Effect of Cangrelor on Infarct Size in ST-Segment Elevation Myocardial Infarction Treated By Primary Percutaneous Coronary Intervention: A Randomized Controlled Trial (The PITRI Trial).

Background: The administration of intravenous cangrelor at reperfusion achieves faster onset of platelet P2Y12 inhibition than oral ticagrelor and has been shown to reduce myocardial infarct (MI) size in the pre-clinical setting. We hypothesized that the administration of cangrelor at reperfusion will reduce MI size and prevent microvascular obstruction (MVO) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Methods: This was a Phase 2, multi-center, randomized, double-blind, placebo controlled clinical trial conducted between November 2017 to November 2021 in six cardiac centers in Singapore (NCT03102723). Patients were randomized to receive either cangrelor or placeboinitiated prior to the PPCI procedure on top of oral ticagrelor. The key exclusion criteria included: presenting <6 hours of symptom onset, prior MI and stroke or transient ischemic attack; on concomitant oral anticoagulants; and a contraindication for cardiovascular magnetic resonance (CMR). The primary efficacy endpoint was acute MI size by CMR within the first week expressed as percentage of the left ventricle mass ( %LVmass). MVO was identified as areas of dark core of hypoenhancement within areas of late gadolinium enhancement. The primary safety endpoint was Bleeding Academic Research Consortium (BARC)-defined major bleeding in the first 48 hours. Continuous variables were compared by Mann-Whitney U test [reported as median (1st quartile- 3rd quartile)] and categorical variables were compared by Fisher's exact test. A 2-sided P<0.05 was considered statistically significant. Results: Of 209 recruited patients, 164 patients (78% ) completed the acute CMR scan. There were no significant differences in acute MI size [placebo: 14.9 (7.3 - 22.6) %LVmass versus cangrelor: 16.3 (9.9 - 24.4)%LVmass, P=0.40] or the incidence [placebo: 48% versus cangrelor: 47%, P=0.99] and extent of MVO [placebo:1.63 (0.60 - 4.65)%LVmass versus cangrelor: 1.18 (0.53 - 3.37)%LVmass, P=0.46] between placebo and cangrelor despite a two-fold decrease in platelet reactivity with cangrelor. There were no BARC-defined major bleeding events in either group in the first 48 hours. Conclusions: Cangrelor administered at time of PPCI did not reduce acute MI size or prevent MVO in STEMI patients given oral ticagrelor despite a significant reduction of platelet reactivity during the PCI procedure.

From metagenomes to metabolism: Systematically assessing the metabolic flux feasibilities for "Candidatus Accumulibacter" species during anaerobic substrate uptake.

With the rapid growing availability of metagenome assembled genomes (MAGs) and associated metabolic models, the identification of metabolic potential in individual community members has become possible. However, the field still lacks an unbiassed systematic evaluation of the generated metagenomic information to uncover not only metabolic potential, but also feasibilities of these models under specific environmental conditions. In this study, we present a systematic analysis of the metabolic potential in species of "Candidatus Accumulibacter", a group of polyphosphate-accumulating organisms (PAOs). We constructed a metabolic model of the central carbon metabolism and compared the metabolic potential among available MAGs for "Ca. Accumulibacter" species. By combining Elementary Flux Modes Analysis (EFMA) with max-min driving force (MDF) optimization, we obtained all possible flux distributions of the metabolic network and calculated their individual thermodynamic feasibility. Our findings reveal significant variations in the metabolic potential among "Ca. Accumulibacter" MAGs, particularly in the presence of anaplerotic reactions. EFMA revealed 700 unique flux distributions in the complete metabolic model that enable the anaerobic uptake of acetate and its conversion into polyhydroxyalkanoates (PHAs), a well-known phenotype of "Ca. Accumulibacter". However, thermodynamic constraints narrowed down this solution space to 146 models that were stoichiometrically and thermodynamically feasible (MDF > 0 kJ/mol), of which only 8 were strongly feasible (MDF > 7 kJ/mol). Notably, several novel flux distributions for the metabolic model were identified, suggesting putative, yet unreported, functions within the PAO communities. Overall, this work provides valuable insights into the metabolic variability among "Ca. Accumulibacter" species and redefines the anaerobic metabolic potential in the context of phosphate removal. More generally, the integrated workflow presented in this paper can be applied to any metabolic model obtained from a MAG generated from microbial communities to objectively narrow the expected phenotypes from community members.

