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Background: Chewing betel quid (BQ) - a preparation commonly containing areca nut and slaked lime wrapped in betel leaf - is entrenched in South Asia. Although BQ consumption during pregnancy has been linked to adverse birth outcomes, its effect on postnatal growth remains largely unexplored., Objective: We examined the associations of BQ use during pregnancy with children's height-for-age and body mass index-for-age z-scores (HAZ and BAZ, respectively) and fat and fat-free mass along with sex-based differences in association in rural Bangladesh., Methods: With a prospective cohort design, we assessed BQ use among mothers enrolled in the Preterm and Stillbirth Study, Matlab ( n  = 3140) with a structured questionnaire around early third trimester. Children born to a subset of 614 women (including 134 daily users) were invited to follow-up between October 2021 and January 2022. HAZ and BAZ were calculated from anthropometric assessment, and fat and fat-free mass were estimated using bioelectric impedance. Overall and sex-specific multiple linear regression models were fitted., Results: Growth data were available for 501 children (mean age 4.9 years): 43.3% of them were born to non-users, 35.3% to those using prior to or less-than-daily during the survey, and 21.3% to daily users. No statistically significant associations were observed after adjusting for sex, parity, maternal height and education, and household wealth., Conclusions: There was no effect of BQ use during pregnancy on postnatal growth in this study. Longitudinal studies following up those born to heavy users beyond childhood are warranted for capturing long-term implications of prenatal BQ exposure.

Oral submucous fibrosis (OSF) is a chronic, progressive condition affecting the oral mucosa associated with areca nut consumption. It leads to restricted tongue movement, loss of papillae, blanching and stiffening of the mucosa, difficulty in opening the mouth, and challenges in eating due to inflammation and fibrosis. This report presents a rare case of oropharyngeal stenosis secondary to OSF in a 43-year-old male with a history of chewing betel nut. A surgical procedure similar to Uvulopalatopharyngoplasty was performed to excise the submucous oropharyngeal stenosis and to reconstruct the uvula, palatoglossal arch, and palatopharyngeal arch. At 8 years postoperatively, the patient exhibited a normal mouth opening and oropharyngeal aperture., (© 2024. The Author(s).)

Introduction: Habitual betel quid chewing, a tobacco product, is a leading cause of oral cancer in Asia-Pacific countries where this practice is most prevalent. However, it is not well understood whether betel quid chewing is also a cause of adverse cardiovascular outcomes. To address this gap, we conducted a systematic literature review of peer-reviewed published studies evaluating the association between habitual betel quid use on the risk of adverse cardiovascular outcomes., Methods: We searched PubMed for studies assessing the correlation between betel quid chewing and cardiovascular health. We included studies if (i) they included human subjects; (ii) were peer-reviewed articles in indexed journals; and (iii) were in English. We extracted data from eligible studies and stratified them by geographical location, study designs and cardiovascular outcomes. Finally, we did a narrative synthesis of the data to identify adverse cardiovascular outcomes associated with chronic betel quid use., Findings: We reviewed data from 19 studies that met the inclusion criteria. Habitual betel quid chewing was associated with hypertension, atherosclerosis, inflammation and ischaemic heart disease. In addition, betel quid use was a risk factor for arrhythmias. Interestingly, betel quid use was an independent risk factor for cardiovascular disease in women. Long-term betel quid consumption was associated with higher risks for all-cause mortality and increased overall cardiovascular risk., Conclusions: Habitual betel quid chewing is an important cardiovascular risk factor in populations where the practice is prevalent., (© 2024 John Wiley & Sons Ltd.)

Background: Betel quid (BQ) chewing is a prevalent habit in the Asian and Pacific regions. It is deeply intertwined within cultural customs, and has been reported to result in oral potentially malignant disorders (OPMDs) and malignant disorders (MDs)., Objective: We aim to present a summative and broad overview of the burden that BQ chewing has imposed on the residents of the Southeast Asian, Pacific, and Australasian regions, allowing us to quantify the level of impact it is currently causing on the risk of people developing oral cancer., Methods: This scoping review and meta-analysis screened databases such as PubMed, MEDLINE, and Google Scholar for publications that investigated the association between BQ and OPMDs and MDs. The search strategy involved MeSH headings relating to BQ, OPMDs, and MDs, and a search for results during the period between January 2010 and June 2023 within the set geographical boundaries of the Southeast Asian and Pacific regions. This systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement for Scoping Reviews (PRISMA-ScR). R software was used to screen outliers. The included studies were further analysed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system., Results: Nine articles ( n  = 19,312 participants) presented odds ratio outcomes from 11 regionally different study groups. We indicated a strong correlation between BQ chewing and the increased risk of OMPDs and MDs. The risk was quantified through meta-analyses with an odds ratio (OR) of 8.18 (5.27-12.72) and an increased OR of 9.93 (7.36-13.39) when the outlier was removed. BQ chewing was further identified within various Australian communities and discovered to be produced locally in North Queensland., Discussion: A meta-analysis of two outcomes revealed substantial heterogeneity and minor evidence of publication bias, thus the association effect was included with and without these articles. The overall GRADE quality of evidence ranged from moderate to very high and highlighted five studies with a high level of imprecision., Conclusion: The lingering high prevalence of BQ in the Southeast Asia and Pacific regions, as well as its rising acceptance among non-ethnic Australians, is alarming and requires prompt and rigorous intervention to prevent the risk of oral cancer., Systematic Review Registration: PROSPERO (CRD42023429694)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Jasim, Li, Octavia, Gunardi, Crocombe and Sari.)

Introduction: The association between areca nut consumption and oral cancer has been a subject of increasing concern in global public health., Global Perspective: Areca nut, often chewed in various forms such as betel quid, is deeply rooted in cultural practices across Asia and other parts of the world. Epidemiological studies consistently reveal a significant correlation between areca nut use and the incidence of oral cancer, emphasizing the need for targeted preventive measures. The complex interplay of areca nut's bioactive compounds, particularly arecoline, with cellular processes, contributes to the initiation and progression of oral carcinogenesis. Mechanistic insights into the genotoxic and cytotoxic effects of its components underscore the urgency for comprehensive public health interventions., Public Health: Efforts to address this public health challenge involve multidisciplinary approaches, encompassing education, policy implementation, and behavioral interventions. Understanding the socio-cultural factors influencing areca nut consumption is pivotal for designing effective awareness campaigns and cessation programs., Conclusion: As oral cancer remains a significant global health burden, unraveling the nuanced relationship between areca nut and its role in oral carcinogenesis is crucial for advancing preventive strategies and mitigating the impact of this modifiable risk factor., (© 2024 Wiley Periodicals LLC.)

Trismus, defined as restricted mouth opening, is a common complication among Taiwanese oral cancer patients, especially those who chew betel quid. However, the impact of trismus on survival outcomes in oral cancer patients undergoing transoral robotic surgery (TORS) is unclear. This study aimed to investigate the associations between trismus and surgical outcomes in Taiwanese male oral cancer patients treated with TORS. We conducted a retrospective propensity score-matched cohort study of 40 Taiwanese male oral cancer patients who underwent TORS between 2016 and 2022. Overall, 20 patients with trismus were matched to 20 patients without trismus. TORS achieved similar operative and short-term clinical outcomes in trismus patients to non-trismus patients. There were no significant differences between groups in operation time, blood loss, margin status, flap reconstruction rates, duration of nasogastric tube feeding, or length of hospital stay. Kaplan-Meier and Cox proportional hazard regression analyses were performed to compare overall survival (OS) and disease-free survival (DFS) between the two groups. The overall survival (OS) rate at three years was significantly lower in patients with trismus than those without trismus (27.1% vs. 95.0%, log-rank p = 0.02). However, there was no significant difference in disease-free survival (DFS) rates between the trismus and non-trismus groups (36.6% vs. 62.7%, log-rank p = 0.87). After adjusting for confounders, trismus was independently associated with a 13-fold increased risk of mortality (adjusted HR 12.87, 95% CI 1.55-106.50, p < 0.05). In conclusion, trismus appears to be an independent prognostic factor for reduced long-term OS in Taiwanese male oral cancer patients undergoing TORS, though short-term surgical outcomes were non-inferior in the trismus patients. Further research is warranted to clarify the mechanisms linking trismus and survival in this population.

