Melbourne Dental School - Theses
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ItemThe Role of Hyaluronic Acid in the Prevention of Neoplastic Therapy-induced Oral Mucositis( 2022)ABSTRACT GENERAL SUMMARY Mucositis is a common and most debilitating complication associated with cancer therapy. Approximately 30–40% of cancer patients treated with chemotherapy develop mucositis; this percentage rises to 60–85% for patients receiving conditioning regimens before hematopoietic stem cell transplantation (HSCT) and can increase to almost 100% for head and neck cancer (HNC) patients receiving radiotherapy concomitant with chemotherapy. The condition affects the entire alimentary canal from the mouth to the anus, causing ulceration and severe pain in both the oral cavity and intestinal tract. The consequences of mucositis are far reaching and can lead to a delay or even cessation of otherwise durable cancer treatment and negatively impacting the benefits of chemoradiation. Mucositis is not only an important driver of patients’ symptoms and infection risk, but its onset is also associated with poor health outcomes, the use of health resources, and incremental costs. Given that mucositis is ultimately a predictable and potentially preventable condition, this project aimed at optimising a pre-clinical model of mucositis and testing the protective effect of a natural compound on chemotherapy-induced mucosal injury. Chapter 1 discusses the generalities of mucositis, its causative agents and risk factors, its pathophysiology diagnosis, and management. After recalling basic concepts of cancer treatment (causative factor) and mucosal structure (target tissue), in this chapter I explain the clinical relevance and economic implications of mucositis. A large section is devoted to the pathophysiology of mucositis as this represents the starting point for the development of novel mechanism-based preventative and therapeutic strategies. The chapter then focuses on oral mucositis and, in this context, types of assessment and scoring scales are extensively discussed. Current management strategies of mucositis are scrutinised in the final part of Chapter 1. Despite its clinically devastating consequences, there is currently little to offer patients in the way of effective treatment to prevent or mitigate mucositis, and this provided the rationale for developing the aims of this project. General materials and methods are detailed in Chapter 2. The experimental design included in vitro experiments using an oxidative stress-induced model of human oral mucosal injury and an in vivo dual murine model of 5-FU-induced oral/intestinal mucositis. Formulations of hyaluronic acid (HA) tested in these models included Mucosamin, cross-linked (xl-), and non-crosslinked high molecular weight HA (H-MW-HA). Cell lines, culture conditions, morphological, functional and molecular assays (e.g. cell viability, cytotoxicity, and proliferation; intracellular ROS production, superoxide dismutase enzyme activity) are described. For the animal study, methodology for clinical, histopathological and morphometric assessment of oral and intestinal mucositis is reported in detail. Specific materials and methods are additionally described in the relevant chapters. In the experiments described in Chapter 3, we aimed to develop and characterise an in vitro model of oral mucosal injury that could mimic the initial events that trigger oral mucositis. Since the molecular mechanisms underlying chemotherapy and radiotherapy-induced oral mucositis involve the production of ROS at early stages and consequent activation of oxidative stress pathways, we established an oxidative stress model on human oral keratinocytes cultures whereby were able to identify optimum concentrations of hydrogen peroxide and incubation period for each of the cell line tested. Such a model allowed the screening of potentially xxx drugs reported later in this thesis. In Chapter 4, the biocompatibility of several hyaluronic acid derivatives in our in vitro cell model system was assessed through an extensive series of experiments. We defined the optimal concentrations of the following compounds: Mucosamin (1%, 5%, 7% and 10% v/v), native high molecular weight HA (H-MW-HA; 0.01%, 0.03%, 0.05%, 0.07% and 0.1% w/v), and cross-linked (xl-) HA (0.01% v/v of xl-HA 5/5, xl-HA 30/30, and xl-HA 100/100). Oral keratinocytes were incubated for 24, 48, and 72 hours in the presence of these HA products and a dose-response curve was developed. All HA compounds tested significantly promoted oral epithelial cell proliferation compared to control, except for Mucosamin; this commercial preparation did not affect cell growth at concentrations of up to 5% (v/v) and was cytotoxic at higher concentrations. Drawing on the results of the pilot experiments described in the previous chapters, in Chapter 5 we tested the protective effects of HA in a model of oxidative stress-induced oral mucosal injury. OKF6 cells were incubated with 400 uM (IC50 value) hydrogen peroxide (H2O2) and the effects of Mucosamin, H-MW-HA, Xl-HA 5/5, Xl-HA 30/30, and Xl-HA 100/100 were tested. While all HA compounds could attenuate to some extent the detrimental effects of ROS, the most