Predicting the impact of temperature on metabolic fluxes using resource allocation modelling: Application to polyphosphate accumulating organisms.

The understanding of microbial communities and the biological regulation of its members is crucial for implementation of novel technologies using microbial ecology. One poorly understood metabolic principle of microbial communities is resource allocation and biosynthesis. Resource allocation theory in polyphosphate accumulating organisms (PAOs) is limited as a result of their slow imposed growth rate (typical sludge retention times of at least 4 days) and limitations to quantify changes in biomass components over a 6 hours cycle (less than 10% of their growth). As a result, there is no direct evidence supporting that biosynthesis is an exclusive aerobic process in PAOs that alternate continuously between anaerobic and aerobic phases. Here, we apply resource allocation metabolic flux analysis to study the optimal phenotype of PAOs over a temperature range of 4 °C to 20 °C. The model applied in this research allowed to identify optimal metabolic strategies in a core metabolic model with limited constraints based on biological principles. The addition of a constraint limiting biomass synthesis to be an exclusive aerobic process changed the metabolic behaviour and improved the predictability of the model over the studied temperature range by closing the gap between prediction and experimental findings. The results validate the assumption of limited anaerobic biosynthesis in PAOs, specifically "Candidatus Accumulibacter" related species. Interestingly, the predicted growth yield was lower, suggesting that there are mechanistic barriers for anaerobic growth not yet understood nor reflected in the current models of PAOs. Moreover, we identified strategies of resource allocation applied by PAOs at different temperatures as a result of the decreased catalytic efficiencies of their biochemical reactions. Understanding resource allocation is paramount in the study of PAOs and their currently unknown complex metabolic regulation, and metabolic modelling based on biological first principles provides a useful tool to develop a mechanistic understanding.

Meeting report: Advancing accelerated regulatory review with Real-Time Oncology Review (RTOR), Project Orbis, and the Product Quality Assessment Aid.

The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Controls (CMC) Community hosted two virtual panel discussions focusing on several novel regulatory review pathways for innovative oncology products: Real-Time Oncology Review (RTOR), Project Orbis, and the Product Quality Assessment Aid (PQAAid). The panel sessions were held on August 27, 2021, for the discussion of RTOR, and January 21, 2022, for the discussion of Project Orbis and the PQAAid. Both panel sessions included representatives from the US Food and Drug Administration (FDA) and subject matter experts from the pharmaceutical and biotechnology industries, with the aim of facilitating knowledge sharing on CMC-specific advantages, challenges, eligibility criteria for participation, and operational modifications instituted through the utilization of these acceleration initiatives. Key topics included managing cross-regional regulatory CMC requirements, adapting to expedited development timelines, coordinating interactions between health authorities and industry, and potential opportunities for future improvement and expansion of these programs. As RTOR, Project Orbis, and PQAAid are relatively new initiatives, the experiences shared by the panel experts are valuable for providing deeper insight into these new regulatory pathways and processes.

Methacrylic monomer derived from cardanol incorporated in dental adhesive as a polymerizable collagen crosslinker.

