Publications
| Title | Abstract | Year Filter | PMID(sorted ascending) Filter |
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| locoregional effects of microbiota in a preclinical model of colon carcinogenesis. | inflammation and microbiota are critical components of intestinal tumorigenesis. to dissect how the microbiota contributes to tumor distribution, we generated germ-free (gf) apc(min/+) and apc(min/+) ;il10(-/-) mice and exposed them to specific-pathogen-free (spf) or colorectal cancer-associated bacteria. we found that colon tumorigenesis significantly correlated with inflammation in spf-housed apc(min/+) ;il10(-/-) , but not in apc(min/+) mice. in contrast, small intestinal neoplasia developmen ... | 2017 | 28416491 |
| invasive fusobacterium nucleatum activates beta-catenin signaling in colorectal cancer via a tlr4/p-pak1 cascade. | the underlying mechanism of fusobacterium nucleatum (fn) in the carcinogenesis of colorectal cancer (crc) is poorly understood. here, we examined fn abundance in crc tissues, as well as β-catenin, tlr4 and pak1 protein abundance in fn positive and fn negative crcs. furthermore, we isolated a strain of fn (f01) from a crc tissue and examined whether fn (f01) infection of colon cancer cells activated β-catenin signaling via the tlr4/p-pak1/p-β-catenin s675 cascade. invasive fn was abundant in 62.2 ... | 2017 | 28423670 |
| antibacterial activity and cytocompatibility of an implant coating consisting of tio2 nanotubes combined with a gl13k antimicrobial peptide. | prevention of implant-associated infections at an early stage of surgery is highly desirable for the long-term efficacy of implants in dentistry and orthopedics. infection prophylaxis using conventional antibiotics is becoming less effective due to the development of bacteria resistant to multiple antibiotics. an ideal strategy to conquer bacterial infections is the local delivery of antibacterial agents. therefore, antimicrobial peptide (amp) eluting coatings on implant surfaces is a promising ... | 2017 | 28442908 |
| effect of preparation method and storage period on the stability of saliva dna. | saliva is an attractive source for oral microbial detection and quantification since sampling is non-invasive and rapid. | 2017 | 28460249 |
| characterization of non-dialyzable constituents from cranberry juice that inhibit adhesion, co-aggregation and biofilm formation by oral bacteria. | an extract prepared from cranberry juice by dialysis known as nondialyzable material (ndm) has been shown previously to possess anti-adhesion activity toward microbial species including oral bacteria, uropathogenic escherichia coli and helicobacter pylori. bioassay-guided fractionation of cranberry ndm was therefore undertaken to identify the anti-adhesive constituents. an aqueous acetone-soluble fraction (ndmac) obtained from sephadex lh-20 inhibited adhesion-linked activities by oral bacteria, ... | 2017 | 28470309 |
| fusobacterium nucleatum subspecies animalis influences proinflammatory cytokine expression and monocyte activation in human colorectal tumors. | chronic infection and associated inflammation have long been suspected to promote human carcinogenesis. recently, certain gut bacteria, including some in the fusobacterium genus, have been implicated in playing a role in human colorectal cancer development. however, the fusobacterium species and subspecies involved and their oncogenic mechanisms remain to be determined. we sought to identify the specific fusobacterium spp. and ssp. in clinical colorectal cancer specimens by targeted sequencing o ... | 2017 | 28483840 |
| influence of chronic azithromycin treatment on the composition of the oropharyngeal microbial community in patients with severe asthma. | this study of the oropharyngeal microbiome complements the previously published azithromycin in severe asthma (azisast) clinical trial, where the use of azithromycin was assessed in subjects with exacerbation-prone severe asthma. here, we determined the composition of the oropharyngeal microbial community by means of deep sequencing of the amplified 16s rrna gene in oropharyngeal swabs from patients with exacerbation-prone severe asthma, at baseline and during and after 6 months treatment with a ... | 2017 | 28486933 |
| microbiota analysis of biofilms on experimental abutments mimicking dental implants: an in vivo model. | the microbiota colonizing dental implants has been said to be similar to the microbiome surrounding teeth. in the absence of inflammation, a biofilm with pathological bacteria can cover implant surfaces exposed to the oral cavity, due for example, to a remodeling process. the aim of the present study was to identify the microbiota surrounding exposed dental implants in patients with and without a history of periodontitis through a deep-sequencing approach. | 2017 | 28492362 |
