Neutrophil extracellular trap-associated risk index for predicting outcomes and response to Wnt signaling inhibitors in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a type of breast cancer with poor prognosis, which is prone to distant metastasis and therapy resistance. The presence of neutrophil extracellular traps (NETs) contributes to the progression of breast cancer and is an efficient predictor of TNBC. We obtained the bulk and single-cell RNA sequencing data from public databases. Firstly, we identified five NET-related genes and constructed NET-related subgroups. Then, we constructed a risk index with three pivotal genes based on the differentially expressed genes between subgroups. Patients in the high-risk group had worse prognosis, clinicopathological features, and therapy response than low-risk group. Functional enrichment analysis revealed that the low-risk group was enriched in Wnt signaling pathway, and surprisingly, the drug sensitivity prediction showed that Wnt signaling pathway inhibitors had higher drug sensitivity in the low-risk group. Finally, verification experiments in vitro based on MDA-MB-231 and BT-549 cells showed that tumor cells with low-risk scores had less migration, invasion, and proliferative abilities and high drug sensitivity to Wnt signaling pathway inhibitors. In this study, multi-omics analysis revealed that genes associated with NETs may influence the occurrence, progression, and treatment of TNBC. Moreover, the bioinformatics analysis and cell experiments demonstrated that the risk index could predict the population of TNBC likely to benefit from treatment with Wnt signaling pathway inhibitors.

LncRNA SEMA3B-AS1 suppresses the tumor-initiating characteristics of triple negative breast cancer via engaging in MLL4-mediated H3K4 trimethylation.

Long noncoding RNAs (lncRNAs) are crucial regulators of tumor-initiating cells (TICs) and hold particular importance in triple negative breast cancer (TNBC). Yet, the precise mechanisms by which TIC-associated lncRNAs influence TNBC remain unclear. Our research utilized The Cancer Genome Atlas Breast Cancer (BC) data set to identify prognostic lncRNAs. We then conducted extensive assays to explore their impact on the tumor-initiating phenotype of TNBC cells and the underlying mechanisms. Notably, we found that low expression of lncRNA SEMA3B-AS1 correlated with unfavorable survival in BC patients. SEMA3B-AS1 was also downregulated in TNBC and linked to advanced tumor stage. Functional experiments confirmed its role as a TIC-suppressing lncRNA, curtailing mammosphere formation, ALDH + TIC cell proportion, and impairing clonogenicity, migration, and invasion. Mechanistic insights unveiled SEMA3B-AS1's nuclear localization and interaction with MLL4 (mixed-lineage leukemia 4), triggering H3K4 methylation-associated transcript activation and thus elevating the expression of SEMA3B, a recognized tumor suppressor gene. Our findings emphasize SEMA3B-AS1's significance as a TNBC-suppressing lncRNA that modulates TIC behavior. This study advances our comprehension of lncRNA's role in TNBC progression, advocating for their potential as therapeutic targets in this aggressive BC subtype.

Long-term efficacy and safety of leflunomide combined with low-dose prednisone in treatment of myasthenia gravis: a retrospective study.

BACKGROUND: Leflunomide and low-dose prednisone (0.25 mg/kg/day) (LEF + Pred) rapidly improved the clinical symptoms of myasthenia gravis (MG) patients. Here, we aimed to analyze the long-term efficacy and safety of LEF + Pred in MG patients. METHODS: This retrospective cohort study enrolled MG patients treated with LEF + Pred in our center between 2012 and 2020. We reviewed all the MG patients continuously treated with LEF + Pred for more than 1 year. MG activities of daily living (MG-ADL) profile score and quantitative MG scale (QMG) score in each clinical follow-up visits were collected for the efficacy analysis. The laboratory testing results of MG patients, the relevant chief complain and physical examination results in each follow-up visits were collected for the safety evaluation. RESULTS: In total, 103 patients were examined. Effective treatment was achieved in 58.3% of patients after 1 month and in 88.4% after 12 months. Overall, 63 patients (61.2%) exhibited only minimal manifestations after 12 months of treatment. The average MG-ADL score decreased from 6.0 to 1.0, while the average QMG score decreased from 10.0 to 4.0. The decrease in MG-ADL and QMG scores of patients with generalized MG was more pronounced than those of the ocular MG patients. Patients with MG who had a thymectomy had a smaller decrease in MG-ADL and QMG scores than those who did not have a thymectomy. Sixteen adverse effects associated with LEF + Pred were observed; none was severe. CONCLUSIONS: Long-term LEF + Pred therapy could considerably improve clinical symptoms in MG patients while being well tolerated with just few side effects.

Association of malnutrition with all-cause and cardiovascular mortality in patients with mild to severe chronic kidney disease undergoing coronary angiography: a large multicenter longitudinal study.