Background: The Betel Nut Intervention Trial (BENIT; ClinicalTrials.gov - NCT02942745) is the first known randomized intervention trial specifically designed for areca nut chewers in the western Pacific region who want to quit. The current study is a separate, exploratory study that examined the experiences of the BENIT facilitators during its implementation in Guam and Saipan of the Northern Mariana Islands and the extent to which the BENIT protocol was adapted to meet the participants' and facilitators' needs., Methods: All six BENIT program facilitators completed an online survey consisting of quantitative (Likert scale) and qualitative (open-ended) questions. Survey items were grouped as follows: facilitator demographics, prior training and preparation, BENIT experience, beliefs about the program's effectiveness, and beliefs about protocol adaptations., Results: Most of the facilitators felt prepared to deliver the BENIT program after several weeks of moderately intensive training. Facilitators felt the BENIT program was generally effective and that the "trigger logs" and "self-monitoring logs" worked as intended. However, they also noted that more time and support would have been helpful to overcome some of the obstacles inherent to implementing a novel program., Conclusion: The current findings can be used to inform, modify, and tailor subsequent areca nut cessation programs in Micronesian communities and to improve future versions of BENIT., (© 2024. The Author(s).)

Introduction: Betel quid (BQ) is globally the fourth most consumed psychoactive substance. It is consumed by an estimated 600 million people worldwide, accounting for nearly 8% of the world's population. There have been very few studies assessing chewers' motivation to quit. Objectives: In the current study, we sought to understand the relationship between several cessation-relevant variables and chewers' motivation to quit. Hypotheses: Based on analogous research on cigarette smoking, we hypothesized that the following cessation-relevant variables would be associated with motivation to quit: health risk perceptions, number of chews per day, cost, degree of BQ dependence, withdrawal symptoms, number of quit attempts, reasons for use, personal health improvement, and type of BQ chewed. Methods: A total of 351 adult BQ chewers from Guam participated in the survey and served as the sample for the analyses. Results: Majority of chewers want to quit and intend to quit. Chewers relatively high in motivation to quit evinced greater health risk perceptions of BQ chewing, greater perceived health benefits to quitting, and a greater number of past quit attempts, compared to those relatively low in motivation to quit. Conclusions: Understanding which factors are associated with chewers' motivation to quit can be helpful for designing BQ cessation programs. The results suggest that BQ cessation programs could be improved by an increased emphasis on information about the negative health effects of BQ chewing and relapse-prevention.

Objective: Assess trace elements in betel leaves and slaked lime from different regions of Karnataka, India using Laser Induced Breakdown Spectroscopy (LIBS). Materials and Method: Betel leaves from six different regions of Karnataka were obtained and named (for the purpose of the study) BL1, BL2, BL3, BL4, BL5, and BL6 and they were sun-dried. A single tube of slaked lime was obtained from the local ‘paan’ shop. Each dried leaf and a single blob of slaked lime was subjected to elemental analysis using Laser-induced breakdown spectroscopy. Results: A ten-trial experiment was carried out in all six leaves and a blob of the slaked lime. The National Institute of Standards and Technology (NIST) database was used to assess the emission lines. The elements that were predominantly present in all six betel leaves from different regions of Karnataka are calcium, copper, and iron. Slaked lime showed only the presence of calcium. Conclusion: It is widely accepted that the consumption of betel quid causes various changes in the oral mucosa including oral potentially malignant disorders (OPMDs) and oral cancer. It is important to analyze each component of betel quid to understand the disease progression. Copper is found to be relatively higher in betel leaves, and it is known that copper-induced fibrogenesis via the lysyl oxidase pathway in oral submucous fibrosis.

Betel quid (BQ) is commonly used in the Asia-Pacific region. Disulfiram is prescribed for people with alcohol use disorders (PwAUDs) after the completion of detoxification as an alternative to rehabilitation. This prospective observational study reported the aversive reactions and common symptoms of disulfiram and BQ in PwAUDs. Participants included PwAUDs admitted to the psychiatric ward at the Jigme Dorji Wangchuck National Referral Hospital for detoxification, who were on Disulfiram and using BQ at the same time. Aversive reactions between disulfiram and BQ were observed for 100 patients over a year. Twenty participants showed aversive reactions between BQ and disulfiram. Common symptoms included sweating, diarrhea, dizziness, tremors, palpitations, shortness of breath, nausea and vomiting, and headache. Since PwAUDs in Bhutan are inducted on disulfiram after detoxification, and most use BQ simultaneously, this study will help inform health care providers to educate people about the aversive reactions of disulfiram and BQ., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

There is a lack of evidence regarding the use of betel quid (BQ) and its potential contribution to oral cancer. Limited attention has been directed towards investigating the involvement of BQ-derived organic acids in the modulation of metabolic-epigenomic pathways associated with oral cancer initiation and progression. We employed novel protocol for preparing saliva-amalgamated BQ filtrate (SABFI) that mimics the oral cavity environment. SABFI and saliva control were further purified by an in-house developed vertical tube gel electrophoresis tool. The purified SABFI was then subjected to liquid chromatography-high resolution mass spectrometry analysis to identify the presence of organic acids. Profiling of SABFI showed a pool of prominent organic acids such as citric acid. malic acid, fumaric acid, 2-methylcitric acid, 2-hydroxyglutarate, cis- aconitic acid, succinic acid, 2-hydroxyglutaric acid lactone, tartaric acid and β-ketoglutaric acid. SABFI showed anti-proliferative and early apoptosis effects in oral cancer cells. Molecular docking and molecular dynamics simulations predicted that SABFI-derived organic acids as potential inhibitors of the epigenetic demethylase enzyme, Ten-Eleven Translocation-2 (TET2). By binding to the active site of α-ketoglutarate, a known substrate of TET2, these organic acids are likely to act as competitive inhibitors. This study reports a novel approach to study SABFI-derived organic acids that could mimic the chemical composition of BQ in the oral cavity. These SABFI-derived organic acids projected as inhibitors of TET2 and could be explored for their role oral cancer., Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest were disclosed., (Copyright © 2023 Korean Society of Cancer Prevention.)

Background: Areca nut and betel quid (ANBQ) chewing is a widespread carcinogenic habit. The BENIT (ClinicalTrials-NCT02942745) is the first known randomized trial designed for ANBQ chewers., Methods: We compared the intensive behavioral treatment intervention condition (IC) with the control condition (CC) in the BENIT and included a 5-stage early stopping rule. We report the primary analysis at stage 3. English-literate adults in Guam and Saipan who self-identified as ANBQ chewers with tobacco were enrolled between August 2016 and August 2020. IC participants ( n = 88) received five in-person sessions over 22 days and a brochure containing quitting advice. CC participants ( n = 88) received only the brochure. Participants were assessed at baseline and on day 22 of follow-up. Self-reported chewing status at day 22 was determined by a composite of two survey items with disparate wording and response options for cross-verification., Results: Cessation rates were 38.6% (IC) and 9.1% (CC). Proportional hazards regression revealed a p = 0.0058, which met the Stage 3 criteria for significance, and an estimated reduction in ANBQ chewing for IC compared to the CC of 71% (95% CI: 41%-88%)., Conclusions: Robust self-reported intervention effects at day 22 suggest that intensive cessation programs such as BENIT should be further developed and implemented on a larger scale.

Areca nut and slaked lime, with or without tobacco wrapped in Piper betle leaf, prepared as betel quid, is extensively consumed as a masticatory product in many countries across the world. Betel Quid can promote the malignant transformation of oral lesions as well as trigger benign cellular and molecular changes. In the oral cavity, it causes changes at the compositional level in oral microbiota called dysbiosis. This dysbiosis may play an important role in Oral Cancer in betel quid chewers. The abnormal presence and increase of bacteria Fusobacterium nucleatum , Capnocytophaga gingivalis , Prevotella melaninogenica , Peptostreptococcus sp., Porphyromonas gingivalis , and Streptococcus mitis in saliva and/or other oral sites of the cancer patients has attracted frequent attention for its association with oral cancer development. In the present review, the authors have analysed the literature reports to revisit the oncogenic potential of betel quid and oral microbiome alterations, evaluating the potential of oral microbiota both as a driver and biomarker of oral cancer. The authors have also shared a perspective that the restoration of local microbiota can become a potentially therapeutic or prophylactic strategy for the delay or reversal of lip and oral cavity cancers, especially in high-risk population groups.

