Hypomineralised second primary molars: the Würzburg concept.

PURPOSE: In addition to molar incisor hypomineralisation, the occurrence of enamel hypomineralisation in the primary dentition has become increasingly important in recent years. Hypomineralised second primary molar (HSPM) is defined as hypomineralisation of systemic origin affecting from one to all four second primary molars. Some years ago, the "Würzburg concept" was introduced, which proposed a grading of MIH findings (MIH treatment need index) in combination with an appropriate treatment plan depending on the severity of the affected tooth. Recently, this concept was updated and new treatment approaches have been added. However, currently, the concept solely addresses the treatment plan for permanent teeth. As there is a need to expand its scope to encompass primary teeth and, consequently, HSPM, this paper seeks to develop the second component of the Würzburg concept, the treatment plan, for the primary dentition in response to the increased focus on the disease in recent years. Although the evidence base for the different treatment options is still weak, there is a need for guidance for clinicians in their day-to-day practice. METHODS: The authors conducted a comprehensive review of the literature, encompassing clinical and laboratory studies along with published guidelines. RESULTS: The treatment plan of the HSPM Würzburg concept contains prophylactic and regenerative aspects, non-invasive interventions, temporary and permanent restorative techniques, and extraction. CONCLUSIONS: The intention is to provide practical guidance to practitioners, acknowledging the necessity for further validation through clinical trials.

Clinical effectiveness of pit and fissure sealants in primary and permanent teeth of children and adolescents: an umbrella review.

PURPOSE: This umbrella review aimed to critically appraise the evidence published in systematic reviews (SRs) on the clinical effectiveness of sealants compared with each other/the non-use in primary/permanent teeth of children and adolescents with at least 12-month follow-up. METHODS: A systematic literature search on 4 electronic databases was conducted up to January 18th, 2023. Following handsearching, two review authors independently screened retrieved articles, extracted data, and assessed the risk of bias (RoB) using the risk of bias in systematic reviews (ROBIS) tool. Based on a citation matrix, the overlap was interpreted by the corrected covered area (CCA). RESULTS: Of 239 retrieved records, 7 SRs met the eligibility criteria with a moderate overlap among them (CCA = 7.4%). For primary molars, in 1120 1.5- to 8-year-old children, data on the clinical effectiveness of sealants were inconclusive. For permanent molars, 3 SRs found a significant caries risk reduction for sealants versus non-use (≤ 36-month follow-up). There was insufficient evidence to proof superiority of sealants over fluoride varnish for caries prevention (3 SRs), and to rank sealant materials according to the best clinical effectiveness in permanent molars. One study was rated at low and 6 at high RoB, which did not allow for a valid quantitative synthesis. CONCLUSION: Considering the limitations of this umbrella review, sealants are more effective for caries prevention in children's permanent molars compared to no treatment. Future well-implemented RCTs are needed to draw reliable conclusions on the clinical effectiveness of sealants in primary and permanent teeth of children and adolescents.

Update of the molar incisor hypomineralization: Würzburg concept.

PURPOSE: Molar incisor hypomineralization (MIH) is playing an increasingly important role in dental practice. MIH is defined as hypomineralization of systemic origin of one to four permanent first molars, often associated with affected incisors. Affected teeth are more susceptible to caries and post-eruptive enamel loss and should be diagnosed and treated as early as possible. In 2016, the Würzburg concept was developed for German-speaking countries including a classification index-the MIH Treatment Need Index (MIH-TNI)-and a treatment plan based on it for the use in daily practice. In the meantime, the concept has also gained international recognition. The aim of this paper is to update part 2 of the Würzburg concept, the treatment plan, as knowledge about MIH has increased and the disease has been studied more extensively in the last years. Other treatment approaches are now available and therefore need to be included in the concept. Although, the evidence of the different treatment options is still weak, practitioners need guidance in their daily practice. METHODS: The authors reviewed the available literature, including clinical and laboratory studies and published guidelines. RESULTS: The updated version of the Würzburg concept includes additional non-invasive strategies and temporary therapy options, as well as treatment approaches for incisors. It therefore covers currently available treatment modalities for MIH-affected teeth, ranging from prophylaxis, non-invasive treatment to restorative approaches and possibly even extraction. CONCLUSIONS: This is intended to help guide the practitioner and will need to be further validated by clinical trials.

