Ultrasound and MR imaging of peripheral nerve tumors: the state of the art.

Peripheral nerve sheath tumors are a heterogeneous subgroup of soft tissue tumors that either arise from a peripheral nerve or show nerve sheath differentiation. On imaging, direct continuity with a neural structure or location along a typical nerve distribution represents the most important signs to suggest the diagnosis. Ultrasound and magnetic resonance imaging are the best modalities to evaluate these lesions. First, it is necessary to differentiate between a true tumor and a non-neoplastic nerve condition such as a neuroma, peripheral nerve ganglion, intraneural venous malformation, lipomatosis of nerve, or nerve focal hypertrophy. Then, with a combination of clinical features, conventional and advanced imaging appearances, it is usually possible to characterize neurogenic tumors confidently. This article reviews the features of benign and malignant peripheral nerve sheath tumors, including the rare and recently described tumor types. Furthermore, other malignant neoplasms of peripheral nerves as well as non-neoplastic conditions than can mimick neurogenic tumor are herein discussed.

Surfactant Protection Efficacy at Surfaces Varies with the Nature of Hydrophobic Materials.

OBJECTIVE: Monoclonal antibodies are in contact with many different materials throughout their life cycle from production to patient administration. Plastic surfaces are commonly found in single use bags, syringes, perfusion bags and tubing and their hydrophobic nature makes them particularly prone for adsorption of therapeutic proteins. The addition of surfactants in therapeutic formulations aims at minimizing surface and interface adsorption of the active molecules. However, their protection efficacy related to the nature of the plastic material is still poorly investigated. METHODS: We use real-time surface-sensitive techniques and immunosorbent assays, to quantify surfactant and monoclonal antibody adsorption on hydrophobic model surfaces and different plastic polymers to analyse the effect of material surface properties on the level of surfactant protection. RESULTS: We show that Polysorbate 80 protects monoclonal antibodies significantly better from adsorption on a polystyrene surface than on a hexadecane self-assembled monolayer, used as a model surface with similar hydrophobicity. This enhanced protective effect on polystyrene is observed for different antibodies and also other surfactants, and its extent depends on the surfactant concentration for a given antibody concentration. A comparative adsorption study allows ranking different in-use plastics and highlights the dependence of Polysorbate 80 protection efficacy on the nature of the plastic material. CONCLUSION: This study demonstrates that, beyond hydrophobicity, the nature of plastic polymer surfaces affects surfactant adsorption and thereby impacts their protection efficacy in therapeutic antibody formulations.

Synthesis of PDMS-b-POEGMA Diblock Copolymers and Their Application for the Thermoresponsive Stabilization of Water-Supercritical Carbon Dioxide Emulsions.

In this study, PDMS13-b-POEGMAx diblock copolymers consisting of a CO2-philic poly(dimethylsiloxane) (PDMS) block connected to a thermosensitive hydrophilic poly(oligoethylene glycol methacrylate) (POEGMA) block were synthesized by reversible addition-fragmentation chain-transfer (RAFT) radical polymerization. Their ability to decrease the water-supercritical CO2 (scCO2) interfacial tension (γ) and to stabilize water-scCO2 emulsions was investigated using an original homemade device developed in the laboratory. This device is able to control the pressure from 1 to 250 bar and the temperature from 40 to 80 °C. It was implemented with 2 visualization windows, a drop tensiometer and a remote optical head for dynamic light scattering (DLS) measurements. These experiments revealed that PDMS-b-POEGMA decreased γ down to 1-2 mN/m and was the most efficient at high pressure (250 bar) and low temperature (40 °C) where PDMS and POEGMA blocks exhibited the highest affinity for their respective phase. The diblock copolymers were shown to stabilize water-scCO2 emulsions. Moreover, the thermosensitive behavior of the POEGMA block in water (with a lower critical solubility temperature around 65 °C) resulted in the formation of temperature-responsive emulsions that could reversibly switch at 100 bar from stable at 40 °C to unstable at 80 °C. These results were rationalized based on the solubility of each individual block of the copolymers in water and scCO2 as a function of temperature and pressure.

Sacroiliac joints: anatomical variations on MR images.

