Prevalence of apical periodontitis in patients with autoimmune diseases: A case-control study.

AIM: The purpose of this case-control study was to compare the prevalence of apical periodontitis (AP) in patients affected by autoimmune disorders (AD) (inflammatory bowel disease [IBD], rheumatoid arthritis [RA] and psoriasis [Ps]) with the prevalence of AP in subjects without AD. The prevalences of AP in patients taking biologic medications, conventional medications and no medication were also compared. METHODOLOGY: Eighty-nine patients (2145 teeth) with AD were investigated and the control group included 89 patients (2329 teeth) with no systemic diseases. Full dental panoramic tomograms were used to determine the periapical status of the teeth. Additional variables investigated included patient's socio-demographic characteristics, medications taken by AD patients, the decayed, missing and filled teeth (DMFT) index. The chi-square test and logistic regression analysis were used to evaluate the correlation between AD and AP. p-Values lower than .05 were considered to be statistically significant. RESULTS: The prevalence of AP was 89.9% in AD patients and 74.2% in control subjects (odds ratio [OR] = 3.75, p = .015). The DMFT score was found to be significantly higher in the AD group (p = .004). Patients with RA had the highest risk of being affected by AP, whereas those with IBD had the lowest risk. Multiple binary logistic regression analysis indicated that the teeth of AD patients who were not taking any medication or were being treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs) had a higher risk of being affected by AP than did the teeth of the control subjects (OR = 1.42 and OR = 2.03, respectively; p = .010). The teeth of patients taking conventional DMARDs (cDMARDs) were less affected by AP compared with those of patients taking bDMARDs. CONCLUSIONS: Patients with AD, whether treated or not with biologic medications, showed a higher prevalence of AP than did those in the control group. The DMFT index score, which was higher in AD patients compared with controls was identified as a significant predictor of AP prevalence.

Combination of leukocyte and platelet-rich fibrin and demineralized bovine bone graft enhanced bone formation and healing after maxillary sinus augmentation: a randomized clinical trial.

BACKGROUND AND OBJECTIVE: The resorption of alveolar ridge bone and maxillary sinus pneumatization are challenges to implant-supported prosthetic rehabilitation. Bone regeneration using bone substitutes and growth factors are alternatives for maxillary sinus augmentation (MSA). Therefore, we sought to evaluate the effects of the association between leukocyte and platelet-rich fibrin (L-PRF) and deproteinized bovine bone mineral (DBBM) in MSA procedures. MATERIALS AND METHODS: Thirty-six maxillary sinuses from 24 individuals were included in this randomized clinical trial. The maxillary sinuses were randomly grafted with LPRF and DBBM (test group) or grafted only with DBBM (positive control). Dental implants were installed in the test group following two periods of evaluation: after 4 (DBBM+LPRF4) and 8 (DBBM+LPFR8) months of sinus graft healing, while the control group received implants only after 8 months. Cone beam computed tomography (CBCT) was taken 1 week after surgery (T1) and before implant placement (T2). Bone samples were collected during implant placement for histomorphometric and immunohistochemical (IHC) analysis. The primary implant stability was assessed by resonance frequency analysis. RESULTS: CBCT analysis demonstrated a significant decrease in bone volume from T1 to T2 in all groups without differences among them. Histologically, the test group showed significantly increase in bone neoformation in both periods of evaluation (LPRF+DBBM4: 44.70±14.01%; LPRF+DBBM8: 46.56±12.25%) compared to the control group (32.34±9.49%). The control group showed the highest percentage of residual graft. IHC analysis showed increased staining intensity of osteocalcin (OCN), vascular endothelial growth factor (VEGF), and runt related transcription factor 2 (RUNX-2) in LPRF+DBBM4 group, and osteopontin (OPN) in the L-PRF+DBBM8. Primary implant stability was successfully achieved (above 60 in implant stability quotient) in all the evaluated groups. CONCLUSION: Combination of L-PRF and DBBM increased and accelerated new bone formation allowing early implant placement probably due to the higher protein expression of RUNX2, VEGF, OCN, and OPN. These data suggest that the use of L-PRF might be an interesting alternative to use in combination with DBBM for augment the maxillary sinuses allowing the installation of appropriate length implants in shorter period of time. CLINICAL RELEVANCE: This study showed improvement in bone neoformation and accelerated healing when associating L-PRF and DBBM for maxillary sinus augmentation procedures. TRIAL REGISTRATION: This study was registered before participant recruitment in Brazilian Registry of Clinical Trials (ReBEC - RBR-95m73t).

