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Antibiotic resistance presents a daunting challenge to health professionals worldwide and has the potential to create major problems for modern health care, resulting in more medical expenditure, extended hospital stays and increased morbidity and mortality. Advanced genome sequencing technologies present a complex picture of resistance, extending our understanding beyond the pharmacotherapeutic interface between pathogens and antibiotics. This review discusses the global scope and scale of antibiotic resistance and contextualizes it for the dental practitioner, emphasizing the role we must play in limiting the progression of resistance through antibiotic stewardship and disease prevention. [ABSTRACT FROM AUTHOR]

The continuing studies of the teeth and faces of Australian twins and their families in the Craniofacial Biology Research Group in the School of Dentistry at the University of Adelaide began 30 years ago. Three main cohorts of twins have been recruited, enabling various objectives and specific hypotheses to be addressed about the roles of genetic, epigenetic and environmental influences on human dentofacial growth and development, as well as oral health. This paper highlights some key findings arising from these studies, emphasizing those of direct relevance to practising oral health professionals. We also draw on published literature to review the significant developments in relation to the use of precision 2D and 3D imaging equipment, the application of modern molecular techniques, and the development of sophisticated computer software for analysing genetic relationships and comparing complex shapes. Such developments are valuable for current and future work. Apart from the classical or traditional twin model, there are several other twin models that can be used in research to clarify the relative contributions of genetic, epigenetic and environmental contributions to phenotypic variation. The monozygotic ( MZ) co-twin model is one particularly valuable method, given that examination of only one pair of MZ twins can provide considerable insights into underlying causes of observed variation. This model can be used in a dental practice environment, with oral health professionals having the opportunity to explore differences in orofacial structures between MZ co-twins who are attending as patients. As researchers have become more aware of the complexities of the interactions between the genome, the epigenome and the environment during development, there is the need to collect more phenotypic data and define new phenotypes that will better characterize variations in growth processes and health status. When coupled with powerful new genetic approaches, including genome-wide association studies and linkage analyses, exciting opportunities are opening up to unravel the causes of problems in craniofacial growth and common oral diseases in human populations. [ABSTRACT FROM AUTHOR]

The field of dental phenomics provides many opportunities to elucidate the roles of genetic, epigenetic and environmental factors in craniofacial development. To date, research findings have helped to clarify the pathogenesis of many conditions, aiding diagnosis and clinical management. This paper provides an overview of dental phenomics research in some commonly encountered oral diseases in everyday clinical practice, as well as research relating to craniofacial growth and development. Clinically, advances in cariology and periodontology have led to better diagnostic capabilities and treatment provision. In the study of growth and development, important information regarding the varying clinical presentation and pathogenesis of many disorders is now apparent through the accurate quantification of phenotypes. Improvements in two-dimensional (2D) and three-dimensional (3D) imaging and analytical techniques have allowed for accurate dental phenotyping, and efforts are ongoing to apply these in vitro techniques to the in vivo setting. The field of dental phenomics represents an exciting avenue that links research findings to practical application, and collaboration between researcher and clinicians will help advance the field further. [ABSTRACT FROM AUTHOR]

In 2007, only four years after the completion of the Human Genome Project, the journal Science announced that epigenetics was the 'breakthrough of the year'. Time magazine placed it second in the top 10 discoveries of 2009. While our genetic code (i.e. our DNA) contains all of the information to produce the elements we require to function, our epigenetic code determines when and where genes in the genetic code are expressed. Without the epigenetic code, the genetic code is like an orchestra without a conductor. Although there is now a substantial amount of published research on epigenetics in medicine and biology, epigenetics in dental research is in its infancy. However, epigenetics promises to become increasingly relevant to dentistry because of the role it plays in gene expression during development and subsequently potentially influencing oral disease susceptibility. This paper provides a review of the field of epigenetics aimed specifically at oral health professionals. It defines epigenetics, addresses the underlying concepts and provides details about specific epigenetic molecular mechanisms. Further, we discuss some of the key areas where epigenetics is implicated, and review the literature on epigenetics research in dentistry, including its relevance to clinical disciplines. This review considers some implications of epigenetics for the future of dental practice, including a 'personalized medicine' approach to the management of common oral diseases. [ABSTRACT FROM AUTHOR]

