Developing a digital informed consent app: opportunities and challenges of a new format to inform and obtain consent in public health research.

BACKGROUND: Informed consent procedures for large population-based cohort studies should be comprehensive and easy-to-use. This is particularly challenging when participants from different socio-economic groups and multicultural ethnic backgrounds are involved. Recently, more and more studies have tried to use multimedia in informed consent procedures. We describe the development and testing of a digital informed consent app and elaborate on whether this may contribute to a comprehensive and practical procedure to obtain informed consent for public health research. METHODS: In a sample of parents with young children, we used a mixed method approach to study the user experience of an informed consent app and evaluate whether it can be used to adequately inform people and register their consent. Through semi-structured interviews we investigated participants' experiences with and opinions about the app, with a special focus on comprehensibility of the content and the usability of the app. Information retention questions were asked to evaluate to what extent participants could recall key aspects of the provided study information. RESULTS: The 30 participants in this study used the app between 4 and 15 min to give their consent. Overall, they found the app well-designed, informative and easy to use. To learn more about the study for which informed consent is asked, most of the participants chose to watch the animated film, which was generally found to convey information in a clear manner. The identification process was met with mixed reactions, with some feeling it as a secure way to give consent, while for others it contradicted their view of using data anonymously. Information retention questions showed that while all participants remembered various aspects of the study, fewer than half answered all four questions satisfactorily. CONCLUSION: Our study shows that a well-designed informed consent app can be an effective tool to inform eligible participants and to record consents. Still, some issues remain, including trust barriers towards the identification procedure and lack of information retention in some participants. When implementing consent procedures that incorporate digital formats, it may be beneficial to also invest in a complementary face-to-face recruitment approach.

Synthesis and characterization of a novel series of agonist compounds as potential radiopharmaceuticals for imaging dopamine D2/3 receptors in their high-affinity state.

Imaging of dopamine D2/3 receptors (D2/3R) can shed light on the nature of several neuropsychiatric disorders in which dysregulation of D2/3R signaling is involved. Agonist D2/3 tracers for PET/SPECT imaging are considered to be superior to antagonists because they are more sensitive to dopamine concentrations and may selectively label the high-affinity receptor state. Carbon-11-labeled D2/3R agonists have been developed, but these short-lived tracers can be used only in centers with a cyclotron. Here, we report the development of a series of novel D2R agonist compounds based on the 2-aminomethylchromane (AMC) scaffold that provides ample opportunities for the introduction of longer-lived [(18)F] or [(123)I]. Binding experiments showed that several AMC compounds have a high affinity and selectivity for D2/3R and act as agonists. Two fluorine-containing compounds were [(18)F]-labeled, and both displayed specific binding to striatal D2/3R in rat brain slices in vitro. These findings encourage further in vivo evaluations.

Ex Vivo Characterization of a Novel Iodine-123-Labelled Aminomethylchroman as a Potential Agonist Ligand for SPECT Imaging of Dopamine D2/3 Receptors.

For imaging of dopamine D2/3 receptors, agonist tracers are favoured over antagonists because they are more sensitive to detection of dopamine release and because they may selectively label the high-affinity receptor state. We have developed novel D2/3 receptor selective agonists that can be radiolabelled with [(123)I], which label is advantageous over most other labels, such as carbon-11, as it has a longer half-life. Particularly, we considered (R) N-[7-hydroxychroman-2-yl]-methyl 4-iodobenzyl amine (compound 1) as an attractive candidate for development as it shows high binding affinity to D2/3 receptors in vitro, and here we report on the characterization of this first [(123)I]-labelled D2/3 receptor agonist radiopharmaceutical intended for SPECT imaging. The appropriate tin precursor for [(123)I]-1 was developed and was successfully radiolabelled with iodine-123 giving a moderate yield (30-35%) and a good purity (>95%) for [(123)I]-1. In biodistribution experiments in Wistar rats intravenous injection of [(123)I]-1 resulted in a fast brain uptake, where the observed binding in the D2/3 receptor-rich striatum was slightly higher than that in the cerebellum 30 min to 4 h p.i. Storage phosphor imaging experiments, however, did not show specific D2/3 receptor binding. In conclusion, despite promising in vitro data for 1, neither specific ex vivo binding nor high signal-to-noise ratios were found in rodents for [(123)I]-1.

