Finding Consensus About the Level of Medication Safety in a Hospital Setting: Development and an Example of Application of a Modified Delphi Method.

A version of the Institute for Safe Medication Practices (ISMP) questionnaire adapted to the Austrian inpatient setting was used to sample the estimates of a group of experts regarding the level of medication safety in a level II hospital. To synthesize expert opinions on a group level reproducibly, classical Delphi method elements were combined with an item weight and performance weight decision-maker. This newly developed information synthesis method was applied to the sample dataset to examine method applicability. Method descriptions and flow diagrams were generated. Applicability was then tested by creating a synthesis of individual questionnaires. An estimate of the level of medication safety in an Austrian level II hospital was, thus, generated. Over the past two decades, initiatives regarding patient safety, in general, and medication safety, in particular, have been gaining momentum. Questionnaires are state of the art for assessing medication practice in healthcare facilities. Acquiring consistent data about medication in the complex setting of a hospital, however, has not been standardized. There are no publicly available benchmark datasets and, in particular, there is no published method to reliably synthesize expertise regarding medication safety on an expert group level. The group-level information synthesis method developed in this study has the potential to synthesize information about the level of medication safety in a hospital setting more reliably than unstructured approaches. A medication safety level estimate for a representative Austrian level II hospital was generated. Further studies are needed to establish convergence characteristics and benchmarks for medication safety on a larger scale.

Multimodal [18 F]FDG PET/CT Is a Direct Readout for Inflammatory Bone Repair: A Longitudinal Study in TNFα Transgenic Mice.

In rheumatoid arthritis (RA), chronic joint inflammation leading to bone and cartilage damage is the major cause of functional impairment. Whereas reduction of synovitis and blockade of joint damage can be successfully achieved by disease modifying antirheumatic therapies, bone repair upon therapeutic interventions has only been rarely reported. The aim of this study was to use fluorodeoxyglucose ([18 F]FDG) and [18 F]fluoride µPET/CT imaging to monitor systemic inflammatory and destructive bone remodeling processes as well as potential bone repair in an established mouse model of chronic inflammatory, erosive polyarthritis. Therefore, human tumor necrosis factor transgenic (hTNFtg) mice were treated with infliximab, an anti-TNF antibody, for 4 weeks. Before and after treatment period, mice received either [18 F]FDG, for detecting inflammatory processes, or [18 F]fluoride, for monitoring bone remodeling processes, for PET scans followed by CT scans. Standardized uptake values (SUVmean ) were analyzed in various joints and histopathological signs of arthritis, joint damage, and repair were assessed. Longitudinal PET/CT scans revealed a significant decrease in [18 F]FDG SUVs in affected joints demonstrating complete remission of inflammatory processes due to TNF blockade. In contrast, [18 F]fluoride SUVs could not discriminate between different severities of bone damage in hTNFtg mice. Repeated in vivo CT images proved a structural reversal of preexisting bone erosions after anti-TNF therapy. Accordingly, histological analysis showed complete resolution of synovial inflammation and healing of bone at sites of former bone erosion. We conclude that in vivo multimodal [18 F]FDG µPET/CT imaging allows to quantify and monitor inflammation-mediated bone damage and reveals not only reversal of synovitis but also bone repair upon TNF blockade in experimental arthritis. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

SNAPshots of the MCHR1: a Comparison Between the PET-Tracers [18F]FE@SNAP and [11C]SNAP-7941.