marked effects were obtained with H-MW-HA. Specifically, pre- and then co-incubation of OKF6 cells with 0.01 % (w/v) H-MW-HA for 24 hours resulted in a sizeable increase in cell viability when compared to H2O2- treated cells. Remarkably, H-MW-HA also reduced the intracellular level of H2O2-induced ROS production, as measured by the ability of cells to oxidize CM-H2DCFDA. Hence, H-MW-HA at 0.01 % (w/v) was selected for the animal study. Chapter 6 describes a detailed set of experiments to show that HA prevents oral and intestinal mucositis induced by chemotherapy in vivo. To overcome the limitations of current models, whereby oral and intestinal mucositis are studied separately using different, organ-specific models, we first characterized a pre-clinical dual (oral and intestinal) murine model of mucositis by using intravenous 5-FU injections (50 mg/kg) every 48 hours for 2 weeks. In the test group, the mice were pre-treated one day prior to the initial 5-FU treatment and then daily thereafter with high molecular weight HA (H-MW-HA) (0.01 % w/v) in drinking water. Mice were monitored clinically for weight loss, diarrhea (as a surrogate of intestinal injury), and incidence and extent of oral mucositis. Microscopically, histomorphometric analyses of the tongue and intestinal tissues were conducted. The results strongly indicated that H-MW-HA prevented 5-FU-induced damage to the intestinal mucosa and tongue epithelium. We also demonstrated that H-MW-HA enhanced the activity of the SOD enzyme in the blood serum of 5-FU treated mice. This thesis comes to a conclusion with Chapter 7, where our results are discussed in light of current literature. These results reported in this thesis provide an experimental rationale to develop a novel HA-derived treatment as a therapeutic agent to protect against oral and intestinal mucositis associated with chemotherapy in cancer patients. We note that systemic administration of HA as a preventive or therapeutic tool in oral and intestinal mucositis may have profound clinical implications in patients, such as potential interference with cancer treatment, that require further elucidation. Future studies will address this important aspect of our research.
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ItemAn investigation of cyclic resistance of files with different working part lengths and electrical resistivity as a possible predictor of niti instrument fracture( 2022)Introduction: Fracture of rotary nickel-titanium (NiTi) instruments is an unpredictable incident that may prevent adequate cleaning and shaping of the root canal system and compromise the outcome of endodontic treatment. Management of a fractured instrument is a sophisticated time-consuming process and sometimes it is impossible. Improvements in instrument design have been attempted as one important way to reduce the risk of fracture of rotary NiTi instruments. However, there have been no previous studies that investigated the effect of changing the active working part length or the shaft length of an instrument on cyclic fracture resistance. Further, electrical resistivity may be a good physical property for investigating the microstructural characteristics of the alloy because it depends on the formation and disappearance of electron-scattering entities in the material during any change or defect in the matrix of the material. Aims and objectives: The aim of this thesis was to investigate cyclic fatigue fracture in rotary NiTi instruments and to develop new methods or approaches to reduce and/or predict fracture. The first objective of this thesis was designed to study the effect of different active working part lengths (AWPL) and shaft lengths (SL) of rotary NiTi instruments on cyclic fatigue resistance. To achieve this objective, the effect of two active working part and shaft lengths of Mtwo instruments on the cyclic fatigue resistance was studied. The second objective was to investigate whether electrical resistivity could predict fracture of rotary NiTi instruments. This included measuring electrical resistivity of rotary NiTi instruments at fracture during cyclic fatigue testing by studying the electrical resistance behaviour of the rotary NiTi instruments during this test. Material and methods: The method used to realise the first objective of this thesis included using a total of 40 Mtwo instruments (VDW, Munich, Germany) of 0.25 mm size, 25 mm length and 0.06 taper. These instruments were divided into two groups of 20 instruments. The first group contained Mtwo instruments with 21 mm AWPL + 4 mm SL, while the second group has 16 mm AWPL + 9 mm SL. The testing apparatus used in this study was a cyclic fatigue testing jig (ISO jig) that was fixed onto a hard wooden base. The simulated canal for this study had a radius of 5 mm and an angle of curvature of 60 degrees. The rotary handpiece was fixed in a mobile supporting device that allowed a precise and reproducible insertion path. The time to fracture was recorded to calculate the number of cycles to fracture (NCF). The method used to address the second objective of this thesis included using simulated curved canals made of glass tubes with internal diameter of 1.2 mm, radius of curvature of 