OBJECTIVES: The aim of this study was to evaluate the influence on MMP inhibition, dentin adhesion and physicochemical properties of an adhesive system incorporated with polymerizable collagen crosslinker monomer derived from cardanol. METHODS: The intermediary cardanol epoxy (CNE) was synthesized through cardanol epoxidation, followed by synthesis of cardanol methacrylate through methacrylic acid solvent-free esterification. Zymographic analysis was performed to evaluate the substances' ability to inhibit gelatinolytic enzymes. Collagen crosslinkers were added into adhesives systems according to the following groups: Ybond Universal® (Control), Ybond® + 2 % proanthocyanidin (PAC), Ybond® + 2 % unsaturated cardanol (Cardanol) and Ybond® + 2 % cardanol methacrylate (CNMA). Degree of conversion (DC) of the adhesives was assessed by FT-IR. Disk-shaped specimens were prepared for water sorption (WS) and solubility (SL) tests. Human third molars were sectioned to expose medium dentin and restored according to the different adhesives used (n = 5). Then, the specimens were cut into 1 mm2 sticks to evaluate, after 24 h and 6-month aging, microtensile bond strength (µTBS) and nanoleakage by scanning electron microscopy. Data were analysed with ANOVA and Tukey's post-test (α = 0.05). RESULTS: CNMA and PAC completely inhibited all forms of gelatinolytic enzymes. Cardanol achieved a significantly lowest DC, while the other groups did not differ from each other (p > 0.05). PAC achieved significantly higher water sorption, while CNMA solubility was significantly lower when compared to the other adhesives (p < 0.05). PAC provided a statistically higher 24 h and 6-month aging bond strength. Intermediary similar µTBS were presented by control and CNMA (p = 0.108). All adhesives applied attained significantly reduced bond strength after aging (p < 0.05). Interfaces created using CNMA were almost devoid of silver deposits initially, however all groups showed large amounts of silver deposits on resin-dentin interface subjected to water aging. SIGNIFICANCE: Although CNMA was effective in inhibiting gelatinolytic enzymes, when incorporated into a universal adhesive it could not promote less degradation of the adhesive interface after water aging. Since it is a hydrophobic monomer, CNMA did not interact well with dentin collagen, however it reduced the solubility of the adhesive system besides not interfering in its polymerization.

Glass-ionomer and calcium silicate-based cements interactions with human dentine in health and disease: Two-photon fluorescence microscopy and Raman spectroscopy analysis.

OBJECTIVES: To investigate the potential mineralising effects of calcium silicate-based dentine replacement material (Biodentine™) in comparison with glass-ionomer cement (GIC) (Fuji IX™) on different human dentine substrates using a multimodal non-invasive optical assessment. METHODS: Cements were applied on artificially demineralised or naturally carious dentine and stored for 4 weeks in phosphate-rich media +/- tetracycline used for mineralisation labelling. Interfacial dentine was examined from the same sample and location before and after aging using two-photon fluorescence microscopy, fluorescence lifetime imaging (FLIM) and second harmonic generation (SHG) imaging. Additionally, Raman spectroscopy was used to detect changes in the mineral content of dentine. RESULTS: Significant changes in the fluorescence intensity and lifetime were detected in partially demineralised dentine and caries-affected dentine underneath both tested cements, after storage (p < 0.001). This was associated with a significant increase in the mineral content as indicated by the increased intensity of the phosphate Raman peak located at 959 cm-1 (p < 0.0001). Caries-infected dentine showed significant fluorescence changes under Biodentine™ after storage (p < 0.001), but not under GIC (p = 0.44). Tetracycline binding induced a reduction in the fluorescence lifetime with comparable increase in the fluorescence intensity in both cements' groups within the affected dentine (p < 0.001). Significance Two-photon fluorescence microscopy can be used efficiently for non-destructive in-vitro dentine caries characterisation providing a technique for studying the same dentine-cement interface over time and detect changes. Biodentine™ demonstrated comparable remineralising potential to GIC, in addition to inducing remineralisation of caries-infected dentine. This may suggest using Biodentine™ as part of minimally invasive operative dentistry (MID) in caries management.

Hysteresis and fiscal stimulus in a recession.

