3D cephalometry on reduced FOV CBCT: skeletal class assessment through AF-BF on Frankfurt plane-validity and reliability through comparison with 2D measurements.

OBJECTIVES: To test the validity of a novel protocol for 3D sagittal jaw discrepancy assessment (skeletal class determination) through comparison with common 2D indexes by the use of reduced FOV (10 × 10) CBCT which shows at least from the Frankfurt plane to the B point vertically, and from the most anterior between A and B point to Po point horizontally. METHODS: A sample of CBCT scans of 109 adult patients (46 females; 63 males; mean age 30 years ± 11.6) equally distributed between I, II and III class was selected. Skeletal class was evaluated with specific software using the distance of A and B point's projection (AF-BF) on FHp (Frankfurt horizontal plane) and compared to 2D common indexes (ANB and Witts appraisal). The validity and reliability of the aforementioned analyses were determined using intra-class correlation coefficients, quadratic weighted Cohen's K and sensitivity. RESULT: A selected range of values of 2.5 ± 2.5 AF-BF showed a solid correlation with the ANB angle (r = 0.846, K = 0.838, p < 0.001) and moderate with Wits appraisal (r = 0.723, K = 0.720, p < 0.001). CONCLUSIONS: AF-BF showed high reliability in skeletal class determination on reduced FOV CBCT without the use of S and N cephalometric landmarks. KEY POINTS: • Reduced FOV CT allows skeletal class determination for orthodontic purposes. • A new 3D-reduced FOV cephalometry is proposed. • AF-BF is a reliable alternative to ANB.

Regeneration of Critical-Sized Mandibular Defects Using 3D-Printed Composite Scaffolds: A Quantitative Evaluation of New Bone Formation in In Vivo Studies.

Mandibular tissue engineering aims to develop synthetic substitutes for the regeneration of critical size defects (CSD) caused by a variety of events, including tumor surgery and post-traumatic resections. Currently, the gold standard clinical treatment of mandibular resections (i.e., autologous fibular flap) has many drawbacks, driving research efforts toward scaffold design and fabrication by additive manufacturing (AM) techniques. Once implanted, the scaffold acts as a support for native tissue and facilitates processes that contribute to its regeneration, such as cells infiltration, matrix deposition and angiogenesis. However, to fulfil these functions, scaffolds must provide bioactivity by mimicking natural properties of the mandible in terms of structure, composition and mechanical behavior. This review aims to present the state of the art of scaffolds made with AM techniques that are specifically employed in mandibular tissue engineering applications. Biomaterials chemical composition and scaffold structural properties are deeply discussed, along with strategies to promote osteogenesis (i.e., delivery of biomolecules, incorporation of stem cells, and approaches to induce vascularization in the constructs). Finally, a comparison of in vivo studies is made by taking into consideration the amount of new bone formation (NB), the CSD dimensions, and the animal model.

Cone-Beam Computed Tomographic Assessment of the Mandibular Condylar Volume in Different Skeletal Patterns: A Retrospective Study in Adult Patients.

The aim of this study was to assess the condylar volume in adult patients with different skeletal classes and vertical patterns using cone-beam computed tomography (CBCT). CBCT scans of 146 condyles from 73 patients (mean age 30 ± 12 years old; 49 female, 24 male) were selected from the archive of the Department of Dentistry and Maxillofacial Surgery of Fondazione IRCCS Ca' Granda, Milan, Italy, and retrospectively analyzed. The following inclusion criteria were used: adult patients; CBCT performed with the same protocol (0.4 mm slice thickness, 16 × 22 cm field of view, 20 s scan time); no systemic diseases; and no previous orthodontic treatments. Three-dimensional cephalometric tracings were performed for each patient, the mandibular condyles were segmented and the relevant volumes calculated using Mimics Materialize 20.0® software (Materialise, Leuven, Belgium). Right and left variables were analyzed together using random-intercept linear regression models. No significant association between condylar volumes and skeletal class was found. On the other hand, in relation to vertical patterns, the mean values of the mandibular condyle volumes in hyperdivergent subjects (688 mm3) with a post-rotation growth pattern (625 mm3) were smaller than in hypodivergent patients (812 mm3) with a horizontal growth pattern (900 mm3). Patients with an increased divergence angle had smaller condylar volumes than subjects with normal or decreased mandibular plane divergence. This relationship may help the clinician when planning orthodontic treatment.