PURPOSE: The melanin-concentrating hormone receptor 1 (MCHR1) has become an important pharmacological target, since it may be involved in various diseases, such as diabetes, insulin resistance, and obesity. Hence, a suitable positron emission tomography radiotracer for the in vivo assessment of the MCHR1 pharmacology is imperative. The current paper contrasts the extensive in vitro, in vivo, and ex vivo assessments of the radiotracers [18F]FE@SNAP and [11C]SNAP-7941 and provides comprehensive information about their biological and physicochemical properties. Furthermore, it examines their suitability for first-in-man imaging studies. PROCEDURES: Kinetic real-time cell-binding studies with [18F]FE@SNAP and [11C]SNAP-7941 were conducted on adherent Chines hamster ovary (CHO-K1) cells stably expressing the human MCHR1 and MCHR2. Small animal imaging studies on mice and rats were performed under displacement and baseline conditions, as well as after pretreatment with the P-glycoprotein/breast cancer resistant protein inhibitor tariquidar. After the imaging studies, detailed analyses of the ex vivo biodistribution were performed. Ex vivo metabolism was determined in rat blood and brain and analyzed at various time points using a quantitative radio-HPLC assay. RESULTS: [11C]SNAP-7941 demonstrates high uptake on CHO-K1-hMCHR1 cells, whereas no uptake was detected for the CHO-K1-hMCHR2 cells. In contrast, [18F]FE@SNAP evinced binding to CHO-K1-hMCHR1 and CHO-K1-hMCHR2 cells. Imaging studies with [18F]FE@SNAP and [11C]SNAP-7941 showed an increased brain uptake after tariquidar pretreatment in mice, as well as in rats, and exhibited a significant difference between the time-activity curves of the baseline and blocking groups. Biodistribution of both tracers demonstrated a decreased uptake after displacement. [11C]SNAP-7941 revealed a high metabolic stability in rats, whereas [18F]FE@SNAP was rapidly metabolized. CONCLUSIONS: Both radiotracers demonstrate appropriate imaging properties for the MCHR1. However, the pronounced metabolic stability as well as superior selectivity and affinity of [11C]SNAP-7941 underlines the decisive superiority over [18F]FE@SNAP.

A new method measuring the interaction of radiotracers with the human P-glycoprotein (P-gp) transporter.

In drug development, biomarkers for cerebral applications have a lower success rate compared to cardiovascular drugs or tumor therapeutics. One reason is the missing blood brain barrier penetration, caused by the tracer's interaction with efflux transporters such as the P-gp (MDR1 or ABCB1). Aim of this study was the development of a reliable model to measure the interaction of radiotracers with the human efflux transporter P-gp in parallel to the radiolabeling process. LigandTracer® Technology was used with the wildtype cell line MDCKII and the equivalent cell line overexpressing human P-gp (MDCKII-hMDR1). The method was evaluated based on established PET tracers with known interaction with the human P-gp transporter and in nanomolar concentration (15 nM). [11C]SNAP-7941 and [18F]FE@SNAP were used as P-gp substrates by comparing the real-time model with an uptake assay and µPET images. [11C]DASB [11C]Harmine, [18F]FMeNER,[18F]FE@SUPPY and [11C]Me@HAPTHI were used as tracers without interactions with P-gp in vitro. However, [11C]Me@HAPTHI shows a significant increase in SUV levels after blocking with Tariquidar. The developed real-time kinetic model uses directly PET tracers in a compound concentration, which is reflecting the in vivo situation. This method may be used at an early stage of radiopharmaceutical development to measure interactions to P-gp before conducting animal experiments.

In vivo evaluation of radiotracers targeting the melanin-concentrating hormone receptor 1: [11C]SNAP-7941 and [18F]FE@SNAP reveal specific uptake in the ventricular system.

The MCHR1 is involved in the regulation of energy homeostasis and changes of the expression are linked to a variety of associated diseases, such as diabetes and adiposity. The study aimed at the in vitro and in vivo evaluation of [11C]SNAP-7941 and [18F]FE@SNAP as potential PET-tracers for the MCHR1. Competitive binding studies with non-radioactive derivatives and small-animal PET/CT and MRI brain studies were performed under baseline conditions and tracer displacement with the unlabelled MCHR1 antagonist (±)-SNAP-7941. Binding studies evinced high binding affinity of the non-radioactive derivatives. Small-animal imaging of [11C]SNAP-7941 and [18F]FE@SNAP evinced high tracer uptake in MCHR1-rich regions of the ventricular system. Quantitative analysis depicted a significant tracer reduction after displacement with (±)-SNAP-7941. Due to the high binding affinity of the non-labelled derivatives and the high specific tracer uptake of [11C]SNAP-7941 and [18F]FE@SNAP, there is strong evidence that both radiotracers may serve as highly suitable agents for specific MCHR1 imaging.

