Thirteen-year viral suppression and immunologic recovery of LPV/r-based regimens in pediatric HIV treatment: a multicenter cohort study in resource-constrained settings of China.

Background: Antiretroviral Therapy (ART) in children remains challenging due to resource-constrained settings. We conducted a 13-year, prospective, multicenter cohort study on the effectiveness and safety of LPV/r-based regimens in ART-naive and ART-experienced children. Methods: From January 2008 to May 2021, children living with HIV-1 were recruited with LPV/r-based regimens from 8 clinical research sites in 6 provinces in China. Effectiveness outcomes were virologic failure (defined as at least two consecutive measurements of VL > 200 copies/mL after 6 months of ART) and immune response (defined as CD4% recovered to more than 25% after 12 months of treatment). The safety outcomes were treatment-related grade 2-4 adverse events and abnormal laboratory test results. Results: A total of 345 ART-naïve children and 113 ART-experienced children were included in this cohort study. The median follow-up time was 7.3 (IQR 5.5-10.5) years. The incidence density of virologic failure was 4.1 (95% CI 3.3-4.9) per 100 person-years in ART-naïve children and 5.0 (95% CI 3.5-6.5) per 100 person-years in ART-experienced children. Kaplan Meyer (KM) curve analysis showed children with ART experience were at a higher risk of virologic failure (p < 0.05). The risk factors of virologic failure in ART-naïve children were clinic setting in rural hospitals (aHR = 2.251, 1.108-4.575), annual missed dose times >5 days of LPV intake (aHR = 1.889, 1.004-3.554); The risk factor of virologic failure in ART-experienced children was missed dose times >5 days (aHR = 2.689, 1.299-5.604) and mother as caregivers for ART administration (aHR = 0.475, 0.238-0.948). However, during long-term treatment, viral suppression rates between ART-naïve and ART-experienced children remained similar. No significant differences were observed in the immune response, treatment-related grade 2-4 events, and abnormal laboratory test results between ART-naïve children and ART-experienced children. Conclusion: Our research underscores that with consistent, long-term treatment of LPV/r-based regimens, ART-experienced children can achieve therapeutic outcomes comparable to ART-naïve children. It provides crucial insights on LPV/r-based regimens in pediatric HIV treatment, especially in resource-limited settings where high-cost Integrase Strand Transfer Inhibitors (INSTs) are inaccessible. This evidence-based understanding provides an essential addition to the global therapeutic strategies for pediatric HIV treatment.

Qishen Yiqi dropping pills improve cardiomyocyte hypertrophy via the lncRNA TINCR/miR-193b-3p/RORA axis.

Background: This study was designed to explore the therapeutic effect and mechanism of action of Qishen Yiqi dropping pills (QYDP) in chronic heart failure (CHF) via a long non-coding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) axis. Here, the mechanism of action of the lncRNA terminal differentiation-induced non-coding RNA (TINCR), miR-193b-3p, and RAR-related orphan receptor A (RORA) mRNA was analyzed in an angiotensin (Ang) II-induced H9C2 cardiomyocyte hypertrophy model treated with QYDP. Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to analyze the gene expression changes of lncRNA, miRNA, and mRNA in H9C2 induced by QYDP on Ang II. The Gene Expression Omnibus (GEO) was used to analyze differentially expressed genes (DEGs) potentially affecting CHF progression. Cell Counting Kit-8 (CCK-8) was used to analyze the effect of QYDP on the proliferation of H9C2, RNA pull-down was used to analyze the binding of lncRNA and miRNA, and dual luciferase was used to analyze the targeting of miRNA and lncRNA or mRNA. Results: Ang II induced TINCR and RORA downregulation, miR-193b-3p upregulation, and hypertrophy in the H9C2 cardiomyocytes, which were alleviated by QYDP. In contrast, TINCR inhibition reversed the effects of QYDP by increasing miR-193b-3p expression and downregulating RORA expression. According to subsequent double luciferase and RNA pull-down experiments, TINCR adsorbed miR-193b-3p by acting as a competitive endogenous RNA sponge and miR-193b-3p directly targeted RORA. Lastly, we showed that the Ang-II-induced inhibition of TINCR and RORA expression and promotion of cardiac hypertrophy were both reversed by a TINCR overexpression plasmid (ov-TINCR), whereas the effects of ov-TINCR were suppressed by a miR-193b-3p mimic. Conclusions: Administration of QYDP improves Ang II-induced H9C2 cardiomyocyte hypertrophy and increase cell proliferation rate through the TINCR/miR-193b-3p/RORA axis.

