Behaviour support in dentistry: A Delphi study to agree terminology in behaviour management.

OBJECTIVES: Dental behaviour support (DBS) describes all specific techniques practiced to support patients in their experience of professional oral healthcare. DBS is roughly synonymous with behaviour management, which is an outdated concept. There is no agreed terminology to specify the techniques used to support patients who receive dental care. This lack of specificity may lead to imprecision in describing, understanding, teaching, evaluating and implementing behaviour support techniques in dentistry. Therefore, this e-Delphi study aimed to develop a list of agreed labels and descriptions of DBS techniques used in dentistry and sort them according to underlying principles of behaviour. METHODS: Following a registered protocol, a modified e-Delphi study was applied over two rounds with a final consensus meeting. The threshold of consensus was set a priori at 75%. Agreed techniques were then categorized by four coders, according to behavioural learning theory, to sort techniques according to their mechanism of action. RESULTS: The panel (n = 35) agreed on 42 DBS techniques from a total of 63 candidate labels and descriptions. Complete agreement was achieved regarding all labels and descriptions, while agreement was not achieved regarding distinctiveness for 17 techniques. In exploring underlying principles of learning, it became clear that multiple and differing principles may apply depending on the specific context and procedure in which the technique may be applied. DISCUSSION: Experts agreed on what each DBS technique is, what label to use, and their description, but were less likely to agree on what distinguishes one technique from another. All techniques were describable but not comprehensively categorizable according to principles of learning. While objective consistency was not attained, greater clarity and consistency now exists. The resulting list of agreed terminology marks a significant foundation for future efforts towards understanding DBS techniques in research, education and clinical care.

Using Virtual Technology for Fear of Medical Procedures: A Systematic Review of the Effectiveness of Virtual Reality-Based Interventions.

BACKGROUND: Innovations in virtual reality (VR) technologies have improved the adaptability of its use in therapeutic settings, and VR has shown to be a promising treatment for fear of medical procedures, with research increasing in this area in recent years. PURPOSE: This review aims to collate evidence for the impact of VR on fear of medical procedures. METHODS: CENTRAL (Cochrane), MEDLINE, EMBASE, and PsychINFO databases were searched up to October 2020. A mix of experimental and case-control studies were included for review, which evaluated the effectiveness of VR for fear, anxiety, and pain of medical procedures for people with needle phobia, dental phobia, claustrophobia of medical scans, and burn wound care anxiety. Risk of bias (RoB) was assessed by Cochrane and ROBINS-I tools. RESULTS: Twenty-eight studies were selected. Some studies included mixed participant groups of young people adults. The interventions varied, with VR used for distraction, hypnosis, or exposure. These were shown to be effective for reducing fear of medical procedures. However, effectiveness for blood-injection-injury phobias and burn wound care patients was unclear. CONCLUSIONS: Evidence on the effectiveness of VR suggests that it does decrease fear of medical procedures in some situations. However, the RoB assessment illustrated a poor quality of studies across those included in this review, limiting the ability to draw firm general conclusions from the study findings. There is a need for further research exploring the use of VR technologies in the management of anxiety in physical health care settings.

An Overview of Dental Anxiety and the Non-Pharmacological Management of Dental Anxiety.

In this article we will seek to provide an overview of dental anxiety and fear, including its most extreme manifestation, dental phobia. We will explore the prevalence of different levels of dental anxiety and outline some broad principles for the management of dental anxiety based on an approach which suggests that management should be proportionate to the level of anxiety.

Evaluation of dynamic contrast-enhanced MRI biomarkers for stratified cancer medicine: How do permeability and perfusion vary between human tumours?

