Asiatic acid inhibits angiogenesis and vascular permeability through the VEGF/VEGFR2 signaling pathway to inhibit the growth and metastasis of breast cancer in mice.

Anti-angiogenic medicines have been evaluated as anticancer therapies, however, their use remains limited in clinical practice due to associated adverse effects. Asiatic acid (AA) is known to have broad-spectrum anticancer properties, however, its effects on angiogenesis in breast cancer remain to be fully established. In this study, we analyzed the inhibitory effects of AA on angiogenesis using human umbilical vein endothelial cells (HUVECs) cultured in vitro and on the growth and metastasis of a subcutaneous breast cancer 4T1 tumor model and a lung metastasis model in vivo. AA significantly inhibited HUVECs proliferation, migration, and tube formation in vitro. In vivo, AA significantly reduced the microvascular density and blood vascular permeability in breast cancer tumors and inhibited growth and lung metastasis. AA inhibited the expression of vascular endothelial growth factor (VEGF) in HUVECs and subsequently downregulated the phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream target proteins including ERK1/2, Src, and FAK. These results indicate that AA significantly inhibits angiogenesis and blood vessel permeability through the VEGF/VEGFR2 signal axis to inhibit the growth and metastasis of breast cancer. Our data strongly demonstrate the potential applications of AA in the treatment of breast cancer.

Recurrent ventricular tachycardia as initial presentation of pheochromocytoma: A case report and literature review.

Pheochromocytoma is a neuroendocrine tumor of the adrenal gland that secretes excess amount of catecholamine, which in turn leads to extremely varied clinical manifestations, such as hypertension, headache, sweating and palpitations. This eventually leads to delay or mistakes in diagnosing the disease. This could be fatal due to misdiagnosis as it receives a totally different treatment. We herein reported a case of pheochromocytoma with recurrent ventricular tachycardia. A literature review was conducted to investigate the clinical features of these patients.

Experimental Realization of Nonadiabatic Shortcut to Non-Abelian Geometric Gates.

When a quantum system is driven slowly through a parametric cycle in a degenerate Hilbert space, the state would acquire a non-Abelian geometric phase, which is stable and forms the foundation for holonomic quantum computation (HQC). However, in the adiabatic limit, the environmental decoherence becomes a significant source of errors. Recently, various nonadiabatic holonomic quantum computation (NHQC) schemes have been proposed, but all at the price of increased sensitivity to control errors. Alternatively, there exist theoretical proposals for speeding up HQC by the technique of "shortcut to adiabaticity" (STA), but no experimental demonstration has been reported so far, as these proposals involve a complicated control of four energy levels simultaneously. Here, we propose and experimentally demonstrate that HQC via shortcut to adiabaticity can be constructed with only three energy levels, using a superconducting qubit in a scalable architecture. With this scheme, all holonomic single-qubit operations can be realized nonadiabatically through a single cycle of state evolution. As a result, we are able to experimentally benchmark the stability of STA+HQC against NHQC in the same platform. The flexibility and simplicity of our scheme makes it also implementable on other systems, such as nitrogen-vacancy center, quantum dots, and nuclear magnetic resonance. Finally, our scheme can be extended to construct two-qubit holonomic entangling gates, leading to a universal set of STAHQC gates.

Two Coxsackievirus B3 outbreaks associated with hand, foot, and mouth disease in China and the evolutionary history worldwide.

BACKGROUND: Coxsackievirus B3 (CV-B3) is usually associated with aseptic meningitis and myocarditis; however, the association between CV-B3 and hand, foot, and mouth disease (HFMD) has not been clearly demonstrated, and the phylogenetic dynamics and transmission history of CV-B3 have not been well summarized. METHOD: Two HFMD outbreaks caused by CV-B3 were described in Hebei Province in 2012 and in Shandong Province in 2016 in China. To analyze the epidemiological features of two CV-B3 outbreaks, a retrospective analysis was conducted. All clinical specimens from CV-B3 outbreaks were collected and disposed according to the standard procedures supported by the WHO Global Poliovirus Specialized Laboratory. EV genotyping and phylogenetic analysis were performed to illustrate the genetic characteristics of CV-B3 in China and worldwide. RESULTS: Two transmissible lineages (lineage 2 and 3) were observed in Northern China, which acted as an important "reservoir" for the transmission of CV-B3. Sporadic exporting and importing of cases were observed in almost all regions. In addition, the global sequences of CV-B3 showed a tendency of geographic-specific clustering, indicating that geographic-driven adaptation plays a major role in the diversification and evolution of CV-B3. CONCLUSIONS: Overall, our study indicated that CV-B3 is a causative agent of HFMD outbreak and revealed the phylogenetic dynamics of CV-B3 worldwide, as well as provided an insight on CV-B3 outbreaks for effective intervention and countermeasures.

