Intubation Decision Based on Illness Severity and Mortality in COVID-19: An International Study.

OBJECTIVES: To evaluate the impact of intubation timing, guided by severity criteria, on mortality in critically ill COVID-19 patients, amidst existing uncertainties regarding optimal intubation practices. DESIGN: Prospective, multicenter, observational study conducted from February 1, 2020, to November 1, 2022. SETTING: Ten academic institutions in the United States and Europe. PATIENTS: Adults (≥ 18 yr old) confirmed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hospitalized specifically for COVID-19, requiring intubation postadmission. Exclusion criteria included patients hospitalized for non-COVID-19 reasons despite a positive SARS-CoV-2 test. INTERVENTIONS: Early invasive mechanical ventilation (EIMV) was defined as intubation in patients with less severe organ dysfunction (Sequential Organ Failure Assessment [SOFA] < 7 or Pa o2 /F io2 ratio > 250), whereas late invasive mechanical ventilation (LIMV) was defined as intubation in patients with SOFA greater than or equal to 7 and Pa o2 /F io2 ratio less than or equal to 250. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mortality within 30 days of hospital admission. Among 4464 patients, 854 (19.1%) required mechanical ventilation (mean age 60 yr, 61.7% male, 19.3% Black). Of those, 621 (72.7%) were categorized in the EIMV group and 233 (27.3%) in the LIMV group. Death within 30 days after admission occurred in 278 patients (42.2%) in the EIMV and 88 patients (46.6%) in the LIMV group ( p = 0.28). An inverse probability-of-treatment weighting analysis revealed a statistically significant association with mortality, with patients in the EIMV group being 32% less likely to die either within 30 days of admission (adjusted hazard ratio [HR] 0.68; 95% CI, 0.52-0.90; p = 0.008) or within 30 days after intubation irrespective of its timing from admission (adjusted HR 0.70; 95% CI, 0.51-0.90; p = 0.006). CONCLUSIONS: In severe COVID-19 cases, an early intubation strategy, guided by specific severity criteria, is associated with a reduced risk of death. These findings underscore the importance of timely intervention based on objective severity assessments.

SuPAR, biomarkers of inflammation, and severe outcomes in patients hospitalized for COVID-19: The International Study of Inflammation in COVID-19.

Severe coronavirus disease 2019 (COVID-19) is a hyperinflammatory syndrome. The biomarkers of inflammation best suited to triage patients with COVID-19 are unknown. We conducted a prospective multicenter observational study of adult patients hospitalized specifically for COVID-19 from February 1, 2020 to October 19, 2022. Biomarkers measured included soluble urokinase plasminogen activator receptor (suPAR), C-reactive protein, interleukin-6, procalcitonin, ferritin, and D-dimer. In-hospital outcomes examined include death and the need for mechanical ventilation. Patients admitted in the United States (US, n = 1962) were used to compute area under the curves (AUCs) and identify biomarker cutoffs. The combined European cohorts (n = 1137) were used to validate the biomarker cutoffs. In the US cohort, 356 patients met the composite outcome of death (n = 197) or need for mechanical ventilation (n = 290). SuPAR was the most important predictor of the composite outcome and had the highest AUC (0.712) followed by CRP (0.642), ferritin (0.619), IL-6 (0.614), D-dimer (0.606), and lastly procalcitonin (0.596). Inclusion of other biomarkers did not improve discrimination. A suPAR cutoff of 4.0 ng/mL demonstrated a sensitivity of 95.4% (95% CI: 92.4%-98.0%) and negative predictive value (NPV) of 92.5% (95% CI: 87.5%-96.9%) for the composite outcome. Patients with suPAR < 4.0 ng/mL comprised 10.6% of the cohort and had a 0.8% probability of the composite outcome. Applying this cutoff to the validation cohort yielded a sensitivity of 93.8% (90.4%-96.7%) and NPV of 95.5% (93.1%-97.8%) for the composite outcome. Among commonly measured biomarkers, suPAR offered stronger discriminatory ability and may be useful in triaging low-risk patients with COVID-19.