BACKGROUND: Solid tumours exhibit enhanced vessel permeability and fenestrated endothelium to varying degree, but it is unknown how this varies in patients between and within tumour types. Dynamic contrast-enhanced (DCE) MRI provides a measure of perfusion and permeability, the transfer constant Ktrans, which could be employed for such comparisons in patients. AIM: To test the hypothesis that different tumour types exhibit systematically different Ktrans. MATERIALS AND METHODS: DCE-MRI data were retrieved from 342 solid tumours in 230 patients. These data were from 18 previous studies, each of which had had a different analysis protocol. All data were reanalysed using a standardised workflow using an extended Tofts model. A model of the posterior density of median Ktrans was built assuming a log-normal distribution and fitting a simple Bayesian hierarchical model. RESULTS: 12 histological tumour types were included. In glioma, median Ktrans was 0.016min-1 and for non-glioma tumours, median Ktrans ranged from 0.10 (cervical) to 0.21min-1 (prostate metastatic to bone). The geometric mean (95% CI) across all the non-glioma tumours was 0.15 (0.05, 0.45)min-1. There was insufficient separation between the posterior densities to be able to predict the Ktrans value of a tumour given the tumour type, except that the median Ktrans for gliomas was below 0.05min-1 with 80% probability, and median Ktrans measurements for the remaining tumour types were between 0.05 and 0.4min-1 with 80% probability. CONCLUSION: With the exception of glioma, our hypothesis that different tumour types exhibit different Ktrans was not supported. Studies in which tumour permeability is believed to affect outcome should not simply seek tumour types thought to exhibit high permeability. Instead, Ktrans is an idiopathic parameter, and, where permeability is important, Ktrans should be measured in each tumour to personalise that treatment.

Tumour regression and improved gastrointestinal tolerability from controlled release of SN-38 from novel polyoxazoline-modified dendrimers.

Irinotecan is used clinically for the treatment of colorectal cancer; however, its utility is limited by its narrow therapeutic index. We describe the use of a generation 5 l-lysine dendrimer that has been part-modified with a polyoxazoline as a drug delivery vehicle for improving the therapeutic index of SN-38, the active metabolite of irinotecan. By conjugating SN-38 to the dendrimer via different linker technologies we sought to vary the release rate of the drug to generate diverse pharmacokinetic profiles. Three conjugates with plasma release half-lives of 2.5h, 21h, and 72h were tested for efficacy and toxicity using a mouse SW620 xenograft model. In this model, the linker with a plasma release half-life of 21h achieved sustained SN-38 exposure in blood, above the target concentration. Control over the release rate of the drug from the linker, combined with prolonged circulation of the dendrimer, enabled administration of an efficacious dose of SN-38, achieving significant regression of the SW620 tumours. The conjugates with 2.5 and 72h release half-lives did not achieve an anti-tumour effect. Intraperitoneal dosing of the clinically used prodrug irinotecan produces high initial and local concentrations of SN-38, which are associated with gastrointestinal toxicity. Administration of the 21h release dendrimer conjugate did not produce a high initial Cmax of SN-38. Consequently, a marked reduction in gastrointestinal toxicity was observed relative to irinotecan treatment. Additional studies investigating the dose concentrations and dose scheduling showed that a weekly dosing schedule of 4mg SN-38/kg was the most efficacious regimen. After 4 doses at weekly intervals, the survival period of the mice extended beyond 70 days following the final dose. These extensive studies have allowed us to identify a linker, dose and dosing regimen for SN-38 conjugated to polyoxazoline-modified dendrimer that maximised efficacy and minimised adverse side effects.

Challenges and strategies in anti-cancer nanomedicine development: An industry perspective.

Successfully translating anti-cancer nanomedicines from pre-clinical proof of concept to demonstration of therapeutic value in the clinic is challenging. Having made significant advances with drug delivery technologies, we must learn from other areas of oncology drug development, where patient stratification and target-driven design have improved patient outcomes. We should evolve our nanomedicine development strategies to build the patient and disease into the line of sight from the outset. The success of small molecule targeted therapies has been significantly improved by employing a specific decision-making framework, such as AstraZeneca's 5R principle: right target/efficacy, right tissue/exposure, right safety, right patient, and right commercial potential. With appropriate investment and collaboration to generate a platform of evidence supporting the end clinical application, a similar framework can be established for enhancing nanomedicine translation and performance. Building informative data packages to answer these questions requires the following: (I) an improved understanding of the heterogeneity of clinical cancers and of the biological factors influencing the behaviour of nanomedicines in patient tumours; (II) a transition from formulation-driven research to disease-driven development; (III) the implementation of more relevant animal models and testing protocols; and (IV) the pre-selection of the patients most likely to respond to nanomedicine therapies. These challenges must be overcome to improve (the cost-effectiveness of) nanomedicine development and translation, and they are key to establishing superior therapies for patients.

