Short-term adverse remodeling progression in asymptomatic aortic stenosis.

OBJECTIVES: Aortic stenosis (AS) is characterised by a long and variable asymptomatic course. Our objective was to use cardiovascular magnetic resonance imaging (MRI) to assess progression of adverse remodeling in asymptomatic AS. METHODS: Participants from the PRIMID-AS study, a prospective, multi-centre observational study of asymptomatic patients with moderate to severe AS, who remained asymptomatic at 12 months, were invited to undergo a repeat cardiac MRI. RESULTS: Forty-three participants with moderate-severe AS (mean age 64.4 ± 14.8 years, 83.4% male, aortic valve area index 0.54 ± 0.15 cm2/m2) were included. There was small but significant increase in indexed left ventricular (LV) (90.7 ± 22.0 to 94.5 ± 23.1 ml/m2, p = 0.007) and left atrial volumes (52.9 ± 11.3 to 58.6 ± 13.6 ml/m2, p < 0.001), with a decrease in systolic (LV ejection fraction 57.9 ± 4.6 to 55.6 ± 4.1%, p = 0.001) and diastolic (longitudinal diastolic strain rate 1.06 ± 0.2 to 0.99 ± 0.2 1/s, p = 0.026) function, but no overall change in LV mass or mass/volume. Late gadolinium enhancement increased (2.02 to 4.26 g, p < 0.001) but markers of diffuse interstitial fibrosis did not change significantly (extracellular volume index 12.9 [11.4, 17.0] ml/m2 to 13.3 [11.1, 15.1] ml/m2, p = 0.689). There was also a significant increase in the levels of NT-proBNP (43.6 [13.45, 137.08] pg/ml to 53.4 [19.14, 202.20] pg/ml, p = 0.001). CONCLUSIONS: There is progression in cardiac remodeling with increasing scar burden even in asymptomatic AS. Given the lack of reversibility of LGE post-AVR and its association with long-term mortality post-AVR, this suggests the potential need for earlier intervention, before the accumulation of LGE, to improve the long-term outcomes in AS. KEY POINTS: • Current guidelines recommend waiting until symptom onset before valve replacement in severe AS. • MRI showed clear progression in cardiac remodeling over 12 months in asymptomatic patients with AS, with near doubling in LGE. • This highlights the need for potentially earlier intervention or better risk stratification in AS.

Plasma Tenascin-C: a prognostic biomarker in heart failure with preserved ejection fraction.

INTRODUCTION: Tenascin-C is a marker of interstitial fibrosis. We assessed whether plasma Tenascin-C differed between heart failure with preserved ejection fraction (HFpEF) and asymptomatic controls and related to clinical outcomes. MATERIALS AND METHODS: Prospective, observational study of 172 age- and sex-matched subjects (HFpEF n = 130; controls n = 42, age 73 ± 9, males 50%) who underwent phenotyping with 20 plasma biomarkers, echocardiography, cardiac MRI and 6-minute-walk-testing. The primary endpoint was the composite of all-cause death/HF hospitalisation. RESULTS: Tenascin-C was higher in HFpEF compared to controls (13.7 [10.8-17.3] vs (11.1 [8.9-12.9] ng/ml, p < 0.0001). Tenascin-C correlated positively with markers of clinical severity (NYHA, E/E', BNP) and plasma biomarkers reflecting interstitial fibrosis (ST-2, Galectin-3, GDF-15, TIMP-1, TIMP-4, MMP-2, MMP-3, MMP-7, MMP-8), cardiomyocyte stress (BNP, NTpro-ANP), inflammation (MPO, hs-CRP, TNFR-1, IL6) and renal dysfunction (urea, cystatin-C, NGAL); p < 0.05 for all. During follow-up (median 1428 days), there were 61 composite events (21 deaths, 40 HF hospitalizations). In multivariable Cox regression analysis, Tenascin-C (adjusted hazard ratio [HR] 1.755, 95% confidence interval [CI] 1.305-2.360; p < 0.0001) and indexed extracellular volume (HR 1.465, CI 1.019-2.106; p = 0.039) were independently associated with adverse outcomes. CONCLUSIONS: In HFpEF, plasma Tenascin-C is higher compared to age- and sex-matched controls and a strong predictor of adverse outcomes. Trial registration: ClinicalTrials.gov: NCT03050593.