OBJECTIVE: To describe the appearance of the anatomical variations of the sacroiliac joints (SIJ) on MR images and to highlight the potential MR features that might be misleading. METHODS: Consecutive MRI examinations of SIJs performed at our department from January 2015 to December 2016 were retrospectively analyzed. As one of our goals was to describe potential misleading edematous or structural changes associated with SIJ anatomical variations, patients fulfilling the ASAS criteria were excluded from this study to ensure that signal intensity changes would not be related to sacroiliitis. Five anatomical variations and a dysmorphic appearance of the SIJ were detected. RESULTS: The final group consisted of 157 patients. Unilateral or bilateral anatomical variations of the SIJ were found in 50 patients (accessory SIJ, iliosacral complex and sacral defect in 17, 18 and 21 patients, respectively, and synostosis in one patient). A dysmorphic appearance of the SIJ was found in 26 patients. No case of an unfused ossification centers was depicted. Structural and/or edematous changes of the facing bones were quite frequently observed in accessory and dysmorphic SIJ. Iliosacral complex and sacral defects could be associated with prominent vessels running along their bony surfaces. CONCLUSION: Several anatomical variations of the SIJs are relatively commonly seen on MR images, particularly in females. These variations may be associated with signal intensity changes, which may be mechanical and not necessarily inflammatory in nature. KEY POINTS: • Anatomical variations of SIJ may involve the cartilaginous or ligamentous part of the joint • Anatomical variations of SIJ are sometimes associated with edematous and/or structural changes of the adjacent bone • Anatomical variations of the SIJ can be misleading on MR imaging.

Assessment of the zonal variation of perfusion parameters in the femoral head: a 3-T dynamic contrast-enhanced MRI pilot study.

OBJECTIVE: The objective was to describe MR perfusion characteristics of the femoral head, with a focus on the subchondral bone. MATERIALS AND METHODS: This prospective monocentric study was approved by our local Ethics Committee. Written informed consent was obtained from all subjects. Dynamic contrast-enhanced MRI of the right hip was performed in 59 adults with suspected spondyloarthritis (32 women, 28 men). Mean age was 37.5 (±12.5) years. Regions of interest were drawn in the femoral head epiphysis, in the subchondral areas the most exposed to mechanical load (superolateral, anterosuperior, and posterior zones) and in areas less exposed to mechanical load (inferior subchondral zone and center of the femoral head). Semi-quantitative and pharmacokinetic parameters were calculated using the Tofts model. Statistical analysis was performed with a linear mixed model to compare the perfusion parameters in the different femoral head zones. RESULTS: Extravascular extracellular volume and area under the curve were lower in the superolateral zone than in the inferior zone (p = 0.0135 and p < 0.0001 respectively) and the central zone (p = 0.007 and p = 0.0134 respectively). Extravascular extracellular volume and rate constant were lower in the anterosuperior zone than in the inferior zones (p = 0.011 and p = 0.029). In the anterosuperior zone, extravascular extracellular volume was lower, and time to peak was higher than in the central zones (p = 0.0056 and p = 0.0013 respectively). No significant differences were found for any values between other paired zones. CONCLUSION: The perfusion of femoral head subchondral bone assessed with dynamic contrast-enhanced magnetic resonance imaging is not homogeneous: the areas exposed to more mechanical loading are less perfused.

Quantitative analysis of scapholunate diastasis using stress speckle-tracking sonography: a proof-of-concept and feasibility study.

OBJECTIVE: To evaluate the feasibility and potential clinical applicability of speckle-tracking sonography for the dynamic evaluation of the scapholunate diastasis during stress manoeuvres. MATERIAL AND METHODS: Two readers used speckle tracking sonography to evaluate scapholunate diastasis during a clenching fist manoeuver in 30 normal wrists. Scapholunate peak strain, mean scapholunate diastasis and the diastasis variation coefficient were analysed. IRB exemption was granted for this study. Conventional and stress wrist radiographs of 26 patients with and without a scapholunate ligament tear were retrospectively analysed to ascertain the range of variation in scapholunate diastasis. RESULTS: Speckle-tracking parameters in normal wrists were similar between the two readers (p > 0.2061). The maximal scapholunate peak strain during stress was relatively low (<0.34-0.47 mm). The normal radiographic diastasis amplitude was similar to maximal strain peak values in normal volunteers (0.49 ± 0.51 mm). The radiographic diastasis amplitude in cases of scapholunate ligament tears was 1.48 ± 0.78 mm, which was higher than the 95% confidence interval of the scapholunate gap peak strain. CONCLUSION: Speckle-tracking sonography could represent an interesting alternative for stress evaluation of the scapholunate ligament in patients with scapholunate diastasis. KEY POINTS: • Speckle-tracking sonography can assess scapholunate diastasis under stress testing. • Scapholunate gap shows little variation under stress in healthy volunteers. • Scapholunate gap measurements are influenced by grip strength. • Sex and BMI have a significant influence on strain measurements.