Qishen Yiqi dropping pills improve isoproterenol-induced cardiomyocyte hypertrophy by regulating X-inactive specific transcript (XIST) expression in rats.

Background: This study aimed to explore the potential mechanism of Qishen Yiqi dropping pills (QYDPs) in the treatment of chronic heart failure (CHF) by regulating the expression of lncRNAs during CHF. Methods: Differences in the expression of the long non-coding RNA (lncRNA), X-inactive specific transcript (XIST), in an isoproterenol (ISO)-induced cardiomyocyte hypertrophy model treated with QYDPs was analyzed by reverse transcription quantitative polymerase chain reaction (RT-qPCR). A cell counting kit-8 (CCK8) assay, flow cytometry (FCM), and enzyme linked immunosorbent assay (ELISA) were used to analyze the protective effects of QYDPs on the proliferation rate, apoptosis, myocardial enzyme, oxidative stress, and inflammation of cardiomyocytes, as well as the molecular mechanism of XIST. Results: Our results showed that in the ISO-induced cardiomyocyte hypertrophy model, XIST expression and apoptosis were increased, the cell proliferation rate was decreased, and myocardial enzyme levels increased [i.e., increased lactate dehydrogenase (LDH) and creatine kinase (CK) levels]. Furthermore, cellular oxidative stress [i.e., increased malondialdehyde (MDA) levels and decreased superoxide dismutase (SOD) levels] and inflammatory response [i.e., increased interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α protein secretion] were also promoted. QYDP treatment effectively mitigated the effects of ISO induction. Subsequently, we found that suppressing XIST expression reversed the effect of ISO induction, whereas overexpression (ov) of XIST enhanced the effect of ISO induction. Finally, this study confirmed that QYDP treatment improved the ISO-induced decrease in proliferation, apoptosis, and promotion of oxidative stress and inflammatory response in cardiomyocytes, whereas ov of XIST partially negated the effect of QYDPs. Conclusions: QYDPs protected H9c2 cells from ISO-induced damage by downregulating XIST expression.

Role of IL-9, IL-2RA, and IL-2RB genetic polymorphisms in coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) is one of the leading causes of disability and death worldwide. Inflammatory cytokines play an essential role in the pathogenesis of CHD. This study aimed to detect the potential association between interleukin (IL)-9, IL-2RA, and IL-2RB variants and CHD in a Han Chinese population. METHODS: This case-control study included 499 CHD patients and 496 healthy controls. Seven single-nucleotide polymorphisms (SNPs) were genotyped to investigate the possible association between the polymorphisms and CHD risk. Interactions between SNPs and CHD risk were analyzed via multifactor dimensionality reduction (MDR). RESULTS: We observed an association between IL­9 rs55692658 (OR = 1.72, p = 0.003) and increased CHD risk. Age-stratified analysis indicated that regardless of the participants' age, IL­9 rs55692658 and IL-2RB rs1573673 contributed significantly to CHD susceptibility (p < 0.05, respectively). Results showed an association between IL­9 rs55692658 and an increased risk for CHD (OR = 2.32, p = 0.003), while IL-2RA rs12722498 was correlated with decreased susceptibility to CHD (OR = 0.54, p = 0.033) in female patients. Furthermore, IL-2RA rs12569923 was related to diabetes risk in CHD patients (OR = 1.50, p = 0.028). The MDR analysis revealed a positive interaction between the SNPs. CONCLUSION: The present study demonstrated that IL­9 rs55692658, IL-2RA rs12569923, IL-2RA rs12722498, and IL-2RB rs3218264 polymorphisms might be related to CHD. The results require validation in larger studies.

