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Background: Epilepsy is a common neurological disorder affecting about 1 in 100 people in the United Kingdom. Many individuals experience a lower quality of life as a result of their epilepsy diagnosis and are more likely to develop mental health problems, such as anxiety and depression. Medical interventions for this client group tend to focus on the treatment of seizures, whereas mental health disorders often remain undiagnosed and untreated. Early identification and treatment of mental health difficulties in people with epilepsy are vital to ensure better outcomes and improvements in quality of life. Objective: The aim of this exploratory randomized controlled trial is to evaluate whether an 8-week cognitive behavioral therapy–based intervention delivered through a mobile app—ThinkNinja for Epilepsy—is a clinically effective tool to improve quality of life, mental health, and emotional well-being in a large sample of people with epilepsy and anxiety or comorbid anxiety and depression. Methods: The study aims to recruit 184 individuals, 18 to 65 years of age, with a self-reported diagnosis of epilepsy and anxiety or comorbid anxiety and depression. Participants will be randomly assigned to the ThinkNinja for Epilepsy app condition (arm A) or the waiting-list control group (arm B). Participants in arm A will receive access to the ThinkNinja for Epilepsy app first. After 8 weeks, participants in arm B will receive the same full access to the ThinkNinja for Epilepsy app as the participants in arm A. This design will allow an initial between-subjects analysis between the two conditions as well as a within-subject analysis including all participants. The primary outcome is participants’ quality of life, measured by the 10-item patient-weighted Quality of Life in Epilepsy questionnaire. The secondary outcomes include measures of anxiety, using the 7-item Generalized Anxiety Disorder assessment; depression, using the 9-item Patient Health Questionnaire; medication adherence, using the Medication Adherence Questionnaire; and impression of change, using the Patient Global Impression of Change questionnaire. Results: Recruitment for this study began in March 2022 and was completed in October 2022. We expect data collection to be finalized by May 2023 and study results to be available within 12 months of the final data collection date. Results of the study will be written up as soon as possible thereafter, with the intention of publishing the outcomes in high-quality peer-reviewed journals. Conclusions: This study aims to determine the clinical efficacy and safety of the ThinkNinja for Epilepsy intervention at improving the quality of life, mental health, and emotional well-being of people with epilepsy. The findings from our study will hopefully contribute to addressing the critical gap in universal provision and accessibility of mental health and emotional well-being support for people with epilepsy. Trial Registration: ISRCTN Registry 16270209 (04/03/2022); https://www.isrctn.com/ISRCTN16270209 International Registered Report Identifier (IRRID): DERR1-10.2196/40261

Urinary collecting tubules form during kidney embryogenesis through the branching of the ureteric bud epithelium. A travelling mesenchyme niche of nephron progenitor cells caps each branching ureteric bud tip. These ‘tip domain’ niches pack more closely over developmental time and their number relates to nephron endowment at birth. Yet, how the crowded tissue environment impacts niche number and cell decision-making remains unclear. Here, through experiments and mathematical modelling, we show that niche packing conforms to physical limitations imposed by kidney curvature. We relate packing geometries to rigidity theory to predict a stiffening transition starting at embryonic day 15 in the mouse, validated by micromechanical analysis. Using a method to estimate tip domain ‘ages’ relative to their most recent branch events, we find that new niches overcome mechanical resistance as they branch and displace neighbours. This creates rhythmic mechanical stress in the niche. These findings expand our understanding of kidney development and inform engineering strategies for synthetic regenerative tissues. Geometric packing of tubules in the developing kidney urinary collecting system leads to tissue stiffening and rhythmic mechanical stresses local to nephron-forming niches that synchronize with tubule branching.

Despite its impressive evidence base, there is a widening access gap to receiving cognitive behavioural therapy (CBT). Video conferencing therapy (VCT) offers an effective solution for logistical barriers to treatment, which has been salient throughout the Coronavirus pandemic. However, research concerning the delivery of CBT via VCT for children and young people (CYP) is in its infancy, and clinical outcome data are limited. The aim of this service evaluation was to explore the effectiveness of a VCT CBT intervention for CYP referred from Child and Adolescent Mental Health Services (CAMHS) in the UK. A total of 989 records of CYP who had completed CBT via VCT in 2020 with Healios, a digital mental health company commissioned by the National Health Service (NHS), were examined to determine changes in anxiety, depression and progress towards personalised goals. Routine outcome measures (ROMs) were completed at baseline and endpoint, as well as session by session. Feedback was collected from CYP and their families at the end of treatment. There was a significant reduction in symptoms of anxiety and depression and significant progress towards goals, with pre- to post-effect sizes (Cohen’s d) demonstrating medium to large effects (d=.45 to d=−1.39). Reliable improvement ranged from 31 to 80%, clinical improvement ranged from 33 to 50%, and 25% clinically and reliably improved on at least one measure; 92% reported that they would recommend Healios. This service evaluation demonstrates that Healios’ CBT delivered via VCT is effective for CYP receiving it as part of routine mental health care.