The COVID-19 pandemic initiated a deep global recession, and with interest rates at very low levels, warrants consideration of the efficacy of different forms of fiscal stimulus in response. History reveals that deep recessions may cause output and total factor productivity (TFP) hysteresis, a permanent or highly persistent fall in the levels of output and TFP relative to pre-recession trends. This article analyses the output and welfare multipliers of fiscal stimulus during a recession using a macro model with TFP and output hysteresis. We find that transfer payments, public consumption and investment all have high output and welfare multipliers due to their positive effects on TFP in a recessionary environment. However, public investment has the highest output and welfare multipliers, because it has a more positive impact on labour productivity due to the increase in the public capital stock.

Outcomes of patients with ST elevation myocardial infarction in the era of second-generation drug eluting stents; five-year follow-up.

AIM: The second-generation everolimus and zotarolimus drug eluting stents (DES) have shown superiority for repeat revascularisation and safety to the first-generation devices for stable patients. However, the benefit of those devices in the setting of ST elevation myocardial infarction (STEMI) has remained questionable due to concern regarding stent thrombosis (ST) seen with the first-generation devices. We review the outcomes of patients with STEMI treated in our centre at a time when the second-generation DES became the standard of care. METHODS: All patients who presented to our institution with STEMI and underwent emergency percutaneous intervention (PCI) in 2012 with second-generation DES were identified. Case notes and electronic records were reviewed. Patients undergoing staged PCI to non-culprit lesions were excluded. Patients who died during the primary cardiac event with cardiogenic shock were also excluded. RESULTS: A total of 399 patients (mean age 65+/-12, 274 (76%) male) were identified. Thirty-five patients (8.7%) died during hospitalisation with cardiogenic shock and were excluded from the subsequent analysis. A further 35 patients died during follow-up. Patients received a mean of 1.15 DES. Median follow-up time was 4.7 years. Median door to reperfusion time was 90 minutes. The all-cause mortality rate for STEMI survivors was 9.6%. Cardiac mortality rate was 3.6%. Thirty-one patients (8.5%) re-presented with symptoms leading to repeat coronary angiography. In-stent restenosis (ISR) was observed only in eight patients (2.2%). The significant factors associated with re-presentation were smoking and medication non-compliance. CONCLUSION: Early mortality rates following emergency PCI for STEMI remain high despite low reperfusion times. The five-year follow-up data would suggest that STEMI survivors have good outcomes with the second-generation DES.

Chitosan-bioglass complexes promote subsurface remineralisation of incipient human carious enamel lesions.

OBJECTIVES: To test the in vitro subsurface remineralisation efficacy of chitosan-bioglass complex on artificial white spot lesions. METHODS: 64 artificial enamel white spot lesions were created by acidic gel and equally separated for static and 7d pH-cycling models. In each model, samples were assigned to 4 groups: (1) bioglass application on chitosan pre-treated lesions (CB); (2) chitosan-bioglass slurry (CBS); (3) "standard" remineralisation solution (RS - positive control); (4) deionised water (NC - negative control). Before each treatment using remineralising agents, 3-minute pellicle was formed on lesions' surfaces. Mineral content changes, surface and subsurface microhardness and ultrastructure were evaluated by Raman intensity mapping, Knoop microhardness and scanning electron microscopy, respectively. Data were statistically analysed using one-way ANOVA with Tukey's test (p < 0.05 is considered as significant). RESULTS: Chitosan-bioglass complexing was found to exhibit greater mineral regain and recovery of surface and subsurface microhardness compared to "standard" remineralisation solution and control groups, after static and dynamic pH-cycling remineralisation for 7 days (p < 0.05). Specifically, dense precipitations with Ca/P ratios similar to that in pure hydroxyapatite (HA) were observed on surfaces and subsurfaces which filled the porosities in the dynamic pH-cycling group, leaving no prismatic enamel structure exposed. CONCLUSIONS: Chitosan-bioglass complex is positive in promoting subsurface mineral deposition in spite of the presence of a short-term salivary pellicle. Clinical significance chitosan-bioglass complexing may provide an alternative clinical strategy in remineralising early enamel carious lesions as well as desensitizing exposed porous vital dental tissues clinically.