PURPOSE: Evidence on the prognostic impact of malnutrition was focused on patients with advanced kidney disease. The relationships between malnutrition and all-cause and cardiovascular mortality in patients with different severity of chronic kidney disease (CKD) have not been adequately addressed. We aimed to reveal the prevalence of malnutrition and its prognostic value in patients with different severity of CKD undergoing coronary angiography (CAG). METHODS: This was a multicenter, longitudinal, and retrospective cohort study of 12,652 patients with non-dialysis dependent CKD (defined as estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2) undergoing CAG from five tertiary hospitals between January 2007 and December 2020. The controlling nutritional status (CONUT) score was applied to assess nutritional status. Cox regression models and competing risk Fine and Gray models were used to examine the relationships between malnutrition, all-cause and cardiovascular mortality. Further stratified analysis was performed according to baseline CKD severity (mild, moderate and severe, defined by eGFR < 30, 30-44 and 45-59 ml/min/1.73 m2). RESULTS: During a median follow-up of 5.5 years (interquartile range: 3.2 to 8.6 years), 3801 patients (30.0%) died, and 2150 (17.0%) definitely died of cardiovascular disease. After controlling for confounders, patients had higher all-cause mortality (mild, moderate, and severe vs. absent: HR 1.27, 95 CI % [1.17-1.39]; HR 1.54, 95 CI % [1.39-1.71]; HR 2.22, 95 CI % [1.78-2.77], respectively; P for trend < 0.001) and cardiovascular mortality (mild, moderate and severe vs. absent: HR 1.35, 95 CI % [1.21-1.52]; HR 1.67, 95 CI % [1.45-1.92]; HR 2.10, 95 CI % [1.55-2.85], respectively; P for trend < 0.001) with the severity of malnutrition. In further stratified analysis, a similar prognostic impact of malnutrition was observed in patients with mild to moderate CKD, while mild malnutrition did not seem to have a consistent effect on severe CKD patients. CONCLUSION: Malnutrition is common among patients with mild to severe CKD undergoing CAG and is strongly associated with increased risk of all-cause and cardiovascular mortality. Malnutrition seems to have a modestly stronger impact on mortality in patients with mild to moderate CKD. This study was registered at Clinicaltrials.gov as NCT05050877.

Predictors of mortality in heart failure with reduced ejection fraction: interaction between diabetes mellitus and impaired renal function.

BACKGROUND: The harmful effect of diabetes mellitus (DM) on mortality in patients with heart failure with reduced ejection fraction (HFrEF) remains controversial. Furthermore, it seems that no consistent conclusion on whether chronic kidney disease (CKD) modifies the relationship of DM and poor prognosis in patients with HFrEF. METHODS: We analyzed the individuals with HFrEF from the Cardiorenal ImprovemeNt (CIN) cohort between January 2007 and December 2018. The primary endpoint was all-cause mortality. The patients were divided into four groups (control vs. DM alone vs. CKD alone vs. DM and CKD). Multivariate Cox proportional hazards analysis was conducted to examine the association among DM, CKD and all-cause mortality. RESULTS: There were 3,273 patients included in this study (mean age: 62.7 ± 10.9 years, 20.4% were female). During a median follow-up of 5.0 years (interquartile range: 3.0-7.6 years), 740 (22.6%) patients died. Patients with DM have a higher risk of all-cause mortality (HR [95% confidence interval (CI)]:1.28[1.07-1.53]) than those without DM. In patients with CKD, DM had a 61% (HR [95% CI]:1.61[1.26-2.06]) increased adjusted risk of death relative to non-DM, while in patients with non-CKD, there was no significantly difference in risk of all-cause mortality (HR [95% CI]:1.01[0.77-1.32]) between DM and non-DM (p for interaction = 0.013). CONCLUSIONS: Diabetes is a potent risk factor for mortality in patients with HFrEF. Furthermore, DM had a substantially different effect on all-cause mortality depending on CKD. The association between DM and all-cause mortality was only observed in patients with CKD.

Association of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and acute kidney disease in patients undergoing coronary angiography: a cohort study.