Complex systems are present in such diverse areas as social systems, economies, ecosystems and biology and, therefore, are highly relevant to dental research, education and practice. A Complex Adaptive System in biological development is a dynamic process in which, from interacting components at a lower level, higher level phenomena and structures emerge. Diversity makes substantial contributions to the performance of complex adaptive systems. It enhances the robustness of the process, allowing multiple responses to external stimuli as well as internal changes. From diversity comes variation in outcome and the possibility of major change; outliers in the distribution enhance the tipping points. The development of the dentition is a valuable, accessible model with extensive and reliable databases for investigating the role of complex adaptive systems in craniofacial and general development. The general characteristics of such systems are seen during tooth development: self-organization; bottom-up emergence; multitasking; self-adaptation; variation; tipping points; critical phases; and robustness. Dental findings are compatible with the Random Network Model, the Threshold Model and also with the Scale Free Network Model which has a Power Law distribution. In addition, dental development shows the characteristics of Modularity and Clustering to form Hierarchical Networks. The interactions between the genes (nodes) demonstrate Small World phenomena, Subgraph Motifs and Gene Regulatory Networks. Genetic mechanisms are involved in the creation and evolution of variation during development. The genetic factors interact with epigenetic and environmental factors at the molecular level and form complex networks within the cells. From these interactions emerge the higher level tissues, tooth germs and mineralized teeth. Approaching development in this way allows investigation of why there can be variations in phenotypes from identical genotypes; the phenotype is the outcome of perturbations in the cellular systems and networks, as well as of the genotype. Understanding and applying complexity theory will bring about substantial advances not only in dental research and education but also in the organization and delivery of oral health care. [ABSTRACT FROM AUTHOR]

The clinical importance of variations of tooth number, size and shape is seen in many dental disciplines. Early diagnosis allows optimal patient management and treatment planning, with intervention at an appropriate time to prevent complications in development and so reduce later treatment need. Understanding the process of dental morphogenesis and the variations in outcomes is an important contribution to the multidisciplinary clinical team approach to treatment. Tooth number, size and shape are determined during the initiation and morphogenetic stages of odontogenesis. The molecular evidence of repetitive signalling throughout initiation and morphogenesis is reflected clinically in the association of anomalies of number, size and shape. This association has been statistically modelled from epidemiological evidence and confirmed by 2D and 3D measurement of human dental study casts. In individuals with hypodontia, the teeth that are formed are smaller than the population mean and often show reduced and simplified shape. In contrast, in individuals with supernumerary teeth, the other teeth are larger than average and may show an enhanced shape. Clinical observations in humans and studies of laboratory animals gave rise to the concept of morphogenetic fields within the dentition. The findings, which can also be considered as reflecting gene expression territories, have been developed to incorporate field, clone and homeobox theories. The clinical distribution of developmental anomalies tends to follow the pattern of these fields or territories. Improved care for patients with these anomalies will come not only from utilizing a multidisciplinary clinical team but also by expanding the approach to include other relevant scientific disciplines. [ABSTRACT FROM AUTHOR]

Study Objective: Alemtuzumab is a monoclonal antibody that targets the cell surface antigen CD52 on lymphocytes. Although it is used for the treatment of hematologic malignancies, such as chronic lymphocytic leukemia, and incorporated into many hematopoietic stem cell transplant (HSCT) conditioning regimens, few studies have evaluated the pharmacology of alemtuzumab in adult patients with sickle cell disease (SCD). We therefore examined the pharmacokinetics (PK) and pharmacodynamics (PD) of alemtuzumab in adults with SCD who received a matched related donor HSCT to determine if the clearance of alemtuzumab affects transplant outcomes., Design: PK and PD analysis of patient data from a single-center clinical trial., Setting: Clinical research center., Patients: Twenty-two adult patients with SCD who received one of two nonmyeloablative allogeneic HSCT regimens: alemtuzumab and total body irradiation (Alem-TBI) or pentostatin, cyclophosphamide, alemtuzumab, and total body irradiation (Pento-Cy-Alem-TBI)., Measurements and Main Results: Alemtuzumab serum concentrations, absolute lymphocyte counts, T-cell (CD3), and myeloid (CD14/15) chimerism were collected at distinct time points and analyzed. A semi-mechanistic PK population model was built to understand inter-individual differences in pharmacology. Alemtuzumab was detectable up to 28 days post-HSCT. The mean alemtuzumab level 7 days after transplant for patients on Alem-TBI was 818 ng/ml, significantly lower than the mean level of 1502 ng/ml for patients on Pento-Cy-Alem-TBI (p < 0.001), but this difference decreased as time progressed. The clearance of alemtuzumab was linear, and the half-life was longer in the Pento-Cy-Alem-TBI group (average half-life = 61.1 h) compared to the Alem-TBI group (average half-life = 44.1 h) (p < 0.001). The CD3 chimerism at 2 and 4 months after transplant positively correlated with alemtuzumab levels collected on day 14 after transplant (R 2  = 0.40 and p = 0.004 at 2 months, R 2  = 0.36 and p = 0.005 at 4 months), but this significance was lost by 6 months after HSCT. No correlation was seen between alemtuzumab levels and CD14/15 chimerism., Conclusion: Between 2 and 4 months after transplant, higher alemtuzumab levels measured 14 days after transplant correlated with patients having better engraftment, suggesting more lymphodepletion may be needed to reduce graft failure in these two non-myeloablative matched related donor HSCT regimens., (© 2021 Pharmacotherapy Publications, Inc.)