Evaluation of the efficacy of calcium silicate vs. glass ionomer cement indirect pulp capping and restoration assessment criteria: a randomised controlled clinical trial-2-year results.

OBJECTIVES: Assess calcium silicate cement (Biodentine™) vs. glass ionomer cement (Fuji IX™, control) as indirect pulp capping (IPC) materials in patients with reversible pulpitis after a 2-year follow-up. Evaluate the integrity of the overlying resin composite restorations using modified USPHS criteria and FDI criteria. Investigate the sensitivity of the modified USPHS criteria compared to the FDI criteria in the assessment of the restorations. MATERIALS AND METHODS: Seventy-two restorations (36 Biodentine™, 36 Fuji IX™) were placed randomly in 53 patients. Periapical radiographs were taken at pre-treatment (T0), 12-month (T12), and 24-month (T24) review. Restorations were assessed using the modified USPHS and FDI criteria at T12 and T24. RESULTS: At 24 months, 15 teeth had failed to maintain vitality (6 Biodentine™, 9 Fuji IX™). Clinical success rate of IPC for both materials was 72% and is related to the intensity of reversible pulpitis symptoms. No difference was found between T12 and T24 in the periapical (PA) radiographs and in the integrity of the resin composite restorations overlying Biodentine™ compared to Fuji IX™. There was no difference in the efficacy of the USPHS criteria compared to the FDI criteria in the assessment of the resin composite restorations. CONCLUSIONS: Biodentine™ and Fuji IX™ were clinically effective when used as IPC materials in teeth with reversible pulpitis at T24. Resin composite restorations overlying both materials performed well at T24. Using the USPHS or FDI criteria is equally efficient at T24; however, longer term follow-up is needed to establish whether there are sensitivity differences between these assessment criteria. CLINICAL SIGNIFICANCE: Teeth with deep carious lesions approaching the pulp and with signs of reversible pulpitis can be treated successfully by indirect pulp capping using either Biodentine™ or Fuji IX™. Using the USPHS or FDI criteria to assess restorations is equally effective at 2 years. TRIAL REGISTRATION: NCT02201641.

Platelet inhibition to target reperfusion injury trial: Rationale and study design.

BACKGROUND: In ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI), current oral P2Y12 platelet inhibitors do not provide maximal platelet inhibition at the time of reperfusion. Furthermore, administration of cangrelor prior to reperfusion has been shown in pre-clinical studies to reduce myocardial infarct (MI) size. Therefore, we hypothesize that cangrelor administered prior to reperfusion in STEMI patients will reduce the incidence of microvascular obstruction (MVO) and limit MI size in STEMI patients treated with PPCI. METHODS: The platelet inhibition to target reperfusion injury (PITRI) trial, is a phase 2A, multi-center, double-blinded, randomized controlled trial, in which 210 STEMI patients will be randomized to receive either an intravenous (IV) bolus of cangrelor (30 µg/kg) followed by a 120-minute infusion (4 µg/kg/min) or matching saline placebo, initiated prior to reperfusion (NCT03102723). RESULTS: The study started in October 2017 and the anticipated end date would be July 2020. The primary end-point will be MI size quantified by cardiovascular magnetic resonance (CMR) on day 3 post-PPCI. Secondary endpoints will include markers of reperfusion, incidence of MVO, MI size, and adverse left ventricular remodeling at 6 months, and major adverse cardiac and cerebrovascular events. SUMMARY: The aim of the PITRI trial is to assess whether cangrelor administered prior to reperfusion would reduce acute MI size and MVO, as assessed by CMR.

Clinical characteristics and outcomes of South-East Asian patients with Takotsubo (stress-induced) cardiomyopathy.