NT5C2 Gene Polymorphisms and the Risk of Coronary Heart Disease.

BACKGROUND: Increasing studies have reported that 5'-nucleotidase cytosolic II (NT5C2) has a strong relationship with coronary heart disease (CHD) development. This study was designed to examine the relationship between NT5C2 polymorphisms and CHD in the Chinese Han population. METHODS: We studied 501 CHD patients and 496 healthy controls from the Second Affiliated Hospital of Hainan Medical University in Hainan Province, China. Four single nucleotide polymorphisms (SNPs) in NT5C2 were selected and genotyped using Agena MassARRAY technology. Odds ratios and 95% confidence intervals were calculated using logistic regression after adjusting for age and gender. Stratification analysis was performed by age and gender in all individuals; we especially investigated the effects of NT5C2 SNPs on hypertension and diabetes among CHD patients. RESULTS: rs2148198 of NT5C2 was strongly associated with an increased risk of CHD (allele: p = 0.045; codominant: p = 0.007; additive: p = 0.016). Stratified analysis revealed that rs2148198 was associated with increased CHD risk in individuals aged ≤61 years and males. For CHD patients, rs2148198 significantly affected the risk of hypertension and diabetes (p < 0.05). Further, rs79237883 of NT5C2 was associated with decreased susceptibility to hypertension in multiple genetic models for individuals with CHD (allele: p = 0.007; codominant: p = 0.001; dominant: p = 0.001; additive: p = 0.008). CONCLUSION: This study reports the association of NT5C2 gene variants and CHD susceptibility in the Chinese Han population. Especially, NT5C2 rs2148198 was significantly associated with CHD risk in the subgroups of males, hypertension, and diabetes.

Association of S100B 3'UTR polymorphism with risk of chronic heart failure in a Chinese Han population.

To study the correlation between single nucleotide polymorphism (SNP) of the 3' untranslated region (UTR) rs9722 locus in S100B and the risk of chronic heart failure (CHF), plasma levels of S100B protein as well as has-miR-340-3p in a Chinese Han population.A total of 215 patients with CHF (124 ischemic cardiomyopathy (ICM) and 91 dilated cardiomyopathy (DCM)) and 215 healthy controls were recruited to analyze the S100B rs9722 genotype by Sanger sequencing. The levels of hsa-miR-340-3p in the plasma were detected by RT-PCR, and S100B levels were detected by ELISA.The risk of CHF in S100B rs9722 locus T allele carriers was 4.24 times higher than that in those with the C allele (95% CI: 2.84-6.33, P < .001). The association of S100B rs9722 locus SNP with ICM and DCM risk was not affected by factors such as age, gender, and body mass index (BMI). The levels of plasma S100B and hsa-miR-340-3p in patients with ICM and DCM were significantly higher than those in the control group (P < .001). There was no significant difference in plasma S100B levels between patients with ICM and DCM (P > .05). Among ICM, DCM, and control subjects, TT genotype carriers had the highest levels of plasma S100B and hsa-miR-340-3p, followed by the CT genotype and TT genotype, and the difference was statistically significant (P < .05). Plasma hsa-miR-340-3p levels were positively correlated with S100B levels in the control subjects and patients with ICM and DCM.The S100B rs9722 locus SNP is associated with CHF risk in a Chinese Han population.

High cystatin C levels predict long-term mortality in patients with ST-segment elevation myocardial infarction undergoing late percutaneous coronary intervention: A retrospective study.

