Background: Medically unexplained symptoms (MUS) are highly prevalent and pose a burden both on patients and on health care. In a pilot study psychosomatic therapy delivered by specialised therapists for patients with MUS showed promising results with regard to patient’s acceptability, feasibility and effects on symptoms. The aim of this study is to establish whether psychosomatic therapy by specialised psychosomatic exercise therapists is costeffective in decreasing symptoms and improving functioning in patients who frequently consult their general practitioner (GP) with MUS. Methods: A randomised effectiveness trial with an economic evaluation in primary care with 158 patients aged 18 years and older who are frequently consulting their GP with MUS. Patients will be assigned to psychosomatic therapy in addition to usual care or usual care only. Psychosomatic therapy is a multi-component and tailored intervention, aiming to empower patients by applying psycho-education, relaxation techniques, mindfulness, cognitive approaches and/or graded activity. Patients assigned to the psychosomatic therapy receive 6 to 12 sessions of psychosomatic therapy, of 30–45 min each, delivered by a specialised exercise or physical therapist. Primary outcome measure is patient-specific functioning and disability, measured with the Patient-Specific Functional Scale (PSFS). Secondary outcome measures are symptom severity, consultation frequency and referrals to secondary care, patient satisfaction, quality of life and costs. Assessments will be carried out at baseline, and after 4 and 12 months. An economic evaluation alongside the trial will be conducted from a societal perspective, with quality-adjusted life years (QALYs) as outcome measure. Furthermore, a mixed-methods process evaluation will be conducted. Discussion: We expect that psychosomatic therapy in primary care for patients who frequently attend the GP for MUS will improve symptoms and daily functioning and disability, while reducing consultation frequency and referrals to secondary care. We expect that the psychosomatic therapy provides value for money for patients with MUS.Trial registration: Netherlands Trial Register, ID: NL7157 (NTR7356). Registered 13 July 2018.Keywords: Psychosomatic therapy, Study protocol, Primary care, Randomised controlled trial, Medically unexplained symptoms, Cost-effectiveness
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Objective: To evaluate the delivery, acceptance and experiences regarding a traditional and teletreatment approach to mirror therapy as delivered in a randomized controlled trial. Design: Mixed methods, prospective study. Setting: Rehabilitation centres, hospital and private practices. Subjects: Adult patients with phantom pain following lower limb amputation and their treating physical and occupational therapists. Interventions: All patients received 4 weeks of traditional mirror therapy (n=51), followed by 6 weeks of teletreatment (n=26) or 6 weeks of self-delivered mirror therapy (n=25). Main measures: Patient files, therapist logs, log files teletreatment, acceptance questionnaire and interviews with patients and their therapists. Results: In all, 51 patients and 10 therapists participated in the process evaluation. Only 16 patients (31%) received traditional mirror therapy according to the clinical framework during the first 4 weeks. Between weeks 5 and 10, the teletreatment was used by 14 patients (56%) with sufficient dose. Teletreatment usage decreased from a median number of 31 (weeks 5–10) to 19 sessions (weeks 11–24). Satisfactory teletreatment user acceptance rates were found with patients demonstrating higher scores (e.g. regarding the usefulness to control pain) than therapists. Potential barriers for implementation of the teletreatment perceived by patients and therapists were related to insufficient training and support as well as the frequency of technical problems. Conclusion: Traditional mirror therapy and the teletreatment were not delivered as intended in the majority of patients. Implementation of the teletreatment in daily routines was challenging, and more research is needed to evaluate user characteristics that influence adherence and how technology features can be optimized to develop tailored implementation strategies.
Phantom limb pain following amputation is highly prevalent as it affects up to 80% of amputees. Many amputees suffer from phantom limb pain for many years and experience major limitations in daily routines and quality of life. Conventional pharmacological interventions often have negative side-effects and evidence regarding their long-term efficacy is low. Central malplasticity such as the invasion of areas neighbouring the cortical representation of the amputated limb contributes to the occurrence and maintenance of phantom limb pain. In this context, alternative, non-pharmacological interventions such as mirror therapy that are thought to target these central mechanisms have gained increasing attention in the treatment of phantom limb pain. However, a standardized evidence-based treatment protocol for mirror therapy in patients with phantom limb pain is lacking, and evidence for its effectiveness is still low. Furthermore, given the chronic nature of phantom limb pain and suggested central malplasticity, published studies proposed that patients should self-deliver mirror therapy over several weeks to months to achieve sustainable effects. To achieve this training intensity, patients need to perform self-delivered exercises on a regular basis, which could be facilitated though the use of information and communication technology such as telerehabilitation. However, little is known about potential benefits of using telerehabilitation in patients with phantom limb pain, and controlled clinical trials investigating effects are lacking. The present thesis presents the findings from the ‘PAtient Centered Telerehabilitation’ (PACT) project, which was conducted in three consecutive phases: 1) creating a theoretical foundation; 2) modelling the intervention; and 3) evaluating the intervention in clinical practice. The objectives formulated for the three phases of the PACT project were: 1) to conduct a systematic review of the literature regarding important clinical aspects of mirror therapy. It focused on the evidence of applying mirror therapy in patients with stroke, complex regional pain syndrome and phantom limb pain. 2) to design and develop a clinical framework and a user-centred telerehabilitation for mirror therapy in patients with phantom limb pain following lower limb amputation. 3) to evaluate the effects of the clinical framework for mirror therapy and the additional effects of the teletreatment in patients with phantom limb pain. It also investigated whether the interventions were delivered by patients and therapists as intended.