Dephasing-Insensitive Quantum Information Storage and Processing with Superconducting Qubits.

A central task towards building a practical quantum computer is to protect individual qubits from decoherence while retaining the ability to perform high-fidelity entangling gates involving arbitrary two qubits. Here we propose and demonstrate a dephasing-insensitive procedure for storing and processing quantum information in an all-to-all connected superconducting circuit involving multiple frequency-tunable qubits, each of which can be controllably coupled to any other through a central bus resonator. Although it is generally believed that the extra frequency tunability enhances the control freedom but induces more dephasing impact for superconducting qubits, our results show that any individual qubit can be dynamically decoupled from dephasing noise by applying a weak continuous and resonant driving field whose phase is reversed in the middle of the pulse. More importantly, we demonstrate a new method for realizing a two-qubit phase gate with inherent dynamical decoupling via the combination of continuous driving and qubit-qubit swapping coupling. We find that the weak continuous driving fields not only enable the conditional dynamics essential for quantum information processing, but also protect both qubits from dephasing during the gate operation.

Demonstration of Topological Robustness of Anyonic Braiding Statistics with a Superconducting Quantum Circuit.

Anyons are quasiparticles occurring in two dimensions, whose topological properties are believed to be robust against local perturbations and may hold promise for fault tolerant quantum computing. Here we present an experiment of demonstrating the path independent nature of anyonic braiding statistics with a superconducting quantum circuit, which represents a 7-qubit version of the toric code model. We dynamically create the ground state of the model, achieving a state fidelity of 0.688±0.015 as verified by quantum state tomography. Anyonic excitations and braiding operations are subsequently implemented with single-qubit rotations. The braiding robustness is witnessed by looping an anyonic excitation around another one along two distinct, but topologically equivalent paths: Both reveal the nontrivial π-phase shift, the hallmark of Abelian 1/2 anyons, with a phase accuracy of ∼99% in the Ramsey-type interference measurement.

Emulating Many-Body Localization with a Superconducting Quantum Processor.

The law of statistical physics dictates that generic closed quantum many-body systems initialized in nonequilibrium will thermalize under their own dynamics. However, the emergence of many-body localization (MBL) owing to the interplay between interaction and disorder, which is in stark contrast to Anderson localization, which only addresses noninteracting particles in the presence of disorder, greatly challenges this concept, because it prevents the systems from evolving to the ergodic thermalized state. One critical evidence of MBL is the long-time logarithmic growth of entanglement entropy, and a direct observation of it is still elusive due to the experimental challenges in multiqubit single-shot measurement and quantum state tomography. Here we present an experiment fully emulating the MBL dynamics with a 10-qubit superconducting quantum processor, which represents a spin-1/2 XY model featuring programmable disorder and long-range spin-spin interactions. We provide essential signatures of MBL, such as the imbalance due to the initial nonequilibrium, the violation of eigenstate thermalization hypothesis, and, more importantly, the direct evidence of the long-time logarithmic growth of entanglement entropy. Our results lay solid foundations for precisely simulating the intriguing physics of quantum many-body systems on the platform of large-scale multiqubit superconducting quantum processors.

Solving Systems of Linear Equations with a Superconducting Quantum Processor.