The effect of digital diagnostic setups on orthodontic treatment planning.

INTRODUCTION: This study aimed to evaluate whether viewing digital treatment simulations influenced orthodontic treatment planning decisions or practitioners' confidence in their selected plans. METHODS: Records of 6 patients representing different case types (eg, missing teeth, crowding, sagittal discrepancies) were collected. A total of 22 orthodontists and 7 orthodontic residents viewed these records and formulated treatment plans for each case, indicating their most recommended plan and up to 2 alternative plans. After treatment planning each case, digital setups of each treatment plan indicated by the practitioner were shown. The practitioners were then asked if they still recommended their original plan, or if they would now recommend a different plan. Their confidence levels in the success of their plans were recorded before and after viewing the setups. RESULTS: After viewing the digital setups, there was a significant change in the treatment plan for 9.2% of the cases. These included modifications like changing the extraction pattern or proposing space closure rather than opening space for an implant. In an additional 14.4% of the cases, treatment plans underwent partial changes, like adding interproximal reduction or temporary anchorage devices. Practitioner confidence levels increased after viewing the setups. In cases where the treatment plan changed, the practitioner's confidence level in the plan increased the most, and the final confidence level was uniformly high among all practitioners. Practitioners reported the most helpful features of digital setups were the ability to superimpose the setup with the original model, determine the amount of tooth movement needed, check the final incisal relationship (overjet and overbite), and establish the amount of interproximal reduction required. CONCLUSIONS: Viewing digital setups resulted in changes to the treatment plans in about 24% of the cases. The use of digital setups was associated with higher levels of confidence in the selected plans.

Fluoride-Releasing Effect of a Modified Resin Denture Containing S-PRG Fillers on Salivary Fluoride Retention: A Randomized Clinical Study.

This study aimed to evaluate the clinical effect of a resin denture base containing 20wt% surface prereacted glass ionomer (S-PRG) fillers on saliva fluoride concentrations as a surrogate evaluation of caries control. The study was a double-blind randomized clinical trial with a total of 110 participants aged 35-60 years who wore a removable partial resin denture for 1.5 years. Subjects were randomly assigned to receive a partial resin denture fabricated either with or without 20wt% S-PRG fillers (n = 55 per group). After 14 days of wearing the dentures, 5,000 ppm fluoride gel was applied nightly on both sides of the denture before storing it in a denture box overnight every night for 1.5 years. The salivary fluoride concentration was measured at baseline, on days 1, 14, and 15, and at 3 months and 1.5 years of wearing the denture. A significant increase in salivary fluoride concentration in the S-PRG denture group was observed from baseline to day 1, followed by a significant decrease to an approximate baseline level. After recharge with 5,000 ppm fluoride gel, salivary fluoride increased markedly on day 15 and remained elevated at month 3 through to 1.5 years. The resin denture base containing 20wt% S-PRG fillers demonstrated an initial fluoride release that increased saliva fluoride concentrations, but the fluoride release from within the material was short lived. The long-term effect of sustained fluoride release from the denture when combined with a regular fluoride recharge regimen may be beneficial for caries prevention.

Effect of silver diamine fluoride and potassium iodide on bonding to demineralized dentin.

PURPOSE: To evaluate the microtensile bond strength (MTBS) of resin composite to demineralized dentin treated with SDF or SDF-KI. METHODS: Occlusal enamel of 30 caries-free extracted human molars was removed to expose flat dentin surfaces. Specimens were immersed in demineralizing solution (pH 4.5) for 7 days. A standard smear layer was created using 600-grit silicon carbide paper. Specimens were distributed into three groups (n=10). Control: Dentin rinsed with deionized water; SDF: Dentin treated with 38% SDF; and SDF-KI: Dentin treated with SDF and KI. Specimens were bonded with composite using Scotchbond Universal in etch-and-rinse mode. MTBS beams were prepared from each specimen after 24 hours and tested. Data was analyzed by one-way ANOVA with Tukey HSD post-hoc test. RESULTS: MTBS test results ranged from 0 to 40 MPa. The highest values were obtained in the Control and lowest in SDF-KI, where pre-test failures were frequently observed. One-way ANOVA showed a significant difference among groups (P< 0.005); post-hoc analysis suggested no statistical difference between Control and SDF, but both groups showed higher MTBS compared with SDF-KI. CLINICAL SIGNIFICANCE: Silver diamine fluoride can be applied precisely and regionally on demineralized dentin before bonding without compromising the bond strength of a universal adhesive used with phosphoric acid etching. Addition of potassium iodide to reduce discoloration will dramatically weaken the bond.

