Biodegradable Cardiac Occluder with Surface Modification by Gelatin-Peptide Conjugate to Promote Endogenous Tissue Regeneration.

Transcatheter intervention has been the preferred treatment for congenital structural heart diseases by implanting occluders into the heart defect site through minimally invasive access. Biodegradable polymers provide a promising alternative for cardiovascular implants by conferring therapeutic function and eliminating long-term complications, but inducing in situ cardiac tissue regeneration remains a substantial clinical challenge. PGAG (polydioxanone/poly (l-lactic acid)-gelatin-A5G81) occluders are prepared by covalently conjugating biomolecules composed of gelatin and layer adhesive protein-derived peptides (A5G81) to the surface of polydioxanone and poly (l-lactic acid) fibers. The polymer microfiber-biomacromolecule-peptide frame with biophysical and biochemical cues could orchestrate the biomaterial-host cell interactions, by recruiting endogenous endothelial cells, promoting their adhesion and proliferation, and polarizing immune cells into anti-inflammatory phenotypes and augmenting the release of reparative cytokines. In a porcine atrial septal defect (ASD) model, PGAG occluders promote in situ tissue regeneration by accelerating surface endothelialization and regulating immune response, which mitigate inflammation and fibrosis formation, and facilitate the fusion of occluder with surrounding heart tissue. Collectively, this work highlights the modulation of cell-biomaterial interactions for tissue regeneration in cardiac defect models, ensuring endothelialization and extracellular matrix remodeling on polymeric scaffolds. Bioinspired cell-material interface offers a highly efficient and generalized approach for constructing bioactive coatings on medical devices.

Noncontact remote sensing of abnormal blood pressure using a deep neural network: a novel approach for hypertension screening.

Background: As the global burden of hypertension continues to increase, early diagnosis and treatment play an increasingly important role in improving the prognosis of patients. In this study, we developed and evaluated a method for predicting abnormally high blood pressure (HBP) from infrared (upper body) remote thermograms using a deep learning (DL) model. Methods: The data used in this cross-sectional study were drawn from a coronavirus disease 2019 (COVID-19) pilot cohort study comprising data from 252 volunteers recruited from 22 July to 4 September 2020. Original video files were cropped at 5 frame intervals to 3,800 frames per slice. Blood pressure (BP) information was measured using a Welch Allyn 71WT monitor prior to infrared imaging, and an abnormal increase in BP was defined as a systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg. The PanycNet DL model was developed using a deep neural network to predict abnormal BP based on infrared thermograms. Results: A total of 252 participants were included, of which 62.70% were male and 37.30% were female. The rate of abnormally high HBP was 29.20% of the total number. In the validation group (upper body), precision, recall, and area under the receiver operating characteristic curve (AUC) values were 0.930, 0.930, and 0.983 [95% confidence interval (CI): 0.904-1.000], respectively, and the head showed the strongest predictive ability with an AUC of 0.868 (95% CI: 0.603-0.994). Conclusions: This is the first technique that can perform screening for hypertension without contact using existing equipment and data. It is anticipated that this technique will be suitable for mass screening of the population for abnormal BP in public places and home BP monitoring.

Feasibility and safety of a percutaneous and non-fluoroscopic procedure for left atrial appendage closure in patients for whom fluoroscopy presents risk: a cohort study.

Background: Most patients undergoing left atrial appendage closure (LAAC) are older adult individuals with atrial fibrillation (AF) and many comorbidities, which may elevate the risk for complications associated with contrast agents with the fluoroscopic image-guided procedure. This retrospective cohort study of patients with AF at high risk for use of contrast agents compared the feasibility and safety of LAAC using percutaneous and non-fluoroscopic procedure with transesophageal echocardiography (TEE) as the only image guidance relative to those under fluoroscopic image guidance. Methods: In this retrospective study, we enrolled 126 patients with AF who underwent LAAC from September 2017 to December 2020. Patients were divided into 2 groups based on the imaging guidance modality: a TEE group (n=32) and a fluoroscopic group (n=94). We analyzed the differences in complete closure rates and device- and procedure-related complications between the 2 groups. Continuous variables were assessed using the Student t-test or Mann-Whitney test, while categorical variables were evaluated using Pearson chi-squared test or Fisher exact test. Propensity-score matching was used to adjust for baseline differences. Results: Propensity-score matching yielded 25 pairs of patients with similarly distributed age (72.9±6.9 vs. 73.1±4.9 years; P=0.925), gender (10:15 vs. 11:14; P>0.99), weight (68.3±11.2 vs. 68.1±12.3 kg; P=0.948), and alanine aminotransferase level (20.0±9.8 vs. 22.5±14.2 U/L; P=0.482). The LAA was successfully occluded in all patients, and the TEE group showed similar results to the fluoroscopic group in terms of success rate (100% vs. 100%; P>0.99) and hospitalization duration [5.0 (IQ1-IQ3: 3.0-7.0) vs. 5.0 (IQ1-IQ3: 3.0-6.0) days; P=0.498]. The groups also demonstrated comparable complication rates, with 1 (4.2%) case of pericardial effusion and 1 (4.2%) case of residual shunt in the TEE group, and 5 (20%) cases of residual shunt, 1 (4.2%) case of pericardial effusion, 1 (4.2%) case of myocardial infarction, and 1 (4.2%) case of access-related complications in the fluoroscopic group. There were no deaths. The overall incidence rate of procedure-related complications (6.2% vs. 18.1%, P=0.153) at mean 22.2±4.5 months follow-up between the 2 groups was similar. Conclusions: In patients with AF of high risk for use of contrast agents, LAAC under non-fluoroscopic guidance appears feasible and safe with similar outcomes to that under fluoroscopic guidance.