Dietary supplements for improving nitric-oxide synthesis.

Nitric oxide (NO) is an essential component of the human body, involved in blood vessel dilation, stimulation of hormone release, signaling and regulation of neurotransmission. Nitric oxide is synthesized by nitric-oxide-synthase-dependent and -independent pathways. Nitric oxide supplementation improves cardiac health, enhances performance during exercise, reduces high blood pressure during pregnancy, reduces erectile dysfunction and improves healing processes and respiratory response. Nitric-oxide-associated benefits are mostly apparent in untrained or moderately trained individuals. L-arginine and L-citrulline supplementation contributes to nitric oxide levels because L-arginine is directly involved in NO synthesis, whereas L-citrulline acts as an L-arginine precursor that is further converted to NO by a reaction catalyzed by NO synthase. L-arginine supplements increase respiratory response and enhance performance during exercise, while L-citrulline with malate and other molecules increase working capacity. Various studies involving beetroot juice have reported a significant increase in plasma nitrite levels, regarded as markers of NO, after intake of beetroot juice. Although NO supplementation may have mild to moderate side-effects, using smaller or divided doses could avoid some of these side-effects. Since nitric oxide supplementation may worsen certain health conditions and may interfere with certain medicines, it should only be taken under medical supervision.

Polyphenols and Lactobacillus reuteri in oral health.

Oral health is one of the necessary preludes to the overall quality of life. Several medical procedures and therapies are available to treat oral diseases in general and periodontal diseases in particular, yet caries, periodontitis, oral cancer, and oral infections remain a global concern. Natural molecules, with their anti-oxidant, anti-inflammatory, and anti-microbic properties, are one of the main sources of oral health and dental health care, and should be supplemented to exploit their beneficial effects. A possible way to improve the intake of these molecules is adhering to a diet that is rich in fruits, vegetables, and probiotics, which has many beneficial properties and can improve overall health and wellbeing. The Mediterranean diet, in particular, provides several beneficial natural molecules, mainly because of the precious nutrients contained in its typical ingredients, mainly plant-based (olives, wine, citrus fruits, and many more). Its beneficial effects on several diseases and in increasing the overall wellbeing of the population are currently being studied by physicians. Among its nutrients, polyphenols (including, among other molecules, lignans, tannins, and flavonoids) seem to be of outmost importance: several studies showed their anticariogenic properties, as well as their effects in decreasing the incidence of non-communicable diseases. Therefore, plant-derived molecules - such as polyphenols - and probiotics - such as Lactobacillus reuteri - have shown a significant potential in treating and curing oral diseases, either alone or in combination, owing to their antioxidant and antimicrobial properties, respectively.

Validating methods for testing natural molecules on molecular pathways of interest in silico and in vitro.

Differentially expressed genes can serve as drug targets and are used to predict drug response and disease progression. In silico drug analysis based on the expression of these genetic biomarkers allows the detection of putative therapeutic agents, which could be used to reverse a pathological gene expression signature. Indeed, a set of bioinformatics tools can increase the accuracy of drug discovery, helping in biomarker identification. Once a drug target is identified, in vitro cell line models of disease are used to evaluate and validate the therapeutic potential of putative drugs and novel natural molecules. This study describes the development of efficacious PCR primers that can be used to identify gene expression of specific genetic pathways, which can lead to the identification of natural molecules as therapeutic agents in specific molecular pathways. For this study, genes involved in health conditions and processes were considered. In particular, the expression of genes involved in obesity, xenobiotics metabolism, endocannabinoid pathway, leukotriene B4 metabolism and signaling, inflammation, endocytosis, hypoxia, lifespan, and neurotrophins were evaluated. Exploiting the expression of specific genes in different cell lines can be useful in in vitro to evaluate the therapeutic effects of small natural molecules.

A machine learning model for separating epithelial and stromal regions in oral cavity squamous cell carcinomas using H&E-stained histology images: A multi-center, retrospective study.