BACKGROUND: Acute kidney disease (AKD) following coronary angiography (CAG) indicates a higher risk of chronic kidney disease and follow-up cardiovascular comorbidities. However, the predictive risk factor of AKD is not clear. We sought to verify whether preoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) level was associated with AKD in patients undergoing CAG. METHOD: We analyzed 7602 patients underwent CAG in this multi-center registry cohort study. Cardiorenal ImprovemeNt II (CIN-II) in five Chinese tertiary hospitals from 2007 to 2020. The primary outcome was AKD, defined as a ≥ 50% increase of serum creatinine within 7-90 days. Multivariable logistic regressions were used to assess the association between NT-proBNP and AKD. RESULT: 1009 patients (13.27%) eventually developed AKD, who were more likely to be female, older, and with comorbidities of chronic heart failure and anemia. After adjusting to the potential confounders, the NT-proBNP level remained an independent predictor of AKD (lnNT-proBNP OR: 1.20, 95% CI 1.13-1.28, p < 0.005). Restricted cubic spline analysis demonstrated a linear relationship between elevated NT-proBNP and AKD (p for trend < 0.001). In the subgroup analysis, elevated NT-proBNP level in patients with percutaneous coronary intervention (p for interaction < 0.001) or without previous congestive heart failure (p for interaction = 0.0346) has a more significant value of AKD prediction. CONCLUSION: Pre-operative NT-proBNP level was independently associated with the risk of AKD in patients following CAG. Perioperative strategies are warranted to prevent AKD in patients with elevated NT-proBNP levels.

Elevation of hemoglobin A1c increases the risk of decline in left ventricular systolic function among patients with coronary artery disease.

AIMS: The aim of this study was to investigate the association of HbA1c and left ventricular (LV) systolic function among patients with coronary artery disease (CAD). METHODS: CAD patients from the Cardiorenal ImprovemeNt II (CIN-II, NCT05050877) registry were included in the study. They were separated into four groups based on HbA1c levels (Q1: HbA1c<5.7%; Q2: 5.7% ≤ HbA1c < 6.1%; Q3: 6.1% ≤ HbA1c < 6.9%; Q4: HbA1c ≥ 6.9%). The endpoint was decline in LV systolic function, defined as an absolute decrease in LV ejection fraction (LVEF) ≥10% from baseline to follow-up with 3-12 months. The association of HbA1c and LVEF was assessed by logistics regression models. RESULTS: CAD patients (n = 3,994) (age 62.9 ± 10.6 years; 22.2% female) were included in the final analysis. A decline in LV systolic function was recorded in 429 (11%) patients during follow-up. After fully adjusting for confounders, HbA1c was significantly associated with the high risk of decline in LV systolic function (OR 1.12 [95%CI 1.05-1.20] P = 0.001). By stratifying HbA1c as four groups, there is a significantly increased risk of decline in LV systolic function when HbA1c ≥6.1% (Q2, Q3 and Q4 vs Q1, with OR 1.22 [0.88-1.68] P = 0.235; OR 1.48 [1.07-2.05] P = 0.019; OR 1.60 [1.160-2.22] P = 0.004, respectively). Meanwhile, patients with decline in LV systolic function had a higher risk of cardiovascular death. CONCLUSIONS: Elevated HbA1c is a predictor of decline in LV systolic function in CAD patients. Clinicians should be aware of the risk of decline in LV systolic function in CAD patients with elevated HbA1c, and take measures as soon as possible.

M7G-Related lncRNAs predict prognosis and regulate the immune microenvironment in lung squamous cell carcinoma.

BACKGROUND: N7-Methylguanosine (m7G) and long non-coding RNAs (lncRNAs) have been widely studied in cancer and have been found to be useful for assessing tumor progression. However, the role of m7G-related lncRNAs in lung squamous cell carcinoma (LUSC) remains unclear. Thus, it is crucial to identify m7G-associated lncRNAs with definitive prognostic value. This study aimed to investigate the prognostic value, correlation with tumor mutation burden, and impact on the tumor immune microenvironment of m7G-related lncRNAs in LUSC.  METHODS: LUSC transcriptome data and clinical data were downloaded from The Cancer Genome Atlas, and an m7G-related lncRNA-mRNA co-expression network was constructed using Pearson's correlation analysis. Cox regression analyses were used to determine a risk model for m7G-associated lncRNAs with prognostic value. The risk signature was verified using the Kaplan-Meier method, receiver operating characteristic curve analysis, and principal component analysis. A nomogram based on risk scores and clinical characteristics was then developed. Gene set enrichment analysis was used for functional annotation to analyze the risk signature. The association among the risk signature, tumor mutational burden, and tumor-infiltrating immune cells was then analyzed. RT-qPCR was used to investigate the expression of 6 m7G-related lncRNAs in LUSC cells. The cytological function of SRP14-AS1 was verified by wound-healing assay and transwell assay. RESULTS: A total of 293 m7G-related lncRNAs were identifed, 27 candidate m7G-related lncRNAs were signifcantly associated with overall survival (OS). Six of these lncRNAs (CYP4F26P, LINC02178, MIR22HG, SRP14-AS1, TMEM99, PTCSC2) were selected for establishment of the risk model. The OS of patients in the low-risk group was higher than that of patients in the high-risk group (p < 0.001). Multivariate cox regression analysis indicated that the model could be an independent prognostic factor for LUSC (HR = 1.859; 95% CI 1.452-2.380, p < 0.001). The ROC curve analysis revealed that the AUCs for OS in the 3-, and 5-year were 0.682, 0.657, respectively. GSEA analysis revealed that the risk model was closely related to immune-related pathways. Compared with normal lung epithelial cells, four m7G-related lncRNAs were higher expressed in cancer cells and two were lower expressed, among which knockdown of SRP14-AS1 promoted the proliferation and migration of LUSC cells. CONCLUSION: A risk model based on six m7G-related lncRNAs with prognostic value may be a promising prognostic tool in LUSC and guide individualized patient treatment.