Use of polyvinyl siloxane impressions to monitor sub-5-µm erosive tooth wear on unpolished enamel.

STATEMENT OF PROBLEM: Whether polyvinyl siloxane impressions are capable of reproducing 5-µm changes on natural freeform enamel and potentially enabling clinical measurements of early surface changes consistent with wear of teeth or materials is unclear. PURPOSE: The purpose of this in vitro study was to investigate and compare polyvinyl siloxane replicas with direct measurements of sub-5-µm lesions on unpolished human enamel lesions by using profilometry, superimposition, and a surface subtraction software program. MATERIAL AND METHODS: Twenty ethically approved unpolished human enamel specimens were randomized to a previously reported cyclic erosion (n=10) and erosion and abrasion (n=10) model to create discrete sub-5-µm lesions on the surface. Low viscosity polyvinyl siloxane impressions were made of each specimen before and after each cycle and scanned by using noncontacting laser profilometry and viewed with a digital microscopy and compared with direct scanning of the enamel surface. The digital maps were then interrogated with surface- registration and subtraction workflows to extrapolate enamel loss from the unpolished surfaces by using step-height and digital surface microscopy to measure roughness. RESULTS: Direct measurement revealed chemical loss of enamel at 3.4 ±0.43 µm, and the polyvinyl siloxane replicas were 3.20 ±0.42 µm, respectively. For chemical and mechanical loss direct measurement was 6.12 ±1.05 µm and 5.79 ±1.06 µm for the polyvinyl siloxane replica (P=.211). The overall accuracy between direct and polyvinyl siloxane replica measurements was 0.13 +0.57 and -0.31 µm for erosion and 0.12 +0.99 and -0.75 µm for erosion and abrasion. Surface roughness and visualization with digital microscopy provided confirmatory data. CONCLUSIONS: Polyvinyl siloxane replica impressions from unpolished human enamel were accurate and precise at the sub-5-µm level.

Scaffolding competence-based learning design in the dental simulation curriculum.

INTRODUCTION: Learning in a clinical domain in dentistry is complex and learners may face uncertain clinical scenarios. A simulation curriculum can be designed to have simple clinical scenarios and learning activities which progress in complexity and employ competence assessments of simulated clinical practice before students can undertake authentic practice on patients. This paper presents how scaffolding of competence can be used for designing learning with simulators (haptics and phantom head) demonstrated in a specific domain in restorative dentistry. METHODS: A collaborative workshop as a research approach was undertaken to inform the iterative analysis, development, and discussion on scaffolding the learning design with respect to competence assessments of learning cavity preparation with simulation-based learning technologies. A workshop was conducted, which was collaborative and involved design negotiations between researchers, technologists, and teachers/practitioners in developing the simulation curriculum. RESULTS: A competence assessment with feedback in a specific domain in preparing interproximal caries was used as a context to describe how the learning activities and outcomes were designed to meet assessment of competence with varied levels of simple to complex learning activities and structured sessions. CONCLUSION: Simulation curriculum can be designed and implemented by scaffolding the level of competence that can be learned using simulation between haptics and phantom-head. This brings impetus to the need in meeting the relevant competence criteria in context to a specific affordance of the simulation-based learning technologies to provide optimal patient-centred holistic care.

Present status and future directions: The restoration of root filled teeth.