New Insights into TETs in Psychiatric Disorders.

Psychiatric disorders are complex and heterogeneous disorders arising from the interaction of multiple factors based on neurobiology, genetics, culture, and life experience. Increasing evidence indicates that sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Over the past decade, the critical, non-redundant roles of the ten-eleven translocation (TET) family of dioxygenase enzymes have been identified in the brain during developmental and postnatal stages. Specifically, TET-mediated active demethylation, involving the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine and subsequent oxidative derivatives, is dynamically regulated in response to environmental stimuli such as neuronal activity, learning and memory processes, and stressor exposure. Here, we review the progress of studies designed to provide a better understanding of how profiles of TET proteins and 5hmC are powerful mechanisms by which to explain neuronal plasticity and long-term behaviors, and impact transcriptional programs operative in the brain that contribute to psychiatric disorders.

Clinical characteristics of severe aortic stenosis patients combined with diabetes mellitus after transcatheter aortic valve replacement and short-term outcome. / ç»å¯¼ç®¡ä¸»åŠ¨è„‰ç“£ç½®æ¢æœ¯åŽé‡åº¦ä¸»åŠ¨è„‰ç“£ç‹­çª„æ‚£è€ åˆå¹¶ç³–å°¿ç— çš„ä¸´åºŠç‰¹å¾åŠå ¶çŸ­æœŸé¢„åŽ.

OBJECTIVES: Type 2 diabetes (T2DM) is a common comorbidity in patients with degenerative aortic stenosis (AS).As a key item of the American Society of Thoracic Surgeons (STS) score, it has a vital impact on the clinical prognosis of traditional thoracic surgery. T2DM has an adverse effect on the morbidity and mortality of cardiovascular diseases. At the same time, studies have shown that T2DM are associated with myocardial hypertrophy and remodeling, decreased left ventricular function, and worsening heart failure symptoms in the AS patients. Transcatheter aortic valve replacement (TAVR) as an interventional method to replace the aortic valve has better safety for middle and high risk patients in surgery, but the impact of T2DM on the clinical outcome of TAVR in AS patients is not clear.By analyzing the clinical and image characteristics of patients with AS and T2DM who received TAVR treatment, so as to explore the effect of T2DM on the perioperative complications and prognosis of TAVR. METHODS: A total of 100 consecutive patients with severe AS, who underwent TAVR treatment and were followed up for more than 1 month, were selectedin the Second Xiangya Hospital of Central South University from January 2016 to December 2020.Among them, 5 patients who were treated with TAVR due to simple severe aortic regurgitation were not included, therefore a total of 95 patients with severe aortic stenosis were enrolled in this study.The age of the patients was (72.7±4.8) years old, and there were 58 males (61.1%), and the patients with moderate or above aortic regurgitation had 30 cases (31.6%). The patients were divided into a diabetic group and a non-diabetic group according to whether they were combined with T2DM.There was no statistical difference in age, gender, body mass index (BMI), STS score, and New York Heart Association (NYHA) cardiac function classification between the 2 groups (all P>0.05). The primary end point was defined as a composite event consisting of all-cause death and stroke one month after surgery, and the secondary end point was defined as TAVR-related complications immediately after surgery and one month after surgery.The preoperative clinical data, cardiac ultrasound data, CT data, postoperative medication and the incidence of each endpoint event were compared between the 2 groups.The predictive model of adverse events was constructed by single factor and multivariate logistic regression. RESULTS: Compared with the non-diabetic group, the diabetic group had high blood pressure and chronic renal insufficiency.There was no significant difference in preoperative ultrasound echocardiography between the 2 groups. Preoperative CT evaluation found that the anatomical structure of the aortic root in the diabetic group was smaller than that in the non-diabetic group, and there was no significant difference in the incidence of bicuspid aortic valve between the 2 groups (all P<0.05). In terms of postoperative medication, the use of statins in the diabetes group was significantly higher than that in the non-diabetic group. In the diabetes group, 6 patients (37.5%) received insulin therapy, and 9 patients (56.3%) received oral medication alone.Univariate logistic regression analysis showed that the all-cause death and stroke compound events was increased in the diabetes group in 30 days after TAVR (OR=6.86; 95% CI: 2.14 to 21.79; P<0.01). Heart disease (OR=2.80; 95% CI: 0.99 to 7.88; P<0.05) and chronic renal insufficiency (OR=3.75; 95% CI: 1.24 to 11.34; P<0.05) were also risk factors for all-cause death and stroke compound events.In a multivariate analysis, after adjusting for age, gender, BMI, comorbidities, N-terminal pro-B type natriuretic peptide (NT-proBNP), total calcification score, ejection fraction, and degree of aortic regurgitation, T2DM was still a risk factor for all-cause death and stroke compound events in 30 days after TAVR (OR=12.68; 95% CI: 1.76 to 91.41; P<0.05). CONCLUSIONS: T2DM is a risk factor for short-term poor prognosis in patients with symptomatic severe AS after TAVR treatment. T2DM should play an important role in the future construction of the TAVR surgical risk assessment system, but the conclusions still need to be further verified by long-term follow-up of large-scale clinical studies.

Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China.

The specific mechanism of pulmonary arterial hypertension (PAH) remains elusive. The present study aimed to explore the underlying mechanism of PAH through the identity of novel biomarkers for PAH using metabolomics approach. Serum samples from 40 patients with idiopathic PAH (IPAH), 20 patients with congenital heart disease-associated PAH (CHD-PAH) and 20 healthy controls were collected and analysed by ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HRMS). Orthogonal partial least square-discriminate analysis (OPLS-DA) was applied to screen potential biomarkers. These results were validated in monocrotaline (MCT)-induced PAH rat model. The OPLS-DA model was successful in screening distinct metabolite signatures which distinguished IPAH and CHD-PAH patients from healthy controls, respectively (26 and 15 metabolites). Unbiased analysis from OPLS-DA identified 31 metabolites from PAH patients which were differentially regulated compared to the healthy controls. Our analysis showed dysregulation of the different metabolic pathways, including lipid metabolism, glucose metabolism, amino acid metabolism and phospholipid metabolism pathways in PAH patients compared to their healthy counterpart. Among these metabolites from dysregulated metabolic pathways, a panel of metabolites from lipid metabolism and fatty acid oxidation (lysophosphatidylcholine, phosphatidylcholine, perillic acid, palmitoleic acid, N-acetylcholine-d-sphingomyelin, oleic acid, palmitic acid and 2-Octenoylcarnitine metabolites) were found to have a close association with PAH. The results from the analysis of both real-time quantitative PCR and Western blot showed that expression of LDHA, CD36, FASN, PDK1 GLUT1 and CPT-1 in right heart/lung were significantly up-regulated in MCT group than the control group.

Molecular mechanisms of apoptosis and autophagy elicited by combined treatment with oridonin and cetuximab in laryngeal squamous cell carcinoma.

Combined oridonin (ORI), a natural and safe kaurene diterpenoid isolated from Rabdosia rubescens, and cetuximab (Cet), an anti-EGFR monoclonal antibody, have been reported to exert synergistic anti-tumor effects against laryngeal squamous cell carcinoma (LSCC) both in vitro and in vivo by our group. In the present study, we further found that ORI/Cet treatment not only resulted in apoptosis but also induced autophagy. AMPK/mTOR signaling pathway was found to be involved in the activation of autophagy in ORI/Cet-treated LSCC cells, which is independent of p53 status. Additionally, chromatin immunoprecipitation (ChIP) assay showed that ORI/Cet significantly increased the binding NF-κB family member p65 with the promotor of BECN 1, and p65-mediated up-regulation of BECN 1 caused by ORI/Cet is coupled to increased autophagy. On the other hand, we demonstrated that either Beclin 1 SiRNA or autophagy inhibitors could increase ORI/Cet induced-apoptosis, indicating that autophagy induced by combination of the two agents plays a cytoprotective role. Interestingly, 48 h after the combined treatment, autophagy began to decrease but apoptosis was significantly elevated. Our findings suggest that autophagy might be strongly associated with the antitumor efficacy of ORI/Cet, which may be beneficial to the clinical application of ORI/Cet in LSCC treatment.