A novel prognostic signature based on N7-methylguanosine-related long non-coding RNAs in breast cancer.

Long non-coding RNA (lncRNA) are closely associated with the occurrence and progression of tumors. However, research on N7-methylguanosine (m7G)-related lncRNA in breast cancer is lacking. Therefore, the present study explored the prognostic value, gene expression characteristics, and effects of m7G-related lncRNA on tumor immune cell infiltration and tumor mutational burden (TMB) in breast cancer. lncRNA expression matrices and clinical follow-up data of patients with breast cancer were obtained from The Cancer Genome Atlas, revealing eight significantly differentially expressed and prognostically relevant m7G-related lncRNAs in breast cancer tissues: BAIAP2-DT, COL4A2-AS1, FARP1-AS1, RERE-AS1, NDUFA6-DT, TFAP2A-AS1, LINC00115, and MIR302CHG. A breast cancer prognostic signature was created based on these m7G-related lncRNAs according to least absolute shrinkage and selection operator Cox regression. The prognostic signature combined with potential prognostic factors showed independent prognostic value, reliability, and specificity. Meanwhile, we constructed a risk score-based nomogram to assist clinical decision-making. Gene set enrichment analysis revealed that low- and high-risk group were associated with metabolism-related pathways. Our study demonstrated the association between tumor immune cell infiltration based on analyses with the CIBERSORT algorithm and prognostic signature. We also assessed the correlation between prognostic signature and TMB. Lastly, quantitative real-time polymerase chain reaction analysis was performed to validate differentially expressed lncRNAs. The effective prognostic signature based on m7G-related lncRNAs has the potential to predict the survival prognosis of patients with breast cancer. The eight m7G-related lncRNAs identified in this study might represent potential biomarkers and therapeutic targets of breast cancer.

Prevalence and Prognostic Impact of Malnutrition in Critical Patients With Acute Myocardial Infarction: Results From Chinese CIN Cohort and American MIMIC-III Database.

Background: Malnutrition is associated with poor prognosis in patients with acute myocardial infarction (AMI). However, the prognostic impact of malnutrition in critical patients with AMI has not been well addressed. Methods: We analyzed two critical AMI cohorts from Cardiorenal ImprovemeNt (CIN) in China and Medical Information Mark for Intensive Care-III (MIMIC-III) in the United States. The primary outcome was all-cause mortality. Cox proportional hazards models were constructed to examine the risk of malnutrition for mortality in critical patients with AMI. Results: There were 2,075 critical patients with AMI (mean age, 62.5 ± 12.3 years, 20.00% were female) from the CIN cohort and 887 critical patients with AMI (mean age, 70.1 ± 12.9 years, 37.43% were female) from MIMIC-III included in this study. Based on the Controlling Nutritional Status (CONUT) score, of the Chinese patients with AMI, the prevalence was 47.5, 28.3, and 3.5% for mild, moderate, and severe malnutrition, respectively. The percentage of mild, moderate, and severe malnutrition was 41.60, 30.55, and 7.32% in the MIMIC-III cohort, respectively. Controlling for confounders, worse nutritional state was significantly associated with increased risk for all-cause mortality [an adjusted hazard ratio for mild, moderate, and severe malnutrition, respectively, 1.10 (95% confidence interval (CI): 0.76-1.59), 1.49 (95% CI: 1.02-2.19), and 1.70 (95% CI: 1.00-2.88) in the CIN cohort and 1.41 (95% CI: 0.95-2.09), 1.97 (95% CI: 1.32-2.95), and 2.70 (95% CI: 1.67-4.37) in the MIMIC-III cohort]. Conclusion: Malnutrition was independently associated with an increased risk of all-cause mortality in critical patients with AMI after full adjustments. Further trials are needed to prospectively evaluate the efficacy of nutritional interventions in critical patients with AMI.

Sex Differences in Characteristics, Treatments, and In-hospital Outcomes of Patients Undergoing Coronary Angiography or Intervention.