Development of an Expert-Level Right Ventricular Abnormality Detection Algorithm Based on Deep Learning.

PURPOSE: Studies relating to the right ventricle (RV) are inadequate, and specific diagnostic algorithms still need to be improved. This essay is designed to make exploration and verification on an algorithm of deep learning based on imaging and clinical data to detect RV abnormalities. METHODS: The Automated Cardiac Diagnosis Challenge dataset includes 20 subjects with RV abnormalities (an RV cavity volume which is higher than 110 mL/m2 or RV ejection fraction which is lower than 40%) and 20 normal subjects who suffered from both cardiac MRI. The subjects were separated into training and validation sets in a ratio of 7:3 and were modeled by utilizing a nerve net of deep-learning and six machine-learning algorithms. Eight MRI specialists from multiple centers independently determined whether each subject in the validation group had RV abnormalities. Model performance was evaluated based on the AUC, accuracy, recall, sensitivity and specificity. Furthermore, a preliminary assessment of patient disease risk was performed based on clinical information using a nomogram. RESULTS: The deep-learning neural network outperformed the other six machine-learning algorithms, with an AUC value of 1 (95% confidence interval: 1-1) on both training group and validation group. This algorithm surpassed most human experts (87.5%). In addition, the nomogram model could evaluate a population with a disease risk of 0.2-0.8. CONCLUSIONS: A deep-learning algorithm could effectively identify patients with RV abnormalities. This AI algorithm developed specifically for right ventricular abnormalities will improve the detection of right ventricular abnormalities at all levels of care units and facilitate the timely diagnosis and treatment of related diseases. In addition, this study is the first to validate the algorithm's ability to classify RV abnormalities by comparing it with human experts.

Automated deep neural network-based identification, localization, and tracking of cardiac structures for ultrasound-guided interventional surgery.

Background: The increase in the use of ultrasound-guided interventional therapy for cardiovascular diseases has increased the importance of intraoperative real-time cardiac ultrasound image interpretation. We thus aimed to develop a deep learning-based model to accurately identify, localize, and track the critical cardiac structures and lesions (9 kinds in total) and to validate the algorithm's performance using independent data sets. Methods: This diagnostic study developed a deep learning-based model using data collected from Fuwai Hospital between January 2018 and June 2019. The model was validated with independent French and American data sets. In total, 17,114 cardiac structures and lesions were used to develop the algorithm. The model findings were compared with those of 15 specialized physicians in multiple centers. For external validation, 516,805 tags and 27,938 tags were used from 2 different data sets. Results: Regarding structure identification, the area under the receiver operating characteristic curve (AUC) of each structure in the training data set, optimal performance in the test data set, and median AUC of each structure identification were 1 (95% CI: 1-1), 1 (95% CI: 1-1), and 1 (95% CI: 1-1), respectively. Regarding structure localization, the optimal average accuracy was 0.83. As for structure identification, the accuracy of the model significantly outperformed the median performance of the experts (P<0.01). The optimal identification accuracies of the model in 2 independent external data sets were 89.5% and 90%, respectively (P=0.626). Conclusions: The model outperformed most human experts and was comparable to the optimal performance of all human experts in cardiac structure identification and localization, and could be used in the external data sets.

Physiological and biochemical regulation of tobacco by oxathiapiprolin under Phytophthora nicotianae infection.