Scientometric analysis is a useful tool that utilizes bibliometric data to measure scientific output of a disease or region in a particular field. In this report, we comprehensively provide bibliometric characteristics of all the papers on betel quid (BQ)-related cancer and precancerous lesions. There are 1403 papers on BQ-related cancer and precancerous lesions published until 2022 in the Scopus database. China (mainland and Taiwan region), India, United States, and United Kingdom contribute 1214 (86.5%) papers and 34,120 (91.9%) citations of all the papers. The number (457), citations (14,573), and h index (60) of the papers originated from Taiwan region stably remain in the first. The most frequent research keyword is arecoline, followed by drug, prevalence, metabolism, carcinogenesis, and pathology. Areca nut and BQ cessation program by Taiwan government has demonstrated a significant positive impact on oral cancer prevention. Collectively, the scientific output of BQ-related cancer and precancerous field represents distinct regional characteristic. BQ-related cancer prevention is still a long way off. Encouragingly, Taiwan region is well ahead in this way., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2023 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Oral cancer is the sixth leading cause of cancer mortality worldwide. Genetic, epigenetic, and epidemiological risk factors were suggested to be correlated with the carcinogenesis of oral cancer. In this study, we focused on the correlations of FOXP3 single-nucleotide polymorphisms (SNPs) to oral cancer susceptibility and clinicopathological characteristics. The FOXP3 SNPs rs3761547, rs3761548, rs3761549, and rs2232365 in 1053 controls and 1175 male patients with oral cancer were analyzed with real-time polymerase chain reaction. The results showed that the betel quid chewer who carried the FOXP3 rs3761548 polymorphic variant "T" were significantly associated with lower risk to develop oral cancer [AOR (95% CI) = 0.649 (0.437-0.964); p = 0.032]. The betel quid chewers with genotypic variant "T" of FOXP3 rs3761548 in male oral cancer patients were associated with lower risk of cell differentiated grade [AOR (95% CI) = 0.592 (0.377-0.930); p = 0.023]. The carriers of FOXP3 rs3761548 polymorphic variant "T" in male oral cancer patients with alcohol consumption were associated with lower risk to develop greater tumor [AOR (95% CI) = 0.609 (0.378-0.983); p = 0.042] and lower risk of cell differentiated grade [AOR (95% CI) = 0.440 (0.248-0.779); p = 0.005]. In conclusion, our results have revealed that the FOXP3 rs3761548 polymorphic variant "T" was associated with lower risk of oral cancer susceptibility, greater tumor size, and cell differentiated grade among betel quid chewers. The FOXP3 rs3761548 polymorphisms may play a role as pivotal biomarkers to predict oral cancer disease development and prognosis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline N -oxide (ANO) is carcinogenic, and the underlying mechanisms remain unclear. In this systematic review, we analyzed recent studies on the roles of arecoline and ANO in cancer and strategies to block carcinogenesis. In the oral cavity, flavin-containing monooxygenase 3 oxidizes arecoline to ANO, and both alkaloids conjugate with N -acetylcysteine to form mercapturic acid compounds, which are excreted in urine, reducing arecoline and ANO toxicity. However, detoxification may not be complete. Arecoline and ANO upregulated protein expression in oral cancer tissue from areca nut users compared to expression levels in adjacent normal tissue, suggesting a causal relationship between these compounds and oral cancer. Sublingual fibrosis, hyperplasia, and oral leukoplakia were diagnosed in mice subjected to oral mucosal smearing of ANO. ANO is more cytotoxic and genotoxic than arecoline. During carcinogenesis and metastasis, these compounds increase the expression of epithelial-mesenchymal transition (EMT) inducers such as reactive oxygen species, transforming growth factor-β1, Notch receptor-1, and inflammatory cytokines, and they activate EMT-related proteins. Arecoline-induced epigenetic markers such as sirtuin-1 hypermethylation, low protein expression of miR-22, and miR-886-3-p accelerate oral cancer progression. Antioxidants and targeted inhibitors of the EMT inducers used reduce the risk of oral cancer development and progression. Our review findings substantiate the association of arecoline and ANO with oral cancer. Both of these single compounds are likely carcinogenic to humans, and their mechanisms and pathways of carcinogenesis are useful indicators for cancer therapy and prognosis.

A disintegrin and metalloproteinase domain-containing protein 10 (ADAM-10) involves in the tumour progression, but the impacts of single-nucleotide polymorphism (SNP) of ADAM-10 on oral squamous cell carcinoma (OSCC) remain unclear. The aim of this study was to investigate the influence of SNP of ADAM-10 on the clinical features of OSCC in male Taiwanese. Five loci of ADAM-10 SNPs including rs653765 (C/T), rs2305421 (A/G), rs514049 (A/C), rs383902 (T/C) and rs2054096 (A/T) were genotyped by TaqMan allelic discrimination in 1138 OSCC patients and 1199 non-OSCC individuals. The ADAM-10 SNP rs2305421 GG (AOR: 1.399, 95% CI: 1.045-1.874, p = 0.024) and G allele (AOR: 1.170, 95% CI: 1.012-1.351, p = 0.034) illustrated a significantly higher genotypic frequencies in the OSCC group compared to the distribution of the ADAM-10 SNP rs2305421 AA wild type. In the subgroup analysis, the ADAM-10 SNP rs383902 TC+CC was significantly correlated to tumour size larger than T2 in betel quid chewer (AOR: 1.375, 95% CI: 1.010-1.872, p = 0.043), while the ADAM-10 SNP rs653765 CT+TT was significantly associated with tumour size larger than T2 in cigarette smoker (AOR: 1.346, 95% CI: 1.023-1.772, p = 0.034). The results from The Cancer Genome Atlas revealed highest ADAM-10 mRNA level in T2 stage of current smokers with head and neck squamous cell carcinoma (HNSCC). In conclusions, the ADAM-10 SNP rs2305421 G allele is associated with the presence of OSCC, and the ADAM-10 SNP rs383902 TC+CC and ADAM-10 SNP rs653765 CT+TT correlates to large tumour size in specific conditions., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Areca nut (AN) is one of the world's most widely used drugs, especially in Asia-Pacific, causing dependence and multiple adverse health impacts. The International Agency for Research on Cancer (IARC) has classified it as a type-1 carcinogen. Despite evidence of harms, its use is culturally ingrained in many regions worldwide; harm perception is low; and the availability of intervention strategies is limited., Methods: To identify the range and efficacy of interventional studies on AN use cessation, a narrative review of studies published between 1990 and 2021 was undertaken using selected electronic databases (PubMed, Embase, and Scopus)., Results: Three types of interventions were identified: educational, psychological, and pharmacological. Overall, educational interventions significantly enhanced knowledge regarding harms related to AN use. Some psychological interventions reported enhancement of motivation to quit as well as helped in reduction/cessation of AN use. Two pharmacological studies on psychiatric patients with depressive disorders and AN use found that antidepressants helped in reducing/cessation of AN use., Conclusion: Overall, the number of interventional studies on AN cessation is limited, and most studies have measured the short-term effects of the intervention. The role of pharmacotherapeutic interventions needs to be evaluated for AN cessation, and evidence-based psychosocial interventions need to be developed for AN cessation. Furthermore, longitudinal research using adequate sample sizes and longer follow-up durations are needed to establish interventions in this important area., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2023 The Author(s).)

Background: Betel quid (BQ) chewing is associated with poor oral hygiene, psychological impairment, and acute and long-term addictive effects, resulting in worse oral-related quality of life (OHRQoL). The purpose of this study was to characterize the factors associated with OHRQoL among BQ users receiving oral mucosal screening., Methods: A cross-sectional study was conducted. Data were collected by random sampling of BQ users who visited outpatient departments receiving oral mucosal screening in a medical center Taiwan. The oral health assessment tool, the state anxiety inventory, the betel quid dependence scale, and the oral health impact profile were used to measure oral health status, anxiety, BQ dependence, and OHRQoL, respectively. Pearson's product-moment coefficient was used to examine the relationship between OHRQoL and the selected independent variables. Independent-samples t-test was used to compare OHRQoL by annual family income, the presence of chronic disease, and BQ dependence. Hierarchical multiple linear regression analysis was used to identify factors associated with OHRQoL., Results: A total of 175 BQ users were surveyed. Factors associated with OHRQoL included oral health status, anxiety, and BQ dependence. BQ users reporting low oral health status, greater anxiety, and more BQ dependence were more likely to have worse OHRQoL., Conclusions: Poor oral health status, anxiety, and BQ dependence negatively impact on OHRQoL among patients with BQ use receiving oral mucosal screening., (© 2023. The Author(s).)