Immune checkpoint inhibitor-induced neurotoxicity is not associated with seroprevalence of neurotropic infections.

BACKGROUND: Immune checkpoint inhibitors (ICI) substantially improve outcome for patients with cancer. However, the majority of patients develops immune-related adverse events (irAEs), which can be persistent and significantly reduce quality of life. Neurological irAEs occur in 1-5% of patients and can induce severe, permanent sequelae or even be fatal. In order to improve the diagnosis and treatment of neurological irAEs and to better understand their pathogenesis, we assessed whether previous neurotropic infections are associated with neurological irAEs. METHODS: Neurotropic infections that might predispose to ICI-induced neurological irAEs were analyzed in 61 melanoma patients from 3 countries, the Netherlands, Australia and Germany, including 24 patients with neurotoxicity and 37 control patients. In total, 14 viral, 6 bacterial, and 1 protozoal infections previously reported to trigger neurological pathologies were assessed using routine serology testing. The Dutch and Australian cohorts (NL) included pre-treatment plasma samples of patients treated with neoadjuvant ICI therapy (OpACIN-neo and PRADO trials; NCT02977052). In the Dutch/Australian cohort a total of 11 patients with neurological irAEs were compared to 27 control patients (patients without neurological irAEs). The German cohort (LMU) consisted of serum samples of 13 patients with neurological irAE and 10 control patients without any documented irAE under ICI therapy. RESULTS: The association of neurological irAEs with 21 possible preceding infections was assessed by measuring specific antibodies against investigated agents. The seroprevalence of all the tested viral (cytomegalovirus, Epstein-Barr-Virus, varicella-zoster virus, measles, rubella, influenza A and B, human herpes virus 6 and 7, herpes simplex virus 1 and 2, parvovirus B19, hepatitis A and E and human T-lymphotropic virus type 1 and 2), bacterial (Borrelia burgdorferi sensu lato, Campylobacter jejuni, Mycoplasma pneumoniae, Coxiella burnetti, Helicobacter pylori, Yersinia enterocolitica and Y. pseudotuberculosis) and protozoal (Toxoplasma gondii) infections was similar for patients who developed neurological irAEs as compared to control patients. Thus, the analysis provided no evidence for an association of described agents tested for seroprevalence with ICI induced neurotoxicity. CONCLUSION: Previous viral, bacterial and protozoal neurotropic infections appear not to be associated with the development of neurological irAEs in melanoma patients who underwent therapy with ICI across 3 countries. Further efforts are needed to unravel the factors underlying neurological irAEs in order to identify risk factors for these toxicities, especially with the increasing use of ICI in earlier stage disease.

Are elevated systemic bile acids involved in the pathophysiology of sarcopenia and liver injury following gastric bypass?

Bariatric surgery is currently the most effective treatment for sustained weight loss in severe obesity. However, recent data describe the development of liver damage and in particular massive steatosis and cholangitis in some patients, for which certain pathophysiological mechanisms are suggested such as bacterial overgrowth, malabsorption or sarcopenia. We describe the case of a patient presenting with a new liver dysfunction 6 years after a gastric bypass. The work-up revealed sarcopenic obesity characterised by low muscle mass and low muscle function as well as elevated fasting bile acids, severe liver steatosis and cholangitis. The pathophysiology of this disease is complex and multifactorial but could include bile acid toxicity. Bile acids are increased in cases of liver steatosis, but also in cases of gastric bypass and malnutrition. In our opinion, they may contribute to the loss of muscle mass and the vicious circle observed in this situation. Treatment with enteral feeding, intravenous albumin supplementation and diuretics reversed the liver dysfunction and the patient was discharged from hospital.

