Co-simulation of human digital twins and wearable inertial sensors to analyse gait event estimation.

We propose a co-simulation framework comprising biomechanical human body models and wearable inertial sensor models to analyse gait events dynamically, depending on inertial sensor type, sensor positioning, and processing algorithms. A total of 960 inertial sensors were virtually attached to the lower extremities of a validated biomechanical model and shoe model. Walking of hemiparetic patients was simulated using motion capture data (kinematic simulation). Accelerations and angular velocities were synthesised according to the inertial sensor models. A comprehensive error analysis of detected gait events versus reference gait events of each simulated sensor position across all segments was performed. For gait event detection, we considered 1-, 2-, and 4-phase gait models. Results of hemiparetic patients showed superior gait event estimation performance for a sensor fusion of angular velocity and acceleration data with lower nMAEs (9%) across all sensor positions compared to error estimation with acceleration data only. Depending on algorithm choice and parameterisation, gait event detection performance increased up to 65%. Our results suggest that user personalisation of IMU placement should be pursued as a first priority for gait phase detection, while sensor position variation may be a secondary adaptation target. When comparing rotatory and translatory error components per body segment, larger interquartile ranges of rotatory errors were observed for all phase models i.e., repositioning the sensor around the body segment axis was more harmful than along the limb axis for gait phase detection. The proposed co-simulation framework is suitable for evaluating different sensor modalities, as well as gait event detection algorithms for different gait phase models. The results of our analysis open a new path for utilising biomechanical human digital twins in wearable system design and performance estimation before physical device prototypes are deployed.

Identifying and characterising sources of variability in digital outcome measures in Parkinson's disease.

Smartphones and wearables are widely recognised as the foundation for novel Digital Health Technologies (DHTs) for the clinical assessment of Parkinson's disease. Yet, only limited progress has been made towards their regulatory acceptability as effective drug development tools. A key barrier in achieving this goal relates to the influence of a wide range of sources of variability (SoVs) introduced by measurement processes incorporating DHTs, on their ability to detect relevant changes to PD. This paper introduces a conceptual framework to assist clinical research teams investigating a specific Concept of Interest within a particular Context of Use, to identify, characterise, and when possible, mitigate the influence of SoVs. We illustrate how this conceptual framework can be applied in practice through specific examples, including two data-driven case studies.

Simulating the impact of noise on gait features extracted from smartphone sensor-data for the remote assessment of movement disorders.

Signs and symptoms of movement disorders can be remotely measured at home through sensor-based assessment of gait. However, sensor noise may impact the robustness of such assessments, in particular in a Bring-Your-Own-Device setting where the quality of sensors might vary. Here, we propose a framework to study the impact of inertial measurement unit noise on sensor-based gait features. This framework includes synthesizing realistic acceleration signals from the lower back during a gait cycle in OpenSim, estimating the magnitude of sensor noise from five smartphone models, perturbing the synthesized acceleration signal with the estimated noise in a Monte Carlo simulation, and computing gait features. In addition, we show that realistic levels of sensor noise have only a negligible impact on step power, a measure of gait.

Presentations with reported methamphetamine use to an urban emergency department in Switzerland.