Background: Whether women have a higher risk of adverse events compared with men following coronary angiography (CAG) and percutaneous coronary intervention (PCI) remains controversial. We aimed to investigate the sex differences in characteristics, treatments and outcomes among patients undergoing CAG and PCI in a large Chinese cohort. Methods: We analyzed patients undergoing CAG and/or PCI in this multi-center registry cohort study Cardiorenal ImprovemeNt II (CIN-II) in 5 Chinese tertiary hospitals from 2007 to 2020. Clinical characteristics, treatment (discharge medication and PCI) and in-hospital outcomes (mortality and major bleeding) were compared between women and men. Results: Totally 141,459 patients underwent CAG (44,362 [31.4%] women), of which 69,345 patients underwent PCI (15,376 [22.2%] women). Women were older (64.4 vs. 60.8 years), had more chronic comorbidities and lower PCI rate for stable coronary artery disease (CAD) than men (52.8 vs. 64.2%). Women received less CAG and PCI procedures. Among women undergoing PCI they received similar discharge medication treatment. In addition, women undergoing PCI had mildly lower rate of major bleeding (0.2 vs. 0.3%, P = 0.033) but higher in-hospital mortality (1.2 vs. 0.8%, P < 0.001). After adjustment, women had a higher risk in the major bleeding (adjusted odds ratio, 2.04 [95% CI: 1.07 to 3.62]), and the in-hospital mortality (adjusted odds ratio, 1.87 [95% CI: 1.36 to 2.56]). Conclusion: Among our Chinese cohort, women are older with more chronic comorbidities, receiving less PCI procedure and similar discharge medication treatment. Women have nearly 90% higher risk of in-hospital mortality and over 1-fold increased risk of major bleeding after PCI compared with men.

Five-year mortality of heart failure with preserved, mildly reduced, and reduced ejection fraction in a 4880 Chinese cohort.

AIMS: Available evidence is incomplete and inconsistent in the outcomes of heart failure (HF) patients with preserved ejection fraction (HFpEF), mildly reduced ejection fraction (HFmrEF), and reduced ejection fraction (HFrEF). There are also limited data on the proportions and long-term prognosis among the three HF phenotypes in China. We aimed to characterize the 5 year prognosis in three HF phenotypes according to EF in a cohort of hospitalized HF patients undergoing coronary angiography in southern China. METHODS AND RESULTS: Hospitalized patients with HF were enrolled from the Cardiorenal ImprovemeNt registry (CIN; ClinicalTrials.gov NCT04407936) between January 2007 and December 2014. HF phenotypes were defined as HFpEF (EF ≥ 50%), HFmrEF (EF 41-49%), and HFrEF (EF ≤ 40%). Kaplan-Meier and Cox proportional hazards models were constructed to examine differences in 5 year outcomes in HF patients with different phenotypes. A total of 4880 HF patients [mean age: 61.8 ± 10.3, male: 3156 (64.7%)] were included: 2768 (57%) had HFpEF, 1015 (21%) had HFmrEF, and 1097 (22%) had HFrEF. Patients with HFrEF were older than those with HFpEF (62.5 ± 10.6 vs. 61.3 ± 10.1, P < 0.001) and more likely to be male (78.0% vs. 55.9%, P < 0.001). With 5 year follow-up through the end of December 2019, 1624 (27.6%) patients died. Controlling confounding variables, declined EF category was independently associated with increased 5 year mortality {HFrEF 25.2% vs. HFpEF 13.4%, adjusted hazard ratio [aHR]: 1.85 [95% confidence interval (CI): 1.45 to 2.35]; HFmrEF 18.1% vs. HFpEF 13.4%, aHR: 1.40 [95% CI: 1.08 to 1.81]; HFrEF 25.2% vs. HFmrEF 18.1%, aHR: 1.32 [95% CI: 1.02 to 1.71]}. CONCLUSIONS: In this Chinese cohort, patients with HFrEF account for less than a fourth of HF patients. One-sixth individuals with HF died in 5 years. HFrEF was associated with a nearly two-fold increased risk of 5 year mortality than HFpEF. Further studies are needed to prospectively evaluate the efficacy of improving treatment on outcomes in all three HF phenotypes.

ADAM12 as a Clinical Prognostic Indicator Associated with Tumor Immune Infiltration in Lung Adenocarcinoma.