Superconducting quantum circuits are a promising candidate for building scalable quantum computers. Here, we use a four-qubit superconducting quantum processor to solve a two-dimensional system of linear equations based on a quantum algorithm proposed by Harrow, Hassidim, and Lloyd [Phys. Rev. Lett. 103, 150502 (2009)PRLTAO0031-900710.1103/PhysRevLett.103.150502], which promises an exponential speedup over classical algorithms under certain circumstances. We benchmark the solver with quantum inputs and outputs, and characterize it by nontrace-preserving quantum process tomography, which yields a process fidelity of 0.837±0.006. Our results highlight the potential of superconducting quantum circuits for applications in solving large-scale linear systems, a ubiquitous task in science and engineering.

10-Qubit Entanglement and Parallel Logic Operations with a Superconducting Circuit.

Here we report on the production and tomography of genuinely entangled Greenberger-Horne-Zeilinger states with up to ten qubits connecting to a bus resonator in a superconducting circuit, where the resonator-mediated qubit-qubit interactions are used to controllably entangle multiple qubits and to operate on different pairs of qubits in parallel. The resulting 10-qubit density matrix is probed by quantum state tomography, with a fidelity of 0.668±0.025. Our results demonstrate the largest entanglement created so far in solid-state architectures and pave the way to large-scale quantum computation.

Receptor for advanced glycation end product blockade enhances the chemotherapeutic effect of cisplatin in tongue squamous cell carcinoma by reducing autophagy and modulating the Wnt pathway.

Tongue squamous cell carcinoma (TSCC) is one of the most severe types of cancer with poor outcomes. Cisplatin is used widely to treat cancer cells, but many patients develop acquired drug resistance. The receptor for advanced glycation end products (RAGE) is expressed widely in TSCC and associated with drug-induced chemotherapy resistance. However, the effect of RAGE and cisplatin on Tca-8113 cells remains unknown. We assayed the combined use of RAGE blockade and cisplatin effect on Tca-8113 cells' viability by MTT and apoptosis rate of Tca-8113 cells on RAGE blockade+cisplatin treatment; cisplatin alone; or RAGE blockade alone by flow cytometry. We observed the expressions of autophagy-related proteins beclin1, LC3II, p62; Wnt signaling-related proteins ß-catenin, GSK3ß, WNT5A, ROR-2; and apoptosis-related protein cleaved caspase-3, bcl-2-associated X proteins using western blot. We determined WNT5A and beclin1 expression on Tca-8113 cells by immunofluorescence. We further observed autophagy vacuoles by monodansylcadaverine staining. We found that RAGE blockade and cisplatin significantly decreased cell viability and increased the cell apoptosis rate compared with cisplatin alone. Furthermore, RAGE blockade suppressed the canonical Wnt pathway proteins ß-catenin and GSK-3ß, but upregulated noncanonical WNT5A and receptor ROR-2. We show that RAGE blockade suppressed the levels of autophagy-related protein LC3II/I, beclin1, accelerated degradation of autophagy for the increasing p62 expression, and increased cell apoptosis for the increasing expressions of cleaved caspase-3 and bcl-2-associated X proteins. We observed the location of WNT5A and beclin1 expressions on cells by immunofluorescence and their trends were consistent with western blotting. Taken together, our findings suggested that RAGE blockade+cisplatin improved chemotherapeutic effects by reducing autophagy and regulating Wnt/ß-catenin to suppress the progression of TSCC.

Primary and Secondary Stroke Prevention Using Left Atrial Appendage Closure with Watchman Devices in Atrial Fibrillation Patients: A Single Center Experience from Mainland China.