AIMS OF THE STUDY: The stimulant methamphetamine (e.g., "crystal meth") is a commonly abused drug in many parts of the world and can cause significant health problems. The present study aims to describe presentations with reported methamphetamine use at an urban emergency department (ED) in Switzerland, to investigate prevalence, patterns and susceptible groups. METHODS: Retrospective study at the ED of the University Hospital of Bern, Switzerland. Cases from June 2012 to July 2019 were retrieved from the electronic patient database using full-text terms and were categorised into three groups based on patient history: "acute", if patients presented within 72 hours of last reported use, "chronic" in cases of regular use but not within the previous 72 hours, and "past" in cases of discontinued consumption. Cases with a positive methamphetamine urine drug screening test with no further information available were described separately. RESULTS: During the study period, 40 cases were categorised as "acute". Among those, the mean age was 29.5 years (standard deviation [SD] 8.7), 75% (n = 30) were male, and agitation (n = 11, 28%), hypertension (n = 11, 28%), tachycardia (n = 11, 28%), sleep disturbances (n = 10, 25%) and aggression (n = 8, 20%) were the most common symptoms. Most patients (n = 22, 55%) were medically discharged, but 35% (n = 14) were admitted to a psychiatric clinic. Most (n = 33, 82.5%) were polydrug users, with alcohol, cocaine and cannabis being the most frequent co-used substances. The "chronic" group included 37 cases. Those patients were mostly male (n = 26, 70%), with a mean age of 31 years (SD 11.0), and 46% (n = 17) presented because of psychiatric symptoms, such as psychosis, depression or aggression. Of the 45 cases in the "past" group (mean age of 30 years, SD 8.6), 69% (n = 31) were male, and 49% (n = 22) and 24% (n = 11), respectively, had medical and psychiatric symptoms as the reason for admission. Of 61 cases with a positive urine drug screening test as the sole indicator of methamphetamine use, 19 patients reported MDMA use (cross-reactivity with methamphetamine in the urine immunoassay used). In the 42 remaining cases, it was unclear if the positive result was due to unreported methamphetamine use or cross-reactivity. CONCLUSIONS: Most patients with reported methamphetamine use were young and male, with signs of sympathomimetic arousal and/or psychiatric symptoms. Although ED visits with reports of methamphetamine use appear to be uncommon, consumption-related health problems can require significant pre- and in-hospital resources.

Retrospective analysis of adverse drug reactions leading to short-term emergency hospital readmission.

AIMS OF THE STUDY: Adverse drug reactions (ADRs) are an important cause of hospital admissions. Insufficient data are available about the frequency and characteristics of ADR-related emergency readmissions in Switzerland. The aim of this retrospective study was to characterise ADRs related to short-term emergency readmissions in a large Swiss University Hospital and to assess their reporting frequency. METHODS: Electronic records of all patients discharged from the University Hospital Bern within a 12-month period (1 January to 31 December 2012) and emergency readmission within 30 calendar days were reviewed. Case inclusion required a known ADR. Cases with intentional overdosing, lack of compliance or insufficient documentation were excluded. Identified ADR-related readmission cases were searched in the Swiss ADR reporting system to assess reporting rate. RESULTS: There were 1294 emergency readmissions among the 4792 readmissions (14% of all admissions) within 30 days after discharge. We identified 270 cases of ADR-related readmissions, corresponding to 21% of emergency readmissions and 6% of all readmissions within 30 days. The most frequent ADRs were gastrointestinal disorders (26%), infections and infestations (19%), and nervous system disorders (10%). The most frequent drug classes leading to ADRs were antineoplastic/immunomodulating (35%) and antithrombotic agents (25%). Only 8 (3%) of the 270 cases were reported to the Swiss ADR reporting system. CONCLUSION: ADR-related readmissions constituted a considerable part of short-term emergency readmissions. Despite being a relevant cause for rehospitalisation, only a minority of the ADRs were reported to the regulatory authorities. Strategies to prevent ADR-related readmissions and to improve reporting rates are needed.

Estimating wearable motion sensor performance from personal biomechanical models and sensor data synthesis.

We present a fundamentally new approach to design and assess wearable motion systems based on biomechanical simulation and sensor data synthesis. We devise a methodology of personal biomechanical models and virtually attach sensor models to body parts, including sensor positions frequently considered for wearable devices. The simulation enables us to synthesise motion sensor data, which is subsequently considered as input for gait marker estimation algorithms. We evaluated our methodology in two case studies, including running athletes and hemiparetic patients. Our analysis shows that running speed affects gait marker estimation performance. Estimation error of stride duration varies between athletes across 834 simulated sensor positions and can soar up to 54%, i.e. 404 ms. In walking patients after stroke, we show that gait marker performance differs between affected and less-affected body sides and optimal sensor positions change over a period of movement therapy intervention. For both case studies, we observe that optimal gait marker estimation performance benefits from personally selected sensor positions and robust algorithms. Our methodology enables wearable designers and algorithm developers to rapidly analyse the design options and create personalised systems where needed, e.g. for patients with movement disorders.

Mobile Health Usage, Preferences, Barriers, and eHealth Literacy in Rheumatology: Patient Survey Study.

