How old are you? A systematic review investigating the relationship between age and mandibular third molar maturity.

INTRODUCTION AND OBJECTIVE: Radiographic evaluation of the maturity of mandibular third molars is a common method used for age estimation of adolescents and young adults. The aim of this systematic review was to examine the scientific base for the relationship between a fully matured mandibular third molar based on Demirjian's method and chronological age, in order to assess whether an individual is above or below the age of 18 years. METHODS: The literature search was conducted in six databases until February 2022 for studies reporting data evaluating the tooth maturity using Demirjian´s method (specifically stage H) within populations ranging from 8 to 30 years (chronological age). Two reviewers screened the titles and abstracts identified through the search strategy independently. All studies of potential relevance according to the inclusion criteria were obtained in full text, after which they were assessed for inclusion by two independent reviewers. Any disagreement was resolved by a discussion. Two reviewers independently evaluated the risk of bias using the assessment tool QUADAS-2 and extracted the data from the studies with low or moderate risk of bias. Logistic regression was used to estimate the relationship between chronological age and proportion of subjects with a fully matured mandibular third molar (Demirjian´s tooth stage H). RESULTS: A total of 15 studies with low or moderate risk of bias were included in the review. The studies were conducted in 13 countries and the chronological age of the investigated participants ranged from 3 to 27 years and the number of participants ranged between 208 and 5,769. Ten of the studies presented the results as mean age per Demirjian´s tooth stage H, but only five studies showed the distribution of developmental stages according to validated age. The proportion of subjects with a mandibular tooth in Demirjian´s tooth stage H at 18 years ranged from 0% to 22% among males and 0 to 16% in females. Since the studies were too heterogenous to perform a meta-analysis or a meaningful narrative review, we decided to refrain from a GRADE assessment. CONCLUSION: The identified literature does not provide scientific evidence for the relationship between Demirjian´s stage H of a mandibular third molar and chronologic age in order to assess if an individual is under or above the age of 18 years.

Organisational models of health services for children and adolescents in out-of-home care: Health technology assessment.

AIM: Decades of research confirm that children and adolescents in out-of-home care (foster family, residential care) have much greater health care needs than their peers. A systematic literature review was conducted to evaluate organisational health care models for this vulnerable group. METHODS: A systematic literature search was undertaken of the following databases: Academic Search Elite, CENTRAL, Cochrane Database of Systematic Reviews, Cinahl, DARE, ERIC, HTA, PsycInfo, Psychology and Behavioural Sciences Collection, PubMed, SocIndex. Randomised and non-randomised controlled trials were to be included. Two pairs of reviewers independently assessed abstracts of the identified published papers. Abstracts meeting the inclusion criteria were ordered in full text. Each article was reviewed independently, by pairs of reviewers. A joint assessment was made based on the inclusion criteria and relevance. Cases of disagreement were resolved by consensus discussion. RESULTS: No study with low or medium risk of bias was identified. CONCLUSION: In the absence of studies of acceptable quality, it is not possible to assess the impact of organisational models intended to ensure adequate health and dental care for children and adolescents in out-of-home care. Therefore, well-designed follow-up studies should be conducted following the implementation of such models.

Oral health and dental care of older persons-A systematic map of systematic reviews.

OBJECTIVES: To examine the current knowledge on oral health status and dental care of older persons through a systematic mapping of systematic reviews of low or moderate risk of bias. BACKGROUND: Geriatric dentistry covers all aspects of oral health and oral care of older persons. Oral health is part of general health and contributes to a person's physical, psychological and social wellbeing. METHODS: A literature search was performed in three different databases (PubMed, The Cochrane Library and Cinahl) within 12 domains: Dental caries, periodontitis, Orofacial pain and temporomandibular joint (TMJ) pain, mucosal lesions, oral motor function, dry mouth, halitosis, interaction between oral status and other medical conditions, ability to interrelate and communicate, quality of life, ethics and organisation of dental care for older persons. Systematic reviews were identified and scrutinised, highlighting scientific knowledge and knowledge gaps. RESULTS: We included 32 systematic reviews of which 14 were judged to be of low/moderate risk of bias. Most of the domains lack systematic reviews with low or moderate risk of bias. In two of the domains evidence was identified; in institutionalised people aged 65 or older, effective oral hygiene can prevent pneumonia. Furthermore, there is an evidence of a relationship between malnutrition (protein energy-related malnutrition, PEM) and poor appetite and edentulousness. CONCLUSIONS: There is an urgent need for further research and evidence-based knowledge within most domains in geriatric dentistry and in other fields related to oral health and dental care for older persons striving for multi-disciplinary research programmes.