5 mm and angle of curvature of 60 degree. A total of 60 ProTaper Next instruments of 25 mm length, 0.25 size and 0.06 taper were divided into three equal groups, for cyclic fatigue testing. Changes in the electrical resistance were measured during instrument preparation. The instruments in Group 1 were used to measure the initial electrical resistance, electrical resistance at fracture and the NCF during cyclic fatigue testing. The instruments in Group 2 were used in the same way as the instruments in Group 1, with a 7-minute fatigue time and a 15-minute rest interval, while the instruments in Group 3 included two 15-minute rest intervals and an additional 3-minute fatigue time. The electrical resistivity was measured and calculated as a function of the electrical resistance and dimensions of the instruments during cyclic fatigue testing. The rotary handpiece was fixed in a mobile supporting device that allowed precise and reproducible insertion. A Dentsply endodontic motor (Dentsply ATR Tecnika, Pistoia, Italy) with a digital torque control motor and 16:1 contra-angle handpiece was used for all test groups, with a speed of 300 rpm and torque of 100 g.cm according to the manufacturer’s recommendation. The electrical resistance was measured using a four-point probe method that included Kelvin clips and a Fluke 8840A digital multimeter (Fluke Corporation, Everett, WA, USA). The results were analysed using the following statistical methods: Descriptive statistics including means, standard deviations and graphical representations. Inferential statistics including one way analysis of variance, Tukey’s post hoc test, Weibull reliability and probability of failure. Results: The findings of the first study revealed that the mean values of the time to fracture, NCF and fragment length in Group 1 were 1.38 minutes, 415 , and 4.4 mm respectively, and in Group 2, they were 0.86 minute, 258 and 6.7 mm, respectively. There was a statistically significant difference in the time to fracture, NCF and fragment lengths between the two groups. The results of the second study revealed that Group 1 had an initial electrical resistance of 0.085 ohm. The electrical resistance of the instruments increased gradually until fracture. The mean electrical resistance at fracture was 0.221 ohm. The mean of the time from starting cyclic fatigue test until fracture was 9.13 minutes. The mean of the NCF was 2738.1. The electrical resistivity at fracture was calculated as 210.207 micro ohm cm. To study the electrical resistance behaviour of ProTaper Next instruments during cyclic fatigue testing, the test was stopped just before fracture occurrence at 7 minutes and a rest interval of 15 minutes taken (Group 2). The electrical resistance decreased gradually during the 15 minutes of rest until it stabilized at 0.107 ohm. The electrical resistance, after the rest interval increased at a faster rate until instrument fracture at 0.222 ohm with a mean time of 5.340 minute. The total mean time to fracture and NCF in the second group were higher than that when there was no rest interval in the first group. The electrical resistivity at fracture for Group 2 was 211.348 micro ohm cm. For Group 3, a second fatigue time interval of 3 minutes was selected. The electrical resistance value decreased gradually during the second rest interval until it stabilized at 0.115 ohm. The electrical resistance after the second rest interval was higher than that after the first rest interval and the original value at the start. After the second rest, the electrical resistance increased at a faster rate until fracture at 0.223 ohm. The total mean time to fracture and NCF in this group were higher than those when there was only one rest interval in Group 2. The electrical resistivity at fracture for Group 3 was 211.728 micro ohm cm. The one-way ANOVA and Tukey HSD tests revealed that there was no significant difference in the electrical resistance at fracture between and within groups. The electrical resistivity values for all groups were close to each other. There was a highly statistically significant difference in the time to fracture and NCF among groups. These significant differences were very prominent between Groups 1 and 2, and between Groups 1 and 3. The lifetime of the instruments increased and depended on the history of the instruments as to whether one or two rest intervals had been used in the cyclic fatigue test. Group 3 showed a higher Weibull modulus (16.49) compared with Group 1 (9.01) and Group 2 (11.80). This correlated with a high reliability and high probability of survival. When comparing the Weibull characteristic life of the groups, it was found that Group 1 failed at a higher level compared with Groups 2 and 3. Conclusions: This suggests that the AWPL may influence the cyclic fatigue resistance of the instrument. A specific value of electrical resistivity (211.1 micro ohm cm) was found at which fracture of ProTaper Next instruments occurred. There was an inverse correlation between the initial starting resistance of a used instrument and the additional NCF. Measuring electrical resistivity may be used to predict fracture of rotary NiTi instruments. Further studies are needed in this area.