BACKGROUND: Mobile health (mHealth) defines the support and practice of health care using mobile devices and promises to improve the current treatment situation of patients with chronic diseases. Little is known about mHealth usage and digital preferences of patients with chronic rheumatic diseases. OBJECTIVE: The aim of the study was to explore mHealth usage, preferences, barriers, and eHealth literacy reported by German patients with rheumatic diseases. METHODS: Between December 2018 and January 2019, patients (recruited consecutively) with rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis were asked to complete a paper-based survey. The survey included questions on sociodemographics, health characteristics, mHealth usage, eHealth literacy using eHealth Literacy Scale (eHEALS), and communication and information preferences. RESULTS: Of the patients (N=193) who completed the survey, 176 patients (91.2%) regularly used a smartphone, and 89 patients (46.1%) regularly used social media. Patients (132/193, 68.4%) believed that using medical apps could be beneficial for their own health. Out of 193 patients, only 8 (4.1%) were currently using medical apps, and only 22 patients (11.4%) stated that they knew useful rheumatology websites/mobile apps. Nearly all patients (188/193, 97.4%) would agree to share their mobile app data for research purposes. Out of 193 patients, 129 (66.8%) would regularly enter data using an app, and 146 patients (75.6%) would welcome official mobile app recommendations from the national rheumatology society. The preferred duration for data entry was not more than 15 minutes (110/193, 57.0%), and the preferred frequency was weekly (59/193, 30.6%). Medication information was the most desired app feature (150/193, 77.7%). Internet was the most frequently utilized source of information (144/193, 74.6%). The mean eHealth literacy was low (26.3/40) and was positively correlated with younger age, app use, belief in benefit of using medical apps, and current internet use to obtain health information. CONCLUSIONS: Patients with rheumatic diseases are very eager to use mHealth technologies to better understand their chronic diseases. This open-mindedness is counterbalanced by low mHealth usage and competency. Personalized mHealth solutions and clear implementation recommendations are needed to realize the full potential of mHealth in rheumatology.

Synthesising motion sensor data from biomechanical simulations to investigate motion sensor placement and orientation variations.

We propose a motion sensor data synthesis approach to investigate the performance effect of sensor placement and orientation variation on health marker estimation. Using OpenSim, we simulate walking motion of patients after stroke and synthesise inertial sensor data. We analyse 384 sensor positions with 192 sensors simulated at each leg's thigh. To demonstrate how synthesised sensor data could be used to analyse the performance of functional ability estimation, we estimated scores from the Lower-Extremity Fugl-Meyer-Assessment (LE-FMA) using regression methods. We evaluated our approach using a public dataset, including 8 stroke patients and showed that LE-FMA scores could be estimated with an error below 0.12 score points on average, compared to manually derived scores. We further show that sensors should be preferably placed at the thigh front. Our approach demonstrates the potential of combining biomechanical simulations and motion sensor data synthesis with algorithms for health marker estimation, thus providing rapid insight into sensor positioning and orientation variation.

Physical Activity Comparison Between Body Sides in Hemiparetic Patients Using Wearable Motion Sensors in Free-Living and Therapy: A Case Series.

Background: Physical activity (PA) is essential in stroke rehabilitation of hemiparetic patients to avoid health risks, and moderate to vigorous PA could promote patients' recovery. However, PA assessments are limited to clinical environments. Little is known about PA in unguided free-living. Wearable sensors could reveal patients' PA during rehabilitation, and day-long long-term measurements over several weeks might reveal recovery trends of affected and less-affected body sides. Methods: We investigated PA in an observation study during outpatient rehabilitation in a day-care center. PA of affected and less-affected body sides, including upper and lower limbs were derived using wearable motion sensors. In this analysis we focused on PA during free-living and clinician guided therapies, and investigated differences between body-sides. Linear regressions were used to estimate metabolic equivalents for each limb at comparable scale. Non-parametric statistics were derived to quantify PA differences between body sides. Results: We analyzed 102 full-day movement data recordings from eleven hemiparetic patients during individual rehabilitation periods up to 79 days. The comparison between free-living and clinician guided therapy showed on average 16.1 % higher PA in the affected arm during therapy and 5.3 % higher PA in the affected leg during therapy. Average differences between free-living and therapy in the less-affected side were below 4.5 %. Conclusion: We analyzed PA of patients with a hemiparesis in two distinct rehabilitation settings, including free-living and clinician guided therapies over several weeks and compared MET values of affected and less-affected body sides. In particular, we investigated PA using individual regression models for each limb. We demonstrated that wearable motion sensors provide insights in patient's PA during rehabilitation. Although, no clear PA trends were found, our analysis showed patients' tendency to sedentary behavior, confirming previous lab study results. Our PA analysis approach could be used beyond clinical rehabilitation to devise personalized patient and limb-specific exercise recommendations in future remote rehabilitation.