As a fungicide, oxathiapiprolin has excellent effects on diseases caused by oomycetes. Fungicides generally protect crops by inhibiting pathogens, but little research has addressed the effects of fungicides on crops. This study combined transcriptomic and metabolomic analyses to systematically analyze the physiological regulatory mechanisms of oxathiapiprolin on tobacco under Phytophthora nicotianae infection. The results showed that under P. nicotianae infection, tobacco's photosynthetic rate and antioxidant enzyme activity increased after the application of oxathiapiprolin. Omics results showed that the genes related to carbon metabolism, disease-resistant proteins, and amino acid synthesis were highly expressed, and the amino acid content increased in tobacco leaves. This study is the first comprehensive investigation of the physiological regulatory effects of oxathiapiprolin on tobacco in response to P. nicotianae infection. These findings provide a basis for the balance between regulating tobacco growth and development and enhancing disease resistance under the stimulation of oxathiapiprolin and provide new research and development opportunities for identifying new disease-resistance genes and the development of high-yielding disease-resistant crop varieties.

Feasibility of a Percutaneous and Non-Fluoroscopic Procedure for Transcatheter Mitral Valve Edge-to-Edge Repair.

Background: Transcatheter edge-to-edge repair (TEER) of the mitral valve has emerged as an alternative treatment for mitral regurgitation (MR). However, the high radiation exposure during the process has been associated with multiple adverse effects for medical staff. In this study, we assessed the feasibility and safety of TEER performed solely under the echocardiographic (echo) guidance. Methods: Between April 2021 to August 2021, we retrospectively collected characteristics of 23 patients with MR who underwent TEER under echocardiographic guidance exclusively. Follow-up evaluations were performed at 1- , 3-months and 1-year post procedure. Results: All 23 patients (mean age, 66.1 ± 12.1 years; 65.2% males) successfully underwent echo-guided TEER, with 22 patients under transesophageal echo (TEE) guidance and 1 patient under transthoracic echo (TTE) guidance for severe esophageal stenosis. Of the patients, 60.9% received 1 implant and 39.1% received 2 implants. The median total procedural time was 130 (interquartile range, IQR: 90-150) min and the device procedure time was 73 (IQR: 58-100) min. The median length of stay was 6 (IQR: 5-9) days. At 3-months follow-up, 63.6% of patients had an MR ≤ 1+ and 90.9% had an MR ≤ 2+ (p < 0.001 vs. baseline). Improvement in functional status was observed, with 40.9% of patients classified as New York Heart Association (NYHA) functional class I and 45.5% as NYHA functional class II (p < 0.001 compared to baseline) at 3-months. At 1-year follow-up, 90.4% maintained MR reduction with MR ≤ 2+ (p < 0.001 vs. baseline). Single leaflet device attachment (SLDA) occurred in one patient (4.3%) 1-week post procedure. Conclusions: This retrospective, single-center, and pilot study demonstrates the feasibility, safety, and low complication rates of TEER guided solely by echocardiography. Our findings support the systematic use of echocardiography as the sole guidance modality for TEER, highlighting its potential as an alternative to fluoroscopy-guided procedures. Further multicenter and comparative studies are warranted to confirm these results and provide a more comprehensive evaluation of this approach.

Bioinformatic analysis of potential biomarkers and mechanisms of immune infiltration in mitral regurgitation complicated by atrial fibrillation.

Background: Mitral regurgitation (MR) is one of the most prevalent valvular diseases. Degenerated MR-induced volume overload leads to left atrial enlargement and eventually, atrial fibrillation (AF). AF has a negative effect on patient prognosis despite recent advances in minimal invasive transcatheter devices for valve surgery. However, more effective strategies aimed at precisely treating from pathophysiology and genetic perspective are scarce. Methods: The gene expression datasets, GSE109744 and GSE79768, were obtained from the Gene Expression Omnibus database and analyzed to identify the differentially expressed genes (DEGs) in patients with mitral value prolapse (MVP) and AF. Subsequently, we predicted the extensive miRNA targets, and the protein-protein interaction (PPI) and miRNA-target gene regulatory networks were established. Functional enrichment analyses were performed for the DEGs. In addition, the co-expressed DEGs coupled with their predicted miRNAs and disease phenotypes involved in MVP and AF were assessed. Finally, the immune infiltration in both datasets was examined. Results: A total of 491 and 180 DEGs were identified in the mitral valve and left atrial specimens, respectively. From these, 11 integrated co-expressed DEGs were identified, namely, PRG4, GPR34, RELN, CA3, IL1B, EPHA3, CHGB, TCEAL2, B3GALT2, ASB11, and CRISPLD1. The enriched Gene Ontology terms and KEGG pathways associated with the DEGs were determined, and the top 10 hub genes and top 3 gene clusters were selected from the PPI network. A prediction of target miRNAs was performed based on the co-expressed DEGs. The enrichment of the co-expressed DEGs suggested that immune and inflammatory responses might be involved in the disease development through multiple immune related pathways, including the interaction of cytokines and chemokines. Notably, this result was consistent with the immune infiltration analysis since the proportions of naïve B cells and memory B cells were significantly different in MVP and AF tissues compared to normal tissues. Conclusions: MR and AF are related, and 11 co-expressed DEGs were found to be significantly associated with MVP with AF, and indeed, these may represent novel biomarkers. Several immune cells were found to contribute to the process of MVP and AF via diverse mechanisms, in particular, antigen-presenting cells.