Twenty-two functional α-disintegrin and metalloproteinases (ADAMs) have been identified in humans, 12 of which have proteolytic activity. The role of ADAMs in cancer has attracted increasing attention. However, the expression and significance of ADAMs in lung adenocarcinoma (LUAD) remain unclear. Most recently, we investigated the transcriptional data of ADAMs and related overall survival in patients with LUAD based on several databases, including TCGA, cBioPortal, Kaplan-Meier Plotter, LinkedOmics, KEGG, TIMER, and TISIDB. Knockdown of ADAM12 was performed in vitro to verify its biological function. According to our findings, 10 ADAMs exhibited significant differential expression in LUAD compared with cancer-adjacent normal tissues. ADAM12 expression was significantly higher in LUAD tissues than in paracancerous tissues, and lower ADAM12 expression was associated with better survival. Genetic alterations of ADAM12 mainly included missense mutations, amplifications, and deep deletions. ADAM12 and positively correlated genes were mainly enriched in protein digestion and absorption, extracellular matrix-receptor interaction, and adhesion plaques. ADAM12 had a moderate correlation with immune cell markers EBIP1, CCNB1, EXO1, KNTC1, PRC1, and FAM198B. Prognostic model was established based on ADAM12 and immune-related genes. In vitro experiments revealed that knocking down ADAM12 inhibited cell proliferation, migration, and invasion. ADAM12 potentially plays an important role in the occurrence of LUAD and may be utilized as an immunotherapy target and a valuable prognostic biomarker for LUAD.

Are There Any Differences in the Prognostic Value of Left Ventricular Ejection Fraction in Coronary Artery Disease Patients With or Without Moderate and Severe Mitral Regurgitation?

Background: Left ventricular ejection fraction (LVEF) is a vital variable to describe left ventricle systolic function and contractility of left ventricle. However, the association between LVEF and the prognostic effect in patients with moderate or severe mitral regurgitation (MR) is still controversial. Methods: This study comprised 30,775 coronary artery disease (CAD) patients who underwent coronary arteriography (CAG) in the Cardiorenal ImprovemeNt (CIN) registry from January 2007 to December 2018. Patients were divided into none or mild MR group and moderate or severe MR group, and 3 levels of LVEF ≥50, 40-50%, and <40% were further distinguished according to hospital baseline. Univariate and multivariate Cox proportional analyses were used to investigate the association between LVEF levels and long-term all-cause mortality in patients with different MR severities. Results: Of 30,775 CAD patients (62.9 ± 10.6 years, females 23.8%), 26,474 (86.0%) patients had none or mild MR. Compared with none or mild MR patients, patients with moderate or severe MR were older and had worse cardio-renal function. In multivariable Cox proportional analysis, LVEF <40% was independently associated with higher mortality compared with LVEF ≥ 50% in all kinds of MR severity {none or mild MR [adjusted hazard ratio (HR): 1.79; 95% CI: 1.56-2.05, p < 0.001], moderate or severe MR [adjusted HR: 1.57; 95% CI: 1.29-1.91, p < 0.001]}. Conclusions: LVEF is a reliable prognostic index in CAD patients, even in those with moderate or severe MR. LVEF monitoring would still be clinically useful in CAD patients with moderate or severe MR. Clinical trials are needed to prospectively evaluate the optimal threshold for LVEF in patients with moderate or severe MR.

Is myasthenia gravis a contraindication for botulinum toxin?

Botulinum toxin (BTX) is a neurotoxin that has been used to treat various disorders and has also become a popular choice for cosmetic indications, yet traditionally, myasthenia gravis (MG) is considered a contraindication for BTX. To determine whether BTX should be avoided in MG patients, clinical data from our MG and dystonia specialist clinic were analyzed retrospectively. In addition, a systematic literature review was conducted to identify all published cases associated with the co-existence of MG and BTX treatments. Here, we described one patient from our clinic, who received BTX injections before being given MG diagnosis. After the literature review, 8 cases with subclinical MG previously treated with BTX for dystonia or cosmetic reasons ("BTX injections before MG diagnosis") were identified. Markedly, 8 out of 8 (100%) patients developed obvious muscle weakness. In contrast, 10 patients presenting MG as comorbidity had received BTX for dystonia or overactive bladder ("BTX injection after MG diagnosis"), and 8 out of 10 (80%) experienced improved symptoms through appropriate dose modifications and adequate treatment for MG before receiving BTX injections. These findings support that, under proper management of co-existing MG, BTX could be used safely and successfully in patients presenting MG comorbidities in the future.

Association of Lipoprotein(a)-Associated Mortality and the Estimated Glomerular Filtration Rate Level in Patients Undergoing Coronary Angiography: A 51,500 Cohort Study.