Establishing allometric relationships between microsomal protein and cytochrome P450 content with body weight in vertebrate species.

Data from in vitro studies are routinely used to estimate in vivo hepatic clearance of chemicals and this information is needed to parameterise physiologically based kinetic models. Such clearance data can be obtained from laboratory experiments using liver microsomes, hepatocytes, precision-cut liver slices or recombinant enzymes. Irrespective of the selected test system, scaling factors are required to convert the in vitro measured intrinsic clearance to a whole liver intrinsic clearance. Scaling factors such as the hepatic microsomal protein per gram of liver and/or the amount of cytochrome P450 per hepatocyte provide a means to calculate the whole liver intrinsic clearance. Here, a database from the peer-reviewed literature has been developed and provides quantitative metrics on microsomal protein (MP) and cytochrome P450 contents in vertebrate orders namely amphibians, mammals, birds, fish and reptiles. This database allows to address allometric relationships between body weight and MP content, and body weight and cytochrome P450 content. A total of 85 and 74 vertebrate species were included to assess the relationships between log10 body weight versus log10 MP, and between log10 body weight and log10 cytochrome P450 content, respectively. The resulting slopes range from 0.76 to 1.45 in a range of vertebrate species. Such data-driven allometric relationships can be used to estimate the MP content necessary for in vitro to in vivo extrapolation of in vitro clearance data. Future work includes applications of these relationships for different vertebrate taxa using quantitative in vitro to in vivo extrapolation models coupled to physiologically based kinetic models using chemicals of relevance as case studies including pesticides, contaminants and feed additives.

Best clinical practice guidance for treating deep carious lesions in primary teeth: an EAPD policy document.

PURPOSE: The European Academy of Paediatric Dentistry (EAPD) has developed this best clinical practice guidance to help clinicians manage deep carious lesions in primary teeth. METHODS: Three expert groups conducted systematic reviews of the relevant literature. The topics were: (1) conventional techniques (2) Minimal Intervention Dentistry (MID) and (3) materials. Workshops were held during the corresponding EAPD interim seminar in Oslo in April 2021. Several clinical based recommendations and statements were agreed upon, and gaps in our knowledge were identified. RESULTS: There is strong evidence that indirect pulp capping and pulpotomy techniques, and 38% Silver Diamine Fluoride are shown to be effective for the management of caries in the primary dentition. Due to the strict criteria, it is not possible to give clear recommendations on which materials are most appropriate for restoring primary teeth with deep carious lesions. Atraumatic Restorative Technique (ART) is not suitable for multi-surface caries, and Pre-formed Metal Crowns (PMCs) using the Hall technique reduce patient discomfort. GIC and RMGIC seem to be more favourable given the lower annual failure rate compared to HVGIC and MRGIC. Glass carbomer cannot be recommended due to inferior marginal adaptation and fractures. Compomers, hybrid composite resins and bulk-fill composite resins demonstrated similar values for annual failure rates. CONCLUSION: The management of deep carious lesions in primary teeth can be challenging and must consider the patient's compliance, operator skills, materials and costs. There is a clear need to increase the use of MID techniques in managing carious primary teeth as a mainstream rather than a compromise option.

Clinical effectiveness of restorative materials for the restoration of carious lesions in pulp treated primary teeth: a systematic review.