T2 Mapping of the Sacroiliac Joints With 3-T MRI: A Preliminary Study.

OBJECTIVE: The objective of this study was to assess the feasibility of T2 relaxation time measurements of the sacroiliac joints. SUBJECTS AND METHODS: The sacroiliac joints of 40 patients were imaged by 3-T MRI using an oblique axial multislice multiecho spin-echo T2-weighted sequence. Manual plotting and automatic subdivision of ROIs allowed us to obtain T2 values for up to 48 different areas per patient (posterior and anterior parts, sacral, intermediate, and iliac parts). Intraand interobserver reproducibility of T2 values were calculated after independent assessment by two musculoskeletal radiologists. RESULTS: A total of 1656 measurement sites could be analyzed. Mean (± SD) T2 values were 40.6 ± 6.7 ms and 41.2 ± 6.3 ms for observer 1 and 39.9 ± 6.6 ms for observer 2. The intraobserver intraclass correlation coefficient was 0.72 (95% CI, 0.70-0.74), and the interobserver intraclass correlation coefficient was 0.71 (95% CI, 0.68-0.72). CONCLUSION: Our study shows the feasibility of T2 relaxation time measurements at the sacroiliac joints.

Imaging of Sports-related Hand and Wrist Injuries: Sports Imaging Series.

Hand and wrist injuries are common occurrences in amateur and professional sports and many of them are sport-specific. These can be divided into two categories: traumatic injuries and overuse injuries. The aim of this article is to review the most common hand and wrist sports-related lesions. Acute wrist injuries are predominantly bone fractures, such as those of the scaphoid, hamate hook, and ulnar styloid. Ligament lesions are more challenging for radiologists and may lead to carpal instability if undiagnosed. Overuse wrist injuries are mainly represented by tendinous disorders, with De Quervain syndrome and extensor carpi ulnaris tendon disorders being the most common among them; however, there are other possible disorders such as impaction syndromes, stress fractures, and neurovascular lesions. Finally, finger lesions, including closed-tendon injuries (mallet and boutonniere injuries, jersey finger, and boxer's knuckle), flexor pulley injuries, and skier's thumb, should also be detected. (©) RSNA, 2016 Online supplemental material is available for this article.

Tractography: Possible Applications in Musculoskeletal Radiology.

Tractography (or fiber tracking) consists of three-dimensional modeling of the preferential movement of water molecules in the form of fiber tracks from the tensor field information. This technique allows a new approach for the microarchitectural analysis of anisotropic structures such as nerves, white matter, and muscles. Many disorders have been studied including cervical myelopathy, carpal tunnel syndrome, nerve root compression, and nerve tumors. Muscles have been less evaluated. Tractography is still a research technique, and its validation and widespread routine clinical use will require a good deal of work toward a harmonization of the MRI protocols and data postprocessing methods.

Study of proximal femoral bone perfusion with 3D T1 dynamic contrast-enhanced MRI: a feasibility study.

OBJECTIVE: The objective of this study was to compare measurements of semi-quantitative and pharmacokinetic parameters in areas of red (RBM) and yellow bone marrow (YBM) of the hip, using an in-house high-resolution DCE T1 sequence, and to assess intra- and inter-observer reproducibility of these measurements. METHODS: The right hips of 21 adult patients under 50 years of age were studied. Spatial resolution was 1.8 × 1.8 × 1.8 mm(3), and temporal resolution was 13.5 seconds. Two musculoskeletal radiologists independently processed DCE images and measured semi-quantitative and pharmacokinetic parameters in areas of YBM and RBM. Signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated. Intra- and inter-observer reproducibility was assessed. RESULTS: Area under the curve (AUC) and initial slope (IS) were significantly greater for RBM than for YBM (p < 0.05). K(trans) and kep were also significantly greater for RBM (p < 0.05). There was no significant difference in time to peak between the regions (p < 0.05). SNR, CNR, and intra- and inter-observer reproducibility were all good. CONCLUSIONS: DCE study of the whole hip is feasible with high spatial resolution using a 3D T1 sequence. Measures were possible even in low vascularized areas of the femoral head. K(trans), kep, AUC, and IS values were significantly different between red and yellow marrow, whereas TTP values were not. KEY POINTS: High-spatial-resolution dynamic contrast-enhanced MRI of hip structures is feasible. Intra- and inter-observer reproducibility is good. Red and yellow bone marrow have different perfusion patterns.