Background: High lipoprotein(a) is associated with poor prognosis in patients at high risk for cardiovascular disease. Renal function based on the estimated glomerular filtration rate (eGFR) is a potential risk factor for the change of lipoprotein(a). However, the regulatory effect of eGFR stratification on lipoprotein(a)-associated mortality has not been adequately addressed. Methods: 51,500 patients who underwent coronary angiography (CAG) or percutaneous coronary intervention (PCI) were included from the Cardiorenal ImprovemeNt (CIN) study (ClinicalTrials.gov NCT04407936). These patients were grouped according to lipoprotein(a) quartiles (Q1-Q4) stratified by eGFR categories (<60 and ≥60 mL/min/1.73m2). Cox regression models were used to estimate hazard ratios (HR) for mortality across combined eGFR and lipoprotein(a) categories. Results: The mean age of the study population was 62.3 ± 10.6 years, 31.3% were female (n = 16,112). During a median follow-up of 5.0 years (interquartile range: 3.0-7.6 years), 13.0% (n = 6,695) of patients died. Compared with lipoprotein(a) Q1, lipoprotein(a) Q2-Q4 was associated with 10% increased adjusted risk of death in all patients (HR: 1.10 [95% CI: 1.03-1.17]), and was strongly associated with about 23% increased adjusted risk of death in patients with eGFR <60 mL/min/1.73m2 (HR: 1.23 [95% CI: 1.08-1.39]), while such association was not significant in patients with eGFR ≥60 mL/min/1.73m2 (HR: 1.05 [95% CI: 0.97-1.13]). P for interaction between lipoprotein(a) (Q1 vs. Q2-Q4) and eGFR (≥60 vs. eGFR <60 mL/min/1.73m2) on all-cause mortality was 0.019. Conclusions: Elevated lipoprotein(a) was associated with increased risk of all-cause mortality and such an association was modified by the baseline eGFR in CAG patients. More attention should be paid to the patients with reduced eGFR and elevated lipoprotein(a), and the appropriate lipoprotein(a) intervention is required.

Does Diabetes Mellitus Increase the Short- and Long-Term Mortality in Patients With Critical Acute Myocardial Infarction? Results From American MIMIC-III and Chinese CIN Cohorts.

Background: The harmful effect of diabetes mellitus (DM) on mortality in patients with acute myocardial infarction (AMI) remains controversial. Furthermore, few studies focused on critical AMI patients. We aimed to address whether DM increases short- and long-term mortality in this specific population. Methods: We analyzed AMI patients admitted into coronary care unit (CCU) with follow-up of ≥1 year from two cohorts (MIMIC-III, Medical Information Mart for Intensive Care III; CIN, Cardiorenal ImprovemeNt Registry) in the United States and China. Main outcome was mortality at 30-day and 1-year following hospitalization. Kaplan-Meier curves and Cox proportional hazards models were constructed to examine the impact of DM on mortality in critical AMI patients. Results: 1774 critical AMI patients (mean age 69.3 ± 14.3 years, 46.1% had DM) were included from MIMIC-III and 3380 from the CIN cohort (mean age 62.2 ± 12.2 years, 29.3% had DM). In both cohorts, DM group was older and more prevalent in cardio-renal dysfunction than non-DM group. Controlling for confounders, DM group has a significantly higher 30-day mortality (adjusted odds ratio (aOR) (95% CI): 2.71 (1.99-3.73) in MIMIC-III; aOR (95% CI): 9.89 (5.81-17.87) in CIN), and increased 1-year mortality (adjusted hazard ratio (aHR) (95% CI): 1.91 (1.56-2.35) in MIMIC-III; aHR (95% CI): 2.62(1.99-3.45) in CIN) than non-DM group. Conclusions: Taking into account cardio-renal function, critical AMI patients with DM have a higher 30-day mortality and 1-year mortality than non-DM group in both cohorts. Further studies on prevention and management strategies for DM are needed for this population. Clinical Trial Registration: clinicaltrials.gov, NCT04407936.

Construction of Prognostic Risk Model of 5-Methylcytosine-Related Long Non-Coding RNAs and Evaluation of the Characteristics of Tumor-Infiltrating Immune Cells in Breast Cancer.

Purpose: The role of 5-methylcytosine-related long non-coding RNAs (m5C-lncRNAs) in breast cancer (BC) remains unclear. Here, we aimed to investigate the prognostic value, gene expression characteristics, and correlation between m5C-lncRNA risk model and tumor immune cell infiltration in BC. Methods: The expression matrix of m5C-lncRNAs in BC was obtained from The Cancer Genome Atlas database, and the lncRNAs were analyzed using differential expression analysis as well as univariate and multivariate Cox regression analysis to eventually obtain BC-specific m5C-lncRNAs. A risk model was developed based on three lncRNAs using multivariate Cox regression and the prognostic value, accuracy, as well as reliability were verified. Gene set enrichment analysis (GSEA) was used to analyze the Kyoto Encyclopedia of Genes and Genomes signaling pathway enrichment of the risk model. CIBERSORT algorithm and correlation analysis were used to explore the characteristics of the BC tumor-infiltrating immune cells. Finally, reverse transcription-quantitative polymerase chain reaction was performed to detect the expression level of three lncRNA in clinical samples. Results: A total of 334 differential m5C-lncRNAs were identified, and three BC-specific m5C-lncRNAs were selected, namely AP005131.2, AL121832.2, and LINC01152. Based on these three lncRNAs, a highly reliable and specific risk model was constructed, which was proven to be closely related to the prognosis of patients with BC. Therefore, a nomogram based on the risk score was built to assist clinical decisions. GSEA revealed that the risk model was significantly enriched in metabolism-related pathways and was associated with tumor immune cell infiltration based on the analysis with the CIBERSORT algorithm. Conclusion: The efficient risk model based on m5C-lncRNAs associated with cancer metabolism and tumor immune cell infiltration could predict the survival prognosis of patients, and AP005131.2, AL121832.2, and LINC01152 could be novel biomarkers and therapeutic targets for BC.

