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Objective: To investigate the microbiome profile and relative abundance changes of the plaque on silver diamine fluoride (SDF)-treated caries in children with early childhood caries., Methods: A single trained examiner assessed the caries as being arrested or active and then collected plaque samples from the caries lesions from fourteen 5-year-old children immediately before, 2 weeks after, and 12 weeks after a one-off application of 38 % SDF. We assigned 16S rRNA gene sequences to operational taxonomic units (OTUs) using a 98.5 % identity cut-off. We also used a variety of taxonomy- and phylogeny-based statistical approaches to compare the biodiversity and relative abundance among different groups., Results: The caries arrest rate were 90 % and 83 % after 2 and 12 weeks, respectively. We studied 46 plaque samples and identified 388 OTUs (254 identified at the species level, 129 identified at the genus level, and 76 identified at the family level). There was no significant change in the diversity in the arrested caries before and 12 weeks after SDF treatment (p = 0.71). The diversity in active caries reduced significantly 12 weeks after SDF treatment (p = 0.006). The relative abundance of certain caries-related species (e.g., Streptococcus mutans and Lactobacillus sp.) was reduced in arrested caries but was increased in active caries after SDF treatment., Conclusion: There was no overall microbiome changes in the caries arrested by SDF. The relative abundance of some caries-related species is reduced in arrested caries, while increased in active caries., Clinical Significance: This study provides information on microbiome changes on SDF-treated caries of children., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Despite evidence that Silver Diamine Fluoride (SDF) can be effective in managing carious lesions in primary teeth, the use of SDF in the UK remains limited. This study explored dental professionals' views and experiences of using SDF for managing carious lesions in children. In addition, it explored what they perceived to be the advantages, disadvantages, barriers and enablers to the use of SDF in practice., Methods: Fifteen semi-structured face-to-face or over-the-phone interviews were conducted with 14 dental professionals from NHS Tayside and NHS Grampian in Scotland. Interviews were transcribed verbatim, coded and analysed using a thematic approach., Results: Thirteen of 14 dental professionals interviewed were familiar with, or had some existing knowledge of, SDF. Four had used it to treat patients. The majority of participants thought that the main advantage of SDF was that it required minimal patient cooperation. SDF was also perceived as a simple, pain-free and non-invasive treatment approach that could help acclimatise children to the dental environment. However, SDF-induced black staining of arrested carious lesions was most commonly reported as the main disadvantage and greatest barrier to using it in practice. Participants believed that this discolouration would concern some parents who may fear that the black appearance may instigate bullying at school and that others may judge parents as neglecting their child's oral health. Participants thought that education of clinicians about SDF use and information sheets for parents would enhance the uptake of SDF in dental practice. Participants believed that younger children might not be as bothered by the discolouration as older ones and they anticipated greater acceptance of SDF for posterior primary teeth by both parents and children., Conclusion: Dental professionals were aware that SDF can be used for arresting carious lesions. They pointed out that the staining effect of carious lesions is a major disadvantage and had preconceived ideas that this could be a barrier for many parents. Participants considered the application process to be simple and non-invasive and requires a minimum level of child cooperation. Participants appreciated the potential of SDF in paediatric dentistry and suggested actions that could help overcome the barriers they highlighted.

Opioid-induced constipation (OIC) is common and can significantly affect quality of life. Naloxegol and methylnaltrexone are peripherally acting µ-opioid receptor antagonists (PAMORAs) which are effective for the management of OIC. We report on a case in the palliative care setting where a patient with established OIC had an inadequate response to naloxegol but an effective and immediate response to methylnaltrexone at the dose recommended for her weight. This is the first reported case of two PAMORAs used concomitantly., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To compare the success rates of restoring untreated and SDF-treated dentine caries lesions in primary teeth with atraumatic restorative treatment (ART) approach., Method: Cavitated dentine caries lesions in preschool children were randomly allocated to two groups to be applied with either 38% silver diamine fluoride (SDF) solution or tonic water (control) ten weeks before being restored with the ART approach. Status of the restorations were assessed every six months by a blinded independent examiner. Multilevel logistic regression and multilevel survival analyses were conducted to assess the restoration success rates., Results: A total of 194 children (SDF group, 101; control group, 93) were included, with 260 and 249 ART restorations placed in the SDF and the control groups, respectively. At 24-month follow-up, 88 (87 %) and 84 (90 %) children remained in the SDF and the control groups, respectively. There was no significant difference between the ART restoration success rates of the two study groups (p > 0.05). The success rate of ART restorations was associated with the class of restorations. Class I restorations had the highest success rate (∼50 %), followed by Class V (∼35 %), Class II (∼15 %) and Class III (<10 %). Besides, the mean time used to place an ART restoration in a SDF-treated caries lesion was shorter than that in untreated lesion (4.8 vs. 5.1 min, p = 0.006)., Conclusion: Prior SDF application does not significantly affect the success rate of ART restorations placed in primary teeth. Besides, it is faster to place ART restorations in caries lesions that have been previously treated with SDF., Clinical Significance: Prior application of silver diamine fluoride solution on cavitated dentine caries lesions in primary teeth can shorten the average time required to place an ART restoration while not jeopardizing the success rate of the restorations., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Antimicrobial agents have become an essential tool in controlling the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and guidelines on their use have been issued by various public health agencies. Through its Emerging Viral Pathogen Guidance for Antimicrobial Pesticides , the US Environmental Protection Agency has approved numerous surface disinfectant products for use against SARS-CoV-2. Despite their widespread use and range of associated health hazards, the majority of active ingredients in antimicrobial products, such as surface disinfectants, lack established occupational exposure limits (OELs) to assist occupational health professionals in characterizing risks from exposures to these chemicals. Based on established approaches from various organizations, a framework for deriving OELs specific to antimicrobial agents was developed that relies on a weight-of-evidence evaluation of the available data. This framework involves (1) a screening-level toxicological assessment based on a review of the existing literature and recommendations, (2) identification of the critical adverse effect(s) and dose-response relationship(s), (3) identification of alternative health-based exposure limits (HBELs), (4) derivation of potential OELs based on identified points of departure and uncertainty factors and/or modification of existing alternative HBELs, and (5) selection of an appropriate OEL. To demonstrate the use of this framework, a case study is described for selection of an OEL for a disinfectant product containing quaternary ammonium compounds (quats). Three potential OELs were derived for this product based on irritation toxicity data, developmental and reproductive toxicity (DART) data, and modification of an existing HBEL. The final selected OEL for the quats-containing product was 0.1 mg/m 3 , derived from modification of an existing HBEL. This value represented the lowest resulting value of the three approaches, and thus, was considered protective of irritation and potential DART.

Objectives: The study aimed to compare the effectiveness of 38% silver diamine fluoride (SDF) solution, and 5% sodium fluoride (NaF) varnish applied semiannually in arresting dentin caries in young children with high caries risk., Methods: Children aged 1-3 years who had at least one active dentin carious lesion were randomly allocated into 2 groups as follows: Group 1 = 38% SDF (Topamine), and Group 2 = 5% NaF varnish (Duraphat). Both agents were applied every 6 months onto the carious surface. Lesion activity was assessed by the visual-tactile examination. Baseline and follow-up examinations were conducted by the same examiner. The children's demographic background, oral health-related habits, and oral hygiene practices, as well as parental satisfaction with children's dental appearance were collected at baseline and the 12-month follow-up., Results: At baseline, 153 and 149 children were recruited in Group 1 and Group 2, respectively. The mean dmfs scores in Groups 1 and 2 were 8.89 and 9.79, respectively. After 12 months, 87.1% remained in the study. The caries arrest rate of Group 1 (35.7%) was significantly higher than that of Group 2 (20.9%) (p < 0.001). The results of the multilevel logistic regression analysis confirmed that the treatment in Group 1 was more effective in arresting dentin carious lesions than that of Group 2 (OR = 2.04; 95% CI, 1.41-2.96). The presence of plaque on caries lesions, tooth type, tooth surface type, frequency of milk feeding, snack taking, and family income influenced on caries activity. Regardless of the intervention groups, there were no differences in parental satisfaction with on the child's dental appearance before and after receiving the intervention., Conclusion: Based on the 12-month results, 38% SDF is more effective than 5% NaF varnish in arresting dentin carious lesions in young children. SDF has no negative impact on parental satisfaction with the child's dental appearance., Clinical Significance: To control dentin carious lesions in young children with high caries risk, 38% SDF is more effective than 5% NaF varnish., 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 © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Hemolysis is a serious side effect of antitumor alkylphospholipids (APLs) that limits dose levels and is a constraint in their use in therapeutic regimen. Nine prodrugs of promising APLs (miltefosine, perifosine, and erufosine) were synthesized so as to decrease their membrane activity and improve their toxicity profile while preserving their antineoplastic potency., Methods: The synthesis of the pro-APLs was straightforwardly achieved in one step starting from the parent APLs. The critical aggregation concentration of the prodrugs, their hydrolytic stability under various pH conditions, their blood compatibility and cytotoxicity in three different cell lines were determined and compared to those of the parent antitumor lipids., Results: The APL prodrugs display antitumor activity which is similar to that of the parent alkylphospholipids but without associated hemolytic toxicity., Conclusion: The pro-APL compounds may be considered as intravenously injectable derivatives of APLs. They could thus address one of the major issues met in cancer therapies involving antitumor lipids and restricting their utilization to oral and topical administration because of limited maximum tolerated dose.

