Recent advances in enterovirus A71 pathogenesis: a focus on fatal human enterovirus A71 infection.

Enterovirus A71 (EV-A71) is one of the major pathogens responsible for hand, foot, and mouth disease (HFMD). Many HFMD outbreaks have been reported throughout the world in the past decades. Compared with other viruses, EV-A71 infection is more frequently associated with severe neurological complications and even death in children. EV-A71 can also infect adults and cause severe complications and death, although such cases are very uncommon. Although fatal cases of EV-A71 infection have been reported, the underlying mechanisms of EV-A71 infection, especially the mode of viral spread into the central nervous system (CNS) and mechanisms of pulmonary edema, which is considered to be the direct cause of death, have not yet been fully clarified, and more studies are needed. Here, we first summarize the pathological findings in various systems of patients with fatal EV-A71 infections, focussing in detail on gross changes, histopathological examination, tissue distribution of viral antigens and nucleic acids, systemic inflammatory cell infiltration, and tissue distribution of viral receptors and their co-localization with viral antigens. We then present our conclusions about viral dissemination, neuropathogenesis, and the mechanism of pulmonary edema in EV-A71 infection, based on pathological findings.

Three-year follow up of biodegradable polymer cobalt-chromium sirolimus-eluting stent (EXCROSSAL) in treating de novo coronary artery disease: Pooled analysis of CREDIT II and CREDIT III trials.

OBJECTIVES: To analyze the 3-year outcomes of the biodegradable polymer cobalt-chromium sirolimus-eluting stent (EXCROSSAL) in CREDIT II AND III TRIALS. BACKGROUND: Though approved by CFDA, the long-term safety and efficacy of EXCROSSAL is still unknown. METHODS: CREDIT II was a randomized trial comparing the EXCROSSAL versus EXCEL stents in patients with up to two de novo coronary lesions, and CREDIT III was a prospective, single-arm study evaluating the efficacy and safety of EXCROSSAL in broad types of de novo coronary artery lesions. We pooled the 3-year follow-up data of the EXCROSSAL arm of the CREDIT II and CREDIT III Trials. The primary outcome was 3-year target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (TV-MI), and clinically indicated target lesion revascularization (CI-TLR). The patient-oriented composite endpoint (PoCE) (all-cause death, all MI, or any revascularization) and stent thrombosis (ST) were also analyzed. RESULTS: A total of 833 patients were included in this study. The incidence of TLF and PoCE in the 3-year follow-up were 7.6% and 12.5%, respectively. ST occurred in 0.6% of patients. In the subgroup analyses, TLF was significantly higher in small target vessels, multi-lesion PCI, and multi-vessel disease. CONCLUSIONS: The 3-year follow-up analysis confirmed low rates of TLF and ST in EXCROSSAL, which is similar to the most widely used new generation durable polymer drug-eluting stent.

A molecularly imprinted polymer based chemiluminescence array sensor for one-step determination of phenothiazines and benzodiazepines in pig urine.

The residues of phenothiazines and benzodiazepines in foods of animal origin are dangerous to consumers. For inspection of their abuses, this study for the first time reported on the use of a chemiluminescence array sensor for the simultaneous determination of four phenothiazines and five benzodiazepines in pig urine. Two molecularly imprinted polymers were coated in different wells of a conventional 96-well microtiter plate as the recognition reagents. After sample loading, the absorbed analytes were initiated directly by using an imidazole enhanced bis(2,4,6-trichlorophenyl)oxalate-hydrogen peroxide system to emit light. The assay process consisted of only one sample-loading step prior to data acquisition, so one test was finished within 10 min. The limits of detection for the nine drugs in the pig urine were in a range of 0.1 to 0.6 pg/mL, and the recoveries from the fortified blank urine samples were in a range of 80.3 to 95%. Furthermore, the sensor could be reused six times. Therefore, this sensor could be used as a simple, rapid, sensitive and reusable tool for routine screening for residues of phenothiazines and benzodiazepines in pig urine.

