OBJECTIVES The aim of this systematic review was to critically analyze available data on gene polymorphisms in odontogenic keratocysts and ameloblastomas, including their possible relationship with clinical and histological features of these lesions. MATERIALS AND METHODS A comprehensive search of Web of Science Scopus, PubMed, Cochrane Central Register of Controlled Trials and EMBASE was conducted using relevant key terms and supplemented by a gray literature search. Quality assessment of included studies was performed using criteria from the Strengthening the Reporting of Genetic Association (STREGA) statement. RESULTS Ten studies were included in the final review. Survivin -31G/C, interleukin IL-1α -889 C/T, p53 codon 72 G/C, tumor necrosis factor TNF-α (-308G>A) and its receptor TNF-R1 (36A>G), glioma-associated oncogene homolog 1 rs2228224 and matrix metalloproteinase 2 rs243865 gene polymorphisms were reported to be associated with odontogenic keratocysts. For ameloblastomas, p53 - codon 72 G/C, X-ray repair cross-complementing protein 1 - codons 194 and 399 and matrix metalloproteinase 9 rs3918242 gene polymorphisms were identified as risk factors. It wasn't possible to establish a relationship between specific polymorphisms and clinical and histological features of investigated lesions. CONCLUSIONS Several gene polymorphisms might be considered as a risk factor for the development of these lesions. Future studies should investigate whether these polymorphisms might be used to identify patients with increased risk of recurrence or aggressive disease.

INTRODUCTION This study aimed to perform a more precise estimation of the association between tumor necrosis factor-alpha (TNF-α) - 308 G/A single nucleotide polymorphism (SNP) and the risk of development of AP and its phenotypes based on all available published studies. METHODS The study was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and is registered in PROSPERO (CRD42020176190). The literature search was conducted via: Clarivate Analytics' Scopus, PubMed, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure databases, from inception to December 2020 with no language restrictions. Two reviewers were involved independently in study selection, data extraction and appraising the studies that were included. The quality of included studies was evaluated using the Strengthening the Reporting of Genetic Association (STREGA) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Frequencies of genotypes and alleles of TNF-alpha (G>A 308, rs1800629) gene, with 95% Odds ratio was used. RESULTS Four studies met the inclusion criteria with moderate risk of bias. This study revealed no significant association between TNF-α - 308 G/A SNP and AP, and the risk of AP development. Moreover, there was no significant association between genotype or allele frequency distribution and clinical manifestations (acute versus chronic) of AP. The certainty of evidence per GRADE was very low. CONCLUSIONS Due to very low certainty of evidence, whether there is an association between TNF-α - 308 G/A SNP and AP, warrants further well-designed multi-centric studies to adjudicate a better understanding of the role of genetic factors in the etiopathogenesis of AP.

AIM To critically evaluate the reporting quality of a random sample of clinical trials published in Endodontics against the PRIRATE 2020 checklist and to analyse the association between the quality of reported trials and a variety of parameters. METHODOLOGY Fifty randomized clinical trials relating to Endodontics were randomly selected from the PubMed database from 2015 to 2019 and evaluated by two independent reviewers. For each trial, a score of '1' was awarded when it fully reported each item in the PRIRATE guidelines whereas a score of '0' was awarded when an item was not reported; when the item was reported inadequately a score of '0.5' was awarded. For the items that were not relevant to the trial, 'Not Applicable (NA)' was given. Based on the interquartile range of the overall scores received, trials were categorized into 'Low' (0-58.4%), 'Moderate' (58.5-72.8%) and 'High' (72.9-100%) quality. The associations between characteristics and quality of clinical trials were investigated. Descriptive statistics, frequency analysis and percentage analyses were used to describe the data. To determine the significance of categorical data, the chi-square test was used. The probability value 0.05 was considered as the level of significance. RESULTS Based on the overall scores, 13 (26%), 25(50%) and 12 (24%) of the reports of clinical trials were categorized as 'High', 'Moderate' and 'Low' quality, respectively. Three items (1b, 6d, 11e) were adequately reported in all manuscripts whilst two items (5k, 5m) were scored 'NA' in all the reports. The reports published from Europe had a significantly greater percentage of 'High'-quality scores, compared to Asia, Middle East, North America and South America (P = 0.0002). The 'High'-quality reports were published significantly more often in impact factor journals (P = 0.045). Reports of clinical trials published in journals that adhered to the CONSORT guidelines had significantly more 'High' scores compared to those that did not (P = 0.008). Clinical trials with protocols registered a priori had a significantly greater percentage of 'High' scores compared to the trials that were not registered in advance (P = 0.003). No significant difference occurred between the quality of clinical trials and the number of authors, journal (Endodontic specialty vs. Non-Endodontic specialty) or year of publication. CONCLUSIONS Reports of randomized clinical trials published in the speciality of Endodontics had a substantial number of deficiencies. To create high-quality reports of clinical trials, authors should comply with the PRIRATE 2020 guidelines.