Extended topoisomerase 1 inhibition through liposomal irinotecan results in improved efficacy over topotecan and irinotecan in models of small-cell lung cancer.

Liposomal irinotecan (irinotecan liposome injection, nal-IRI), a liposomal formulation of irinotecan, is designed for extended circulation relative to irinotecan and for exploiting discontinuous tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN-38. Sustained inhibition of topoisomerase 1 by extended SN-38 exposure as a result of delivery by nal-IRI is hypothesized to enable superior antitumor activity compared with traditional topoisomerase 1 inhibitors such as conventional irinotecan and topotecan. We evaluated the antitumor activity of nal-IRI compared with irinotecan and topotecan in preclinical models of small-cell lung cancer (SCLC) including in a model pretreated with carboplatin and etoposide, a first-line regimen used in SCLC. Nal-IRI demonstrated antitumor activity in xenograft models of SCLC at clinically relevant dose levels, and resulted in complete or partial responses in DMS-53, DMS-114, and NCI-H1048 cell line-derived models as well as in three patient-derived xenograft models. The antitumor activity of nal-IRI was superior to that of topotecan in all models tested, which generally exhibited limited control of tumor growth and was superior to irinotecan in four out of five models. Further, nal-IRI demonstrated antitumor activity in tumors that progressed following treatment with topotecan or irinotecan, and demonstrated significantly greater antitumor activity than both topotecan and irinotecan in NCI-H1048 tumors that had progressed on previous carboplatin plus etoposide treatment. These results support the clinical development of nal-IRI in patients with SCLC.

Effects of carbodiimide dentin surface treatment on resin-dentin bonding.

PURPOSE: To assess the effects of ethanol-based 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide (EDC) dentin surface treatment on resin-dentin bonding and dentin collagen fibril biodegradation. METHODS: Acid-etched dentin surfaces were pretreated with different concentrations of ethanol-based EDC solutions (0.01-2M) for 60 seconds, followed by two-step etch-and-rinse dentin adhesive application and resin composite bonding. Dentin surfaces pretreated with either ethanol alone or no pretreatment were used as controls. The specimens were subjected to microtensile bond strength testing after storage in 0.9% NaCl solution at 37°C for either 24 hours or 90 days. Furthermore, demineralized dentin slabs with and without ethanol-based EDC pretreatment were exposed to a collagenase solution for 24 hours, and subsequent hydroxyproline release was measured using ELISA. Data were analyzed with ANOVA and multiple comparison tests at α= 0.05. RESULTS: The bond strength values were significantly lower for dentin surfaces pretreated with 1 and 2 M ethanol-based EDC than for the control surfaces (P< 0.05). The 0.01, 0.1, and 0.3 M ethanol-based EDC pretreated groups obtained significantly higher bond strength values at 90 days compared to controls. Hydroxyproline release measurements revealed that there were significantly lower levels released in the 0.3 and 1 M ethanol-based EDC pretreated specimens than for controls (P< 0.05). CLINICAL SIGNIFICANCE: Pretreatment of dentin surfaces with ethanol-based EDC solution ≤ 0.3M before resin composite bonding can improve the stability of the resin-dentin bond and prevent dentin collagen fibril biodegradation.

Critical appraisal: approaches to caries removal: what the clinical evidence says.

Every day in the United States, complete caries removal in vital, asymptomatic teeth with deep carious lesions ends in unavoidable exposure of the pulp. As a result, the complexity and cost of treatment increases dramatically and many patients are left with extraction as their only viable option. This review appraises evidence which supports alternative treatments designed to preserve the vitality of the tooth and thus avoid extraction.

Toward Elimination of Electrochemical Corrosion in Dental Implants: A Zirconia-Titanium Composite Prototype.