Molecularly imprinted polymer based microtiter chemiluminescence array for determination of phenothiazines and benzodiazepines in pork.

In this study, a molecularly imprinted polymer based chemiluminescence array capable of simultaneous determining phenothiazines and benzodiazepines was first reported. Two polymers were coated in different wells of the conventional 96-well microtiter plate as the recognition reagents, and the added analytes competed with a horseradish peroxidase-labeled bi-hapten conjugate to bind the recognition reagents. The light signal was induced by using a highly effective luminol-H2O2-IMP system. The assay procedure consisted of only one sample-loading step prior to data acquisition. Then, the array was used to determine 4 phenothiazines and 5 benzodiazepines in pork simultaneously. The limits of detection for the 9 drugs were in a range of 0.001-0.01 ng/mL, and the recoveries from the fortified blank pork were in a range of 63.5%-94.1%. Furthermore, the array could be reused for 8 times. The detection results for some real pork samples were consistent with an ultra performance liquid chromatography method.

Efficacy and safety of a biodegradable polymer Cobalt-Chromium sirolimus-eluting stent (EXCROSSAL) in treating de novo coronary artery disease: A pooled analysis of the CREDIT II and CREDIT III trials.

BACKGROUND: The safety and efficacy of the second-generation biodegradable polymer Cobalt-Chromium sirolimus-eluting stent (EXCEL2) in daily clinical practice remains unknown. Additionally, to meet the China Food and Drug Administration requirements, we conducted an objective performance criterion study from the CREDIT II and CREDIT III trials. METHODS: CREDIT II was a randomized trial comparing the EXCEL2 versus EXCEL stent in patients with up to 2 de novo coronary lesions. CREDIT III was a prospective, single-arm study evaluating the efficacy and safety of EXCEL2 in broad types of de novo coronary artery lesions. This pooled analysis included patients in the CREDIT III and EXCEL2 arm of the CREDIT II trial. The primary outcome was 12-month target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (TV-MI), and clinical indicated target lesion revascularization (CI-TLR). The patient-oriented composite endpoint (PoCE) of all-cause death, all MI, or any revascularization was also analyzed. RESULTS: A total of 833 patients were included, consisting of 625 in the CREDIT III trial and 208 in the EXCEL2 arm of the CREDIT II trial. Twelve-month TLF occurred in 6.1% patients, cardiac death in 0.4%, TV-MI in 5%, and CI-TLR in 1.1%. Additionally, 64 (7.7%) PoCE and 3 probable late stent thromboses (0.4%) were recorded. CONCLUSION: EXCEL2 stent met the objective performance criterion on efficacy and safety with a low level of 12-month TLF as well as stent thrombosis when treating patients with de novo coronary lesions. © 2017 Wiley Periodicals, Inc.

First-in-man study evaluating the safety and efficacy of a second generation biodegradable polymer sirolimus-eluting stent in the treatment of patients with de novo coronary lesions: clinical, Angiographic, and OCT outcomes of CREDIT-1.

OBJECTIVE: To evaluate the preliminary safety and efficacy of the EXCEL II stent system. BACKGROUND: Although the first biodegradable polymer drug-eluting stent (BP-DES), EXCEL, was launched nearly a decade ago, in-stent restenosis and stent thrombosis remain pertinent clinical problems in practice. A new cobalt-chromium BP-DES EXCEL II has been developed with the aim of improving stent safety and efficacy. METHODS: Forty-five patients with single de novo native coronary lesions were enrolled and randomized to two groups in a 2:1 ratio, the 4-month follow-up group (n = 30) and the 12-month follow-up group (n = 15). All patients underwent percutaneous coronary intervention (PCI) with the EXCEL II stent system. Quantitative coronary angiography (QCA) and optical coherence tomography (OCT) were used to assess coronary vasculature at the designated 4- or 12-month follow-up. The primary outcome was major adverse cardiac events (MACE) at 30 days post-PCI. RESULTS: No MACE, thrombotic events, or target lesion failure was found in the 45 patients during the 12-month follow-up. There was no significant difference (P > 0.05) between the two groups in terms of in-stent and in-segment late lumen loss (LLL). No in-stent and in-segment restenosis was found in either group. At follow-up, the ratio of >10% uncovered struts per lesion was 26.67% in the 4-month group and 0% in the 12-month group (P < 0.05). Neointimal coverage in the 12-month group was significantly better than in the 4-month group (98.58% vs. 93.51%, P < 0.01). CONCLUSIONS: This first-in-man study demonstrates promising feasibility, safety, and efficacy of EXCEL II stents. These stents were found to have rapid endothelialization and low LLL rates at 4 and 12 months after implantation.