Organoids derived from human stem cells are a promising approach for disease modeling, regenerative medicine, and fundamental research. However, organoid variability and limited control over morphological outcomes remain as challenges. Engineering control over culture conditions may guide organoids toward specific outcomes in self-organization, including tissue composition and architecture. Here, we extend DNA-Programmed Assembly of Cells (DPAC), a DNA ‘velcro’ cell patterning approach. We first modify DPAC to a photolithographic method (pDPAC) that expands DNA patterning from the millimeter- to the centimeter-scale. We then apply pDPAC to build self-folding constructs of co-patterned cells on extracellular (ECM) matrix protein sheets, termed kinomorphs. We show that rationally designed configurations of 3T3 fibroblasts apply traction forces, which actuate prescribed folding of ECM sheets. In turn, ECM compaction guides the coalescence and tubulogenesis of adjacent, patterned epithelial Madin-Darby canine kidney cells along crease patterns that partially mimic the branched ureteric epithelium of the kidney. Kinomorphs and other large-scale pDPAC applications may significantly advance organ-scale tissue construction by extending the spatial range of cell self-organization in emerging model systems such as organoids. In a second study, we use pDPAC to precisely control the number and ratio of human induced pluripotent stem cell-derived progenitors contributing to nephron progenitor (NP) organoids and mosaic NP/ureteric bud (UB) tip cell organoids within arrays of microwells. We demonstrate long-term control over organoid size and morphology, decoupled from geometric constraints. We then show emergent trends in organoid tissue proportions and organization that depend on initial progenitor cell composition. Our findings verify the utility of pDPAC in guiding organotypic self-organization. Finally, we consider our research's current limitations and future directions, beginning to explore how 2D patterns of kidney progenitors may transition to 3D geometries of higher physiologic relevance. Our cell patterning approach shows great potential as a blueprinting strategy to one day build complex, customizable, and fully functional tissues and organs. Alleviating substantial health and financial burdens, our work could help pave the way to revolutionized healthcare where access to a lifesaving organ transplant is no longer a waiting game.

Human organoids are a promising approach for disease modeling and regenerative medicine. However, organoid variability and limited control over morphological outcomes remain significant challenges. Here we extend a DNA 'velcro' cell patterning approach, precisely controlling the number and ratio of human stem cell-derived progenitors contributing to nephron and mosaic nephron/ureteric bud organoids within arrays of microwells. We demonstrate long-term control over organoid size and morphology, decoupled from geometric constraints.

Replicating organizational principles that establish fine-scale tissue structure is critical to our capacity for building functional replacement tissues. Tissue boundaries such as epithelial-mesenchymal interfaces are engines for morphogenesis in vivo. However, despite a wealth of micropatterning approaches available to control tissue size, shape, and mechanical environment in vitro, fine-scale spatial control of cell composition within tissue constructs remains an engineering challenge. To address this, we augment DNA velcro technology for selective patterning of ssDNA-labeled cells with long-term culture on mechanically defined polyacrylamide hydrogels. We co-functionalize photoactive benzophenone-containing polyacrylamide gels (BP-PA gels) with spatially precise ssDNA features that confer temporary cell adhesion and with extracellular matrix (ECM) proteins that confer long-term adhesion. We find that co-functionalization does not compromise ssDNA patterning fidelity or cell capture, nor hydrogel mechanical properties or mechanosensitive fibroblast spreading, enabling mechanobiology studies of precise cell interfaces. We then co-pattern colonies of fibroblasts and epithelial cells to study interface formation and extracellular signal-related kinase (ERK) activity at cellular contacts. Combining DNA velcro and ECM functionalization approaches provides independent control of initial cell placement, adhesion, and mechanical environment, constituting a new tool for studying biological interfaces and for programming multicellular interactions in engineered tissues.Competing Interest StatementThe authors have declared no competing interest.