This narrative review will focus on a number of contemporary considerations relating to the restoration of root filled teeth and future directions for research. Clinicians are now more than ever, aware of the interdependence of the endodontic and restorative aspects of managing root filled teeth, and how these aspects of treatment are fundamental to obtaining the best long-term survival. To obtain the optimal outcomes for patients, clinicians carrying out endodontic treatment should have a vested interest in the restorative phase of the treatment process, as well as an appreciation for the structural and biomechanical effects of endodontic-restorative procedures on restoration and tooth longevity. Furthermore, the currently available research, largely lacks appreciation of occlusal factors in the longevity of root filled teeth, despite surrogate outcomes demonstrating the considerable influence this variable has. Controversies regarding the clinical relevance of minimally invasive endodontic and restorative concepts are largely unanswered with respect to clinical data, and it is therefore, all too easy to dismiss these ideas due to the lack of scientific evidence. However, conceptually, minimally invasive endodontic-restorative philosophies appear to be valid, and therefore, in the pursuit of improved clinical outcomes, it is important that the efficacies of these treatment protocols are determined. Alongside an increased awareness of the preservation of tooth structure, developments in adhesive bonding, ceramic materials and the inevitable integration of digital dentistry, there is also a need to evaluate the efficacy of new treatment philosophies and techniques with well-designed prospective clinical studies.

Quantitative Swept-Source Optical Coherence Tomography of Early Enamel Erosion in vivo.

Swept-source optical coherence tomography (SS-OCT) shows potential for the in vivo quantitative evaluation of micro-structural enamel surface phenomena occurring during early erosive demineralization. This randomized controlled single-blind cross-over clinical study aimed to evaluate the use of SS-OCT for detecting optical changes in the enamel of 30 healthy volunteers subjected to orange juice rinsing (erosive challenge) in comparison to mineral water rinsing (control), according to wiped and non-wiped enamel surface states. Participants were randomly allocated to 60 min of orange juice rinsing (pH 3.8) followed by 60 min of water rinsing (pH 6.7) and vice versa, with a 2-week wash-out period. In addition, the labial surfaces of the right or left maxillary incisors were wiped prior to SS-OCT imaging. An automated ImageJ algorithm was designed to analyse the back-scattered OCT signal intensity (D) after orange juice rinsing compared to after water rinsing. D was quantified as the OCT signal scattering from the 33 µm sub-surface enamel, normalised by the total OCT signal intensity entering the enamel. The back-scattered OCT signal intensity increased by 3.1% (95% CI 1.1-5.1%) in the wiped incisors and by 3.5% (95% CI 1.5-5.5%) in the unwiped incisors (p < 0.0001). Wiping reduced the back-scattered OCT signal intensity by 1.7% (95% CI -3.2 to -0.3%; p = 0.02) in comparison to the unwiped enamel surfaces for both rinsing solutions (p = 0.2). SS-OCT detected OCT signal changes in the superficial sub-surface enamel of maxillary central incisor teeth of healthy volunteers after orange juice rinsing.

Assessment of residual coronal tooth structure postendodontic cavity preparation using digital dental impressions and micro-computed tomography.

OBJECTIVES: To evaluate the in vitro accuracy of digital impressions for three-dimensional (3D) volumetric measurement of residual coronal tooth structure postendodontic cavity preparation, with reference to micro-computed tomography (µCT). METHODS: Quantification of the accuracy and precision of the intraoral digital scanner (3M True Definition Scanner - IOS) was performed using a metrology gauge block and a profilometric calibration model. Thirty-four human extracted molars with endodontic access cavities were scanned using both intraoral scanning (test scanner) in high-resolution mode, and µCT (reference scanner: GE Locus SP µCT scanner) in high- (HiResCT) and low- (LoResCT) resolution modes. Comparisons of volumetric accuracy and 3D profilometric deviations were performed using surface metrology software. One-way repeated measures analysis of variance (ANOVA), in combination with the Bonferroni post hoc test, was implemented to compare the differences in volume measurements between scanning methods. RESULTS: Digital scanning revealed smaller volume measurements by 1.36% and 0.68% compared to HiResCT and LoResCT, respectively. There was a statistically significant difference in the volumetric measurements obtained from the IOS scanner and both HiResCT and LoResCT scans (P < 0.001). Analysis of the mean 3D profilometric deviations revealed that the IOS displayed greater surface deviation (± 27/33 µm) vs HiResCT and LoResCT (± 16/32 µm). CONCLUSIONS: Although volumetric measurements of endodontically accessed teeth were up to 1.36% smaller in comparison to µCT, the digital scanner was able to reliably measure the extra- and intracoronal aspect of the endodontically accessed tooth.