Dual antiplatelet therapy over 6 months increases the risk of bleeding after biodegradable polymer-coated sirolimus eluting stents implantation: insights from the CREATE study.

BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation remains controversial. The primary aim of our study was to evaluate the impact of optimal DAPT duration on bleeding events between 6 and 12 months after biodegradable polymer-coated DES implantation. The secondary aim is to determine the predictors and prognostic implications of bleeding. METHODS: This study is a post hoc analysis of the Multi-Center Registry of EXCEL Biodegradable Polymer Drug Eluting Stents (CREATE) study population. A total of 2,040 patients surviving at 6 months were studied, including 1,639 (80.3%) who had received 6-month DAPT and 401 (19.7%) who had received DAPT greater than 6 months. Bleeding events were defined according to the bleeding academic research consortium (BARC) definitions as described previously and were classified as major/minor (BARC 2-5) and minimal (BARC 1). A left censored method with a landmark at 6 months was used to determine the incidence, predictors, and impact of bleeding on clinical prognosis between 6 and 12 months. RESULTS: At 1-year follow-up, patients who received prolonged DAPT longer than 6 months had a significantly higher incidence of overall (3.0% vs. 5.5%, P = 0.021) and major/minor bleeding (1.1% vs. 2.5%, P = 0.050) compared to the patients who received 6-month DAPT. Multivariate analysis showed that being elderly (OR = 1.882, 95% CI: 1.109-3.193, P = 0.019), having diabetes (OR = 1.735, 95% CI: 1.020-2.952, P = 0.042), having a history of coronary artery disease (OR = 2.163, 95% CI: 1.097-4.266, P = 0.026), and duration of DAPT longer than 6 months (OR = 1.814, 95% CI: 1.064-3.091, P = 0.029) were independent predictors of bleeding. Patients with bleeding events had a significantly higher incidence of cardiac death, myocardial infarction, target lesion revascularization, and stent thrombosis. CONCLUSIONS: Prolonged DAPT (greater than 6 months) after biodegradable polymer-coated DES increases the risk of bleeding, and is associated with adverse cardiac events at 1-year follow-up. (J Interven Cardiol 2014;27:119-126).

Drug-coated balloon angioplasty versus drug-eluting stent implantation in ACS patients with different angiographic patterns of in-stent restenosis.