BACKGROUND: There is limited data on the natural history of Takotsubo (stress-induced) cardiomyopathy in South-East Asian patients. We aim to evaluate the clinical characteristics, predisposing factors and outcomes of patients diagnosed with Takotsubo cardiomyopathy in our region. METHODS: From January 2010 to March 2017, 98 patients were diagnosed with Takotsubo cardiomyopathy in our institution. Data were collected retrospectively on baseline clinical characteristics, presenting symptoms, precipitating factors, clinical investigations and in-hospital clinical outcomes. RESULTS: 82% of the patients were female. An antecedent physical stressor was more common than emotional trigger with 35% of patients having no identifiable stressor. The most common presenting symptoms were chest pain (53.1%), dyspnea (45%) and diaphoresis (18.5%).The apical variant (89%) was the most common form of Takotsubo cardiomyopathy followed by the mid-ventricular type (5.1%). The mean left ventricular ejection fraction was 35 ±â€¯11%.In-hospital mortality due to cardiovascular causes was 4.1%. 38% of patients developed in-hospital complications. By multi-variable analysis, lower left ventricular function was an independent predictor of in-hospital complication. CONCLUSION: South-East Asian patients with Takotsubo cardiomyopathy are characterised by female predominance, higher incidence of physical triggers and low cardiovascular mortality. Lower left ventricular function was an independent predictor of adverse outcomes.

In-vitro subsurface remineralisation of artificial enamel white spot lesions pre-treated with chitosan.

OBJECTIVE: To test the null hypothesis that chitosan application has no impact on the remineralisation of artificial incipient enamel white spot lesions (WSLs). METHODS: 66 artificial enamel WSLs were assigned to 6 experimental groups (n=11): (1) bioactive glass slurry, (2) bioactive glass containing polyacrylic acid (BG+PAA) slurry, (3) chitosan pre-treated WSLs with BG slurry (CS-BG), (4) chitosan pre-treated WSLs with BG+PAA slurry (CS-BG+PAA), (5) remineralisation solution (RS) and (6) de-ionised water (negative control, NC). Surface and cross-sectional Raman intensity mapping (960cm-1) were performed on 5 samples/group to assess mineral content. Raman spectroscopy and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were used to identify the type of newly formed minerals. Surface and cross-sectional Knoop microhardness were implemented to evaluate the mechanical properties after remineralisation. Surface morphologies and Ca/P ratio were observed using scanning electron microscopy (SEM) coupled with energy dispersive X-ray spectroscopy (EDX). Data were statistically analysed using one-way ANOVA with Tukey's test. RESULTS: BG+PAA, CS-BG, RS presented significantly higher mineral regain compared to NC on lesion surfaces, while CS-BG+PAA had higher subsurface mineral content. Newly mineralised crystals consist of type-B hydroxycarbonate apatite. CS-BG+PAA showed the greatest hardness recovery, followed by CS-BG, both significantly higher than other groups. SEM observations showed altered surface morphologies in all experimental groups except NC post-treatment. EDX suggested a higher content of carbon, oxygen and silicon in the precipitations in CS-BG+PAA group. There was no significant difference between each group in terms of Ca/P ratio. SIGNIFICANCE: The null hypothesis was rejected. Chitosan pre-treatment enhanced WSL remineralisation with either BG only or with BG-PAA complexes. A further investigation using dynamic remineralisation/demineralisation system is required with regards to clinical application.

The effect of dentine pre-treatment using bioglass and/or polyacrylic acid on the interfacial characteristics of resin-modified glass ionomer cements.