Objectives: This study generates a series of narrow-sense heritability estimates for crown morphology of the deciduous and permanent dentition with two overarching aims. The first is to test the hypothesis that deciduous teeth provide a more faithful reflection of genetic information than their permanent successors. The second is to use quantitative genetic methods to evaluate assumptions underlying common data collection and analysis practices in biodistance research., Materials and Methods: Dental morphology data were collected from longitudinal dental casts representing Australian twins and families using Arizona State Dental Anthropology System standards. Polygenic models and estimates of narrow-sense heritability were generated using SOLAR v.8.1.1. Each model considered age, sex, and age/sex interaction as covariates., Results: Heritability estimates significantly differed from zero for the majority of morphological crown characters. Most estimates fell within the 0.4-0.8 range typically observed for crown morphology. Mean heritability was stable across the dental complex, but for paired homologues, permanent traits often yielded higher estimates than their deciduous counterparts. Results indicate directional asymmetry in environmental influence for crown morphology and inform biodistance "best practices" related to data collection and treatment., Conclusions: Overall, results for this sample support the use of crown morphology as a proxy for genetic variation in evolutionary research. This includes the deciduous dentition, which justifies the expansion of efforts to incorporate subadults into reconstructions of past microevolutionary processes. Results do not indicate that deciduous phenotypes more closely approximate underlying genotype, at least for deciduous/permanent homologues., (© 2020 Wiley Periodicals, Inc.)

Aims: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib., Materials and Methods: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151., Results: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo., Conclusions: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity., (© 2017 John Wiley & Sons Ltd.)

Aim: To assess the efficacy, safety and tolerability of beloranib treatment for obesity., Methods: This phase II, double-blind, randomized study investigated the effects of beloranib suspension (0.6, 1.2 and 2.4 mg) or placebo, administered subcutaneously, for 12 weeks in 147 participants (primarily white women) with obesity. No diet or exercise advice was administered., Results: At week 12, beloranib resulted in dose-dependent progressive weight loss of -5.5 ± 0.5, -6.9 ± 0.6 and -10.9 ± 1.1 kg for the 0.6, 1.2 and 2.4 mg beloranib doses, respectively, compared with -0.4 ± 0.4 kg with placebo (all p < 0.0001 vs placebo). Weight loss with beloranib was associated with corresponding reductions in waist circumference and body fat mass, as well as improvements in lipids, high-sensitivity C-reactive protein and blood pressure. Sleep disturbance and gastrointestinal adverse events were more common with beloranib than with placebo; these were generally mild to moderate, transient and dose-related, and led to more early study withdrawals in participants in the group with the highest dose of beloranib., Conclusions: In this 12-week phase II study, beloranib produced clinically and statistically significant weight loss and corresponding improvements in cardiometabolic risk factors. Beloranib appeared safe, and the 0.6 and 1.2 mg doses were generally well tolerated. The 2.4 mg dose was associated with increased sleep latency and mild to moderate gastrointestinal adverse events over the first month of treatment. These findings represent a novel mechanism for producing clinically meaningful weight loss., (© 2015 John Wiley & Sons Ltd.)