OBJECTIVES: Late percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI), defined as time of PCI > 7 days from symptom onset, is a common practice with clinical benefits. This study aimed to evaluate the predictive value of admission cystatin C (cys C) level on long-term mortality in STEMI patients receiving late PCI. METHODS: Medical records of STEMI patients who were hospitalized between 2009 and 2011 from eight PCI-capable hospitals in Northwest China were retrospectively analyzed. Cys C level ≥ 1.105 mg/L was considered as the best predictor of long-term mortality based on the receiver-operating characteristic analysis. Patients were followed up by phone or face-to-face interviews, and the long-term mortality was obtained by reviewing medical records. RESULTS: The final analysis included 716 STEMI patients who received late PCI and had available cys C levels prior to PCI, and 524 were assigned into the high cys C group and 192 the low cys C group. Patients were followed up for an average length of 40.37 months. Compared with the low cys C group, the high cys C group had a higher long-term all-cause mortality (10.4% vs 2.9%, P < 0.001) and a higher cardiac mortality (6.8% vs 2.1%, P = 0.004). Multivariate Cox regression analysis showed that high cys C level was an independent predictor for both long-term all-cause mortality and cardiac mortality. CONCLUSIONS: High cys C level at admission is an independent predictor of long-term mortality in STEMI patients undergoing late PCI.

The long noncoding RNA XIST protects cardiomyocyte hypertrophy by targeting miR-330-3p.

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are implicated in numerous kinds of cardiovascular diseases, and their vital role in regulating cardiac hypertrophy still needs to be explored. In this study, we demonstrated that lncRNA X-inactive specific transcript (XIST) was upregulated in hypertrophic cardiac of mice and phenylephrine (PE)-treated cardiomyocytes. Next, we observed that inhibition of XIST induced hypertrophic response of cardiomyocyte and overexpression of XIST attenuated cardiomyocyte hypertrophy induced by PE. Furthermore, through online predictive tools and functional experiments, we demonstrated that XIST and S100B were targets of miR-330-3p. XIST and miR-330-3p suppressed each other in a reciprocal way in cardiomyocytes. Additionally, XIST promoted S100B expression through harboring the complementary binding sites with miR-330-3p, eventually prevented cardiac hypertrophy. In conclusion, our findings revealed a novel molecular mechanism that XIST/miR-330-3p/S100B pathway modulates the progression of cardiomyocyte hypertrophy.

Associations between polymorphisms of the CXCL12 and CNNM2 gene and hypertension risk: A case-control study.

BACKGROUND: Hypertension is the most important risk factor for cardiovascular and cerebrovascular diseases. The study found that CXCL12 and CNNM2 gene affects the risk of coronary heart disease, but the relationship with hypertension is unclear. The aim of this research is to explore the association between CXCL12 and CNNM2 gene and hypertension in Chinese Han population. METHODS: Genotypes at 11 CHD-relevant SNPs were determined in 350 Hypertension patients and 483 controls in Chinese Han population using χ2 test, genetic model analysis and haplotype analysis. RESULTS: In the allele model, CXCL12 rs1065297 "G" allele, CXCL12 rs4948878 "G" allele and CXCL12 rs10793538 "T" allele were associated with decreased risk of hypertension (rs1065297: OR = 0.53, p = 0.005; rs4948878: OR = 0.51, p = 0.004; rs10793538: OR = 0.58, p = 0.005). CNNM2 rs12413409 "A" allele and CNNM2 rs11191514 "T" allele were also associated with reduced risk of hypertension (rs12413409: OR = 0.71, p = 0.003; rs11191514: OR = 0.70, p = 0.002). Further stratified analysis by sex and age found that CXCL12, CNNM2 gene also influence the risk of hypertension. Model analysis found that CXCL12 rs1093538 TA-TT genotype was associated with decreased risk of hypertension in the dominant model (OR = 0.57, p = 0.0015); Log-additive model revealed that rs1065297 and rs4948878 in CXCL12 gene have a potential association with essential hypertension (rs1065297: OR = 0.54, p = 0.005; rs4948878: OR = 0.52, p = 0.0038). For CNNM2 gene, rs12413409 GA-AA genotype and rs11191514 CT-TT genotype was associated with reduced risk of hypertension in the dominant model (rs12413409: OR = 0.64, p = 0.012; rs11191514: OR = 0.63, p = 0.0082). CXCL12 "GCGCCGT" and CNNM2 "ATAG" haplotype were associated with reduced risk of hypertension with 0.57-fold and 0.75-fold. CONCLUSIONS: Our analysis suggests that CXCL12, CNNM2 gene influence the risk of hypertension in Chinese Han population.