Longitudinal Walking Analysis in Hemiparetic Patients Using Wearable Motion Sensors: Is There Convergence Between Body Sides?

Background: Longitudinal movement parameter analysis of hemiparetic patients over several months could reveal potential recovery trends and help clinicians adapting therapy strategies to maximize recovery outcome. Wearable sensors offer potential for day-long movement recordings in realistic rehabilitation settings including activities of daily living, e.g., walking. The measurement of walking-related movement parameters of affected and non-affected body sides are of interest to determine mobility and investigate recovery trends. Methods: By comparing movement of both body sides, recovery trends across the rehabilitation duration were investigated. We derived and validated selected walking segments from free-living, day-long movement by using rules that do not require data-based training or data annotations. Automatic stride segmentation using peak detection was applied to walking segments. Movement parameters during walking were extracted, including stride count, stride duration, cadence, and sway. Finally, linear regression models over each movement parameter were derived to forecast the moment of convergence between body sides. Convergence points were expressed as duration and investigated in a patient observation study. Results: Convergence was analyzed in walking-related movement parameters in an outpatient study including totally 102 full-day recordings of inertial movement data from 11 hemiparetic patients. The recordings were performed over several months in a day-care centre. Validation of the walking extraction method from sensor data yielded sensitivities up to 80 % and specificity above 94 % on average. Comparison of automatically and manually derived movement parameters showed average relative errors below 6 % between affected and non-affected body sides. Movement parameter variability within and across patients was observed and confirmed by case reports, reflecting individual patient behavior. Conclusion: Convergence points were proposed as intuitive metric, which could facilitate training personalization for patients according to their individual needs. Our continuous movement parameter extraction and analysis, was feasible for realistic, day-long recordings without annotations. Visualizations of movement parameter trends and convergence points indicated that individual habits and patient therapies were reflected in walking and mobility. Context information of clinical case reports supported trend and convergence interpretation. Inconsistent convergence point estimation suggested individually varying deficiencies. Long-term recovery monitoring using convergence points could support patient-specific training strategies in future remote rehabilitation.

Effects of Cytochrome P450 Inhibition and Induction on the Phenotyping Metrics of the Basel Cocktail: A Randomized Crossover Study.

BACKGROUND AND OBJECTIVE: Activity of human cytochrome P450 enzymes (CYPs) shows high inter-and intra-individual variability, which is determined by genetic and non-genetic factors. Using a combination of CYP-specific probe drugs, phenotyping cocktails allow simultaneous assessment of the activity of different CYP isoforms. The objective of this study was to characterize the phenotyping metrics of the Basel cocktail in healthy male subjects with induced and inhibited CYP activity. METHODS: In a randomized crossover study, the probe drugs for simultaneous phenotyping of CYP1A2 (caffeine), CYP2B6 (efavirenz), CYP2C9 (losartan), 2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A4 (midazolam) were administered to 16 subjects without pretreatment (baseline), after pretreatment with a combination of CYP inhibitors (ciprofloxacin, ketoconazole, and paroxetine), and after CYP induction with rifampicin. All subjects were genotyped. Pharmacokinetic profiles of the probe drugs and their main metabolites and metabolic ratios 2, 4, 6, and 8 h after probe drug application were determined in plasma and compared with the corresponding area under the plasma concentration-time curve (AUC) ratios. RESULTS: The Basel phenotyping cocktail was well tolerated by all subjects independent of pretreatment. Good correlations of metabolic ratios with AUC ratios of the corresponding probe drugs and their metabolites for all three conditions (baseline, CYP inhibition, and CYP induction) were found at 2 h after probe drug administration for CYP3A4, at 4 h for CYP1A2 and CYP2C19, and at 6 h for CYP2B6 and CYP2D6. While CYP inhibition significantly changed AUC ratios and metabolic ratios at these time points for all six CYP isoforms, CYP induction did not significantly change AUC ratios for CYP2C9. For CYP3A4, total 1'-hydroxymidazolam concentrations after pretreatment of samples with ß-glucuronidase were needed to obtain adequate reflection of CYP induction by the metabolic ratio. CONCLUSIONS: Inhibition of CYP activity can be detected with the Basel phenotyping cocktail for all six tested CYP isoforms at the proposed time points. The AUC ratio of losartan:losartan carboxylic acid in plasma does not seem suitable to detect induction of CYP2C9. The observed metabolic ratios for inhibited and induced CYP activity need to be confirmed for extensive metabolizers, and typical ratios for subjects with genetically altered CYP activity will need to be established in subsequent studies. ClinicalTrials.gov-ID: NCT01386593.

