and platelet biology. METHODS: Mice with megakaryocyte/platelet deletion of Mfn2 (Mfn2-/- [Mfn2 conditional knockout]) were generated using Pf4-Cre crossed with floxed Mfn2 mice. Human megakaryocytes were generated from cord blood and platelets isolated from healthy subjects genotyped for rs1474868. Ex vivo approaches assessed mitochondrial morphology, function, and platelet activation responses. In vivo measurements included endogenous/transfused platelet life span, tail bleed time, transient middle cerebral artery occlusion, and pulmonary vascular permeability/hemorrhage following lipopolysaccharide-induced acute lung injury. RESULTS: Mitochondria was more fragmented in megakaryocytes derived from Mfn2-/- mice and from human cord blood with MFN2 T/T genotype compared with control megakaryocytes. Human resting platelets of MFN2 T/T genotype had reduced MFN2 protein, diminished mitochondrial membrane potential, and an increased rate of phosphatidylserine exposure during ex vivo culture. Platelet counts and platelet life span were reduced in Mfn2-/- mice accompanied by an increased rate of phosphatidylserine exposure in resting platelets, especially aged platelets, during ex vivo culture. Mfn2-/- also decreased platelet mitochondrial membrane potential (basal) and activated mitochondrial oxygen consumption rate, reactive oxygen species generation, calcium flux, platelet-neutrophil aggregate formation, and phosphatidylserine exposure following dual agonist activation. Ultimately, Mfn2-/- mice showed prolonged tail bleed times, decreased ischemic stroke infarct size after cerebral ischemia-reperfusion, and exacerbated pulmonary inflammatory hemorrhage following lipopolysaccharide-induced acute lung injury. Analysis of MFN2 SNPs in the iSPAAR study (Identification of SNPs Predisposing to Altered ALI Risk) identified a significant association between MFN2 and 28-day mortality in patients with acute respiratory distress syndrome. CONCLUSIONS: Mfn2 preserves mitochondrial phenotypes in megakaryocytes and platelets and influences platelet life span, function, and outcomes of stroke and lung injury.

Asunto(s)

Lesión Pulmonar Aguda , Lipopolisacáridos , Anciano , Animales , Humanos , Ratones , Lesión Pulmonar Aguda/metabolismo , Plaquetas/metabolismo , Hemorragia/metabolismo , Mitocondrias/metabolismo , Fosfatidilserinas/metabolismo

RESUMEN

Digestive disorders are a significant contributor to the global burden of disease and seriously affect human quality of life. Research has already confirmed the presence of pleiotropic genetic loci among digestive disorders, and studies have explored shared genetic factors among pan-cancers, including various malignant digestive disorders. However, most cross-phenotype studies within the digestive tract system have been limited to a few traits, with no systematic coverage of common benign and malignant digestive disorders. Here, we analyzed data from the UK Biobank to investigate 21 digestive disorders, exploring the genetic correlations and causal relationships between diseases, as well as the common genetic factors and potential biological pathways driving these relationships. Our findings confirmed the extensive genetic correlation and causal relationship between digestive disorders, providing important insights into the genetic etiology, causality, disease prevention, and clinical treatment of diseases.

RESUMEN

Modelling and predicting the behaviour of infectious diseases is essential for early warning and evaluating the most effective interventions to prevent significant harm. Compartmental models produce a system of ordinary differential equations (ODEs) that are renowned for simulating the transmission dynamics of infectious diseases. However, the parameters in compartmental models are often unknown, and they can even change over time in the real world, making them difficult to determine. This study proposes an advanced artificial intelligence approach based on physics-informed neural networks (PINNs) to estimate time-varying parameters from given data for the compartmental model. Our proposed PINNs method captures the complex dynamics of COVID-19 by integrating a modified Susceptible-Exposed-Infectious-Recovered-Death (SEIRD) compartmental model with deep neural networks. Specifically, we modelled the system of ODEs as one network and the time-varying parameters as another network to address significant unknown parameters and limited data. Such structure of the PINNs method is in line with the prior epidemiological correlations and comprises the mismatch between available data and network output and the residual of ODEs. The experimental findings on real-world reported data data have demonstrated that our method robustly and accurately learns the dynamics and forecasts future states. Moreover, as more data becomes available, our proposed PINNs method can be successfully extended to other regions and infectious diseases.

Asunto(s)

COVID-19 , Modelos Epidemiológicos , Humanos , Inteligencia Artificial , COVID-19/epidemiología , Redes Neurales de la Computación , Física