PURPOSE: To systematically review the clinical performance of restorative materials after pulp therapy of carious primary teeth. It is part 2 of a systematic review on the clinical effectiveness of restorative materials for the management of carious primary teeth supporting the European Academy of Paediatric Dentistry (EAPD) guideline development. METHODS: Four electronic databases were systematically searched up to December 28th, 2020. Randomised controlled clinical trials (RCTs) on restorative materials for the restoration of carious primary teeth after pulp therapy were included. Failure rate, annual failure rate (AFR) and reasons for failure were recorded. Studies were sorted by restorative materials. The Cochrane Risk of bias tool for randomised trials (RoB 2.0) was used for quality assessment. RESULTS: After identification of 1685 articles and screening of 41 papers from EAPD review group 1, 5 RCTs were included. Restored primary molars with pulpotomy presented the following AFRs: composite resin (CR) 0%, preformed metal crowns (PMCs) 2.4-2.5%, resin-modified glass-ionomer cement combined with CR 3.8%, compomer 8.9%, and amalgam 14.3%. Maxillary primary incisors receiving pulpectomy exhibited AFRs of 0-2.3% for composite strip crowns (CSCs) depending on the post chosen. Reasons for failure were secondary caries, poor marginal adaptation, loss of retention and fracture of restoration. All studies were classified as high risk of bias. Meta-analyses were not feasible given the clinical/methodological heterogeneity amongst studies. CONCLUSION: Considering any limitations of this review, CR and PMCs can be recommended for primary molars after pulpotomy, and CSCs for primary incisors receiving pulpectomy. However, a need for further well-designed RCTs was observed.

Caries-inhibiting Effect of Microencapsulated Active Components in Pit and Fissure Sealants.

OBJECTIVE: The aim of the present in vitro study was to examine the caries-inhibiting effect of a pit and fissure sealant (PFS) containing ion-releasing microcapsules under cariogenic conditions in a biofilm artificial mouth. METHODS AND MATERIALS: Forty-eight human third molars were divided into four groups (n=12 per group). Fissures were extended with burs and sealed with experimental PFS. The four groups of specimens were treated as follows: 1) EPFS 1: EPFS (Premier Dental) of increasing viscosity, containing microcapsules loaded with remineralizing agents (calcium, phosphate, and fluoride ions); 2) US: fluoride-releasing PFS (UltraSeal XT plus, UltraDent Products, South Jordan, UT, USA); 3) EPFS 2: experimental PFS of constant viscosity containing microcapsules loaded with calcium, phosphate, and fluoride ions; and 4) FT: glass ionomer cement (GIC) (GC Fuji Triage CAPSULE WHITE glass ionomer cement, GC Europe NV, Leuven, Belgium). FT and US were used as control groups. EPFS 1 and EPFS 2 were the experimental groups. Specimens were stored in distilled water for 14 days at 37°C, subjected to 10,000 thermocycles (5°C and 55°C) and finally exposed to microbiological cycling in a Streptococcus mutans-based artificial mouth for 10 days. Replicas were made for scanning electron microscopic (SEM) evaluation and specimens were cut for fluorescence microscopy. RESULTS: Overall demineralization depths at the margin of Fuji Triage were significantly shallower than in the other groups (p<0.05). Overall demineralization depths adjacent to the experimental pit and fissure sealant EPFS 2 (59±15 µm) were comparable to the values of the resin-based pit and fissure sealant UltraSeal XT plus (58±10 µm, p≥0.05). SEM revealed surface roughness of the GIC-based PFS. CONCLUSIONS: The experimental PFS with microcapsules containing active components for remineralization did not show a caries-inhibiting effect compared to a fluoride-releasing resin-based PFS. Lower demineralization depths adjacent to GIC sealants indicate an anticariogenic effect through fluoride ion release.

Clinical effectiveness of restorative materials for the restoration of carious primary teeth without pulp therapy: a systematic review.

