Saltatory Conduction along Myelinated Axons Involves a Periaxonal Nanocircuit.

The propagation of electrical impulses along axons is highly accelerated by the myelin sheath and produces saltating or "jumping" action potentials across internodes, from one node of Ranvier to the next. The underlying electrical circuit, as well as the existence and role of submyelin conduction in saltatory conduction remain, however, elusive. Here, we made patch-clamp and high-speed voltage-calibrated optical recordings of potentials across the nodal and internodal axolemma of myelinated neocortical pyramidal axons combined with electron microscopy and experimentally constrained cable modeling. Our results reveal a nanoscale yet conductive periaxonal space, incompletely sealed at the paranodes, which separates the potentials across the low-capacitance myelin sheath and internodal axolemma. The emerging double-cable model reproduces the recorded evolution of voltage waveforms across nodes and internodes, including rapid nodal potentials traveling in advance of attenuated waves in the internodal axolemma, revealing a mechanism for saltation across time and space.

Appreciating the Good Things in Life During the Covid-19 Pandemic: A Randomized Controlled Trial and Evaluation of a Gratitude App.

The Covid-19 pandemic has had many negative consequences on the general public mental health. The aim of this study was to test the effectiveness of and satisfaction with an app with gratitude exercises to improve the mental health of people with reduced mental well-being due to the Covid-19 pandemic, as well as potential mechanisms of well-being change and dose-response relationships. A two-armed randomized controlled trial design was used, with two groups receiving the 6-week gratitude intervention app either immediately (intervention group, n = 424) or after 6 weeks (waiting list control group, n = 425). Assessments took place online at baseline (T0), six weeks later (T1) and at 12 weeks (T2), measuring outcomes (i.e., mental well-being, anxiety, depression, stress), and potential explanatory variables (i.e., gratitude, positive reframing, rumination). Linear mixed models analyses showed that when controlled for baseline measures, the intervention group scored better on all outcome measures compared to the control group at T1 (d = .24-.49). These effects were maintained at T2. The control group scored equally well on all outcome measures at T2 after following the intervention. Effects of the intervention on well-being were partially explained by gratitude, positive reframing, and rumination, and finishing a greater number of modules was weakly related to better outcomes. The intervention was generally appealing, with some room for improvement. The results suggest that a mobile gratitude intervention app is a satisfactory and effective way to improve the mental health of the general population during the difficult times of a pandemic.

Loss of CRB2 in Müller glial cells modifies a CRB1-associated retinitis pigmentosa phenotype into a Leber congenital amaurosis phenotype.

Variations in the human Crumbs homolog-1 (CRB1) gene lead to an array of retinal dystrophies including early onset of retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) in children. To investigate the physiological roles of CRB1 and CRB2 in retinal Müller glial cells (MGCs), we analysed mouse retinas lacking both proteins in MGC. The peripheral retina showed a faster progression of dystrophy than the central retina. The central retina showed retinal folds, disruptions at the outer limiting membrane, protrusion of photoreceptor nuclei into the inner and outer segment layers and ingression of photoreceptor nuclei into the photoreceptor synaptic layer. The peripheral retina showed a complete loss of the photoreceptor synapse layer, intermingling of photoreceptor nuclei within the inner nuclear layer and ectopic photoreceptor cells in the ganglion cell layer. Electroretinography showed severe attenuation of the scotopic a-wave at 1 month of age with responses below detection levels at 3 months of age. The double knockout mouse retinas mimicked a phenotype equivalent to a clinical LCA phenotype due to loss of CRB1. Localization of CRB1 and CRB2 in non-human primate (NHP) retinas was analyzed at the ultrastructural level. We found that NHP CRB1 and CRB2 proteins localized to the subapical region adjacent to adherens junctions at the outer limiting membrane in MGC and photoreceptors. Our data suggest that loss of CRB2 in MGC aggravates the CRB1-associated RP-like phenotype towards an LCA-like phenotype.

CRB2 in immature photoreceptors determines the superior-inferior symmetry of the developing retina to maintain retinal structure and function.