The prevalence of stomatitis, especially that caused by Candida albicans, has highlighted the need for new antifungal agents. We previously found that a type of quaternary ammonium salts, dimethylaminododecyl methacrylate (DMADDM), incorporated in dental materials inhibited the growth and hyphal development of C. albicans. However, how the quaternary ammonium salts inhibited the fungal pathogens and whether the oral condition, such as salivary pH variation under different diseases, can affect the antimicrobial capacity of quaternary ammonium salts is unknown. This study evaluated the antifungal effects of DMADDM at different pH in vitro and in vivo. A pH-dependent antifungal effect of DMADDM was observed in planktonic and biofilm growth. DMADDM enhanced antifungal activity at alkaline pH. Two pH-regulated genes (PHR1/PHR2) of C. albicans were correlated with the pH-dependent antifungal effects of DMADDM. The PHR1/PHR2 genes and pH values regulated the zeta potential of C. albicans, which then influenced the binding between C. albicans cells and DMADDM. The pH-dependent antifungal activity of DMADDM was then substantiated in a murine oropharyngeal candidiasis model. We directly demonstrated that the antifungal abilities of quaternary ammonium salts relied on the cell zeta potential which affected the binding between fungal cells and quaternary ammonium salts. These findings suggest a new antifungal mechanism of quaternary ammonium under different pH and that DMADDM can be a potential antifungal agent applied in dental materials and stomatitis therapy.Key Points • DMADDM has stronger antifungal activity in alkaline than in acidic pH conditions. • The pH values and pH-regulated genes can affect the zeta potential of fungal cells. • Zeta potential of fungal cells directly affect the binding between DMADDM and cells. Graphical abstract Schematic diagram of the antifungal activities of DMADDM at different pH values.

Background: Silver diamine fluoride (SDF) solution is effective in arresting early childhood caries (ECC). Previous studies have suggested that it might exert a preventive effect in managing ECC. However, no well-designed clinical trials have yet been performed to study the effect of SDF on caries prevention. The objective of this randomised clinical trial is to determine whether 38% SDF solution is superior to 5% sodium fluoride (NaF) varnish in preventing new carious lesions in primary anterior teeth., Methods/design: This is a phase II, single-centre, randomised, double-blind, active-controlled, parallel-group pragmatic trial. The hypothesis tested is that 38% SDF would be more effective than 5% NaF in preventing new caries development in primary anterior teeth. Approximately 730 3-year-old children who are generally healthy and with parental consent will be recruited from Hong Kong kindergartens. This sample size will be sufficient for appropriate statistical analysis of a superiority trial with 90% power, allowing for a 20% drop-out rate. Stratified randomisation will be adopted for allocating the intervention. The intervention will either be 38% SDF or 5% NaF (as a positive control) therapy on primary upper anterior teeth. A single trained examiner will conduct a dental examination every 6 months until 30 months in kindergarten. Another operator will provide fluoride therapy immediately after each dental examination. The examiner, children and children's parents will be blinded to the treatment allocation. A questionnaire survey will be conducted to study the children's oral health-related behaviours and socioeconomic backgrounds. Chi-square tests, t tests, regression analyses and survival analyses will be adopted for data analysis., Discussion: The effectiveness of 38% SDF in preventing ECC remains uncertain. If the results are as anticipated, care standards using 5% NaF for ECC prevention will be changed. In addition, the results will be widely available and increase the adoption of SDF in other countries to reduce the global burden of ECC., Trial Registration: ClinicalTrials.gov, NCT04075474. Registered on 30 Aug 2019.

Background: Interest in aqueous silver diamine fluoride (SDF) has been growing as a treatment for caries arrest. A cross-sectional study was conducted to identify factors associated with caregiver acceptance of SDF treatment for children presenting with caries at 8 Federally Qualified Health Centers. The study purpose was to examine associations between caregiver acceptance of SDF treatment for children with caries and (1) sociodemographic and acculturation characteristics of caregivers and (2) clinical assessments of the children by dentists., Methods: A caregiver survey collected information on: sociodemographic characteristics; acculturation characteristics, measured using the validated Short Acculturation Scale for Hispanics (SASH); perceived benefits and barriers of SDF treatment, including caregiver comfort; and perceived health-related knowledge. Chart reviews were conducted to assess: the medical / dental insurance of pediatric patients; cumulative caries experience, measured using decayed, missing, filled teeth total scores (dmft / DMFT); whether operating room treatment was needed; and a record of caregiver acceptance of SDF treatment (the outcome measure). Standard logistic regression models were developed for caregiver acceptance of SDF treatment for their children as the binary outcome of interest (yes / no) to calculate unadjusted odds ratios (OR) and adjusted ORs for covariates of interest., Results: Overall, 434 of 546 caregivers (79.5%) accepted SDF treatment for their children. A U-shaped relationship between caregiver odds of accepting SDF treatment and age group of pediatric patients was present, where caregivers were most likely to accept SDF treatment for their children who were either < 6 years or 9-14 years, and least likely to accept SDF treatment for children 6 to < 9 years. The relationship between acculturation and caregiver acceptance of SDF treatment depended upon whether or not caregivers were born in the United States: greater acculturation was associated with caregiver acceptance of SDF treatment among caregivers born in this country, and lower acculturation was associated with caregiver acceptance of SDF treatment among caregivers born elsewhere., Conclusions: Caregiver acceptance of SDF treatment is high; child's age and caregiver comfort are associated with acceptance. Providers need to communicate the risks and benefits of evidence-based dental treatments to increasingly diverse caregiver and patient populations.

High osteopontin (OPN) expression is linked to breast cancer bone metastasis. In this study we modulated osteopontin levels conditionally and investigated any related antineoplastic effects. Therefore, we established cell clones from human breast cancer MDA-MB-231 cells, in which the expression of OPN is regulated by the Tet-Off tet-off system. These cells, which conditionally express a specific miRNA targeting OPN, were used for in vitro studies as well as for a bone metastasis model in nude rats. Changes in whole-genome expression elicited by conditional OPN knockdown and vesicle formation were also analyzed. The alkylphosphocholine erufosine was used for combination therapy. Conditional OPN knockdown caused mild anti-proliferative, but more intensive anti-migratory and anti clonogenic effects, as well as partial and complete remissions of soft tissue and osteolytic lesions. These effects were associated with specific gene and protein expression modulations following miRNA-mediated OPN knockdown. Furthermore, high levels of OPN were detected in vesicles derived from rats harboring breast cancer skeletal metastases. Finally, the combination of OPN inhibition and erufosine treatment caused an additive reduction of OPN levels in the investigated breast cancer cells. Thus, knockdown of OPN alone or in combination with erufosine is a promising strategy in breast cancer skeletal metastasis treatment.