Background Titanium dental implants (e.g., Nobel Biocare, Switzerland) are routinely used as support for dental restoration. Titanium has been the material of choice due to its corrosion resistance and ability to integrate with bone. Nevertheless, corrosion and titanium dissolution do occur. Compared to control, peri-implantitis tissue biopsies have been shown to contain high concentrations of dissolved titanium as well as metal particles. Dissolved titanium species have been found to be associated with the structure/diversity of the subgingival plaque microbiome and the extent of global methylation. Of note, peri-implantitis and peri-implant mucositis are common biological complications of implant therapy. Microorganisms and local inflammation together with a gradient of oxygen have been proven to form an electrochemical fuel cell, which generates the current that flows through the body of the titanium implant. Effectively, the fuel cell reduces oxygen and oxidizes titanium that turns into a soluble form. We are proposing a new zirconia-titanium composite implant design whereby the electrical current is disrupted while other properties are still conducive to osseointegration. Methodology Biocompatible zirconia bolts were treated with hydrofluoric acid (HF) and coated with titanium in a vacuum evaporator. The coating was masked with nail polish, and unmasked areas were etched with HF followed by mask removal with a solvent. Microbial challenges were conducted with a volunteer's plaque. Regular implant (control) and the prototype were inserted into simulated peri-implant environments implemented as a fiberglass sleeve immersed into a growth medium. After a five-day growth, samples were taken and HNO3 digested. Dissolved titanium was evaluated by inductively coupled plasma mass spectrometry. Results Proof-of-concept implant prototypes were successfully created. Vacuum deposition results in reproducible stable titanium coating. The thickness of the titanium coating was estimated using atomic force microscopy. A microbial challenge revealed that compared to the commercial titanium implant, the new implant prototype showed decreased amounts of corrosion-leached titanium. Conclusions We demonstrate a path forward toward a new design of a dental implant, whereby corrosion-induced electrical currents are interrupted resulting in a decreased amount of dissolved titanium.

Prevalence and Prognostic Significance of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The pathophysiological and clinical significance of microvascular dysfunction (MVD) in patients with heart failure with preserved ejection fraction (HFpEF) remains uncertain. OBJECTIVES: The aim of this study was to use cardiovascular magnetic resonance to: 1) quantify coronary microvascular function; 2) examine the relationship between perfusion and fibrosis; and 3) evaluate the impact of MVD and fibrosis on long-term clinical outcomes. METHODS: In a prospective, observational study, patients with HFpEF and control subjects underwent multiparametric cardiovascular magnetic resonance (comprising assessment of left ventricular volumetry, perfusion, and fibrosis [focal by late gadolinium enhancement and diffuse by extracellular volume]). The primary endpoint was the composite of death or hospitalization with heart failure. RESULTS: One hundred and one patients with HFpEF (mean age 73 ± 9 years, mean ejection fraction 56% ± 5%) and 43 control subjects (mean age 73 ± 5 years, mean ejection fraction 58% ± 5%) were studied. Myocardial perfusion reserve (MPR) was lower in patients with HFpEF versus control subjects (1.74 ± 0.76 vs 2.22 ± 0.76; P = 0.001). MVD (defined as MPR <2.0) was present in 70% of patients with HFpEF (vs 48% of control subjects; P = 0.014). There was no significant linear correlation between MPR and diffuse fibrosis (r = -0.10; P = 0.473) and no difference in MPR between those with and without focal fibrosis (mean difference -0.03; 95% CI: -0.37 to 0.30). In the HFpEF group, during median follow-up of 3.1 years, there were 45 composite events. MPR was independently predictive of clinical outcome following adjustment for clinical, blood, and imaging parameters (1 SD increase: HR: 0.673 [95% CI: 0.463 to 0.978; P = 0.038]; HR: 0.694 [95% CI: 0.491 to 0.982; P = 0.039]; and HR: 0.690 [95% CI: 0.489 to 0.973; P = 0.034], respectively). CONCLUSIONS: MVD is highly prevalent among patients with HFpEF and is an independent predictor of prognosis. The lack of correlation between MVD and fibrosis may challenge the assertion of a direct causal link between these entities. (Developing Imaging and Plasma Biomarkers in Describing Heart Failure With Preserved Ejection Fraction [DIAMONDHFpEF]; NCT03050593).

Effect of silver diammine fluoride and glass ionomer on remineralisation of natural dentine caries.