The physical and chemical properties of various constitutional ingredients of betel quid (BQ) are well known in the literature. However, BQ as a whole has been rarely investigated for identifying its physical properties that can impact and modulate the disease progression of various pathologies, mainly oral submucous fibrosis (OSMF). It is quite conceivable that in the oral cavity environment, the amalgamated BQ might absorb saliva by virtue of its hygroscopic properties. As a proof of concept, we developed a methodology to quantify the hygroscopicity of the 'whole BQ' when it is mixed with saliva. To the best of our knowledge, this is the first study to report and quantify the hygroscopicity of BQ when mixed with saliva, and this forms a proof of concept for future implications in the pathogenesis of various pathologies., Competing Interests: All the authors associated with the present manuscript declared no potential conflict of interest concerning the research, authorship, and/or publication of this article., (© 2022 Craniofacial Research Foundation. Published by Elsevier B.V.)

Background: The Betel Nut Intervention Trial (BENIT) is the first known randomized controlled intervention trial designed to help minority Pacific Islanders in Guam and Saipan quit chewing the carcinogenic Areca catechu nut (AN). We report the BENIT's saliva bioverification results against the self-reported chewing status ("quitter" or "chewer") at day 22 follow-up., Material and Methods: AN-specific (arecoline, arecaidine, guvacoline, and guvacine) and tobacco-specific (nicotine, cotinine, and hydroxycotinine) alkaloids were analyzed in saliva from 176 BENIT participants by an established and sensitive liquid chromatography mass spectrometry-based assay., Results: The combined four AN alkaloid levels decreased from baseline in quitters (n = 50) and chewers (n = 108) by 32% and 9%, respectively. In quitters, decreases were significant for arecoline (p = 0.044)-the most prominent AN alkaloid, along with arecaidine (p = 0.042) and nicotine (p = 0.011). In chewers, decreases were significant only for hydroxycotinine (p = 0.004). Similar results were obtained when quitters and chewers were stratified by treatment arm., Discussion: Salivary AN alkaloid levels generally agreed with self-reported chewing status, which suggests the former can be used to verify the latter., Conclusion: Our results can help to objectively evaluate compliance and program effectiveness in AN cessation programs., (© 2022 John Wiley & Sons, Ltd.)

Global estimates indicate that over 600 million individuals worldwide consume the areca (betel) nut in some form. Nonetheless, its consumption is associated with a myriad of oral and systemic ailments, such as precancerous oral lesions, oropharyngeal cancers, liver toxicity and hepatic carcinoma, cardiovascular distress, and addiction. Users commonly chew slivers of areca nut in a complex consumable preparation called betel quid (BQ). Consequently, the user is exposed to a wide array of chemicals with diverse pharmacokinetic behavior in the body. However, a comprehensive understanding of the metabolic pathways significant to BQ chemicals is lacking. Henceforth, we performed a literature search to identify prominent BQ constituents and examine each chemical's interplay with drug disposition proteins. In total, we uncovered over 20 major chemicals (e.g., arecoline, nicotine, menthol, quercetin, tannic acid) present in the BQ mixture that were substrates, inhibitors, and/or inducers of various phase I (e.g., CYP, FMO, hydrolases) and phase II (e.g., GST, UGT, SULT) drug metabolizing enzymes, along with several transporters (e.g., P-gp, BCRP, MRP). Altogether, over 80 potential interactivities were found. Utilizing this new information, we generated theoretical predictions of drug interactions precipitated by BQ consumption. Data suggests that BQ consumers are at risk for drug interactions (and possible adverse effects) when co-ingesting other substances (multiple therapeutic classes) with overlapping elimination mechanisms. Until now, prediction about interactions is not widely known among BQ consumers and their clinicians. Further research is necessary based on our speculations to elucidate the biological ramifications of specific BQ-induced interactions and to take measures that improve the health of BQ consumers., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Betel quid (BQ) is the fourth most commonly used psychoactive substance and its use is highly prevalent among southeast Asian countries due to the influence of psychosocial, behavioral, and environmental factors. As a result, even young children and women are becoming addicted and find it difficult to achieve long-term abstinence. Systematic research addressing the influence of behavioral and psychosocial factors on BQ chewing is scarce, hence pointing to the need for understanding the interplay of these factors to develop tailored intervention strategies for BQ cessation., Objective: The objective of this systematic review is to assess various behavioral and psychosocial risk factors from pre-existing literature that lead individuals to initiate and/or maintain BQ chewing in developed and developing countries., Materials and Methods: The electronic retrieval systems and databases PUBMED [MEDLINE], EMBASE, SCOPUS, WEB OF SCIENCE, GOOGLE SCHOLAR, and SCIENCE DIRECT were searched independently by two authors for relevant articles from January 2011 to July 2021 using combinations of keywords. Primary studies published in English focusing on the behavioral and psychosocial risk factors for BQ chewing were included., Results: Out of the initial 264 articles searched, 12 articles met the selection criteria. Included studies addressed the influence of behavioral and psychosocial factors toward the initiation and/or maintenance of BQ chewing. Included studies reported that dependent BQ was not able to quit BQ chewing due to habituation, addiction, and withdrawal symptoms. Few social BQ chewers in Southeast Asian countries were not willing to initiate quitting as they considered AN as an important social and cultural identifier and claimed that they could not resist chewing in a peer group, and it has become part of their social life., Conclusion: In the future, studies should take into consideration behavioral and psychosocial risk factors, which are major barriers toward successful quitting. These factors should be integrated into areca nut cessation guidelines, and there is a need to develop more comprehensive culture-specific intervention approaches to achieve long-term abstinence.

Introduction: TikTok has gained increasing popularity over the past year. The social media may affect awareness and perceptions of betel quid (BQ) and smokeless tobacco (SLT) by utilizing content generated by TikTok users. The purpose of this study is to examine how BQ and SLT are portrayed on TikTok., Methods: The 28 most viewed hashtag-based keywords were used to identify popular BQ and SLT-related videos on TikTok (n=513) from June 2018 to September 2021. Two researchers independently coded the number of likes, shares, views, user category and themes., Results: A final sample of 513 videos containing BQ and SLT that met the study criteria were included. Collectively, these videos were viewed over 725 million times, with a median 'view' count of 17,300 (range 152-155,000,000) and a median 'likes' count of 831 (range 4-2,400,000) and a median 'share' count of 21 (range 0-48,400). Majority of the videos showed BQ and SLT use positively i.e promoting the product (390/513; 76%) and these had more than 686 million times views. Neutral depictions of BQ and SLT use were viewed 15 million times (72/513; 14%) and negative portrayals of BQ and SLT have been viewed 193 million times (105/808; 13%). The video themes included 'life style' (349/513; 68.0%), 'marketing' (62/513; 12.09%), 'comedy' (44/513; 8.6%), 'warning' (25/513; 4.87%), 'awareness' (12/513; 2.3%), 'sports and other' (12/513; 2.3%) and social events or culture (9/513; 1.75%)., Conclusion: Our results demonstrated that video clips related to BQ and SLT on TikTok, a fast-growing, popular video-sharing platform among teens, which is available with no age restrictions has been viewed multiple times. Majority (76%) promoted these two products, that could be detrimental to oral health. Therefore, the age restrictions especially for the videos containing BQ and SLT is mandatory in order to reduce the potential exposure of adolescents/young adults.

Areca nut (AN) is consumed by millions of people for its therapeutic and psychoactive effects, making it one of the most widely self-administered psychoactive substances in the world. Even so, AN use/abuse is associated with myriad oral and systemic side effects, affecting most organ systems in the body. Alkaloids abundant in the nut (e.g. arecoline, arecaidine, guvacoline, and guvacine), collectively called the areca alkaloids, are presumably responsible for the major pharmacological effects experienced by users, with arecoline being the most abundant alkaloid with notable toxicological properties. However, the mechanisms of arecoline and other areca alkaloid elimination in humans remain poorly documented. Therefore, the purpose of this review is to provide an in-depth review of areca alkaloid pharmacokinetics (PK) in biological systems, and discuss mechanisms of metabolism by presenting information found in the literature. Also, the toxicological relevance of the known and purported metabolic steps will be reviewed. In brief, several areca alkaloids contain a labile methyl ester group and are susceptible to hydrolysis, although the human esterase responsible remains presumptive. Other notable mechanisms include N -oxidation, glutathionylation, nitrosamine conversion, and carbon-carbon double-bond reduction. These metabolic conversions result in toxic and sometimes less-toxic derivatives. Arecoline and arecaidine undergo extensive metabolism while far less is known about guvacine and guvacoline. Metabolism information may help predict drug interactions with human pharmaceuticals with overlapping elimination pathways. Altogether, this review provides a first-of-its-kind comprehensive analysis of AN alkaloid metabolism, adds perspective on new mechanisms of metabolism, and highlights the need for future metabolism work in the field.

