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BackgroundUser-centered design processes are infrequently employed and not fully explored for building mobile health (mHealth) apps that are particularly targeted to health professionals as end users. The authors have used a user-centered design–based approach to build an mHealth app for health professionals, tasked to deliver medical laboratory-related information on a daily basis. ObjectiveOur objective is to generate a simple and functional user-centered design process for mHealth apps for health professionals. This paper presents the key learnings from design activities. MethodsA stratified random sample of doctors and nurses was recruited for the study. The design activities were planned in the following sequence: focus group discussion for situation analysis and information architecture, design activity 1 for wireframe designing, design activity 2 for wireframe testing, and user testing sessions 1 and 2. ResultsThe final design and functions of the app, information architecture, and interactive elements were largely influenced by the participatory design–based user-centered design activities. As a result of the design process, we could identify the mental models of processing requests for information and personal preferences based on the experience. These findings were directly or indirectly incorporated into the app design. Furthermore, finding alternative ways of working within time constraints and cultural barriers and the methods employed to manage the challenges of interdisciplinary discourse stood out among the lessons learned. ConclusionsWe recommend a user-centered design process based on a participatory design approach in mHealth app design, enriched with focus group discussions where possible.

Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

To explore the temporal profile of retinal proteomes specific to primary and secondary retinal ganglion cell (RGC) loss. Unilateral partial optic nerve transection (pONT) was performed on the temporal side of the rat optic nerve. Temporal and nasal retinal samples were collected at 1, 4 and 8 weeks after pONT (n = 4 each) for non-biased profiling with a high-resolution hybrid quadrupole time-of-flight mass spectrometry running on label-free SWATHTM acquisition (SCIEX). An information-dependent acquisition ion library was generated using ProteinPilot 5.0 and OneOmics cloud bioinformatics. Combined proteome analysis detected 2531 proteins with a false discovery rate of

The field of regenerative engineering relies primarily on the dual technical platforms of cell selection/conditioning and biomaterial fabrication to support directed cell differentiation. As the field has matured, an appreciation for the influence of biomaterials on cell behaviors has resulted in engineered matrices that meet biomechanical and biochemical demands of target pathologies. Yet, despite advances in methods to produce designer matrices, regenerative engineers remain unable to reliably orchestrate behaviors of therapeutic cells in situ. Here, we present a platform named MATRIX whereby cellular responses to biomaterials can be custom defined by combining engineered materials with cells expressing cognate synthetic biology control modules. Such privileged channels of material-to-cell communication can activate synthetic Notch receptors and govern activities as diverse as transcriptome engineering, inflammation attenuation, and pluripotent stem cell differentiation, all in response to materials decorated with otherwise bioinert ligands. Further, we show that engineered cellular behaviors are confined to programmed biomaterial surfaces, highlighting the potential to use this platform to spatially organize cellular responses to bulk, soluble factors. This integrated approach of co-engineering cells and biomaterials for orthogonal interactions opens new avenues for reproducible control of cell-based therapies and tissue replacements.

Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer's disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance. However, mechanisms of small molecule binding to the amyloid core is poorly understood. We used cryo-electron microscopy to determine a 2.7 Å structure of AD patient-derived tau paired-helical filaments bound to the PET ligand GTP-1. The compound is bound stoichiometrically at a single site along an exposed cleft of each protofilament in a stacked arrangement matching the fibril symmetry. Multiscale modeling reveals pi-pi aromatic interactions that pair favorably with the small molecule-protein contacts, supporting high specificity and affinity for the AD tau conformation. This binding mode offers critical insight into designing compounds to target different amyloid folds found across neurodegenerative diseases.

In microscopy-based drug screens, fluorescent markers carry critical information on how compounds affect different biological processes. However, practical considerations, such as the labor and preparation formats needed to produce different image channels, hinders the use of certain fluorescent markers. Consequently, completed screens may lack biologically informative but experimentally impractical markers. Here, we present a deep learning method for overcoming these limitations. We accurately generated predicted fluorescent signals from other related markers and validated this new machine learning (ML) method on two biologically distinct datasets. We used the ML method to improve the selection of biologically active compounds for Alzheimer's disease (AD) from a completed high-content high-throughput screen (HCS) that had only contained the original markers. The ML method identified novel compounds that effectively blocked tau aggregation, which had been missed by traditional screening approaches unguided by ML. The method improved triaging efficiency of compound rankings over conventional rankings by raw image channels. We reproduced this ML pipeline on a biologically independent cancer-based dataset, demonstrating its generalizability. The approach is disease-agnostic and applicable across diverse fluorescence microscopy datasets.