Fropofol decreases force development in cardiac muscle.

Supranormal contractile properties are frequently associated with cardiac diseases. Anesthetic agents, including propofol, can depress myocardial contraction. We tested the hypothesis that fropofol, a propofol derivative, reduces force development in cardiac muscles via inhibition of cross-bridge cycling and may therefore have therapeutic potential. Force and intracellular Ca2+ concentration ([Ca2+]i) transients of rat trabecular muscles were determined. Myofilament ATPase, actin-activated myosin ATPase, and velocity of actin filaments propelled by myosin were also measured. Fropofol dose dependently decreased force without altering [Ca2+]i in normal and pressure-induced hypertrophied-hypercontractile muscles. Similarly, fropofol depressed maximum Ca2+-activated force ( Fmax) and increased the [Ca2+]i required for 50% of Fmax (Ca50) at steady state without affecting the Hill coefficient in both intact and skinned cardiac fibers. The drug also depressed cardiac myofibrillar and actin-activated myosin ATPase activity. In vitro actin sliding velocity was significantly reduced when fropofol was introduced during rigor binding of cross-bridges. The data suggest that the depressing effects of fropofol on cardiac contractility are likely to be related to direct targeting of actomyosin interactions. From a clinical standpoint, these findings are particularly significant, given that fropofol is a nonanesthetic small molecule that decreases myocardial contractility specifically and thus may be useful in the treatment of hypercontractile cardiac disorders.-Ren, X., Schmidt, W., Huang, Y., Lu, H., Liu, W., Bu, W., Eckenhoff, R., Cammarato, A., Gao, W. D. Fropofol decreases force development in cardiac muscle.

The caveolin-3 P104L mutation in LGMD-1C patients inhibits non-insulin-stimulated glucose metabolism and growth but promotes myocyte proliferation.

The caveolin-3 (CAV3) protein is known to be specifically expressed in various myocytes, and skeletal muscle consumes most of the blood glucose as an energy source to maintain normal cell metabolism and function. The P104L mutation in the coding sequence of the human CAV3 gene leads to autosomal dominant disease limb-girdle muscular dystrophy type 1C (LGMD-1C). We previously reported that C2C12 cells transiently transfected with the P104L CAV3 mutant exhibited decreased glucose uptake and glycogen synthesis after insulin stimulation. The present study aimed to examine whether the P104L mutation affects C2C12 cell glucose metabolism, growth, and proliferation without insulin stimulation. C2C12 cells stably transfected with CAV3-P104L were established, and biochemical assays, western blot analysis and confocal microscopy were used to observe glucose metabolism as well as cell growth and proliferation and to determine the effect of the P104L mutation on the PI3K/Akt signaling pathway. Without insulin stimulation, C2C12 cells stably transfected with the P104L CAV3 mutant exhibited decreased glucose uptake and glycogen synthesis, decreased CAV3 expression and reduced localization of CAV3 and GLUT4 on the cell membrane. The P104L mutant significantly reduced the cell diameters, but accelerated cell proliferation. Akt phosphorylation was inhibited, and protein expression of GLUT4, p-GSK3ß, and p-p70s6K, which are molecules downstream of Akt, was significantly decreased. The CAV3-P104L mutation inhibits glycometabolism and cell growth but accelerates C2C12 cell proliferation by reducing CAV3 protein expression and cell membrane localization, which may contribute to the pathogenesis of LGMD-1C.

Biological and pharmacological effects of hexahydrocurcumin, a metabolite of curcumin.