Objectives: To find out the effects of placement of atraumatic restorative treatment (ART) restorations on parental satisfaction and oral health related quality of life (OHRQoL) of preschool children with SDF-treated or untreated dentine caries lesions., Methods: In a randomized controlled trial conducted in Hong Kong, preschool children who had cavitated dentine caries lesions were randomly assigned to receive application of silver diamine fluoride (SDF) solution or placebo (tonic water) on their caries lesions 10 weeks before receiving ART restorations. Parents were asked to rate their satisfaction with their child's teeth using a 5-point scale (5 = very satisfied, 1 = very dissatisfied) before and six months after the restorative treatment. Besides, the Chinese version of Early Childhood Oral Health Impact Scale (C-ECOHIS) was used to assess the children's OHRQoL., Results: A total of 194 children participated in this study, with 101 and 93 children receiving SDF and placebo application before ART restorations, respectively. There was no significant difference in parental satisfaction and C-ECOHIS score between the SDF and placebo groups at baseline. At the 6-month follow-up, the mean parental satisfaction score regarding their child's dental health status increased significantly (p < 0.001) from 2.2 ± 0.7 to 2.8 ± 1.0 in the SDF group and from 2.3 ± 0.8 to 2.7 ± 0.9 in the placebo group. However, no significant changes (p > 0.05) in C-ECOHIS scores were found in either of the two groups after ART restoration placement., Conclusions: Placement of ART restorations can improve parental satisfaction with the health and appearance of their child's teeth but has no significant effect on the OHRQoL., Clinical Significance: This study provides valuable information about the effects of ART restoration placement on SDF-treated or untreated dentine caries lesions regarding parental satisfaction and OHRQoL of preschool children., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: This clinical trial investigated the efficacy of silver diamine fluoride (SDF) in arresting dentine caries in primary molars of preschoolers. Time required for treatment, adverse effects, parental aesthetic perception, anxiety and oral health related to quality of life (OHRQoL) was evaluated., Materials and Methods: Children, 2-5 years old, with active dentine caries lesions on the occlusal surface of primary molars were randomly allocated to test group (SDF) or control group (atraumatic restorative treatment/ART). The dmf-t/DMF-T and ICDAS indexes determined the presence of caries and activity. The main outcome after 3, 6 and 12-month follow-up was assessed by a blind examiner. The time required to perform the treatments was recorded and a facial image scale was applied to assess anxiety before and after treatment. Adverse events and aesthetic perception were assessed through questions addressed to caregivers; and the OHRQoL through the B-ECOHIS questionnaire., Results: In 68 patients that were randomized, the mean number of treated teeth per child was 2.42(1.04) and 2.09(1.18) in the SDF and ART groups (p = 0.074), respectively. The mean difference of arrested lesions between the groups after 12 months was -0,07(0.05; - 0.17-0.30). The time required to treat with SDF was lower than the ART (p < 0.001). There was no difference in the percentage of adverse events + aesthetic perception (p = 0.709), and the change in anxiety (p = 0.155). There was a less impact in OHRQoL after ART treatment, but only when the parents' distress subscale was considered (p = 0.012)., Conclusion: SDF requires much less chair-time and have similar results as ART in arresting caries lesion, anxiety, adverse effects, aesthetic perception and quality of life., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Endoscopic retrograde cholangiopancreaticography (ERCP) is performed for diagnostic and therapeutic purposes in patients with pancreaticobiliary diseases. We investigated the role of simethicone and concomitant otilonium bromide during ERCP., Patients and Methods: This prospective randomized study included 120 patients who underwent ERCP (study and control group=60 patients each). The study group received otilonium bromide and simethicone. The control group received no medication., Results: The quantity of duodenal foam and bubbles in the study group was significantly lesser than that in the control group. The duodenal motility score was 2.1±0.7 and 4.3±0.9 in the study and the control groups, respectively. Endoscopist satisfaction was good in 82%, moderate in 15%, and poor in 3% of ERCPs in the study group and good in 15%, moderate in 65%, and poor in 25% of ERCPs in the control group. The study group showed a shorter ERCP duration than the control group., Conclusions: Simethicone and otilonium bromide administered concomitantly reduce duodenal motility and foam/bubble formation, which facilitates papilla of Vater catheterization to reduce procedure time.

Opioid-induced constipation (OIC) has become increasingly prevalent with the rise of prescription opioid use and can significantly impact quality of life, especially in patients with advanced illness. Methylnaltrexone has proven effective in treating cancer patients with OIC who have not responded adequately to conventional laxative therapy, though use is relatively contraindicated in those with peritoneal carcinomatosis due to theoretical risk and reported cases of perforation. The aim of this study was to evaluate the safety of methylnaltrexone in patients with carcinomatosis. We performed a retrospective review of 3058 pediatric and adult patients who received methylnaltrexone at Memorial Sloan Kettering Cancer Center from 2009-2016. Data collected included age, cancer diagnosis, history of abdominal surgery, prior radiation therapy, evidence of peritoneal carcinomatosis, and complications. Charts were reviewed for any complications at 24 hours, 72 hours, and one week following drug administration, as well as at present. We identified 3058 patients (median age 56, range 1-95) who received a total of 3995 doses of methylnaltrexone. Three hundred thirty three (median age 55, range 4-88) had peritoneal carcinomatosis. The most common primary malignancies included pancreatic (17.7%), ovarian (13.5%), colon (7.2%), and lung (6.6%). 228/333 (68.4%) had a history of abdominal surgery and 85/333 (25.5%) underwent prior radiation therapy. Three patients had adverse outcomes or complications, with only one (0.3%) thought to be related to methylnaltrexone use. To our knowledge, this is the largest study to evaluate the outcomes of patients with carcinomatosis receiving methylnaltrexone and the first to include pediatric patients. We found one perforation attributed to methylnaltrexone. Methylnaltrexone should be considered for treatment of refractory OIC in cancer patients with peritoneal carcinomatosis due to low risk of complications.

Small molecules that disrupt leukocyte trafficking have proven effective in treating patients with multiple sclerosis (MS). We previously reported that chemerin receptor chemokine-like receptor 1 (CMKLR1) is required for maximal clinical and histological experimental autoimmune encephalomyelitis (EAE); and identified CMKLR1 small molecule antagonist 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) that significantly suppressed disease onset in vivo. Here we directly compared α-NETA versus FDA-approved MS drug Tecfidera for clinical efficacy in EAE; characterized key safety/toxicity parameters for α-NETA; identified structure-activity relationships among α-NETA domains and CMKLR1 inhibition; and evaluated improved α-NETA analogs for in vivo efficacy. α-NETA proved safe and superior to Tecfidera in suppressing clinical EAE. In addition, we discovered structurally differentiated α-NETA analogs (primarily ortho- or para-methoxy substitutions) with significantly improved target potency in vitro and improved efficacy in vivo. These findings suggest that α-NETA-based CMKLR1 inhibitors may prove safe and effective in treating demyelinating diseases and potentially other autoimmune disorders.

Treatment of carious root surfaces remains challenging due to the complex pathological processes and difficulty in restoring the original structure of root dentine. Current treatments targeting the de-/re-mineralisation processes are not entirely satisfactory in terms of the protection of the dentinal organic matrix and the highly organised structure of dentine. In this in vitro study, a cross-linking agent - proanthocyanidin (PA) was used in conjunction with a fluoride-based treatment - silver diamine fluoride/potassium iodide (SDF/KI) to putatively stabilise the organic dentinal framework as well as strengthen the collagen-mineral phase interaction. The effectiveness of this strategy was evaluated 24 h after application in terms of the distribution of ion uptake and microstructure of dentine after treatment as well as analysis of the nano-mechanical properties using a dynamic behaviour model. Results showed that individual use of SDF/KI significantly improved the surface microhardness and integrated mineral density (Z) up to 60 µm depth and the recovery of creep behaviour of demineralised dentine in the surface area compared to that treated with deionised distilled water (DDW). The combined treatment of PA and SDF/KI achieved a more homogenous mineral distribution throughout the lesions than SDF/KI alone; a more significant incremental increase in surface microhardness and Z was observed. Specifically, a superior effect on the subsurface area occurred with PA + SDF/KI, with significant improvements in microhardness, elastic modulus and recovery of creep behaviour of the demineralised dentine. Application of SDF/KI induced small discrete crystal formation distributed over the dentine surface and PA contributed to the formation of slit-shaped orifices of the dentinal tubules that were partially occluded. STATEMENT OF SIGNIFICANCE: Demographic transitions and improved oral health behaviour have resulted in increased tooth retention in elderly people. As a consequence, the risk of root dentine caries is increasing due to the age-associated gingival recession and the related frequent exposure of cervical root dentine. Root caries is difficult to repair because of the complex aetiology and dentine structure. The recovery of dentine quality depends not only on reincorporation of minerals but also an intact dentinal organic matrix and the organic-inorganic interfacial structure, which contribute to the biomechanics of dentine. With the capability of dentine modification, cross-linking agents were applied with a fluoride regimen, which improved its treatment efficacy of root caries regarding the distribution of ion uptake and recovery of dentine biomechanics., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Opioids are prescribed in over 40% of patients with advanced cancer, but side effects occur frequently. In this study we evaluated the development and treatment of opioid induced constipation (OIC), and OIC resolving effect of methylnaltrexone for different opioid subtypes in daily clinical practice., Methods: Patients with cancer using opioids were included in a retrospective chart analysis. Baseline characteristics, data on opioid use, laxative use, and OIC were collected. Patients with OIC who were prescribed methylnaltrexone, were included in a prospective observational trial (NCT01955213)., Results: Thirty-nine of 327 patients (pts) with cancer who were treated with opioids suffered from OIC (overall prevalence 12%; 95%-CI: 8-15%). The prevalence of OIC was similar in patients treated with oxycodone or fentanyl (12 of 81 pts. vs. 18 of 110 pts., RR 0.9; 95%CI 0.4-2.0). The morphine equivalent daily dose did not significantly differ between opioid subtypes (fentanyl 89 mg (IQR 60-180) vs. oxycodone 40 mg (40-80), P = 0.231). Twenty-two individual patients (7%) were admitted for OIC. Most effective laxatives in admitted patients were enemas, methylnaltrexone, or 4-l polyethylene-glycol solution. In the prospective observational study, the effect of methylnaltrexone could be evaluated in 23 patients. Eleven patients achieved the primary endpoint of ≥2 laxation responses out of the first four doses methylnaltrexone, independent of opioid subtype., Conclusions: OIC is a burdensome clinical problem independent of opioid subtype. Timely intensification of prophylactic laxative treatment, especially when opioid doses increase, may help to prevent OIC. Clinically overt OIC requires a more intensive laxative regimen with for example methylnaltrexone., Trial Registration: NCT01955213 .