PURPOSE: To systematically search the available evidence and evaluate the clinical effectiveness of restorative materials for restoration of carious primary teeth. The findings aimed to support the European Academy of Paediatric Dentistry (EAPD) guidelines development. METHODS: Literature search was performed by searching 4 electronic databases for eligible randomised controlled clinical trials (RCTs) comparing restorative materials for the restoration of carious primary teeth up to December 28th, 2020. Quality assessment was performed with the revised Cochrane risk-of-bias tool for randomized trials (RoB 2). RESULTS: Of 1685 identified articles 29 RCTs were finally deemed as eligible for inclusion. Annual failure rates were: Amalgam 1-28%; atraumatic restorative treatment 1.2-37.1%; glass-ionomer cement (GIC) 7.6-16.6%, metal-reinforced GIC 29.9%, resin-modified GIC 1.9-16.9%, high-viscosity GIC 2.9-25.6%; glass carbomer ≤ 46.2%; compomer 0-14.7%; composite resin (CR) 0-19.5%, bulk-fill CR 0-16.9%; zirconia crowns 3.3%, composite strip crowns 15%, and preformed metal crowns (Hall-Technique) 3.1%. Secondary caries, poor marginal adaptation, loss of retention, and fracture of restoration were reported as reasons for failure. Four studies were evaluated at unclear and 25 at high risk of bias. Clinical and methodological heterogeneity, and the diversity of tested materials across included studies did not allow for meta-analyses. CONCLUSIONS: Within the limitations of this systematic review, namely, the heterogeneity and the overall high risk of bias among included studies, clear recommendations based on solid evidence for the best restorative approach in primary teeth cannot be drawn. There is a need for future thoroughly implemented RCTs evaluating restorations in primary teeth to close this knowledge gap.

Toothbrushing Performance and Oral Cleanliness after Brushing in 12-Year-Old Children.

OBJECTIVES: Nationwide prevention programs in Germany aim to promote oral health. The group prevention program starts in kindergarten and ends when the children are about 12 y old. While in a recent study, toothbrushing behavior of 12-y-old children was analyzed, the present study's objective was to examine the children's ability to achieve oral cleanliness and to analyze how toothbrushing behavior and compliance with the toothbrushing recommendations taught in the group prevention programs predict oral cleanliness. METHODS: Twelve-year-old randomly selected children (N = 174) were asked to brush their teeth to the best of their abilities, and simultaneously a video was recorded for behavioral analyses. Plaque levels were measured before and immediately after toothbrushing. In addition, dental status and gingival bleeding were assessed. RESULTS: After brushing to the best of their abilities, there was plaque on 50% (±24.72%) of all measured sites at the gingival margin (Marginal Plaque Index). Regression analyses revealed approximately 22% of the variance of marginal plaque on the outer surfaces to be explained by the time brushed by circular movements (ß = -0.41;P < 0.001) and the number of sextants brushed for at least 7.5 s (ß = -0.171; P < 0.05). Circular movements explained most additional variance (ΔR2 = 0.113; P < 0.001). With respect to inner surfaces, none of the behavioral aspects explained any variance of oral cleanliness. CONCLUSION: Despite regular group prevention measures, 12-y-old children show limited skills to clean their teeth adequately. Furthermore, none of the recommended behaviors relates to oral cleanliness after toothbrushing at inner surfaces. As a consequence, it is necessary to explore further which behavioral sequences effectively improve oral cleanliness. KNOWLEDGE TRANSFER STATEMENT: This study illustrates that children's compliance to toothbrushing recommendations is not necessarily related to toothbrushing effectiveness. Clinicians should therefore assess the effectivity of recommendations individually and provide individual guidance for improvement.

The effect of different liners on the bond strength of a compomer to primary teeth dentine: in vitro study.

OBJECTIVE: This in vitro investigation should identify the effect of protective liners on dentine bond strength of a polyacid modified resin composite to dentine of primary teeth. METHODS: Forty-two extracted caries-free primary molars were randomly assigned to seven groups (n = 6) and flattened. Six test groups were centrally covered with different protective liners/base materials: Kerr Life (KL), IRM zinc oxide eugenol cement (IRM), Ketac Bond (KB), Vitrebond (VB), Dycal (DY), and mineral trioxide aggregate (MTA). Specimens were bonded with Prime&Bond NT (PB) and restored with Dyract eXtra. The control group (C) did not receive liner pretreatment. After 24-h storage in Aqua dest. (37 °C), specimens were cut and regional microtensile bond strengths of the uncovered areas were tested. Fractography was conducted under a light microscope and further interface/surface analyses were performed under a SEM. Statistical appraisal was carried out using oneway ANOVA (mod. LSD test; p < 0.05). RESULTS: Independent of the distance to the applied liner, all groups exhibited inferior µ-TBS to dentine of primary teeth compared to the control group (p < 0.05). The results were as follows in MPa(SD) x:significance level/percentage of adhesive fractures: PB: 34 (10)A/72%; KL: 23 (25)B/64%; KB: 15 (12)C/76%; DY 15 (13)C/55%; IRM: 14 (10)C/68%; VB: 12 (10)C/61%; MTA 12 (10)C/69%. CONCLUSIONS: Protective liners significantly reduced µ-TBS to dentine of primary teeth.