Every year in the Netherlands around 10.000 people are diagnosed with non-small cell lung cancer, commonly at advanced stages. In 1 to 2% of patients, a chromosomal translocation of the ROS1 gene drives oncogenesis. Since a few years, ROS1+ cancer can be treated effectively by targeted therapy with the tyrosine kinase inhibitor (TKI) crizotinib, which binds to the ROS1 protein, impairs the kinase activity and thereby inhibits tumor growth. Despite the successful treatment with crizotinib, most patients eventually show disease progression due to development of resistance. The available TKI-drugs for ROS1+ lung cancer make it possible to sequentially change medication as the disease progresses, but this is largely a ‘trial and error’ approach. Patients and their doctors ask for better prediction which TKI will work best after resistance occurs. The ROS1 patient foundation ‘Stichting Merels Wereld’ raises awareness and brings researchers together to close the knowledge gap on ROS1-driven oncogenesis and increase the options for treatment. As ROS1+ lung cancer is rare, research into resistance mechanisms and the availability of cell line models are limited. Medical Life Sciences & Diagnostics can help to improve treatment by developing new models which mimic the situation in resistant tumor cells. In the current proposal we will develop novel TKI-resistant cell lines that allow screening for improved personalized treatment with TKIs. Knowledge of specific mutations occurring after resistance will help to predict more accurately what the next step in patient treatment could be. This project is part of a long-term collaboration between the ROS1 patient foundation ‘Stichting Merels Wereld’, the departments of Pulmonary Oncology and Pathology of the UMCG and the Institute for Life Science & Technology of the Hanzehogeschool. The company Vivomicx will join our consortium, adding expertise on drug screening in complex cell systems.
How does a specific lung cancer become resistant towards medication.The occurrence of a chromosomal translocation resulting in a ROS1 gene fusion in lung cancer is relatively rare with around 1-2% of all cases. Both Dutch (Stichting Merels Wereld) and world-wide (ROS1ders) patient advocacy groups work hard to raise awareness and bring researchers together to close the knowledge gap on ROS1 driven oncogenesis and increase the optionsfor treatment. A notorious hurdle is to achieve durable responses due to development of resistance.Ongoing mutations occurring in tumour cells lead to a heterogeneous genomic landscape and will result in outgrowth of the fastest growing tumour cell population resistant to the applied drug. The currently known resistance mechanisms can be divided in on-target (i.e. mutations in the kinasedomain of ROS1) and off-target (providing ROS1 independent growth support) mechanisms. The currently available drugs target the ROS1-fusion gene positive lung cancer cells. In addition, some of the drugs also target cancer cells with specific ROS1 resistance mutations allowing effective sequentialtreatment upon disease progression. Selection of the most optimal treatment is largely a ‘trial and error’ approach. Patients and their doctors ask for better prediction of the most effective follow-up treatment upon development of resistance. Medical Life Science & Diagnostics can help to improvetreatment by developing cell culture models which mimic the situation in resistant tumour cells.Understanding the impact of specific mutations on disease behaviour will aid in the development of patient-tailored therapeutic approaches, ultimately improving patient outcomes.
Biotherapeutic medicines such as peptides, recombinant proteins, and monoclonal antibodies have successfully entered the market for treating or providing protection against chronic and life-threatening diseases. The number of relevant commercial products is rapidly increasing. Due to degradation in the gastro-intestinal tract, protein-based drugs cannot be taken orally but need to be administered via alternative routes. The parenteral injection is still the most widely applied administration route but therapy compliance of injection-based pharmacotherapies is a concern. Long-acting injectable (LAI) sustained release dosage forms such as microparticles allow less frequent injection to maintain plasma levels within their therapeutic window. Spider Silk Protein and Poly Lactic-co-Glycolic Acid (PLGA) have been attractive candidates to fabricate devices for drug delivery applications. However, conventional microencapsulation processes to manufacture microparticles encounter drawbacks such as protein activity loss, unacceptable residual organic solvents, complex processing, and difficult scale-up. Supercritical fluids (SCF), such as supercritical carbon dioxide (scCO2), have been used to produce protein-loaded microparticles and is advantageous over conventional methods regarding adjustable fluid properties, mild operating conditions, interfacial tensionless, cheap, non-toxicity, easy downstream processing and environment-friendly. Supercritical microfluidics (SCMF) depict the idea to combine strengths of process scale reduction with unique properties of SCF. Concerning the development of long-acting microparticles for biological therapeutics, SCMF processing offers several benefits over conventionally larger-scale systems such as enhanced control on fluid flow and other critical processing parameters such as pressure and temperature, easy modulation of product properties (such as particle size, morphology, and composition), cheaper equipment build-up, and convenient parallelization for high-throughput production. The objective of this project is to develop a mild microfluidic scCO2 based process for the production of long-acting injectable protein-loaded microparticles with, for example, Spider Silk Protein or PLGA as the encapsulating materials, and to evaluate the techno-economic potential of such SCMF technology for practical & industrial production.