Assessment of reduced field of view in diffusion tensor imaging of the lumbar nerve roots at 3 T.

OBJECTIVES: To assess the value of reduced field of view (rFOV) imaging in diffusion tensor imaging (DTI) and tractography of the lumbar nerve roots at 3 T from the perspective of future clinical trials. METHODS: DTI images of the lumbar nerves were obtained in eight healthy volunteers, with and without the rFOV technique. Non-coplanar excitation and refocusing pulses associated with outer volume suppression (OVS) were used to achieve rFOV imaging. Tractography was performed. A visual evaluation of image quality was made by two observers, both senior musculoskeletal radiologists. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were measured in L5 and S1 roots. RESULTS: rFOV images of the L5 and S1 roots were assessed as being superior to full FOV (fFOV) images. Image quality was rated as good to excellent by both observers. Interobserver agreement was good. No significant difference was found in FA and ADC measurements of the L5 or S1 roots. On the contrary, only poor-quality images could be obtained with fFOV imaging as major artefacts were present. CONCLUSION: The rFOV approach was essential to achieve high-quality DTI imaging of lumbar nerve roots on 3-T MRI. KEY POINTS: • Diffusion tensor 3-T MR imaging of lumbar nerve roots creates severe artefacts. • A reduced field of view drastically reduces artefacts, thereby improving image quality. • Good-quality tractography images can even be obtained with rFOV imaging. • rFOV DTI is better than fFOV DTI for clinical studies.

Interfacial tension of ethanol, water, and their mixtures in high pressure carbon dioxide: Measurements and modeling.

HYPOTHESIS: It is particularly noteworthy to study interfacial tension behavior under pressurized carbon dioxide for supercritical processes such as crystallization or fractionation. For the latter, a liquid phase and a supercritical phase are in contact, and interfacial properties influence mass transfer phenomena and hydrodynamics. Ethanol-water mixture is a good theoretical study case also involved in a wide range of applications. EXPERIMENTAL: Interfacial tensions of ethanol, water and three mixtures, with an ethanol mass fraction from 0.25 to 0.75, under pressurized CO2 were measured for pressures ranging from 0.1 MPa to 15.1 MPa at 313.15 K and 333.15 K. A specific experimental set-up was used for CO2 phase saturation. FINDINGS: This work brings interfacial tension data of five different solutions including water and ethanol in contact with CO2. Effects of pressure, temperature, carbon dioxide density and ethanol mass fraction are discussed regarding the literature. Significant discrepancies are found with previous literature data for ethanol-water mixtures. The "two-step" decrease observed when pressure or density increase is also discussed regarding both the concept of Widom line, and the polar and dispersive contributions of the surface tension of a component. For the first time, fair accurate interfacial tension modeling involving these contributions is addressed.

Adsorption rate constants of therapeutic proteins and surfactants for material surfaces.

Adsorption of therapeutic proteins to material surfaces can be a pivotal issue in drug development, especially for low concentration products. Surfactants are used to limit adsorption losses. For each formulation component, surface adsorption is the result of a combination of its diffusion and surface adsorption rates. The latter are difficult to measure accurately because a depletion layer forms rapidly in the bulk solution above a bare surface, slowing down adsorption. Adapting flow conditions and local surface chemistry, we are able to minimize depletion limitations and measure apparent adsorption rate constants of three monoclonal antibodies, other proteins and surfactants with a hydrophobic surface. We show that surface adsorption rates scale with the molecular mass of the molecule, with polysorbates therefore showing thousand times slower rates than antibodies. Moreover, we observed that the desorption dynamic of polysorbates from a given hydrophobic surface depends on surface coverage, whereas this is not the case for Poloxamer 188. These novel contributions to surface adsorption dynamics enable a new perspective on the evaluation of drug surface compatibility and can, together with diffusion rates, be used to predict the protective potential of surfactants in given conditions.

