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The integration of dentistry into primary health care is crucial for promoting patient well-being. However, clinical studies in dentistry face challenges, including issues with study design, transparency, and relevance to primary care. Clinical trials in dentistry often focus on specific issues with strict eligibility criteria, limiting the generalizability of findings. Randomized clinical trials (RCTs) face challenges in reflecting real-world conditions and using clinically relevant outcomes. The need for more pragmatic approaches and the inclusion of clinically relevant outcomes (CROs) is discussed, such as tooth loss or implant success. Solutions proposed include well-controlled observational studies, optimized data collection tools, and the integration of artificial intelligence (AI) for predictive modelling, computer-aided diagnostics and automated diagnosis. In this position paper advocates for more efficient trials with a focus on patient-centred outcomes, as well as the adoption of pragmatic study designs reflecting real-world conditions. Collaborative research networks, increased funding, enhanced data retrieval, and open science practices are also recommended. Technology, including intraoral scanners and AI, is highlighted for improving efficiency in dental research. AI is seen as a key tool for participant recruitment, predictive modelling, and outcome evaluation. However, ethical considerations and ongoing validation are emphasized to ensure the reliability and trustworthiness of AI-driven solutions in dental research. In conclusion, the efficient conduct of clinical research in primary care dentistry requires a comprehensive approach, including changes in study design, data collection, and analytical methods. The integration of AI is seen as pivotal in achieving these objectives in a meaningful and efficient way., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Originally believed to primarily affect neurons, Parkinson's disease (PD) has recently been recognized to also affect the functions and integrity of microglia and astroglia, two cell categories of fundamental importance to brain tissue homeostasis, defense, and repair. Both a loss of glial supportive-defensive functions and a toxic gain of glial functions are implicated in the neurodegenerative process. Moreover, the chronic treatment with L-DOPA may cause maladaptive glial plasticity favoring a development of therapy complications. This chapter focuses on the pathophysiology of PD from a glial point of view, presenting this rapidly growing field from the first discoveries made to the most recent developments. We report and compare histopathological and molecular findings from experimental models of PD and human studies. We moreover discuss the important role played by astrocytes in compensatory adaptations taking place during presymptomatic disease stages. We finally describe examples of potential therapeutic applications stemming from an increased understanding of the important roles of glia in PD., (© 2020 Elsevier B.V. All rights reserved.)

Animal models of Parkinson's disease (PD) are essential to investigate pathogenic pathways at the whole-organism level. Moreover, they are necessary for a preclinical investigation of potential new therapies. Different pathological features of PD can be induced in a variety of invertebrate and vertebrate species using toxins, drugs, or genetic perturbations. Each model has a particular utility and range of applicability. Invertebrate PD models are particularly useful for high throughput-screening applications, whereas mammalian models are needed to explore complex motor and non-motor features of the human disease. Here, we provide a comprehensive review and critical appraisal of the most commonly used mammalian models of PD, which are produced in rats and mice. A substantial loss of nigrostriatal dopamine neurons is necessary for the animal to exhibit a hypokinetic motor phenotype responsive to dopaminergic agents, thus resembling clinical PD. This level of dopaminergic neurodegeneration can be induced using specific neurotoxins, environmental toxicants, or proteasome inhibitors. Alternatively, nigrostriatal dopamine degeneration can be induced via overexpression of α-synuclein using viral vectors or transgenic techniques. In addition, protein aggregation pathology can be triggered by inoculating preformed fibrils of α-synuclein in the substantia nigra or the striatum. Thanks to the conceptual and technical progress made in the past few years a vast repertoire of well-characterized animal models are currently available to address different aspects of PD in the laboratory., (© 2020 Elsevier B.V. All rights reserved.)