OBJECTIVE: Tissue slides from Oral cavity squamous cell carcinoma (OC-SCC), particularly the epithelial regions, hold morphologic features that are both diagnostic and prognostic. Yet, previously developed approaches for automated epithelium segmentation in OC-SCC have not been independently tested in a multi-center setting. In this study, we aimed to investigate the effectiveness and applicability of a convolutional neural network (CNN) model to perform epithelial segmentation using digitized H&E-stained diagnostic slides from OC-SCC patients in a multi-center setting. METHODS: A CNN model was developed to segment the epithelial regions of digitized slides (n = 810), retrospectively collected from five different centers. Deep learning models were trained and validated using well-annotated tissue microarray (TMA) images (n = 212) at various magnifications. The best performing model was locked down and used for independent testing with a total of 478 whole-slide images (WSIs). Manually annotated epithelial regions were used as the reference standard for evaluation. We also compared the model generated results with IHC-stained epithelium (n = 120) as the reference. RESULTS: The locked-down CNN model trained on the TMA image training cohorts with 10x magnification achieved the best segmentation performance. The locked-down model performed consistently and yielded Pixel Accuracy, Recall Rate, Precision Rate, and Dice Coefficient that ranged from 95.8% to 96.6%, 79.1% to 93.8%, 85.7% to 89.3%, and 82.3% to 89.0%, respectively for the three independent testing WSI cohorts. CONCLUSION: The automated model achieved a consistently accurate performance for automated epithelial region segmentation compared to manual annotations. This model could be integrated into a computer-aided diagnosis or prognosis system.

Modern vision of the Mediterranean diet.

The Mediterranean diet is the most well-known and researched dietary pattern worldwide. It is characterized by the consumption of a wide variety of foods, such as extra-virgin olive oil (EVOO), legumes, cereals, nuts, fruits, vegetables, dairy products, fish, and wine. Many of these foods provide several phytonutrients, among which polyphenols and vitamins play an important role. Data from several studies have strongly established that nutrition is a key factor in promoting a healthy lifestyle and preventing many chronic diseases. In particular, a large number of studies have established the protective effects of the Mediterranean diet against several chronic diseases, among which are diabetes, cardiovascular diseases, cancer, aging disorders, and against overall mortality. Animal and human translational studies have revealed the biological mechanisms regulating the beneficial effects of the traditional Mediterranean diet. Indeed, several studies demonstrated that this nutritional pattern has lipid-lowering, anticancer, antimicrobial, and anti-oxidative effects. Moreover, the Mediterranean diet is considered environmentally sustainable. In this review, we describe the composition of the Mediterranean diet, assess its beneficial effects, and analyze their epigenomic, genomic, metagenomic, and transcriptomic aspects. In the future it will be important to continue exploring the molecular mechanisms through which the Mediterranean diet exerts its protective effects and to standardize its components and serving sizes to understand more precisely its effects on human health.

Dietary supplements for the management of COVID-19 symptoms.

SARS-CoV-2, the etiological agent of COVID-19, caused a pandemic in 2020, which is only recently slowing down. The symptoms of COVID-19 range from cough to fever and pneumonia and may persist beyond the active state of the infection, in a condition called post-COVID syndrome. The aim of this paper is to review the relationship between COVID-19 and nutrition and to discuss to most up-to-date dietary supplements proposed for COVID-19 treatment and prevention. Nutrition and nutritional dysregulations, such as obesity and malnutrition, are prominent risk factors for severe COVID-19. These factors exert anti-inflammatory and proinflammatory effects on the immune system, thus exacerbating or reducing the immunological response against the virus. As for the nutritional habits, the Western diet induces a chronic inflammatory state, whereas the Mediterranean diet exerts anti-inflammatory effects and has been proposed for ameliorating COVID-19 evolution and symptoms. Several vaccines have been researched and commercialized for COVID-19 prevention, whereas several drugs, although clinically tested, have not shown promising effects. To compensate for the lack of treatment, several supplements have been recommended for preventing or ameliorating COVID-19 symptoms. Thus, it is critical to review the dietary supplements proposed for COVID-19 treatment. Supplements containing α-cyclodextrin and hydroxytyrosol exhibited promising effects in several clinical trials and reduced the severity of the outcomes and the duration of the infection. Moreover, a supplement containing hydroxytyrosol, acetyl L-carnitine, and vitamins B, C, and D improved the symptoms of patients with post-COVID syndrome.

Physical activity for health.