| inflammatory bacteriome featuring fusobacterium nucleatum and pseudomonas aeruginosa identified in association with oral squamous cell carcinoma. | studies on the possible association between bacteria and oral squamous cell carcinoma (oscc) remain inconclusive, largely due to methodological variations/limitations. the objective of this study was to characterize the species composition as well as functional potential of the bacteriome associated with oscc. dna obtained from 20 fresh oscc biopsies (cases) and 20 deep-epithelium swabs (matched control subjects) was sequenced for the v1-v3 region using illumina's 2 × 300 bp chemistry. high qual ... | 2017 | 28500338 |
| antimicrobial activities of stearidonic and gamma-linolenic acids from the green seaweed enteromorpha linza against several oral pathogenic bacteria. | we found that the edible green seaweed enteromorpha linza displayed potent antimicrobial activity against prevotella intermedia and porphyromonas gingivalis. to elucidate the active component of e. linza, isolation procedures were performed. | 2013 | 28510876 |
| herpes simplex 1 and periopathogen role in peri-implantitis. | the objectives of this study were to compare the qualitative and quantitative profiles of herpes simplex virus type i (hsv-1) in implant surfaces between participants with peri-implantitis (pi) and healthy peri-implant tissues and to quantitatively assess the relation between hsv-1 and periopathogens inside the microbiological profile associated with pi. | 2017 | 28512280 |
| detection of fusobacterium nucleatum in culture-negative brain abscess by broad-spectrum bacterial 16s rrna gene pcr. | fusobacterium nucleatum is a strict anaerobic microorganism commensal to the human oropharynx and gastrointestinal tract, which causes a wide spectrum of human diseases and it is an important pathogen in abscesses. | 2017 | 28516038 |
| new bicyclic brominated furanones as potent autoinducer-2 quorum-sensing inhibitors against bacterial biofilm formation. | bacterial behaviors such as virulence factor secretion and biofilm formation are critical for survival, and are effectively regulated through quorum sensing, a mechanism of intra- and interspecies communication in response to changes in cell density and species complexity. many bacterial species colonize host tissues and form a defensive structure called a biofilm, which can be the basis of inflammatory diseases. periodontitis, a chronic inflammatory disease affecting the periodontium, is caused ... | 2017 | 28554093 |
| biofilm-induced changes to the composite surface. | composites may undergo biodegradation in the oral cavity. the objective was to investigate the effect of single- and multi-species biofilms on the surface roughness and topography of two composites. | 2017 | 28554609 |
| crystal structure of n-acetylmannosamine kinase from fusobacterium nucleatum. | sialic acids comprise a varied group of nine-carbon amino sugars that are widely distributed among mammals and higher metazoans. some human commensals and bacterial pathogens can scavenge sialic acids from their environment and degrade them for use as a carbon and nitrogen source. the enzyme n-acetylmannosamine kinase (nank; ec 2.7.1.60) belongs to the transcriptional repressors, uncharacterized open reading frames and sugar kinases (rok) superfamily. nank catalyzes the second step of the sialic ... | 2017 | 28580924 |
| fusobacterium and colorectal cancer: causal factor or passenger? results from a large colorectal cancer screening study. | colorectal cancer is a leading cause of morbidity and mortality worldwide in both men and women. the gut microbiome is increasingly recognized as having an important role in human health and disease. fusobacterium has been identified in former studies as a leading gut bacterium associated with colorectal cancer, but it is still not clear if it plays an oncogenic role. in the current study, fecal samples were collected prior to bowel preparation from participants of screening colonoscopy in the g ... | 2017 | 28582482 |
| bactericidal effects of 310 nm ultraviolet light-emitting diode irradiation on oral bacteria. | ultraviolet (uv) light is used for phototherapy in dermatology, and uvb light (around 310 nm) is effective for treatment of psoriasis and atopic dermatitis. in addition, it is known that uvc light (around 265 nm) has a bactericidal effect, but little is known about the bactericidal effect of uvb light. in this study, we examined the bactericidal effects of uvb-light emitting diode (led) irradiation on oral bacteria to explore the possibility of using a 310 nm uvb-led irradiation device for treat ... | 2017 | 28587675 |