Increased Cystatin C Level in ST-Elevation Myocardial Infarction Predisposes the Prognosis of Angioplasty.

BACKGROUND: The study aimed to evaluate the prognostic value of cystatin C in ST-elevation acute myocardial infarction (STEMI) patients who underwent elective percutaneous coronary intervention (PCI). METHODS: A retrospective study was conducted on 664 STEMI patients from 7 centers who were treated with elective PCI. These patients were divided into 3 groups according their admission cystatin C levels as < 0.84, 0.84-1.03 and ≥1.04mg/L. The all-cause mortalities and the composite endpoints, including mortality, reinfarction, rehospitalization for heart failure and angina or repeat target vessel revascularization were observed for up to 5 years. RESULTS: As cystatin C levels from low to high, all-cause mortalities were progressively increased 0.9%, 3.7% and 9.5% (P < 0.001), as well as the composite endpoints, 11.1%, 21.7% and 40.7%, respectively (P < 0.001). When patients had the level of cystatin C ≥0.84mg/L, their risks of composite endpoints increased 2- to 3-fold of those with <0.84mg/L, with the adjusted hazard ratio of 2.096 (95% CI: 1.047-4.196, P = 0.037) and 3.608 (95% CI: 1.939-6.716, P < 0.001), respectively. CONCLUSIONS: Increased cystatin C levels may be associated with enhanced risks of composite endpoints in patients with STEMI undergoing elective PCI.

The prognostic value of autoantibodies against ß1-adrenoceptor and cardiac troponin-I for clinical outcomes in STEMI.

AIMS: The prevalence and potential role of autoantibodies against the ß1-adrenoceptor autoantibody (ß1-aab) and cardiac troponin-I (anti-cTnI) in patients with ST-elevation myocardial infarction (STEMI) are unknown. The aim of this study is to test whether ß1-aab and anti-cTnI are prevalent in STEMI patients and to investigate their prognostic value for left ventricular remodeling and clinical outcomes in STEMI patients. METHODS: This study included 491 patients with first STEMI at two centers. Serum samples were obtained. ß1-aab and anti-cTnI were detected by enzyme-linked immunoabsorbent assay. Echocardiographic assessments were performed at admission and following 1 year. The major adverse cardiovascular events (MACEs) were evaluated during a median follow-up period of 37 months. RESULTS: The positive rates of ß1-aab and anti-cTnI in STEMI patients were 39.1 and 19.1%, respectively. The extent of left ventricular remodeling correlated with the presence of ß1-aab and/or anti-cTnI (double positive > single positive > double negative). Logistic regression revealed that both ß1-aab [odds ratio (OR) 2.298, 95% confidence interval (CI) 1.561-3.384, P < 0.001] and anti-cTnI (OR 2.389, 95% CI 1.460-3.909, P = 0.001) were predictive of left ventricular remodeling. Cox proportional-hazard regression revealed that ß1-aab, but not anti-cTnI, was strongly predictive of MACEs (hazard ratio 1.802, 95% CI 1.301-2.496, P < 0.001). CONCLUSION: ß1-aab and anti-cTnI were prevalent in STEMI patients. Both ß1-aab and anti-cTnI were independent predictors of left ventricular remodeling, whereas only ß1-aab was an independent predictor of MACEs. Our findings suggest that ß1-aab and anti-cTnI may actively participate in the process of left ventricular remodeling after STEMI.