British Society of Prosthodontics Debate on the Implications of the Minamata Convention on Mercury to Dental Amalgam--Should our Patients be Worried?.

In 2013, the Minamata Convention on Mercury called for a global phase-down of amalgam use, with a view to reduce environmental mercury pollution. This will significantly impact UK dentistry, given the still extensive use of amalgam in U.K. general dental practice. However, until now there has been little national discussion or debate. In Spring 2015, The British Society of Prosthodontics dedicated a significant part of its Annual Conference to debating the implications of this issue. Clinical case examples were discussed with audience interaction and voting facilitated using innovative Audience Response System Technology. A remarkable range of concerns and opinions were given. The debate elicited specific concerns amongst clinicians regarding the suitability of mercury-free alternatives to amalgam; particularly where cavities are large and extend beneath the gingival anatomy. There are also anecdotal reports of Dental Foundation (DF) dentists not being adequately taught the use of dental amalgam in undergraduate dental schools. CPD/CLINICAL RELEVANCE: Many clinicians, especially those treating patients for whom moisture control is challenging, feel that amalgam should remain available for clinicians to choose in certain clinical circumstances for the restoration of posterior teeth, even in the event of a complete phase-down.

Discovery and evaluation of a novel monocyclic series of CXCR2 antagonists.

Antagonism of the chemokine receptor CXCR2 has been proposed as a strategy for the treatment of inflammatory diseases such as arthritis, chronic obstructive pulmonary disease and asthma. Earlier series of bicyclic CXCR2 antagonists discovered at AstraZeneca were shown to have low solubility and poor oral bioavailability. In this Letter we describe the design, synthesis and characterisation of a new series of monocyclic CXCR2 antagonists with improved solubility and good pharmacokinetic profiles.

CAD/CAM leucite-reinforced glass-ceramic for simulation of attrition in human enamel in vitro.

OBJECTIVE: Investigate attrition simulation using CAD/CAM leucite-reinforced glass-ceramic antagonists on occlusal vs. buccal enamel. METHODS: Three dental materials with known wear rates (resin-modified glass-ionomer, micro-filled, and fine particle composites) validated the wear simulator (CAD/CAM glass-ceramic antagonists, 200 cycles, 80 N load, deionised water irrigation, 0.7 mm sliding movement). Following this, human molars were sectioned into paired occlusal and buccal polished samples (n = 8/gp). Exposed 1.5 mm Ø enamel areas were subjected to attritional wear with and without pre-immersion in citric acid (5 min, 0.3%, pH 3.8). Profilometry measured step-height enamel wear and surface microhardness at different depths was calculated using Vickers indentation at 0.1 N and 0.5 N loads. RESULTS: Dental material wear using the CAD/CAM antagonists showed consistency with previous data: mean (SD) resin-modified glass ionomer material loss of 177.77 (16.89) µm vs. 22.15 (1.30) µm fine particle hybrid composite resin wear vs. 13.63 (1.02) µm micro filled composite resin wear (P < 0.001). The coefficient of variation was less than 10%. Following validation, enamel sample wear was significantly increased when attrition was introduced (P < 0.001) independent of buccal vs. occlusal sample location (P < 0.05). Attrition resulted in occlusal wear of 26.1 ± 4.5 µm vs. buccal 26.3 ± 1.2 µm and attrition/erosion resulted in occlusal wear of 26.05 ± 4.46 µm vs. buccal 25.27 ± 1.16 µm. Whereas erosion-alone resulted in occlusal wear of 1.65 ± 0.13 µm and buccal 1.75 ± 0.03 µm. Microhardness testing at different loads revealed significantly greater hardness reductions in occlusal enamel vs. buccal enamel for 0.1 KgF indentations (P < 0.001) whereas in contrast 0.5 KgF indentations showed no differences. SIGNIFICANCE: Wear simulation with CAD/CAM glass ceramic antagonists produced consistent wear in dental materials and human enamel, regardless of enamel surface origin. Lighter (0.1 KgF) hardness testing of occlusal vs. buccal origin revealed damage to the mechanical integrity of the superficial worn enamel.