Effects of Bacterial Contamination on Dental Implants During Surgery: A Systematic Review.

INTRODUCTION: Contamination during surgery negatively influences the prognosis of orthopaedic implants; however, it has not been proven whether contamination influences the success of dental implant treatment. The aim of the systematic review was to investigate if there exists evidence in the literature whether contamination of dental implants during surgery affects osseointegration and clinical success. MATERIALS AND METHODS: Four data bases were used for the literature search. Primary studies and reviews regarding both clinical and preclinical research were eligible. Rating of the summarized quality of the evidence was performed. RESULTS: Five preclinical studies were included. Because of the estimated high risk of bias in all included studies and extensive differences in study design between the included studies, meta-analysis was not performed and no reliable aggregated data could be extracted. CONCLUSIONS: It is suggested that the scientific evidence with regard to the current topic is insufficient. Further controlled studies are warranted.

The GRADE Working Group clarifies the construct of certainty of evidence.

OBJECTIVE: To clarify the grading of recommendations assessment, development and evaluation (GRADE) definition of certainty of evidence and suggest possible approaches to rating certainty of the evidence for systematic reviews, health technology assessments, and guidelines. STUDY DESIGN AND SETTING: This work was carried out by a project group within the GRADE Working Group, through brainstorming and iterative refinement of ideas, using input from workshops, presentations, and discussions at GRADE Working Group meetings to produce this document, which constitutes official GRADE guidance. RESULTS: Certainty of evidence is best considered as the certainty that a true effect lies on one side of a specified threshold or within a chosen range. We define possible approaches for choosing threshold or range. For guidelines, what we call a fully contextualized approach requires simultaneously considering all critical outcomes and their relative value. Less-contextualized approaches, more appropriate for systematic reviews and health technology assessments, include using specified ranges of magnitude of effect, for example, ranges of what we might consider no effect, trivial, small, moderate, or large effects. CONCLUSION: It is desirable for systematic review authors, guideline panelists, and health technology assessors to specify the threshold or ranges they are using when rating the certainty in evidence.

TOP TEN RESEARCH PRIORITIES FOR ATTENTION DEFICIT/HYPERACTIVITY DISORDER TREATMENT.

OBJECTIVES: The aim of this project was to identify the ten most important research questions for attention deficit/hyperactivity disorder (ADHD) treatment as identified by people with ADHD together with personnel involved in the treatment of ADHD in school, health, and correction services. METHODS: A working group consisting of consumers and personnel was established. The method for prioritization was primarily based on James Lind Alliance's guidebook, consisting of an interim priority setting exercise and a workshop. RESULTS: The top ten list includes the risk of drug dependency later in life when treated with methylphenidate as a child, teacher support, multimodal therapy, comparisons between atomoxetine and methylphenidate, methylphenidate treatment in substance abusers, parental support programmes, supported conversation, computer-aided working memory training, psychoeducative treatment, and melatonin. CONCLUSIONS: We have shown that consumers and personnel can reach consensus on research priorities for treatments for ADHD. We encourage researchers and funders to consider the list for future studies.

Arginine and Caries Prevention: A Systematic Review.

OBJECTIVES: To evaluate the available evidence that the use of arginine-containing dental care products prevents the development of new caries lesions and the progression of existing lesions. SEARCH METHODS: We performed a systematic literature search of databases including PubMed, the Cochrane Library and EMBASE. SELECTION CRITERIA: We selected randomized controlled trials of treatment with arginine in fluoride-containing dental products measuring dental caries incidence or progression in children, adults and elderly subjects. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for risk of bias and evaluated overall study quality using the GRADE classification. MAIN RESULTS: Due to conflicts of interest and weak transferability to Swedish conditions, no conclusions can be drawn from studies on the effects of arginine-fluoride toothpaste in children. Arginine-containing toothpaste costs about 40% more than basic fluoride toothpaste; to determine whether it is more cost-effective, the higher cost must be considered in relation to any additional caries-preventive effect. The literature review also disclosed some questionable research ethics: in several of the studies, the children in the control group used non-fluoride toothpaste. Toothpaste without fluoride is not as effective against dental caries as the standard treatment - fluoride toothpaste - which has a well-documented effect. This contravenes the fundamental principles of research ethics. CONCLUSION: At present there is insufficient evidence in support of a caries-preventive effect for the inclusion of arginine in toothpastes. More rigorous studies, and studies which are less dependent on commercial interests, are required.