[Drug-induced acute kidney injury]. / Medikamentös bedingte akute Nierenschädigung.

Due to their physiological function, the kidneys are exposed to high concentrations of numerous drugs and their metabolites, making them vulnerable to drug-related injuries. This article provides an overview of the pathophysiological mechanisms involved in nephrotoxicity, the most common nephrotoxic drugs, and the risk factors for the occurrence of drug-induced acute kidney injuries. NSAIDs, diuretics, ACE inhibitors, and angiotensin II receptor blockers (ARBs} are the most frequent prerenal causes of an acute elevation in creatinine levels. Primary vascular damage arises from thrombotic microangiopathy (e. g. due to cic/osporin, tacrolimus, muromonab-CD3, mitomycin C, quinine, ticlopidine, clopidogrel}. Anticoagulants and thrombolytic medications lead to secondary blood vessel damage by cholesterol emboli, embolism of thrombus material into the periphery or bleeding. Tubulopathies can be observed on treatment with ifosfamide and cisplatin (rarely with cyclophosphamide or carboplatin), aminoglycosides, vancomycin, and radiocontrast agents. Immunological mechanisms underlie interstitial nephritides, which are induced by drugs in about 85% of cases. In drug-induced glomerulopathies;- renal biopsy allows closer identification of the triggering medication. Drug-induced systemic lupus erythematosus (SLE} represents a special form of immune complex glomerulonephritis and can be triggered by procainamide, hydralazine, isoniazid, methyldopa, quinidine, chlorpromazine, and propylthiouracil. Crystal-induced kidney injury is caused by precipitation of drugs (e. g. aciclovir, sulfonamide antibiotics, methotrexate, indinavir) in the renal tubules and the urine-conducting organs with consecutive obstruction thereof.

Therapeutic drug monitoring of once daily aminoglycoside dosing: comparison of two methods and investigation of the optimal blood sampling strategy.

PURPOSE: Therapeutic drug monitoring of patients receiving once daily aminoglycoside therapy can be performed using pharmacokinetic (PK) formulas or Bayesian calculations. While these methods produced comparable results, their performance has never been checked against full PK profiles. We performed a PK study in order to compare both methods and to determine the best time-points to estimate AUC0-24 and peak concentrations (C max). METHODS: We obtained full PK profiles in 14 patients receiving a once daily aminoglycoside therapy. PK parameters were calculated with PKSolver using non-compartmental methods. The calculated PK parameters were then compared with parameters estimated using an algorithm based on two serum concentrations (two-point method) or the software TCIWorks (Bayesian method). RESULTS: For tobramycin and gentamicin, AUC0-24 and C max could be reliably estimated using a first serum concentration obtained at 1 h and a second one between 8 and 10 h after start of the infusion. The two-point and the Bayesian method produced similar results. For amikacin, AUC0-24 could reliably be estimated by both methods. C max was underestimated by 10-20% by the two-point method and by up to 30% with a large variation by the Bayesian method. CONCLUSIONS: The ideal time-points for therapeutic drug monitoring of once daily administered aminoglycosides are 1 h after start of a 30-min infusion for the first time-point and 8-10 h after start of the infusion for the second time-point. Duration of the infusion and accurate registration of the time-points of blood drawing are essential for obtaining precise predictions.

The basel cocktail for simultaneous phenotyping of human cytochrome P450 isoforms in plasma, saliva and dried blood spots.

