Protocol for CARES-HAPIN: an ambidirectional cohort study on exposure to environmental tobacco smoke and risk of early childhood caries.

INTRODUCTION: Prenatal and postnatal exposure to environmental tobacco smoke (ETS) has been linked with early childhood caries (ECC), but the specific molecular mechanisms and pathways remain largely unknown. The Caries Risk from exposure to Environmental tobacco Smoke (CARES) within the Household Air Pollution Intervention Network (HAPIN) study aims to establish the association between ETS and ECC by employing epidemiological and novel biomarker-based approaches. Here, we outline the overall design and rationale of the project. METHODS AND ANALYSIS: We will leverage the infrastructure and data from the HAPIN trial (India) to mount the CARES study. In this ambidirectional cohort study, children (n=735, aged: 3-5 years) will undergo ECC examination by a trained dentist using standard criteria and calibrated methods. Structured questionnaires will be used to gather information on sociodemographic variables, dietary habits, oral hygiene, oral health-related quality of life and current exposure to ETS. We will collect non-invasive or minimally invasive biospecimens (i.e., saliva, buccal cells, dried blood spots and urine) from a subset of HAPIN children (n=120) to assess a battery of biomarkers indicative of exposure to ETS, early biological effect and epigenetic modifications. Both self-reported and objective measures of ETS exposure collected longitudinally during in utero and early postnatal periods will be accessed from the HAPIN database. We will apply current science data techniques to assess the association and interrelationships between ETS, ECC, and multiple biomarkers. ETHICS AND DISSEMINATION: Information gathered in this research will be published in peer-reviewed journals and summaries will be shared with the key stakeholders as well as patients and their parents/guardians involved in this study. Sri Ramachandra Institute of Higher Education and Research Ethics Board has approved the study protocol (IEC-NI22/JUL/83/82). TRIAL REGISTRATION NUMBER: NCT02944682.

Association between polymorphisms of immune response genes and early childhood caries - systematic review, gene-based, gene cluster, and meta-analysis.

BACKGROUND: Early childhood caries is a significant public health concern affecting about 600 million children globally. The etiology of early childhood caries can be explained as an interplay between genetic and environmental factors. Single nucleotide polymorphisms are the most common variations in the human genome. Genetic variations of immune response genes can modify the defense response of the host, and alter the susceptibility to bacterial colonization of the oral cavity and early childhood caries. The aim of this systematic review is to identify genetic variants of immune response genes associated with early childhood caries. RESULTS: A total of 7124 articles were identified by conducting an elaborate search across various electronic databases and genome-wide association studies databases. Subsequent to exclusion at various stages, fifteen articles qualified to be included into the present review. Risk of bias assessment was done with the Q-genie tool. Quantitative synthesis revealed that the odds ratio for TT and CC genotypes of rs11362 was 1.07 (0.67-1.71) and 1.16 (0.84-1.60), respectively. Gene-based analysis revealed a statistically significant association between variants of tumor necrosis factor-alpha gene and T-cell receptor alpha variable 4 locus with early childhood caries. Gene clustering showed the presence of three functional clusters. To comprehend the protein-protein interaction, the bioinformatic tool of "Search Tools for the Retrieval of Interacting Genes and Proteins" was used. Among the biological processes and the reactome pathways, complement activation through the lectin pathway showed the highest strength of association with early childhood caries. To understand the interaction and functionality of the genes, "gene function prediction using Multiple Association Network Integration Algorithm" was used, which revealed that the genes were linked by physical interaction (39.34%) and through co-expression (34.88%). CONCLUSIONS: Genotype TT of rs7217186 of arachidonate 15-lipoxygenase gene was a risk factor for early childhood caries. Multiple genetic variants of T-cell receptor alpha variable 4 locus and tumor necrosis factor-alpha gene were associated with increased susceptibility to early childhood caries. Polymorphisms of genes regulating the lectin pathway of complement activation can modify the susceptibility to early childhood caries.

Environmental tobacco smoke and children's health: a bibliometric and altmetric analysis of 100 most cited articles.