OBJECTIVES: Silver diammine fluoride (SDF) is a caries-arresting agent for dentine lesions. This study investigated the effect of application frequency of SDF when used with glass ionomer cement (GI) for remineralising carious dentine. METHODS: Freshly extracted human posterior teeth with advanced caries were used. After superficial removal of infected dentine, single (G3), double (G4), triple (G5) applications of SDF (Advantage Arrest SDF 38 %) followed by a layer of GI (GC Fuji IX GP) were compared to no treatment (negative control-G2), and GI only (G1). All teeth were stored in artificial saliva between treatments and for 2-weeks after final treatment. Micro-computed X-ray tomography (NSI) scans were obtained at each stage and analysed to plot mineral density-depth profile, lesion depth (LD) and mineral loss (ΔZ). Data was statistically analysed at a significance level of 0.05. RESULTS: Mean LD values were 837 µm, 735 µm, 841 µm, 1008 µm, 707 µm at baseline and 785 µm, 727 µm, 712 µm, 855 µm, 639 µm after treatment for groups G1 to G5, respectively. Mean ΔZ values were 6327 vol%µm, 5995 vol%µm, 10014 vol%µm, 7192 vol%µm, 5649 vol%µm at baseline and 3686 vol%µm, 5126 vol%µm, 5539 vol%µm, 2327 vol%µm, 3218 vol%µm after treatment for groups G1 to G5, respectively. Paired t-test showed that LD and ΔZ changed significantly within all groups from baseline to treatment weeks following storage (p < 0.05) except LD in the control (p > 0.05). ANCOVA showed significant difference among groups in net lesion depth recovery and net mineral gain (p < 0.05), and G3 and G4 showed the highest mineral gains. CONCLUSION: One or two applications of SDF prior to placement of GI, were effective in remineralising advanced dentine lesions, while additional applications, when combined with GI, did not demonstrate additional benefit in this study. CLINICAL SIGNIFICANCE: This short-term laboratory research study showed that one or two applications of SDF followed by GI coverage could remineralise advanced dentine caries in the presence of artificial saliva. This procedure carries potential in the treatment of difficult lesions where conventional restorations would require significant tooth structure removal through traumatic procedures.

Use of a Knowledge-Based Governance Approach to Plan a Post-COVID-19 Predoctoral Dental.

COVID-19 abruptly changed dental education, forcing educators out of their comfort zones and into using new technologies and teaching approaches. At the University of Washington School of Dentistry, a task force evaluated the curricular changes that resulted from COVID and made recommendations for the future predoctoral dental curriculum. This manuscript reports the process employed, the findings of the task force, and how these findings will impact the curriculum. A knowledge-based governance (KBG) approach was employed. KBG focuses on gathering all relevant information and identifying all choices. It separates dialogue from deliberation. Information was gathered via literature review, focus group interviews, electronic surveys, and other metrics. The task force evaluated: (1) delivering didactic content remotely; (2) administering assessments remotely; (3) duplicating preclinical simulation lab courses due to social distancing; and (4) the conversion from a numerical to a credit/no credit grading scale. Key recommendations resulted from focus groups and electronic surveys that allowed any student or faculty member an opportunity to provide input. Some topics were relatively non-controversial and strong recommendations were evident. The most controversial issue was which grading scale should be utilized. A KBG approach is an effective means to address mega issues in the dental school environment.

In Vitro Study on the Effect of a New Bioactive Desensitizer on Dentin Tubule Sealing and Bonding.

Bioactive mineral-based dentin desensitizers that can quickly and effectively seal dentinal tubules and promote dentin mineralization are desired. This in vitro study evaluated a novel nanohydroxyapatite-based desensitizer, Predicta (PBD, Parkell), and its effect on bond strength of dental adhesives. Human dentin discs (2-mm thick) were subjected to 0.5 M EDTA to remove the smear layer and expose tubules, treated with PBD, and processed for surface and cross-sectional SEM examination before and after immersion in simulated body fluid (SBF) for four weeks (ISO 23317-2014). The effects of two dental desensitizers on the microshear bond strength of a universal adhesive and a two-step self-etch system were compared. SEM showed coverage and penetration of nanoparticles in wide tubules on the PBD-treated dentin at the baseline. After four weeks in SBF, untreated dentin showed amorphous mineral deposits while PBD-treated dentin disclosed a highly mineralized structure integrated with dentin. Desensitizers significantly reduced microshear bond strength test (MSBS) of adhesives by 15-20% on average, depending on the bonding protocol. In conclusion, PBD demonstrated effective immediate tubules sealing capability and promoted mineral crystal growth over dentin and into the tubules during SBF-storage. For bonding to desensitizer-treated dentin, a two-step self-etching adhesive or universal bond with phosphoric acid pretreatment are recommended.