Laws and ethics require that before conducting human clinical trials, a new material, device or drug may have to undergo animal testing in order to minimize the health risks to humans, unless suitable supporting grandfather data already exists. The Preferred Reporting Items for Animal Studies in Endodontology (PRIASE) 2021 guidelines were developed exclusively for the specialty of Endodontology by integrating and adapting the ARRIVE (Animals in Research: Reporting In Vivo Experiments) guidelines and the Clinical and Laboratory Images in Publications (CLIP) principles using a validated consensus-based methodology. The implementation of the PRIASE 2021 guidelines will reduce potential sources of bias and thus improve the quality, accuracy, reproducibility, completeness and transparency of reports describing animal studies in Endodontology. The PRIASE 2021 guidelines consist of a checklist with 11 domains and 43 individual items and a flowchart. The aim of the current document is to provide an explanation for each item in the PRIASE 2021 checklist and flowchart and is supplemented with examples from the literature in order for readers to understand their significance and to provide usage guidance. A link to the PRIASE 2021 explanation and elaboration document and PRIASE 2021 checklist and flowchart is available on the Preferred Reporting Items for study Designs in Endodontology (PRIDE) website (http://pride-endodonticguidelines.org/priase/).

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION Association between human cytomegalovirus and periodontitis: A systematic review and meta-analysis. Botero JE, Rodríguez-Medina C, Jaramillo-Echeverry A, Contreras A. J Periodontal Res. 2020;55(4):551-558. SOURCE OF FUNDING Information not available TYPE OF STUDY/DESIGN: Systematic review with meta-analysis of data.

INTRODUCTION This study aimed to summarize data on apical periodontitis (AP) and nonsurgical root canal treatment (NSRCT) prevalence and risk factors related to age, gender, and quality of restorative and endodontic treatment in the general population from cross-sectional studies published between 2012 and 2020. METHODS An electronic search was performed in the following databases: Web of Science, Scopus, and PubMed. The conducted literature search covered studies published between 2012 and 2020, without restrictions on language. The STROBE and NOS tools were used for quality assessment of the included studies. RESULTS Sixteen articles were included in the review. In total, 200.041 teeth were examined. On average, 6.3% of teeth had AP, and 7.4% had NSRCT. Forty-one percent of RCT teeth had AP, while 3.5% of untreated teeth had AP. Females are less prone to AP in endodontically treated teeth only, compared to males (P < .001). Variable stratification of age subgroups among included studies prevented us from conducting a meta-analysis. An increase in AP frequency was found in teeth with inadequate restorative and endodontic treatment (P < .001, and P < .001, respectively). Due to high heterogeneity, these results should be taken with caution. CONCLUSIONS There is an increased AP prevalence in the adult general population compared to data from 2012 (6.3% versus 5.4 %), both in endodontically treated (41.3% versus 35.9%) and untreated teeth (3.5% versus 2.1 %). Additionally, AP developed more frequently in females with endodontically treated teeth and in teeth with inadequate compared to adequate restorative and endodontic treatment.