Clinical and radiographic success of (partial) pulpotomy and pulpectomy in primary teeth: A systematic review.

AIM: The aim of this systematic review was to evaluate the clinical outcome of partial pulpotomy, pulpotomy and pulpectomy for treating primary teeth with normal or infected pulp or with irreversible pulpitis. METHODS: Two reviewers on Pubmed and ISI Web of Science performed a comprehensive literature review of publications from 1966 until July 2019. Pico outline was used to facilitate literature research. Among abstracts, publications were selected according to the following criteria: prospective clinical study, correct indication for the performed treatment, clear definition of clinical and/or radiographic success criteria and at least 6-month follow-up period. The strict selection criteria under the keywords "pulpotomy", "partial pulpotomy" and "pulpectomy" resulted in a limited amount of randomised controlled trials (RCT) or controlled clinical trials (CT). Qualitative assessment of the selected clinical studies and level of evidence was included according to the criteria described by the Oxford Centre for Evidence-Based Medicine (CEBM). CONCLUSION: Prerequisites for a successful pulpotomy are symptom-free teeth, sterile removal of coronal pulp and haemostasis. Both MTA and formocresol perform well for partial pulpotomies after caries exposure. Formocresol had been the most popular amputation material for pulpotomies. Due to the potential side effects, other medicaments, such as ferric sulfate, mineral trioxide aggregate (MTA) or NaOCl are suggested. Grey and white MTA yeld the same results. Lasers are not recommended due to their large diversity. Regarding pulpectomy, the conditions, procedures, and evaluation for the treatment were not well defined in the studies. Nevertheless, there is evidence to use calcium hydroxide, zinc oxide eugenol paste or iodoform based pastes as root filling materials for non-vital molars. Pulpectomies showed better success rates than pulpotomies. Stainless steel crowns are recommended as definite restorations after both endodontic treatments. Longer follow-up periods, further clinical studies with comparable conditions and clear definition of evaluation criteria are needed to further confirm the results of endodontic treatment in primary teeth.

Prevalence of molar-incisor-hypomineralisation (MIH) among 6-12-year-old children in Central Hesse (Germany).

AIM: The aim of the present cross-sectional study was to assess and compare the prevalence of MIH among 6-12-year-old school children living either in a rural area of Central Hesse (Germany) or in the city of Frankfurt on the Main (Germany). A possible association between hypomineralised second primary molars (HSPM) and MIH was investigated. Furthermore, the MIH prevalence data of the rural area were compared with those of a previous study conducted in this area in the school year 2002/2003. METHODS: In the school year 2014/2015, 2103 children (6-12 years of age) were examined during the annual school-based dental examinations prescribed by law at nine schools in the rural area of Central Hesse (LDK) and five schools in the city of Frankfurt on the Main (Ffm). Eight previously calibrated dentists working for the public healthcare authorities assessed the prevalence of HSPM/MIH (EAPD criteria/severity scale by Wetzel and Reckel) and the caries experience (dmft/DMFT). RESULTS: The prevalence of HSPM/MIH amounted 3.2%/9.4% in LDK and 2.9%/17.4% in Ffm. In the majority of cases, children with MIH had demarcated opacities. In LDK, hypomineralised first permanent molars were most commonly affected by severity degree 2, whereas in Ffm, severity degree 1 was predominant. Children suffering from HSPM had an odds ratio of 11.32 (95% CI: 6.73-19.03) for having MIH as well. Compared with the results of 2002/2003 in LDK (prevalence of MIH 5.9%), the MIH prevalence increased by 3.5% in the rural area. All in all, the caries experience among children under investigation was low (DMFT 0.14-0.15). SIGNIFICANCE: MIH may be diagnosed in school children living in different areas of Germany with regional variations (rural-urban comparison). The presence of HSPM is of predictive value for MIH. The increasing number of hypomineralised first permanent molars over 12 years of time in the rural area indicates a need for further investigation on the aetiology of MIH.

Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors.

UDP-glucuronosyltransferases (UGTs) are involved in phase II conjugation reactions of xenobiotics and differences in their isoform activities result in interindividual kinetic differences of UGT probe substrates. Here, extensive literature searches were performed to identify probe substrates (14) for various UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) and frequencies of human polymorphisms. Chemical-specific pharmacokinetic data were collected in a database to quantify interindividual differences in markers of acute (Cmax) and chronic (area under the curve, clearance) exposure. Using this database, UGT-related uncertainty factors were derived and compared to the default factor (i.e. 3.16) allowing for interindividual differences in kinetics. Overall, results show that pharmacokinetic data are predominantly available for Caucasian populations and scarce for other populations of different geographical ancestry. Furthermore, the relationships between UGT polymorphisms and pharmacokinetic parameters are rarely addressed in the included studies. The data show that UGT-related uncertainty factors were mostly below the default toxicokinetic uncertainty factor of 3.16, with the exception of five probe substrates (1-OH-midazolam, ezetimibe, raltegravir, SN38 and trifluoperazine), with three of these substrates being metabolised by the polymorphic isoform 1A1. Data gaps and future work to integrate UGT-related variability distributions with in vitro data to develop quantitative in vitro-in vivo extrapolations in chemical risk assessment are discussed.

Bayesian meta-analysis of inter-phenotypic differences in human serum paraoxonase-1 activity for chemical risk assessment.

Human variability in paraoxonase-1 (PON1) activities is driven by genetic polymorphisms that affect the internal dose of active oxons of organophosphorus (OP) insecticides. Here, an extensive literature search has been performed to collect human genotypic frequencies (i.e. L55M, Q192R, and C-108T) in subgroups from a range of geographical ancestry and PON1 activities in three probe substrates (paraoxon, diazoxon and phenyl acetate). Bayesian meta-analyses were performed to estimate variability distributions for PON1 activities and PON1-related uncertainty factors (UFs), while integrating quantifiable sources of inter-study, inter-phenotypic and inter-individual differences. Inter-phenotypic differences were quantified using the population with high PON1 activity as the reference group. Results from the meta-analyses provided PON1 variability distributions and these can be implemented in generic physiologically based kinetic models to develop quantitative in vitro in vivo extrapolation models. PON1-related UFs in the Caucasian population were above the default toxicokinetic UF of 3.16 for two specific genotypes namely -108CC using diazoxon as probe substrate and, -108CT, -108TT, 55MM and 192QQ using paraoxon as probe substrate. However, integration of PON1 genotypic frequencies and activity distributions showed that all UFs were within the default toxicokinetic UF. Quantitative inter-individual differences in PON1 activity are important for chemical risk assessment particularly with regards to the potential sensitivity to organophosphates' toxicity.

Let the river erode! Enabling lateral migration increases geomorphic unit diversity.