Association of Malnutrition, Left Ventricular Ejection Fraction Category, and Mortality in Patients Undergoing Coronary Angiography: A Cohort With 45,826 Patients.

Background: The regulatory effect of the left ventricular ejection fraction (LVEF) categories on the association of malnutrition and all-cause mortality in patients undergoing coronary angiography (CAG) have not been adequately addressed. Methods: Forty-five thousand eight hundred and twenty-six patients consecutively enrolled in the Cardiorenal ImprovemeNt (CIN) study (ClinicalTrials.gov NCT04407936) from January 2008 to July 2018 who underwent coronary angiography (CAG). The Controlling Nutritional Status (CONUT) score was applied to 45,826 CAG patients. The hazard ratios of mortality across combined LVEF and/or malnutrition categories were estimated by Cox regression models. Variables adjusted for in the Cox regression models included: age, gender, hypertension (HT), DM, PCI, coronary artery disease (CAD), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TRIG), chronic kidney disease (CKD), statins, atrial fibrillation (AF), anemia, and stroke. Population attributable risk (PAR) was estimated for eight groups stratified by nutritional status and LVEF categories. Results: In our study, 42,181(92%) of patients were LVEF ≥ 40%, of whom, 41.55 and 9.34% were in mild and moderate or severe malnutrition status, respectively, while 46.53 and 22.28% in mild and moderate or severe malnutritional status among patients with LVEF < 40%. During a median follow-up time of 4.5 years (percentile 2.8-7.1), 5,350 (11.7%) patients died. After fully adjustment, there is no difference of mortality on malnutrition in LVEF < 40% group (mild, moderate and severe vs. normal, HR (95%CI): [1.00 (0.83-0.98)], [1.20 (0.95-1.51)], [1.41 (0.87-2.29)], respectively, p for trend =0.068), but malnutrition was related to markedly increased risk of mortality in LVEF ≥ 40% group (mild, moderate, and severe vs. normal, HR (95%CI): [1.21 (1.12-1.31)], [1.56 (1.40-1.74)], and [2.20(1.67-2.90)], respectively, p for trend < 0.001, and p for interaction < 0.001). Patients with LVEF ≥ 40% had a higher malnutrition-associated risk of mortality and a higher PAR than those with LVEF < 40%. Conclusions: Malnutrition is common in CAG patients and it has a greater effect on all-cause mortality and a higher PAR in patients with LVEF ≥ 40% than LVEF < 40%.

m5C-Related lncRNAs Predict Overall Survival of Patients and Regulate the Tumor Immune Microenvironment in Lung Adenocarcinoma.

Long non-coding RNAs (lncRNAs), which are involved in the regulation of RNA methylation, can be used to evaluate tumor prognosis. lncRNAs are closely related to the prognosis of patients with lung adenocarcinoma (LUAD); thus, it is crucial to identify RNA methylation-associated lncRNAs with definitive prognostic value. We used Pearson correlation analysis to construct a 5-Methylcytosine (m5C)-related lncRNAs-mRNAs coexpression network. Univariate and multivariate Cox proportional risk analyses were then used to determine a risk model for m5C-associated lncRNAs with prognostic value. The risk model was verified using Kaplan-Meier analysis, univariate and multivariate Cox regression analysis, and receiver operating characteristic curve analysis. We used principal component analysis and gene set enrichment analysis functional annotation to analyze the risk model. We also verified the expression level of m5C-related lncRNAs in vitro. The association between the risk model and tumor-infiltrating immune cells was assessed using the CIBERSORT tool and the TIMER database. Based on these analyses, a total of 14 m5C-related lncRNAs with prognostic value were selected to build the risk model. Patients were divided into high- and low-risk groups according to the median risk score. The prognosis of the high-risk group was worse than that of the low-risk group, suggesting the good sensitivity and specificity of the constructed risk model. In addition, 5 types of immune cells were significantly different in the high-and low-risk groups, and 6 types of immune cells were negatively correlated with the risk score. These results suggested that the risk model based on 14 m5C-related lncRNAs with prognostic value might be a promising prognostic tool for LUAD and might facilitate the management of patients with LUAD.