Quantifying error introduced by iterative closest point image registration.

OBJECTIVES: The aim of this paper was to quantify the analysis error introduced by iterative closest point (ICP) image registration. We also investigated whether a subsequent subtraction process can reduce process error. METHODS: We tested metrology and two 3D inspection software using calibration standards at 0.39 µm, and 2.64 µm and mathematically perfect defects (softgauges) at 2 and 20 µm, on free form surfaces of increasing complexity and area, both with and without registration. Errors were calculated in percentage relative to the size of the defect being measured. Data were analysed in GraphPad Prism 9, normal and two-way ANOVA with post-hoc Tukey's was applied. Significance was inferred at p < 0.05. RESULTS: Using ICP registration introduced errors from 0 % to 15.63 % of the defect size depending on the surface complexity and size of the defect. Significant differences were observed in analysis measurements between metrology and 3D inspection software and within different 3D inspection software, however, one did not show clear superiority over another. Even in the absence of registration, defects at 0.39 µm, and 2.64 µm produced substantial measurement error (13.39-77.50 % of defect size) when using 3D inspection software. Adding an additional data subtraction process reduced registration error to negligible levels (<1 % independent of surface complexity or area). CONCLUSIONS: Commercial 3D inspection software introduces error during direct measurements below 3 µm. When using an ICP registration, errors over 15 % of the defect size can be introduced regardless of the accuracy of adjacent registration surfaces. Analysis output between software are not consistently repeatable or comparable and do not utilise ISO standards. Subtracting the datasets and analysing the residual difference reduced error to negligible levels. CLINICAL SIGNIFICANCE: This paper quantifies the significant errors and inconsistencies introduced during the registration process even when 3D datasets are true and precise. This may impact on research diagnostics and clinical performance. An additional data processing step of scan subtraction can reduce this error but increases computational complexity.

Pilot clinical study to evaluate the efficacy of a professionally delivered high fluoride varnish on erosive tooth wear in an in-situ model.

OBJECTIVES: The aim for this pilot study was to investigate the effect of a sodium fluoride varnish on step height measured by a profilometer from human enamel worn by healthy volunteers with a novel in situ/ex vivo erosion design. METHOD: Healthy volunteers aged 18-70 years wore a palatal splint containing 8 human enamel samples and underwent two 3-day treatment periods for 6 h a day with a varnish containing sodium fluoride at 22,600 ppm and the control with the same ingredients but without fluoride. Each splint contained 4 polished and 4 unpolished samples. The interventions were applied to the surface of the enamel samples in randomised order, removed after 6 h, then immersed ex-vivo in 1 %, pH 2.7 citric acid for 2 min, repeated 4 times a day, over 2 days. Measurements of enamel were assessed blindly by microhardness on day 2 and by non-contact laser profilometry on day 3 for the two treatments. RESULTS: 24 volunteers, 2 males and 22 females aged 27-54 years, were screened and recruited. The delta microhardness, from polished samples removed at the end of day 2, for the control and fluoride treatment was 95.7 (22.9) kgf/mm2 and 123.7 (28.9) kgf/mm2, respectively (p < .005). The mean (SD) step height for the control polished enamel surfaces was 3.67 (2.07) µm and for the fluoride varnish was 1.79 (1.01) µm (p < .0005). The control unpolished enamel surfaces had a mean 2.09 (1.53) µm and the fluoride varnish was 2.11 (1.53) µm but no statistical difference was detected. CONCLUSIONS: The results from this pilot study, utilizing an in-situ model where enamel was exposed to acid over the course of 2 days, demonstrated that a high fluoride varnish containing sodium fluoride at 22,600 ppm prevented erosive wear compared to a control on the polished enamel surfaces. CLINICAL SIGNIFICANCE: Intra-oral study demonstrated that a high fluoride varnish containing sodium fluoride at 22,600 ppm reduced erosive tooth wear.