New approaches for the reliable in vitro assessment of binding affinity based on high-resolution real-time data acquisition of radioligand-receptor binding kinetics.

BACKGROUND: Resolving the kinetic mechanisms of biomolecular interactions have become increasingly important in early-phase drug development. Since traditional in vitro methods belong to dose-dependent assessments, binding kinetics is usually overlooked. The present study aimed at the establishment of two novel experimental approaches for the assessment of binding affinity of both, radiolabelled and non-labelled compounds targeting the A3R, based on high-resolution real-time data acquisition of radioligand-receptor binding kinetics. A novel time-resolved competition assay was developed and applied to determine the Ki of eight different A3R antagonists, using CHO-K1 cells stably expressing the hA3R. In addition, a new kinetic real-time cell-binding approach was established to quantify the rate constants k on and k off, as well as the dedicated K d of the A3R agonist [125I]-AB-MECA. Furthermore, lipophilicity measurements were conducted to control influences due to physicochemical properties of the used compounds. RESULTS: Two novel real-time cell-binding approaches were successfully developed and established. Both experimental procedures were found to visualize the kinetic binding characteristics with high spatial and temporal resolution, resulting in reliable affinity values, which are in good agreement with values previously reported with traditional methods. Taking into account the lipophilicity of the A3R antagonists, no influences on the experimental performance and the resulting affinity were investigated. CONCLUSIONS: Both kinetic binding approaches comprise tracer administration and subsequent binding to living cells, expressing the dedicated target protein. Therefore, the experiments resemble better the true in vivo physiological conditions and provide important markers of cellular feedback and biological response.

Rehabilitation after hallux valgus surgery: importance of physical therapy to restore weight bearing of the first ray during the stance phase.

BACKGROUND: Operative treatment of people with hallux valgus can yield favorable clinical and radiographic results. However, plantar pressure analysis has demonstrated that physiologic gait patterns are not restored after hallux valgus surgery. OBJECTIVE: The purpose of this study was to illustrate the changes of plantar pressure distribution during the stance phase of gait in patients who underwent hallux valgus surgery and received a multimodal rehabilitation program. DESIGN: This was a prospective descriptive study. METHODS: Thirty patients who underwent Austin (n=20) and scarf (n=10) osteotomy for correction of mild to moderate hallux valgus deformity were included in this study. Four weeks postoperatively they received a multimodal rehabilitation program once per week for 4 to 6 weeks. Plantar pressure analysis was performed preoperatively and 4 weeks, 8 weeks, and 6 months postoperatively. In addition, range of motion of the first metatarsophalangeal joint was measured, and the American Orthopaedic Foot and Ankle Society (AOFAS) forefoot questionnaire was administered preoperatively and at 6 months after surgery. RESULTS: The mean AOFAS score significantly increased from 60.7 points (SD=11.9) preoperatively to 94.5 points (SD=4.5) 6 months after surgery. First metatarsophalangeal joint range of motion increased at 6 months postoperatively, with a significant increase in isolated dorsiflexion. In the first metatarsal head region, maximum force increased from 117.8 N to 126.4 N and the force-time integral increased from 37.9 N.s to 55.6 N.s between the preoperative and 6-month assessments. In the great toe region, maximum force increased from 66.1 N to 87.2 N and the force-time integral increased from 18.7 N.s to 24.2 N.s between the preoperative and 6-month assessments. LIMITATIONS: A limitation of the study was the absence of a control group due to the descriptive nature of the study. CONCLUSIONS: The results suggest that postoperative physical therapy and gait training may lead to improved function and weight bearing of the first ray after hallux valgus surgery.