BACKGROUND: Drug-coated balloon (DCB) angioplasty and drug-eluting stents (DES) are two widely used treatments for in-stent restenosis (ISR). Focal and non-focal types of ISR affect the clinical outcomes. The present study aims to compare DES reimplantation versus DCB angioplasty in acute coronary syndrome (ACS) patients with focal ISR and non-focal ISR lesions. METHODS: Patients with ISR lesions underwent percutaneous coronary intervention (PCI) were retrospectively evaluated and divided into DES group and DCB group. The primary endpoint was the incidence of target lesion failure (TLF) at 24 months follow up. Propensity score matching (PSM) was conducted to balance the baseline characteristics. RESULTS: For focal ISR, TLF was comparable in the DES and DCB groups at 24 months of follow-up (Before PSM, hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.39-1.27; p = 0.244; After PSM, HR: 0.83; 95% CI: 0.40-1.73; p = 0.625). For non-focal ISR, TLF was significantly decreased in DES compared with DCB group (Before PSM, HR: 0.43; 95% CI: 0.29-0.63; p < 0.001; After PSM, HR: 0.33; 95% CI: 0.19-0.59; p < 0.001), which was mainly attributed to the lower incidence of clinically indicated target lesion revascularization (CD-TLR) (Before PSM, HR: 0.39; 95% CI: 0.26-0.59; p < 0.001; After PSM, HR: 0.28; 95% CI: 0.15-0.54; p < 0.001). CONCLUSIONS: The clinical outcomes for DES and DCB treatment are similar in focal type of ISR lesions. For non-focal ISR, the treatment of DES showed a significant decrease in TLF which was mainly attributed to a lower incidence of CD-TLR.

Clinical efficacy and safety of biodegradable polymer-based sirolimus-eluting stents in patients with diabetes mellitus insight from the 4-year results of the create study.

BACKGROUND: Diabetes mellitus is an independent predictor of adverse clinical events after drug-eluting stent implantation. OBJECTIVES: The objective of this study is to evaluate the long-term clinical efficacy and safety of biodegradable polymer-based sirolimus-eluting stents in diabetic versus non-diabetic patients. METHODS: A total of 2077 "all comers," including 440 (21.2%) diabetic patients and 1637 (78.8%) non-diabetic patients, were prospectively enrolled in the CREATE study at 59 centers in four countries. The recommended antiplatelet regimen was clopidogrel and aspirin for 6 months followed by chronic aspirin therapy. The primary outcome was the rate of major adverse cardiac events (MACE), defined as a composite of cardiac death, non-fatal myocardial infarction (MI), and target lesion revascularization (TLR). RESULTS: Diabetic patients had higher risks of all-cause death (8.2% vs. 3.4%, P < 0.001) and cardiac death (4.1% vs. 1.4%, P < 0.001) compared with non-diabetic patients at 4 years. The rates of non-fatal MI (0.2% vs. 0.9%, P = 0.218), TLR (2.0% vs. 2.8%, P = 0.357), MACE (5.9% vs. 4.4%, P = 0.227), and overall stent thrombosis (1.6% vs. 1.6%, P = 0.932) were not significantly different between diabetic and non-diabetic patients. A landmark analysis showed that prolonged clopidogrel therapy (>6 months) was not beneficial in reducing the cumulative hazards of MACE either in diabetic or non-diabetic patients (log rank P = 0.810). CONCLUSIONS: Biodegradable polymer-based sirolimus-eluting stents for the treatment of diabetic patients had a similar clinical event rate at 4 years compared with non-diabetic patients, except for a higher mortality rate.

A Novel Updated Full-Discretization Method for Prediction of Milling Stability.

This paper presents an updated full-discretization method for milling stability prediction based on cubic spline interpolation. First, the mathematical model of the time-delay milling system considering regenerative chatter is represented by a dynamic delay differential equation. Then, in a single tooth passing period, the time is divided into a finite time intervals, the state item and the time-delay item are approximated in each time interval by cubic spline interpolation and third-order Newton interpolation, respectively. Afterward, a transition matrix is constructed to represent the transfer relationship of the teeth in a period. Finally, based on Floquet theory, the milling stability lobes can be obtained. Meanwhile, in order to improve computational efficiency, an optimized method is proposed based on the traditional algorithm and the proposed method has high precision without losing high efficiency. Finally, several milling experiments are conducted to verify the accuracy of the proposed method, and the results show that the predicted results agree well with the experimental results.

Semi-automated registration and segmentation for gingival tissue volume measurement on 3D OCT images.