The use of silver diamine fluoride (SDF) for management of dental caries has gained considerable attention due to recent regulatory clearance in the United States. The primary focus of policies, presentations, and publications has been the arrest of caries lesions (cavities) because of the material's unique ability to non-invasively achieve this elusive and clinically important goal. However, SDF also has proven efficacy in prevention, ie, decreasing the incidence of new caries lesions. Analysis of nine clinical trials in children shows that SDF prevented 61% of new lesions compared to controls. To prevent one new caries lesion, clinicians need to treat four primary teeth (one patient) or 12.1 permanent molars (three patients) with SDF. The preventive effect appears to be immediate and maintains at the same fraction over time. Direct comparisons of SDF applied once per year with alternative treatments show that SDF is more effective than other topical fluorides placed two to four times per year and more cost-effective than dental sealants. Enamel lesions may be even more responsive than cavitated dentin lesions. Annual application of SDF to high-risk surfaces (eg, mesial surfaces of permanent first molars where the distal surface of the second primary molar is carious) in patients with any risk of new caries lesions appears to be the most cost-effective approach available to prevent dental caries. SDF is an underutilized evidence-based preventive agent for dental caries.

Bone cancer metastasis is extremely painful and decreases the quality of life of the affected patients. Available pharmacological treatments are not able to sufficiently ameliorate the pain, and as patients with cancer are living longer, new treatments for pain management are needed. Decitabine (5-aza-2'-deoxycytidine), a DNA methyltransferases inhibitor, has analgesic properties in preclinical models of postsurgical and soft-tissue oral cancer pain by inducing an upregulation of endogenous opioids. In this study, we report that daily treatment with decitabine (2 µg/g, intraperitoneally) attenuated nociceptive behavior in the 4T1-luc2 mouse model of bone cancer pain. We hypothesized that the analgesic mechanism of decitabine involved activation of the endogenous opioid system through demethylation and reexpression of the transcriptionally silenced endothelin B receptor gene, Ednrb. Indeed, Ednrb was hypermethylated and transcriptionally silenced in the mouse model of bone cancer pain. We demonstrated that expression of Ednrb in the cancer cells lead to release of β-endorphin in the cell supernatant, which reduced the number of responsive dorsal root ganglia neurons in an opioid-dependent manner. Our study supports a role of demethylating drugs, such as decitabine, as unique pharmacological agents targeting the pain in the cancer microenvironment.

Dental caries can compromise quality of life and is associated with demineralization of tooth structure by organic acids produced by microorganisms. This study systematically reviewed the dentine caries arrest capabilities of silver diamine fluoride (SDF) and sodium fluoride (NaF). A comprehensive search strategy was developed to identify the relevant publications in electronic databases and hand searched journals and reviews (to March 2018). By applying strict inclusion and exclusion criteria, only six papers (two randomized controlled trials, two follow-up articles and two secondary statistical analysis studies) were considered for full text qualitative and quantitative assessment. The included studies were critically appraised and statistically evaluated. Only four articles were considered for meta-analysis, as the other two were secondary analyses of included studies. When comparing the caries arrest lesions of SDF and NaF, SDF was found to be statistically more effective in dentine caries arrest of primary teeth during the 18 and 30 month clinical examinations. The weighted total effect size of the differences between SDF and NaF regarding arrested caries surfaces was calculated and showed nearly double the effectiveness of SDF to NaF at 30 months. Therefore, SDF is a more effective caries management reagent than NaF. Further clinical research is needed to consolidate the findings of this systematic review.

Aim: Silver diammine fluoride (SDF) is an anticaries agent that binds to tooth tissue. The aim of the present study was investigate the dose-response effect of SDF on demineralized dentine in basal medium mucin (BMM) saliva substitute and human saliva., Methods: Dentine discs stored in saliva substitute, BMM, and human unstimulated whole saliva (UWS) were chemically demineralized, and 10 μL of 10 wt%, 24 wt%, or 38 wt% SDF was applied and then stored in its respective saliva (BMM or UWS) for 5 days. Dentine disc samples were digested in 70% HNO 3 , and silver was quantitatively detected by inductively coupled plasma mass spectroscopy., Results: For both the BMM and UWS groups, the presence of silver increased proportionally with increasing concentrations of SDF (P < 0.05). For the 38 wt% SDF application, the mean absorption percentage of silver in dentine was 3.90% for the UWS group and 6.61% for the BMM group. The BMM group was found to yield a significantly higher amount of silver compared to UWS at 10 wt% and 38 wt% SDF application (α = 0.05); 38 wt% SDF interacts more with BMM with higher silver deposition than UWS., Conclusion: The amount of silver found in dentine was in proportion to the concentration of SDF. Extrapolation of in vitro investigations using artificial saliva for SDF tooth interactions should be interpreted with caution., (© 2018 John Wiley & Sons Australia, Ltd.)

Silver diamine fluoride (SDF) is an inexpensive treatment for arresting cavitated carious lesions in a minimally invasive way. The aims of this study were to assess U.S. pediatric dentists' SDF educational experiences, knowledge, attitudes, and professional behavior and to explore the relationships among these constructs. For the cross-sectional survey, recruitment emails were sent to all 6,230 members of the American Academy of Pediatric Dentistry (AAPD). Responses were received from 582 members (response rate 9.34%). In the results, only 3% of the respondents reported having been well/very well educated about SDF in classroom settings in dental school and only 9.6% during their residency. Positive SDF professional development was reported frequently (education through publications 53%, online resources 41%, continuing education courses 38%). The majority knew much/very much about what SDF is used for in dentistry (77%), about treating caries in pediatric patients (80%), and which problems SDF use can have (62%). Their SDF attitudes were positive: SDF use was considered a good treatment alternative for restorations in children with behavioral problems (85%) and for patients who were medically fragile (85%) or had severe dental anxiety (81%). Among the respondents, 31% used SDF often/very often to arrest carious lesions in primary teeth, and 87% expected increased future SDF use. The more SDF professional education the respondents had, the more self-reported knowledge they had (r=0.52; p<0.001), the more positive their SDF-related attitudes (r=0.25; p<0.001), and the more likely they were to use SDF (r=0.37; p<0.001). These results suggest that expanded education about the proper use, benefits, and limitations of SDF is needed and is likely to increase pediatric dentists' SDF utilization.

Objectives: The aim of the study was to investigate the effect of silver diamine fluoride (SDF) therapy on the oral health-related quality of life (OHRQoL) of preschool children and their families in a school-based setting., Methods: A prospective study was conducted in six kindergartens in Hong Kong. Parents of the children were invited to complete an oral health questionnaire and to have their child undergo a dental examination. The decayed, missing and filled teeth (dmft) index was adopted for recording oral health status. The Chinese Early Childhood Oral Health Impact Scale (C-ECOHIS) was used to evaluate the OHRQoL of the children and their families. Children with untreated caries were treated with SDF. The Wilcoxon Signed Ranks Test was used to determine the changes in C-ECOHIS scores before and after SDF treatment for six months., Results: At baseline, 117 preschool children aged 4-5 years received SDF treatment for caries arrest. Their mean(SD) dmft score at baseline was 4.9(3.8). After six months, 113(96.6%) returned a completed questionnaire. Their mean(SD) C-ECOHIS scores at baseline and follow-up were 7.4(6.6) and 7.8(6.4), respectively. The overall differences between pre- and post-treatment scores were not significant (p = 0.301). Concerning parent section, a negative impact was found (p = 0.014), whereas no significant impact was found in the child section (p = 0.831)., Conclusion: Based on the 6-month results, the SDF treatment conducted in a school setting did not affect the overall OHRQoL of preschool children and families., Clinical Significance: These results can provide important information to dental professionals regarding the use of SDF for caries control., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: In the United States, silver diamine fluoride (SDF) is a new method to arrest dental caries. Protocols for using SDF are under development as the research evolves and experience is gained with different populations and settings. The purpose of this study was to develop a comprehensive SDF protocol for young children tailored to safety net dental clinics (SNDCs).
Methods: We developed the SDF protocol for SNDCs through a two-step process: (1) an expert panel of pediatric dentists reviewed, modified, and expanded existing SDF protocols including clinical, pre- and post-clinical components; and (2) the new SDF protocol was implemented in three SNDCs in North Carolina with on-site didactic training, clinical observations and discussion. We obtained feedback from SNDC dentists, staff, and administrators to further refine the SDF protocol.
Results: The SDF protocol was tailored to SNDCs based on recommendations from SNDCs themselves. Suggested improvements were primarily non-clinical in nature, such as the provision of laminated SDF information with color pictures of staining in each operatory, a timer for SDF procedure, and templates for documentation, coding, and billing.
Conclusion: To facilitate SDF use in SNDCs, we developed an expert-consensus protocol that incorporated the clinical experience of SNDCs that implemented the protocol. (J Dent Child 2019;86(1):32-9)
Received September 17, 2018; Last Revision November 7, 2018; Accepted November 7, 2018.