The mammalian apical-basal determinant Crumbs homolog-1 (CRB1) plays a crucial role in retinal structure and function by the maintenance of adherens junctions between photoreceptors and Müller glial cells. Patients with mutations in the CRB1 gene develop retinal dystrophies, including early-onset retinitis pigmentosa and Leber congenital amaurosis. Previously, we showed that Crb1 knockout mice developed a slow-progressing retinal phenotype at foci in the inferior retina, although specific ablation of Crb2 in immature photoreceptors leads to an early-onset phenotype throughout the retina. Here, we conditionally disrupted one or both alleles of Crb2 in immature photoreceptors, on a genetic background lacking Crb1, and studied the retinal dystrophies thereof. Our data showed that disruption of one allele of Crb2 in immature photoreceptors caused a substantial aggravation of the Crb1 phenotype in the entire inferior retina. The photoreceptor layer showed early-onset progressive thinning limited to the inferior retina, although the superior retina maintained intact. Surprisingly, disruption of both alleles of Crb2 in immature photoreceptors further aggravated the phenotype. Throughout the retina, photoreceptor synapses were disrupted and photoreceptor nuclei intermingled with nuclei of the inner nuclear layer. In the superior retina, the ganglion cell layer appeared thicker because of ectopic nuclei of photoreceptors. In conclusion, the data suggest that CRB2 is required to maintain retinal progenitor and photoreceptor cell adhesion and prevent photoreceptor ingression into the immature inner retina. We hypothesize, from these animal models, that decreased levels of CRB2 in immature photoreceptors adjust retinitis pigmentosa because of the loss of CRB1 into Leber congenital amaurosis phenotype.

Degenerated Cones in Cultured Human Retinas Can Successfully Be Optogenetically Reactivated.

Biblical references aside, restoring vision to the blind has proven to be a major technical challenge. In recent years, considerable advances have been made towards this end, especially when retinal degeneration underlies the vision loss such as occurs with retinitis pigmentosa. Under these conditions, optogenetic therapies are a particularly promising line of inquiry where remaining retinal cells are made into "artificial photoreceptors". However, this strategy is not without its challenges and a model system using human retinal explants would aid its continued development and refinement. Here, we cultured post-mortem human retinas and show that explants remain viable for around 7 days. Within this period, the cones lose their outer segments and thus their light sensitivity but remain electrophysiologically intact, displaying all the major ionic conductances one would expect for a vertebrate cone. We optogenetically restored light responses to these quiescent cones using a lentivirus vector constructed to express enhanced halorhodopsin under the control of the human arrestin promotor. In these 'reactivated' retinas, we show a light-induced horizontal cell to cone feedback signal in cones, indicating that transduced cones were able to transmit their light response across the synapse to horizontal cells, which generated a large enough response to send a signal back to the cones. Furthermore, we show ganglion cell light responses, suggesting the cultured explant's condition is still good enough to support transmission of the transduced cone signal over the intermediate retinal layers to the final retinal output level. Together, these results show that cultured human retinas are an appropriate model system to test optogenetic vision restoration approaches and that cones which have lost their outer segment, a condition occurring during the early stages of retinitis pigmentosa, are appropriate targets for optogenetic vision restoration therapies.

The use of technology in the context of frailty screening and management interventions: a study of stakeholders' perspectives.

BACKGROUND: Health and social care interventions show promise as a way of managing the progression of frailty in older adults. Information technology could improve the availability of interventions and services for older adults. The views of stakeholders on the acceptability of technological solutions for frailty screening and management have not been explored. METHODS: Focus groups were used to gather data from healthy and frail/pre-frail older adults, health and social care providers, and caregivers in three European countries - Italy, Poland and UK. Data were analysed using framework analysis in terms of facilitators or determinants of older adults' adoption of technology. RESULTS: Our findings clustered around the perceived value; usability, affordability and accessibility; and emotional benefits of frailty screening and management technology to stakeholders. We also noted issues relating to social support, previous experience of technology and confidence of stakeholders. CONCLUSIONS: Professionals and caregivers understand the benefits of technology to facilitate frailty care pathways but these views are tempered by concerns around social isolation. Frail older adults raised legitimate concerns about the accessibility and usability of technology, specifically around the potential for their personal information to be compromised. Solutions must be developed within a framework that addresses social contexts and avoids stigma around frailty and ageing.

Gene therapy into photoreceptors and Müller glial cells restores retinal structure and function in CRB1 retinitis pigmentosa mouse models.