Effect of the 2017 European Guidelines on Reclassification of Severe Aortic Stenosis and Its Influence on Management Decisions for Initially Asymptomatic Aortic Stenosis.

BACKGROUND: The 2017 European Society of Cardiology guidelines for valvular heart disease included changes in the definition of severe aortic stenosis (AS). We wanted to evaluate its influence on management decisions in asymptomatic patients with moderate-severe AS. METHODS: We reclassified the AS severity of the participants of the PRIMID-AS study (Prognostic Importance of Microvascular Dysfunction in Asymptomatic Patients With AS), using the 2017 guidelines, determined their risk of reaching a clinical end point (valve replacement for symptoms, hospitalization, or cardiovascular death) and evaluated the prognostic value of aortic valve calcium score and biomarkers. Patients underwent echocardiography, cardiac magnetic resonance imaging, exercise tolerance testing, and biomarker assessment. RESULTS: Of the 174 participants, 45% (56/124) classified as severe AS were reclassified as moderate AS. This reclassified group was similar to the original moderate group in clinical characteristics, gradients, calcium scores, and remodeling parameters. There were 47 primary end points (41 valve replacement, 1 death, and 5 hospitalizations-1 chest pain, 2 dyspnea, 1 heart failure, and 1 syncope) over 368±156 days follow-up. The severe and reclassified groups had a higher risk compared with moderate group (adjusted hazard ratio 4.95 [2.02-12.13] and 2.78 [1.07-7.22], respectively), with the reclassified group demonstrating an intermediate risk. A mean pressure gradient ≥31 mm Hg had a 7× higher risk of the primary end point in the reclassified group. Aortic valve calcium score was more prognostic in females and low valve area but not after adjusting for gradients. NT-proBNP (N-terminal pro-brain-type natriuretic peptide) and myocardial perfusion reserve were associated with the primary end point but not after adjusting for positive exercise tolerance testing. Troponin was associated with cardiovascular death or unplanned hospitalizations. CONCLUSIONS: Reclassification of asymptomatic severe AS into moderate AS was common using the European Society of Cardiology 2017 guidelines. This group had an intermediate risk of reaching the primary end point. Exercise testing, multimodality imaging, and lower mean pressure gradient threshold of 31 mm Hg may improve risk stratification. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01658345.

Characterizing heart failure with preserved and reduced ejection fraction: An imaging and plasma biomarker approach.

INTRODUCTION: The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains incompletely defined. We aimed to characterize HFpEF compared to heart failure with reduced ejection fraction (HFrEF) and asymptomatic hypertensive or non-hypertensive controls. MATERIALS AND METHODS: Prospective, observational study of 234 subjects (HFpEF n = 140; HFrEF n = 46, controls n = 48, age 73±8, males 49%) who underwent echocardiography, cardiovascular magnetic resonance imaging (CMR), plasma biomarker analysis (panel of 22) and 6-minute walk testing (6MWT). The primary end-point was the composite of all-cause mortality and/or HF hospitalization. RESULTS: Compared to controls both HF groups had lower exercise capacity, lower left ventricular (LV) EF, higher LV filling pressures (E/E', B-type natriuretic peptide [BNP], left atrial [LA] volumes), more right ventricular (RV) systolic dysfunction, more focal and diffuse fibrosis and higher levels of all plasma markers. LV remodeling (mass/volume) was different between HFpEF (concentric, 0.68±0.16) and HFrEF (eccentric, 0.47±0.15); p<0.0001. Compared to controls, HFpEF was characterized by (mild) reductions in LVEF, more myocardial fibrosis, LA remodeling/dysfunction and RV dysfunction. HFrEF patients had lower LVEF, increased LV volumes, greater burden of focal and diffuse fibrosis, more RV remodeling, lower LAEF and higher LA volumes compared to HFpEF. Inflammatory/fibrotic/renal dysfunction plasma markers were similarly elevated in both HF groups but markers of cardiomyocyte stretch/damage (BNP, pro-BNP, N-terminal pro-atrial natriuretic peptide and troponin-I) were higher in HFrEF compared to HFpEF; p<0.0001. Focal fibrosis was associated with galectin3, GDF-15, MMP-3, MMP-7, MMP-8, BNP, pro-BNP and NTproANP; p<0.05. Diffuse fibrosis was associated with GDF-15, Tenascin-C, MMP-2, MMP-3, MMP-7, BNP, proBNP and NTproANP; p<0.05. Composite event rates (median 1446 days follow-up) did not differ between HFpEF and HFrEF (Log-Rank p = 0.784). CONCLUSIONS: HFpEF is a distinct pathophysiological entity compared to age- and sex-matched HFrEF and controls. HFpEF and HFrEF are associated with similar adverse outcomes. Inflammation is common in both HF phenotypes but cardiomyocyte stretch/stress is greater in HFrEF.