River restoration practice frequently employs conservative designs that create and maintain prescribed, static morphology. Such approaches ignore an emerging understanding of resilient river systems that typically adjust their morphology in response to hydrologic, vegetative and sediment supply changes. As such, using increased dynamism as a restoration design objective will arguably yield more diverse and productive habitats, better managed expectations, and more self-sustaining outcomes. Here, we answer the following question: does restoring lateral migration in a channelised river that was once a wandering gravel-bed river, result in more diverse in-channel geomorphology? We acquired pre- and post-restoration topographic surveys on a segment of the Allt Lorgy, Scotland to quantify morphodynamics and systematically map geomorphic units, using Geomorphic Unit Tool (GUT) software. GUT implements topographic definitions to discriminate between a taxonomy of fluvial landforms that have been developed from an extension of the River Styles framework, using 3-tiered hierarchy: (1) differentiation based on stage or elevation relative to channel; (2) classification of form based on shape (mound, bowl, trough, saddle, plane, wall); and (3) mapping geomorphic units based on attributes (e.g., position and orientation). Results showed restoration increased geomorphic unit diversity, with the Shannon Diversity Index increasing from 1.40 pre-restoration (2012) to 2.04 (2014) and 2.05 (2016) after restoration. Channel widening, due to bank erosion, caused aerial coverage of in-channel geomorphic units to increase 23% after restoration and 6% further in the two-years following restoration. Once bank protection was removed, allowing bank erosion yieled a local supply of sediment to enable the formation and maintenance of lateral and point bars, riffles and diagonal bar complexes, and instream wood created structurally-forced pools and riffles. The methodology used systematically quantifies how geomorphic unit diversity increases when a river is given back its freedom space. The framework allows for testing restoration design hypotheses in post-project appraisal.

Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making.

The fields of toxicology and chemical risk assessment seek to reduce, and eventually replace, the use of animals for the prediction of toxicity in humans. In this context, physiologically based kinetic (PBK) modelling based on in vitro and in silico kinetic data has the potential to a play significant role in reducing animal testing, by providing a methodology capable of incorporating in vitro human data to facilitate the development of in vitro to in vivo extrapolation of hazard information. In the present article, we discuss the challenges in: 1) applying PBK modelling to support regulatory decision making under the toxicology and risk-assessment paradigm shift towards animal replacement; 2) constructing PBK models without in vivo animal kinetic data, while relying solely on in vitro or in silico methods for model parameterization; and 3) assessing the validity and credibility of PBK models built largely using non-animal data. The strengths, uncertainties, and limitations of PBK models developed using in vitro or in silico data are discussed in an effort to establish a higher degree of confidence in the application of such models in a regulatory context. The article summarises the outcome of an expert workshop hosted by the European Commission Joint Research Centre (EC-JRC) - European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), on "Physiologically-Based Kinetic modelling in risk assessment - reaching a whole new level in regulatory decision-making" held in Ispra, Italy, in November 2016, along with results from an international survey conducted in 2017 and recently reported activities occurring within the PBK modelling field. The discussions presented herein highlight the potential applications of next generation (NG)-PBK modelling, based on new data streams.

Relative effectiveness of direct and indirect pulp capping in the primary dentition.

INTRODUCTION: Carious or traumatised teeth with a normal pulp status or with reversible pulpitis need an indirect or direct pulp capping procedure to keep the pulp vital. AIM: To evaluate the clinical outcome of both interventions for treating vital primary teeth. STUDY DESIGN: Two reviewers on Pubmed and ISI Web of Science performed a comprehensive literature review of publications from 1966 until December 2017. Among PubMed abstracts, publications were selected according to the following criteria: prospective clinical study, correct indication for the performed treatment, and clear definition of clinical and/or radiographic success criteria. The strict selection criteria limited the amount of randomised controlled trials (RCT) or controlled clinical trials (CT); especially for "indirect pulp therapy", "direct pulp capping" and the number of RCTs was limited. CONCLUSIONS: Based on a systematic review (20 controlled clinical studies or randomised controlled clinical studies), the following statements can be given: Due to the opportunity of tissue repair, indirect pulp treatment can be an acceptable procedure for reversible pulp inflammation. The use of adhesives for indirect pulp capping in a single-visit procedure after gentle caries removal can be recommended. Successful pulp capping is possible under defined conditions (symptom-free tooth, disinfection of pulp exposures, Class-I cavity) and appropriate sealing of the cavity with an effective dentine seal being a conditio sine qua non. There is maximum evidence for the use of disinfecting solutions prior to pulp capping and Dycal as pulp capping material. Longer follow-up periods, more clinical studies, comparable conditions, and clear definitions of evaluation criteria are needed to confirm the results of endodontic treatment in primary teeth.