| intratumoral fusobacterium nucleatum abundance correlates with macrophage infiltration and cdkn2a methylation in microsatellite-unstable colorectal carcinoma. | fusobacterium nucleatum (fn), a specific species of gut microbiota, has been suggested to be enriched in the microsatellite instability-high (msi-h) molecular subtype of colorectal carcinomas (crcs). however, the clinicopathologic and molecular factors that interact with fn in msi-h crcs are poorly understood. in this study, 16s ribosomal rna gene dna sequence of fn was quantitatively measured by real-time polymerase chain reaction in tumor dna samples from a total of 160 surgically resected msi ... | 2017 | 28597080 |
| effectiveness in the removal of endotoxins and microbiological profile in primary endodontic infections using 3 different instrumentation systems: a randomized clinical study. | this clinical study was conducted to correlate the microbiological profile and levels of endotoxins found in primary endodontic infection with the presence of clinical features and to evaluate the removal of microorganisms and endotoxins using rotary, reciprocating, and hybrid systems for biomechanical preparation. | 2017 | 28606669 |
| fusobacterial liver abscess: a case report and review of the literature. | fusobacteriae are facultative anaerobic gram-negative bacilli which cause a range of invasive infections, amongst which pyogenic liver abscesses are rare. we describe a case of fusobacterium nucleatum liver abscess and review the relevant literature. | 2017 | 28633639 |
| structure of the lps o-chain from fusobacterium nucleatum strain 12230. | fusobacterium nucleatum is an anaerobic bacterium found in the human mouth where it causes periodontitis. it was also found in colorectal cancer tissues and is linked with pregnancy complications, including pre-term and still births. cell surface structures of the bacterium could be implicated in pathogenesis. here we report the following structure of the lipopolysaccharide o-chain of f. nucleatum strain 12230: -6-α-d-glc-4-β-d-glcnhbu3nhbua-3-β-d-quinac4nabu- where abu and hbu indicate (r)-3-am ... | 2017 | 28651243 |
| microbial analysis of root canal and periradicular lesion associated to teeth with endodontic failure. | the quantification of ten microorganisms at the root ends and in the surrounding periradicular lesions was performed. thirty 3 mm samples root ends and 30 samples of the surrounding chronic periapical infection were collected during apical microsurgery. samples were triturated, and the bacterial dna was obtained. the bacterial quantification was performed by using the sybr green system. at least one microorganism was detected in all patients. in both the root end and periapical samples, fusobact ... | 2017 | 28666877 |
| investigation of a novel predictive biomarker profile for the outcome of periodontal treatment. | an ability to predict the response to conventional non-surgical treatment of a periodontal site would be advantageous. however, so far the biomarkers or tests devised to achieve this have lacked sensitivity. the aim of this study was to assess the ability of a novel combination of biomarkers to predict the outcome of treatment of patients with chronic periodontitis. | 2017 | 28671508 |
| genome-based reclassification of fusobacterium nucleatum subspecies at the species level. | fusobacterium nucleatum is classified as four subspecies, subsp. nucleatum, polymorphum, vincentii, and animalis, based on dna-dna hybridization (ddh) patterns, phenotypic characteristics, and/or multilocus sequence analysis (mlsa). the gold standards for classification of bacterial species are ddh and 16s ribosomal rna gene (16s rdna) sequence homology. the thresholds of ddh and 16s rdna similarity for delineation of bacterial species have been suggested to be >70 and 98.65%, respectively. aver ... | 2017 | 28687946 |
| periodontal microbioma and rheumatoid arthritis: the role of porhyromonas gingivalis. | rheumatoid arthritis is a disease, which can be described as an autoimmune response after molecular mimicry caused by infective agents. the current study aims at evaluating the correlation between rhematoid arthritis (ra) and periodontal disease (pd), with special attention to the microbioma detected in the gums. thirty-four patients with rd were recruited into the current study. among rheumatic parameters, rheumatoid factor (rf), anti-citrullinated protein antibody (ccp), hla-bdr1 and das28 wer ... | 2017 | 28691459 |
| comparisons of gut microbiota among healthy control, patients with conventional adenoma, sessile serrated adenoma, and colorectal cancer. | studies on gut microbiota regarding colorectal carcinogenesis, including sessile serrated adenoma (ssa), have been scarce. the aim of this study is to investigate the role of mucosa-associated gut microbiota in the colorectal carcinogenesis. | 2017 | 28698865 |