Mutations in the Crumbs-homologue-1 (CRB1) gene lead to severe recessive inherited retinal dystrophies. Gene transfer therapy is the most promising cure for retinal dystrophies and has primarily been applied for recessive null conditions via a viral gene expression vector transferring a cDNA encoding an enzyme or channel protein, and targeting expression to one cell type. Therapy for the human CRB1 disease will be more complex, as CRB1 is a structural and signaling transmembrane protein present in three cell classes: Müller glia, cone and rod photoreceptors. In this study, we applied CRB1 and CRB2 gene therapy vectors in Crb1-retinitis pigmentosa mouse models at mid-stage disease. We tested if CRB expression restricted to Müller glial cells or photoreceptors or co-expression in both is required to recover retinal function. We show that targeting both Müller glial cells and photoreceptors with CRB2 ameliorated retinal function and structure in Crb1 mouse models. Surprisingly, targeting a single cell type or all cell types with CRB1 reduced retinal function. We show here the first pre-clinical studies for CRB1-related eye disorders using CRB2 vectors and initial elucidation of the cellular mechanisms underlying CRB1 function.

Extracellular ATP hydrolysis inhibits synaptic transmission by increasing ph buffering in the synaptic cleft.

Neuronal computations strongly depend on inhibitory interactions. One such example occurs at the first retinal synapse, where horizontal cells inhibit photoreceptors. This interaction generates the center/surround organization of bipolar cell receptive fields and is crucial for contrast enhancement. Despite its essential role in vision, the underlying synaptic mechanism has puzzled the neuroscience community for decades. Two competing hypotheses are currently considered: an ephaptic and a proton-mediated mechanism. Here we show that horizontal cells feed back to photoreceptors via an unexpected synthesis of the two. The first one is a very fast ephaptic mechanism that has no synaptic delay, making it one of the fastest inhibitory synapses known. The second one is a relatively slow (τ≈200 ms), highly intriguing mechanism. It depends on ATP release via Pannexin 1 channels located on horizontal cell dendrites invaginating the cone synaptic terminal. The ecto-ATPase NTPDase1 hydrolyses extracellular ATP to AMP, phosphate groups, and protons. The phosphate groups and protons form a pH buffer with a pKa of 7.2, which keeps the pH in the synaptic cleft relatively acidic. This inhibits the cone Ca²âº channels and consequently reduces the glutamate release by the cones. When horizontal cells hyperpolarize, the pannexin 1 channels decrease their conductance, the ATP release decreases, and the formation of the pH buffer reduces. The resulting alkalization in the synaptic cleft consequently increases cone glutamate release. Surprisingly, the hydrolysis of ATP instead of ATP itself mediates the synaptic modulation. Our results not only solve longstanding issues regarding horizontal cell to photoreceptor feedback, they also demonstrate a new form of synaptic modulation. Because pannexin 1 channels and ecto-ATPases are strongly expressed in the nervous system and pannexin 1 function is implicated in synaptic plasticity, we anticipate that this novel form of synaptic modulation may be a widespread phenomenon.

Specific connectivity between photoreceptors and horizontal cells in the zebrafish retina.

The functional and morphological connectivity between various horizontal cell (HC) types (H1, H2, H3, and H4) and photoreceptors was studied in zebrafish retina. Since HCs are strongly coupled by gap junctions and feedback from HCs to photoreceptors depends strongly on connexin (Cx) hemichannels, we characterized the various HC Cxs (Cx52.6, Cx52.7, Cx52.9, and Cx55.5) in Xenopus oocytes. All Cxs formed hemichannels that were conducting at physiological membrane potentials. The Cx hemichannels differed in kinetic properties and voltage dependence, allowing for specific tuning of the coupling of HCs and the feedback signal from HCs to cones. The morphological connectivity between HC layers and cones was determined next. We used zebrafish expressing green fluorescent protein under the control of Cx promoters. We found that all HCs showed Cx55.5 promoter activity. Cx52.7 promoter activity was exclusively present in H4 cells, while Cx52.9 promoter activity occurred only in H1 cells. Cx52.6 promoter activity was present in H4 cells and in the ventral quadrant of the retina also in H1 cells. Finally, we determined the spectral sensitivities of the HC layers. Three response types were found. Monophasic responses were generated by HCs that contacted all cones (H1 cells), biphasic responses were generated by HCs that contacted M, S, and UV cones (H2 cells), and triphasic responses were generated by HCs that contacted either S and UV cones (H3 cells) or rods and UV cones (H4 cells). Electron microscopy confirms that H4 cells innervate cones. This indicates that rod-driven HCs process spectral information during photopic and luminance information during scotopic conditions.