The change in gingival tissue volume may be used to indicate changes in gingival inflammation, which may be useful for the clinical assessment of gingival health. Properly quantifying gingival tissue volume requires a robust technique for accurate registration and segmentation of longitudinally captured 3-dimensional (3D) images. In this paper, a semi-automated registration and segmentation method for micrometer resolution measurement of gingival-tissue volume is proposed for 3D optical coherence tomography (OCT) imaging. For quantification, relative changes in gingiva tissue volume are measured based on changes in the gingiva surface height using the tooth surface as a reference. This report conducted repeatability tests on this method drawn from repeated scans in one patient, indicating an error of the point cloud registration method for oral OCT imaging is 63.08 ± 4.52µm (1σ), and the measurement error of the gingival tissue average thickness is -3.40 ± 21.85µm (1σ).

Dummy molecularly imprinted polymer based microplate chemiluminescence sensor for one-step detection of Sudan dyes in egg.

The objective of this study is to report a molecularly imprinted polymer-based chemiluminescence method for determination of Sudan dyes. A dummy-template molecularly imprinted polymer capable of recognizing seven Sudan dyes was first synthesized and its recognition mechanism was studied by using computation simulation method. The polymer was coated in the wells of conventional microplate to prepare a chemiluminescence sensor and the assay process consisted of only one sample-loading step prior to signal acquisition. The optimized sensor was used to determine the seven dyes in egg yolk and the results were confirmed with a high performance liquid chromatography. Results showed that this sensor achieved ultrahigh sensitivity (1.0-5.0 pg/mL), rapid assay process (10 min) and satisfactory recovery (70.5%-92.2%). Furthermore, the sensor could be reused for 5 times. Therefore, this sensor could be used as a useful tool for screening the residues of Sudan dyes in egg.

Long-term clinical, angiographic, and intravascular ultrasound outcomes of biodegradable polymer-coated sirolimus-eluting stents.

BACKGROUND: The residual drug carriers on drug-eluting stents (DES) surfaces are considered to be one of the most significant reasons causing late thrombosis. There is no documented data currently available on the safety/benefit profile beyond 6 months of EXCEL stent, a novel sirolimus-eluting stent with biodegradable polymer coating, in treating patients with coronary artery disease (CHD). OBJECTIVE: To evaluate the long-term efficacy and safety of EXCEL stent on treating CHD patients. METHODS: Between February and March 2006, a consecutive cohort of complex patients treated with the EXCEL stent was prospectively enrolled in this single-center registry. Antiplatelet protocol was 6-month dual antiplatelet therapy with clopidogrel and aspirin followed by aspirin alone indefinitely. The primary outcome was major adverse cardiac events (MACE) at 12 months. Secondary outcomes included in-segment and in-stent late lumen loss and binary restenosis rate measured by quantitative coronary angiography (QCA) analysis at 8 months postindex PCI procedure. RESULTS: A total of 100 patients with 153 lesions were included in this analysis. Most lesions (83.0%) were classified as complex (B2/C). At 12 months, four patients (4.0%) experienced MACE, which were four target-lesion revascularizations due to in-stent restenosis (ISR). All patients received follow-up up to 24 +/- 0.4 months and no cardiac death, MI, and in-stent thrombosis occurred during the 6 months of dual antiplatelet therapy or the subsequent 15 months of aspirin treatment alone. QCA analysis of 112 lesions from 75 patients showed 3.6% (4/112) in-stent lesion restenosis, 5.4% (6/112) in-segment lesion restenosis, 0.12 +/- 0.34 mm in-stent late lumen loss, and 0.08 +/- 0.35 mm in-segment late lumen loss. CONCLUSIONS: In this single-center experience with complex patients and lesions, the EXCEL stent implantation with 6-month dual antiplatelet treatment proved to markedly reduce the incidence of 24-month ISR and MACE. These preliminary findings require further validation by large scale, randomized trials.

Dummy template molecularly imprinted polymer for solid phase extraction of phenothiazines in meat based on computational simulation.