Safety of chronic high-dose calcium channel blockers exposure in children with pulmonary arterial hypertension.

Background: Chronic calcium channel blockers (CCBs) are indicated in children with idiopathic/heritable pulmonary arterial hypertension (IPAH/HPAH) and positive response to acute vasodilator challenge. However, minimal safety data are available on the long-term high-dose exposure to CCBs in this population. Methods: Patients aged 3 months to 18 years who were diagnosed with IPAH/HPAH and treated with CCB in the past 15 years were retrospectively reviewed. The maximum tolerated dose and the long-term safety of high-dose CCBs on the cardiovascular and noncardiovascular systems were assessed. Results: Thirty-two eligible children were enrolled in the study, with a median age of 9 (6-11) years old. Thirty-one patients were treated with diltiazem after diagnosis. The median maximum tolerated dose was 12.9 (9.8-16.8) mg/kg/day. Children younger than 7 years used higher doses than children in the older age group, 16.4 (10.5-28.5) mg/kg/day vs. 12.7 (6.6-14.4) mg/kg/day, P < 0.05. Patients were followed up for a median period of 6.2 (2.6-10.8) years. One patient died from a traffic accident, and others showed a stable or improved WHO functional class status. Thirteen (40.6%) and 10 (31.3%) patients developed arrhythmias and hypotension. Nine (28.1%) patients had sinus bradycardia, five (21.9%) had first-degree or second-degree type II atrial-ventricular blocks, and two (6.3%) had second-degree type II atrial-ventricular blocks. Most of these arrhythmias were transient and relieved after CCB dose adjustment. The most reported noncardiovascular adverse effect was gingival hyperplasia (13, 40.6%), accompanied by different degrees of dental dysplasia. No liver or kidney dysfunction was reported. Conclusion: Diltiazem was used in a very high dose for eligible children with IPAH/HPAH. The toxicity of long-term CCB use on the cardiovascular system is mild and controllable. Clinicians should also monitor the noncardiovascular adverse effects associated with drug therapy.

Oxidative stress and detoxification mechanisms of earthworms (Eisenia fetida) after exposure to flupyradifurone in a soil-earthworm system.

Flupyradifurone (FLU) has great application potential in agricultural production as a new generation of neonicotinoid insecticide after imidacloprid. Nevertheless, the toxic effects of FLU on non-target soil organisms remain unclear, resulting in considerable environmental risks. We evaluated the acute and subchronic toxicities of FLU to earthworms. The results of acute toxicity show that the median lethal concentration (LC50) values (14 d) of FLU were 186.9773 mg kg-1 for adult earthworms and 157.6502 mg kg-1 for juveniles, respectively. The subchronic toxicity of FLU that focused on the activities of antioxidant and detoxication enzymes showed the superoxide dismutase (SOD), catalase (CAT), and glutathione-S transferase (GST) activities in earthworms increased while the peroxidase (POD) and acetylcholinesterase (AChE) activities decreased after exposure to FLU. Oxidative damage analyses revealed that the reactive oxygen species (ROS) level and malonaldehyde (MDA) content in earthworms were increased by FLU, resulting in DNA damage. Transcriptomics and RT-qPCR confirmed that FLU influenced the expression of genes related to antioxidant response and detoxification of earthworms. Ultimately detoxification metabolism, environmental information processing, cell processes, and immune system pathways are significantly enriched to respond jointly to FLU. Our study fills the gaps in the toxicity of FLU to earthworms, providing a basis for its risk assessment of soil ecosystems and non-target biological toxicity.

Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins.

Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8+ cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately fivefold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels were reduced even in the absence of ORF7a, suggesting additional mechanisms of MHC-I down-regulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I down-regulation and, unlike SARS-CoV-2, the ORF7a protein from SARS-CoV lacked MHC-I downregulating activity. A single amino acid at position 59 (T/F) that is variable among sarbecovirus ORF7a proteins governed the difference in MHC-I downregulating activity. SARS-CoV-2 ORF7a physically associated with the MHC-I heavy chain and inhibited the presentation of expressed antigen to CD8+ T cells. Specifically, ORF7a prevented the assembly of the MHC-I peptide loading complex and caused retention of MHC-I in the endoplasmic reticulum. The differential ability of ORF7a proteins to function in this way might affect sarbecovirus dissemination and persistence in human populations, particularly those with infection- or vaccine-elicited immunity.

Antibody and Memory B-Cell Immunity in a Heterogeneously SARS-CoV-2-Infected and -Vaccinated Population.

Global population immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is accumulating through heterogeneous combinations of infection and vaccination. Vaccine distribution in low- and middle-income countries has been variable and reliant on diverse vaccine platforms. We studied B-cell immunity in Mexico, a middle-income country where five different vaccines have been deployed to populations with high SARS-CoV-2 incidences. Levels of antibodies that bound a stabilized prefusion spike trimer, neutralizing antibody titers, and memory B-cell expansion correlated with each other across vaccine platforms. Nevertheless, the vaccines elicited variable levels of B-cell immunity, and the majority of recipients had undetectable neutralizing activity against the recently emergent omicron variant. SARS-CoV-2 infection, experienced before or after vaccination, potentiated B-cell immune responses and enabled the generation of neutralizing activity against omicron and SARS-CoV for all vaccines in nearly all individuals. These findings suggest that broad population immunity to SARS-CoV-2 will eventually be achieved but by heterogeneous paths. IMPORTANCE The majority of studies on SARS-CoV-2 vaccine-elicited immunity and immune evasion have focused on single vaccines corresponding to those distributed in high-income countries. However, in low- and middle-income countries, vaccine deployment has been far less uniform. It is therefore important to determine the levels of immunity elicited by vaccines that have been deployed globally. Such data should help inform policy. Thus, this paper is very much a "real-world" study that focuses on a middle-income country, Mexico, in which five different vaccines based on mRNA, adenovirus, and inactivated-virus platforms have been extensively deployed, while (as documented in our study) SARS-CoV-2 variants with increasing degrees of immune evasiveness have propagated in the Mexican population, culminating in the recent emergence of B.1.1.529 (omicron).

Effects of blood oxygen saturation on pulmonary artery remodeling in an in vitro perfusion circuit model.

BACKGROUND: Patients with transposition of the great arteries are likely to survive surgery despite severe pulmonary artery hypertension. However, the underlying mechanisms remain largely unknown. The present study aimed to test the hypothesis that high blood oxygen saturation may protect the pulmonary artery from remodeling. METHODS: An in vitro pulmonary artery perfusion model was successfully performed by connecting rabbit pulmonary artery to a closed perfusion circuit. Twenty-five rabbits were divided randomly into 5 groups according to exposure conditions: Normal Control (NC) group (unperfused normal pulmonary artery), High Saturation (HS) group (oxygen saturation range: 90-100%), Medium Saturation (MS) group (oxygen saturation: 65-75%); Low Saturation (LS) group (oxygen saturation: 40-50%), and anti-hypoxia inducible factor-1α (anti-HIF-1α) group (oxygen saturation range: 40-50%, and LW6, which is a novel HIF-1α inhibitor; was added). By staining and optical microscopy examination, pathological morphology was analyzed, and the protein expression levels of HIF-1α, angiotensin-II (Ang-II), endothelin-1 (ET-1), Rho-associated protein kinase-1 (Rock-1), and matrix metallopeptidase-2 (MMP-2) were determined by Western blotting. RESULTS: The amounts of elastin, muscle, and collagen and the protein levels of ET-1, HIF-1α, Rock-1, and MMP-2, increased significantly with decreased oxygen saturation in the perfusion circuit. A significant improvement in pathological morphology was observed in the anti-HIF1α group. The expression of HIF-1α, ET-1, Ang-II, Rock-1, and MMP-2 in the anti-HIF1α group was also significantly lower than that in the LS group. CONCLUSIONS: In the closed perfusion model, high blood oxygen saturation alleviated pulmonary vascular structural remodeling. Similar beneficial effects were observed when inhibiting the HIF-1α protein, suggesting a key role for HIF-1α in pulmonary artery remodeling.

