Excess multi-cause mortality linked to influenza virus infection in China, 2012-2021: a population-based study.

Objectives: The aim of this study is to estimate the excess mortality burden of influenza virus infection in China from 2012 to 2021, with a concurrent analysis of its associated disease manifestations. Methods: Laboratory surveillance data on influenza, relevant population demographics, and mortality records, including cause of death data in China, spanning the years 2012 to 2021, were incorporated into a comprehensive analysis. A negative binomial regression model was utilized to calculate the excess mortality rate associated with influenza, taking into consideration factors such as year, subtype, and cause of death. Results: There was no evidence to indicate a correlation between malignant neoplasms and any subtype of influenza, despite the examination of the effect of influenza on the mortality burden of eight diseases. A total of 327,520 samples testing positive for influenza virus were isolated between 2012 and 2021, with a significant decrease in the positivity rate observed during the periods of 2012-2013 and 2019-2020. China experienced an average annual influenza-associated excess deaths of 201721.78 and an average annual excess mortality rate of 14.53 per 100,000 people during the research period. Among the causes of mortality that were examined, respiratory and circulatory diseases (R&C) accounted for the most significant proportion (58.50%). Fatalities attributed to respiratory and circulatory diseases exhibited discernible temporal patterns, whereas deaths attributable to other causes were dispersed over the course of the year. Conclusion: Theoretically, the contribution of these disease types to excess influenza-related fatalities can serve as a foundation for early warning and targeted influenza surveillance. Additionally, it is possible to assess the costs of prevention and control measures and the public health repercussions of epidemics with greater precision.

Interactions between MDSCs and the Autonomic Nervous System: Opportunities and Challenges in Cancer Neuroscience.

Myeloid-derived suppressor cells (MDSC) are a population of heterogeneous immune cells that are involved in precancerous conditions and neoplasms. The autonomic nervous system (ANS), which is composed of the sympathetic nervous system and the parasympathetic nervous system, is an important component of the tumor microenvironment that responds to changes in the internal and external environment mainly through adrenergic and cholinergic signaling. An abnormal increase of autonomic nerve density has been associated with cancer progression. As we discuss in this review, growing evidence indicates that sympathetic and parasympathetic signals directly affect the expansion, mobilization, and redistribution of MDSCs. Dysregulated autonomic signaling recruits MDSCs to form an immunosuppressive microenvironment in chronically inflamed tissues, resulting in abnormal proliferation and differentiation of adult stem cells. The two components of the ANS may also be responsible for the seemingly contradictory behaviors of MDSCs. Elucidating the underlying mechanisms has the potential to provide more insights into the complex roles of MDSCs in tumor development and lay the foundation for the development of novel MDSC-targeted anticancer strategies.

Prognostic role of different PD-L1 expression patterns and tumor-infiltrating lymphocytes in high-grade serous ovarian cancer: a systematic review and meta-analysis.

Background: The prognostic value of programmed cell death ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) in high-grade serous ovarian cancer (HGSOC) remains a controversial topic in the research field. To comprehensively assess the importance of PD-L1 and TILs in this particular subtype of ovarian cancer, we performed a meta-analysis. Methods: We conducted a comprehensive search of PubMed, Embase, Scopus, Web of Science, and Cochrane Library databases up to December 25, 2022. The association between PD-L1, TILs, and survival outcomes was evaluated using the combined hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs). Results: This meta-analysis comprised 11 trials involving a total of 1746 cases. The results revealed no significant association between PD-L1 expression in tumor cells (TCs) and overall survival (OS, HR = 0.76, 95% CI: 0.52-1.09, p = 0.136) or progression-free survival (PFS, HR = 0.71, 95% CI: 0.4 -1.24, p = 0.230). Nevertheless, a correlation was observed between PD-L1 expression in immune cells (ICs) and OS (HR = 0.73, 95% CI: 0.55-0.97, p = 0.031). Furthermore, the presence of CD8+ and PD-1+ TILs was found to significantly enhance OS (HR = 0.70, 95% CI = 0.55-0.87, p = 0.002; HR = 0.57, 95% CI = 0.40-0.80, p = 0.001, respectively) and PFS (HR = 0.62, 95% CI = 0.41-0.92, p = 0.019; HR = 0.52, 95% CI = 0.35-0.78, p = 0.002, respectively), whereas the presence of CD3+ and CD4+ TILs was positively associated with OS (HR = 0.50, 95% CI = 0.29-0.87, p = 0.014; HR = 0.55, 95% CI = 0.34-0.91, p = 0.020, respectively). Conclusion: This study indicates a positive correlation between ICs-derived PD-L1 and survival, while no significant correlation was observed between TCs-derived PD-L1 and prognosis. These results highlight the importance of studying PD-L1 expression in ICs as a prognostic predictor. In addition, the presence of TILs was found to significantly improve patient survival, suggesting that TILs may be a valuable prognostic biomarker. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022366411.