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ItemEvaluation of physical/mechanical properties, ion release, and rechargeable efficacy of contemporary ion-leaching restorative materials( 2021)Aims: This thesis aimed to evaluate mechanical properties, ion release, and recharge ability of ion-leaching restorative materials (ILMs) consisting of glass-ionomer (GI) based materials and resin-based ion-leaching restorative materials (RB-ILMs). Implementation: The thesis began with a systematic review of ‘comparison of atraumatic restorative treatment and conventional restorative techniques on clinical performance of glass-ionomer cement restorations in load-bearing areas of permanent and primary dentitions. The results informed that the current paradigm has shown the tendency to shift to the use of GI-based materials as alternative ‘occlusal’ restorations with conventional restorative techniques, irrespective of the dentition. Based on this initial finding, the first experiment aimed to investigate the flexural mechanical properties of recently introduced and contemporary GI-based cements and RB-ILMs with their relative porosity and microstructures. Manufacturers claimed that several ILMs have been improved with respect to their ion-leaching abilities. Additionally, various new oral care products were introduced for recharging fluoride, calcium, and phosphate ions of the ILMs. These provided the rationale for the second and third experiments to investigate ion release and recharge efficacy of ILMs, as well as the influence of various recharge agents. Main results: The results showed that material type played a major role by affecting the four-point bending flexural strength (4PB-FS). The 4PB-FS values were in the sequence: RB-ILMs>RMGICs>high-viscosity GICs (HVGICs). The porosity seemed to have a minor effect on 4PB-FS for each group of materials. Regarding the ion release/re-release capacities, Zirconomer (an HVGIC) displayed a versatile behaviour for ion-release/re-release, particularly for fluoride. Interestingly, Cention N (an RB-ILM) showed an excellent capacity for calcium release and rechargeability of calcium/phosphate. The fluoride elution in deionised water from Cention N was significantly higher than that for some GI-based materials. For the experiment of various recharge agents, it was shown that the ion re-release capability after recharge is very much dependent not only on the restorative material even within the same category but also on the material/recharge agent combination.
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ItemOvercoming barriers to access and provision of dental care for patients with special needs in the Australian public dental system( 2021)Background Individuals with special needs report being unable to find oral health professionals with adequate experience who are willing to treat them despite the recognition of a dedicated dental specialty, special needs dentistry, to advocate for and assist with their oral health treatment needs. Aims: The aims of this study were: 1. To develop a profile of the patients receiving specialist dental care in special needs dentistry around Australia, 2. To explore the challenges associated with providing dental care to individuals with special needs in the public dental system, and 3. To identify ways to overcome barriers to treating individuals with special needs. Methods: A cross-sectional clinical audit of patient appointments was conducted at two of Australia’s largest and most well-established specialist units in special needs dentistry: the Integrated Special Needs Department at the Royal Dental Hospital of Melbourne and the Special Needs Unit at the Adelaide Dental Hospital, as well as specialised dental clinics operated by Oral Health Services Tasmania; the Special Care Dental Units. Quantitative methods were used to analyse patient demographics, referrals, medical profiles, and treatment received. Qualitative methods were used to explore the views of specialists in special needs dentistry and other oral health professionals in relation to the challenges they faced in providing care to individuals with special needs. Semi-structured interviews and focus groups were employed to understand their perspectives towards the factors that influenced specialist services and the willingness of clinicians to treat patients with special needs. Results: Inconsistencies were noted between the patient cohorts being treated at the two specialist clinics that may have reflected differences in referrals, available services and facilities, and the local oral health care systems. Specialists in special needs dentistry felt that the biggest challenge facing specialist services was the strain placed on the limited specialist workforce and resources by referrals from oral health professionals not willing to treat individuals with special needs. Oral health professionals working in the primary care setting felt that the two most significant barriers to providing care for patients with special needs were insufficient training and experience in special needs dentistry or a lack of support within their work environment. Additional education and training, opportunities for networking with more experienced clinicians, and a more supportive work environment were identified as ways to overcome these barriers. Additional support provided by specialists in special needs dentistry, in the form of a network arrangement or visiting specialist, were found to improve the willingness of oral health professionals to treat patients with special needs. Conclusions: The profile of patients receiving dental care from specialist dental clinics in special needs dentistry is variable and largely influenced the willingness of oral health professionals to treat them. Providing additional support to these oral health professionals, to overcome their perceived lack of training and experience and barriers within the public dental system, will be vital to improving the willingness of clinicians to treat patients with special needs and addressing access to care issues for this population.