Transcatheter Closure of Patent Ductus Arteriosus under Echocardiography Guidance: A Randomized Controlled Noninferiority Trial.

BACKGROUND: Percutaneous occlusion under fluoroscopy guidance has become the preferred method for the treatment of patent ductus arteriosus (PDA). To avoid radiation exposure and contrast agent use, PDA occlusion under transthoracic echocardiography (TTE) guidance was conducted. OBJECTIVES: We assessed the hypothesis that the success rate of percutaneous PDA occlusion under TTE was noninferior to that under fluoroscopy guidance. METHODS: In this single-center trial, 100 patients were randomly assigned in a 1 : 1 ratio to the TTE group (n = 50) or to the fluoroscopy group (n = 50). The primary endpoint was the success rate of occlusion, with the noninferiority margin set at 8% for the between-group difference in intention-to-treat analysis. Secondary endpoints were hospitalization duration, cost, procedure time, and rate of adverse events including occluder migration, hemolysis, peripheral vascular complications, and residual shunt at 1-month and 12-month follow-up. RESULTS: Patient, defect, and device characteristics were similarly distributed between groups. The success rate of occlusion was 98% for the TTE group and 100% for the fluoroscopy group (absolute difference: -2%; 95% confidence interval: -5.9% to 1.9%). Cost and procedure duration were significantly lower in the TTE group, without adverse events in either group at a median of 12.0 months (range, 10.0-15.5 months) of follow-up. CONCLUSION: Percutaneous PDA occlusion can be performed via TTE guidance safely and effectively, and the success rate of the TTE-guided procedure was noninferior to that under fluoroscopy guidance, with reduced cost and procedure time. The trial is registered with http://www.chictr.org.cn (ChiCTR-ICR-15006334).

HIV-1 Vpr induces cell cycle arrest and enhances viral gene expression by depleting CCDC137.

The HIV-1 Vpr accessory protein induces ubiquitin/proteasome-dependent degradation of many cellular proteins by recruiting them to a cullin4A-DDB1-DCAF1 complex. In so doing, Vpr enhances HIV-1 gene expression and induces (G2/M) cell cycle arrest. However, the identities of Vpr target proteins through which these biological effects are exerted are unknown. We show that a chromosome periphery protein, CCDC137/cPERP-B, is targeted for depletion by HIV-1 Vpr, in a cullin4A-DDB1-DCAF1 dependent manner. CCDC137 depletion caused G2/M cellcycle arrest, while Vpr-resistant CCDC137 mutants conferred resistance to Vpr-induced G2/M arrest. CCDC137 depletion also recapitulated the ability of Vpr to enhance HIV-1 gene expression, particularly in macrophages. Our findings indicate that Vpr promotes cell-cycle arrest and HIV-1 gene expression through depletion of CCDC137.

Like all viruses, the human immunodeficiency virus 1 (HIV-1) cannot replicate on its own; to multiply, it needs to exploit the molecular machinery of a cell. A set of HIV-1 proteins is vital in this hijacking process, and they are required for the virus to make more of itself. However, HIV-1 also carries accessory proteins that are not absolutely necessary for the replication process, but which boost the growth of the virus by deactivating the defences of the infected cells. Amongst these proteins, the role of Viral Protein R (Vpr for short) has been particularly enigmatic. Previous experiments have shown that, in infected cells, Vpr is linked to several biological processes: it tags for destruction a large number of proteins, it causes the cells to stop dividing, and it encourages them to express the genetic information of the virus. How these different processes are connected and triggered by Vpr is still unknown. It particular, it remains unclear which protein is responsible for these changes when it is destroyed by Vpr. To investigate, Zhang and Bieniasz conducted a series of experiments to spot the proteins that interact with Vpr in human cells. This screening process highlighted a protein known as CCDC137, which is depleted in cells infected by HIV-1. To investigate the role of CCDC137, Zhang and Bieniasz decreased the levels of the protein in human cells. This stopped the cells from dividing, just like during HIV-1 infection. Destroying CCDC137 also mimicked the effects of Vpr on HIV-1 gene expression, increasing the levels of virus proteins in infected cells. Finally, Zhang and Bieniasz made a mutant version of CCDC137 that Vpr could not destroy. When infected cells carried this mutant protein, they kept on dividing as normal. Taken together, these results suggest that Vpr works by triggering the destruction of the CCDC137 protein. Overall, this work represents the first step to understand the role of CCDC137 in both infected and healthy cells.

Personalized Three-Dimensional Printing and Echoguided Procedure Facilitate Single Device Closure for Multiple Atrial Septal Defects.