BACKGROUND: Exposure to environmental tobacco smoke (ETS) is arguably the most ubiquitous and hazardous, even at very low levels, starting in early life. The objective of this study was to describe the state of research and future trends on ETS exposure and Children's Health (CH) topics with bibliometrics and altmetrics. METHODS: An electronic search was performed in Scopus database on January 31, 2023. Consensus was arrived on 100 most-cited articles by two reviewers. These papers were then cross matched with citations harvested from Web of Science (WoS) and Google Scholar. Altmetric Attention Score (AAS) and Dimension counts were also collected. Analysis and network visualization of authors, countries, and keywords were generated using VOSviewer software. RESULTS: Among a total of 1107 articles published on ETS and CH, the 100 top-cited articles appeared in 54 journals, with Pediatrics (n = 12) contributing a maximum number of articles. The time period between 2000 and 2009 accounted for 44% of all publications. With respect to the research design employed across these studies, cross-sectional design took precedence over others accounting for approximately 40%. Predominantly, articles focused on childhood asthma; however, current research trends have shifted towards emerging fields such as children's oral health and DNA methylation. Twitter, policy documents, and news outlets were the main platforms where outputs were discussed. The AAS was not associated with journal impact factor or access type. Weak correlations were observed between AAS and citation count in Scopus, WoS, and Google Scholar (r = 0.17 to 0.27) while a positive association existed between dimension count and the number of citations across all three databases (r = 0.84 to 0.98). CONCLUSION: This study demonstrates the evolution, digital dissemination and research hotspots in the field of ETS and CH, predicting the possible future research directions. High-quality studies with more specific exposure classification are warranted to better understand the relationship between ETS and CH.

Single nucleotide polymorphisms of enamel formation genes and early childhood caries - systematic review, gene-based, gene cluster and meta-analysis.

Introduction: Genetic polymorphisms of genes regulating amelogenesis can alter susceptibility to Early Childhood Caries (ECC). This systematic review aims to analyze associations between single-nucleotide polymorphisms of enamel formation genes and ECC. Methods: Search was conducted across PUBMED, CINAHL, LILACS, SCOPUS, EMBASE, Web of Science, Genome-Wide Association Studies databases from January 2003 to September 2022. This was supplemented by hand search. Totally 7124 articles were identified and 21 articles that satisfied the inclusion criteria proceeded to data extraction. Quality assessment was done using the Q-Genie tool. Results: Quantitative synthesis revealed that homozygous genotype AA of rs12640848 was significantly higher in children with ECC with an odds ratio of 2.36. Gene-based analysis revealed significant association between six variants of AMBN, four variants of KLK4, two variants of MMP20, and a single variant of each of MMP9 and MMP13 genes and ECC. The Bonferroni corrected-log10 P value of amelogenesis gene Cluster was 2.25 (0.05/88 = 5.6 × 10-4). Search Tool for Retrieval of Interacting Genes and Proteins plot constructed to comprehend the protein-protein interaction revealed the presence of four functional clusters. Gene function prediction using Multiple Association Network Integration Algorithm revealed that physical interaction between these genes was 69.3%. Conclusion: Polymorphisms of genes regulating amelogenesis can influence the susceptibility to ECC. AA genotype of rs12640848 may increase the susceptibility to ECC. Gene-based analysis revealed a significant association between multiple polymorphisms of genes regulating amelogenesis and ECC.

Systematic review of clinical practice guidelines for traumatic dental injuries.

BACKGROUND/AIMS: Traumatic dental injuries (TDI) are considered a public health problem due to their high prevalence and associated physical, economic, psychological and social consequences. Hence, good Clinical Practice Guidelines are essential to achieving a favourable prognosis. The aim of this review was to appraise the existing Clinical Practice Guidelines (CPGs) on TDI using AGREE II and AGREE-REX. MATERIALS AND METHODS: A systematic search for existing guidelines on TDI was performed on PubMed, EMBASE, CINAHL, Cochrane Library, ProQuest, National Institute for Health Care Excellence, BMJ Best Practice, Trip database, Guideline International Network, Scottish Intercollegiate Guidelines Network, World Health Organisation, Web of Science and 'Ministry of Health worldwide' databases. Four appraisers independently appraised the included CPGs. The AGREE II tool was applied to assess the methodological quality, while AGREE REX assessed the quality of recommendations of the included guidelines. RESULTS: Of the 7736 titles screened, three guidelines, namely the International Association of Dental Traumatology Guidelines (IADT), and the Italian and Malaysian guidelines, were included for the final analysis. These guidelines were published between 2019 and 2020. The AGREE II analysis demonstrated scores above 80% for the IADT and Italian guidelines for the scope and purpose domain. Overall, the Malaysian guidelines achieved the highest score for all domains. The AGREE REX analysis indicated variability in implementation across the nine items, with five that scored above the midpoint of 4.0 on the response scale. Both the Italian and the IADT guidelines had a similar score for the values and preference domains (36.36%). CONCLUSIONS: Several deficiencies exist in the methodological quality of existing CPGs on TDI. Future guidelines should consider improvements for domains such as 'rigour of development', 'stakeholder involvement' and 'applicability' to overcome the existing limitations.