Curcumin, one of the most precious pharmacologically relevant natural products, has gained considerable attention among scientists for decades because of its multi-pharmacological activities in the clinical. However, critical studies on its pharmacological and toxicological activities are needed to understand how this compound can have these biological functions considering its poor oral bioavailability and the low plasma concentration. Moreover, curcumin undergoes extensive and rapid metabolism in vivo, indicating that the pharmacological activity of consuming curcumin might be mediated partly by its metabolites. And as one of the major curcumin metabolites, hexahydrocurcumin (HHC), exhibits similar or more potent bioactivity than curcumin by in vitro and in vivo studies, such as antioxidant, anti-inflammatory, antitumor and cardiovascular protective properties, which may provide important information for us to have a profound comprehension of the effectiveness of curcumin. This review mainly summarizes the current knowledge and underlying molecular mechanisms of the biological activities of HHC and its potential effects on the development of various human diseases.

Genome-wide analysis of the GST gene family in Gossypium hirsutum L.

Glutathione-S-transferase (GST) is a ubiquitous multi-functional protein superfamily that plays important roles in plant primary and secondary metabolism, stress and intercellular signal transduction. Concomitantly, it also functions as a ligand in the metabolism of plant hormones and substance transport. In order to understand the GST gene family in upland cotton (Gossypium hirsutum L.), herein we analyzed the species, evolutionary relationship, physical location, gene structure, conserved motifs and expression patterns. We identified 70 GST genes in the whole genome of upland cotton, and divided them into U, F, T, Z, EF1Bγ and TCHQD groups by phylogenetic tree and gene structure analyses. The gene mapping analysis indicated that the GST genes were on every chromosome except chromosome AD/At2, AD/At4, AD/At5, AD/Dt5 and AD/Dt10. Moreover, the GST gene cluster appeared on four chromosomes (AD/At9, AD/Dt7, AD/Dt12 and AD/Dt13). qRT-PCR assays showed that eight genes (GhGSTF2-9) were expressed in the root, stem, leave and fiber of different developmental stages while GhGSTF1 might be a pseudogene. Combining qRT-PCR and bioinformatic analysis, we speculated that GhGSTF8 might be involved in the transport and accumulation of proanthocyanidins/anthocyanins; GhGSTF4, 6 and 9 might play roles in regulating the growth and stress response of upland cotton; the function of GhGSTF2, 3, 5 and 7 remains to be further investigated. Our work provides a theoretical basis for further studies on the molecular evolution and function of the GST gene family in upland cotton.

[Clinical value of ADMA in patients with pulmonary arterial hypertension combination with congenital heart disease].

OBJECTIVE: To study the concentration of the asymmetrical dimethyl-L-arginine (ADMA) in patients with pulmonary arterial hypertension (PAH) commbination with congenital heart disease (CHD) and its clinical value as a biomaker for diagnosis and prognosis.
 Methods: A total of 100 patients with CHD and 25 healthy adult subjects were recruited. CHD patients were divided into three groups: normal pulmonary arterial pressure group (group A, n=25), mild-to-moderate PAH group (group B, n=25), severe PAH group (group C, n=50). Twenty patients in Group C were treated with sildenafil and followed up for 6 months. The clinical data, including echocardiographic measurements, hemodynamic parameters and ADMA levels, for all subjects were collected.
 Results: The ADMA concentrations in patients with CHD-PAH significantly increased compared with that in the CHD patients without PAH or the health controls, and the ADMA concentrations in CHD patients with severe PAH were significantly higher than that in the CHD patients with mild-to-moderate PAH; serum ADMA concentration was correlated with mean pulmonary arterial pressure (mPAP) (r=0.61, P<0.001) and pulmonary vascular resistance (PVR) (r=0.417, P<0.001) in CHD patients; when using AMDA>0.485 µmol/L as criteria for diagnosis of CHD-PAH, the specificity was 82.7% and the sensitivity was 92.0%; the pulmonary arterial pressure significantly decreased after sildenafil therapy for 6 months, same as the ADMA levels.
 Conclusion: Plasma ADMA could be used as a biomarker to identify PAH in patients with CHD and as a prognosic index to reflect the sildenafil treatment effect.