Framework for systematic identification of ethical aspects of healthcare technologies: the SBU approach.

OBJECTIVES: Assessment of ethical aspects of a technology is an important component of health technology assessment (HTA). Nevertheless, how the implementation of ethical assessment in HTA is to be organized and adapted to specific regulatory and organizational settings remains unclear. The objective of this study is to present a framework for systematic identification of ethical aspects of health technologies. Furthermore, the process of developing and adapting the framework to a specific setting is described. METHODS: The framework was developed based on an inventory of existing approaches to identification and assessment of ethical aspects in HTA. In addition, the framework was adapted to the Swedish legal and organizational healthcare context, to the role of the HTA agency and to the use of non-ethicists. The framework was reviewed by a group of ethicists working in the field as well as by a wider set of interested parties including industry, interest groups, and other potential users. RESULTS: The framework consists of twelve items with sub-questions, short explanations, and a concluding overall summary. The items are organized into four different themes: the effects of the intervention on health, its compatibility with ethical norms, structural factors with ethical implications, and long term ethical consequences of using the intervention. CONCLUSIONS: In this study, a framework for identifying ethical aspects of health technologies is proposed. The general considerations and methodological approach to this venture will hopefully inspire and present important insights to organizations in other national contexts interested in making similar adaptations.

Bioportide: an emergent concept of bioactive cell-penetrating peptides.

Cell-penetrating peptides (CPPs) have proven utility for the highly efficient intracellular delivery of bioactive cargoes that include peptides, proteins, and oligonucleotides. The many strategies developed to utilize CPPs solely as pharmacokinetic modifiers necessarily requires them to be relatively inert. Moreover, it is feasible to combine one or multiple CPPs with bioactive cargoes either by direct chemical conjugation or, more rarely, as non-covalent complexes. In terms of the message-address hypothesis, this combination of cargo (message) linked to a CPP (address) as a tandem construct conforms to the sychnological organization. More recently, we have introduced the term bioportide to describe monomeric CPPs that are intrinsically bioactive. Herein, we describe the design and biochemical properties of two rhegnylogically organized monometic CPPs that collectively modulate a variety of biological and pathophysiological phenomena. Thus, camptide, a cell-penetrant sequence located within the first intracellular loop of a human calcitonin receptor, regulates cAMP-dependent processes to modulate insulin secretion and viral infectivity. Nosangiotide, a bioportide derived from endothelial nitric oxide synthase, potently inhibits many aspects of the endothelial cell morphology and movement and displays potent anti-angiogenic activity in vivo. We conclude that, due to their capacity to translocate and target intracellular signaling events, bioportides represent an innovative generic class of bioactive agents.

Overcoming methotrexate resistance in breast cancer tumour cells by the use of a new cell-penetrating peptide.

Resistance to chemotherapy limits the effectiveness of anti-cancer drug treatment. Here, we present a new approach to overcome the setback of drug resistance by designing a conjugate of a cell-penetrating peptide and the cytostatic agent methotrexate (MTX). Two different peptides, YTA2 and YTA4, were designed and their intracellular delivery efficiency was characterized by fluorescence microscopy and quantified by fluorometry. MTX was conjugated to the transport peptides and the ability of the peptide-MTX conjugates to inhibit dihydrofolate reductase, the target enzyme of MTX, was found to be 15 and 20 times less potent than MTX. In addition, in vitro studies were performed in a drug resistant cell model using the 100-fold MTX resistant breast cancer cells MDA-MB-231. At a concentration of 1 microM, the peptide-MTX conjugates were shown to overcome MTX resistance and kill the cells more efficiently than MTX alone. Estimated EC50's were determined for MTX, MTX-YTA2 and YTA2 to be 18.5, 3.8 and 20 microM, respectively. In summary, cell-penetrating peptide conjugation of MTX is a new way of increasing delivery, and thereby, the potency of already well-characterized therapeutic molecules into drug resistant tumour cells.

Increased levels of insulin and insulin-like growth factor-1 hybrid receptors and decreased glycosylation of the insulin receptor alpha- and beta-subunits in scrapie-infected neuroblastoma N2a cells.