Main Diagnostic Pitfalls in Reading the Sacroiliac Joints on MRI.

Magnetic resonance imaging of the sacroiliac joints is now frequently performed to help identify patients with early axial spondyloarthritis. However, differential diagnoses exist and should be recognized. The aim of this article is to review the most frequent differential diagnoses that may mimic inflammatory sacroiliitis in clinical practice.

Medial meniscal ossicles: Associated knee MRI findings in a multicenter case-control study.

PURPOSE: The purpose of this study was to assess and compare the prevalence of meniscal, ligament and cartilage lesions on knee MRI in a series of age- and sex-matched patients with and without medial meniscal ossicle. MATERIALS AND METHODS: Forty-two knee MRI examinations obtained in 42 patients (36 men, 6 women; mean age, 42.5±22.2 [SD] years; range: 19-65years) on which a medial meniscal ossicle was present were compared to 42 knee MRI examinations obtained in 42 age- and sex-matched patients (36 men, 6 women; mean age, 41.8±20.6 [SD] years; range: 19-65years) on which no medial meniscal ossicles were present. Two radiologists (R1, R2) blinded to the presence of meniscal ossicle by reading only the fat-saturated intermediate-weighted MR images separately assessed the presence of meniscal, ligament and cartilage lesions on these 84 knee MRI examinations. Prevalence of meniscal and ligament lesions and degree of cartilage degradation at MRI were compared between knees with and those without medial meniscal ossicle. RESULTS: In knees with medial meniscal ossicle, R1 and R2 detected 33 (79%) and 38 (90%) medial meniscal lesions, respectively that involved the posterior root (n=25/32 for R1/R2), the posterior horn (n=19/14 for R1/R2) or the body (n=8/10 for R1/R2). The prevalence of posterior root tear (60% [25/42]/76% [32/42] for R1/R2) and that of anterior cruciate ligament (ACL) lesions (48% [20/42]/57% [24/42] for R1/R2) as well as the medial cartilage degradation score (3.35±0.87 [SD] for R1 and 3.92±0.78 [SD] for R2) were significantly greater in knees with than in knees without medial meniscal ossicle (root lesions: P<0.01 for both readers; ACL lesions and medial cartilage score: P<0.01 for both readers). CONCLUSION: On MRI examination, knees with a medial meniscal ossicle demonstrate a greater frequency of medial posterior root tear and of ACL lesions and a greater degree of medial femoro-tibial cartilage degradation by comparison with knees without medial ossicle.

Correction: Galenic lab-on-a-chip concept for lipid nanocapsules production.

Correction for 'Galenic Lab-on-a-Chip concept for lipid nanocapsules production' by Nicolas Rolley et al., Nanoscale, 2021, 13, 11899-11912, DOI: 10.1039/D1NR00879J.

Galenic Lab-on-a-Chip concept for lipid nanocapsules production.

The continuous production of drug delivery systems assisted by microfluidics has drawn a growing interest because of the high reproducibility, low batch-to-batch variations, narrow and controlled particle size distributions and scale-up ease induced by this kind of processes. Besides, microfluidics offers opportunities for high throughput screening of process parameters and the implementation of process characterization techniques as close to the product as possible. In this context, we propose to spotlight the GALECHIP concept through the development of an instrumented microfluidic pilot considered as a Galenic Lab-on-a-Chip to formulate nanomedicines, such as lipid nanocapsules (LNCs), under controlled process conditions. In this paper we suggest an optimal rational development in terms of chip costs and designs. First, by using two common additive manufacturing techniques, namely fused deposition modelling and multi-jet modelling to prototype customized 3D microfluidic devices (chips and connectors). Secondly, by manufacturing transparent Silicon (Si)/Glass chips with similar channel geometries but obtained by a new approach of deep reactive ion etching (DRIE) technology suitable with in situ small angle X-ray scattering characterizations. LNCs were successfully produced by a phase inversion composition (PIC) process with highly monodispersed sizes from 25 nm to 100 nm and formulated using chips manufactured by 3D printing and DRIE technologies. The transparent Si/Glass chip was also used for the small angle X-ray scattering (SAXS) analysis of the LNC formulation with the PIC process. The 3D printing and DRIE technologies and their respective advantages are discussed in terms of cost, easiness to deploy and process developments in a GALECHIP point of view.