Copanlisib population pharmacokinetics from phase I-III studies and exposure-response relationships in combination with rituximab.

Copanlisib dose selection was established under the maximum tolerated dose paradigm, and no dedicated dose-finding studies have investigated copanlisib dose selection when used in combination with rituximab. In CHRONOS-3, copanlisib plus rituximab demonstrated significantly improved progression-free survival versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (iNHL). We conducted a comprehensive investigation of copanlisib population pharmacokinetics (PopPK) from a pooled analysis of 712 patients across nine copanlisib phase I-III studies and exposure-response (ER) relationships for efficacy and safety from the 1-year follow-up of CHRONOS-3. PopPK analyses examined the impact of demographic, laboratory, and comedication covariates on copanlisib between-patient PK variability. Individual static and time-varying exposure estimates were derived to investigate exposure-efficacy and exposure-safety relationships. Multivariate Cox proportional hazards and logistic regression analyses examined ER relationships with consideration of predefined potentially prognostic demographic-, laboratory-, and/or disease-related baseline covariates. Copanlisib PK were best described by a three-compartment model with first-order elimination. Individual identified covariates had modest effects on copanlisib PK and were generally in line with known copanlisib disposition properties. In CHRONOS-3, ER analyses showed a significant relationship between time-varying exposure estimates and progression-free survival, and no significant exposure-safety relationships. Thus, lower copanlisib doses may result in reduced efficacy but not necessarily improved safety or tolerability. These outcomes substantiate the current intermittent dosing regimen of copanlisib 60 mg on days 1, 8, and 15 of a 28-day cycle and support the observed clinical results of copanlisib in combination with rituximab in the iNHL population.

Contemporary management of tooth replacement in the traumatized dentition.

Dental trauma can result in tooth loss despite best efforts at retaining and maintaining compromised teeth (Dent Traumatol, 24, 2008, 379). Upper anterior teeth are more likely to suffer from trauma, and their loss can result in significant aesthetic and functional problems that can be difficult to manage (Endod Dent Traumatol, 9, 1993, 61; Int Dent J 59, 2009, 127). Indeed, teeth of poor prognosis may not only present with compromised structure but trauma may also result in damage to the support tissues. Injury to the periodontium and alveolus can have repercussions on subsequent restorative procedures (Fig. 19). Where teeth are identified as having a hopeless prognosis either soon after the incident or at delayed presentation; planning for eventual tooth loss and replacement can begin at the early stages. With advances in both adhesive and osseointegration technologies, there are now a variety of options for the restoration of edentate spaces subsequent to dental trauma. This review aims to identify key challenges in the provision of tooth replacement in the traumatized dentition and outline contemporary methods in treatment delivery.

The threshold of an intra oral scanner to measure lesion depth on natural unpolished teeth.