BACKGROUND: To evaluate the feasibility of using a single device to close multiple atrial septal defects (ASDs) under the guidance of transthoracic echocardiography (TTE) and with the aid of three-dimensional (3D) printing models. METHODS: Sixty-two patients with multiple ASDs were retrospectively analyzed. Thirty of these patients underwent TTE-guided closure (3D printing and TTE group) after a simulation of occlusion in 3D printing models. The remaining 32 patients underwent ASD closure under fluoroscopic guidance (conventional group). Closure status was assessed immediately and at 6 months after device closure. RESULTS: Successful transcatheter closure with a single device was achieved in 26 patients in the 3D printing and TTE group and 27 patients in the conventional group. Gender, age [18.8 ± 15.9 (3-51) years in the 3D printing and TTE group; 14.0 ± 11.6 (3-50) years in the conventional group], mean maximum distance between defects, prevalence of 3 atrial defects and large defect distance (defined as distance ≥7 mm), and occluder size used were similarly distributed between groups. However, the 3D printing and TTE group had lower frequency of occluder replacement (3.8% vs 59.3%, p < 0.0001), prevalence of mild residual shunts (defined as <5 mm) immediately (19.2% vs 44.4%, p < 0.05) and at 6 months (7.7% vs 29.6%, p < 0.05) after the procedure, and cost (32960.8 ± 2018.7 CNY vs 41019.9 ± 13758.2 CNY, p < 0.01). CONCLUSION: The combination of the 3D printing technology and ultrasound-guided interventional procedure provides a reliable new therapeutic approach for multiple ASDs, especially for challenging cases with large defect distance.

A novel double-balloon catheter for percutaneous balloon pulmonary valvuloplasty under echocardiographic guidance only.

BACKGROUND: Percutaneous balloon pulmonary valvuloplasty (PBPV) is the procedure of choice for uncomplicated severe or symptomatic pulmonary stenosis. Echocardiography (echo)-guided PBPV can completely avoid the use of radiation and contrast agents compared to fluoroscopy-guided PBPV. Although we have confirmed that echo-guided PBPV is feasible in humans, the poor visibility of the traditional catheter under echo greatly limits the promotion of this new technology. METHODS: We produced a novel double-balloon catheter to make the catheter easy to be detected by echo through adding a guiding balloon at the distal end of the catheter. Echo-guided PBPV was performed on thirty healthy swine using either a novel catheter or a traditional catheter to evaluate the feasibility and safety of the novel double-balloon catheter. The feasibility was evaluated by the success rate of balloon inflation at the pulmonary valve annulus and the operating time. The safety was evaluated by the frequency of balloon slippage and the incidence of complications. RESULTS: There were no significant between-group differences in terms of weight and the ratio of balloon diameter to pulmonary annulus diameter. The success rate was 93.3% and 60% in the novel and traditional groups, respectively. The novel group had significantly (p<0.05) lower mean procedure time (6.33±6.86min vs 24.8±9.79min) and lower frequency of balloon slippage (0.07±0.26 vs 0.53±0.52), arrhythmia (0.07±0.26 vs 0.47±0.52), and tricuspid regurgitation (6.7% vs 40%) than the traditional group. No myocardial hematoma or pericardial tamponade occurred in the novel catheter group. CONCLUSION: Although further studies and improvements are required, the study results indicate that the novel double-balloon catheter for echo-guided PBPV is feasible and safe.

Multicenter Comparison of Percutaneous and Surgical Pulmonary Valve Replacement in Large RVOT.

BACKGROUND: A percutaneous approach for pulmonary valve replacement (PVR) is a feasible alternative to surgical PVR in selected patients with severe pulmonary regurgitation after repair of tetralogy of Fallot. However, large right ventricular outflow tract (diameter ≥ 25 mm) remains challenging. METHODS: This retrospective multicenter study enrolled consecutive patients with large right ventricular outflow tract who underwent percutaneous PVR (Venus P-valve, Venus MedTech Inc, Hangzhou, China) (n = 35) or surgical PVR (homograft valve; n = 30) between May 2014 and April 2017. Patients were followed up at 1, 3, 6, and 12 months, and yearly thereafter. Main study outcomes were pulmonary valve function and right ventricular function at discharge and midterm follow-up. RESULTS: PVR was successful in all patients. Percutaneous compared with surgical PVR group had: similarly distributed baseline characteristics; shorter hospitalization, intensive care unit stay, and endotracheal intubation duration; lower cost; lower pulmonary valve gradient before discharge; lower pulmonary valve regurgitant grade (mean difference, -0.63; 95% CI -1.11 to -0.20, P = .022), pulmonary valve gradient (mean difference, -5.7 mm Hg; 95% CI -9.4 to -2.2 mm Hg, P = .005), and right ventricular end-diastolic volume index (mean difference, -9.5 mL/m2; 95% CI -16.9 to -3.1 mL/m2, P = .022); and greater right ventricular ejection fraction (mean difference, 5.4%; 95% CI 2.4%-8.3%, P = .002) at median 36 months follow-up, without deaths in either group. CONCLUSIONS: Percutaneous PVR using Venus P-valve appeared to be a safe, efficacious and minimally invasive alternative to surgical PVR in selected patients with large right ventricular outflow tract yielding better right ventricular and pulmonary valve function at midterm follow-up.