Combining Sedation and Cognitive Behavioural Therapy (CBT) to Overcome Dental Phobia: a Case Report.

This case report presents a Cognitive Behavioural Therapy (CBT) intervention provided for a 63-year-old male, who had experienced dental phobia for over 50-years. This gentleman initially received intravenous sedation (IVS) for 5-years within a Specialist Sedation and Special Care dental department, before being referred for the long-term management of his dental phobia, within the embedded specialist Dental Health Psychology Service in a London Dental Hospital. This brief report will consider aspects of the CBT intervention delivered in relation to assessment, case conceptualisation, course of treatment and outcomes; reflecting on the complementary aspects of sedation and CBT. Learning points will be identified for the role of CBT or CBT-based techniques within dental anxiety management settings.

Exploring patients' attitudes to different intervention approaches for supporting psychosocial needs.

BACKGROUND: Many patients with end-stage kidney disease (ESKD) have significant psychosocial needs as a consequence of their illness and treatment. Unmet needs can impact negatively on their health and well-being. Patients want improved psychosocial support particularly in relation to coping and adjustment. Little is known about the relevance and applicability to patients of intervention approaches to support their psychosocial needs. OBJECTIVES: To explore patients' attitudes to different intervention approaches that could be developed to help them cope with the psychosocial stressors of ESKD, and to assess the potential acceptability of these approaches. METHODS AND MATERIALS: Qualitative interviews and mini-focus groups were undertaken with 15 patients who have ESKD. Different intervention approaches were shown to participants through use of audio-visual films. Constant comparative data analysis was employed to derive a framework of categories and themes, guided by stress and coping theory. RESULTS: Psychosocial support was viewed by patients as an essential constituent of quality care. While some intervention approaches were more or less popular than others, responses were overall variable and individualistic, seemingly influenced by participants' personal coping strategies. Any perceived connection with depression could make an intervention approach less attractive; physical exercise was particularly acceptable because there was no explicit association with someone not coping. CONCLUSIONS: There is value in clinicians making available a choice of appropriately timed and tailored interventions to meet patients' different psychosocial support needs at key points of distress across the ESKD pathway. Congruence between intervention features and patient coping style could stimulate interest and take-up.

Improving clinical skills to support the emotional and psychological well-being of patients with end-stage renal disease: a qualitative evaluation of two interventions.

BACKGROUND: Many patients with end-stage renal disease (ESRD) need and want improved emotional and psychological support. Explicit attention to patients' emotional issues during consultations can help, yet renal consultants rarely address emotional problems. This qualitative study aimed to evaluate whether two different low-cost interventions could individually enable consultants to talk with patients about their emotional concerns during routine outpatient consultations. METHOD: One intervention involved patients using a Patient Issues Sheet to identify two to three issues they would like to talk about in their consultation and the second involved consultants asking patients a direct question about their emotional feelings. Consultants were trained to handle any emotional issues raised. Semi-structured interviews were conducted with five consultants and 36 ESRD patients from two UK renal units. Interviews were transcribed verbatim and analysed using the constant comparative method. RESULTS: Although consultants and patients tended to use the two interventions in different ways, they expressed generally positive views about how helpful the interventions were in promoting discussion of emotional issues. Consultants appreciated the training for facilitating empathetic handling of patients' emotional disclosures and containment of discussion. Most patients who raised emotional concerns were satisfied with their consultant's responses, while others were dissuaded from more explicit discussion by their consultant's concentration on physical considerations. CONCLUSIONS: These qualitative study findings suggest that both interventions are feasible and acceptable and have the potential to help consultants improve emotional and psychological patient care, providing cognitive and behavioural tools to enable discussion of emotional issues during routine outpatient consultations.

