Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10−9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies. Delineation of the genetic architecture of hematological traits in a multi-ethnic dataset allows identification of rare variants with strong effects specific to non-European populations and improved fine mapping of GWAS variants using the trans-ethnic approach

The influence of resin chemistry on a composite's inherent biochemical stability

grantor: University of TorontoStudies have shown that inflammatory and salivary enzymes can degrade bis-phenyl glycidyl dimethacrylate (bisGMA) and triethylene glycol dimethacrylate (TEGDMA), two dental composite resin components. In other work, commercial composite resins containing a urethane modified bisGMA-TEGDMA (u-bis) based monomer showed a 10-fold reduction in the release of bisGMA derived product, bis-hydroxy-propoxyphenyl propane (bisHPPP), as compared with that found for bisGMA-TEGDMA (bis) based composites. These observations have motivated the further study of interactions between composites and enzymes. Photopolymerized model composite resin samples based on bis or u-bis resins were incubated in pseudocholinesterase (PCE), cholesterol esterase (CE) or both, and in the presence of a specific esterase inhibitor, phenylmethylsulfonyl fluoride (PMSF), for 16 and 32 days (pH 7.0 at 37°C). Degradation rates for the monomers were assessed for each enzyme. Incubation solutions were analyzed for resin degradation products by high performance liquid chromatography (HPLC), UV spectroscopy and mass spectrometry. The composite surfaces were characterized by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The vinyl group conversion was characterized by Fourier transform infra red spectroscopy (FT-IR). Hydrolase activity in human saliva was analyzed and compared to stock enzymes. The results showed that both enzymes degrade the composite in a dose dependent manner. In the presence of CE, the u-bis system showed a 15 to 180 (depending on the specific product) fold decrease in the amount of isolated products relative to the bis system. SEM analysis confirmed the relative degradation levels. CE showed a greater ability to cleave bisGMA monomer while PCE showed more specificity towards TEGDMA. Addition of PMSF inhibited the degradation process, confirming the implication of the serine active site in the enzymes. Saliva was found to contain CE and PCE-like hydrolase activity, at levels that could degrade composite resins. The study suggests that the level of degradation products generated for a material will be dependent on the esterase make-up for an individual's saliva and the specific formulation of monomer components. Since resin formulation has a significant effect on the composite's chemical stability, manufacturers should consider testing biochemical stability as part of their routine product evaluation.Ph.D

Minimally Invasive Therapies for the Management of Dental Caries—A Literature Review

In recent years, due to a better understanding of the caries pathology and advances in dental materials, the utilization of non-invasive and minimally invasive techniques that delay/obviate the need for traditional restorations has started gaining momentum. This literature review focuses on some of these approaches, including fluoride varnish, silver diamine fluoride, resin sealants, resin infiltration, chemomechanical caries removal and atraumatic restorative treatment, in the context of their chemistries, indications for use, clinical efficacy, factors determining efficacy and limitations. Additionally, we discuss strategies currently being explored to enhance the antimicrobial properties of these treatment modalities to expand the scope of their application

Simulating the Intraoral Aging of Dental Bonding Agents: A Narrative Review

Despite their popularity, resin composite restorations fail earlier and at higher rates than comparable amalgam restorations. One of the reasons for these rates of failure are the properties of current dental bonding agents. Modern bonding agents are vulnerable to gradual chemical and mechanical degradation from a number of avenues such as daily use in chewing, catalytic hydrolysis facilitated by salivary or bacterial enzymes, and thermal fluctuations. These stressors have been found to work synergistically, all contributing to the deterioration and eventual failure of the hybrid layer. Due to the expense and difficulty in conducting in vivo experiments, in vitro protocols meant to accurately simulate the oral environment’s stressors are important in the development of bonding agents and materials that are more resistant to these processes of degradation. This narrative review serves to summarize the currently employed methods of aging dental materials and critically appraise them in the context of our knowledge of the oral environment’s parameters

Drug self-assembly for synthesis of highly-loaded antimicrobial drug-silica particles