Purpose: This study evaluated the impact of silver diamine fluoride (SDF) by investigating coverage and reimbursement policies. Methods: We performed a population-level retrospective cohort analysis (N equals 117,599) using claims. We evaluated two policy events: (1) dental board approval permitting SDF use by expanded practice dental hygienists (EPDHs); (2) approval of SDF by Medicaid. Coincident with coverage, Advantage Dental Services instituted EPDH practice algorithms. To evaluate changes, we: estimated CDT code 1354 utilization and average quarterly costs; stratified the population into patients who initiated preventive care from an EPHD or dentist; estimated outcome differences with either policy in quarterly trends; and counted SDF use with claims by quarter and calculated utilization per 1,000 patients. Results: Average per-patient quarterly dental costs (June 2017) ranged from $384 to $423. SDF use grew associated with Medicaid policy: rates increased from $0.32 per 1,000 to $156 per 1,000 in six quarters. Care initiated by EPDHs had lower costs, with quarterly savings of $201 (P=0.011) per patient, without differences in SDF utilization. Conclusions: Policy makers can use our results to improve access and reduce costs. Clinical experts should address more clearly when SDF substitutes for or is used in conjunction with restorative treatment.

This article reviews current evidence on the effectiveness of silver diamine fluoride (SDF) as a caries arresting and preventive agent. It provides clinical recommendations around SDF's appropriate use as part of a comprehensive caries management program. Systematic reviews confirm that SDF is effective for caries arrest on cavitated lesions in primary teeth and root caries in the elderly. It may also prevent new lesions. Application is easy, noninvasive, affordable, and safe. Although it stains the lesions dark as it arrests them, it provides clinicians with an additional tool for caries management when esthetics are not a primary concern., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Methylnaltrexone Reverses Chronic Opioid-induced Constipation: A Randomized, Controlled Trial. By Yuan CS, Foss JF, O'Connor M, Osinski J, Karrison T, Moss J, Roizen MF. JAMA 2000; 130:142-8. Reprinted with permission., Context: Constipation is the most common chronic adverse effect of opioid pain medications in patients who require long-term opioid administration, such as patients with advanced cancer, but conventional measures for ameliorating constipation often are insufficient., Objective: To evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation., Design: Double-blind, randomized, placebo-controlled trial conducted between May 1997 and December 1998., Setting: Clinical research center of a university hospital., Participants: Twenty-two subjects (9 men and 13 women; mean [SD] age, 43.2 [5.5] years) enrolled in a methadone maintenance program and having methadone-induced constipation., Main Outcome Measures: Laxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups., Results: The 11 subjects in the placebo group showed no laxation response, and all 11 subjects in the intervention group had laxation response after intravenous methylnaltrexone administration (P<.001). The oral-cecal transit times at baseline for subjects in the methylnaltrexone and placebo groups averaged 132.3 and 126.8 minutes, respectively. The average (SD) change in the methylnaltrexone-treated group was -77.7 (37.2) minutes, significantly greater than the average change in the placebo group (-1.4 [12.0] minutes; P<.001). No opioid withdrawal was observed in any subject, and no significant adverse effects were reported by the subjects during the study., Conclusions: Our data demonstrate that intravenous methylnaltrexone can induce laxation and reverse slowing of oral cecal-transit time in subjects taking high opioid dosages. Low-dosage methylnaltrexone may have clinical utility in managing opioid-induced constipation.

The aim of this study was to determine the effects of 38% silver diamine fluoride (SDF) on carious lesions of human deciduous teeth. Ten extracted deciduous incisors with caries were collected and treated with SDF. After the treatment, the teeth were sectioned through the center of the carious lesion. The extent of sliver precipitation was examined using quantitative backscattered electron scanning electron microscopy (qBSE-SEM), energy-dispersive X-ray spectroscopy (EDX), and micro-computed tomography (micro-CT). The qBSE-SEM images revealed that the silver particles could penetrate through the pellicle complex, along with the rod sheaths into the demineralized enamel rods and the dentinal tubules, and form silver-enriched barriers surrounding the carious lesions at depths up to 2,490.2 μm (mean 744.7 ± 448.7 μm) within the dentinal tubules of the carious lesions, but less likely in the sound enamel. The EDX spectrum analysis revealed that carbon, oxygen, phosphorus, chlorine, silver, and calcium were the main elements detected in the lesions treated with SDF. Additionally, sodium, magnesium, aluminum, silicon, zinc, sulfur, and fluorine were detected as the minor elements within the SDF precipitation "zone." The micro-CT analysis further showed that in the deep cavitated lesions, the silver precipitation could be observed in the pulp chamber. These findings provide new evidence defining the SDF mode of action for arresting caries and suggest that the application of a highly concentrated SDF solution on deciduous teeth should be used with caution for various carious lesions., (© 2019 S. Karger AG, Basel.)

Objectives: To investigate whether silver diamine fluoride (SDF) is effective in preventing new caries lesions in primary teeth when compared to placebo or active treatments., Methods: Systematic review (CRD42016036963) of controlled clinical trials. Searches were performed in 9 electronic databases, 5 registers of ongoing trials, and reference lists of identified review articles. Two researchers carried out data extraction and quality appraisal independently. The primary outcome was the difference in caries increment (decayed, missing, and filled surfaces or teeth - dmfs or dmft) between SDF and control groups. These differences were pooled as weighted mean differences (WMD) and prevented fractions (PF)., Results: Searches yielded 2,366 unique records; 6 reports of 4 trials that randomized 1,118 and analyzed 915 participants were included. Two trials compared SDF to no treatment, 1 compared SDF to placebo and sodium fluoride varnish (FV), and 1 compared SDF to high-viscosity glass ionomer cement (GIC). All studies had at least 1 domain with unclear or high risk of bias. After 24 months of follow-up, in comparison to placebo, no treatment, and FV, SDF applications significantly reduced the development of new dentin caries lesions (placebo or no treatment: WMD = -1.15, PF = 77.5%; FV: WMD = -0.43, PF = 54.0%). GIC was more effective than SDF after 12 months of follow-up but the difference between them was not statistically significant (WMD, dmft: 0.34, PF: -6.09%)., Conclusion: When applied to caries lesions in primary teeth, SDF compared to no treatment, placebo or FV appears to effectively prevent dental caries in the entire dentition. However, trials specifically designed to assess this outcome are needed., (© 2018 S. Karger AG, Basel.)

Silver diamine fluoride (SDF), a low-cost topical agent used in many countries to arrest dental caries, was cleared as a desensitizing agent by the Food & Drug Administration for the U.S. market in 2014. The aim of this study was to survey U.S. dental schools regarding their teaching of SDF. Email invitations were sent to all accredited U.S. predoctoral dental education programs (n=66) in September 2016. Deans, chairs, and selected faculty members were asked to respond or forward the survey-link provided to the appropriate person in their school. Under the assumption that some respondents from the same school were unaware of SDF implementation across departments, multiple responses from the same school were collapsed for analysis. A total of 62 schools (94% response rate) responded to the survey, and 67.7% of them reported that SDF was part of their curricula. There was a wide variation across dental schools' teaching about SDF indications and protocols of application. All but one school consistently agreed on using SDF for arresting caries on primary teeth. Only 18 respondents were able to confirm if there was an existing protocol at their school for the use of SDF. When re-application after initially arresting caries with SDF was taught, 50% of respondents advocated 2×/year re-application. Schools not teaching SDF (n=20) planned on including it in their curricula in the future. These findings suggest that, with the use of SDF increasing rapidly in the U.S. and its adoption in most dental schools, there is a need for the development of standardized evidence-based protocols.