Oxygen-Driven Tumour Growth Model: A Pathology-Relevant Mathematical Approach.

Xenografts--as simplified animal models of cancer-differ substantially in vasculature and stromal architecture when compared to clinical tumours. This makes mathematical model-based predictions of clinical outcome challenging. Our objective is to further understand differences in tumour progression and physiology between animal models and the clinic. To achieve that, we propose a mathematical model based upon tumour pathophysiology, where oxygen--as a surrogate for endocrine delivery--is our main focus. The Oxygen-Driven Model (ODM), using oxygen diffusion equations, describes tumour growth, hypoxia and necrosis. The ODM describes two key physiological parameters. Apparent oxygen uptake rate (k'R) represents the amount of oxygen cells seem to need to proliferate. The more oxygen they appear to need, the more the oxygen transport. k'R gathers variability from the vasculature, stroma and tumour morphology. Proliferating rate (kp) deals with cell line specific factors to promote growth. The KH,KN describe the switch of hypoxia and necrosis. Retrospectively, using archived data, we looked at longitudinal tumour volume datasets for 38 xenografted cell lines and 5 patient-derived xenograft-like models. Exploration of the parameter space allows us to distinguish 2 groups of parameters. Group 1 of cell lines shows a spread in values of k'R and lower kp, indicating that tumours are poorly perfused and slow growing. Group 2 share the value of the oxygen uptake rate (k'R) and vary greatly in kp, which we interpret as having similar oxygen transport, but more tumour intrinsic variability in growth. However, the ODM has some limitations when tested in explant-like animal models, whose complex tumour-stromal morphology may not be captured in the current version of the model. Incorporation of stroma in the ODM will help explain these discrepancies. We have provided an example. The ODM is a very simple -and versatile- model suitable for the design of preclinical experiments, which can be modified and enhanced whilst maintaining confidence in its predictions.

Tumour stromal morphology impacts nanomedicine cytotoxicity in patient-derived xenografts.

It is challenging to evaluate how tumour pathophysiology influences nanomedicine therapeutic effect; however, this is a key question in drug delivery. An advanced analytical method was developed to quantify the spatial distribution of drug-induced effect in tumours with varied stromal morphologies. The analysis utilises standard immunohistochemistry images and quantifies the frequency of positive staining as a function of distance from the stroma. Two stromal morphologies - Estuary and Tumour Island - were classified in 28 tumours from a lung cancer explant model in mice treated with liposomal doxorubicin. Analysis demonstrated that Estuary-like tumours presented a highly convoluted tumour-stroma interface, with most tumour cells in close proximity to vessels; these tumours were 8.8-fold more responsive to liposomal doxorubicin than were Tumour Island-like tumours, which were nearly unresponsive to liposomal doxorubicin. SDARS analysis allows the relative treatment effect to be assessed in tumours individually, and enables investigation of nanomedicine delivery in complex tumour pathophysiologies. FROM THE CLINICAL EDITOR: Advances in nanotechnology have brought about many novel treatment modalities for cancer. Nonetheless, there is no standard evaluation technique for tumor cells' drug response. The authors here utilized patient-derived tumour xenograft (PDTX) models to have a more translatable pre-clinical evaluation platform for nanomedicine drugs. They then used advanced imaging acquisition technique to analyze tumor stromal morphology, which they named Spatial Distribution of Apoptosis Relative to Stroma (SDARS). The findings would have significant clinical impact as it would help predict the eventual clinical drug response.

A randomized controlled trial to evaluate the effectiveness of a cognitive behavioural group approach to improve patient adherence to peritoneal dialysis fluid restrictions: a pilot study.