OBJECTIVES: To investigate the threshold and accuracy of intraoral scanning in measuring freeform human enamel surfaces. METHODS: Software softgauges, ranging between 20 and 160 µm depth, were used to compare four workflow analysis techniques to measure step height on a freeform surface; with or without reference areas and in combination with surface-subtraction to establish which combination produced the most accurate outcome. Having established the optimum combination, 1.5 mm diameter, individual depths ranging from 11 to 81 µm were created separately on 14 unpolished human enamel samples and then scanned with gold standard laboratory optical profilometry (NCLP, TaiCaan Technologies™, XYRIS2000CL, UK) and a clinical intraoral scanner (TrueDefinition™, Midmark Corp., USA). The sequence of surface registration and subtraction determined from the softgauges was used to measure step height on natural human enamel surfaces. Step heights (µm) were compared using two-way ANOVA with post-hoc Bonferroni (p < 0.05) and Bland-Altman analyses. RESULTS: Software differences were significantly reduced from - 29.7 to - 32.5% without, to - 2.4 to - 3.6% with reference areas (p < 0.0001) and the addition of surface-subtraction after registration reduced this further to 0.0 to - 0.3% (p < 0.0001). The intraoral scanner had a depth discrimination threshold of 73 µm on unpolished natural enamel and significant differences (p < 0.05) were observed compared to NCLP below this level. SIGNIFICANCE: The workflow of combining surface-registration and subtraction of surface profiles taken from intraoral scans of freeform unpolished enamel enabled confident measurement of step height above 73 µm. The limits of the scanner is related to data capture and these results provide opportunities for clinical measurement.

Inflammation and cardiovascular status impact midazolam pharmacokinetics in critically ill children: An observational, prospective, controlled study.

Altered physiology caused by critical illness may change midazolam pharmacokinetics and thereby result in adverse reactions and outcomes in this vulnerable patient population. This study set out to determine which critical illness-related factors impact midazolam pharmacokinetics in children using population modeling. This was an observational, prospective, controlled study of children receiving IV midazolam as part of routine care. Children recruited into the study were either critically-ill receiving continuous infusions of midazolam or otherwise well, admitted for elective day-case surgery (control) who received a single IV bolus dose of midazolam. The primary outcome was to determine the population pharmacokinetics and identify covariates that influence midazolam disposition during critical illness. Thirty-five patients were recruited into the critically ill arm of the study, and 54 children into the control arm. Blood samples for assessing midazolam and 1-OH-midazolam concentrations were collected opportunistically (critically ill arm) and in pre-set time windows (control arm). Pharmacokinetic modeling demonstrated a significant change in midazolam clearance with acute inflammation (measured using C-Reactive Protein), cardio-vascular status, and weight. Simulations predict that elevated C-Reactive Protein and compromised cardiovascular function in critically ill children result in midazolam concentrations up to 10-fold higher than in healthy children. The extremely high concentrations of midazolam observed in some critically-ill children indicate that the current therapeutic dosing regimen for midazolam can lead to over-dosing. Clinicians should be aware of this risk and intensify monitoring for oversedation in such patients.

Oral disease prevention for older people.

This opinion paper reviews trends in oral disease and its management in older people, in response to a challenge, in an editorial in The Lancet, to the traditional curative model of dentistry and the publication of the most recent Adult Dental Health Survey. It highlights the challenge of an ageing population and its oral health needs and management. Professional issues in relation to preventive care are discussed with emphasis on the importance of identifying patient risk and providing preventive care, together with improving the uptake of dental care among older people.

The measurement threshold and limitations of an intra-oral scanner on polished human enamel.

OBJECTIVE: To investigate the measurement threshold of an intra-oral scanner (IOS) on polished human enamel. METHODS: The optical performance of an IOS was compared to a gold-standard non contacting laser profilometer (NCLP), on a painted microscope slide, compared to increasing particle size of silicon-carbide papers (21.8-269.0 µm) and separately on polished human enamel with increasing step-heights. The enamel samples were randomised (n = 80) and scanned using the IOS and NCLP at increasing step-height depths (µm) (1.87-86.46 µm) and quantified according to ISO:5436-1. The measurement threshold of the IOS was determined using a custom designed automated lesion localisation algorithm, corroborated by Gaussian skewness (Ssk) and kurtosis (Sku) analysis, to assess the minimum step-height measured on each enamel sample. RESULTS: The NCLP showed statistically increased Sq surface roughness for all silicon carbide particle sizes compared to the microscope slide, whereas, the IOS Sq roughness discriminated silicon-carbide particles above 68.0 µm compared to the glass slide (p ≤ 0.02). On polished enamel, the automated minimum detectable step-height measurable on each sample was 44 µm. No statistically significantly different step-height enamel lesion measurements were observed between NCLP and IOS above this threshold (p > 0.05). SIGNIFICANCE: This study revealed the fundamental optical metrological parameters for the IOS, was step-heights above 44 µm and this reflects the data acquisition of the system. These results highlight the limitations of IOS used in this study, mandating further research to optimise the performance of other IOS systems, for measuring wear of materials or tooth wear on human unpolished natural enamel surfaces.