Current methods for building tissues usually start with a non-biological blueprint, or rely on self-organization, which does not extend to organ-scales. This has limited the construction of large tissues that simultaneously encode fine-scale cell organization. Here we bridge scales by mimicking developmental dynamics using \"kinomorphs\", tissue scaffolds that undergo globally programmed shape and density changes to trigger local self-organization of cells in many locations at once. In this first report, we focus on mimicking the extracellular matrix (ECM) compaction and division into leaflets that occurs in kidney collecting duct development. We start by creating single-cell resolution cell patterns in ECM-mimetic hydrogels that are >10x larger than previously described, by leveraging photo-lithographic technology. These patterns are designed to mimic the branch geometry of the embryonic kidney collecting duct tree. We then predict the shape dynamics of kinomorphs driven by cell contractility-based compaction of the ECM using kinematic origami simulations. We show that these dynamics spur centimeter-scale assembly of structurally mature ~50 μm-diameter epithelial tubules that are locally self-organized, but globally programmed. Our approach prescribes tubule network geometry at ~5x smaller length-scales than currently possible using 3D printing, and at local cell densities comparable to in vivo tissues. Kinomorphs could be used to scaffold and \"plumb\" arrays of organoids in the future, by guiding the morphogenesis of epithelial networks. Such hybrid globally programmed/locally self-organized tissues address a major gap in our ability to recapitulate organ-scale tissue structure. Footnotes * https://doi.org/10.6084/m9.figshare.9751661.v1

The mammalian kidney achieves massive parallelization of function by exponentially duplicating nephron-forming niches during development. Each niche caps a tip of the ureteric bud epithelium (the future urinary collecting duct tree) as it undergoes branching morphogenesis, while nephron progenitors within niches balance self-renewal and differentiation to early nephron cells. Nephron formation rate approximately matches branching rate over a large fraction of mouse gestation, yet the nature of this apparent pace-maker is unknown. Here we correlate spatial transcriptomics data with branching 'life-cycle' to discover rhythmically alternating signatures of nephron progenitor differentiation and renewal across Wnt, Hippo-Yap, retinoic acid (RA), and other pathways. We then find in human stem-cell derived nephron progenitor organoids that Wnt/β-catenin-induced differentiation is converted to a renewal signal when it temporally overlaps with YAP activation. Similar experiments using RA activation indicate a role in setting nephron progenitor exit from the naive state, the spatial extent of differentiation, and nephron segment bias. Together the data suggest that nephron progenitor interpretation of consistent Wnt/β-catenin differentiation signaling in the niche may be modified by rhythmic activity in ancillary pathways to set the pace of nephron formation. This would synchronize nephron formation with ureteric bud branching, which creates new sites for nephron condensation. Our data bring temporal resolution to the renewal vs. differentiation balance in the nephrogenic niche and inform new strategies to achieve self-sustaining nephron formation in synthetic human kidney tissues.Competing Interest StatementThe authors have declared no competing interest.Footnotes* General updates, new Fig. 3F analysis, new Fig. 5.* https://doi.org/10.6084/m9.figshare.24585114.v1

The developing mammalian kidney exponentially duplicates nephron-forming stem cell niches at the tips of the urinary collecting duct tree to achieve massively parallel function. Nephron formation rate has a clinically meaningful effect on person-to-person variability in nephron endowment1–5, while exerting in vitro control could enable sustained waves of nephrogenesis in organoid-derived synthetic kidney tissues6,7. However, how the kidney arrives at an appropriate number and ratio of nephrons to collecting ducts is unclear. Here we show that nephron formation is rhythmic and synchronized with branching of the ureteric bud tree (the future urinary collecting ducts). We correlate human and mouse spatial transcriptomics data with the branching ‘life-cycle’ to uncover rhythmically alternating signatures of nephron progenitor differentiation and renewal. The nephron progenitor rhythm parallels rhythmic nuclear elongation and other hallmarks of mechanical tension in surrounding stromal cells that we attribute to branching-induced deformation. Stroma-specific knockdown of actomyosin activity leads to a striking loss of synchronization between nephron formation and ureteric bud branching without blocking either. These results suggest that the stroma acts as a mechanically entrained pacemaker for nephron formation. Together, our findings uncover a feedback mechanism for clock-like coordination of organ composition during exponential growth.

As pediatric medicine continues to advance, a growing number of special needs children depend on medical devices for both survival and to lead a more functional life. With this dependence, it is imperative that the emergency care community understand how to best assess these patients and troubleshoot their devices. In this article, we discuss some of the common devices used to assist the special needs patient, their nursing implications, and optimal care. This review will also include guidance for troubleshooting these devices.