Optimising Multi-stakeholder Practices in Patient Engagement: A Gap Analysis to Enable Focused Evolution of Patient Engagement in the Development and Lifecycle Management of Medicines.

BACKGROUND: The PARADIGM consortium aimed to make patient engagement in the development and lifecycle management of medicines easier and more effective for all, with the development of new tools that fulfil robustly defined gaps where engagement is suboptimal. AIMS: To generate an inventory of gaps in patient engagement practices and process from existing global examples. METHODS: A large set of criteria for effective patient engagement previously defined via a multi-stakeholder Delphi method, were mapped under fourteen overarching themes. A gap analysis was then performed by twenty-seven reviewers against the resulting forty-six mapped criteria, on a sample of seventy initiatives from global databases. RESULTS: An inventory of gaps was identified including contextual information as to why the gaps exist. Our work identified general patterns where patient engagement was suboptimal-defined as; fragmented reporting and dissemination of patient engagement activities, and the fundamental principles defined in frameworks or guidance being poorly adhered to in actual practice. Specific gaps were identified for sixteen criteria. Additionally, it was also common to observe primary aspects of a process were addressed for a given criteria (i.e. training for roles and responsibilities) but a secondary context element was lacking (i.e. making training material accessible/understandable/meaningful to all participants). CONCLUSION: The results show that the evolution towards meaningful and systematic patient engagement is occurring, yet more importantly they provide clear directional insights to help enhance collaborative practices and co-design solutions. This targeted impact to catalyse a needs-oriented health system that integrates patient engagement at its core is essential.

Successful private-public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines.

UNLABELLED: The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public-funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMA-Paediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres. CONCLUSION: Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private-public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of off-patent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes.

Management of neuronopathic Gaucher disease: revised recommendations.

The original guidelines drawn up for the management of the neuronopathic forms of Gaucher disease were felt to be in need of revision; in particular, the role of high-dose enzyme replacement therapy (120 IU/kg of body weight every 2 weeks) in stabilizing neurological disease. The existing published evidence was analysed; it was concluded that it did not support the role of high-dose ERT, although this might be required to treat severe visceral disease.

Outcome of type III Gaucher disease on enzyme replacement therapy: review of 55 cases.

The European Task Force for Neuronopathic Gaucher Disease (NGD) met in 2006 to review its 2001 guidelines. Fifty-five patients from five European countries were reviewed; 29 were male and 26 female. The majority of the patients were homozygous for the L444P mutation. All had been on enzyme replacement therapy (ERT). However, there was considerable variation in the dose of ERT, as well as an uneven distribution of risk factors. Thus, the oldest patients were on the lowest doses, and several had had a total splenectomy, while the youngest patients had a high proportion of compound heterozygosity and were on the highest doses, and very few had had a splenectomy. This heterogeneity rendered analysis very difficult. However, some observations were possible. The older patients appeared to remain relatively stable despite a low dose of ERT. In the younger patients, there was no clear effect of high-dose ERT. However, the period of follow-up was too short in many patients to draw valid conclusions. These data will be used to draw up revised guidelines.

A severity scoring tool to assess the neurological features of neuronopathic Gaucher disease.

Type III Gaucher disease is one of the three recognized subtypes of Gaucher disease, an inherited deficiency of lysosomal glucocerebrosidase. Phenotypically there is a wide spectrum of visceral and neurological manifestations. Enzyme replacement is effective in managing the visceral disease; however, the neurological manifestations remain a more challenging obstacle. There is an unfulfilled need to reliably monitor neurological disease and its response to treatment. A severity scoring tool was developed through neurological domain identification, item generation and tool formation. Domain identification was established based on a retrospective single centre study (n = 15) and a systematic review of publications. Forty-seven patients with neuronopathic Gaucher disease were then assessed using the tool to establish the clinical and statistical reliability of each domain. Judgement quantification of the tool was established through a process of content validity involving five European experts. Content validity is considered to be most effective when undertaken systematically. Concurrent validity and feasibility of the tool was also highlighted. This process allowed a revised and validated version of the tool to be developed.