Sustainable development goals and ending ECC as a public health crisis.

Early Childhood Caries (ECC) remains a global issue despite numerous advancements in research and interventional approaches. Nearly, 530 million children suffer from untreated dental caries of primary teeth. The consequences of such untreated dental caries not only limit the child's chewing and eating abilities but also, significantly impact the child's overall growth. Research has demonstrated that ECC is associated with nearly 123 risk factors. ECC has also been associated with local pain, infections, abscesses, and sleep pattern. Furthermore, it can affect the child's emotional status and decrease their ability to learn or perform their usual activities. In high-income countries, dental care continues to endorse a "current treatment-based approach" that involves high-technology, interventionist, and specialized approaches. While such approaches provide immediate benefit at an individual level, it fails to intercept the underlying causes of the disease at large. In low-income and middle-income countries (LMICs), the "current treatment approach" often remains limited, unaffordable, and unsuitable for the majority of the population. Rather, dentistry needs to focus on "sustainable goals" and integrate dental care with the mainstream healthcare system and primary care services. Dental care systems should promote "early first dental visits," when the child is 1 year of age or when the first tooth arrives. The serious shortages of appropriately trained oral healthcare personnel in certain regions of the world, lack of appropriate technologies and isolation of oral health services from the health system, and limited adoption of prevention and oral health promotion can pose as critical barriers. The oral health care systems must focus on three major keystones to combat the burden of ECC-1. Essential oral health services are integrated into healthcare in every country ensuring the availability of appropriate healthcare accessible and available globally, 2. Integrating oral and general healthcare to effectively prevent and manage oral disease and improve oral health, 3. Collaborating with a wide range of health workers to deliver sustainable oral health care tailored to cater to the oral health care needs of local communities.

Targeting the translational machinery in gastrointestinal stromal tumors (GIST): a new therapeutic vulnerability.

Although KIT-mutant GISTs can be effectively treated with tyrosine kinase inhibitors (TKIs), many patients develop resistance to imatinib mesylate (IM) as well as the FDA-approved later-line agents sunitinib, regorafenib and ripretinib. Resistance mechanisms mainly involve secondary mutations in the KIT receptor tyrosine kinase gene indicating continued dependency on the KIT signaling pathway. The fact that the type of secondary mutation confers either sensitivity or resistance towards TKIs and the notion that secondary mutations exhibit intra- and intertumoral heterogeneity complicates the optimal choice of treatment in the imatinib-resistant setting. Therefore, new strategies that target KIT independently of its underlying mutations are urgently needed. Homoharringtonine (HHT) is a first-in-class inhibitor of protein biosynthesis and is FDA-approved for the treatment of chronic myeloid leukemia (CML) that is resistant to at least two TKIs. HHT has also shown activity in KIT-mutant mastocytosis models, which are intrinsically resistant to imatinib and most other TKIs. We hypothesized that HHT could be effective in GIST through downregulation of KIT expression and subsequent decrease of KIT activation and downstream signaling. Testing several GIST cell line models, HHT led to a significant reduction in nascent protein synthesis and was highly effective in the nanomolar range in IM-sensitive and IM-resistant GIST cell lines. HHT treatment resulted in a rapid and complete abolishment of KIT expression and activation, while KIT mRNA levels were minimally affected. The response to HHT involved induction of apoptosis as well as cell cycle arrest. The antitumor activity of HHT was confirmed in a GIST xenograft model. Taken together, inhibition of protein biosynthesis is a promising strategy to overcome TKI resistance in GIST.

Crown dimensions of primary teeth-A systematic review and meta-analysis.