Geminin is Essential to Prevent DNA Re-Replication-Dependent Apoptosis in Pluripotent Cells, but not in Differentiated Cells.

Geminin is a dual-function protein unique to multicellular animals with roles in modulating gene expression and preventing DNA re-replication. Here, we show that geminin is essential at the beginning of mammalian development to prevent DNA re-replication in pluripotent cells, exemplified by embryonic stem cells, as they undergo self-renewal and differentiation. Embryonic stem cells, embryonic fibroblasts, and immortalized fibroblasts were characterized before and after geminin was depleted either by gene ablation or siRNA. Depletion of geminin under conditions that promote either self-renewal or differentiation rapidly induced DNA re-replication, followed by DNA damage, then a DNA damage response, and finally apoptosis. Once differentiation had occurred, geminin was no longer essential for viability, although it continued to contribute to preventing DNA re-replication induced DNA damage. No relationship was detected between expression of geminin and genes associated with either pluripotency or differentiation. Thus, the primary role of geminin at the beginning of mammalian development is to prevent DNA re-replication-dependent apoptosis, a role previously believed essential only in cancer cells. These results suggest that regulation of gene expression by geminin occurs only after pluripotent cells differentiate into cells in which geminin is not essential for viability.

Physalin A induces G2/M phase cell cycle arrest in human non-small cell lung cancer cells: involvement of the p38 MAPK/ROS pathway.

Physalin A (PA) is an active withanolide isolated from Physalis alkekengi var. franchetii, a traditional Chinese herbal medicine named Jindenglong, which has long been used for the treatment of sore throat, hepatitis, and tumors in China. In the present study, we firstly investigated the effects of PA on proliferation and cell cycle distribution of the human non-small cell lung cancer (NSCLC) A549 cell line, and the potential mechanisms involved. Here, PA inhibited cell growth in dose- and time-dependent manners. Treatment of A549 cells with 28.4 µM PA for 24 h resulted in approximately 50 % cell death. PA increased the amount of intracellular ROS and the proportion of cells in G2/M. G2/M arrest was attenuated by the addition of ROS scavenger NAC. ERK and P38 were triggered by PA through phosphorylation in a time-dependent manner. The phosphorylation of ERK and P38 were not attenuated by the addition of NAC, but the use of the p38 inhibitor could reduce, at least in part, PA-induced ROS and the proportion of cells in G2/M. PA induces G2/M cell cycle arrest in A549 cells involving in the p38 MAPK/ROS pathway. This study suggests that PA might be a promising therapeutic agent against NSCLC.

[Influencial factors for in-hospital patients with ST segment elevation myocardial infarction after emergency percutaneous coronary intervention].

OBJECTIVE: To analyze the clinical outcomes of emergency percutaneous intervention in acute myocardial infarction (AMI) during hospital, and to find the relevant risk factors for the prognosis and cardiac events. 
 Methods: We retrospective analyzed the patient with acute ST segment elevation myocardial infarction, who was successfully performed emergency percutaneous coronary intervention (PCI) in the Cardiac Cath Lab of the Second Xiangya Hospital from January 2010 to December 2014. According to situation for cardiovascular events, patients were divided into 2 groups. The clinical factors were compared between the 2 groups.
 Results: The incidence of adverse event was 22% (67/304). By using t test and χ2 analysis, we found that Cr, NT-proBNP, HCT, WBC, age>75, Killip grade≥2, TIMI flow after PCI≤2, arrhythmia, multi-vessel lesion, ST-segment resolution≥50%, long D2B time are statistically different between the 2 groups. Logistic analysis revealed that HCT, NT-proBNP, Killip grade≥2, TIMI flow after PCI≤2, ST-segment resolution≥50%, long D2B time were important predictors for cardiac events in-hospital.
 Conclusion: HCT, NT-proBNP, Killip grade≥2, TIMI flow after PCI≤2, ST-segment resolution≥50%, long D2B time are important predictors for cardiac events in-hospital. The prognosis for AMI patient after emergency PCI could be improved and the incidence of cardiac event in hospital could be reduced if the high risk factors can be properly handled.