Clinical evaluation of ferric oxalate in relieving dentine hypersensitivity.

Previous in vitro permeability and scanning electron microscopic (SEM) studies have demonstrated the effectiveness of the oxalate ion in dentine permeability reduction and effective tubule occlusion. The aim of this randomized double-blind, split mouth 4-week clinical study, therefore was to determine whether a 1-min application of ferric oxalate (Sensodyne Sealant) on exposed root dentine was effective in reducing dentine hypersensitivity (DH). Thirteen subjects [8F:5M, mean age 46.2 (s.d. 4.15) years] completed the study. The subjective response was evaluated by tactile, thermal and evaporative methods of assessment. Data were collected at baseline and post-application at +5 min and 4 weeks. Analysis was based on paired t-test (P=0.05) and Wilcoxon-Mann-Whitney tests. No statistically significant differences were noted between ferric oxalate and placebo preparations at +5 min and 4 weeks for any of the test stimuli. There was, however, a clear trend towards immediate reduction (+5 min) in DH reverting back to baseline values at 4 weeks with the exception of the Biomat Thermal Probe mean values, which maintained the reductions in DH compared with placebo. The results of the present study demonstrated that a 1-min application of ferric oxalate is both rapid and effective in reducing DH although its long-term effectiveness still needs to be determined.

The effects of reconditioning on the slot dimensions and static frictional resistance of stainless steel brackets.

This study investigated the effects of reconditioning on the slot dimensions and the static frictional resistance of stainless steel brackets at 0, 5, and 10 degrees bracket/archwire angulation. A sample of 45 used, commercially reconditioned 0.018 x 0.030 inch stainless steel standard edgewise brackets was compared with a matched sample of 45 new brackets. The slot dimensions of 15 new and 15 reconditioned brackets were examined using a photomicroscope. With new brackets both the occluso-gingival slot width (mean = 0.0197 inch) and slot depth (mean = 0.0304 inch) exceeded the manufacturer's nominal dimensions of 0.018 x 0.030 inch. The reconditioning process resulted in a further increase in slot width (mean = 0.0205 inch), which was statistically significant (P = 0.028), and a reduction in slot depth (mean = 0.0291 inch), which was highly statistically significant (P = 0.002). This may be attributable to preferential metal removal by the electro-polishing phase of the reconditioning process. Friction testing of 30 new and 30 reconditioned brackets demonstrated that both showed an increase in binding effects as the bracket/archwire angulation was increased from 0 to 5-10 degrees. However, the changes in slot dimensions secondary to reconditioning did not result in a statistically significant difference in mean static frictional resistance when the two bracket types were compared. Although the brackets were altered physically by the reconditioning process, their performance during simulated sliding mechanics was not adversely affected. This implies that reconditioning may not result in clinically significant effects.

The crystal growth technique--a laboratory evaluation of bond strengths.

An ex vivo study was carried out to determine differences in the bond strengths achieved with brackets placed using a crystal growth technique compared with a conventional acid-etch technique. A solution of 37 per cent phosphoric acid was used for acid-etching and a commercially available polyacrylic acid gel, Crystal-lok for crystal growth. A heavily-filled composite resin was used for all samples to bond brackets to healthy premolar teeth extracted for orthodontic purposes. Polycrystalline ceramic and stainless steel brackets were used and tested to both tensile and shear failure using an Instron Universal Testing machine. The tensile and shear bond strengths were recorded in kgF. In view of difficulties experienced with previous authors using different units to describe their findings, the data were subsequently converted to a range of units in order to facilitate direct comparison. The crystal growth technique produced significantly lower bond strengths than the acid-etch technique for ceramic and stainless steel brackets, both in tensile and shear mode. The tensile bond strength for stainless steel brackets with crystal growth was 2.2 kg compared with 6.01 kg for acid-etch, whilst with ceramic brackets the tensile bond strengths were 3.9 kg for crystal growth and 5.55 kg for acid-etch. The mean shear bond strength for stainless steel brackets with crystal growth was 12.61 kg compared with 21.55 kg for acid-etch, whilst with ceramic brackets the shear bond strengths were 7.93 kg with crystal growth compared with 16.55 kg for acid-tech. These bond strengths were below those previously suggested as clinically acceptable.