Physical activity plays a substantial role in maintaining people's good health and mental wellbeing, but that is not all: not only it positively affects the individuals' mental and physical health, but a lack of physical exercise exerts a negative impact also on the overall economy of a nation. In addition, physical inactivity not only increases the risk of non-communicable diseases (NCD), but also contributes significantly to the increased morbidity and mortality in patients suffering from these diseases. On the contrary, physical activity reduces the risk of NCDs - such as cardiovascular diseases, type 2 diabetes, and cancer - in a dose-dependent manner; regular exercise is also associated with many health benefits and delayed mortality. However, understanding the role of physical activity in modern society and creating an awareness in the general population is one of the most important tasks of health and recreation promoters. Correspondingly, there is a dire need to enhance our knowledge, perception, and awareness of physical activity and its impacts on an individual's health, ultimately contributing to developing a healthy society. The current review will focus on the health benefits of the two most widely studied modifiable lifestyle risk factors, physical activity and diet, focusing particularly on the Mediterranean diet.

Main nutritional deficiencies.

Nutrition is the source of energy that is required to carry out all the processes of human body. A balanced diet is a combination of both macro- and micronutrients. "Nutritional inadequacy" involves an intake of nutrients that is lower than the estimated average requirement, whereas "nutritional deficiency" consists of severely reduced levels of one or more nutrients, making the body unable to normally perform its functions and thus leading to an increased risk of several diseases like cancer, diabetes, and heart disease. Malnutrition could be caused by environmental factors, like food scarcity, as well as disease conditions, like anorexia nervosa, fasting, swallowing inability, persistent vomiting, impaired digestion, intestinal malabsorption, or other chronic diseases. Nutritional biomarkers - like serum or plasma levels of nutrients such as folate, vitamin C, B vitamins, vitamin D, selenium, copper, zinc - could be used for the evaluation of nutrient intake and dietary exposure. Macronutrients deficiencies could cause kwashiorkor, marasmus, ketosis, growth retardation, wound healing, and increased infection susceptibility, whereas micronutrient - like iron, folate, zinc, iodine, and vitamin A - deficiencies lead to intellectual impairment, poor growth, perinatal complications, degenerative diseases associated with aging and higher morbidity and mortality. Preventing macro- and micronutrient deficiency is crucial and this could be achieved through supplementation and food-based approaches.

Metabolomics application for the design of an optimal diet.

Precision nutrition is an emerging branch of nutrition science that aims to use modern omics technologies (genomics, proteomics, and metabolomics) to assess an individual's response to specific foods or dietary patterns and thereby determine the most effective diet or lifestyle interventions to prevent or treat specific diseases. Metabolomics is vital to nearly every aspect of precision nutrition. It can be targeted or untargeted, and it has many applications. Indeed, it can be used to comprehensively characterize the thousands of chemicals in foods, identify food by-products in human biofluids or tissues, characterize nutrient deficiencies or excesses, monitor biochemical responses to dietary interventions, track long- or short-term dietary habits, and guide the development of nutritional therapies. Indeed, metabolomics can be coupled with genomics and proteomics to study and advance the field of precision nutrition. Integrating omics with epidemiological and clinical data will begin to define the beneficial effects of human food metabolites. In this review, we present the metabolome and its relationship to precision nutrition. Moreover, we describe the different techniques used in metabolomics and present how metabolomics has been applied to advance the field of precision nutrition by providing notable examples and cases.

Methodology for clinical research.

A clinical research requires a systematic approach with diligent planning, execution and sampling in order to obtain reliable and validated results, as well as an understanding of each research methodology is essential for researchers. Indeed, selecting an inappropriate study type, an error that cannot be corrected after the beginning of a study, results in flawed methodology. The results of clinical research studies enhance the repertoire of knowledge regarding a disease pathogenicity, an existing or newly discovered medication, surgical or diagnostic procedure or medical device. Medical research can be divided into primary and secondary research, where primary research involves conducting studies and collecting raw data, which is then analysed and evaluated in secondary research. The successful deployment of clinical research methodology depends upon several factors. These include the type of study, the objectives, the population, study design, methodology/techniques and the sampling and statistical procedures used. Among the different types of clinical studies, we can recognize descriptive or analytical studies, which can be further categorized in observational and experimental. Finally, also pre-clinical studies are of outmost importance, representing the steppingstone of clinical trials. It is therefore important to understand the types of method for clinical research. Thus, this review focused on various aspects of the methodology and describes the crucial steps of the conceptual and executive stages.