Prognostic Value of the Percentage of Neutrophils on Admission in Patients with ST-elevated Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

BACKGROUND AND AIMS: An elevated neutrophil count or neutrophil/lymphocyte ratio on admission has been reported to be an independent predictor of adverse cardiac events in patients with acute coronary syndrome (ACS). The relationship between the percentage of neutrophils (N%) at the time of admission and the long-term outcomes in patients with ST-segment elevated myocardial infarction (STEMI) who have undergone primary percutaneous coronary intervention (PCI) remains unclear. The aim of this study was to investigate the usefulness of the admission N% in predicting long-term mortality in patients with STEMI who were undergoing primary PCI. METHODS: We evaluated 701 consecutive patients admitted to nine medical institutions in northwest China within 24 h after symptom onset from January 1, 2009-December 31, 2011. Using a receiver-operating characteristic analysis, N% ≥82.1% was the best predictor of long-term mortality. Patients were divided into two groups according to this criterion. Mean follow-up time was 39.03 months. RESULTS: The long-term all-cause mortality rate was significantly higher in patients with a high N% level (7.17 vs. 3.11%, p = 0.015) as was the rate of cardiac mortality (6.48 vs. 2.59%, p = 0.013). In a multivariate logistic analysis, a high N% level was an independent predictor of long-term all-cause mortality (odds ratio 2.59, 95% confidence interval 1.21-5.53, p = 0.002) and long-term cardiac mortality (odds ratio 2.79, 95% confidence interval 1.24-6.28, p = 0.013). CONCLUSIONS: A high N% level on admission is an independent predictor of long-term mortality in STEMI patients undergoing primary PCI.

Late percutaneous coronary intervention prevents left ventricular remodeling and improves clinical outcomes in patients with ST-elevation myocardial infarction.

BACKGROUND: The optimal strategy for treating late presenters of ST-elevation myocardial infarction (STEMI) remains uncertain. HYPOTHESIS: percutaneous coronary intervention (PCI) has a favorable effect on left ventricular (LV) remodeling and clinical outcomes in late presenters of STEMI. METHODS: Patients with STEMI who were hospitalized between 2009 and 2011 at 7 PCI-capable hospitals in China were selected. Cardiac characteristics were reassessed by echocardiography between August 2013 and January 2014. The clinical endpoints were evaluated during a median follow-up period of 36 months. RESULTS: 1090 patients who either underwent late PCI (n = 786) or received standard medical therapy alone (n = 304) was analyzed. Left ventricular remodeling was more pronounced in the conservative-treatment group. Logistic regression revealed that late PCI was independently and negatively correlated with LV remodeling (odds ratio: 0.356, 95% confidence interval [CI]: 0.251-0.505, P < 0.001). Kaplan-Meier analysis showed the lower risks of major adverse cardiovascular events (MACE), all-cause death, and rehospitalization for heart failure in the late-PCI group. Multivariate Cox regression revealed that late PCI was significantly associated with lower risks for MACE, all-cause death, and rehospitalization for heart failure both in all patients (hazard ratio [HR]: 0.507, 95% CI: 0.412-0.625, P < 0.001; HR: 0.419, 95% CI: 0.314-0.559, P < 0.001; and HR: 0.583, 95% CI: 0.379-0.896, P = 0.014, respectively) and in the matched patients (HR: 0.466, 95% CI: 0.358-0.607, P < 0.001; HR: 0.398, 95% CI: 0.277-0.571, P < 0.001; and HR: 0.498, 95% CI: 0.283-0.878, P = 0.016, respectively) by propensity-score analysis. CONCLUSIONS: Late-PCI strategy prevents LV remodeling and improves clinical outcomes in STEMI patients compared with conservative strategies.

An efficient procedure for the preparation of (1S,3R)- and (1S,3S)-1-amino-3-(hydroxymethyl)cyclopentanes.

Enantiomerically pure (1S,3S)- and (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentanes have been efficiently synthesized from L-aspartic acid. The title compounds are isosteres of ribose and may be used to construct nucleoside analogs with important antiviral and antineoplastic activities as demonstrated by a concise total synthesis of (+)-4'-deoxycarbapentostatin nucleoside.