Asymmetric Dimethyl-L-Arginine is a Biomarker for Disease Stage and Follow-Up of Pulmonary Hypertension Associated with Congenital Heart Disease.

This study investigated the clinical value of plasma asymmetrical dimethyl-L-arginine (ADMA) level in the diagnosis, staging, and treatment response in congenital heart disease (CHD) patients with pulmonary arterial hypertension (PAH). This was a single-center prospective observational study in 80 CHD patients. Plasma ADMA levels were measured by enzyme-linked immunosorbent assay. Plasma ADMA levels were significantly increased in CHD patients with PAH compared with CHD patients without PAH (P < 0.01) and healthy controls (P < 0.001). In CHD patients with severe PAH, plasma ADMA levels were significantly higher in patients with Eisenmenger's syndrome (ES) than in patients exhibiting low pulmonary vascular resistance (P < 0.001). The plasma ADMA levels significantly correlated with pulmonary arterial pressure (P < 0.001) and pulmonary vascular resistance (P < 0.001) in patients with CHD. Severe PAH was identified by plasma ADMA with a cutoff value of 0.485 µmol/L (P < 0.001) with a specificity of 82.8 % and a sensitivity of 90 %. ES was identified by plasma ADMA with a cutoff value of 0.85 µmol/L (P < 0.05) with a specificity of 85.2 % and a sensitivity of 64.3 %. ADMA levels were significantly decreased after sildenafil therapy for 6 months compared with before therapy levels (0.91 ± 0.22 vs. 0.57 ± 0.30, P < 0.01). Our study suggests that plasma ADMA level may be used as a biomarker for identifying PAH in patients with CHD, assessing pulmonary vascular remodeling, and evaluating the treatment response of CHD patients with PAH to sildenafil.

Long-term outcomes of transcatheter closure of ruptured sinus valsalva aneurysms using patent ductus arteriosus occluders.

BACKGROUND: Transcatheter closure (TCC) of ruptured sinus of Valsalva aneurysm (RSVA) is an alternative strategy to surgery, but there is a lack of long-term outcome data. METHODS AND RESULTS: From 2004 to 2012, 17 patients (8 males, 9 females) were treated with patent ductus arteriosus (PDA) occluders by antegrade venous approach and were followed for 18-102 months. Of the 17 patients, transthoracic echocardiography revealed rupture of the right coronary sinus into the right ventricle in 9 and into the right atrium in 4, and noncoronary sinus rupture into the right ventricle in 3 and into the right atrium in 1. Most (10/17) were in New York Heart Association (NYHA) functional class III or IV. Aortography showed that the size of the defect was 7.71±2.84 mm (4-15 mm). TCC was attempted using PDA occluders 2-5 mm larger than the aortic end of the defects. The device sizes ranged from 8/6 to 18/16 mm (median, 10/8 mm). The procedure was successful in 16 (94.1%), and all of them had complete occlusion at discharge. On a median follow-up of 42 months, 14 patients were in NYHA class I and 2 were in class II, and there was no residual shunt, device embolization, infective endocarditis, or aortic regurgitation. CONCLUSIONS: TCC of RSVA is a safe and effective alternative to surgery with favorable long-term follow-up results.

Essential roles of BCCIP in mouse embryonic development and structural stability of chromosomes.