BACKGROUND: Atrial fibrillation (AF) is associated with increased stroke risk resulting from cardiac embolism of the left atrial appendage (LAA). Stroke tends to recur in NVAF patients. Yet safety and feasibility of secondary stroke preventions with LAA closure (LAAC) have not been assessed in detail. This retrospective study was designed to compare the feasibility and safety of LAAC in primary and secondary stroke preventions, in a real-world setting of Chinese patients. METHODS: From 2014 to 2015, non-valvular AF patients with CHA2DS2-VASc ≥1 were selected for percutaneous LAAC operations. Outcome observations of primary and secondary stroke preventions with Watchman devices were analyzed and compared. RESULTS: Overall, 122 patients were included. LAAC with Watchman devices were attempted in 115 patients, of whom 68 were for primary stroke prevention and 47 were for secondary prevention. Both the CHA2DS2-VASc score and the HASBLED score were significantly higher in the secondary prevention group (4.09 ± 1.06 vs. 1.93 ± 1.09 for CHA2DS2-VASc and 1.83 ± 1.03 vs. 1.26 ± 0.87 for HASBLED, P < 0.01). In both groups LAAC were achieved with high successful rate (98.53% in the primary prevention group and 100% in the secondary prevention group, P > 0.05) and low complication rates. The stroke rates were at a low level in both groups (1.47% in primary prevention group vs. 2.13% in secondary prevention group, P > 0.05). CONCLUSIONS: In our initial single-center experience, percutaneous LAA closure was a feasible and safe procedure for both primary and secondary stroke preventions in Chinese patients with nonvalvular AF.

Targeting non-canonical autophagy overcomes erlotinib resistance in tongue cancer.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) frequently occurs in many human cancers and hampers their therapeutic use. A large body of evidence has demonstrated the pro-survival role of autophagy in many human cancers. However, whether autophagy is involved in the induction of erlotinib resistance in tongue squamous cell carcinoma (TSCC) remains unknown. In this report, we found that autophagy prior to or induced by erlotinib treatment plays an important role in erlotinib resistance in tongue cancer cells. Using LC3 transfection, we observed that autophagy is upregulated and further induced when treated with erlotinib. Moreover, we found that autophagy plays a cytoprotective role by MTT analysis of the cell viability in TSCCs when treated with rapamycin or hydroxychloroquine (HCQ) in combination with erlotinib. However, 3-methyladenine (3-MA) did not influence the autophagy. Then, through siRNA technology and WB, we found that erlotinib-induced autophagy is mediated by ATG5 but not Beclin1. Also, knockdown of ATG5 significantly decreased the erlotinib resistance and knockdown of Beclin1 did not affect the sensitivity to erlotinib in TSCCs. Taken together, this indicates the critical role of non-canonical autophagy in erlotinib resistance in TSCCs.

The upregulated α-catulin expression was involved in head-neck squamous cell carcinogenesis by promoting proliferation, migration, invasion, and epithelial to mesenchymal transition.

Rho signaling component, α-catulin, is a cytoskeletal linker protein and plays an important role in apoptotic and senescence resistance, cytoskeletal reorganization, mobility, invasion, and epithelial to mesenchymal transition (EMT) of cancer cells. Here, we transfected α-catulin-expressing plasmid into head and neck squamous cell carcinoma (HNSCC) cell and examined the phenotypes and relevant molecules. α-catulin expression was detected on tissue microarray containing squamous epithelium, dysplasia, and cancer of head and neck by immunohistochemistry. It was found that α-catulin overexpression resulted in faster growth, migration and invasion, lower apoptosis, G2/M progression, and EMT than the mock and control (P < 0.05). α-catulin overexpression increased the expression of Cyclin E1, cdc2, survivin, Bcl-2, MMP-2, MMP-9, and N-cadherin but decreased the expression of Caspase-3 and E-cadherin by real-time PCR (P < 0.05). α-catulin expression was stronger in primary cancers than those in normal squamous epithelium and dysplasia (P < 0.05), but not correlated with aggressive behaviors or adverse prognosis of HNSCC patients (P > 0.05). Multivariate survival analysis showed that distant metastasis and TNM staging were independent prognostic factors for overall survival of the HNSCC patients (P < 0.05). These data indicated that upregulated expression of α-catulin protein might have impact on the tumorigenesis of HNSCC possibly by reducing apoptosis, enhancing proliferation, cell cycle progression, migration, invasion, and EMT. It might be regarded as a potential marker for head and neck carcinogenesis or a target of gene therapy for HNSCCs.

Chest circumference and sitting height among children and adolescents from Lhasa, tibet compared to other high altitude populations.