Consumption of areca nut alone, or in the form of betel quid (BQ), has negative health effects and is carcinogenic to humans. Indonesia is one of the largest producers of areca nuts worldwide, yet little is known about the biomolecular composition of Indonesian areca nuts and BQs. We have recently shown that phenolic and alkaloid content of Indonesian BQs exhibits distinct geographical differences. Here, we profiled for the first time the metabolomics of BQ constituents from four regions of Indonesia using non-targeted gas chromatography-mass spectrometry (GC-MS) analysis. In addition to well-known alkaloids, the analysis of small-molecule profiles tentatively identified 92 phytochemicals in BQ. These included mainly benzenoids and terpenes, as well as acids, aldehydes, alcohols, and esters. Safrole, a potentially genotoxic benzenoid, was found abundantly in betel ( Piper betle ) inflorescence from West Papua and was not detected in areca nut samples from any Indonesian region except West Papua. Terpenes were mostly detected in betel leaves and inflorescence/stem. Areca nut, husk, betel leaf, the inflorescence stem, and BQ mixture expressed distinctive metabolite patterns, and a significant variation in the content and concentration of metabolites was found across different geographical regions. In summary, this was the first metabolomic study of BQs using GC-MS. The results demonstrate that the molecular constituents of BQs vary geographically and suggest that the differential disease-inducing capacity of BQs may reflect their distinct chemical composition.

Natural products and traditional ethnomedicines are of great effect in therapeutics. Such types of medicine have been practiced in certain areas of the world to treat different health conditions. This pilot investigation aims to review the cumulative health effect of addendums used in betel quid such as areca nut, lime, and tobacco-associated betel quid chewing and without tobacco-associated chewing. This review shows that betel leaf extract and its essential oil could inhibit growth of microbes and damage different gram-positive and gram-negative bacteria as well as various fungus species. Some studies concluded that the combination of Piper leaves essential oil with antibiotics have potential effect on oral microorganisms. Long-term consumption of betel quid with tobacco is known to cause cancer, chromosomal aberrations, and pharynx tumors. However, consumption of betel leaf without tobacco has health benefits because of ethnomedicinal properties. Its essential is oil utilized as raw material for perfumes and mouth fresheners manufacturing. Scientific researches on this plant revealed that it possesses many beneficial activities to be used for developing novel drugs. However, compounds of betel leaves have beneficial natural antioxidant. Chewing and intake of leaves have effect on moving parts of salivary gland which is the main step of digestion. Its components also act as heartbeat regulators in relaxing the blood vessels to reduce hypertension. So this review discussed the natural compounds of betel leaves which is used as traditional medicine to further develop drug discovery., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The use of areca nuts (areca) in the form of betel quids constitutes the fourth most common addiction in the world, associated with high risk for oral disease and cancer. Areca is a complex natural product, making it difficult to identify specific components associated with the addictive and carcinogenic properties. It is commonly believed that the muscarinic agonist arecoline is at the core of the addiction. However, muscarinic receptor activation is not generally believed to support drug-taking behaviour. Subjective accounts of areca use include descriptions of both sedative and stimulatory effects, consistent with the presence of multiple psychoactive agents. We have previously reported partial agonism of α4-containing nicotinic acetylcholine receptors by arecoline and subsequent inhibition of those receptors by whole areca broth. In the present study, we report the inhibition of nicotinic acetylcholine receptors and other types of neurotransmitter receptors with compounds of high molecular weight in areca and the ability of low molecular weight areca extract to activate GABA and glutamate receptors. We confirm the presence of a high concentration of GABA and glutamate in areca. Additionally, data also indicate the presence of a dopamine and serotonin transporter blocking activity in areca that could account for the reported stimulant and antidepressant activity. Our data suggest that toxic elements of high molecular weight may contribute to the oral health liability of betel quid use, while two distinct low molecular weight components may provide elements of reward, and the nicotinic activity of arecoline contributes to the physical dependence of addiction., (© 2022 Society for the Study of Addiction.)

Areca nut chewing is one of the major risk factors for oral cancer, with large-magnitude risks reported in studies comparing betel quid chewers and never users, and it has been evaluated as a group 1 carcinogen by the International Agency for Research on Cancer. Data from a high-quality meta-analysis examining risk estimates are presented in summary form with additional information from more recent studies (pooled adjusted relative risk, 7.9; 95% CI, 7.1 to 8.7). The risk of oral cancer increases in a dose-response manner with the daily number of quids consumed and the number of years chewing. In the Indian subcontinent and in Taiwan, approximately half of oral cancers reported are attributed to betel quid chewing (population attributable fraction, 53.7% for residents in Taiwan and 49.5% for the Indian population), a disease burden that could be prevented. Oral leukoplakia and oral submucous fibrosis are 2 main oral potentially malignant disorders caused by areca nut chewing that can progress to oral cancer with continued use. Ex-chewers seem to demonstrate lower risks than current chewers, but the impact of areca nut cessation on oral cancer risk has not been scientifically evaluated on the basis of randomized controlled studies. These data strongly reconfirm that betel quid chewing, primarily areca nut use, should be taken into account in assessing the cancer risk of South Asian, East Asian populations and Pacific Islanders for the development of oral cancer.

The neuroactive alkaloids in betel quid (BQ) can induce BQ addiction. We conducted a case-control study to investigate the effects of BQ-associated DSM-5 symptoms, pathological behaviors, and BQ use disorder (BUD) on oral squamous cell carcinoma (OSCC) risk. A total of 233 patients with newly diagnosed and histopathologically confirmed OSCC and 301 sex- and age-matched controls were included. BQ-related DSM-5 symptoms in the 12 months prior to disease onset were used to measure psychiatric characteristics and BUD. Compared with nonchewers, chewers with the symptoms of unsuccessful cutdown of BQ consumption, neglecting major roles, social or interpersonal problems, abandoning or limiting activities, hazardous use, and continued use despite the awareness of the dangers had a 54.8-, 49.3-, 49.9-, 40.4-, 86.2-, and 42.9-fold higher risk of developing OSCC, respectively. Mild-to-moderate and severe BUD were, respectively, associated with a 8.2-8.5- and 42.3-fold higher OSCC risk, compared with BQ nonuse. Risky BQ use of pathological behavior was associated with a 12.5-fold higher OSCC risk in chewers with no BUD or mild BUD and a 65.0-fold higher risk in chewers with moderate-to-severe BUD ( p for risk heterogeneity between the two BUD groups, 0.041). In conclusion, BQ-associated DSM-5 symptoms, pathological behaviors, and BUD severity are associated with the impact of BQ chewing on OSCC development. The pathological behavior of risky BQ use enhances OSCC risk in chewers with moderate-to-severe BUD. Preventing BUD in new BQ users and treating BUD in chewers who already have the disorder are two priorities in areas where BQ chewing is prevalent.