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ItemManagement of the mandibular Kennedy Class I situation using a removable partial denture supported by short implants and retained with a resilient attachment system: A within-subject crossover clinical trial( 2020)The mandibular Kennedy Class I (KCI) situation is regarded as one of the more challenging clinical situations to successfully manage with a conventional removable partial denture (CRPD). Acceptance of this treatment option is generally poor. Stabilising the distal extension bases of such dental prostheses through association with strategically placed dental implants has been described; however, the evidence-levels supporting this treatment concept are low. Clinical trials employing multiple objective and subjective measures comparing implant-retained removable partial dentures (IRRPD) with CRPDs, and even with the baseline situation (shortened dental arch (SDA)), are rare. The objective of this research project was to use multiple objective and subjective measures to compare these three situations and to determine if a) a removable dental prosthesis (CRPD and/or IRRPD) can significantly improve function, Oral Health Related Quality of Life (OHRQoL), and patient satisfaction relative to the SDA situation, and b) if implant association significantly improves the function, OHRQoL, and patient satisfaction over the CRPD. This clinical trial was conducted as a within-subject crossover trial, whereby each subject experienced both a CRPD and an IRRPD to manage a mandibular KCI situation comprising of less than twenty teeth. Seventeen subjects completed the clinical trial. Subjects were randomly allocated into one of two groups; group A – CRPD first, and group B – IRRPD first. At the completion of the first phase of the trial, the dental prosthesis being worn was converted to the other design. Both objective and subjective measurements were recorded at baseline, the time of each dental prosthesis insert, and after a minimum adaptation time of three months. Based on the objective tests, the presence of a lower dental prosthesis shows a tendency to improve the SDA situation, however this improvement is not significant when using a chewing test and when assessing maximum bite pressure. The CRPD demonstrated no significant improvement in OHRQoL and satisfaction relative to the SDA situation, whilst the IRRPD demonstrated significant improvements in physical pain and physical disability domains. When comparing the CRPD and IRRPD head-to-head, it is obvious that the IRRPD is significantly superior in terms of OHRQoL and patient satisfaction, however similar in terms of objective measures. As a result of this research, a decision-making treatment-planning rubric has been proposed to help assist patients, clinicians, and funding bodies (i.e., governments, insurance industry, etc.) in providing appropriate treatment in a cost-effective manner.
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ItemApplication of Proanthocyanin as Adjunctive Treatment for Root Carious Lesions( 2020)In an aging world population, improvement in oral health awareness and behaviours has resulted in the progressively increasing retention of natural teeth in the geriatric population in developed countries. As a result, the number of root surfaces at risk of developing caries is increasing due to age-associated gingival recession and subsequent exposure of caries-prone cervical root dentine to the oral environment. Root carious lesions (RCLs) have a complex aetiology and can be challenging to treat, due to, in part, difficulties in restoring the structural composition of root dentine. Specifically, root dentine contains a considerable amount of organic materials which play a crucial role in the progression and treatment of root caries. Application of a naturally derived collagen cross-linking agent - proanthocyanidins (PA), which could cross-link and bio-modify the dentinal collagen, has been considered as a promising adjunct in RCL treatments. The aim of the thesis was to investigate the effects of PA used as an adjunctive treatment for RCLs. In addition, further evidence was provided regarding the efficacy of currently recommended treatments for RCLs in the laboratory setting. Using an in vitro artificial RCL model, the effects of several frequently used fluoride (F) regimens on RCLs were investigated. It was observed that the application of silver diammine fluoride/potassium iodide (SDF/KI) improved the nano-mechanical properties and mineral density (MD) of demineralised root dentine. Both F varnishes and 5,000 ppm F toothpastes promoted the remineralisation of artificial RCLs and their treatment efficacy could be enhanced by combined application. The performance of different glass ionomer cements (GICs) such as resin-modified GIC (RMGIC), high viscosity GIC (HVGIC) and casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) modified low viscosity GIC when used as restorative materials for RCLs was partially dependent on the characteristics of the dentine substrate for bonding and the inherent formulations and properties of the GIC material itself. When PA was used as an adjunct to the above-mentioned F agents, it had the potential in strengthening the demineralised dentine matrix and enhancing collagen-mineral interactions for improved uptake and distribution of remineralising ions, nano-mechanical properties and MD of demineralised root dentine in the subsurface areas. Furthermore, considering the acidic nature of PA in addition to its cross-linking capability and multiplicity of functional groups, PA was used as a dentine conditioner for GIC bonding. It was determined that PA conditioning did not influence the bond strength of GICs to both sound and demineralised root dentine significantly in the short term. However, the interfacial interaction between GICs and PA-conditioned root dentine was compromised with an increased failure mode of interfacial debonding. The results expounded in this thesis indicate the potential remineralisation-enhancing effects of PA when used as an adjunct to F regimens in non-invasive treatments of demineralised root dentine in the laboratory setting. However, using PA as a conditioner for GICs in the restorative treatment of demineralised root dentine did not show additional benefits for bonding in the short-term.