Ethical considerations regarding animal experimentation.

Animal experimentation is widely used around the world for the identification of the root causes of various diseases in humans and animals and for exploring treatment options. Among the several animal species, rats, mice and purpose-bred birds comprise almost 90% of the animals that are used for research purpose. However, growing awareness of the sentience of animals and their experience of pain and suffering has led to strong opposition to animal research among many scientists and the general public. In addition, the usefulness of extrapolating animal data to humans has been questioned. This has led to Ethical Committees' adoption of the 'four Rs' principles (Reduction, Refinement, Replacement and Responsibility) as a guide when making decisions regarding animal experimentation. Some of the essential considerations for humane animal experimentation are presented in this review along with the requirement for investigator training. Due to the ethical issues surrounding the use of animals in experimentation, their use is declining in those research areas where alternative in vitro or in silico methods are available. However, so far it has not been possible to dispense with experimental animals completely and further research is needed to provide a road map to robust alternatives before their use can be fully discontinued.

Clinical Outcome of Dental Implants after Maxillary Sinus Augmentation with and without Bone Grafting: A Retrospective Evaluation.

(1) Background: The purpose of the present study was to retrospectively evaluate and compare the outcome of two sinus augmentation grafting protocols using a xenograft or blood clot alone over a 72-month follow-up. (2) Methods: Patients who received simultaneous lateral sinus floor augmentation and implant placement were included. Subjects were divided into two groups according to the grafting material, namely xenograft or blood clot, and into sub-groups based on the residual alveolar bone height (RABH) below the maxillary sinus, namely 4 to 6 mm or >6 mm. Kaplan-Meier survival estimates were calculated for each material group and for each sub-group at 1, 3, and 6 years. (3) Results: In total, 289 implants inserted in 136 patients with a one-stage procedure were considered. A total of 35 failures were registered. Overall survival rates were 94.2% for xenograft and 85.9% for blood clot alone at 1 year, 91.1% and 81.6% at 3 years, and 91.1% and 78.7% at 6 years. (4) Conclusions: In patients with 4-6 mm RABH, graftless interventions exploiting blood clot alone were not as successful as those using xenograft. When the RABH is low, sinus floor augmentation associated with grafting materials should be preferred whenever possible.

Recent advances in graphene-based nanobiosensors for salivary biomarker detection.

As biosensing research is rapidly advancing due to significant developments in materials, chemistry, and electronics, researchers strive to build cutting-edge biomedical devices capable of detecting health-monitoring biomarkers with high sensitivity and specificity. Biosensors using nanomaterials are highly promising because of the wide detection range, fast response time, system miniaturization, and enhanced sensitivity. In the recent development of biosensors and electronics, graphene has rapidly gained popularity due to its superior electrical, biochemical, and mechanical properties. For biomarker detection, human saliva offers easy access with a large variety of analytes, making it a promising candidate for its use in point-of-care (POC) devices. Here, we report a comprehensive review that summarizes the most recent graphene-based nanobiosensors and oral bioelectronics for salivary biomarker detection. We discuss the details of structural designs of graphene electronics, use cases of salivary biomarkers, the performance of existing sensors, and applications in health monitoring. This review also describes current challenges in materials and systems and future directions of the graphene bioelectronics for clinical POC applications. Collectively, the main contribution of this paper is to deliver an extensive review of the graphene-enabled biosensors and oral electronics and their successful applications in human salivary biomarker detection.

Electroporation technique for joint pain - Pilot feasibility study on TMD patients.

OBJECTIVE(S): It is well appreciated that traditional analgesic delivery routes used to treat pain associated with temporomandibular disorder (TMD) often have harmful unintended side effects as a consequence of systemic distribution. Further, localized delivery of analgesic medication via intra-articular injections involves a different set of issues limiting their clinical viability. As an option, transdermal analgesic delivery provides for prolonged pain relief and flexibility in dose administration, while limiting systemic exposure and minimizing adverse events. Incorporation of a novel electroporation technique may further increase transdermal drug penetration into synovial tissue/fluid and enhance pain reduction. The present feasibility study compares the effectiveness of an electroporation-enhanced transdermal application of diclofenac sodium to a conventional intra-articular injection of triamcinolone acetonide suspension (corticosteroids) to treat patients with TMD associated pain. METHODS: Pre- and post-treatment maximal incisal mouth opening (MIO), pain visual analog scale (VAS) and surface electromyography (EMG) of 22 patients treated with electroporation-enhanced diclofenac and 37 patients treated with corticosteroids injections were collected and analyzed. RESULTS: In general, patients treated with electroporation exhibited better results in terms of pain improvement (corrected p-value = .01) compared to the standard treatment, but both methods were similarly effective for improvement of MIO (corrected p-value = .71) and improvement of all EMG indices (corrected p-values ≥ .05). CONCLUSION: The enhancing effect of electroporation in transdermal delivery of diclofenac sodium was demonstrated by decreased pain, increase MIO and EMG improvement to normal values. Its analgesic and inflammatory results are comparable with standard treatment offered by corticosteroids.