Objectives: To investigate the association between screen-time behavior and diet, including a potentially cariogenic diet, in children younger than 12 years old., Sources: Four electronic databases were searched, from their earliest records up to April 2018., Study Selection: Observational studies were included, assessing time spent in sedentary behavior (viewing of TV, DVDs, computer and electronic games) and dietary intake in preschoolers and school-aged children. The quality of the studies was assessed using the Newcastle-Ottawa Scale. The strength of the evidence was evaluated by the GRADE system., Data: Nineteen articles were included, all providing cross-sectional analysis. Sedentary behavior was assessed by parent-reported or self-reported questionnaires. In 10 studies, food frequency questionnaires were the method of dietary assessment. Most studies only assessed television viewing time (13). A significant relationship was found in all the studies, between television and/or total screen-time viewing and adverse dietary outcomes, including fewer fruits and vegetables, and greater consumption of unhealthy foods. In 15 studies, higher TV viewing and/or screen-time rates were associated with higher intake of cariogenic foods, like energy-dense snacks and sugar-sweetened beverages., Conclusions: There may be an association between sedentary behavior, particularly television viewing, and an unhealthy diet in young people involving increased intake of cariogenic foods. However, the strength of the evidence studies was limited., Clinical Significance: Further efforts are needed to limit television viewing in young children, aimed at promoting health and preventing lifestyle-associated diseases, such as dental caries., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The aim of this systematic review and meta-analysis was to evaluate the efficacy of cryotherapy in reducing pain, trismus, and facial swelling in patients undergoing third-molar surgery., Types of Studies Reviewed: The authors searched for randomized clinical trials in PubMed, Web of Science, SCOPUS, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Google Scholar, and OpenThesis. Eligibility criteria were population: patients submitted to removal of impacted third molars; intervention and comparison: postoperative cryotherapy versus no cold therapy; and outcomes: primary outcome was postoperative pain, and secondary outcomes were facial swelling and trismus. Eligible studies must have reported at least 1 of the outcomes of interest. After extracting data and assessing quality, the authors performed the meta-analyses., Results: The authors included 6 studies in the quantitative synthesis analysis. Differences in pain intensity were found on postoperative day 2 (weighted mean difference, -0.72; 95% confidence interval, -1.45 to 0.01; P = .05) and postoperative day 3 (weighted mean difference, -0.36; 95% confidence interval, -0.59 to -0.13; P = .002). No evidence was found that cryotherapy was effective in reducing trismus and facial swelling. The quality of evidence was graded as low., Conclusions and Practical Implications: Evidence suggests that cryotherapy may have a small benefit in reducing pain after third-molar surgery, but it is not effective on facial swelling and trismus. Owing to the lack of standardization of cold application, effective evidence-based treatment protocols for cryotherapy after third-molar surgery still need to be established., (Copyright © 2019 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Objectives: This study investigated the influence of very small gaps in secondary caries (SC) development and additionally linked the threshold gap size with the caries activity level from volunteers., Methods: For 21 days, 15 volunteers wore a modified occlusal splint loaded with dentin-composite samples restored with different interfaces: bonded (B = samples restored with complete adhesive procedure), no-bonded (NB = restored with composite resin without adhesive procedure), and 30, 60 and 90 μm (no adhesive procedure and with intentional gap). The splint was dipped in a 20% sucrose solution (10 min) 8 x per day. Samples were imaged with transversal wavelength independent microradiography (T-WIM) and lesion depth and mineral loss were calculated. Average wall lesion depth from each volunteer was determined and according to the values the volunteers were grouped as high, mid and low caries activity levels., Results: No wall lesion formation was observed in B and NB groups. In general, intentional gaps led to SC lesion depth progression independent of caries activity level of volunteers. No substantial wall lesions were found for two volunteers. A trend for deeper lesion in larger gaps was observed for the high activity group., Conclusion: Very small gaps around or wider than 30 μm develop SC independent of the caries activity level of the patient and SC wall lesion progression seemed to be related to individual factors even in this standardized in situ model., Significance: Independently of caries activity level of the patient, the threshold gap size for secondary caries wall lesion seems to be 30 μm at most., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: This in situ study aimed to investigate whether the dentin treatment with MMPs inhibitor (CHX 2%) could influence the development of secondary caries wall lesions in different dentin-composite interfaces., Material and Methods: For 21 days, 15 volunteers wore a modified-occlusal splint loaded with dentin-composite samples treated or not with CHX and restored according 4 different interface conditions: Bonding (B = samples restored with complete adhesive procedure), no bonding (NB = restored with composite resin without adhesive procedure), 100 μm (no adhesive procedure and with intentional gap) and 100 μm + B (adhesive material on composite side and intentional gap). Eight times per day, the splint with samples was dipped in a 20% sucrose solution for 10 min. Before and after caries development, samples were imaged with T-WIM and lesion depth (LD) and mineral loss (ML) were calculated., Results: Linear mixed effect analysis showed that dentin treatment with CHX did not significantly affect the caries lesion progression (LD and ML; p ≤ 0.797). Dentin wall lesions were observed in the 100 μm and 100 μm + B groups independently of MMP inhibitor treatment., Conclusion: The treatment of dentin with MMP inhibitor was not able to slow down the secondary caries wall lesion development in this in situ study., Significance: The dentin treatment with 2% CHX did not prevent secondary caries wall lesion initiation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: We hypothesized that KRAS mutations function as a marker of poor sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR wild-type (WT) non-small-cell lung cancer (NSCLC)., Patients and Methods: Consecutive advanced nonsquamous EGFR WT NSCLCs treated at the Medical Oncology of Perugia with simultaneous assessment of KRAS mutation status were eligible. Anaplastic lymphoma kinase (ALK) gene status was known in roughly half of the patients who had KRAS WT., Results: Two hundred four patients were included. Among them, the 77 individuals carrying a KRAS-mutant phenotype experienced a significantly inferior outcome in terms of response rate (P = .04), disease control rate (P = .05), and progression-free survival (PFS) (P = .05) compared with the EGFR WT/KRAS WT population. The association between KRAS mutation and shorter PFS remained statistically significant at multivariate analysis (hazard ratio [HR], 1.45). In addition, patients with KRAS mutations reported a significantly shorter overall survival (OS) compared with patients with EGFR WT/KRAS WT/ALK negativity (n = 64) (P = .02). Among patients with KRAS mutations, those harboring a mutation at codon 13 (n = 12) performed worse than those with a mutation at codon 12 (n = 62) in terms of both PFS and OS (P = .09 for both)., Conclusion: KRAS mutation appears to negatively affect sensitivity to first-line platinum-based chemotherapy in patients with advanced nonsquamous EGFR WT NSCLC. Studies on larger case series are needed to address differences in clinical outcome according to the type of mutation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Dopamine (DA) replacement therapy with l-DOPA remains the most effective treatment for Parkinson's disease, but causes dyskinesia (abnormal involuntary movements) in the vast majority of the patients. The basic mechanisms of l-DOPA-induced dyskinesia (LID) have become the object of intense research focusing on neurochemical and molecular adaptations in the striatum. Here we review this vast literature and highlight trends that converge into a unifying pathophysiological interpretation. We propose that the core molecular alteration of striatal neurons in LID consists in an inability to turn down supersensitive signaling responses downstream of DA D1 receptors (where supersensitivity is primarily caused by DA denervation). The sustained activation of intracellular signaling pathways induced by each dose of l-DOPA leads to abnormal cellular plasticity and high bioenergetic expenditure. The over-exploitation of signaling pathways and energy reserves during treatment impairs the ability of striatal neurons to dynamically gate cortically driven motor commands. LID thus exemplifies a disorder where 'too much' molecular plasticity leads to plasticity failure in the striatum., (2010 Elsevier B.V. All rights reserved.)

Background: Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia., Methods: The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion. Fourteen days later, L-DOPA treatment was initiated., Results: Isradipine-treated animals displayed a dose-dependent reduction in L-DOPA-induced rotational behavior and abnormal involuntary movements. Dendritic spine counting at electron microscopy level showed that isradipine (.2 mg/kg/day) prevented the 6-OHDA-induced spine loss and normalized preproenkephalin-A messenger RNA expression. Involuntary movements were not reduced when isradipine treatment was started concomitantly with L-DOPA., Conclusions: These results indicate that isradipine, at a therapeutically relevant dose, might represent a treatment option for preventing L-DOPA-induced dyskinesia in PD.