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ItemDental therapeutic guideline adherence in Australia( 2020)Background: Dentists prescribe a variety of medicines, the most common being antibiotics, analgesics and anxiolytics. Drugs have a limited role in dentistry, usually being recommended as an adjunct to dental treatment. In Australia, the Therapeutic Guidelines Oral and Dental are the national prescribing guidelines. Literature shows that dentists worldwide tend to overprescribe antibiotics and do not prescribe in accordance with guidelines. The aims of this thesis were to establish current dental prescribing patterns, determine reasons behind and influences on prescribing decisions, and to design and implement a targeted intervention to optimise dental prescribing. Methods: A three-phase project was conducted. In Phase 1, publicly available data on dispensed dental medicines (2013-2016) was accessed from the Department of Health to analyse dental prescribing trends in Australia. Phase 2 involved two studies of dentists to determine reasons for prescribing decisions: 1. postal survey (n=1,468; response rate=26%) of dentists in Victoria and Queensland and 2. individual qualitative interviews (n=15) of dentists in Victoria. Phase 3 involved designing and conducting a pilot intervention with the aim of improving prescribing. The intervention comprised targeted education and a dental-specific clinical-decision prescribing tool. Participants (n=26) self-recorded their prescriptions for 12 weeks, with the intervention delivered at the six-week mark. Effectiveness was evaluated by comparing total number of prescriptions, indications for prescribing and prescription regimens before and after the intervention. Results: Phase 1 (Chapter 3): Dentists in Australia make some inappropriate prescribing choices, and prefer moderate- to broad-spectrum antibiotics over more appropriate narrow spectrum options, as recommended in the guidelines. The use of opioids and benzodiazepines increased over the study period, indicating need for more education about abuse potential as well as the appropriate role of opioids in dental pain. Phase 2 (Chapter 4): Antibiotics were overprescribed in approximately 55% of cases. Between 16-27% of dentists would preference other analgesics over NSAIDs for dental pain, and almost half (46%) of the participants who prescribed anxiolytics did so inappropriately, with regimens and choices outside the guidelines. Surveys showed a significant proportion of dentists tended to overprescribe antibiotics, prescribe for incorrect clinical indications and inappropriately preference other analgesics and opioids for dental pain over NSAIDs. Several non-clinical factors, such as time pressure and patient expectations, influenced prescribing. Phase 3 (Chapters 5 and 6): Comparing prescribing after the intervention to before revealed a 41% reduction in prescribing of antibiotics and a 45% reduction in inappropriate prescribing. Prescribing of paracetamol/codeine reduced by 57%. For the three most commonly prescribed antibiotics (amoxicillin, metronidazole and phenoxymethylpenicillin), there was an improvement in the accuracy of prescriptions ranging from 0-65% to 75-100% using Australian therapeutic guidelines as reference. Conclusions: Australian dentists overprescribe antibiotics; many factors that influence prescribing (both clinical and non-clinical). Data on prescribing choices and reasons for inappropriate prescribing can inform future dental education and the development of stewardship programs for dental practice. Targeted interventions addressing specific misconceptions and areas that are lacking can produce positive changes with public health benefits. The context-specific intervention that was developed shows substantial promise for implementation into dental practice.