Background/aim: Programmed cell death 6 (PDCD6) is up-regulated and highly expressed in early apoptotic cells. In several types of cancer, such as cervical, breast and lung cancers, the association of PDCD6 genotypes have been investigated. However, the contribution of PDCD6 variant genotypes to oral cancer has never been examined. The current study aimed to evaluate the contribution of the PDCD6 rs4957014 and rs3756712 genotypes to the risk of oral cancer in Taiwan., Patients and Methods: The contribution of PDCD6 genotypes to oral cancer risk was examined among 958 patients with lung cancer and 958 age- and sex-matched healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR- RFLP)., Results: The data showed that the hetero-variant GT and homo-variant GG genotypes of PDCD6 rs4957014 were associated with a decreased risk of oral cancer [odds ratio (OR)=0.81 and 0.39, 95% confidence interval (CI)=0.67-0.97 and 0.27-0.56, respectively]. The recessive and dominant models also showed that G carriers have protective effects (OR=0.43 and 0.72, 95% CI=0.30-0.61 and 0.61-0.87, respectively). The analysis of allelic frequency distributions showed that the G allele of PDCD6 rs4957014 was associated with reduced oral cancer risk (OR=0.71, 95% CI=0.62-0.82). There was no significant association between any PDCD6 rs3756712 genotype and oral cancer risk. In addition, the GG genotype at PDCD6 rs4957014 significantly decreased the risk of oral cancer among both males (adjusted OR=0.31, 95%CI=0.24-0.56) and females (adjusted OR=0.44, 95% CI=0.22-0.91). Furthermore, the GG genotype at PDCD6 rs4957014 significantly decreased the risk of oral cancer among smokers (adjusted OR=0.35, 95% CI=0.22-0.58), alcohol drinkers (adjusted OR=0.33, 95% CI=0.18-0.49), non-betel quid chewers (adjusted OR=0.33, 95% CI=0.17- 0.81), betel quid chewers (adjusted OR=0.34, 95% CI=0.21- 0.59), but not among never-smokers and non-alcohol drinkers., Conclusion: The G allele carriers of PDCD6 rs4957014 may have protective effects on oral cancer risk and serve as a practical marker for early detection of oral cancer in Taiwan., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: This study aimed to investigate brain spontaneous neural activity changes in betel quid dependence (BQD) chewers using the percent amplitude of fluctuation (PerAF) method., Methods: This study included 48 BQD chewers. The healthy control (HC) group comprised 35 volunteers who were matched with BQD chewers in age, gender, and educational status. All subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological tests. The PerAF method was used to identify BQD-related regional brain activity changes. An independent samples t -test was used to evaluate the PerAF difference across two groups. The association between PerAF changes and clinical features such as BQD scores, duration of BQD, Hamilton Depression Rating Scale-24 item (HAMD-24), and Hamilton Anxiety Rating Scale-14 item (HAMA-14) was evaluated by using Spearman's correlation analysis. It assessed the ability of the PerAF method to distinguish between BQD chewers and HCs using a receiver operating characteristic (ROC) curve., Results: Compared to the control group, BQD chewers showed decreased PerAF in right anterior cingulate cortex (ACC), right middle frontal gyrus (MFG), right insula, right precuneus, left putamen, left supramarginal gyrus (SMG), and left cerebellum and increased PerAF in right orbitofrontal and left superior temporal gyrus (STG) [ P < 0.05, Gaussian random field (GRF) corrected]. PerAF values of the right MFG and right ACC had a significant negative relationship with the duration of BQD ( P < 0.05). The average values of PerAF in the left putamen, left cerebellum, and left STG showed significant discriminatory power in distinguishing BQD chewers from HCs, with relatively prime area under the curve (AUC) values., Conclusion: Our findings suggested that betel quid chewing is associated with spontaneous neural activity alterations in the impulsivity areas (MFG and ACC), cognitive (MFG, ACC, precuneus, and the cerebellum), and reward (orbitofrontal, putamen, and insula) systems, which may be correlated with neuropathological mechanisms of BQD. Also, PerAF may be useful as a potential sensitive biomarker for identifying spontaneous brain activity changes in BQD chewers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fu, Chen, Liu, Liu, Fu, Huang and Chen.)

Oral submucous fibrosis (OSF) is a potentially malignant condition of the oral cavity characterized by progressive fibrosis of the submucosal tissues. OSF is typically associated with the use of betel quid (BQ), a chewing package made of natural products (e.g., areca nut, betel leaves), with or without smokeless tobacco. BQ ingredients contain pro-carcinogenic bioactive compounds, but also potentially protective biomolecules, and we have shown recently that the chemical properties of different BQ recipes vary, which may explain the unequal prevalence of OSF and oral cancer in BQ users in different geographical regions. Hence, this scoping review was aimed at evaluating the existing literature regarding different BQ compounds and their association with OSF. The repository of the National Library of Medicine (MEDLINE/PubMed), medRxiv databases, Google scholar, Baidu scholar, CNKI, and EBSCO were used to search for publications that investigated the association between BQ chewing and OSF up to November 2021. The search terminology was constructed using the keywords "betel quid" and "oral submucous fibrosis", and their associated terms, with the use of Boolean operators. The search was conducted under Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, together with clear inclusion and exclusion criteria. The review showed that the risk of developing OSF varied between different BQ recipes, and that chewing BQ mixtures containing betel inflorescence (BI) significantly increased the risk of OSF, as did the addition of tobacco. Conversely, the use of betel leaf in the mixture was likely to be protective, which may be due to the presence of polyphenols. Although further research is needed to determine the effect of individual BQ ingredients in the development of OSF, our pilot results provide the scope and rationale for informing future chemopreventive strategies for OSF and oral cancer in BQ chewers.

Areca nut and tobacco are frequently used in combination. Cigarette smoking and betel quid (BQ) chewing habits impose greater oral cancer risk than either habit alone. Saliva is a better noninvasive diagnostic material as it is in direct contact with oral mucosa and cancerous lesions. This study describes the application of isotope-dilution LC-MS/MS for simultaneous quantitation of five areca nut-specific alkaloids (ASAs) and three tobacco-specific alkaloids (TSAs) in human saliva. With this method, we demonstrate that the distribution of ASAs vary significantly in smokers who chew BQ habitually, due to the hydrolysis of ASAs and metabolic activity in the oral cavity. The alkaline condition formed due to slaked lime in BQ, plays an important role in the distribution of ASAs and TSAs, by catalyzing the hydrolysis of ester forms of ASAs to their respective carboxylic acid forms besides facilitating the TSA (i.e., nicotine) absorption in the oral cavity. Moreover, our results reveal that oral mucosa rather than saliva contributes to the metabolism of ASAs at oral cavity. Less than 2.1% of ASAs were metabolized by saliva, as determined by in vitro test. Our findings may provide a better insight into the pathobiology of oral carcinogenesis due to BQ chewing., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Betel quid chewing is associated with metabolic disorders, oral cancer, cardiovascular disease, and chronic liver diseases. Metabolic syndrome (MetS) is also a factor associated with liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). However, studies on the relationship between betel quid and liver fibrosis while also considering MetS are lacking. The aim of this study was thus to investigate the association of betel quid chewing and liver fibrosis with MetS., Methods: A total of 9,221 subjects were enrolled after excluding subjects <18 years of age, with past history of chronic liver diseases, cancer, significant alcohol consumption, and incomplete data. Betel nut chewing habit was classified into three groups: none, former-chewing, and current-chewing, and cumulative exposure was calculated by multiplying the duration with the quantity. Liver fibrosis was evaluated based on the NAFLD fibrosis score (NFS), which is a composite score of age, hyperglycemia, BMI, platelet count, albumin, and the AST/ALT ratio. Significant liver fibrosis was defined as NFS ≥-1.455., Results: After adjusting for other variables, MetS was positively associated with significant liver fibrosis. Subjects with both MetS and betel quid chewing had a higher associated risk of significant liver fibrosis than those with neither MetS nor betel quid chewing (adjusted OR: 3.03, 95% CI: 2.04-4.50, p < 0.001). Betel quid chewing was associated with significant liver fibrosis (adjusted OR: 2.00, 95% CI: 1.14-3.49, p = 0.015) in subjects with MetS, but not in subjects without., Conclusion: Metabolic syndrome increased the associated risk of significant liver fibrosis. Cumulative betel quid exposure increased the associated risk of significant liver fibrosis in subjects with MetS, but not in subjects without., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chou, Sun, Shen, Yang, Lu, Chang, Li and Wu.)

Background: Indigenous populations have higher substance use than non-indigenous populations. Current evidence on indigenous substance use is largely derived from national household surveys, while there are no specifically designed, culturally specific methodological studies available to determine the prevalence of substance abuse among the indigenous tribes. The present study examined the prevalence and predictors of alcohol use, smoking, and betel quid chewing among indigenous tribes in South India., Method: We conducted a cross-sectional population-based random survey of 2186 tribal households in the Wayanad District, Kerala. A self-prepared, pilot-tested structured interview schedule was used to collect information on sociodemographic variables and substance use. Multivariate logistic regression models were used to examine the sociodemographic predictors of substance use., Results: The overall prevalence of current alcohol use, current smoking and daily betel quid use was 17.2%, 18.8% and 47.6% respectively. Consistently, male gender (alcohol use OR = 13.55; smoking OR = 3.42; betel quid use OR = 1.65), increasing age (OR = 1.32; OR = 1.01; OR = 1.03), Paniya tribe status (OR = 2.24; OR = 1.39; OR = 5.38) and employment status being working (OR = 2.07; OR = 1.77; OR = 1.26) increased the risk of alcohol use, smoking and betel quid chewing. Furthermore, having 'no formal education' was associated with smoking (OR = 1.35), and betel quid chewing (OR = 3.27)., Conclusion: Substance use was high among the indigenous tribes. The male gender, increasing age, Paniya tribe and working status significantly influenced alcohol use, smoking and betel quid chewing. The results underscore the need for indigenous specific de-addiction policies and programmes, alongside a consideration of the critical sociodemographic predictors., (© 2021. W. Montague Cobb-NMA Health Institute.)