| bactericidal effect of different anti-microbial agents on fusobacterium nucleatum biofilm. | the root canal anatomy of the teeth is very complex. complete debridement of the root canals is a challenge and is very important for the success of the root canal treatment. hence, this study was done to find an effective irrigant which can be used during root canal treatment. | 2017 | 28706760 |
| tumor targeting by fusobacterium nucleatum: a pilot study and future perspectives. | colorectal adenocarcinoma (crc) is a common tumor with high mortality rates. interestingly, crc was found to be colonized by the oral anaerobic bacteria fusobacterium nucleatum, which accelerates tumor progression and enables immune evasion. the crc-specific colonization by fusobacteria is mediated through the recognition of tumor displayed gal-galnac moieties by the fusobacterial fap2 gal-galnac lectin. here, we show high gal-galnac levels in additional adenocarcinomas including those found in ... | 2017 | 28713780 |
| functional biomarkers for chronic periodontitis and insights into the roles of prevotella nigrescens and fusobacterium nucleatum; a metatranscriptome analysis. | periodontitis is the most prevalent inflammatory disease worldwide and is caused by a dysbiotic subgingival biofilm. here we used metatranscriptomics to determine the functional shift from health to periodontitis, the response of individual species to dysbiosis and to discover biomarkers. | 2015 | 28721234 |
| periodontal disease and intra-amniotic complications in women with preterm prelabor rupture of membranes. | periodontal disease is frequently suggested as a possible causal factor for preterm delivery. the link between periodontal disease and preterm delivery is a possible translocation of periopathogenic bacteria to the placenta and amniotic fluid as well as a systemic response to this chronic inflammatory disease. however, there is a lack of information on whether there is an association between clinical periodontal status in women with preterm prelabor rupture of membranes (pprom) and the presence ... | 2017 | 28724342 |
| a case of liver abscess and fusobacterium septicemia. | fusobacterium species are well described as the causative pathogen in lemierre's syndrome, a suppurative thrombophlebitis of the jugular vein. however, they are less recognized for a unique variant of lemierre's syndrome presenting with invasive intraabdominal infection and associated portal vein thrombosis. we describe a case of fusobacterium nucleatum with hepatic abscess and septic pylephlebitis. | 2017 | 28736715 |
| porphyromonas gingivalis suppresses invasion of fusobacterium nucleatum into gingival epithelial cells. | invasion of periodontal pathogens into periodontal tissues is an important step that can cause tissue destruction in periodontal diseases. porphyromonas gingivalis is a keystone pathogen and its gingipains are key virulence factors. fusobacterium nucleatum is a bridge organism that mediates coadhesion of disease-causing late colonizers such as p. gingivalis and early colonizers during the development of dental biofilms. the aim of this study was to investigate how p. gingivalis, in particular it ... | 2017 | 28748028 |
| drugs, bugs, and cancer: fusobacterium nucleatum promotes chemoresistance in colorectal cancer. | the tumor microenvironment has recently been shown to play decisive roles in chemotherapeutic response. in this issue of cell, yu et al. add to these findings by identifying the bacterium fusobacterium nucleatum as a previously unrecognized chemoresistance mediator in colorectal cancer, thereby establishing the microbiota as a potential therapeutic target. | 2017 | 28753421 |
| fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. | gut microbiota are linked to chronic inflammation and carcinogenesis. chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. we found that fusobacterium (f.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. furthermore, ... | 2017 | 28753429 |
| do quaternary ammonium monomers induce drug resistance in cariogenic, endodontic and periodontal bacterial species? | antibacterial monomers were developed to combat oral biofilm acids and caries; however, little is known on whether quaternary ammonium monomers (qams) would induce drug resistance in oral bacteria. the objective of this study was to investigate the effects of new antimicrobial monomers dimethylaminohexadecyl methacrylate (dmahdm) and dimethylaminododecyl methacrylate (dmaddm) on the induction of drug resistance in eight species of cariogenic, endodontic and periodontal bacteria for the first tim ... | 2017 | 28755761 |