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ItemIndonesian Betel Quid and Oral Cancer( 2020)Purpose Oral cancer (OC) is considered as a public health problem that carries significant morbidity and mortality. The disease represents a group of conditions with a range of sites and varied etiology. Indonesia has insufficient data of epidemiology studies in relation with oral pre-malignant disorders (OPMD) or OC prevalence and their risk factors. It is also important to understand the knowledge of GDPs in recognizing OC risk factors, early symptoms of OC, as well as in performing conventional oral examination. Without a comprehensive understanding of these factors, efforts to prevent, detect and manage this disease are likely to be ineffective in terms of outcomes and use of resources. Hypothesis and Aim The overall hypothesis was that Indonesia has a high prevalence of OPMD or OC that are strongly associated with the actual found risk factors. The overall aims of the epidemiology studies were to understand the prevalence and risk factors of OC and OPMD among Indonesians as well as to assess Indonesian GDP’s knowledge in risk factors for OC and in performing COE. The aims of the laboratory studies were to identify antioxidants activities and phytochemical components of Indonesian BQ using HPLC, LCMS, and GC-MS, as well as to know the pathobiological response of Indonesian BQ components on oral keratinocyte (OKF-6) and oral fibroblast (MMF-1). Materials and Methods A cross-sectional study was undertaken using a pre and post-training questionnaire and training intervention with both theory and practical based. The study conducted in five different provinces of Indonesia; Aceh, Banda Aceh (BA); Bandung, West Java (WJ); special district Jakarta, Jakarta (JKT); Pontianak, West Kalimantan (WK); and Sorong, West Papua (WP). The local Dental Association or Faculty of Dentistry invited the GDPs to attend a one-day standardized education program of oral malignant and OPMDs detection and 3 days hospital-based or community service-based practice. A cross-sectional study was undertaken in multiple geographical areas within five Indonesian provinces, namely West Java (WJ), Jakarta (JKT), West Papua (WP), West Kalimantan (WK) and Banda Aceh (BA) regions. Individuals attending community health services, dental hospitals and selected villages were recruited. Volunteer respondents answered a previously validated extensive questionnaire that included socio-demographic factors, oral hygiene practices, diet, adverse oral habits and frequency of dental visits. An oral examination was undertaken using standardized WHO methodology. Data were analyzed using ANOVA, Chi-Square, and logistic regression to assess association between risk factors and mucosal disease. The total phenolic content (TPC), antioxidant activity (by mean of ferric reducing antioxidant power, FRAP), radical scavenging activity (DPPH test), phenolics profile and arecoline content in different components of BQ which were AN, Leaf or SI, Husk, and blended BQ (BQ mixture). BQ mixture were a blending form contained AN, Leaf or SI and slaked lime. Samples were imported from 4 major regions of Indonesia, namely: Banda Aceh (BA), North Sumatra (NS), West Kalimantan (WK) and West Papua (WP). The highest TPC, FRAP, and DPPH values were detected in AN samples compared to other BQ components, while samples from WP region were of higher values compared to the other regions. High performance liquid chromatography - Mass Spectrometry (LC-MS) analysis was used to identified and quantified polyphenols and arecoline. The gas chromatography mass spectrometry (GC-MS) platform was used to analyse the alkaloids present in betel quid originated from four different regions of Indonesia, Banda Aceh (BA), North Sumatra (NS), West Kalimantan (WK), and West Papua (WP). Further, our study profiled the plant metabolites present in different components of betel quid, including areca nuts, betel leaf, stem inflorescence and betel quid as whole originated from each region. Fluorescein diacetate assay (FDA) was used as a cell cytotoxicity test of BQ components on oral keratinocytes (OKF-6) and oral fibroblast (MMF-1) cells. The cytotoxicity effects of areca nut (AN), leaf of piper betle (Leaf) or stem inflorescence of piper betle (SI), areca husk (Husk) and whole BQ Mixture was tested on the growth of oral keratinocytes (OKF-6) and oral primary fibroblasts (MMF-1). On the basis of their chemical characteristics, BQ from Banda Aceh (BA) and West Papua (WP) regions were selected for in vitro testing. Results 177 GDPs were registered in the one-day standardised training and 3 days practice. The highest number of registered GDPs was from WJ region (n=63), followed by GDPs from BA (n=44), JKT (n=27), WK (N=23), and WP (20) region respectively in rank. A total of 144 (81.37%) GDPs sent back their response to the post-training questionnaire 2-6 weeks after attending the training. Female respondents predominated with 157 (88.7%) returning the pre-training questionnaire and 126 (87.5%) returning the post-training questionnaire. Only 20 (11.3%) and 18 (12.5%) male GDPs answered the pre- and post-training questionnaire, respectively. Most of Indonesian GDPs demonstrated inadequate knowledge, awareness, and confidence in performing COE. The OC training could positively increase their knowledge and confidence of early screening. A total of 973 respondents were enrolled (WJ 35.5%; JKT 13.3%, WP 18.3%, WK 9%; BA 23.9%). Smoking (14.8%), BQ chewing (12.6%) and alcohol drinking (4%) varied geographically. An OPMD was detected in 14.3% respondents and 0.2% had history of OC. Leukoplakia was the most common OPMD (8.6%), while the prevalence of erythroplakia/erythroleukoplakia was 0.6%, and oral submucous fibrosis (OSMF) 1.9%. Leukoplakia was the most common type OPMD found in the survey most likely due to high number of smoking habit related. Overall, there was a strong correlation between the prevalence of OPMD and risk factors for OC. In particular, high use of BQ chewing in WK and WP, related to high prevalence of OPMD. The knowledge of OC risk factors, oral hygiene behaviour, ethnicities and low-income SES group were significantly associated with OPMD. High performance liquid chromatography - Mass Spectrometry (LC-MS) analysis showed that Husk contains the widest range of polyphenols, including hydroxybenzoic acids, hydroxycinnamic acids, flavanols, flavonols and stilbenes. Catechin and epicatechin were the main polyphenols detected in BQ, and they were present at the highest concentrations in WP-AN sample. Arecoline was detected in all AN and BQ mix samples and was significantly correlated with catechin and epicatechin, and significantly negatively correlated with p-hydroxybenzoic acid. The current study is the first to extensively characterise the chemical composition of BQ and provides insight for the interactions of BQ alkaloids and phenolics in the development of oral submucous fibrosis and oral cancer. Three types of alkaloids (arecoline, arecaidine, and guvacoline) were successfully identified using GC-MS. However, guvacine could not be analysed due to low volatility. This currently also profiled the metabolites in different BQ components and identified high concentrations of benzenoid and terpense, in stem inflorescence samples, especially the carcinogenic constitute, safrole. Interestingly, high concentrations of sesquiterpenes, such as gamma-cadinene, spatulenol, alpha-copaene, linalool, alpha-gurjunene, gamma-amorphene were also identified in stem inflorescence. The study found that WP-AN exhibited cytotoxic effect on OKF-6 at a concentration of 100 micro g/ml, as measured by a 50% reduction of cell viability (IC50), while BA-AN exhibited cytotoxic effect at a higher concentration (500 micro g/ml) after 2 days of incubation. WP-SI also showed cytotoxic effect at 500 micro g/ml after 2 days incubation. In contrast, the extract of Leaf, BQ Mixture and Husk did not exhibit cytotoxic effect for up to 3 days of incubation. The exposure of BQ components to MMF-1 showed no cytotoxicity at any concentration assessed. Incubation of MMF-1 with BA-AN and WP-AN led to an increase of cell proliferation (1 day) followed by a decline of cell growth (2 days) in a dose and time dependent manner. Thus, the results of our study showed distinctive cytotoxic profiles in stromal and epithelial cells of the oral cavity induced by BQ components. Conclusion A previously underestimated high prevalence of OPMD in Indonesia strongly correlates with OC risk behaviour. There is an urgent need for primary prevention of OC programs in Indonesia. GDP knowledge of OC risk factors and COE is important to be addressed, as the lack of their knowledge and awareness can impact to delaying OC early screening and diagnosis. Therefore, improving the national curriculum in Indonesia on OC is more likely the best way for GDPs to have sufficient knowledge and confidence regarding OC before graduation. The ripeness of AN is directly related to the amount of both polyphenols and arecoline. The unripe AN contained a higher concentration of polyphenols and arecoline compared to ripe AN, suggesting that consuming the ripe AN could lower the potential of developing OSMF. Further, our finding that safrole was detected in betel stem inflorescence (SI) as well as husk. This finding suggests that adding betel SI and husk into BQ compound could raise the risk of having OSMF and oral cancer even more as safrole is a possible potential human carcinogen