Betel quid (BQ) is a package of mixed constituents that is chewed by more than 600 million people worldwide, particularly in Asia. The formulation of BQ depends on a variety of factors but typically includes areca nut, betel leaf, and slaked lime and may or may not contain tobacco. BQ chewing is strongly associated with the development of potentially malignant and malignant diseases of the mouth such as oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC), respectively. We have shown recently that the constituents of BQ vary geographically and that the capacity to induce disease reflects the distinct chemical composition of the BQ. In this review, we examined the diverse chemical constituents of BQ and their putative role in oral carcinogenesis. Four major areca alkaloids-arecoline, arecaidine, guvacoline and guvacine-together with the polyphenols, were identified as being potentially involved in oral carcinogenesis. Further, we propose that fibroblast senescence, which is induced by certain BQ components, may be a key driver of tumour progression in OSMF and OSCC. Our study emphasizes that the characterization of the detrimental or protective effects of specific BQ ingredients may facilitate the development of targeted BQ formulations to prevent and/or treat potentially malignant oral disorders and oral cancer in BQ users.

Background: Areca nut (AN) is one of the addictive substances known to cause deleterious effects on oral cavity as well as on various body organs including liver. But, scanty information is available reporting the adverse effects of AN chewing on the liver., Aim: To study the risk of liver disease in AN habitual based on the relevant published data., Methods: The literature search was performed by an electronic search of the PubMed/Medline, Scopus and Google Scholar databases using proper MESH headings and retrieved the articles published from 1998 to 2021. The eligibility criteria included: Human studies, AN habitual as study participants, use of controls and articles published in English. Data were extracted regarding characteristics of studies, characteristics of AN exposure, effect estimate and outcome of the studies., Results: Total 253 articles were identified from various databases and 15 studies were selected that met the inclusion criteria. Among these, thirteen studies showed an association between AN habit and attenuation of risk of liver disease as determined by relative risk/odds ratio/hazard ratio. Eleven studies described additive effect of AN and HBsAg and/or Anti hepatitis C virus status on development of liver disease. However, two of the studies showed opposite results. The heterogeneity in the study designs, exposure characteristics, outcomes and confounders precluded further meta-analysis., Conclusion: The association between AN chewing and an increased risk of developing liver disease is noted which necessitates the need for AN cessation campaign., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Oral and Maxillofacial Pathology.)

Objective: The current study asked whether BQ dependence level could affect working memory (WM) and remote memory for the chewers with concurrent use of cigarettes and alcohol, a common phenomenon in Taiwan., Methods: The standardized neuropsychological tests (Wechsler Memory Scale III (WMS-III) and Remote Memory Test) were adopted to address the BQ chewers' verbal WM, spatial WM and remote memory. The Spatial Span Test and the Digit Span Test from WMS-III and the Remote Memory Test were adopted. The Betel Nut Dependency Scale (BNDS), the Fagerstrom Test for Nicotine Dependence (FTND), and the Alcohol Use Disorders Identification Test (AUDIT) were adopted to measure the dependence levels., Results: The BQ dependence level and Last BQ did not affect spatial WM, verbal WM, and remote memory. Last Cigarette is critical in affecting WM; namely, longer interval led to worse performance. Finally, higher alcohol dependence level could lead to better remote memory., Conclusions: To our knowledge, there are no BQ studies addressing the effects of concurrent use of cigarettes and alcohol on memory. The current results suggest that cigarette smoking and alcohol drinking, rather than BQ chewing, are critical for memory performance.

Oral submucous fibrosis (OSF) is a precancerous condition of the oral cavity associated with habitual chewing of quid, with a high incidence among populations of the Indian subcontinent and Southeast Asia. Clinically, its initial manifestation may mimic oral lichen planus or lichen sclerosus. If the habit is not halted, the mucosa gets leathery and thickened, and fibrous bands form causing significant morbidity. Microscopically, it is characterized by atrophic epithelium, loss of rete ridges, and hyalinization of lamina propria. Of note, these hallmark histopathological features may be overlooked in the unusual presence of lichenoid interface changes, which may lead to the wrong diagnosis. We present herein five cases in which the rare joint appearance of OSF and lichenoid reaction features posed a diagnostic challenge. Due to its progressive nature and malignant potential, the presence of oral lichenoid changes overlying submucous hyalinization, in the right clinical and demographic setting, should raise suspicion of OSF and prompt actions directed at quid-chewing discontinuation., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The postoperative outcomes of patients with oral cavity squamous cell carcinoma (OCSCC) vary greatly. To improve risk stratification, we sought to identify genetic biosignatures by whole-exome sequencing (WES)., Materials and Methods: We retrieved patients with OCSCC patients with paired freshly frozen malignant and non-malignant tissue specimens and performed WES by Illumina HiSeq4000 platform. We further applied a tree-based method to analyze copy number variations and obtain signature classification and driver-gene identification. We further confirmed the prognostic impact of the WES biosignature in an external independent validation set., Results: We examined 168 paired samples from patients with surgically treated OCSCC. Similar to the literature, the most commonly mutated genes were TP53 (66%), FAT1 (32%), and NOTCH1 (24%). The signatures 13 (APOBEC Cytidine deaminase [C > G]), 1 (spontaneous deamination of 5-methylcytosine), and 7 (UV exposure) showed the highest concordance rates. Using the MutSigCV, MuSiC, 20/20+, OncodriveFML, e-Driver, OncodriveCLUST, and tree-based methods, we identified a nine-gene OCSCC panel (RYR1, HLA-B, TSHZ2, PCDH17, DNAH17, GRID1, SBNO2, KSR2, and GCN1L1) predicting survival outcomes in our sample. We used the TCGA database to validate the prognostic value of the panel independently. Furthermore, gene-gene covariance analysis confirmed the coexistence of several gene alterations., Conclusion: We identified and independently validated a WES biosignature that predicts outcomes in surgically treated OCSCC in Taiwan, a betel-quid-chewing-prevent area. We proposed that the panel might help clinical trial designation for adjuvant therapy based on the risk stratification from the novel gene panel and identify targets for liquid biopsy monitoring during surveillance., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The primary objective of this study was to identify the metabolic pattern in the brains of betel quid dependent (BQD) individuals using 18 F-2-fluoro-2-deoxy-D-glucose-positron emission tomography ( 18 F-FDG-PET). A total of 42 individuals (16 BQD individuals and 26 healthy controls, HCs) enrolled at the Department of Nuclear Medicine of Xiangya Hospital underwent brain 18 F-FDG-PET. Group comparisons using statistical parametric mapping (SPM) were performed to identify the 18 F-FDG-PET patterns. Standardized uptake value ratios of anterior cingulate, frontal, thalamus, parietal, occipital, temporal and cerebellum were calculated by SPM. The characteristics of abnormal metabolism in brain regions were quantified using the xjView toolbox, and a 3-D brain map was drawn using BrainNet Viewer. We found significant metabolic reduction in the bilateral middle prefrontal cortex (PFC) and the left orbital frontal gyrus (OFC). In contrast, hypermetabolism was observed in the inferior cerebellum, fusiform, superior cerebellum, parahippocampal, vermis, lingual and thalamus. However, we found no significant difference between the BQD and HC group in the anterior cingulate, thalamus, cerebellum and frontal, temporal, parietal and occipital lobes. In summary, we found abnormal 18 F-FDG-PET metabolic pattern in BQD individuals, and this pattern may help the treatment of BQD., (© 2021 Society for the Study of Addiction.)