Plasma proteomic approach in patients with heart failure: insights into pathogenesis of disease progression and potential novel treatment targets.

AIMS: To provide insights into pathogenesis of disease progression and potential novel treatment targets for patients with heart failure by investigation of the plasma proteome using network analysis. METHODS AND RESULTS: The plasma proteome of 50 patients with heart failure who died or were rehospitalised were compared with 50 patients with heart failure, matched for age and sex, who did not have an event. Peptides were analysed on two-dimensional liquid chromatography coupled to tandem mass spectrometry (2D LC ESI-MS/MS) in high definition mode (HDMSE). We identified and quantified 3001 proteins, of which 51 were significantly up-regulated and 46 down-regulated with more than two-fold expression changes in those who experienced death or rehospitalisation. Gene ontology enrichment analysis and protein-protein interaction networks of significant differentially expressed proteins discovered the central role of metabolic processes in clinical outcomes of patients with heart failure. The findings revealed that a cluster of proteins related to glutathione metabolism, arginine and proline metabolism, and pyruvate metabolism in the pathogenesis of poor outcome in patients with heart failure who died or were rehospitalised. CONCLUSIONS: Our findings show that in patients with heart failure who died or were rehospitalised, the glutathione, arginine and proline, and pyruvate pathways were activated. These pathways might be potential targets for therapies to improve poor outcomes in patients with heart failure.

Combination of 2-methoxyestradiol (2-ME2) and eugenol for apoptosis induction synergistically in androgen independent prostate cancer cells.

Lack of effective treatment options for the management of hormone refractory prostate cancer (PCA) reinforce the great need to develop novel compounds that act singly or in combination. 2-Methoxyestradiol (2-ME(2)) is an endogenous estrogenic metabolite that has been reported to work as an antiproliferative agent in various tumor models including prostate. Recently conducted clinical trial in hormone refractory prostate cancer (HRPC) patients concluded that 2-ME(2) was safe and well tolerated. However this study identified bioavailability of 2-ME(2) as a limiting factor. Here we report the ability of a combination of 2-ME(2) and eugenol (4-allyl-2-methoxyphenol) as an approach for enhancing anticancerous activities in prostate cancer cells. Combining 2-ME(2) with eugenol (i) inhibited growth of prostate cancer cells and induced apoptosis at lower concentrations than either single agent alone; (ii) analysis of the data using combination index (CI) showed CI values of 0.4 indicating strong synergistic interaction; (iii) increased population of cells G(2)/M phase by 4.5-fold (p=0.01); (iv) significantly reduced expression of antiapoptotic protein Bcl-2 and enhanced expression of proapoptotic protein Bax. Combination induced apoptosis was not affected in PC-3 cells that over-express or lack Bcl-2 but was associated with loss of mitochondrial membrane potential. Since 2-ME(2) was well tolerated in phase II trail in patients with HRPC; and eugenol is consumed by humans in the form of spices, the combination of 2-ME(2) with eugenol may offer a new clinically relevant treatment regimen. Combining these agents may allow ameliorating any adverse effects of either 2-ME(2) or eugenol alone by reducing their individual concentrations should these two agents be developed for human use.