A comparison between the wear resistance of three types of denture resin to three different dentifrices.

This study compares the abrasive effects of three dentifrices on three different denture base resins, a heat cured acrylic resin, a self cured acrylic resin and a light activated urethane dimethacrylate-based resin. Specimens of the resins were subjected to a regimen of mechanical brushing using measured amounts of paste on standard toothbrushes driven by a reciprocating device. The apparent wear of each specimen was assessed qualitatively using scanning electron microscopy and quantitatively using profilometry and reflex microscopy. The study showed that cleaning pastes play a significant role in the wear of conventional acrylic resins, the relative abrasivity of the dentifrices being substrate related. However, wear was less evident on the light activated urethane dimethacrylate resin. Brushing with water alone produced no detectable wear on any of the specimens.

Adhesive composite resins for artificial teeth: a laboratory investigation of bond strength to a cobalt-chromium alloy.

Adhesive resin systems are reported to improve the bond strength between resins and cast cobalt-chromium alloy. This investigation compares the behaviour of three resin systems. Cylinders and beams of cobalt-chromium, with 0.6-mm-diameter retention beads regularly cast onto the bonding surfaces, were air-abraded and ultrasonically cleaned. Resin veneers 4 mm deep on the cylinders and 2 mm on the bars were polymerized by heat and pressure or by light. Specimens were water-stored for 7 or 90 days, including thermocycling between 4, 37 and 60 degrees C, before testing in a Universal Testing Machine to examine the shear bond strength or the effect of the bonded resin spine on the flexural strength of the beams using a three-point bend test. Specimens were examined with an optical microscope to attempt to determine the nature of the failures that occurred. The investigation showed that, overall, the heat- and pressure-cured urethane dimethacrylate resin with and adhesive based upon methacrylic acid performed significantly less well than a conventional acrylic resin, or a hybrid composite resin with and adhesive monomer.

The bactericidal effects of dental ultrasound on Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. An in vitro investigation.

This study investigated the possible bactericidal acoustic effects of the dental ultrasonic scaler. Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis suspensions, were subjected to the vibrations of a Cavitron P1 insert for 2.5 and 5.0 min in an acoustically-simulated pocket model and the survivors enumerated. The extent of any cavitation occurring within the pocket model to which the statistically significant bactericidal activity observed might be attributed, was determined by 'sonoluminescence', which was then investigated by photomultiplication techniques. However, these failed to detect any sonoluminescence within the pocket space and, moreover, the necessary deflection of the water coolant away from the insert tip, to avoid flooding of the experimental pocket, proved to result in temperatures of 47.6 degrees C and 52.3 degrees C at the respective time intervals, and thereby constituted an alternative possible bactericidal mechanism. Examination of the effects of such temperature changes on the target bacteria then revealed statistically significant differences in the viable counts of both microorganisms after 5.0-min periods, and as such were comparable to those previously detected in relation to the pocket model. Whilst it must be presumed that the bacteriolytic effect observed in the main investigation was due to the incidental temperature changes, in the absence of acoustic cavitation the influence of any associated acoustic microstreaming cannot be discounted. Further investigations to assess the bactericidal potential of acoustic phenomena using a modified experimental to exclude any hyperthermic effects are therefore necessary.

A comparison of self-ligating and conventional orthodontic bracket systems.