Opioids have been used for centuries, mostly as a sedative and to treat pain. Currently, they are used on a global scale for the treatment of acute and chronic pain in diseases as osteoarthritis, fibromyalgia, and low back pain. Binding of opioids on opioid receptors can cause a range of different effects such as changes in stress response, analgesia, motor activity and autonomic functions. This review provide a synthetic summary of the most recent literature on the use of drugs acting on mu-receptors to treat two prevalent functional bowel disorders, presenting with opposite bowel habit. Eluxadoline and naloxegol, methylnaltrexone and naldemedine are recently FDA and/or EMA approved drugs demonstrated to be effective and safe for treatment respectively of irritable bowel syndrome subtype diarrhea and opioid induced constipation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: To investigate the remineralising effect and bacterial growth inhibition of 38% silver diamine fluoride (SDF) solution and 5% sodium fluoride (NaF) varnish on artificial dentine caries lesions., Methods: Demineralised dentine blocks were treated with SDF + NaF (Group 1), SDF (Group 2), NaF (Group 3) and water (Group 4) and subjected to a Streptococcus mutans biofilm challenge. Lesion depth, precipitates' characteristics and matrix (collagen)-to-mineral ratio were evaluated by micro-computer tomography (micro-CT), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR), respectively. The biofilm kinetics, viability and topography were assessed by counts of colony forming units (CFUs), confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM), respectively. Data were analysed by two-way ANOVA test., Results: The lesion depths of Groups 1-4 were 170 ± 28 μm, 160 ± 32 μm, 353 ± 38 μm and 449 ± 24 μm, respectively. The addition of NaF to SDF did not show better remineralisation than SDF (p = 0.491). Metallic silver and silver chloride were found in Groups 1 and 2. The amide I-to-hydrogen phosphate ratios of the four groups were 0.14 ± 0.02, 0.14 ± 0.01, 0.29 ± 0.05 and 0.49 ± 0.16, respectively, and the addition of NaF to SDF did not offer better protection against collagen exposure than SDF (p = 0.986). The Log 10 CFUs of Groups 1-4 were 5.75 ± 0.56, 4.49 ± 0.57, 6.55 ± 0.39 and 6.40 ± 0.38, respectively. The presence of NaF reduced the antibacterial effect of SDF (p < 0.001). The SEM and CLSM images supported the findings., Conclusion: Application of SDF with or without NaF reduced the demineralisation of dentine caries, but SDF exerted stronger inhibition of biofilm growth than SDF with NaF., Clinical Significance: NaF varnish affects the antibacterialeffects of SDF, the adjunctive application of SDF solution and NaF varnish is not recommended to arrest dentine caries in clinic., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Dental caries is the most prominent childhood disease in the world. In the United States, more than 50% of children have experienced caries. Untreated caries can have negative impacts on quality of life, academic performance, and school attendance. To reduce oral health disparities, multiple organizations recommend school-based caries prevention., Methods/design: A longitudinal, cluster randomized, non-inferiority trial will be conducted in low-income children from primarily Hispanic/Latino backgrounds currently enrolled in public elementary schools in New York City, New York, United States, from 2018 to 2023. The primary objective is to compare the non-inferiority of silver diamine fluoride and fluoride varnish versus glass ionomer therapeutic sealants and fluoride varnish in the arrest and prevention of dental caries. Secondary objectives are to evaluate differences in effectiveness when care is provided by nurses versus dental hygienists and assess the impact of prevention on oral health-related quality of life and educational outcomes. Caries arrest will be evaluated after 2 years, and caries prevention and secondary outcomes will be assessed at the completion of the study. Data analysis will follow intent-to-treat, and statistical analyses will be conducted using a two-sided significance level of 0.05., Discussion: The comparative effectiveness of alternative caries prevention delivery models is considered to be one of the highest research priorities in the United States. Many treatments are currently available to prevent and arrest dental caries. The simplicity and affordability of silver diamine fluoride may be a viable alternative for the prevention of dental caries in high-risk children., Trial Registration: U.S. National Library of Medicine, www.clinicaltrials.gov , ID: NCT03442309 . Registered on 22 February 2018.

This review deals with various microbiological activities of ionic liquids, which constitute the first anti-infective defense against multi-drug-resistant bacteria-with a particular emphasis placed on medicine and pharmacology. The quoted data on the biological activity of ionic liquids including their antimicrobial properties (depending on the type of a cation or an anion) and are discussed in view of possible applications in nosocomial infections. Dedicated attention is given to finding infections with the Klebsiella pneumoniae New Delhi strain, Acinetobacter baumannii , and Enterococcus species, which are responsible for the induction of antibiotic resistance in intensive care units. Diagnosis and treatment using current antibiotics is a significant problem in hospital care, and the relevant burden on the health systems of the European Union member states induces the search for new, effective methods of treatment. Ionic liquids, due to their antibacterial effect, can be considered topical and general medications and may provide the basis for treatment to eliminate the antibiotic resistance phenomenon in the future. At present, the number of infections with resistant pathogens in hospitals and outpatient clinics in the European Union is growing. In 2015⁻2017, a significant incidence of respiratory and bloodstream infections with bacteria resistant to antibiotics from the 3rd generation group of cephalosporins, glycopeptides, and carbapenems were observed. The paper presents examples of synthesized bifunctional salts with at least one pharmaceutically active ion in obtaining a controlled release, controlled delivery, and biological impact on the pathogenic bacteria, viruses and fungi. The ionic liquids obtained in the presented way may find applications in the treatment of wounds and infections.

Aims: Recently, there has been interest in biological approaches for caries management, with techniques such as interim therapeutic restorations and Hall technique crowns showing comparative effectiveness against conventional restorative methods. One of these approaches is the use of silver diamine fluoride (SDF) as a restorative option. In this invited review, the aim was to critically appraise the currently available literature with regards to the indication, technique and outcome of SDF., Methods: A review of the literature on SDF with a focus on its use in the primary dentition was conducted., Results: There has been a recent explosion in the literature regarding the use of SDF, from in vitro studies on the mechanism to clinical studies on the effectiveness and patient acceptance of the technique. A systematic review in 2016 concluded that SDF application resulted in caries arrest in 81% of active lesions in primary teeth over 30 months. Additionally, over 60% of parents reported being satisfied with the aesthetic outcome with most children finding the procedure to be acceptable, comfortable and relatively pain-free., Conclusions: Silver diamine fluoride is a safe and effective alternative technique to caries management in the paediatric population. Given the ongoing worldwide debate on cost-effectiveness of biological approaches coupled with the increasing concerns and limited accessibility of treatment under general analgesia, SDF should form an important addition to every dentist's armamentarium.

Introduction: The extensive and alarming use of opioids for pain management in patients with chronic pain receiving palliative care is associated with non-tolerable gastrointestinal (GI) adverse effects. Opioid-induced constipation (OIC) is the most common adverse effect impairing patient quality of life (QOL). In addition, OIC is one of the treatment limiting consequences of opioid analgesics. Management of OIC is becoming a challenge since traditional laxatives have limited efficiency. Peripherally acting mu-opioid receptor antagonists (PAMORA) have been developed for the treatment of OIC with methylnaltrexone bromide being the first approved to treat OIC in adults with advanced illness undergoing palliative care. Areas covered: The authors systematically review the clinical evidence for methylnaltrexone bromide including a review of the pharmacokinetic and pharmacodynamic data along with clinical effectiveness and cost-effectiveness. Though there is a need for further long-term clinical investigation, there is a large body of evidence for both its efficacy and safety in the treatment of OIC. Expert opinion: Methylnaltrexone has both subcutaneous injection and oral dosage forms available in the market. The lack of more evidence in specific populations such as pregnant women, pediatrics and elderly still remains. The global consumption of methylnaltrexone shows a projection of increased use since its approval worldwide in 2008.