CRB2 acts as a modifying factor of CRB1-related retinal dystrophies in mice.

Mutations in the CRB1 gene lead to retinal dystrophies ranging from Leber congenital amaurosis (LCA) to early-onset retinitis pigmentosa (RP), due to developmental defects or loss of adhesion between photoreceptors and Müller glia cells, respectively. Whereas over 150 mutations have been found, no clear genotype-phenotype correlation has been established. Mouse Crb1 knockout retinas show a mild phenotype limited to the inferior quadrant, whereas Crb2 knockout retinas display a severe degeneration throughout the retina mimicking the phenotype observed in RP patients associated with CRB1 mutations. Crb1Crb2 double mutant retinas have severe developmental defects similar to the phenotype observed in LCA patients associated with CRB1 mutations. Therefore, CRB2 is a candidate modifying gene of human CRB1-related retinal dystrophy. In this study, we studied the cellular localization of CRB1 and CRB2 in human retina and tested the influence of the Crb2 gene allele on Crb1-retinal dystrophies in mice. We found that in contrast to mice, in the human retina CRB1 protein was expressed at the subapical region in photoreceptors and Müller glia cells, and CRB2 only in Müller glia cells. Genetic ablation of one allele of Crb2 in heterozygote Crb1(+/-) retinas induced a mild retinal phenotype, but in homozygote Crb1 knockout mice lead to an early and severe phenotype limited to the entire inferior retina. Our data provide mechanistic insight for CRB1-related LCA and RP.

Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa.

In humans, the Crumbs homolog-1 (CRB1) gene is mutated in autosomal recessive Leber congenital amaurosis and early-onset retinitis pigmentosa. In mammals, the Crumbs family is composed of: CRB1, CRB2, CRB3A and CRB3B. Recently, we showed that removal of mouse Crb2 from retinal progenitor cells, and consequent removal from Müller glial and photoreceptor cells, results in severe and progressive retinal degeneration with concomitant loss of retinal function that mimics retinitis pigmentosa due to mutations in the CRB1 gene. Here, we studied the effects of cell-type-specific loss of CRB2 from the developing mouse retina using targeted conditional deletion of Crb2 in photoreceptors or Müller cells. We analyzed the consequences of targeted loss of CRB2 in the adult mouse retina using adeno-associated viral vectors encoding Cre recombinase and short hairpin RNA against Crb2. In vivo retinal imaging by means of optical coherence tomography on retinas lacking CRB2 in photoreceptors showed progressive thinning of the photoreceptor layer and cellular mislocalization. Electroretinogram recordings under scotopic conditions showed severe attenuation of the a-wave, confirming the degeneration of photoreceptors. Retinas lacking CRB2 in developing photoreceptors showed early onset of abnormal lamination, whereas retinas lacking CRB2 in developing Müller cells showed late onset retinal disorganization. Our data suggest that in the developing retina, CRB2 has redundant functions in Müller glial cells, while CRB2 has essential functions in photoreceptors. Our data suggest that short-term loss of CRB2 in adult mouse photoreceptors, but not in Müller glial cells, causes sporadic loss of adhesion between photoreceptors and Müller cells.

Mice with megalencephalic leukoencephalopathy with cysts: a developmental angle.