BCCIP is a BRCA2- and CDKN1A(p21)-interacting protein that has been implicated in the maintenance of genomic integrity. To understand the in vivo functions of BCCIP, we generated a conditional BCCIP knockdown transgenic mouse model using Cre-LoxP mediated RNA interference. The BCCIP knockdown embryos displayed impaired cellular proliferation and apoptosis at day E7.5. Consistent with these results, the in vitro proliferation of blastocysts and mouse embryonic fibroblasts (MEFs) of BCCIP knockdown mice were impaired considerably. The BCCIP deficient mouse embryos die before E11.5 day. Deletion of the p53 gene could not rescue the embryonic lethality due to BCCIP deficiency, but partially rescues the growth delay of mouse embryonic fibroblasts in vitro. To further understand the cause of development and proliferation defects in BCCIP-deficient mice, MEFs were subjected to chromosome stability analysis. The BCCIP-deficient MEFs displayed significant spontaneous chromosome structural alterations associated with replication stress, including a 3.5-fold induction of chromatid breaks. Remarkably, the BCCIP-deficient MEFs had a ∼20-fold increase in sister chromatid union (SCU), yet the induction of sister chromatid exchanges (SCE) was modestly at 1.5 fold. SCU is a unique type of chromatid aberration that may give rise to chromatin bridges between daughter nuclei in anaphase. In addition, the BCCIP-deficient MEFs have reduced repair of irradiation-induced DNA damage and reductions of Rad51 protein and nuclear foci. Our data suggest a unique function of BCCIP, not only in repair of DNA damage, but also in resolving stalled replication forks and prevention of replication stress. In addition, BCCIP deficiency causes excessive spontaneous chromatin bridges via the formation of SCU, which can subsequently impair chromosome segregations in mitosis and cell division.

Dissecting Mismatch Negativity: Early and Late Subcomponents for Detecting Deviants in Local and Global Sequence Regularities.

Mismatch negativity (MMN) is commonly recognized as a neural signal of prediction error evoked by deviants from the expected patterns of sensory input. Studies show that MMN diminishes when sequence patterns become more predictable over a longer timescale. This implies that MMN is composed of multiple subcomponents, each responding to different levels of temporal regularities. To probe the hypothesized subcomponents in MMN, we record human electroencephalography during an auditory local-global oddball paradigm where the tone-to-tone transition probability (local regularity) and the overall sequence probability (global regularity) are manipulated to control temporal predictabilities at two hierarchical levels. We find that the size of MMN is correlated with both probabilities and the spatiotemporal structure of MMN can be decomposed into two distinct subcomponents. Both subcomponents appear as negative waveforms, with one peaking early in the central-frontal area and the other late in a more frontal area. With a quantitative predictive coding model, we map the early and late subcomponents to the prediction errors that are tied to local and global regularities, respectively. Our study highlights the hierarchical complexity of MMN and offers an experimental and analytical platform for developing a multitiered neural marker applicable in clinical settings.

Residential Address Amplifies Health Disparities and Risk of Infection in Individuals With Diabetic Foot Ulcers.

OBJECTIVE: To determine the association between social determinants of health (SDOH) and a diagnosis of diabetic foot ulcer (DFU) infection. RESEARCH DESIGN AND METHODS: Targeted interrogation of electronic health record data using novel search engines to analyze individuals with a DFU infection during a 5-year period (2013-2017) was performed. We extracted geolocated neighborhood data and SDOH characteristics from the National Neighborhood Data Archive and used univariate and multiple logistic regression to evaluate associations with outcomes in the population with diabetes. RESULTS: Among 4.3 million people overall and 144,564 individuals with diabetes seen between 2013 and 2017, 8,351 developed DFU, of which cases 2,252 were complicated by a DFU infection. Sex interactions occurred, as men who experienced a DFU infection more frequently identified as having nonmarried status than their female counterparts. For the population with DFU infection, there were higher rates for other SDOH, including higher neighborhood disadvantaged index score, poverty, nonmarriage, and less access to physician/allied health professionals (all P < 0.01). In multiple logistic regression, those individuals who developed DFU infection came from neighborhoods with greater Hispanic and/or foreign-born concentrations (odds ratio 1.11, P = 0.015). CONCLUSIONS: We found significant differences in neighborhood characteristics driving a higher risk for DFU infection in comparisons with the grouping of individuals with diabetes overall, including increased risk for individuals with Hispanic and/or foreign-born immigration status. These data strongly support the need to incorporate SDOH, particularly ethnic and immigration status, into triage algorithms for DFU risk stratification to prevent severe diabetic foot complications and move beyond biologic-only determinants of health.