Agonist signalling properties of radiotracers used for imaging of dopamine D2/3 receptors.

BACKGROUND: Dopamine D2/3 receptor (D2/3R) agonist radiopharmaceuticals are considered superior to antagonists to detect dopamine release, e.g. induced by amphetamines. Agonists bind preferentially to the high-affinity state of the dopamine D2R, which has been proposed as the reason why agonists are more sensitive to detect dopamine release than antagonist radiopharmaceuticals, but this theory has been challenged. Interestingly, not all agonists similarly activate the classic cyclic adenosine mono phosphate (cAMP) and the ?-arrestin-2 pathway, some stimulate preferentially one of these pathways; a phenomenon called biased agonism. Because these pathways can be affected separately by pathologies or drugs (including dopamine releasers), it is important to know how agonist radiotracers act on these pathways. Therefore, we characterized the intracellular signalling of the well-known D2/3R agonist radiopharmaceuticals NPA and PHNO and of several novel D2/3R agonists. METHODS: cAMP accumulation and ?-arrestin-2 recruitment were measured on cells expressing human D2R. RESULTS: All tested agonists showed (almost) full agonism in both pathways. CONCLUSIONS: The tested D2/3R agonist radiopharmaceuticals did not exhibit biased agonism in vitro. Consequently, it is likely that drugs (including psychostimulants like amphetamines) and/or pathologies that influence the cAMP and/or the ?-arrestin-2 pathway may influence the binding of these radiopharmaceuticals.

A simple breath sampling method in intubated and mechanically ventilated critically ill patients.

Volatile organic compounds (VOCs) in breath may serve as biomarkers of pulmonary infection or inflammation. We developed and validated a new breath sampling method for VOC analysis in ventilated patients. Breath was collected from the ventilatory circuit using cheap disposables. VOCs were identified by gas-chromatography and mass-spectrometry (GC-MS) at various minute volumes during ventilation of an artificial lung (in vitro) and ventilated patients (in vivo). Sixty-four VOCs emendated from the ventilator and tubing. Their concentrations had an inverse correlation with minute volume in in vitro experiments (median correlation coefficient: -0.61 [25-75th percentile: -0.66 to -0.43]). Forty-four of these "ventilator-associated VOCs" were also observed in vivo, without correlations with minute volume. In vivo experiments showed that only positive end-expiratory pressure influenced the concentration of breath VOCs. The sampling method was highly reproducible (median intra-class correlation 0.95 [25-75th percentile: 0.87-0.97]). In conclusion, a novel, simple and repeatable sampling method was developed and validated for capturing exhaled VOCs in ventilated patients, which could allow for large-scale breath analysis in clinical studies.

Usability of digital media in patients with COPD: a pilot study.

BACKGROUND: Digital media can be integrated in tele-monitoring solutions, serving as the main interface between the patient and the caregiver. Consequently, the selection of the most appropriate digital medium for the specified target group is critical to ensure compliance with the tele-monitoring system. OBJECTIVES: This pilot study aims to gather insights from patients with chronic obstructive pulmonary disease (COPD) on the ease-of-use, efficacy, effectiveness, and satisfaction of different types of digital media. METHODS: Five off-the-shelf digital media devices were tested on nine patients at CIRO+ in Horn, The Netherlands. Usability was evaluated by asking patients to use each device to answer questions related to their symptoms and health status. Subsequently, patients completed a paper-based device usability questionnaire, which assessed prior experience with digital media, device dimensions, device controllability, response speed, screen readability, ease-of-use, and overall satisfaction. After testing all the devices, patients ranked the devices according to their preference. RESULTS: We identified the netbook as the preferred type of device due to its good controllability, fast response time, and large screen size. The smartphone was the least favorite device as patients found the size of the screen to be too small, which made it difficult to interact with. CONCLUSION: The pilot study has provided important insights to guide the selection of the most appropriate type of digital medium for implementation in tele-monitoring solutions for patients with COPD. As the digital medium is an important interface to the patient in tele-monitoring solutions, it is essential that patients feel motivated to interact with the digital medium on a regular basis.