We have previously shown that ScN2a cells (scrapie-infected neuroblastoma N2a cells) express 2-fold- and 4-fold-increased levels of IR (insulin receptor) and IGF-1R (insulin-like growth factor-1 receptor) respectively. In addition, the IR alpha- and beta-subunits are aberrantly processed, with apparent molecular masses of 128 and 85 kDa respectively, as compared with 136 and 95 kDa in uninfected N2a cells. Despite the 2-fold increase in IR protein, the number of (125)I-insulin-binding sites was slightly decreased in ScN2a cells [Ostlund, Lindegren, Pettersson and Bedecs (2001) Brain Res. 97, 161-170]. In order to determine the cellular localization of IR in ScN2a cells, surface biotinylation was performed, showing a correct IR trafficking and localization to the cell surface. The present study shows for the first time that neuroblastoma N2a cells express significant levels of IR-IGF-1R hybrid receptors, and in ScN2a cells the number of hybrid receptors was 2-fold higher than that found in N2a cells, potentially explaining the apparent loss of insulin-binding sites due to a lower affinity for insulin compared with the homotypic IR. Furthermore, the decreased molecular mass of IR subunits in ScN2a cells is not caused by altered phosphorylation or proteolytic processing, but rather by altered glycosylation. Enzymic deglycosylation of immunoprecipitated IR from N2a and ScN2a cells with endoglycosidase H, peptide N-glycosidase F and neuraminidase all resulted in subunits with increased electrophoretic mobility; however, the 8-10 kDa shift remained. Combined enzymic or chemical deglycosylation using anhydrous trifluoromethane sulphonic acid treatment ultimately showed that the IR alpha- and beta-subunits from ScN2a cells are aberrantly glycosylated. The increased formation of IR-IGF-1R hybrids in ScN2a cells may be part of a neuroprotective response to prion infection. The degree and functional significance of aberrantly glycosylated proteins in ScN2a cells remain to be determined.

Loss of lipopolysaccharide-induced nitric oxide production and inducible nitric oxide synthase expression in scrapie-infected N2a cells.

In scrapie-infected cells, the conversion of the cellular prion protein to the pathogenic prion has been shown to occur in lipid rafts, which are suggested to function as signal transduction platforms. Neuronal cells may respond to bacterial lipopolysaccharide (LPS) treatment with a sustained and elevated nitric oxide (NO) release. Because prions and the major LPS receptor CD14 are colocalized in lipid rafts, the LPS-induced NO production in scrapie-infected neuroblastoma cells was studied. This study shows that LPS induces a dose- and time-dependent increase in NO release in the murine neuroblastoma cell line N2a, with a 50-fold increase in NO production at 1 microg/ml LPS after 96 hr, as measured by nitrite in the medium. This massive NO release was not caused by activation of the neuronal NO synthase (nNOS), but by increased expression of the inducible NOS (iNOS) mRNA and protein. However, in scrapie-infected N2a cells (ScN2a), the LPS-induced NO production was completely abolished. The absence of LPS-induced NO production in ScN2a was due not to abolished enzymatic activity of iNOS but to a complete inhibition of the LPS-induced iNOS gene expression as measured by Western blot and RT-PCR. These results indicate that scrapie infection inhibits the LPS-mediated signal transduction upstream of the transcriptional step in the signaling cascade and may reflect the important molecular and cellular changes induced by scrapie infection.

Delineation of the proinflammatory cytokine cascade in fever induction.

Bacterial lipopolypolysaccharide (LPS)-induced fever involves induction of the proinflammatory cytokines interleukin (IL)-1 alpha, IL-1 beta, tumor necrosis factor-alpha (TNF-alpha), and IL-6, both in the periphery and in the brain. These molecules can induce expression of each other and also regulate expression of their own receptors in a complex manner. The functional hierarchy of these highly inducible proteins is therefore difficult to determine. Using mice strains carrying the null mutations of IL-1 beta, IL-1RI, IL-1RAcP, or IL-6, respectively, we show that LPS-induced fever involves IL-1 beta, which acts at a complex consisting of the type I IL-1 receptor and the IL-1RAcP. This action occurs prior to central IL-6 release, which has been shown to be a necessary component of fever responses induced by LPS, IL-1 beta, and also TNF-alpha. In the absence of IL-1 beta, as in IL-1 beta-deficient mice, LPS, IL-1 alpha, and IL-1 beta cause hyperresponsive fevers when exogenously applied. Murine TNF-alpha is a poor pyrogen in mice even when mice are kept at thermoneutral temperature (30 degrees C). TNF-alpha-mediated fever depends on central IL-6 expression.