OBJECTIVES: The adaptation of human beings to a high altitude environment during growth has been reported in several populations but is less known for Tibetans. The objective of this study was to investigate similarities and differences of Tibetans in patterns and characteristics of physical growth and development in comparison to other high altitude populations. METHODS: We measured the stature, weight, chest circumference and sitting height of 2,813 healthy children and adolescents aged 6- to 21-year-old living at 3,658-4,500 m in Tibet, China, and compared them with published data from other high altitude populations. Eligible participants must have been born and raised in Tibet, and both their parents' families have to be Tibetan for at least the past three generations. RESULTS: The physical growth and development of children and adolescents in Tibet and the Andes followed similar patterns, such as delayed growth, short stature and sitting height, and large chest dimensions. Relative to stature, Tibetan sitting heights are similar to Andeans, but chest circumferences are smaller. CONCLUSIONS: Findings from this study reinforce the conclusion that Tibetan and Andean populations have adapted differently to high altitude hypoxia. The physical features of each population may result from unique adaptation to hypoxia, as well as socio-ecological factors, such as poor nutrition.

The clinicopathological significances and biological functions of parafibromin expression in head and neck squamous cell carcinomas.

Downregulated parafibromin expression is involved in the pathogenesis and progression of parathyroid, breast, gastric, colorectal, and lung cancers. To investigate the roles of parafibromin expression in tumorigenesis, progression, and prognostic evaluation of head and neck squamous cell carcinomas (HNSCCs), we transfected parafibromin-expressing plasmid into HNSCC cell and examined the phenotypes and their relevant molecules. Parafibromin expression was detected on tissue microarray containing squamous epithelium, dysplasia, and carcinoma of head and neck by immunohistochemistry. Parafibromin overexpression was found to suppress growth, migration, and invasion, and induce apoptosis, S arrest, and mesenchymal to epithelial transition (EMT), compared with the mock and control (P < 0.05). Both overexpression of Cyclin E1, Bax, and E-cadherin and hypoexpression of c-myc, Bcl-xL, and slug were detected in B88 transfectants, in comparison to mock and control by real-time PCR. Parafibromin expression was weaker in primary cancers than those in normal squamous tissue and dysplasia (P < 0.05), but stronger than the metastatic cancers in lymph node (P < 0.05). Parafibromin expression was negatively correlated with lymph node metastasis, tumor-node-metastasis (TNM) staging, but positively with human papillomavirus (HPV) positivity (P < 0.05). The HNSCCs in tongue showed more parafibromin expression than those in larynx (P < 0.05). There was stronger parafibromin expression in moderately-than poorly-differentiated carcinomas (P < 0.05). The significantly positive correlation was observed between parafibromin expression and relapse-free survival rate by Kaplan-Meier curves (P < 0.05). Cox's proportional hazard model indicated that distant metastasis and parafibromin expression were independent prognostic factors for overall and relapse-free survival of HNSCC, respectively (P < 0.05). These findings suggest that downregulated expression of parafibromin protein plays an important role in the pathogenesis, differentiation, and metastasis of HNSCCs possibly by inducing apoptosis, suppressing proliferation, cell cycle progression, migration, invasion, and EMT. Parafibromin expression is an independent factor for relapse-free survival of HNSCCs.

Left bundle branch pacing in third-degree atrioventricular block following morrow surgery: a case report.

Left bundle branch pacing (LBBP) has proven to be an alternative method for delivering physiological pacing to achieve electrical synchrony of the left ventricle (LV), especially in patients with atrioventricular block and left bundle branch block (LBBB). However, it is unclear whether it still achieved in patients whose left bundle branch (LBB) has had surgery-induced damage. The Morrow operation (Morrow septal myectomy) is regarded as one of the most effective treatments for hypertrophic obstructive cardiomyopathy (HOCM). The surgery resects small sections of muscle tissue in the proximal ventricular septum nearby or contains the LBB, which means that physical damage to the LBB is almost inevitable. Approximately 2%-12% of patients may need pacemaker implanted after Morrow surgery. LBBP is a feasible and effective method for achieving electric resynchronization of LBBB compared to right ventricular pacing (RVB). Nevertheless, there is a dearth of data on LBBP in third-degree atrioventricular block (AVB) following Morrow surgery. We report a case of successful LBBP in those patients.