Synthesis and in vitro evaluation of novel nortropane derivatives as potential radiotracers for muscarinic m(2) receptors.

Disturbances of the cerebral cholinergic neurotransmitter system are present in neurodegenerative disorders. SPECT or PET imaging, using radiotracers that selectively target muscarinic receptor subtypes, may be of value for in vivo evaluation of such conditions. 6ß-acetoxynortropane, a potent muscarinic M(2) receptor agonist, has previously demonstrated nanomolar affinity and high selectivity for this receptor. Based on this compound we synthesized four nortropane derivatives that are potentially suitable for SPECT imaging of the M(2) receptor. 6ß-acetoxynortropane and the novel derivatives were tested in vitro for affinity to the muscarinic M(1-3) receptors. The original 6ß-acetoxynortropane displayed high affinity (K(i) = 70-90 nM) to M(2) receptors and showed good selectivity ratios to the M(1) (65-fold ratio) and the M(3) (70-fold ratio) receptors. All new derivatives showed reduced affinity to the M(2) subtype and loss of subtype selectivity. It is therefore concluded that the newly synthesized derivatives are not suitable for human SPECT imaging of M(2) receptors.

In vivo prediction of response to antiestrogen treatment in estrogen receptor-positive breast cancer.

UNLABELLED: In metastatic breast cancer, the estrogen receptor (ER) is a well-known prognostic factor predictive of response to hormonal treatment in most, but not all, patients. Recently, a receptor-specific radioligand for in vivo imaging of the ER in breast cancer patients was developed: (123)I-labeled cis-11beta-methoxy-17alpha-iodovinyl-estradiol (Z-(123)I-MIVE). It showed high sensitivity and specificity for the in vivo detection of ER-positive breast cancer. The aim of this study was to determine whether Z-(123)I-MIVE scintigraphy is able to predict response or resistance to antiestrogen therapy in patients with metastatic ER-positive breast carcinoma. METHODS: Twenty-three patients with first metastases of their breast cancer and positive Z-(123)I-MIVE scintigraphy were included and treated with tamoxifen, 40 mg/d. Scintigraphy was repeated, on average, 4 wk later. The results of these scintigraphies were compared with the clinical outcome. RESULTS: On baseline scintigraphy, 21 of 23 patients had clear uptake and 2 of 23 patients had faint uptake of Z-(123)I-MIVE. After initiation of antiestrogen treatment, 17 of 21 patients with clear uptake on baseline scintigraphy showed complete blockade of ER activity on the Z-(123)I-MIVE scintigraphy. Four of 21 patients showed mixed or no ER blockade. All patients with faint baseline uptake or mixed or no ER blockade after tamoxifen showed progressive disease despite antiestrogen treatment. Patients with clear baseline uptake and complete ER blockade after tamoxifen had a significantly longer progression-free interval (mean +/- SEM, 14.4 +/- 1.6 vs. 1.8 +/- 0.8 mo; P < 0.01). CONCLUSION: Z-(123)I-MIVE scintigraphy seems to be a useful tool to predict response or resistance to antiestrogen treatment in ER-positive metastatic breast cancer patients and to depict nonresponders before the clinical manifestation of progression.

Synthesis and evaluation of iodinated TZTP-derivatives as potential radioligands for imaging of muscarinic M2 receptors with SPET.

A series of iodinated thiadiazolyltetrahydro-1-methyl-pyridine (TZTP) compounds was synthesized and evaluated in vitro and in vivo as potential radioligands for imaging of the muscarinic M2 receptor subtype with SPET. One of these compounds, 5-(E)-iodopentenylthio-TZTP, has high in vitro affinity (Ki = 4.9 nM) and moderate selectivity for the muscarinic M2 receptor subtype. Although the uptake pattern in the biodistribution studies in rats is consistent with muscarinic M2 receptor disribution, specific in vivo binding to these receptors could not be demonstrated. The usefulness of this tracer in human SPET imaging may therefore be limited.