BACKGROUND The existence of an association between cardiovascular diseases (CVDs) and apical periodontitis (AP) remains unclear because results obtained from previous clinical studies and reviews are inconsistent or inconclusive. OBJECTIVE To conduct an umbrella review to determine whether there is an association between CVDs and the prevalence of the AP in adults. METHODS The protocol of the review was registered in the PROSPERO database (CRD42020185753). The literature search was conducted using the following electronic databases: Clarivate Analytics' Web of Science Scopus, PubMed, and Cochrane Database of Systematic Reviews (CDSR), from inception to May, 2020, with no language restrictions. Systematic reviews with or without meta-analysis that evaluated the association between CVDs and AP were included. Other types of studies, including narrative reviews, were excluded. Two reviewers independently performed a literature search, data extraction, and quality assessment of included studies. Any disagreements or doubts were resolved by a third reviewer. The quality of the reviews was assessed using the AMSTAR 2 tool (A measurement tool to assess systematic reviews), with 16 items. A final categorization of the systematic reviews classified each as of "high", "moderate", "low", or "critically low" quality. RESULTS Four systematic reviews were included in the current review. Three reviews were graded by AMSTAR 2 as "moderate" quality, whereas one review was graded as "critically low" quality. DISCUSSION Only one systematic review included a meta-analysis. Substantial heterogeneity amongst the primary studies included within each systematic review was notable in preventing pooled analysis. CONCLUSIONS From the limited and moderate to low quality evidence available, the current umbrella review concluded that a weak association exists between CVDs and AP. In future, well-designed, longitudinal clinical studies with long-term follow-up are required.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION Association between diabetes and the outcome of root canal treatment in adults: an umbrella review. Nagendrababu V, Segura-Egea JJ, Fouad AF, Pulikkotil SJ, Dummer PMH. Int Endod J 2020;53(4):455-66. SOURCE OF FUNDING Authors declared that no funding was received to support the study. TYPE OF STUDY/DESIGN Umbrella review (ie, overarching systematic review of systematic reviews).

Apical periodontitis (AP) represents a persistent inflammatory reaction within periapical tissues of teeth devoid of vital pulp. Although it is considered as a multifactorial disease, in most of the cases it develops from the exposure of the vital pulp to different oral microbiota as a result of dental caries, accidental trauma or iatrogenic causes. Healthy dental pulp is a sterile environment, and, hypothetically, any microbe from the oral cavity may cause endodontic infection with subsequent destruction of tooth supporting tissues in the periapical region. The presence of herpesviral DNA in samples of periapical lesions was identified for the first time in 2003, suggesting its potential implication in the pathogenesis of AP. Namely, Slots and co-workers proposed a herpesviral-bacterial hypothesis by which herpesviruses may cause the destruction of periapical tissues as a result of direct cytopathogenic effects of different cell types in periapical region. They also claimed that herpesviruses may impair the local host defense and enhance aggressiveness of resident bacterial pathogens by several indirect mechanisms including inhibition of the major histocompatibility complex class I and II expression on the surface of macrophages, induction of pro-

AIM To investigate the possible association between TNFα (-308 G/A) and IL-1β (-511 C/T) single nucleotide polymorphisms (SNPs) and GSTT and GSTM deletion polymorphisms and risk of apical periodontitis (AP) development, and determine the association of different genotypes with the presence of herpesviral infection in AP. METHODOLOGY The study included 120 periapical lesions and 200 control samples. Gene polymorphism analysis was performed using either polymerase chain reaction (PCR) or PCR/ restriction fragment length polymorphism (RFLP). Relative gene expression of TNF-α and IL-1β was analysed using reverse transcriptase - real-time PCR. The presence of Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) was assessed by nested PCR. Chi square and Fisher exact tests, and logistic regression analyses were done for polymorphisms, while Mann Whitney U-test was performed for the expression analysis. The expected frequency of variants was analysed by the Hardy-Weinberg equilibrium test. RESULTS TNF-α (-308 G/A) SNP increased AP susceptibility for heterozygous (Odds Ratio (OR) = 1.72, 95% Confidence Interval (CI) = 1.06-2.80, P = 0.027) and homozygous (OR = 8.55, 95% CI = 1.77-41.36, P < 0.001) carriers of the variant A allele. On the other hand, IL-1β (-511 C/T) polymorphism exerted a protective effect both in heterozygotes (OR = 0.540, 95% CI = 0.332-0.880, P = 0.013) and homozygotes (OR = 0.114, 95% CI = 0.026-0.501, P < 0.001). In addition, GSTM1 and GSTT1 null genotypes separately, as well as concomitantly were associated with an increased risk for AP development (P < 0.001). The null GSTT1 genotype increased approximately twice the risk of Epstein-Barr infection (EBV) in AP (OR= 2.17, 95% CI=1-4.71, P=0.048), while TNF-α SNP decreased it, both in heterozygotes (OR=0.20, 95% CI= 0.08-0.48, P<0.001) and AA homozygotes (OR=0.07, 95% CI=0.01-0.37, P=0.001). CONCLUSIONS GSTM and GSTT deletion polymorphisms, as well as TNFα (-308 G/A) SNP, are associated with increased risk, whereas IL-1β (-511 C/T) polymorphism decreases the risk of AP development. GSTT and TNFα polymorphisms also appear to modulate the risk of EBV infection in Serbian patients with apical periodontitis.