Calcium phosphate nanoparticles for potential application as enamel remineralising agent tested on hydroxyapatite discs.

Calcium phosphate exhibits excellent biocompatibility, and with particle size in the nanoscale, calcium phosphate nanoparticles (CPNPs) were explored to replace the hydroxyapatite lost in the nanoporous teeth due to dental erosion. CPNPs (2% w/v) colloidally stabilised by sodium citrate were synthesised via co-precipitation. They were characterised in terms of particle size, morphology, crystallinity, Ca/P ratio and calcium ion release. To ensure uniformity of the substrate, hydroxyapatite (HA) discs were examined as an alternative substrate model to enamel. They were eroded in acetate buffer (0.5 M; pH 4.0) at various timepoints (1, 5, 10, 30 min, and 2, 4 h), and their physical differences compared to enamel were assessed in terms of surface microhardness, surface roughness and step height. The remineralisation properties of the synthesised CPNPs on eroded HA discs at different pH levels were investigated. It was established that CPNPs were heterogeneously deposited on the HA discs at pH 9.2, whereas newly precipitated minerals from CPNPs were potentially formed at pH 6.2.

Population Pharmacokinetics and Pharmacodynamics of Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Vericiguat, a stimulator of soluble guanylate cyclase, has been developed as a first-in-class therapy for worsening chronic heart failure in adults with left ventricular ejection fraction < 45%. OBJECTIVE: The objective of this article was to characterize the pharmacokinetics and pharmacokinetic variability of vericiguat combined with guideline-directed medical therapy (standard of care), and identify exposure-response relationships for safety (hemodynamics) and pharmacodynamic markers of efficacy (N-terminal pro-B-type natriuretic peptide concentration [NT-proBNP]) in patients with heart failure and left ventricular ejection fraction < 45% in the SOCRATES-REDUCED study (NCT01951625). METHODS: Vericiguat and NT-proBNP plasma concentrations in 454 and 432 patients in SOCRATES-REDUCED, respectively, were analyzed using nonlinear mixed-effects modeling. RESULTS: Vericiguat pharmacokinetics were well described by a one-compartment model with apparent clearance, apparent volume of distribution, and absorption rate constant. Age, bodyweight, plasma bilirubin, and creatinine clearance were identified as significant covariates on apparent clearance; sex and bodyweight on apparent volume of distribution; and bodyweight and plasma albumin level on absorption rate constant. Pharmacokinetic/pharmacodynamic analysis showed initial minor and transient effects of vericiguat on blood pressure with low clinical impact. There were no changes in heart rate following initial or repeated vericiguat administration. An exposure-dependent and time-dependent turnover pharmacokinetic/pharmacodynamic model for NT-proBNP described production and elimination rates and an demonstrated exposure-dependent reduction in [NT-proBNP] by vericiguat plus standard of care compared with placebo plus standard of care. This effect was dependent on baseline [NT-proBNP]. CONCLUSIONS: Vericiguat has predictable pharmacokinetics, with no long-term effects on blood pressure in patients with heart failure and left ventricular ejection fraction < 45%. A pharmacokinetic/pharmacodynamic model described a vericiguat exposure-dependent reduction of NT-proBNP. CLINICAL TRIAL IDENTIFIER: NCT01951625.