BACKGROUND: Peritoneal dialysis (PD) requires patients to take an active role in their adherence to fluid restrictions. Although fluid non-adherence had been identified among this patient group, no specific interventions have been researched or published with in the PD population. The current study sought to investigate whether an applied cognitive behavioural therapy (CBT-based intervention) used among haemodialysis patients would improve fluid adherence among PD patients; utilizing clinical indicators used in practice. METHODS: Fifteen PD patients identified as fluid non-adherent were randomly assigned to an intervention group (IG) or a deferred-entry control group (CG). The study ran for a total of 21 weeks, with five data collection points; at baseline, post-intervention and at three follow-up points; providing a RCT phase and a combined longitudinal analysis phase. The content of the group intervention encompassed educational, cognitive and behavioural components, aimed to assist patients' self-management of fluid. RESULTS: No significant differences in weight (kg) reduction were found in either phase and undesirable changes in blood pressure (BP) were observed. However, in the longitudinal phase, a statistically significant difference in oedematous status was observed at 6-week follow-up; which may be indicative of fluid adherence. Positive and significant differences were observed in the desired direction for measures of psychological well-being, quality of life and health beliefs; areas correlated with enhanced fluid adherence in other research. CONCLUSIONS: This study reveals encouraging and significant changes in predictors of fluid adherence. Although there were no significant changes in weight as a crude clinical measure of fluid intake, significant reductions in oedematous status were observed as a consequence of this CBT-based group intervention.

Treatment of colorectal cancer using a combination of liposomal irinotecan (Irinophore C™) and 5-fluorouracil.

PURPOSE: To investigate the use of liposomal irinotecan (Irinophore C™) plus or minus 5-fluorouracil (5-FU) for the treatment of colorectal cancer. EXPERIMENTAL DESIGN: The effect of irinotecan (IRI) and/or 5-FU exposure times on cytotoxicity was assessed in vitro against HT-29 or LS174T human colon carcinoma cells. The pharmacokinetics and biodistribution of Irinophore C™ (IrC™) and 5-FU, administered alone or in combination, were compared in vivo. A subcutaneous model of HT-29 human colorectal cancer in Rag2-M mice was utilized to assess the efficacy of IrC™ alone, and in combination with 5-FU. RESULTS: The cytotoxicity of IRI and 5-FU were strongly dependent on exposure time. Synergistic interactions were observed following prolonged exposure to IRI/5-FU combinations. Pharmacokinetics/biodistribution studies demonstrated that the 5-FU elimination rate was decreased significantly when 5-FU was co-administered intravenously with IrC™, versus alone. Significant decreases in 5-FU elimination were also observed in plasma, with an associated increase of 5-FU in some tissues when 5-FU was given by intraperitoneal injection and IrC™ was given intravenously. The elimination of IrC™ was not significantly different when administered alone or in combination with 5-FU. Therapeutic studies demonstrated that single agent IrC™ was significantly more effective than the combination of IRI/5-FU; surprisingly, IrC™/5-FU combinations were no more effective than IrC™ alone. The administration of combinations of 5-FU (16 mg/kg) and IrC™ (60 mg IRI/kg) showed increased toxicity when compared to IrC™ alone. Treatment with IrC™ alone (60 mg IRI/kg) delayed the time required for a 5-fold increase in initial tumor volume to day 49, compared to day 23 for controls. When IrC™ (40 mg IRI/kg) was used in combination with 5-FU (16 mg/kg), the time to increase tumor volume 5-fold was 43 days, which was comparable to that achieved when using IrC™ alone (40 mg IRI/kg). CONCLUSIONS: Single agent IrC™ was well tolerated and has significant therapeutic potential. IrC™ may be a suitable replacement for IRI treatment, but its use with free 5-FU is complicated by IrC™-engendered changes in 5-FU pharmacokinetics/biodistribution which are associated with increased toxicity when using the combination.

Targeting combinations of liposomal drugs to both tumor vasculature cells and tumor cells for the treatment of HER2-positive breast cancer.