OBJECTIVE: To evaluate the effect of load-cycle aging and/or 6 months artificial saliva (AS) storage on bond durability and interfacial ultramorphology of resin-modified glass ionomer cement (RMGIC) applied onto dentine air-abraded using Bioglass 45S5 (BAG) with/without polyacrylic acid (PAA) conditioning. METHODS: RMGIC (Ionolux, VOCO) was applied onto human dentine specimens prepared with silicon-carbide abrasive paper or air-abraded with BAG with or without the use of PAA conditioning. Half of bonded-teeth were submitted to load cycling (150,000 cycles) and half immersed in deionised water for 24 h. They were cut into matchsticks and submitted immediately to microtensile bond strength (µTBS) testing or 6 months in AS immersion and subsequently µTBS tested. Results were analysed statistically by two-way ANOVA and Student-Newman-Keuls test (α = 0.05). Fractographic analysis was performed using FE-SEM, while further RMGIC-bonded specimens were surveyed for interfacial ultramorphology characterisation (dye-assisted nanoleakage) using confocal microscopy. RESULTS: RMGIC applied onto dentine air-abraded with BAG regardless PAA showed no significant µTBS reduction after 6 months of AS storage and/or load cycling (p > 0.05). RMGIC-dentine interface showed no sign of degradation/nanoleakage after both aging regimens. Conversely, interfaces created in PAA-conditioned SiC-abraded specimens showed significant reduction in µTBS (p < 0.05) after 6 months of storage and/or load cycling with evident porosities within bonding interface. CONCLUSIONS: Dentine pre-treatment using BAG air-abrasion might be a suitable strategy to enhance the bonding performance and durability of RMGIC applied to dentine. The use of PAA conditioner in smear layer-covered dentine may increase the risk of degradation at the bonding interface. CLINICAL SIGNIFICANCE: A combined dentine pre-treatment using bioglass followed by PAA may increase the bond strength and maintain it stable over time. Conversely, the use of PAA conditioning alone may offer no significant contribute to the immediate and prolonged bonding performance.

Cellular differentiation, bioactive and mechanical properties of experimental light-curing pulp protection materials.

OBJECTIVE: Materials for pulp protection should have therapeutic properties in order to stimulate remineralization and pulp reparative processes. The aim of this study was to evaluate the mechanical properties, biocompatibility, cell differentiation and bioactivity of experimental light-curable resin-based materials containing bioactive micro-fillers. METHODS: Four calcium-phosphosilicate micro-fillers were prepared and incorporated into a resin blend: 1) Bioglass 45S5 (BAG); 2) zinc-doped bioglass (BAG-Zn); 3) ßTCP-modified calcium silicate (ß-CS); 4) zinc-doped ß-CS (ß-CS-Zn). These experimental resins were tested for flexural strength (FS) and fracture toughness (FT) after 24h and 30-day storage in simulated body fluid (SBF). Cytotoxicity was evaluated using MTT assay, while bioactivity was evaluated using mineralization and gene expression assays (Runx-2 & ALP). RESULTS: The lowest FS and FT at 24h was attained with ß-CS resin, while all the other tested materials exhibited a decrease in FS after prolonged storage in SBF. ß-CS-Zn maintained a stable FT after 30-day SBF aging. Incorporation of bioactive micro-fillers had no negative effect on the biocompatibility of the experimental materials tested in this study. The inclusion of zinc-doped fillers significantly increased the cellular remineralization potential and expression of the osteogenic genes Runx2 and ALP (p<0.05). SIGNIFICANCE: The innovative materials tested in this study, in particular those containing ß-CS-Zn and BAG-Zn may promote cell differentiation and mineralization. Thus, these materials might represent suitable therapeutic pulp protection materials for minimally invasive and atraumatic restorative treatments.

Remineralisation of enamel white spot lesions pre-treated with chitosan in the presence of salivary pellicle.