OBJECTIVE: Megalencephalic leukoencephalopathy with cysts (MLC) is a genetic disease characterized by infantile onset white matter edema and delayed onset neurological deterioration. Loss of MLC1 function causes MLC. MLC1 is involved in ion-water homeostasis, but its exact role is unknown. We generated Mlc1-null mice for further studies. METHODS: We investigated which brain cell types express MLC1, compared developmental expression in mice and men, and studied the consequences of loss of MLC1 in Mlc1-null mice. RESULTS: Like humans, mice expressed MLC1 only in astrocytes, especially those facing fluid-brain barriers. In mice, MLC1 expression increased until 3 weeks and then stabilized. In humans, MLC1 expression was highest in the first year, decreased, and stabilized from approximately 5 years. Mlc1-null mice had early onset megalencephaly and increased brain water content. From 3 weeks, abnormal astrocytes were present with swollen processes abutting fluid-brain barriers. From 3 months, widespread white matter vacuolization with intramyelinic edema developed. Mlc1-null astrocytes showed slowed regulatory volume decrease and reduced volume-regulated anion currents, which increased upon MLC1 re-expression. Mlc1-null astrocytes showed reduced expression of adhesion molecule GlialCAM and chloride channel ClC-2, but no substantial changes in other known MLC1-interacting proteins. INTERPRETATION: Mlc1-null mice replicate early stages of the human disease with early onset intramyelinic edema. The cellular functional defects, described for human MLC, were confirmed. The earliest change was astrocytic swelling, substantiating that in MLC the primary defect is in volume regulation by astrocytes. MLC1 expression affects expression of GlialCAM and ClC-2. Abnormal interplay between these proteins is part of the pathomechanisms of MLC.

Synaptic transmission from horizontal cells to cones is impaired by loss of connexin hemichannels.

In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina.

MPP3 regulates levels of PALS1 and adhesion between photoreceptors and Müller cells.

MPP3 and CRB1 both interact directly with PALS1/MPP5 and through this scaffold protein may form a large protein complex. To investigate the role of MPP3 in the retina we have analyzed conditional mutant Mpp3 knockout mice. Ultrastructural localization studies revealed that MPP3 is predominantly localized in apical villi of Müller glia cells. Retinas lacking MPP3 developed late onset retinal degeneration, with sporadic foci of rosette formation in the central part of the retina. Retinal degeneration in Mpp3 cKO mice was accelerated by exposure to moderate levels of white light. Electroretinography recordings in aging mice under both scotopic and photopic conditions ranged from normal to mildly subnormal, while the magnitude correlated with the strength and extent of morphological alterations. Loss of MPP3 resulted in significant loss of PALS1 at the subapical region adjacent to adherens junctions, and loss of MPP3 in Pals1 conditional knockdown retinas significantly accelerated the onset of retinal degeneration. These data suggest that MPP3 is required for maintaining proper levels of PALS1 at the subapical region, and indicate that the MPP3 gene is a candidate modulator of the Crumbs complex.

Challenges and opportunities in mobile e-coaching.

Background: Mobile e-health technologies have proven to provide tailored assessment, intervention, and coaching capabilities for various usage scenarios. Thanks to their spread and adoption, smartphones are one of the most important carriers for such applications. Problem: However, the process of design, realization, evaluation, and implementation of these e-health solutions is wicked and challenging, requiring multiple stakeholders and expertise. Method: Here, we present a tailorable intervention and interaction e-health solution that allows rapid prototyping, development, and evaluation of e-health interventions at scale. This platform allows researchers and clinicians to develop ecological momentary assessment, just-in-time adaptive interventions, ecological momentary intervention, cohort studies, and e-coaching and personalized interventions quickly, with no-code, and in a scalable way. Result: The Twente Intervention and Interaction Instrument (TIIM) has been used by over 320 researchers in the last decade. We present the ecosystem and synthesize the main scientific output from clinical and research studies in different fields. Discussion: The importance of mobile e-coaching for prediction, management, and prevention of adverse health outcomes is increasing. A profound e-health development strategyand strategic, technical, and operational investments are needed to prototype, develop, implement, and evaluate e-health solutions. TIIM ecosystem has proven to support these processes. This paper ends with the main research opportunities in mobile coaching, including intervention mechanisms, fine-grained monitoring, and inclusion of objective biomarker data.

PALS1 is essential for retinal pigment epithelium structure and neural retina stratification.