Afatinib and Dacomitinib Efficacy, Safety, Progression Patterns, and Resistance Mechanisms in Patients with Non-Small Cell Lung Cancer Carrying Uncommon EGFR Mutations: A Comparative Cohort Study in China (AFANDA Study).

(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (EGFR) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon EGFR mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon EGFR Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon EGFR mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, p = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, p = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; p = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; p = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 (p = 0.006), but fewer G3 (p = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, p = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, p = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon EGFR mutations.

A real-world study of dacomitinib in later-line settings for advanced non-small cell lung cancer patients harboring EGFR mutations.

OBJECTIVE: Dacomitinib has been approved for the first-line treatment of non-small cell lung cancer (NSCLC) carrying classical epidermal growth factor receptor (EGFR) mutations; however, real-world data on its later-line application are lacking. MATERIALS AND METHODS: Patients' data were retrospectively collected from the Chinese National Cancer Center and the PLA hospital between August 2019 and August 2021. Kaplan-Meier method and Log-rank test were utilized to assess progression-free survival (PFS) and overall survival (OS). Univariate and multivariate Cox regression analysis was conducted to determine prognostic indicators. RESULTS: In total, 56 NSCLC patients harboring EGFR mutations treated with later-line single dacomitinib or combinatory dacomitinib were enrolled. A total of 53 patients (94.6%) had treatment-related adverse events; eight patients (14.3%) had grade 3 or 4 events. Among 49 evaluable patients, 26.5% (13 patients) had a confirmed partial response and 73.5% (36 patients) had disease control; the median duration of follow-up was 9.6 months (95% confidence interval [CI], 8.4-10.8 months), the median progression-free survival was 5.4 months (95% CI, 3.5-7.3 months), and the half-year, 1-year, and 2-year OS rate were 79.2%, 70.6%, and 64.1%, respectively. Univariate analysis suggested that smoking, line of dacomitinib, and interval between last EGFR-tyrosine kinase inhibitor (TKI) and dacomitinib were associated with PFS and OS; chemotherapy between last EGFR-TKI and dacomitinib, and EGFR-TKI generation followed by dacomitinib were respectively associated with PFS and OS; multivariate analysis indicated chemotherapy between last EGFR-TKI and dacomitinib negatively affect PFS, and smoking and third-generation EGFR-TKI followed by dacomitinib negatively affect OS. CONCLUSIONS: This real-world study has shown that dacomitinib is active and well-tolerated in NSCLC patients harboring different EGFR mutations in later-line settings, even for those with brain metastases. Patients who benefited more from the first TKI were more likely to benefit from dacomitinib, and earlier application of dacomitinib after front-line TKI resistance may be considered.

[Protective effect of atrovastatin against myocardial ischemia-reperfusion injury and on liver and kidney functions in aged rats].