Management of idiopathic subgingival amalgam hypertrophy--the common amalgam overhang.

An amalgam overhang is defined as an extension of amalgam restorative material beyond the confines of a cavity preparation. The pseudo pathology term "idiopathic subgingival amalgam hypertrophy" is used in the title for shock effect and as a scare tactic to catch the attention of our readers. From various studies, it is apparent that such overhangs are alarmingly common. The overhang is largely iatrogenic, caused by poor operator skill exacerbated by unusual dental morphology. Creep may also play a role in the gingival overhang of large amalgam restorations. Maybe we, as clinicians, are becoming complacent and lax in our techniques and matrixing while restoring such a routine restoration. This article revisits the pros and cons of different methods of amalgam overhang management with clinical cases for illustration.

A comparison of human raters and an intra-oral spectrophotometer.

Consistently choosing an accurate shade match is far more difficult than it appears. Recently, several electronic shade-matching devices have been marketed. One device is an intraoral spectrophotometer, Easyshade. The current study compared the accuracy and consistency of the Easyshade (ES) device to three clinicians experienced in tooth whitening trials and trained in the use of the Vitapan 3D Master shade. The maxillary anteriors of 16 participants were matched on three separate occasions one month apart. At each appointment, the three clinicians (R1, R2 & R3) and ES independently chose a single 3D Master tab. A trained research assistant used the Easyshade device to record CIE L*, C* and H* and a shade tab. In addition, color differences between shade tabs were calculated using the Delta E 2000 (delta e 00) formula. The CIE L*C*H* data were also used to establish standards for the five lightness groups of the 3D Master. An intrarater agreement was evaluated using an intraclass correlation statistic, and an inter-rater agreement was evaluated using a weighted Kappa statistic. The percentages of exact matches were: ES = 41%; R1 = 27%; R2 = 22% and R3 = 17%. Matches within a half-shade were also calculated. This represents a mismatch that is perceptible but acceptable. The percentages of matches within a half-tab were: ES = 91%; R1 = 69%; R2 = 85% and R3 = 79%. In terms of lightness, the intra-rater agreement was considered to be very good for ES and R2 and good for R1 and R3. For chroma, agreement for ES was considered good, and for the three clinicians, it was considered moderate. The mean color difference for the L*, C*, H* data recorded at each evaluation was 1.5, or only slightly greater than the color difference between the same tab on different guides (1.2). The delta e 00 data were the most accurate data collected, and they were used to establish a standard to which the tab choices of the four raters were compared. A weighted Kappa statistic was performed and, in terms of lightness, agreement was found to be good for all raters. For chroma, agreement was very good for ES and it was good for the clinicians. In terms of the number of exact matches and matches within a half-shade, the performance of ES was at least comparable to, if not better than, the dentists. Statistically, the same was true in terms of consistency and accuracy when making repeated matches of lightness and chroma using the 3D Master shade guide.

Dental School Patient Preferences for Receiving and Returning Patient Satisfaction Surveys.

The aims of this study were to investigate dental school patient, parent, and caregiver preferences for receiving and returning patient satisfaction surveys and to determine how modes of receiving and returning surveys impacted return rates. Two studies were conducted, both of which are reported. In Study 1, adult patients, parents of child patients, and caregivers of patients with special needs were asked to indicate their preferred mode of receiving and returning surveys. In Study 2, patients, parents, and caregivers were randomly assigned to different modes of receiving and returning surveys, and return rates were compared between modes and according to whether the individuals had been assigned to their preferred mode or not. The overall response rates were 90.4% for the first study and 48.1% for the second study. In both studies, the preferred mode was receiving and returning the survey in the clinic (chi-square=84.902 and 32.116; df=3; p<0.001). Younger respondents were more likely to prefer receiving and returning the survey by email (K-W statistics=13.406, 10.241; df=3; p=0.004 and 0.017). In Study 2, respondents were significantly more likely to return surveys in the clinic (chi-square=44.994; df=2; p<0.001) and were also significantly more likely to return surveys if they had received them in their preferred mode (binomial test p<0.001). Although receiving and returning the survey in the clinic was the preferred mode, these respondents' preferences were also related to their age. These results suggest that dental school clinics may be able to expect higher return rates if they can follow patients' preferences for receipt and delivery of surveys.