Hybrid Balloon Valvuloplasty for the Treatment of Severe Congenital Aortic Valve Stenosis in Infants.

BACKGROUND: Surgical or percutaneous interventional treatment of severe congenital aortic valve stenosis (CAS) in early infancy remains challenging. This single-center, retrospective study analyzed midterm outcomes of a hybrid balloon valvuloplasty procedure through the ascending aorta by way of median sternotomy, including cases with improved technique. METHODS: Included were 45 consecutive infants (aged <90 days) with CAS and selected for biventricular repair who underwent hybrid balloon valvuloplasty in a hybrid or ordinary operating room from October 2010 to March 2016. Patients were assessed at 1, 3, 6, and 12 months and yearly thereafter. RESULTS: Hybrid balloon valvuloplasty was successful in all patients, with the last 8 treated in an ordinary operating room under only echocardiography guidance with a new sheath. Thirty-two patients were successfully rescued from low heart rate or left ventricular systolic dysfunction, or both, by cardiac massage under direct visualization; none required cardiopulmonary bypass. The degree of new aortic insufficiency was mild in 7 patients and changed from mild to moderate in 1 patient. Aortic valve pressure gradient decreased from 70.6 ± 17.5 mm Hg preoperatively to 15.2 ± 4.2 mm Hg immediately postoperatively (p < 0.001). Fluoroscopy time was 4.8 ± 2.3 minutes. At a median of 32.1 months (range, 1 to 68 months) follow-up, all patients were alive and healthy. Aortic valve pressure gradient remained low (19.1 ± 5.2 mm Hg). Left ventricular ejection fraction increased from 0.515 ± 0.134 (range, 0.21 to 0.70) preoperatively to 0.633 ± 0.035 (range, 0.58 to 0.75; p < 0.001). No aortic insufficiency developed, and no patient required reintervention. CONCLUSIONS: For infants with severe CAS, hybrid balloon valvuloplasty through the ascending aorta by way of a median sternotomy appears efficacious and safe up to midterm follow-up.

Perventricular device closure of perimembranous ventricular septal defect: effectiveness of symmetric and asymmetric occluders.

Objectives: To assess safety and effectiveness of symmetric and asymmetric occluders in perventricular device closure without cardiopulmonary bypass of perimembranous ventricular septal defects (pmVSDs). Methods: The present retrospective study enrolled 581 patients who underwent perventricular device closure of pmVSDs under transoesophageal echocardiography guidance from May 2011 to April 2016, and outpatient electrocardiography and transthoracic echocardiography assessments at 1, 3, 6 and 12 months, and yearly thereafter. Results: The overall success rate of device implantation was 92.6% (43 surgical conversions immediately). Between patients receiving symmetric ( n = 353) and asymmetric ( n = 185) occluders, there were no significant differences in age, weight and defect diameter distributions; however, both before discharge and at mean 28.6 ± 21.2 (range, 1-60)-month follow-up, the symmetric group had lower rates of trivial residual shunt (5.7% vs 11.4%, P = 0.018; and 0.8% vs 5.9%, P = 0.001) and bundle branch block (0.8% vs 5.4%, P = 0.002; and 0.6% vs 3.8%, P = 0.009); and at follow-up, the asymmetric group had lower residual shunt (47.6% vs 85.0%, P = 0.020) and similar branch block (30.0% vs 33.3%, P = 1.000) disappearance rates. There were no severe complications, i.e. aortic regurgitation, malignant arrhythmias, haemolysis or device dislocation. Conclusions: Perventricular device closure of pmVSDs appears safe and effective with symmetric and asymmetric occluders. However, the lower residual shunt disappearance and higher branch block incidence rates for asymmetric occluders would favour more proactive conversion to surgical repair immediately when residual shunt is present intraoperatively.