PURPOSE: We used two ligand-modified liposomal drugs to selectively deliver two different chemotherapeutics to tumor cells (TC) and tumor vasculature endothelial (TV) cells, and examined the therapeutic effect of altering the order of treatment administration, and the effect of the temporal spacing of the treatments on the accumulation of a second dose of liposomes and therapeutic activity. METHODS: Studies were completed in an orthotopic mouse model of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, utilizing liposomal doxorubicin, targeted to TC via αHER2 Fab' fragments, and liposomal vincristine, targeted to CD13 on TV cells via NGR peptides. RESULTS AND DISCUSSION: Combination treatment with TV-targeted plus TC-targeted therapies was therapeutically superior to either single agent; switching the order of administration of the combination did not alter treatment efficacy. The tumor accumulation of a second dose of liposomes was increased if administered at 4 days after pre-treatment with TV-targeted therapy. Using a treatment schedule exploiting this increase, the dose of simultaneously administered combination therapy was halved without compromising therapeutic effect. CONCLUSION: Proof-of-concept studies revealed the therapeutic potential of a dual-targeted two drug approach against HER2-positive breast cancer, and may be applicable to the treatment of other solid tumors.

Development of a liposomal nanoparticle formulation of 5-fluorouracil for parenteral administration: formulation design, pharmacokinetics and efficacy.

5-Fluorouracil (5-FU) is a small, very membrane permeable drug that is poorly retained within the aqueous compartment of liposomal nanoparticles (LNP). To address this problem a novel method relying on formation of a ternary complex comprising copper, low molecular weight polyethylenimine (PEI) and 5-FU has been developed. More specifically, in the presence of entrapped copper and PEI, externally added 5-FU can be efficiently encapsulated (>95%) in DSPC/Chol (1,2-Distearoyl-sn-Glycero-3-Phosphocholine/cholesterol; 55:45 mol%) liposomes (130-170 nm) to achieve drug-to-lipid ratios of 0.1 (mol:mol). Drug release studies completed using this LNP formulation of 5-FU demonstrated significant improvements in drug retention in vitro and in vivo. Plasma concentrations of 5-FU were 7- to 23-fold higher when the drug was administered intravenously to mice as the LNP 5-FU formulation compared to free 5-FU. Further, the therapeutic effects of the LNP 5-FU formulation, as determined in a HT-29 subcutaneous colorectal cancer model where treatment was given QDx5, was greater than that which could be achieved with free 5-FU when compared at equivalent doses. This is the first time an active loading method has been described for 5-FU. The use of ternary metal complexation strategy to encapsulate therapeutic agents may define a unique platform for preparation of LNP drug formulations.

Accurate predictions of crystal densities using quantum mechanical molecular volumes.

A quantum mechanically based procedure for estimation of crystal densities of neutral and ionic crystals is presented. In this method, volumes within 0.001 electrons/bohr3 isosurfaces of electron density for the constituent isolated neutral and ionic molecules are calculated to define the molecular volume or formula unit volumes used in predicting the crystal density. The B3LYP density functional theory in conjunction with the 6-31G** basis set were employed to generate the electron densities. The suitability of this method of crystal density prediction was assessed by subjecting a large number (289) of molecular and ionic crystals to the procedure and comparing results with experimental information. The results indicate that, for neutral molecular crystals, the root-mean-square (rms) deviation from experiment is within 4%, whereas the rms deviation is somewhat larger for the 71 ionic crystals evaluated (within 5%).

Pharmacokinetics and pharmacodynamics of lipidic nano-particles in cancer.

Nanoscale drug delivery systems (DDS) are used to circumvent some of the non-ideal properties of conventional anticancer chemotherapy drugs. Manipulation of the physical properties of DDS provides improved control over the pharmacokinetics (PK) and pharmacodynamics (PD) of the encapsulated drugs relative to free drugs. Liposomes are the archetypical nanoscale DDS and the first of these received clinical approval in 1990. DOXIL, liposomal doxorubicin, was the first commercially available liposomal anticancer drug (1995). It has an enhanced circulation half-life compared to the free drug because of its surface-grafted polyethylene glycol coating. DOXIL passively targets solid tumors, and once the liposomes localize in the tumor interstitial space, the cytotoxic drug is slowly released within the tumor. Liposomes can act as sustained release delivery system and manipulation of properties such as, liposome diameter, drug release rate, bioavailability and dosing schedule can significantly impact the therapeutic outcome of the liposomal drugs. This review will focus on how alteration of these properties can impact the therapeutic efficacy and side effect profiles of DDS.