OBJECTIVE: To observe the effect of atorvastatin against myocardial ischemia-reperfusion injury and its protective effect on liver and kidney functions. METHODS: Ten-month-old Wistar rats were fed to the age of 20 months, and atorvastatin statins gavage was administered till 24 months. The rats were divided into high-dose statin group, small-dose statin group, aged control group and young control group. The myocardial ischemia-reperfusion model was established by ligating the coronary artery. The mortality, hemodynamic changes, infarct size and liver and kidney functions of the rats were recorded or measured. RESULTS: Compared with the aged control group, the young control group and high-dose statin group showed significantly lower mortality rate, reduced hemodynamic abnormalities, and smaller myocardial infarct size following myocardial ischemia-reperfusion (P<0.05). The liver and kidney functions of the young control group and high-dose statin group underwent no significant deterioration after myocardial ischemia and reperfusion, but those in the small-dose statin group and aged control group showed significant deteriorations (P<0.05). CONCLUSION: Atorvastatin offers protective effects on the heart, liver, and kidney in the event of myocardial ischemia-reperfusion in aged rats.

[Effect of pioglitazone on hypoxia/reoxygenation injury and protein kinase C expression in neonatal rat cardiomyocytes].

OBJECTIVE: To observe the effect of pioglitazone on hypoxia/reoxygenation injury and the expression of protein kinase C (PKC) in neonatal rat cardiomyocytes. METHODS: Neonatal Sprague-Dawley rat cardiomyocytes in primary culture were treated with pioglitazone or GW9662 for 24 h prior to hypoxia/reoxygenation injury. Cardiomyocyte apoptosis was evaluated with Hoechst33258 staining and the expression of PKC was detected using Western blotting. RESULTS: In the early stage of hypoxia/reoxygenation injury, the apoptosis rates of the cardiomyocytes increased significantly from (0.20∓0.03)% of the control level to (12.22∓1.45)% (P<0.05). Pretreatment with pioglitazone significantly lowered the apoptosis rate of the cardiomyocytes with hypoxia/reoxygenation injury to (8.32∓0.89)%, and this effect was antagonized by GW9662, a specific blocker of peroxisome proliferators activated receptors γ (PPARγ). Pioglitazone did not cause increased expression of PKC in the cardiomyocytes. CONCLUSION: Pioglitazone can ameliorate neonatal rat cardiomyocyte injury induced by hypoxia/reoxygenation partially by activating PPARγ and does not increase the expression of PKC in the cells.

Influence of low high-density lipoprotein cholesterol on arterial stiffening and left ventricular diastolic dysfunction in essential hypertension.

The authors investigated whether high-density lipoprotein (HDL) cholesterol plays a role in arterial stiffening and left diastolic dysfunction in essential hypertension. Carotid arterial stiffness parameter and left ventricular (LV) diastolic function index were evaluated in 217 patients with essential hypertension. The correlations of dyslipidemia, especially low HDL cholesterol, to LV diastolic function and arterial stiffness were investigated in these patients. Arterial stiffness parameter increased with the increasing of E/Em (LV diastolic function index: the ratio of transmitral peak velocity of early filling to peak early diastolic motion velocity of mitral annulus) (r = 0.26, P<.01). In univariate regression analysis, HDL cholesterol was inversely associated with arterial stiffness parameter and E/Em (r = -0.23 and r = -0.27, respectively, P<.01). The association of HDL cholesterol with arterial stiffness and LV diastolic function was observed in both men and women. Triglycerides were weakly correlated with arterial stiffness parameter and E/Em, while low-density lipoprotein and total cholesterol were not. In multiple regression analysis, only low HDL cholesterol was found as an independent predictor for both arterial stiffness and LV diastolic dysfunction. Enhanced arterial stiffness is associated with LV diastolic dysfunction. Low HDL cholesterol may lead to the deterioration of both arterial stiffness and LV diastolic function in patients with essential hypertension.

[Clinical usefulness of carotid arterial wave intensity in noninvasively assessing left ventricular performance in different hypertensive remodeling hearts].