The membrane-associated palmitoylated protein 5 (MPP5 or PALS1) is thought to organize intracellular PALS1-CRB-MUPP1 protein scaffolds in the retina that are involved in maintenance of photoreceptor-Müller glia cell adhesion. In humans, the Crumbs homolog 1 (CRB1) gene is mutated in progressive types of autosomal recessive retinitis pigmentosa and Leber congenital amaurosis. However, there is no clear genotype-phenotype correlation for CRB1 mutations, which suggests that other components of the CRB complex may influence the severity of retinal disease. Therefore, to understand the physiological role of the Crumbs complex proteins, especially PALS1, we generated and analyzed conditional knockdown mice for Pals1. Small irregularly shaped spots were detected throughout the PALS1 deficient retina by confocal scanning laser ophthalmoscopy and spectral domain optical coherence tomography. The electroretinography a- and b-wave was severely attenuated in the aged mutant retinas, suggesting progressive degeneration of photoreceptors. The histological analysis showed abnormal retinal pigment epithelium structure, ectopic photoreceptor nuclei in the subretinal space, an irregular outer limiting membrane, half rosettes of photoreceptors in the outer plexiform layer, and a thinner photoreceptor synaptic layer suggesting improper photoreceptor cell layering during retinal development. The PALS1 deficient retinas showed reduced levels of Crumbs complex proteins adjacent to adherens junctions, upregulation of glial fibrillary acidic protein indicative of gliosis, and persisting programmed cell death after retinal maturation. The phenotype suggests important functions of PALS1 in the retinal pigment epithelium in addition to the neural retina.

Addendum: The Dutch COVID-19 Notification App: Lessons Learned From a Mixed Methods Evaluation Among End Users and Contact-Tracing Employees.

[This corrects the article DOI: 10.2196/38904.].

The Dutch COVID-19 Notification App: Lessons Learned From a Mixed Methods Evaluation Among End Users and Contact-Tracing Employees.

BACKGROUND: The Dutch CoronaMelder (CM) app is the official Dutch contact-tracing app (CTA). It has been used to contain the spread of the SARS-CoV-2 in the Netherlands. It allows its users and those of connected apps to anonymously exchange warnings about potentially high-risk contacts with individuals infected with the SARS-CoV-2. OBJECTIVE: The goal of this mixed methods study is to understand the use of CTA in the pandemic and its integration into the Municipal Health Services (MHS) efforts of containment through contact tracing. Moreover, the study aims to investigate both the motivations and user experience-related factors concerning adherence to quarantine and isolation measures. METHODS: A topic analysis of 56 emails and a web-based survey of 1937 adults from the Netherlands, combined with a series of 48 in-depth interviews with end users of the app and 14 employees of the Dutch MHS involved in contact tracing, were conducted. Mirroring sessions were held (n=2) with representatives from the development (n=2) and communication teams (n=2) responsible for the creation and implementation of the CM app. RESULTS: Topic analysis and interviews identified procedural and technical issues in the use of the CTA. Procedural issues included the lack of training of MHS employees in the use of CTAs. Technical issues identified for the end users included the inability to send notifications without phone contact with the MHS, unwarranted notifications, and nightly notifications. Together, these issues undermined confidence in and satisfaction with the app's use. The interviews offered a deeper understanding of the various factors at play and their effects on users; for example, the mixed experiences of the app's users, the end user's own fears, and uncertainties concerning the SARS-CoV-2; problematic infrastructure at the time of the app's implementation on the side of the health services; the effects of the society-wide efforts in containment of the SARS-CoV-2 on the CM app's perception, resulting in further doubts concerning the app's effectiveness among MHS workers and citizens; and problems with adherence to behavioral measures propagated by the app because of the lack of confidence in the app and uncertainty concerning the execution of the behavioral measures. All findings were evaluated with the app's creators and have since contributed to improvements. CONCLUSIONS: Although most participants perceived the app positively, procedural and technical issues identified in this study limited satisfaction and confidence in the CM app and affected its adoption and long-term use. Moreover, these same issues negatively affected the CM app's effectiveness in improving compliance with behavioral measures aimed at reducing the spread of the SARS-CoV-2. This study offers lessons learned for future eHealth interventions in pandemics. Lessons that can aid in more effective design, implementation, and communication for more effective and readily adoptable eHealth applications.

Integrating Top-down and Bottom-up Requirements in eHealth Development: The Case of a Mobile Self-compassion Intervention for People With Newly Diagnosed Cancer.