| prevalence of periodontal pathogens among italian patients with chronic periodontitis: a retrospective study on 2992 patients. | the aim of the present study was to evaluate the prevalence of some periodontal pathogens in italian adults with chronic periodontitis. | 2017 | 28757933 |
| involvement of nlrp10 in il-1α induction of oral epithelial cells by periodontal pathogens. | this study investigated the pathogenesis of periodontitis and the role of nucleotide-binding oligomerization domain-like receptor protein 10 (nlrp10). the human oral epithelial cell line hok-16b was infected with two periodontal pathogens, tannerella forsythia and fusobacterium nucleatum, at various mois. rt-pcr and immunoblotting demonstrated that infection increased mrna and protein expression of nlrp10, respectively. the sirna-mediated nlrp10 knockdown significantly reduced il-1α expression a ... | 2017 | 28766990 |
| mechanisms by which porphyromonas gingivalis evades innate immunity. | the oral cavity is home to unique resident microbial communities whose interactions with host immunity are less frequently studied than those of the intestinal microbiome. we examined the stimulatory capacity and the interactions of two oral bacteria, porphyromonas gingivalis (p. gingivalis) and fusobacterium nucleatum (f. nucleatum), on dendritic cell (dc) activation, comparing them to the effects of the well-studied intestinal microbe escherichia coli (e. coli). unlike f. nucleatum and e. coli ... | 2017 | 28771533 |
| assessment of the involvement of the macrophage migration inhibitory factor-glucocorticoid regulatory dyad in the expression of matrix metalloproteinase-2 during periodontitis. | macrophage migration inhibitory factor (mif) is a proinflammatory cytokine and counter-regulator of endogenous glucocorticoids (gcs). it is implicated in acute and chronic inflammatory diseases. this study investigated the role of the mif-gc regulatory dyad in the expression and release of matrix metalloproteinase-2 (mmp-2) during periodontitis, in vivo and in vitro. in a mif-knockout (ko) mouse model of ligature-induced periodontitis, gingival tissues and blood were collected and analysed for l ... | 2017 | 28776753 |
| veillonellae catalase protects the growth of fusobacterium nucleatum in microaerophilic and streptococcus gordonii-present environments. | the oral biofilm is a multispecies community in which antagonism and mutualism coexist amongst friends and foes to keep an ecological balance of community members. the pioneer colonizers such as streptococcus gordonii produce h2o2 to inhibit the growth of competitors like the mutans streptococci as well as strict anaerobic middle and later colonizers of the dental biofilm. interestingly, the veillonella species, as early colonizers, physically interact (coaggregate) with s. gordonii a putative c ... | 2017 | 28778894 |
| fusobacterium nucleatum promotes autophagy-mediated chemoresistance. | abundant f. nucleatum is associated with disease recurrence in patients with colorectal cancer. | 2017 | 28778903 |
| perturbed human sub-networks by fusobacterium nucleatum candidate virulence proteins. | fusobacterium nucleatum is a gram-negative anaerobic species residing in the oral cavity and implicated in several inflammatory processes in the human body. although f. nucleatum abundance is increased in inflammatory bowel disease subjects and is prevalent in colorectal cancer patients, the causal role of the bacterium in gastrointestinal disorders and the mechanistic details of host cell functions subversion are not fully understood. | 2017 | 28793925 |
| combined antioxidant effects of neem extract, bacteria, red blood cells and lysozyme: possible relation to periodontal disease. | the common usage of chewing sticks prepared from neem tree (azadirachta indica) in india suggests its potential efficacy in periodontal diseases. the objective of this study is to explore the antibacterial effects of neem leaf extract on the periodontophatic bacteria porphyromonas gingivalis and fusobacterium nucleatum, and its antioxidant capacities alone and in combination with bacteria and polycationic peptides that may be at the site of inflammation. | 2017 | 28797303 |
| planktonic growth of pseudomonas aeruginosa around a dual-species biofilm supports the growth of fusobacterium nucleatum within that biofilm. | the goal of this study was to understand the potential interaction between pseudomonas aeruginosa and fusobacterium nucleatum within the middle ear. | 2017 | 28798773 |