Thoracic Outlet Syndrome: Diagnostic Accuracy of MRI.

BACKGROUND: Thoracic outlet syndrome (TOS) is challenging to diagnose, as the physical findings and investigations lack sensitivity and/or specificity. Magnetic resonance imaging (MRI) with dynamic manoeuvres can rule out a tumour and detect anatomical abnormalities potentially responsible for compression. The objective of this study was to assess the sensitivity and specificity of MRI for identifying anatomical structures responsible for compression in TOS, using intra-operative findings as the diagnostic reference standard. HYPOTHESIS: MRI is effective in diagnosing the source of compression in TOS, notably within the scalene triangle and at the pleural apex. METHODS: We retrospectively included 48 patients who underwent surgery for TOS after a work-up that included MRI (1.5-T, n=29 and 3-T, n=19). The MRI scans were reviewed for the study by a specialised radiologist who was unaware of the intra-operative findings. The sensitivity and specificity of MRI for diagnosing TOS were estimated using the intra-operative findings as the reference standard. RESULTS: MRI identified a structure potentially responsible for TOS in 34 (71%) patients; thus, the false-negative rate was 14/48 (29%). The sensitivity of MRI was 28% for compression at the suspensory ligament of the pleural dome, 81% for hypertrophy of the anterior scalene muscle, and 50% for an accessory scalene muscle. For diagnosing a cervical rib, MRI had 100% sensitivity and 100% specificity. CONCLUSION: MRI can contribute to the diagnosis of TOS. Specificity is sufficiently high to provide guidance for planning the surgical procedure. Sensitivity, however, is too low for MRI to be useful as a screening test. MRI should be used in combination with the clinical assessment and other investigations to assist in the diagnosis of TOS. LEVEL OF EVIDENCE: IV, retrospective cohort study.

Joint Effusion and Bone Outlines of the Knee: Radiographic/MR Imaging Correlation.

Knee radiographs are widely used in clinical practice. Many features can be depicted when a systematic analysis of the different views is performed. This article focuses on different types of joint effusion and on the analysis of the bone outlines of the knee, particularly on the lateral view. Systematic analysis of these bone outlines and knowledge of several key points are particularly useful for the depiction of abnormal bone morphology or positioning, and of several conditions, such as trochlear dysplasia, patellar dislocation, impaction fractures, or ligament injuries and avulsion fractures.

Exercise referral schemes enhanced by self-management strategies to reduce sedentary behaviour and increase physical activity among community-dwelling older adults from four European countries: protocol for the process evaluation of the SITLESS randomised controlled trial.

INTRODUCTION: SITLESS is a randomised controlled trial determining whether exercise referral schemes can be enhanced by self-management strategies to reduce sedentary behaviour and increase physical activity in the long term, in community-dwelling older citizens. The intervention is complex and requires a process evaluation to understand how implementation, causal mechanisms and context shape outcomes. The specific aims are to assess fidelity and reach of the implementation, understand the contextual aspects of each intervention site, evaluate the mechanisms of impact, and explore perceived effects. METHODS AND ANALYSIS: Following the Medical Research Council guidance on complex interventions, a combination of qualitative and quantitative procedures is applied, including observational checklists and attendance registries, standardised scales (ie, Marcus's Self-Efficacy Questionnaire, Physical Activity Self-Regulation Scale and the Lubben Social Network Scale) at baseline, postintervention and follow-up assessments, semistructured questionnaires gathering contextual characteristics, and participant observations of the sessions. Semistructured interviews and focus groups with the participants and trainers are conducted at postintervention and during the follow-up to explore their experiences. Outcomes from the standardised scales are analysed as moderators within the impact evaluation. Descriptive results on context and perceived effects complement results on impact. The qualitative and quantitative findings will help to refine the logic model to finally support the interpretation of the results on the effectiveness of the intervention. ETHICS AND DISSEMINATION: The study design was approved by the respective Ethical Committee of Ramon Llull University, Southern Denmark, Northern Ireland and Ulm University. Participation is voluntary, and all participants are asked to sign informed consent before starting the study. A dissemination plan operationalises how to achieve a social impact by reaching academic and non-academic stakeholders. A data management plan describes the specific data sets and regulates its deposition and curation. All publications will be open access. TRIAL REGISTRATION NUMBER: NCT02629666; Pre-results.