Role of the GRP78-c-Src signaling pathway on osteoblast differentiation of periodontal ligament fibroblasts induced by cyclic mechanical stretch.

OBJECTIVES: This study aims to investigate the influence of glucose regulated protein (GRP) 78 on osteoblast differentiation in periodontal ligament fibroblasts (PDLFs) under cyclic mechanical stretch and determine the underlying mechanism. METHODS: FlexCell 5000 cell mechanical device was applied to simulate the stress environment of orthodontic teeth. GRP78High and GRP78Low subpopulation were obtained by flow sorting. Gene transfection was performed to knockdown GRP78 and c-Src expression and overexpress c-Src. Western blot analysis was used to detect the protein expression of Runt-related gene 2 (RUNX2), Osterix, osteocalcin (OCN), and osteopontin (OPN). Immunoprecipitation assay was used to determine the interaction of GRP78 with c-Src. The formation of cellular mineralized nodules was determined by alizarin red staining. RESULTS: GRP78 was heterogeneously expressed in PDLFs, and GRP78High and GRP78Low subpopulations were obtained by flow sorting. The osteogenic differentiation ability and phosphorylation level of c-Src kinase in the GRP78High subpopulation were significantly increased compared with those in GRP78Low subpopulation after cyclic mechanical stretch (P<0.05). GRP78 interacted with c-Src in PDLFs. The overexpression c-Src group showed significantly increased osteogenic differentiation ability than the vector group (P<0.05), and the sic-Src group showed significantly decreased osteogenic differentiation ability (P<0.05) after cyclic mechanical stretch. CONCLUSIONS: GRP78 upregulates c-Src expression by interacting with c-Src kinase and promotes osteogenic differentiation under cyclic mechanical stretch in PDLFs.

Upregulation of vesicle-associated membrane protein 7 in breast cancer tissues.

BACKGROUND: Vesicle-associated membrane protein 7 (VAMP7) plays oncogenic roles in cancers. However, its clinical significance in breast cancer (BC) tissues remains unknown. OBJECTIVE: To elucidate the clinical implications of VAMP7, as well as its involvement in the tumor microenvironment and molecular pathways of breast cancer. METHODS: BC (n=100) and non-cancerous breast tissues (n= 100) were collected for an immunohistochemical experiment (1:200). The protein expression level of VAMP7 was determined by using a semi-quantitative scoring method. High-throughput RNA-sequencing data of BC tissues were analyzed to confirm the mRNA expression trend of VAMP7. Additionally, the largest BC prognosis cohort data were collected to mine the potential impact VAMP7 has on BC progression. The association between VAMP7 and the microenvironment of BC was evaluated by using a CIBERSORT algorithm. Moreover, we explored the co-expressed molecular mechanisms of VAMP7 in BC by calculating Pearson correlation coefficients and overexpressed genes. Finally, the biological mechanism underlying the relationship between VAMP7 and the key pathways was also explored using gene set enrichment analysis (GSEA). Potential therapeutic strategies were predicted targeting VAMP7. RESULTS: VAMP7 protein was significantly over-expressed in BC tissue than that in controls (p< 0.001). Compared with 459 normal breast tissues and 113 non-cancerous breast tissues, the expression level of VAMP7 mRNA was significantly increased in 1111 BC tissues. CD4+T cells, macrophages, and naïve B cells had a higher infiltration rate in BC tissues with high VAMP7 expression, while regulatory T cells and CD8+T cells had a lower infiltration rate. Over-expressed VAMP7 was associated with macrophages activation and transition from M1 to M2 polarization. Upregulated VAMP7 could predicted poorer OS, DMFS, PPS, and RFS outcomes. Upregulated VAMP7 co-expressed genes were significantly enriched in the cell cycle checkpoints. GSEA confirmed that over-expressed VAMP7 are markedly associated with functional enrichment in cell cycle related categories, including mitotic spindle, G2M checkpoint, and E2F targets. KU-55933 was predicted as a putative therapeutic drug for BC targeting VAMP7. CONCLUSIONS: VAMP7 was upregulated in BC tissue and correlated with poor prognosis of BC patients. VAMP7 may promote BC progression by targeting the cell cycle pathway.