Objective: To explore the correlations between the habit of betel quid and areca nut (BQ-AN) chewing and the prognosis of oral cancer (OC)., Methods: We performed a systematic review and meta-analysis to clarify this issue. Data searches were performed using PubMed, Web of Science, Epistemonikos, and Embase databases through November 2019. The primary outcome was the difference in the prognosis of OC between BQ-AN chewers and non-chewers, measured in terms of 5-year overall survival (OS) and 5-year disease-specific survival (DSS) log (HR) reported in articles. The pooled HR with 95% CI of 5-year OS and 5-year DSS was calculated using a fixed-effects model., Results: Ten articles with eleven OS or DSS survival studies (one of the articles contained two studies), which were published between 2003 and 2017, were eligible for inclusion in the present study. All the 11 studies were observational studies, among which 10 were retrospective and 1 was prospective. One study measured both OS and DSS. Eight studies, with a total of 2,761 patients, used 5-year OS as the primary endpoint and four studies, with a total of 2,551 patients, used 5-year DSS. Overall, the pooled HR evaluating BQ-AN chewers was 1.26 (95% CI: 1.09-1.46) for 5-year OS and 1.40 (95% CI: 1.15-1.70) for 5-year DSS, compared with non-chewers. There was a significant association between BQ-AN chewing and OC survival., Conclusions: Betel quid and areca nut chewing is significantly associated with poor prognosis in patients with OC., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Betel quid (BQ) is one of the most popular addictive substances in the world. However, the neurophysiological mechanism underlying BQ addiction remains unclear. This study aimed to investigate whether and how BQ chewing would affect brain function in the framework of a dynamic brain network model. Resting-state functional magnetic resonance imaging scans were collected from 24 male BQ-dependent individuals and 26 male non-addictive healthy individuals before and promptly after chewing BQ. Switching rate, a measure of temporal stability of functional brain networks, was calculated at both global and local levels for each scan. The results showed that BQ-dependent and healthy groups did not significantly differ on switching rate before BQ chewing ( F = 0.784, p = 0.381, analysis of covariance controlling for age, education, and head motion). After chewing BQ, both BQ-dependent ( t = 2.674, p = 0.014, paired t -test) and healthy ( t = 2.313, p = 0.029, paired t -test) individuals showed a significantly increased global switching rate compared to those before chewing BQ. Significant corresponding local-level effects were observed within the occipital areas for both groups, and within the cingulo-opercular, fronto-parietal, and cerebellum regions for BQ-dependent individuals. Moreover, in BQ-dependent individuals, switching rate was significantly correlated with the severity of BQ addiction assessed by the Betel Quid Dependence Scale scores (Spearman's rho = 0.471, p = 0.020) before BQ chewing. Our study provides preliminary evidence for the acute effects of BQ chewing on brain functional dynamism. These findings may provide insights into the neural mechanisms of substance addictions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huang, Wu, Liu, Liu, Huang and Long.)

This study's objective was to describe the relationship between the main risk factors for oral cancer, including tobacco (in the form of cigarettes, smokeless tobacco (SLT), secondhand smoking (SS)), alcohol, and betel quid (BQ), and the occurrence of oral potentially malignant disorders (OPMDs). A community-based case-control study was conducted with a population of 1448 adults aged 40 years or above in northeastern Thailand. Patients aged 60 years or above (OR 1.79, p < 0.001) and female patients (OR 2.17, p < 0.001) had a significant chance of having OPMDs. Our multivariate analysis showed that the most potent risk factor for OPMDs occurrence was betel quid (BQ) (adjusted OR 4.65, p < 0.001), followed by alcohol (OR 3.40, p < 0.001). Even former users were at risk of developing OPMDs. The synergistic effect between these main risk factors was significantly shown in the group exposed to SLT, SS, BQ, and alcohol. The most potent synergistic effect was found in the group exposed to SLT, BQ and alcohol with the OR = 20.96.

Although recent medical studies have found a significant correlation between betel quid chewing and oral cancer, some Taiwanese aboriginal people continue the traditional betel quid culture. Using the transtheoretical model framework, we conducted a qualitative study to examine the stages of behavioral change in betel quid chewing in the Paiwan sociocultural context. We conducted in-depth interviews with 20 aboriginal chewers of betel quid. Results of a content analysis showed significant patterns in the precontemplation, contemplation, action, and maintenance stages, but none in the preparation stage. Relapse was most likely to occur between the contemplation and action stages. In the precontemplation stage, interviewees showed no motivation to change their chewing behavior due to shared positive attitudes of psychosocial benefits and cultural identity. In the contemplation stage, dependent-type chewers were aware of oral damage and pain caused by chewing betel quid but could not resist their cravings; social-type chewers showed approach-avoidance conflicts between social needs and cessation. Chewers entered the action stage once they decided to quit; "to stop immediately" or "reduce quantity" were the most frequent strategies reported. In this stage, chewers endured withdrawal symptoms and refused betel quid from others but tended to relapse easily. Participants entering the maintenance stage were not affected by withdrawal symptoms and did not have ulcers or pain. Future research should identify ways to preserve traditional aboriginal culture while encouraging aboriginal people to quit betel quid chewing to promote the prevention and treatment of oral cancer.

Betel quid (BQ), a group I human carcinogen, strongly contributes to an increased risk of oral potentially malignant disorders (OPMD) and cancers of the oral cavity and pharynx. This study was conducted to discover whether monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) variants play a potential role in the risk assessment of oral cavity and pharynx cancers and OPMD, particularly among BQ users. We applied a case-control study to confirm the polymorphism of MAO and COMT using single-nucleotide polymorphisms. We used qRT-PCR, Western blotting, and immunohistochemistry (IHC) to determine MAO and COMT expression. Carriers of the MAOA rs6323 G-allele, MAOB rs6324 G-allele, and COMT rs4633 C/C-genotype had a prominently increased risk of oral cavity and pharynx cancers (AOR = 56.99; p < 0.001). Compared to adjacent noncancerous tissues, a significant downregulation of MAO and COMT expression was exhibited in cancerous tissues ( p < 0.01). Furthermore, in different cell models, MAO and COMT expression was significantly downregulated with an increased dose of arecoline ( p < 0.01). In personalized preventive medicine for oral and pharyngeal cancers, our findings are the first to demonstrate the potential role of lower MAO and COMT expression levels, with the risk polymorphisms utilized as clinical biomarkers.

Areca nut (AN) was identified as carcinogenic to humans. Around 600 million people globally use AN in some form, yet no effective therapeutic drug is available to overcome AN addiction. This preclinical study examines the effects of antidepressants on AN use with animal models. We produced AN powder and dissolved it into drinking water, training 55 C57BL/6 mice in free self-selection to drink AN water or normal water. Then, the mice were randomly divided into four groups. Selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs) were given as three treatment groups and one placebo group for four weeks. In the follow-up period, the preference and amount of free selection of AN and normal water, and oral pathological change were evaluated. There was a significant decrease in preference for AN drinking during the first four weeks, and the 36th week after drug withdrawal in the MAOI and SSRI groups (all p < 0.05). The drug-reducing effect of AN water in the 1-4-week period was significant in the MAOI group ( p < 0.0001) and was also significant in the 3-4-week period in the SSRI group ( p = 0.03). The TCA group did not show a decrease effect. At the endpoint (60 weeks), oral mucosal fibrosis (OSF) levels and risk in the SSRI ( p = 0.0081) and MAOI ( p = 0.01) groups were significantly lower than those in the control group. Antidepressant drugs MAOIs and SSRIs could reduce the amount of AN use and decrease the early stage of oral fibrosis in mice, but SSRIs may need to be boosted again.

Betel quid (BQ) is one of the most commonly used psychoactive substances in some parts of Asia and the Pacific. Although some studies have shown brain function alterations in BQ chewers, it is virtually impossible for radiologists' to visually distinguish MRI maps of BQ chewers from others. In this study, we aimed to construct autoencoder and machine-learning models to discover brain alterations in BQ chewers based on the features of resting-state functional magnetic resonance imaging. Resting-state functional magnetic resonance imaging (rs-fMRI) was obtained from 16 BQ chewers, 15 tobacco- and alcohol-user controls (TA), and 17 healthy controls (HC). We used an autoencoder and machine learning model to identify BQ chewers among the three groups. A convolutional neural network (CNN)-based autoencoder model and supervised machine learning algorithm logistic regression (LR) were used to discriminate BQ chewers from TA and HC. Classifying the brain MRIs of HC, TA controls, and BQ chewers by conducting leave-one-out-cross-validation (LOOCV) resulted in the highest accuracy of 83%, which was attained by LR with two rs-fMRI feature sets. In our research, we constructed an autoencoder and machine-learning model that was able to identify BQ chewers from among TA controls and HC, which were based on data from rs-fMRI, and this might provide a helpful approach for tracking BQ chewers in the future.