Abstract Antimicrobial drug release from biomaterials for orthopedic repair and dental restorations can prevent biofilm growth and caries formation. Carriers for drug incorporation would benefit from long-term drug storage, controlled release, and structural stability. Mesoporous silica, synthesized through a co-assembly of silica and surfactant template, is an ideal drug encapsulation scaffold that maintains structural integrity upon release. However, conventional loading of drug within meso-silica pores via concentration-gradient diffusion limits the overall payload, concentration uniformity, and drug release control. Herein we demonstrate the co-assembly of an antimicrobial drug (octenidine dihydrochloride, OCT), and silica, to form highly-loaded (35% wt.) OCT-silica nanocomposite spheres of 500 nm diameter. Drug release significantly outlasted conventional OCT-loaded mesoporous silica, closely fit Higuchi models of diffusive release, and was visualized via electron microscopy. Extension of this concept to the broad collection of self-assembling drugs grants biomedical community a powerful tool for synthesizing drug-loaded inorganic nanomaterials from the bottom-up

The Role of Bacterial, Dentinal, Salivary, and Neutrophil Degradative Activity in Caries Pathogenesis

Until recently, it was widely accepted that bacteria participate in caries pathogenesis mainly through carbohydrate fermentation and acid production, which promote the dissolution of tooth components. Neutrophils, on the other hand, were considered white blood cells with no role in caries pathogenesis. Nevertheless, current literature suggests that both bacteria and neutrophils, among other factors, possess direct degradative activity towards both dentinal collagen type-1 and/or methacrylate resin-based restoratives and adhesives, the most common dental restoratives. Neutrophils are abundant leukocytes in the gingival sulcus, where they can readily reach adjacent tooth roots or gingival and cervical restorations and execute their degradative activity. In this review, we present the latest literature evidence for bacterial, dentinal, salivary, and neutrophil degradative action that may induce primary caries, secondary caries, and restoration failure

Interfacial Biomaterial–Dentin Bacterial Biofilm Proliferation and Viability Is Affected by the Material, Aging Media and Period

Biomaterial–dentin interfaces undergo degradation over time, allowing salivary, tissue fluid, and bacterial movement between the root filling or restoration and dentin. This study aims to investigate the effect of aging in simulated human salivary/bacterial/blood esterases (SHSE) on proliferation and viability of Enterococcus faecalis biofilm within the dentin interface with four materials used to fill/restore the endodontic space. Root canals of human anterior teeth were prepared and filled with gutta-percha and one of the following: self-cured resin composite (BisfilTM 2B, Bisco, Schaumburg, IL, USA) with either self-etch (SE) (EasyBond) or total-etch (TE) (ScotchbondTM, 3M, Saint Paul, MN, USA) methacrylate-based adhesives, epoxy-resin sealer (AH Plus®, Dentsply Sirona, York, PA, USA), or bioceramic sealer (EndoSequence® BC Sealer™, Brasseler USA, Savannah, GA, USA). Specimens were aged in SHSE or phosphate-buffered saline (PBS) for up to 360 days, followed by cultivation of steady-state E. faecalis biofilm. Depth and viability of interfacial bacterial biofilm proliferation were assessed by confocal laser scanning microscopy and live/dead staining. Data were analyzed using three-way ANOVA and Scheffe’s post hoc analyses. Initial depths of biofilm proliferation were similar among material groups (p > 0.05). All groups showed significantly deeper biofilm proliferation with increased aging period (p < 0.05). SHSE aging increased interfacial biofilm depth for TE, SE and BC (p < 0.05) but not AH. For unaged interfaces, BC exhibited the lowest ratio of live bacteria, followed by AH, TE, and SE (p < 0.05). Interfacial bacterial biofilm proliferation and viability were dependent on the biomaterial, aging media, and period

Matrix metalloproteinase inhibitor modulates esterase-catalyzed degradation of resin-dentin interfaces

Assess the modulating effect of matrix metalloproteinase (MMP) inhibition on simulated human salivary enzyme (SHSE)-catalyzed degradation of interfacial fracture-toughness (FT) of self-etched and total-etched resin-dentin interfaces