Abstract Objectives: This study aimed to investigate whether Epstein-Barr virus (EBV) positive periapical lesions exhibited higher mRNA levels of Notch signalling molecules (Notch2 and Jagged1), bone resorption regulators (receptor activator of nuclear factor kappa-β ligand (RANKL) and osteoprotegerin (OPG)), and proinflammatory cytokines (tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and IL-6) compared to EBV negative lesions. Additionally, the potential correlation between investigated molecules in periapical lesions was analyzed. Materials and methods: Sixty-four apical periodontitis lesions were obtained subsequent to standard apicoectomy procedure. The presence of EBV was determined using nested PCR. Based on the presence of EBV all periapical lesions were divided into two groups, 29 EBV positive and 35 EBV negative lesions. A reverse transcriptase real-time PCR was used to determine mRNA levels of Notch2, Jagged1, RANKL, OPG, TNF-α, IL-1β and IL-6. Results: Significantly higher mRNA levels of Notch2, Jagged1, RANKL and IL-1β were observed in EBV positive compared to EBV negative lesions. Significant positive correlation was present between Notch2 and Jagged1, Jagged1 and RANKL, and IL-β and TNF-α in EBV positive periapical lesions. Conclusions: Notch signalling pathway may be involved in alveolar bone resorption in apical periodontitis lesions infected by EBV.

Mohammad Sabeti1*, Kory J Golchert1, Neveed Shirgill1, Aleksandar Jakovljevic2, Miroslav Andric3 and Jelena Milasin4 1Department of Endodontics, School of Dentistry, University of California, San Francisco, USA 2Department of Pathophysiology, School of Dental Medicine, University of Belgrade, Serbia 3Department of Oral Surgery, School of Dental Medicine, University of Belgrade, Serbia 4Department of Human Genetics, School of Dental Medicine, University of Belgrade, Serbia

Apical periodontitis represents a chronic inflammatory process within periapical tissues, mostly caused by etiological agents of endodontic origin. Progressive bone resorption in the periapical region represents the hallmark of apical periodontitis and occurs as the consequence of interplay between polymicrobial infections and host response. The Notch signaling pathway is an evolutionary conserved cell-signaling system that plays an important role in a variety of cell functions including proliferation, differentiation and apoptosis. In recent years its involvement in bone homeostasis has attracted a significant consideration. We hypothesized that Notch signaling pathway, which has a complex interplay with proinflammatory cytokines and bone resorption regulators, contributes to alveolar bone resorption via increased Notch receptors on immune cell surface and stimulates Notch receptor intracellular domain (NICD) translocation into the nucleus. The potential benefit of medications aimed to down-regulate these pathways in apical periodontitis treatment remains to be assessed.

Introduction The exact mechanisms of periapical bone resorption have not been fully elucidated. This study aimed to analyze the expression of Notch signaling molecules (Notch2, Jagged1, and Hey1) and proinflammatory cytokines (tumor necrosis factor alpha [TNF‐&agr;], interleukin [IL]‐1&bgr;, and IL‐6) in human apical periodontitis lesions with different receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegerin (OPG) ratios and determine their potential correlation. Methods The study group consisted of 50 periapical lesions collected in conjunction with apicoectomy. The relative gene expression of the investigated molecules (Notch2, Jagged1, Hey1, RANKL, OPG, TNF‐&agr;, IL‐1&bgr;, and IL‐6) in all tissue samples was analyzed using reverse transcriptase real‐time polymerase chain reaction. The Student t test, Mann‐Whitney U test, and Spearman correlation were used for statistical analysis. Results Based on the RANKL/OPG ratio, periapical lesions were either RANKL predominant (RANKL > OPG, n = 33) or OPG predominant (RANKL < OPG, n = 17). Symptomatic lesions occurred more frequently in RANKL‐predominant compared with OPG‐predominant lesions (24 vs 7, P = .029). Notch2, Jagged1, Hey1, and TNF‐&agr; were significantly overexpressed in lesions with predominant RANKL compared with lesions with predominant OPG (P = .001, P = .001, P = .027, and P = .016, respectively). Significant correlations were observed between the investigated genes in periapical lesions. Conclusions Notch signaling appeared to be activated in periapical inflammation. An increase in Notch2, Jagged1, Hey1, and TNF‐&agr; expression in RANKL‐predominant periapical lesions corroborates their joined involvement in extensive periapical bone resorption.