The 3D structures of two dummy templates and four phenothiazine drugs were studied by using computational simulation method. Then the two dummy templates were used to synthesize two molecularly imprinted polymers respectively. Results showed that the recognition abilities of the two polymers were consistent with the theoretical calculation. Then a solid phase extraction column was developed for extraction of the four phenothiazines in meat (pork, chicken) followed by determination with high performance liquid chromatography. The column showed high adsorption capacities (850-962ng analyte per milligram of polymer) and high recoveries (93-98%) to the four drugs, and could be recycled for sixty times. The limits of detection were in the range of 1.0-10ng/g, and the recoveries from the fortified blank samples were in the range of 70.3-96.1%. This is the first study reporting the use of molecularly imprinted polymer-based method for determination of phenothiazines residues in foods.

Spray freeze drying with polyvinylpyrrolidone and sodium caprate for improved dissolution and oral bioavailability of oleanolic acid, a BCS Class IV compound.

Spray-freeze-drying (SFD) of oleanolic acid (OA), a BCS Class IV compound, with polyvinylpyrrolidone-40 (PVP-40) as stabilizer and sodium caprate (SC) as wetting agent and penetration enhancer produced kinetically stable, amorphous solid dispersion systems with superior in vitro dissolution performance, and better and more uniform absorption in comparison with commercial OA tablet. Relative to the SC-free formulation, the presence of SC in the formulation resulted in a significant increase in the in vivo absorption rate of OA while exerting no apparent impact on the extent of OA absorption. The SFD-processed OA formulations and commercial OA tablet generally exhibited large inter-animal variability in oral bioavailability, consistent with the absorption characteristics of BCS Class IV compounds. Inclusion of SC coupled with the replacement of OA with its sodium salt (OA-Na) in the formulation was shown to substantially decrease the observed absorption variability. Above results suggested that increases in both dissolution rate and intestinal permeability of BCS Class IV compounds, as exemplified by the SFD-processed dispersion system containing both OA-Na and SC, are critical to reducing the large inter-individual absorption variability commonly observed with this class of drugs.

Relationship between dental erosion and respiratory symptoms in patients with gastro-oesophageal reflux disease.

OBJECTIVES: Both dental erosion and respiratory symptoms are extra-oesophageal manifestations of gastro-oesophageal reflux disease (GERD). The aim of this study was to determine whether dental erosion was correlated with respiratory symptoms in GERD patients. METHODS: 88 GERD patients were recruited and assigned to three groups mainly according to the frequency of respiratory symptoms: Group I: never; Group II: occasional (1-2 days a week or less); Group III: frequent (3-5 days a week or more). All patients underwent medical evaluations, including medical history, questionnaire answering and alimentary tract examinations. Dental examinations were carried out on these patients and 36 healthy controls. Dental erosions were measured by modified method of Smith and Knight Tooth Wear Index (TWI). Location and severity of dental erosion were recorded. RESULTS: The prevalence of dental erosion in Group III (64.52%) was higher (p<0.05) than that in Groups I (36.67%) and II (44.44%). GERD patients were presented with dental erosion with TWI scores ranging from 1 to 4. Though proportion of dental erosion with Score 2 (7/20) in Group III was higher than that in Group I (2/11) and Group II (3/12), there was no statistical significance in the proportions of erosion scores among three patient groups. Correlation coefficient between airway symptoms and scores of dental erosion was 0.231 (p<0.05). Palatal erosion of upper incisor was seen in 8 persons (72.7%) in Group I, 9 persons (75%) in Group II and 16 persons (80%) in Group III (p>0.05). Labial erosion of upper incisors was found in 1 person in Groups I and II respectively and 4 persons in Group III. All patients with labial erosion on upper incisors had palatal erosion, except 1 patient in Group III. CONCLUSIONS: In GERD patients, dental erosions are more prevalent in patients with frequent respiratory symptoms than those in patients with occasional and without respiratory symptoms. Palatal erosion of upper incisor is the main manifestation in patients. Acid reflux is the main causative factor of dental erosion in GERD patients with airway symptoms.