This ex-vivo study compared the static frictional resistance of three self-ligating brackets with a conventional steel-ligated Ultratrimm bracket. The effects of archwire size (0.020, 0.019 x 0.025 and 0.021 x 0.025-inch), bracket/archwire angulation (0, 5 and 10 degrees) and the presence of unstimulated human saliva were investigated. The study demonstrated that both increases in wire size and bracket/archwire angulation resulted in increased static frictional resistance for all bracket types tested, with the presence of saliva having an inconsistent effect. Mobil-Lock Variable-Slot had the least friction for all wires for 0 degree angulation. However, with the introduction of angulation, the values were comparable to those of the other brackets. Activa brackets had the second lowest frictional resistance, although high values were found with 0.019 x 0.025-inch wires. SPEED brackets demonstrated low forces with round wires, although with rectangular wires or in the presence of angulation, friction was greatly increased. Ultratrimm brackets produced large individual variation, confirming the difficulty in standardizing ligation force, although under certain conditions, significantly larger frictional forces were observed. In conclusion, self-ligating brackets showed reduced frictional resistance in comparison to steel ligated brackets only under certain conditions.

Method for enhancing the fluoride release of a glass-ionomer cement.

The cariostatic action of the glass-ionomer cement has been attributed to its sustained release of fluoride. The fluoride in the set cement originates from the glass particles which are eroded, in part, during the setting reaction. In this study a water-activated glass-ionomer was mixed with sodium fluoride (NaF) solutions of different concentrations (0%, 2% and 4%). The different cements were used to prepare discs which were stored individually in demineralized water at 37 degrees C, the fluoride concentration of the storage solutions were measured, at intervals, until the specimens were 80 days old. The effect of the different mixing solutions on the working and setting times and compressive strength were also determined. It was found that the cement mixed with the 4% solution of NaF released significantly more fluoride than the water mixed control. The fluoride solution mixed materials had longer setting times than the control, but there was no significant difference in the compressive strengths. All the materials became progressively stronger on storage. Mixing the cement with a 4% solution of NaF increased the initial fluoride release of the glass-ionomer without seriously affecting other physical properties.

The effects of cross-infection control procedures on the tensile and flexural properties of superelastic nickel-titanium wires.

The development of superelastic nickel-titanium archwires has simplified the alignment phase of orthodontic treatment by permitting the use of highly flexible, resilient archwires and avoiding the need for complex loops. The majority of these archwires appear undistorted when removed from the mouth after use. This feature, coupled with the disadvantage of relatively high cost has led to sterilization and recycling of these wires by some clinicians. This study was designed to examine the effects of currently used infection control procedures on the mechanical properties of superelastic nickel-titanium alloy (SENTA) archwires. One-hundred-and-forty lengths of a SENTA wire were subjected to various sterilization and disinfection procedures. These included cold disinfection in 2 per cent glutaraldehyde solution for 3- and 24-hour cycles, and steam autoclaving. Single and double cycles were used. The properties investigated were the 0.1 per cent yield strength, the ultimate tensile strength, and the flexural rigidity. No statistically significant differences were found between the groups or against an untreated control.

The ex vivo effect of ligation technique on the static frictional resistance of stainless steel brackets and archwires.

This ex vivo investigation compared the effect of various orthodontic ligation techniques on the static frictional resistance of stainless steel brackets and archwires under both dry and wet conditions. The techniques studied were: elastomeric modules tied conventionally and in a 'figure of 8' pattern, stainless steel ligatures, and Teflon-coated ligatures. The first part of the investigation involved the construction of calibration curves for each of the materials, so an estimate of the normal force exerted by the ligatures could be ascertained. Secondly, a pair of ligature locking pliers were modified so that ligatures could be placed with a standardized force. Finally, the four methods of ligation were directly compared on a specially constructed testing apparatus. Results revealed that elastomeric modules tied in a 'figure of 8' pattern produced significantly more friction than any other method tested, under both dry and wet conditions. No significant differences in frictional resistance were found between conventionally tied elastomeric modules and stainless steel ligatures. Teflon-coated ligatures, however, were associated with the lowest frictional forces. The results of the calibration tests indicated that the normal forces exerted by all four methods of ligation may be higher than previously estimated.

Effects of cyclic stressing on attachment bond strength using glass ionomer cement and composite resin.