Odontometrics, also known as metric traits, includes mesiodistal, buccolingual dimensions, and crown height. The purpose of this study was to assess pancontinental odontometric variations in the crown dimensions of primary teeth. Ten electronic databases were searched to identify studies that measured crown dimensions of primary teeth, published in English language, without year restriction up to July 2020. Studies included cross-sectional research measuring on casts, subjects, and on radiographs of healthy children. Meta-analysis was performed, and risk of bias was assessed using modified Newcastle-Ottawa Scale. Eighty-seven observational studies were included, with 24,634 participants (9487 males, 11,083 females; 19 studies lacked gender information). Only one study showed a low bias risk, whereas 81 and 5 studies had moderate and high risk, respectively. Sixty-five studies included for meta-analysis revealed heterogeneity in mean mesiodistal dimensions of maxillary first molars from Asia (I2 -99.7%), buccolingual measurements of mandibular first molars from Europe (I2 -99.9%), crown height of mandibular second molars from Africa and Europe (I2 -79.8%). Among mesiodistal and buccolingual dimensions, Australians have larger while Asians have smaller teeth. Pertaining to crown height, very few studies could be found in the literature. This review highlights the variations in crown dimensions of primary teeth among populations.

Early Childhood Caries and Iron Deficiency Anaemia: A Systematic Review and Meta-Analysis.

Identification of the association between Early Childhood Caries (ECC) and Iron Deficiency Anaemia (IDA) will aid paediatricians and paediatric dentists to enhance health promotion measures to reduce the related morbidity in children. This systematic review aims to determine an evidence-based association between ECC and IDA. A systematic search was carried out from MEDLINE via PubMed, EMBASE, LILACS, Cochrane Oral Health Group's Specialized Register, CINAHL via EBSCO, Web of Science, and Scopus up to May 2020. Hand searching and grey literature screening were also conducted. Cross-sectional, case-control, and cohort studies in English language which assessed the association was included. Two reviewers independently assessed the study quality and extracted the outcome data. A total of 1,434 studies were identified. Fourteen studies qualified for qualitative review and 7 of them for a meta-analysis. In comparison with children not affected by ECC, those affected had an increased likelihood of IDA (OR = 6.07 [3.61, 10.21]). The meta-analysis showed no statistical difference when comparing blood parameters (Hb, MCV, and serum ferritin) in children with and without ECC. This systematic review demonstrates an association between ECC and increased odds of IDA rather than it being the cause for IDA. Further longitudinal studies with robust methodology are required to determine an evidence-based association.

Prevalence of the Cusp of Carabelli: a systematic review and meta-analysis.

CONTEXT: The Cusp of Carabelli (CoC) is the most commonly occurring dental morphological trait. OBJECTIVE: To provide a pancontinental overview on the prevalence of the CoC in primary maxillary second molars and permanent maxillary molars. METHODS: An electronic search was conducted on ten databases without year restrictions up to July 2020. All cross-sectional studies published in the English language reporting prevalence estimate of CoC were included. A modified version of the Newcastle-Ottawa scale was used to assess study quality. Meta-analyses were conducted for studies that reported data using Dahlberg and ASUDAS classification across continents. RESULTS: For qualitative synthesis, 142 studies (45,327 participants) were included, of which 130 studies had moderate risk of bias. Random effects meta-analysis was performed for 41 studies. For prevalence of CoC in primary maxillary second molars, the estimate was 72% (2,829 participants). The overall percentage attained for permanent maxillary molars was 59% (16,607 participants) for first molars; 8% (2,277 participants) for second molars; and 10% (89 participants) for third molars. Subgroup analysis revealed the European continent reported the highest prevalence in permanent maxillary first and second molars. CONCLUSION: Primary maxillary second molars recorded highest prevalence of CoC followed by permanent maxillary first, third and second molars. Pancontinental studies with regard to primary maxillary second molars are warranted.

Fluoride release and fluoride-recharging ability of three different sealants.

BACKGROUND: We aimed to determine the fluoride release and fluoride-recharging ability of a sealant containing surface pre-reacted glass (S-PRG) ionomer filler particles (BeautiSealant) with a fluoride-releasing resin sealant (Helioseal F), and a glass-ionomer sealant (Fuji VII). METHODOLOGY: Forty-eight disc-shaped specimens of each material were immersed in deionized water to determine the fluoride release utilizing a fluoride ion-selective electrode. After 21 days, 8 specimens were soaked in 0.22% Sodium Fluoride solution for 2 min; 8 specimens were coated with 1.23% Acidulated Phosphate Fluoride (APF) gel for 4 min, and the fluoride-recharging ability was evaluated for 40 days. Data were analyzed using one way-ANOVA and Bonferroni post hoc tests. RESULTS: Total fluoride release over the 21-day period was: Fuji VII > BeautiSealant > Helioseal F, (P = 0.000). After refluoridation of the specimens with 0.22% Sodium Fluoride solution, the cumulative fluoride release during the 40-day period for each material was: BeautiSealant > Fuji VII > Helioseal (P = 0.000). After exposure to 1.23% APF gel, the cumulative fluoride release during the 40-day period for each material was: BeautiSealant > Fuji VII > Helioseal F (P = 0.000). CONCLUSION: Glass ionomer-based sealants (Fuji VII) exhibited higher initial fluoride release whilst the surface pre-reacted glass-ionomer filler containing sealant (BeautiSealant) demonstrated superior fluoride recharging properties.

Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumor (GIST) cells.

The majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, most GISTs develop imatinib resistance through secondary KIT mutations. The type of resistance mutation determines sensitivity to approved second-/third-line TKIs but shows high inter- and intratumoral heterogeneity. Therefore, therapeutic strategies that target KIT independently of the mutational status are intriguing. Inhibiting the ubiquitin-proteasome machinery with bortezomib is effective in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of the pro-apoptotic histone H2AX but clinically problematic due to the drug's adverse effects. We therefore tested second-generation inhibitors of the 20S proteasome (delanzomib, carfilzomib and ixazomib) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination (b-AP15, MLN4924) for their effectiveness and mechanism of action in GIST. All three 20S proteasome inhibitors were highly effective in vitro and in vivo, including in imatinib-resistant models. In contrast, b-AP15 and MLN4924 were only effective at high concentrations or had mostly cytostatic effects, respectively. Our results confirm 20S proteasome inhibitors as promising strategy to overcome TKI resistance in GIST, while highlighting the complexity of the ubiquitin-proteasome machinery as a therapeutic target.

A bibliometric analysis of the 100 most cited articles on early childhood caries.

BACKGROUND: Bibliometric analysis aids to quantify the research prolificacy. The citation count acquired by a scientific article is one of the measures of its influence within a field. AIM: To employ bibliometrics to offer a quantitative-qualitative analysis of publications on early childhood caries (ECC) published between 1950 and 2019. DESIGN: Two researchers independently read all the titles and abstracts of articles retrieved from Scopus database on 16 October 2019. The articles were categorized according to citation and study characteristics. Collaboration network amongst authors, countries, and keywords were generated using VOSviewer software. RESULTS: Amongst a total of 10 578 articles published on ECC, 100 most cited articles were sorted. The top-cited articles appeared in 34 journals, with Community Dentistry and Oral Epidemiology journal (n = 18) contributing maximum number of articles. The papers originated from 25 countries, with the United States (n = 54) accounting for largest number. Amid the papers with high levels of evidence, 11 were systematic reviews and 8 were randomized clinical trials. The topic most commonly addressed was aetiology/associated factors (63%). Amongst a total of 990 keywords, 'dental caries' appeared 89 times. CONCLUSION: The findings of this paper will help researchers, academicians, and students for appropriate article referrals for evidence-based clinical decision-making.

Opposing roles of KIT and ABL1 in the therapeutic response of gastrointestinal stromal tumor (GIST) cells to imatinib mesylate.

Most gastrointestinal stromal tumors (GISTs) are caused by activating mutations of the KIT receptor tyrosine kinase. The small molecule inhibitor imatinib mesylate was initially developed to target the ABL1 kinase, which is constitutively activated through chromosomal translocation in BCR-ABL1-positive chronic myeloid leukemia. Because of cross-reactivity of imatinib against the KIT kinase, the drug is also successfully used for the treatment of GIST. Although inhibition of KIT clearly has a major role in the therapeutic response of GIST to imatinib, the contribution of concomitant inhibition of ABL in this context has never been explored. We show here that ABL1 is expressed in the majority of GISTs, including human GIST cell lines. Using siRNA-mediated knockdown, we demonstrate that depletion of KIT in conjunction with ABL1 - hence mimicking imatinib treatment - leads to reduced apoptosis induction and attenuated inhibition of cellular proliferation when compared to depletion of KIT alone. These results are explained by an increased activity of the AKT survival kinase, which is mediated by the cyclin-dependent kinase CDK2, likely through direct phosphorylation. Our results highlight that distinct inhibitory properties of targeted agents can impede antitumor effects and hence provide insights for rational drug development. Novel KIT-targeted agents to treat GIST should therefore comprise an increased specificity for KIT while at the same time displaying a reduced ability to inhibit ABL1.