A Call for Action to Safely Deliver Oral Health Care during and Post COVID-19 Pandemic.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak started just a couple of months ago and it grew rapidly causing several deaths and morbidities. The mechanism behind the transmission of the virus is still not completely understood despite a multitude of new specific manuscripts being published daily. This article highlights the oral cavity as a possible viral transmission route into the body via the Angiotensin converting enzyme 2 receptor. It also provides guidelines for routine protective measures in the dental office while delivering oral health care.

Adverse events associated with home use of mouthrinses: a systematic review.

BACKGROUND: Poor oral hygiene is strongly associated with oral and systemic diseases. Alongside mechanical tooth cleaning, the adjunctive use of mouthrinses has been widely advocated. Although research on the efficacy of various mouthrinse formulations is very active, there are a lack of conclusive data regarding their adverse effects. METHODS: We undertook a systematic review in accordance wih PRISMA guidelines of electronic databases of clinical trials of any duration with daily home use of mouthwashes, presenting clinical and subjective side effects (PROSPERO registration: CRD42016054037). RESULTS: After evaluating 614 titles and abstracts, 154 studies were selected for full-text analysis; 85 final papers were included. Based on the active ingredient in the test product, nine categories were created: cetyl pyridinium chloride, essential oils, chlorhexidine, triclosan, natural products, diclofenac, fluorides, delmopinol, and miscellaneous active substances. Most of the studies were of short duration (less than 6 months) with a defective 'methods' description; the reporting of adverse events often being overlooked. Both local morphological (oral mucosa and dental-crown staining, mucosal lesions) and functional (taste modifications, abnormal oral sensation) alterations were reported. Tooth staining was the most commonly listed adverse event, but it was quantitatively assessed only in a very small number of papers; most studies relied on patient reports. Staining was time associated; the longer the study, the higher its reported incidence and severity. CONCLUSIONS: The reduced report of side effects may partly be due to a lack of an objective measure and lack of general guidelines that demand studies report their adverse events. The most frequently reported adverse effect was teeth staining. As in most studies, the effect was associated with trial duration; clinical trials should be of sufficient duration. New investigations meeting the suggested criteria of a minimal duration of 6 months should be planned.

Mouthwashes in the 21st century: a narrative review about active molecules and effectiveness on the periodontal outcomes.

INTRODUCTION: Poor oral hygiene is a major risk factor for oral diseases. Regular home-based care is essential to maintain good oral hygiene. In particular, mouthrinses can support conventional tooth brushing in reducing accumulation of oral plaque. Areas covered: The most common molecules contained in mouthrinses (chlorhexidine, essential oils, cetyl pyridinium chloride, triclosan, octeneidine, delmopinol, polyvinylpyrrolidone, hyaluronic acid, natural compounds) are discussed, together with relevant clinical and in vitro studies, focusing on their effects on periodontal health. Currently, chlorhexidine is the most efficacious compound, with both antiplaque and antibacterial activities. Similar results are reported for essential oils and cetyl pyridinium chloride, although with a somewhat reduced efficacy. Considering the adverse effects of chlorhexidine and its time-related characteristics, this molecule may best be indicated for acute/short-term use, while essential oils and cetyl pyridinium chloride may be appropriate for long-term, maintenance treatment. Expert opinion: The literature has not clearly demonstrated which compound is the best for mouthrinses that combine good efficacy and acceptable side effects. Research should focus on substances with progressive antibacterial activity, prompting a gradual change in the composition of oral biofilm and mouthrinses that combine two or more molecules acting synergistically in the mouth.