OBJECTIVE: To investigate the remineralisation of chitosan pre-treated enamel white spot lesions (WSLs) by bioglass in the presence of the pellicle layer. METHODS: 50 artificial enamel white spot lesions were created by acidic gel. Two lesions were used to investigate the formation of the pellicle layer by treating with human whole saliva for 3 min. 48 lesions were assigned to 6 experimental groups (n = 8): (1) bioactive glass slurry, (2) bioactive glass containing polyacrylic acid (BG + PAA) slurry, (3) chitosan pre-treated WSLs with BG slurry (CS-BG), (4) chitosan pre-treated WSLs with BG + PAA slurry (CS-BG + PAA), (5) "standard" remineralisation solution (RS) and (6) de-ionised water (negative control, NC). Remineralisation was carried out using a pH-cycling model for 7 days. Before each treatment using remineralising agents, 3-min pellicle was formed on lesions' surfaces. Mineral content changes, surface and subsurface microhardness and ultrastructure were evaluated by Raman intensity mapping, Knoop microhardness and scanning electron microscopy, respectively. Data were statistically analysed using one-way ANOVA with Tukey's test (p < 0.05 is considered as significant). RESULTS: Despite the heterogeneously formed pellicle layer, all groups showed an increase in surface mineral content after pH-cycling. Chitosan pre-treatment enhanced the subsurface remineralisation of WSLs using bioglass as both pre-treated groups showed greater surface and subsurface microhardness compared to NC. CS-BG exhibited denser subsurface structure than BG, while in CS-BG + PAA the crystals were bigger in size but resemble more enamel-like compared to BG + PAA as shown in SEM observations. Remineralisation of RS was limited to the surface as no significant subsurface changes of mechanical properties and structure were found. CONCLUSIONS: Chitosan pre-treatment can enhance WSL remineralisation with bioglass biomaterials when a short-term salivary pellicle is present. A further investigation using a long-term pH-cycling model with mature pellicle is suggested with regards to clinical application. CLINICAL SIGNIFICANCE: Chitosan pre-treatment has the potential in clinical application to remineralise subsurface lesions to achieve lesion consolidation.

Long and short of optimal stent design.

The ideal stent must fulfil a broad range of technical requirements. Stents must be securely crimped onto the delivery balloon and, in this form, must have a low profile and be sufficiently flexible to facilitate deliverability to the lesion site without distortion or displacement. Following expansion, stents must exert sufficient radial force on the vessel wall to overcome lesion resistance and elastic recoil. To achieve an optimal lumen diameter, the lesion must be uniformly and adequately scaffolded, with minimal tissue prolapse between struts but without compromising side-branch access. Furthermore, the deployed stent must conform to the vessel curvature to minimise vessel distortion, particularly at the stent edges. Radio-opacity is also important to guide safe positioning, adequate deployment and postdilataion and to permit assessment of optimal stent expansion. Equally though, the stent lumen must also be sufficiently visible to allow radiographic assessment of flow dynamics and restenosis. Efforts to optimise one characteristic of stent design may have detrimental effects on another. Thus, currently available stents all reflect a compromise between competing desirable features and have subtle differences in their performance characteristics. Striving to achieve stents with optimal deliverability, conformability and radial strength led to a reduction in longitudinal strength. The importance of this parameter was highlighted by complications occurring in the real-world setting where percutaneous coronary intervention is often undertaken in challenging anatomy. This review focuses on aspects of stent design relevant to longitudinal strength.

Causes of delay in door-to-balloon time in south-east Asian patients undergoing primary percutaneous coronary intervention.

OBJECTIVE: To evaluate causes and impact of delay in the door-to-balloon (D2B) time for patients undergoing primary percutaneous coronary intervention (PPCI). SUBJECTS AND METHODS: From January 2009 to December 2012, 1268 patients (86% male, mean age of 58 ± 12 years) presented to our hospital for ST-elevation myocardial infarction (STEMI) and underwent PPCI. They were divided into two groups: Non-delay defined as D2B time ≤ 90 mins and delay group defined as D2B time > 90 mins. Data were collected retrospectively on baseline clinical characteristics, mode of presentation, angiographic findings, therapeutic modality and inhospital outcome. RESULTS: 202 patients had delay in D2B time. There were more female patients in the delay group. They were older and tend to self-present to hospital. They were less likely to be smokers and have a higher prevalence of prior MI. The incidence of posterior MI was higher in the delay group. They also had a higher incidence of triple vessel disease. The 3 most common reasons for D2B delay was delay in the emergency department (39%), atypical clinical presentation (37.6%) and unstable medical condition requiring stabilisation/computed tomographic imaging (26.7%). The inhospital mortality was numerically higher in the delay group (7.4% versus 4.8%, p = 0.12). CONCLUSIONS: Delay in D2B occurred in 16% of our patients undergoing PPCI. Several key factors for delay were identified and warrant further intervention.