BACKGROUND: Psychosocial eHealth interventions for people with cancer are promising in reducing distress; however, their results in terms of effects and adherence rates are quite mixed. Developing interventions with a solid evidence base while still ensuring adaptation to user wishes and needs is recommended to overcome this. As most models of eHealth development are based primarily on examining user experiences (so-called bottom-up requirements), it is not clear how theory and evidence (so-called top-down requirements) may best be integrated into the development process. OBJECTIVE: This study aims to investigate the integration of top-down and bottom-up requirements in the co-design of eHealth applications by building on the development of a mobile self-compassion intervention for people with newly diagnosed cancer. METHODS: Four co-design tasks were formulated at the start of the project and adjusted and evaluated throughout: explore bottom-up experiences, reassess top-down content, incorporate bottom-up and top-down input into concrete features and design, and synergize bottom-up and top-down input into the intervention context. These tasks were executed iteratively during a series of co-design sessions over the course of 2 years, in which 15 people with cancer and 7 nurses (recruited from 2 hospitals) participated. On the basis of the sessions, a list of requirements, a final intervention design, and an evaluation of the co-design process and tasks were yielded. RESULTS: The final list of requirements included intervention content (eg, major topics of compassionate mind training such as psychoeducation about 3 emotion systems and main issues that people with cancer encounter after diagnosis such as regulating information consumption), navigation, visual design, implementation strategies, and persuasive elements. The final intervention, Compas-Y, is a mobile self-compassion training comprising 6 training modules and several supportive functionalities such as a mood tracker and persuasive elements such as push notifications. The 4 co-design tasks helped overcome challenges in the development process such as dealing with conflicting top-down and bottom-up requirements and enabled the integration of all main requirements into the design. CONCLUSIONS: This study addressed the necessary integration of top-down and bottom-up requirements into eHealth development by examining a preliminary model of 4 co-design tasks. Broader considerations regarding the design of a mobile intervention based on traditional intervention formats and merging the scientific disciplines of psychology and design research are discussed.

The Dutch COVID-19 Contact Tracing App (the CoronaMelder): Usability Study.

BACKGROUND: Adoption and evaluation of contact tracing tools based on information and communications technology may expand the reach and efficacy of traditional contact tracing methods in fighting COVID-19. The Dutch Ministry of Health, Welfare and Sports initiated and developed CoronaMelder, a COVID-19 contact tracing app. This app is based on a Google/Apple Exposure Notification approach and aims to combat the spread of the coronavirus among individuals by notifying those who are at increased risk of infection due to proximity to someone who later tests positive for COVID-19. The app should support traditional contact tracing by faster tracing and greater reach compared to regular contact tracing procedures. OBJECTIVE: The main goal of this study is to investigate whether the CoronaMelder is able to support traditional contact tracing employed by public health authorities. To achieve this, usability tests were conducted to answer the following question: is the CoronaMelder user-friendly, understandable, reliable and credible, and inclusive? METHODS: Participants (N=44) of different backgrounds were recruited: youth with varying educational levels, youth with an intellectual disability, migrants, adults (aged 40-64 years), and older adults (aged >65 years) via convenience sampling in the region of Twente in the Netherlands. The app was evaluated with scenario-based, think-aloud usability tests and additional interviews. Findings were recorded via voice recordings, observation notes, and the Dutch User Experience Questionnaire, and some participants wore eye trackers to measure gaze behavior. RESULTS: Our results showed that the app is easy to use, although problems occurred with understandability and accessibility. Older adults and youth with a lower education level did not understand why or under what circumstances they would receive notifications, why they must share their key (ie, their assigned identifier), and what happens after sharing. In particular, youth in the lower-education category did not trust or understand Bluetooth signals, or comprehend timing and follow-up activities after a risk exposure notification. Older adults had difficulties multitasking (speaking with a public health worker and simultaneously sharing the key in the app). Public health authorities appeared to be unprepared to receive support from the app during traditional contact tracing because their telephone conversation protocol lacks guidance, explanation, and empathy. CONCLUSIONS: The study indicated that the CoronaMelder app is easy to use, but participants experienced misunderstandings about its functioning. The perceived lack of clarity led to misconceptions about the app, mostly regarding its usefulness and privacy-preserving mechanisms. Tailored and targeted communication through, for example, public campaigns or social media, is necessary to provide correct information about the app to residents in the Netherlands. Additionally, the app should be presented as part of the national coronavirus measures instead of as a stand-alone app offered to the public. Public health workers should be trained to effectively and empathetically instruct users on how to use the CoronaMelder app.