Bonded orthodontic brackets were subjected to cyclic loading in order to simulate the effect of occlusal forces. The subsequent effect on bond strength was determined. Stainless steel, mesh-based brackets were bonded to extracted teeth with either composite resin or glass ionomer cement. A jig was designed to subject each bracket to a preselected loading level and the 24-hour shear/peel bond strength of both stressed and unstressed brackets was subsequently measured. Cyclic loading brought about a comparative decrease in bond strength when using both types of material. The potential implications of selecting these different types of bonding material for clinical use are discussed.

A study to compare the effects of simulated torquing forces on pre-adjusted orthodontic brackets.

The transmission of torquing forces between three types of preadjusted bracket was investigated. 0.022-inch Roth prescription 'A'-Company (stainless steel), Silkon (reinforced polycarbonate), and Allure III (polycrystalline ceramic) brackets were used. A selection of stainless steel archwires were chosen, 0.018 x 0.025, 0.019 x 0.025, and 0.021 x 0.025 inch. The brackets were torqued with respect to the archwire and force v. angular deflection was recorded on an Instron machine. The dimension of angular change was in part dependent on the ability of the bracket to elastically or plastically deform. There were no significant differences between bracket types with the 0.018 x 0.025-inch archwire. 'A'-Company brackets demonstrated a significantly lower resistance to loading compared to Silkon brackets in the 0.019 x 0.025-inch group. The greatest amount of distortion was seen in Silkon brackets with an 0.021 x 0.025-inch archwire. Allure III brackets demonstrated the greatest resistance to loading in all groups. As no apparent distortion under loading is seen in Allure III brackets, it is assumed that the load is largely transmitted to the tooth. Full thickness stainless steel rectangular wires should be avoided with these brackets, in order to prevent overloading.

Properties of acrylic resins incorporating 4META for bonding to cobalt-chromium alloys.

Polymer substitution into proprietary 4-methacryloxyethyltrimellitate anhydride (4META) resins creates tooth coloured veneers for cobalt-chromium overlay dentures. The elastic moduli and shear-bond strengths of proprietary resins (matched) and resins polymerised from 4META monomers and substituted polymers (unmatched) were determined. Bond strengths were similar for matched and unmatched heat curing resins (mean 14.1 (SD 1.6 MPa)) but differed for matched (6.9 (SD 1.3) MPa) and unmatched self-curing resins (5.7 (SD 0.9) MPa). Preparation of the alloy surface immediately before packing with resin dough provided significantly higher bond strengths. Structural examination in a scanning electron microscope suggested that bonds developed by unmatched resins may provide less satisfactory clinical performance.

A comparison of the frictional characteristics of five initial alignment wires and stainless steel brackets at three bracket to wire angulations--an in vitro study.

The study investigated static planar frictional resistance between five initial alignment wires and stainless steel brackets at three bracket to wire angulations (0, 5 and 10 degrees). It was demonstrated that static frictional resistance increased significantly with increasing bracket to wire angulation due to binding within the system. Epoxy-coated steel had the highest static frictional resistance and coaxial stainless steel the lowest. Fibre-optic glass (Optiflex) had low frictional resistance. The coefficient of friction followed the trends of static frictional resistance in all respects.

The physical properties of a polyacetal denture resin.

A polyacetal injection-moulded resin is being marketed for the construction of retentive and supportive components of removable partial dentures (RPDs). Specimens of poly(oxymethylene) cast by commercial laboratories were tested to examine the following physical characteristics: the modulus of elasticity in compression, extension and flexure, stress relaxation, the force displacement behaviour of clasp forms, impact strength and glass transition temperature. Results showed that the material has a flexural modulus lower than that of poly(methylmethacrylate) and is insufficiently rigid to be used as a supporting element for partial dentures. Resin clasps may be resilient enough to engage undercuts for the retention of RPDs but the low flexural modulus requires that the resin be used in greater cross-sectional area than metal alloys in order to gain useful retention. This greater bulk has implications for plaque accumulation and maintenance of periodontal health.