Background: Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of treatment for pain in cancer and in palliative care, resulting in increased morbidity and reduced quality of life.This is an update of two Cochrane reviews. One was published in 2011, Issue 1 on laxatives and methylnaltrexone for the management of constipation in people receiving palliative care; this was updated in 2015 and excluded methylnaltrexone. The other was published in 2008, Issue 4 on mu-opioid antagonists (MOA) for OIBD. In this updated review, we only included trials on MOA (including methylnaltrexone) for OIBD in people with cancer and people receiving palliative care., Objectives: To assess the effectiveness and safety of MOA for OIBD in people with cancer and people receiving palliative care., Search Methods: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and Web of Science to August 2017. We also searched clinical trial registries and regulatory websites. We contacted manufacturers of MOA to identify further data., Selection Criteria: We included randomised controlled trials (RCTs) that assessed the effectiveness and safety of MOA for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease they experienced., Data Collection and Analysis: Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across the trials. Our primary outcomes were laxation, impact on pain relief, and adverse events. Impact on pain relief was a primary outcome because a possible adverse effect of MOAs is a reduction in pain relief from opioids. We assessed the evidence on these outcomes using GRADE., Main Results: We identified four new trials for this update, bringing the total number included in this review to eight. In total, 1022 men and women with cancer irrespective of stage or at a palliative care stage of any disease were randomised across the trials. The MOAs evaluated were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared with MOA with a placebo or with the active intervention administered at different doses or in combination with other drugs. The trial of naldemedine and the two of naloxone in combination with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. The four trials on methylnaltrexone were undertaken in palliative care where most participants had cancer. All trials were vulnerable to biases; four were at a high risk as they involved a sample of fewer than 50 participants per arm.In the trial of naldemedine compared to placebo in 225 participants, there were more spontaneous laxations over the two-week treatment for the intervention group (risk ratio (RR) 1.93, 95% confidence intervals (CI) 1.36 to 2.74; moderate-quality evidence). In comparison with higher doses, lower doses resulted in fewer spontaneous laxations (0.1 mg versus 0.2 mg: RR 0.73, 95% CI 0.55 to 0.95; 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89; moderate-quality evidence). There was moderate-quality evidence that naldemedine had no effect on opiate withdrawal. There were five serious adverse events. All were in people taking naldemedine (low-quality evidence). There was an increase in the occurrence of other (non-serious) adverse events in the naldemedine groups (RR 1.36, 95% CI 1.04 to 1.79, moderate-quality evidence). The most common adverse event was diarrhoea.The trials on naloxone taken either on its own, or in combination with oxycodone (an opioid) compared to oxycodone only did not evaluate laxation response over the first two weeks of administration. There was very low-quality evidence that naloxone alone, and moderate-quality evidence that oxycodone/naloxone, had no effect on analgesia. There was low-quality evidence that oxycodone/naloxone did not increase the risk of serious adverse events and moderate-quality evidence that it did not increase risk of adverse events.In combined analysis of two trials of 287 participants, we found methylnaltrexone compared to placebo induced more laxations within 24 hours (RR 2.77, 95% CI 1.91 to 4.04. I² = 0%; moderate-quality evidence). In combined analysis, we found methylnaltrexone induced more laxation responses over two weeks (RR 9.98, 95% CI 4.96 to 20.09. I² = 0%; moderate-quality evidence). The proportion of participants who had a rescue-free laxation response within 24 hours of the first dose was 59.1% in the methylnaltrexone arms and 19.1% in the placebo arm. There was moderate-quality evidence that the rate of opioid withdrawal was not affected. Methylnaltrexone did not increase the likelihood of a serious adverse event; there were fewer in the intervention arm (RR 0.59, 95% CI 0.38 to 0.93; I² = 0%; moderate-quality evidence). There was no difference in the proportion of participants experiencing an adverse event (RR 1.17, 95% CI 0.94 to 1.45; I² = 74%; low-quality evidence). Methylnaltrexone increased the likelihood of abdominal pain and flatulence.Two trials compared differing methylnaltrexone schedules of higher doses with lower doses. For early laxation, there was low-quality evidence of no clear difference between doses on analgesia and adverse events. Both trials measured laxation response within 24 hours of first dose (trial one: RR 0.82, 95% CI 0.41 to 1.66; trial two: RR 1.07, 95% CI 0.81 to 1.42)., Authors' Conclusions: In this update, the conclusions for naldemedine are new. There is moderate-quality evidence to suggest that, taken orally, naldemedine improves bowel function over two weeks in people with cancer and OIBD but increases the risk of adverse events. The conclusions on naloxone and methylnaltrexone have not changed. The trials on naloxone did not assess laxation at 24 hours or over two weeks. There is moderate-quality evidence that methylnaltrexone improves bowel function in people receiving palliative care in the short term and over two weeks, and low-quality evidence that it does not increase adverse events. There is a need for more trials including more evaluation of adverse events. None of the current trials evaluated effects in children.

Surgical site infection after breast reconstruction is associated with increased length of hospital stay, readmission rates, cost, morbidity, and mortality. Identifying methods to reduce surgical site infection without the use of antibiotics may be beneficial at reducing antimicrobial resistance, reserving the use of antibiotics for more severe cases. Quaternary ammonium salts have previously been shown to be a safe and effective antimicrobial agent in the setting of in vitro and in vivo animal experiments. A retrospective study was conducted to investigate the antimicrobial properties of a quaternary ammonium salt, 3-trimethoxysilyl propyldimethyloctadecyl ammonium chloride (QAS-3PAC; Bio-spear), at reducing surgical drain site colonization and infection after breast reconstruction (deep inferior epigastric perforator flap reconstruction or tissue expander placement). Twenty patients were enrolled, with 14 surgical drains covered with nonimpregnated gauze and 17 surgical drains covered with QAS-3PAC impregnated gauze, for the purposes of investigating bacterial colonization. Antibiotic sensitivity analysis was also conducted when bacterial cultures were positive. The overall incidence of bacterial colonization of surgical drains was lower in the treatment group compared with the control group (17.6% vs 64.3%, respectively; P = 0.008). QAS-3PAC impregnated gauze reduced the incidence of bacterial colonization of surgical drains during the first (0.0% vs 33.3%) and second (33.3% vs 87.5%; P = 0.04) postoperative week. Furthermore, no enhanced antibiotic resistance was noted on drains treated with QAS-3PAC impregnated gauze. The results of this study suggest that QAS-3PAC impregnated gauze applied over surgical drains may be an effective method for reducing the incidence of bacterial colonization.

Data sourcesPubMed, Scopus, Web of Science, the Latin American and Caribbean Health Sciences Literature database (LILACS), the Brazilian Library in Dentistry (BBO), Cochrane Library and grey literature.Study selectionTwo reviewers selected randomised clinical trials (RCTs) that compared the efficacy of SDF application with other active treatments or placebo in arresting carious lesions.Data extraction and synthesisThree authors extracted data using customised extraction forms, and risk of bias was assessed by two independent reviewers. Meta-analyses were performed on studies classified at 'low' or 'unclear' risk of bias, where similar outcomes were recorded in primary teeth, and that compared SDF to active treatments.ResultsEleven studies were included; five studies were at 'low', two at 'unclear' and four studies at 'high' risk of bias. Eight were conducted with primary teeth, two with permanent first molars and one conducted on both. Six studies used 38% SDF, two 30% SDF, one 12% SDF, one compared 38% SDF to 12% SDF and one used Nano Silver Fluoride (NSF).ConclusionsSDF is more effective than active treatments or placebo for carious lesion arrest in primary teeth. The body of evidence was of high quality for primary teeth. However, there was not enough high quality evidence to draw conclusions about carious lesion arrest in first permanent molars.

Data sourcesPubMed, Pubmed Clinical Queries, EMBASE, the American Dental Associations Evidence-Based Dentistry Website, Cochrane Library, Web of Science, repository of the Journal of the American Dental Association and Google Scholar.Study selectionFour authors independently assessed the abstracts of studies resulting from the above searches which compared treatment of root caries in an older population with SDF versus other preventive agents or placebos.Data extraction and synthesisTitles and abstracts of all reports identified through the electronic searches were assessed independently by four authors based on agreed upon inclusion and exclusion criteria. Of the selected studies for final inclusion in the systematic review, study quality was assessed using the critical appraisal worksheet for randomised controlled trials from the Oxford Centre for Evidence-Based Medicine (CEBM 2005). Prevented fraction (PF), number needed to treat (NNT) and relative risk (RR) were calculated as outcome measures in each study. In addition, the published evidence on SDF was reviewed in order to formulate clinical recommendations on safety and effectiveness when treating root or coronal caries in an adult population with SDF, as well as treatment of dental hypersensitivity.ResultsThree randomised controlled trials were identified that addressed the effectiveness of SDF on root caries in older adults, but none addressed coronal caries. Root caries prevented fraction and arrest rate for SDF were significantly higher than placebo. The prevented fraction for caries prevention for SDF compared to placebo was 71% in a three-year study and 25% in a two-year study. The prevented fraction for caries arrest for SDF was 725% greater in a 24-month study and 100% greater than placebo in a 30-month study. No severe adverse effects were observed.ConclusionsExisting reports of SDF trials support effectiveness in root caries prevention and arrest, remineralisation of deep occlusal lesions and treatment of hypersensitive dentine.