OBJECTIVE: To evaluate wave intensity (WI) on left ventricular (LV) performance in the different hypertensive remolding hearts. METHODS: 105 hypertensive and 98 control subjects were underwent noninvasive evaluation of carotid arterial wave intensity, LV structure and function. RESULTS: (1) There were increasing trends in the levels of blood pressure, LV end-diastolic diameter and LV mass index in the control, normal geometry group, concentric remodeling group, concentric and eccentric hypertrophy group. LV ejection fraction increased in the concentric hypertrophy group and decreased in the eccentric hypertrophy group in which mid-wall fractional shortening showed a decreasing trend. LV diastolic filling pressure presented increased progression accompanied by LV remodeling (P < 0.05). (2) Transient acceleration wave intensity (W1) in hypertensive subjects were higher than that in the control (P < 0.05). Transient deceleration wave intensity (W2) was lower than that in the control (P < 0.05). (3) W1 in the concentric hypertrophy group was higher and lower in the eccentric hypertrophy, compared with that in the control group, normal geometry group and concentric remodeling group (P < 0.05). W2 was lower in concentric hypertrophy group and eccentric hypertrophy group than that in the control, normal geometry group and concentric remodeling group (P < 0.05). CONCLUSION: WI is a noninvasively obtained, clinically useful parameter for evaluation of LV performance.

[Evaluation on left ventricular function by non-invasive transient deceleration wave intensity (W2) of carotid artery].

OBJECTIVE: To evaluate transient deceleration wave intensity (W2) of carotid artery on left ventricular diastolic function. METHODS: 40 patients with hypertension and 43 healthy volunteers were enrolled and W2 of carotid artery of the both sides were measured. The parameters of left ventricular diastolic function by traditional and tissue Doppler imaging and NT-proBNP (N-terminal probrain natriuretic peptide) were measured. RESULTS: (1) W2 is not different between two sides of carotid artery. W2 in hypertension was lower than the control, especially in left side(1126 +/- 996 mmHg x m/s3 vs 1690 +/- 1126 mmHg x m/s3, P < 0.01). (2) The correlation of W2 and else parameters were analyzed. There were notably decreasing in left ventricular diastolic function of the hypertensive group than the control, for example, the ratio of peak velocity of early filling of mitral flow to peak early diastolic motion velocity of mitral annulus (E/Em, 9.37 +/- 3.32 vs 7.39 +/- 1.83, P < 0.01) and NT-proBNP (94.6 +/- 48.5 vs 45.2 +/- 13.8, P < 0.01). (3) The correlation analysis showed negative relation between W2 and E/Em (r = - 0.46, P < 0.05) and negative relation between W2 and NT-proBNP (r = -0.21, P < 0.05). CONCLUSION: New carotid W2 by non-invasive technology for hemodynamics is a deserving parameter in early evaluating left ventricular diastolic function.

[Effects of pioglitazone on mitochondrial membrane potential of neonate rat's myocardial cells after hypoxia/reoxygenation].

OBJECTIVE: To explore the effectiveness and mechanism of pioglitazone on mitochondrial membrane potential of neonate rat's myocardial cells after hypoxia/reoxygenation. METHODS: Primary cultured myocardial cells of neonate Sprague-Dawley rats were pretreated with different concentrations of pioglitazone, pioglitazone's inhibitor and Chelerythrine, an inhibitor of protein kinase C (PKC). Hypoxia/reoxygenation model was established after 24 h of pretreatment. Subsequently, the mitochondrial membrane potential was detected with JC-1 staining under laser confocal microscopy during reoxygenation phase. RESULTS: Compared with the control group, red/green fluorescent ratio of myocardial cells in the H-r model group decreased significantly after hypoxia/reoxygenation (red/green fluorescent ratio reduced from 1.20 +/- 0.05 to 1.13 +/- 0.02, P<0.01 ), and also decreased in 0.1 micromol/ L, 1 micromol/L and 2 micromol/L pioglitazone group (1.11 +/- 0.01, 1.10 +/- 0.01, 1.16 +/- 0.03, P<0.01, respectively). The red/green fluorescent ratio in pioglitazone + GW9662 group (1.12 +/- 0.02) and pioglitazone + Chelerythrine group (1.07 +/- 0.01) were both significantly lower than those in 2 micromol/L pioglitazone group (P<0.01). CONCLUSION: The mitochondrial membrane potential of neonate rat's myocardial cells was descend after hypoxia/ reoxygenation, while pioglitazone can interrupt the process, indicating that the activation may be relevant to peroxisome proliferator-activated receptor gamma (PPARgamma) ligand and PKC pathway.