BACKGROUND AND OBJECTIVE: Phenotyping cocktails use a combination of cytochrome P450 (CYP)-specific probe drugs to simultaneously assess the activity of different CYP isoforms. To improve the clinical applicability of CYP phenotyping, the main objectives of this study were to develop a new cocktail based on probe drugs that are widely used in clinical practice and to test whether alternative sampling methods such as collection of dried blood spots (DBS) or saliva could be used to simplify the sampling process. METHODS: In a randomized crossover study, a new combination of commercially available probe drugs (the Basel cocktail) was tested for simultaneous phenotyping of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Sixteen subjects received low doses of caffeine, efavirenz, losartan, omeprazole, metoprolol and midazolam in different combinations. All subjects were genotyped, and full pharmacokinetic profiles of the probe drugs and their main metabolites were determined in plasma, dried blood spots and saliva samples. RESULTS: The Basel cocktail was well tolerated, and bioequivalence tests showed no evidence of mutual interactions between the probe drugs. In plasma, single timepoint metabolic ratios at 2 h (for CYP2C19 and CYP3A4) or at 8 h (for the other isoforms) after dosing showed high correlations with corresponding area under the concentration-time curve (AUC) ratios (AUC0-24h parent/AUC0-24h metabolite) and are proposed as simple phenotyping metrics. Metabolic ratios in dried blood spots (for CYP1A2 and CYP2C19) or in saliva samples (for CYP1A2) were comparable to plasma ratios and offer the option of minimally invasive or non-invasive phenotyping of these isoforms. CONCLUSIONS: This new combination of phenotyping probe drugs can be used without mutual interactions. The proposed sampling timepoints have the potential to facilitate clinical application of phenotyping but require further validation in conditions of altered CYP activity. The use of DBS or saliva samples seems feasible for phenotyping of the selected CYP isoforms.

Sympathomimetic toxicity in a case of analytically confirmed recreational use of naphyrone (naphthylpyrovalerone).

CONTEXT: Naphyrone (naphthylpyrovalerone) is a cathinone derivative and recreational drug related to mephedrone. CASE: We report a 31-year-old man who ingested a dose of naphyrone (100 mg), which produced acute sympathomimetic toxicity with restlessness, insomnia, anxiety, and hallucinations lasting for 2 days. Naphyrone was detected in the patient's plasma by gas chromatography with mass spectrometry at concentrations of 0.03 and 0.02 mg/L, 40 and 60 h after drug intake, respectively. DISCUSSION: Based on the present case report and user web-reports, as well as on the chemical structure and pharmacological characteristics, naphyrone produces stimulant-like psychotropic effects and sympathomimetic toxicity.

[Rash, fever, eosinophilia and elevated liver enzymes. DRESS syndrome (drug reaction or rash with eosinophilia and systemic symptoms)]. / Exanthem, Fieber, Eosinophilie und erhöhte Leberwerte. DRESS syndrome (drug reaction or rash with eosinophilia and systemic symptoms).

We report on a patient with Pneumocystis jirovecii pneumonia who developed fever, rash, eosinophilia and hepatitis 10 days after initiation of a therapy with sulfamethoxazole and trimethoprim. A DRESS syndrome was diagnosed and the therapy was changed successfully to pyrimethamine and dapsone. We describe the clinical picture, causative drugs, pathogenesis, differential diagnoses and therapy of this life-threatening disease to acquaint the general practitioner with it.

Functional definition of the mutation cluster region of adenomatous polyposis coli in colorectal tumours.

The mutation cluster region (MCR) of adenomatous polyposis coli (APC) is located within the central part of the open reading frame, overlapping with the region encoding the 20 amino acid repeats (20R) that are beta-catenin-binding sites. Each mutation in the MCR leads to the synthesis of a truncated APC product expressed in a colorectal tumour. The MCR extends from the 3' border of the first 20R coding region to approximately the middle of the third 20R coding region, reflecting both positive and negative selections of the N- and C-terminal halves of the APC protein in colon cancer cells, respectively. In contrast, the second 20R escapes selection and can be either included or excluded from the truncated APC products found in colon cancer cells. To specify the functional outcome of the selection of the mutations, we investigated the beta-catenin binding capacity of the first three 20R in N-terminal APC fragments. We found in co-immunoprecipitation and intracellular co-localization experiments that the second 20R is lacking any beta-catenin binding activity. Similarly, we also show that the tumour-associated truncations abolish the interaction of beta-catenin with the third 20R. Thus, our data provide a functional definition of the MCR: the APC fragments typical of colon cancer are selected for the presence of a single functional 20R, the first one, and are therefore equivalent relative to beta-catenin binding.