A technique for using silver diamine fluoride (SDF) as part of a regimen to help maintain dental prostheses in a patient with scleroderma and at high risk of caries is presented. Medically compromised, xerostomic, or elderly patients generally face greater risk of caries and specifically with prosthetic retainer teeth. SDF is a minimally invasive solution to this problem. A technique is described for using SDF to arrest and prevent new caries with the goal of maintaining fixed and removable prostheses and supporting teeth in a cost-effective manner., (Copyright © 2017 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

Objective: To review the evidence regarding the mechanisms of silver diamine fluoride (SDF) for arresting caries., Methods: A literature search was conducted using the keywords silver diamine fluoride, and its alternative names, in seven databases: PubMed, Embase and Scopus (English); China National Knowledge Infrastructure (Chinese); Bilioteca Virtual em Saude (Portuguese); Biblioteca Virtual en Salud Espana (Spanish); and Ichushi-Web (Japanese). The titles and abstracts were screened. Full texts were retrieved for publications that studied mechanisms of actions of SDF, including its effects on remineralisation of carious lesions and on cariogenic bacteria., Results: A total of 1,123 publications were identified. Twenty-nine articles were included and they investigated the effect of SDF on cariogenic bacteria and dental hard tissues. Eleven studies investigated the antibacterial properties of SDF. They found that SDF was bactericidal to cariogenic bacteria, mainly Streptococcus mutans. It inhibited the growth of cariogenic biofilms on teeth. Twenty studies reported the remineralisation of demineralised enamel or dentine by SDF. They found that mineral loss of demineralised enamel and dentine was reduced after SDF treatment. A highly mineralised surface rich in calcium and phosphate was formed on arrested carious lesions. Four studies examined the effect of SDF on dentine collagen. They found that SDF inhibited collagenases (matrix metalloproteinases and cysteine cathepsins) and protected dentine collagen from destruction., Conclusion: SDF is a bactericidal agent and reduces the growth of cariogenic bacteria. It inhibits demineralisation and promotes the remineralisation of demineralised enamel and dentine. It also hampers degradation of the dentine collagen., (© 2017 FDI World Dental Federation.)

Objective: To summarize and evaluate the existing literature regarding medications to treat opioid-induced constipation (OIC) in patients with chronic noncancer pain (CNCP)., Data Sources: PubMed, EMBASE, and Web of Science were searched using the following terms: constipation, opioid, chronic, pain, noncancer, nonmalignant, methylnaltrexone, alvimopan, lubiprostone, naloxegol, and naldemedine., Study Selection and Data Extraction: The search was limited to randomized controlled trials reporting human outcomes. Data extracted included the following: study design, population, intervention, control, outcomes related to OIC and safety, and potential biases assessed using Cochrane Collaboration's Risk of Bias Assessment Tool., Data Synthesis: After assessment, 16 of the 190 studies were included: methylnaltrexone (n = 4), naloxegol (n = 3), naldemedine (n = 2), lubiprostone (n = 3), and alvimopan (n = 4). Lubiprostone was the only nonperipherally acting µ-opioid receptor antagonist included. Only 1 study (naloxegol) used "usual care" (nonstudy laxative) rather than placebo as a comparator. Placebo-controlled trials demonstrated benefit for methylnaltrexone, naloxegol, naldemedine, and lubiprostone, with conflicting evidence for alvimopan. No data suggest that one agent is better than another. Overall risk of bias across all studies was low to moderate., Conclusions: With risk of bias determined to be low to moderate, published data to date suggest that methylnaltrexone, naloxegol, and naldemedine may be appropriate to treat OIC in patients with CNCP.

Objective: To compare the effectiveness of three applications of silver diammine fluoride (SDF) solution at yearly interval and three applications of SDF solution or sodium fluoride (NaF) varnish at weekly interval at baseline in arresting active caries in the primary teeth of preschool children., Methods: Children aged 3-4 years (n = 371) who had at least one active caries lesion (ICDAS codes 3-6) in their primary teeth were randomly allocated into three groups: Group 1 - annual application of 30% SDF solution; Group 2 - three applications of 30% SDF at weekly intervals; and Group 3 - three applications of 5% NaF varnish at weekly intervals. Follow-up examinations were performed every 6 mo nths by the same masked examiner., Results: After 30 months, 309 (83%) children with 1877 caries lesions remained in the study. For cavitated lesions (ICDAS code 5 or 6), the caries arrest rate of Group 1 (48%) was significantly higher than those of Group 2 (33%) and Group 3 (34%), (p < 0.001). Results of multi-level survival analysis showed that the arrest times of cavitated lesions in both SDF groups (Groups 1 and 2) were significantly shorter than that of the NaF varnish group. For moderate caries lesions without visible dentine (ICDAS code 3 or 4), the caries arrest rates were 45%, 44% and 51% in Groups 1, 2 and 3, respectively (p > 0.05). Presence of plaque on caries lesion, tooth type and tooth surface type had an influence on caries arrest., Conclusion: Over a 30-month period, annual applications of SDF solution is more effective than three weekly applications of NaF varnish or SDF solution at baseline in arresting active cavitated dentine caries lesions in primary teeth., Clinical Significance: As annual application of SDF solution was found to be more effective than 3 weekly applications of NaF varnish or SDF solution at baseline in arresting active cavitated dentine caries lesions, the former application protocol is preferred for young children who are available for regular caries arrest treatment., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Serotonin (5-hydroxytryptamine or 5-HT) is a neurotransmitter in itch and impaired serotonin signaling has been linked to a variety of itch conditions. Intradermal injection of 5-HT induces scratching behavior in mice through stimulation of 5-HT receptors. Previous studies have demonstrated that selective 5-HT1B/1D receptors agonists, including sumatriptan, inhibits neurotransmission. We have also reported that sumatriptan suppresses chloroquine-induced itch. Therefore, we investigated if sumatriptan has inhibitory effects on serotonin-induced itch in mice. Here, we show that intradermal and intraperitoneal administration of sumatriptan significantly reduce 5-HT-induced scratching behavior in mice. While intradermal injection of GR-127935, a selective 5-HT1B/1D receptors antagonist, reverses the anti-pruritic effects of sumatriptan. In addition, we show that intradermal and intraperitoneal naltrexone (NTX), a non-specific opioid receptor antagonist, and methylnaltrexone (MNTX), a peripherally acting opioid receptor antagonist, significantly decrease the 5-HT-induced scratching behavior. Additionally, combined treatment with sub-effective doses of sumatriptan and an opioid receptor antagonist, naltrexone, decreases 5-HT-evoked scratching responses. We conclude that sumatriptan inhibits 5-HT-induced itch by activating the peripheral 5-HT1B/1D receptors. Moreover, peripheral opioid receptors have a role in serotonin-induced itch, and anti-pruritic effects of sumatriptan seem to involve the opioid system. These data suggest that 5-HT1B/1D receptors agonists maybe useful to treat a variety of pathologic itch conditions with impaired serotonergic system.

Objectives: To investigate the remineralizing effect of 38% silver diamine fluoride (SDF) application on enamel artificial caries in adjunct to 1000ppm fluoride toothpaste compared with fluoride toothpaste alone by analyzing the mineral density, depth of remineralization, and remineralization percentage of the lesions., Methods: Eighteen artificial caries slabs were created from the proximal surfaces of nine chemically demineralized premolars. The slabs were scanned by Micro-Computed Tomography (Micro-CT) to determine the baseline mineral density of the initial lesions and randomly allocated into 2 groups. The test group was applied with 38% SDF in adjunct to fluoride toothpaste and the control group was treated with fluoride toothpaste alone. The specimens underwent bacterial pH-cycling for 5 d and were re-evaluated using Micro-CT. The pre-treatment and post-treatment mineral densities were plotted and the areas under the curves were used to calculate the remineralization percentage of both groups., Results: Mineral density significantly increased in both groups after pH-cycling (p<0.05) although to different depths (control group=260μm, test group=300μm). The test group demonstrated a significantly higher mineral density to a depth of 120μm and higher remineralization percentage (p<0.05) compared with the control group., Conclusion: The adjunctive use of 38% SDF enhances the remineralization of initial carious lesions based on mineral density, depth, and remineralization percentage compared with the use of 1000ppm fluoride toothpaste alone. SDF might be used as an adjunct to fluoride toothpaste to remineralize incipient caries lesions on smooth tooth surfaces., Clinical Significance: In non-compliant patients, the application of 38% SDF might be used as an adjunct to fluoride toothpaste, to remineralize incipient caries lesions of permanent teeth where esthetics is not a concern., (Copyright © 2017 Elsevier Ltd. All rights reserved.)