Background: The use of growth hormone (GH) in deficient adults has already been demonstrated to result in several benefits regarding metabolic parameters, body composition and quality of life. Due to the similarities between GH deficiency in adults and the aging process, the concept of somatopause has emerged., Objectives: Correlate the GH secretion profile in healthy men older than 50 years with anthropometric parameters and exercise capacity., Patients and Methods: Twenty-nine healthy male were selected, with a mean age of 57.9+/-4.2 years (range 50-66). After hospital admission, body mass index (BMI), body composition (fat mass) and abdominal circumference, 24-h GH profile, GH peak and basal IGF-I were evaluated, and all the patients underwent a treadmill stress testing to estimate exercise capacity with the Bruce protocol, with evaluation of the maximum oxygen peak, maximum heart rate and METs. All the results are shown as mean+/-Std deviation: BMI -26.5+/-4.9kg/m2, percent fat mass -27.1+/-6.2%, abdominal circumference -92.1+/-10.1cm, 24h GH profile -0.3+/-0.2ng/dl, peak GH -2.5+/-2.0ng/dl, IGF-I -202.4+/-72.4ng/dl, maximum oxygen peak -31.9+/-6.8L, maximum heart rate - 161.4+/-7.5 bpm and METs - 9.1+/-1.9. After regression analysis using the GH secretion profile (mean GH in 24h, spontaneous peak GH and basal IGF-I) as dependent variable, no correlations were found between these and the other evaluated parameters.

Background: We examined the activation pattern of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and its dependence on D1 versus D2 dopamine receptors in hemiparkinsonian rats treated with 3,4-dihydroxyphenyl-L-alanine (L-DOPA)., Methods: 6-Hydroxydopamine-lesioned rats were treated acutely or chronically with L-DOPA in combination with antagonists for D1 or D2 receptors. Development of dyskinesia was monitored in animals receiving chronic drug treatment. Phosphorylation of ERK1/2, mitogen- and stress-activated protein kinase-1 (MSK-1), and the levels of FosB/DeltaFosB expression were examined immunohistochemically., Results: L-DOPA treatment caused phosphorylation of ERK1/2 in the dopamine-denervated striatum after acute and chronic administration. Similar levels were observed in matrix and striosomes, and in enkephalin-positive and dynorphin-positive neurons. The severity of dyskinesia was positively correlated with phospho-ERK1/2 levels. Phosphorylation of ERK1/2 and MSK-1 was dose-dependently blocked by SCH23390, but not by raclopride. SCH23390 also inhibited the development of dyskinesia and the induction of FosB/DeltaFosB., Conclusions: L-DOPA produces pronounced activation of ERK1/2 signaling in the dopamine-denervated striatum through a D1-receptor-dependent mechanism. This effect is associated with the development of dyskinesia. Phosphorylated ERK1/2 is localized to both dynorphinergic and enkephalinergic striatal neurons, suggesting a general role of ERK1/2 as a plasticity molecule during L-DOPA treatment.

Objective: To determine the relationship between leakage and microtensile bond strength in the same specimen of direct Class II composite restorations performed with two polymerization techniques., Methods: Class II slot preparations were made in 40 non-carious human third molars and restored using Single Bond and P-60 (3M ESPE) according to the manufacturer's indications. Half of the preparations had the cervical margin in enamel and half in dentin. Teeth were incrementally restored either with direct polymerization from occlusal surface or with indirect polymerization through translucent matrices and reflective wedges. Teeth were isolated with nail varnish and immersed in fucsin for 24h. Subsequently, they were sectioned into slabs that were measured for leakage (mm), and trimmed to obtain hour-glass shaped specimens for microtensile bond test. Fractured specimens were examined under magnification (40 x) to evaluate the fracture mode. Data were analyzed with Mann-Whitney and Kruskal-Wallis (microleakage), two-way ANOVA and Student-Newman-Keuls tests (bond strength). The relationship between microleakage and microtensile bond strength were analyzed with Spearman's correlation test., Results: There were no significant effects of polymerization technique and margin location on both leakage and bond strength (p>0.05). Bond strengths were higher in preparations with enamel margins than in preparations with dentin margins, when restored with indirect polymerization technique (p<0.05). No significant correlation was found between leakage and bond strength (p>0.05)., Conclusions: Polymerization techniques had no influence on microleakage and bond strength of Class II composite restorations, and there was no relationship between these variables when evaluated in the same specimen.