[The correlation between postural hypotension and myocardial infarction in the elderly population].

OBJECTIVE: To investigate the association between the systolic/diastolic orthostatic hypotension (OH-S/OH-D) and myocardial infarction (MI) in the elderly. METHODS: Health screening physical examination were carried in 1081 subjects without MI aged over 65 years in Guangzhou Military region. The orthostatic blood pressure and heart rate were measured in supine position after resting for more than 5 minutes and at 0 and 2 minutes after standing. All the cases were divided into systolic or diastolic group on the basis of definition of orthostatic hypotension and followed up by telephone or inpatient medical records with mean period of 315.8 days. The primary endpoint was MI occurrence. RESULTS: The prevalence of OH in this cohort was 24.5% (OH-S/OH-D: 19.3%/17.2%). Significant differences in the occurrence of OH and OH-S were found in the elderly and the very elderly subjects (≥ 80 years) (26.1% vs 20.1%, P = 0.045 ; 21.0% vs 14.6%, P = 0.018), while no difference was found in OH-D. The prevalence of MI in the OH positive subjects was significantly higher than that in the OH negative subjects, as well as in OH-S or OH-D group. After adjustment of age, supine blood pressure, creatinine and cerebrovascular history by logistic regression, the association was observed between MI and OH (HR 15.635, 95%CI 3.299 - 74.091, P = 0.001), OH-S(HR 8.760, 95%CI 2.487-30.851, P = 0.001)and OH-D(HR 3.889, 95%CI 1.097 - 13.790, P = 0.035). CONCLUSION: OH-S and OH-D hypotension are robust predictors for MI in the elderly.

Genomic Epidemiology and Phylodynamic Analysis of Enterovirus A71 Reveal Its Transmission Dynamics in Asia.

Enterovirus A71 (EV-A71) is one of the main pathogens causing hand, foot, and mouth disease (HFMD) outbreaks in Asian children under 5 years of age. In severe cases, it can cause neurological complications and be life-threatening. In this study, 200 newly sequenced EV-A71 whole-genome sequences were combined with 772 EV-A71 sequences from GenBank for large-scale analysis to investigate global EV-A71 epidemiology, phylogeny, and Bayesian phylodynamic characteristics. Based on the phylogenetic analysis of the EV-A71 3Dpol region, six new evolutionary lineages (lineages B, J, K, O, P, and Q) were found in this study, and the number of evolutionary lineages was expanded from 11 to 17. Temporal dynamics and recombination breakpoint analyses based on genotype C revealed that recombination of nonstructural protein-coding regions, including 3Dpol, is an important reason for the emergence of new lineages. The EV-A71 epidemic in the Asia-Pacific region is complex, and phylogeographic analysis found that Vietnam played a key role in the spread of subgenotypes B5 and C4. The origin of EV-A71 subgenotype C4 in China is East China, which is closely related to the prevalence of subgenotype C4 in the south and throughout China. Selection pressure analysis revealed that, in addition to VP1 amino acid residues VP1-98 and VP1-145, which are associated with EV-A71 pathogenicity, amino acid residues VP1-184 and VP1-249 were also positively selected, and their functions still need to be determined by biology and immunology. This study aimed to provide a solid theoretical basis for EV-A71-related disease surveillance and prevention, antiviral research, and vaccine development through a comprehensive analysis. IMPORTANCE EV-A71 is one of the most important pathogens causing HFMD outbreaks; however, large-scale studies of EV-A71 genomic epidemiology are currently lacking. In this study, 200 new EV-A71 whole-genome sequences were determined. Combining these with 772 EV-A71 whole-genome sequences in the GenBank database, the evolutionary and transmission characteristics of global and Asian EV-A71 were analyzed. Six new evolutionary lineages were identified in this study. We also found that recombination in nonstructural protein-coding regions, including 3Dpol, is an important cause for the emergence of new lineages. The results provided a solid theoretical basis for EV-A71-related disease surveillance and prevention, antiviral research, and vaccine development.