| fusobacterium nucleatum as a prognostic marker of colorectal cancer in a japanese population. | accumulating evidence shows an overabundance of fusobacterium nucleatum in colorectal tumor tissues. however, the correlation between the absolute copy number of f. nucleatum in colorectal cancer tissues and colorectal cancer progression is unclear from previous reports. therefore, we performed a study to compare the abundance of f. nucleatum in colorectal tissues with clinicopathologic and molecular features of colorectal cancer. | 2017 | 28823057 |
| fusobacterium nucleatum detected simultaneously in a pyogenic liver abscess and advanced sigmoid colon cancer. | fusobacterium nucleatum is an invasive, adherent, and pro-inflammatory anaerobic bacterium involved in various infections and colorectal cancer. we report a case with pyogenic liver abscess, diagnosed with advanced sigmoid colon cancer, in whom f. nucleatum was simultaneously detected. in this patient, f. nucleatum was systematically analyzed using the molecular biological techniques of metagenome analysis, conventional pcr, and microbial fluorescence in situ hybridization. | 2017 | 28823592 |
| periopathogens differ in terms of the susceptibility to toluidine blue o-mediated photodynamic inactivation. | the main goal of periodontal therapy is to eliminate the infection spreading in periodontium. antimicrobial photodynamic therapy may be applied in order to eradicate pathogens remaining in periodontal tissues after conventional mechanical debridement, thus, improve the treatment results. the aim of this in vitro study was to evaluate the susceptibility of selected key periopathogens to toluidine blue o-mediated photodynamic inactivation and the influence of photosensitizer's concentration and li ... | 2017 | 28826733 |
| cancer associated faecal microbial markers in colorectal cancer detection. | colorectal cancer (crc) is the second most common cause of cancer death in the western world. an effective screening program leading to early detection of disease would severely reduce the mortality of crc. alterations in the gut microbiota has been linked to crc, but the potential of microbial markers for use in crc screening has been largely unstudied. we used a nested case-control study of 238 study subjects to explore the use of microbial markers for clba+ bacteria harbouring the pks pathoge ... | 2017 | 28833079 |
| impaired polymorphonuclear neutrophils in the oral cavity of edentulous individuals. | oral health is characterized by functional oral polymorphonuclear neutrophils (opmns). edentulism might be associated with a loss of opmns because these cells enter the oral cavity primarily through the gingival crevices. the main aim of this study was to investigate the numbers of opmns in rinse samples obtained from edentulous (n = 21) and dentate (n = 20) subjects. a second study aim was to investigate possible differences between opmns and peripheral blood polymorphonuclear neutrophils (cpmn ... | 2017 | 28833699 |
| relatively low invasive capacity of porphyromonas gingivalis strains into human gingival fibroblasts in vitro. | bacterial invasion into host cells is a common strategy to escape the host immune system. gingival fibroblasts (gfs) are the most predominant non-phagocytic cell type in gingival connective tissue. therefore, invasion into gfs was thought to be the first strategy for the survival of porphyromonas gingivalis. the present study compared the invasive ability of p. gingivalis into gfs with those of other red-complex and relatively less pathogenic bacterial strains, especially fusobacterium nucleatum ... | 2017 | 28841474 |
| the oral microbiome and adverse pregnancy outcomes. | significant evidence supports an association between periodontal pathogenic bacteria and preterm birth and preeclampsia. the virulence properties assigned to specific oral pathogenic bacteria, for example, fusobacterium nucleatum, porphyromonas gingivalis, filifactor alocis, campylobacter rectus, and others, render them as potential collaborators in adverse outcomes of pregnancy. several pathways have been suggested for this association: 1) hematogenous spread (bacteremia) of periodontal pathoge ... | 2017 | 28848365 |
| quantification by qpcr of pathobionts in chronic periodontitis: development of predictive models of disease severity at site-specific level. | currently, there is little evidence available on the development of predictive models for the diagnosis or prognosis of chronic periodontitis based on the qpcr quantification of subgingival pathobionts. our objectives were to: (1) analyze and internally validate pathobiont-based models that could be used to distinguish different periodontal conditions at site-specific level within the same patient with chronic periodontitis; (2) develop nomograms derived from predictive models. subgingival plaqu ... | 2017 | 28848499 |