RESUMEN

BACKGROUND: Left bundle branch pacing (LBBP) achieves resynchrony and improves cardiac function in heart failure (HF) patients with reduced ejection fraction (EF) by correcting left bundle branch block (LBBB). Few data on the efficacy of early LBBP in HF with mildly reduced EF (HFmrEF) and LBBB have been reported. OBJECTIVE: The purpose of this study was to explore the efficacy of early LBBP in patients with HFmrEF and LBBB. METHODS: Consecutive patients with HFmrEF (left ventricular EF [LVEF] 35%-50%) and LBBB were prospectively enrolled to receive LBBP (Early-LBBP group) plus guideline-directed medical therapy (GDMT) or GDMT alone (GDMT group). Study outcomes included changes in LVEF, LV end-diastolic diameter (LVEDD), New York Heart Association (NYHA) functional classification, and N-terminal pro-brain natriuretic peptide (NT-proBNP), and clinical events (HF rehospitalization or syncope). Subgroup analysis compared efficacy of LBBP between patients with LBBB only without comorbidities or late gadolinium enhancement (LGE) (LBBB-Only group) and patients with either comorbidities or LGE (LBBB-Combined group). RESULTS: Fifty-four patients were enrolled and analyzed (37 Early-LBBP group; 15 GDMT group). LBBP achieved greater improvement in LVEF (+14.75% ± 7.37% vs -2.42% ± 2.84%; P <.001), reduction of LVEDD (-7.51 ± 5.40 mm vs -0.87 ± 4.36 mm; P <.001) and NYHA classification (-0.84 ± 0.76 vs -0.13 ± 0.74; P = .004), and similar reduction of NT-proBNP (-408.83 ± 920.29 pg/mL vs -229.05 ± 1579.17 pg/mL; P = .610) at 6 months. Early LBBP showed significantly reduced clinical events (0.0% vs 40.0%; P <.001) after 20.68 ± 13.55 months of follow-up. Subgroup analysis showed patients in the LBBB-Only group benefited more from LBBP with regard to LVEF improvement and LVEDD reduction than the LBBB-Combined group. CONCLUSION: Early LBBP with GDMT demonstrated greater improvement of cardiac function and reduced clinical events than GDMT alone in patients with HFmrEF and LBBB.

Asunto(s)

Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Humanos , Bloqueo de Rama/diagnóstico , Bloqueo de Rama/terapia , Bloqueo de Rama/etiología , Volumen Sistólico , Medios de Contraste , Resultado del Tratamiento , Electrocardiografía , Gadolinio , Función Ventricular Izquierda , Fascículo Atrioventricular , Estimulación Cardíaca Artificial/efectos adversos

RESUMEN

BACKGROUND: Long-term clinical outcomes after pulmonary artery denervation (PADN) in patients with Group 1 pulmonary arterial hypertension (PAH) have not been reported. AIMS: We aimed to investigate the effect of PADN on 1-year outcomes in patients with PAH. METHODS: In the multicentre PADN-CFDA trial, 128 patients with Group 1 PAH were randomly assigned to PADN plus a phosphodiesterase-5 inhibitor (PDE-5i) versus a sham PADN procedure plus a PDE-5i. The principal endpoint of interest for the present study was clinical worsening at 1 year after randomisation, the composite of worsening of PAH (increase in WHO functional class, need for additional PAH treatments or PAH-related hospitalisation), atrial septostomy, listing for lung transplantation, or all-cause death. RESULTS: One-year clinical follow-up was available in all patients. At 1 year, clinical worsening had occurred in 3 (4.8%) patients in the PADN plus PDE-5i group and in 15 patients (23.1%) in the sham plus PDE-5i group (adjusted hazard ratio: 0.17; 95% confidence interval [CI]: 0.05-0.60; p=0.006), driven by significantly increased rates of PAH-related hospitalisations, worsening functional class and the requirement for additional PAH treatments in the sham group. Results were consistent in high-risk, intermediate-risk and low-risk patients (pinteraction=0.186). Patients treated with PADN plus PDE-5i had an improvement in the between-group change in the six-minute walking distance (6MWD) from baseline to 1 year of 81.2 m (95% CI: 50.3-112.2; p<0.001) compared with PDE-5i treatment alone. CONCLUSIONS: In this multicentre sham-controlled randomised trial, PADN treatment for Group 1 PAH significantly reduced clinical worsening and improved the 6MWD during 1-year follow-up in patients treated with a PDE-5i.

RESUMEN

Late-onset (more than 48 h after ICU admission) acute respiratory distress syndrome (ARDS) is associated with shorter survival time and higher mortality; however, the underlying molecular targets remain unclear. As the WNT gene family is known to drive inflammation, immunity, and tissue fibrosis, all of which are closely related to the pathogenesis and prognosis of ARDS, we aim to investigate the associations of the WNT family with late-onset ARDS and 28-day survival. Genetic (n = 380), epigenetic (n = 185), transcriptional (n = 160), and protein (n = 300) data of patients with ARDS were extracted from the MEARDS (Molecular Epidemiology of ARDS) cohort. We used sure independence screening to identify late onset-related genetic biomarkers and constructed a genetic score on the basis of eight SNPs, which was associated with risk for late-onset ARDS (odds ratio [OR], 2.72; P = 3.81 × 10-14) and survival (hazard ratio [HR], 1.28; P = 0.008). The associations were further externally validated in the iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk) (ORlate onset, 2.49 [P = 0.006]; HRsurvival, 1.87 [P = 0.045]) and MESSI (Molecular Epidemiology of Severe Sepsis in the ICU) (ORlate onset, 4.12 [P = 0.026]; HRsurvival, 1.45 [P = 0.036]) cohorts. Furthermore, we functionally interrogated the six mapped genes of eight SNPs in the multiomics data and noted associations of WNT9A (WNT family member 9A) in epigenetic (ORlate onset, 2.95 [P = 9.91 × 10-4]; HRsurvival, 1.53 [P = 0.011]) and protein (ORlate onset, 1.42 [P = 0.035]; HRsurvival, 1.38 [P = 0.011]) data. The mediation analysis indicated that the effects of WNT9A on ARDS survival were mediated by late onset (HRindirect, 1.12 [P = 0.014] for genetic data; HRindirect, 1.05 [P = 0.030] for protein data). The essential roles of WNT9A in immunity and fibrosis may explain the different trajectories of recovery and dysfunction between early- and late-onset ARDS, providing clues for ARDS treatment.

Asunto(s)

Síndrome de Dificultad Respiratoria , Sepsis , Humanos , Multiómica , Síndrome de Dificultad Respiratoria/genética , Sepsis/complicaciones , Fibrosis , Proteínas Wnt