The α-synuclein protein can adopt several different conformations that cause neurodegeneration. Different α-synuclein conformers cause at least three distinct α-synucleinopathies: multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and Parkinson's disease (PD). In earlier studies, we transmitted MSA to transgenic (Tg) mice and cultured HEK cells both expressing mutant α-synuclein (A53T) but not to cells expressing α-synuclein (E46K). Now, we report that DLB is caused by a strain of α-synuclein prions that is distinct from MSA. Using cultured HEK cells expressing mutant α-synuclein (E46K), we found that DLB prions could be transmitted to these HEK cells. Our results argue that a third strain of α-synuclein prions likely causes PD, but further studies are needed to identify cells and/or Tg mice that express a mutant α-synuclein protein that is permissive for PD prion replication. Our findings suggest that other α-synuclein mutants should give further insights into α-synuclein prion replication, strain formation, and disease pathogenesis, all of which are likely required to discover effective drugs for the treatment of PD as well as the other α-synucleinopathies.

The syntactic structure of sentences in which a new word appears may provide listeners with cues to that new word's form class. In English, for example, a noun tends to follow a determiner ("a"/"an"/"the"), while a verb precedes the morphological inflection [ing]. The presence of these markers may assist children in identifying a word's form class and thus glean some information about its meaning. This study examined whether Mandarin, a language that has a relatively impoverished morphosyntactic system, offers reliable morphosyntactic cues to the noun-verb distinction in child-directed speech (CDS). Using the CHILDES Beijing corpora, Study 1 found that Mandarin CDS has reliable morphosyntactic markers to the noun-verb distinction. Study 2 examined the relationship between mothers' use of a set of early-acquired nouns and verbs in the Beijing corpora and the age of acquisition (AoA) of these words. Results showed that the occurrence of the form class markers is a reliable predictor of the AoA for the early-acquired nouns and verbs.

Post-transplant lymphoproliferative disorders (PTLDs) are lymphoid or plasmacytic proliferations ranging from polyclonal reactive proliferations to overt lymphomas that develop as consequence of immunosuppression in recipients of solid organ transplantation (SOT) or allogeneic bone marrow/hematopoietic stem cell transplantation. Immunosuppression and Epstein-Barr virus (EBV) infection are known risk factors for PTLD. Patients with documented histopathologic diagnosis of primary PTLD at our institution between January 2000 and October 2019 were studied. Sixty-six patients with PTLD following SOT were followed for a median of 9.0 years. The overall median time from transplant to PTLD diagnosis was 5.5 years, with infant transplants showing the longest time to diagnosis at 12.0 years, compared to pediatric and adolescent transplants at 4.0 years and adult transplants at 4.5 years. The median overall survival (OS) was 19.0 years. In the monomorphic diffuse large B-cell (M-DLBCL-PTLD) subtype, median OS was 10.7 years, while median OS for polymorphic subtype was not yet reached. There was no significant difference in OS in patients with M-DLBCL-PTLD stratified by quantitative EBV viral load over and under 100,000 copies/mL at time of diagnosis, although there was a trend towards worse prognosis in those with higher copies.

Tau prions feature in the brains of patients suffering from Alzheimers disease and other tauopathies. For the development of therapeutics that target the replication of tau prions, a high-content, fluorescence-based cell assay was developed. Using this high-content phenotypic screen for nascent tau prion formation, a 4-piperazine isoquinoline compound (1) was identified as a hit with an EC50 value of 390 nM and 0.04 K p,uu. Analogs were synthesized using a hypothesis-based approach to improve potency and in vivo brain penetration resulting in compound 25 (EC50 = 15 nM; K p,uu = 0.63). We investigated the mechanism of action of this series and found that a small set of active compounds were also CDK8 inhibitors.

The radiation environment astronauts are exposed to in deep space includes galactic cosmic radiation (GCR) with different proportions of all naturally occurring ions. To assist NASA with assessment of risk to the brain following exposure to a mixture of ions broadly representative of the GCR, we assessed the behavioral and cognitive performance of female and male C57BL/6J × DBA2/J F1 (B6D2F1) mice two months following rapidly delivered, sequential 6 beam irradiation with protons (1 GeV, LET = 0.24 keV, 50%), 4He ions (250 MeV/n, LET = 1.6 keV/μm, 20%), 16O ions (250 MeV/n, LET = 25 keV/μm 7.5%), 28Si ions (263 MeV/n, LET = 78 keV/μm, 7.5%), 48Ti ions (1 GeV/n, LET = 107 keV/μm, 7.5%), and 56Fe ions (1 GeV/n, LET = 151 keV/μm, 7.5%) at 0, 25, 50, or 200 cGy) at 4-6 months of age. When the activity over 3 days of open field habituation was analyzed in female mice, those irradiated with 50 cGy moved less and spent less time in the center than sham-irradiated mice. Sham-irradiated female mice and those irradiated with 25 cGy showed object recognition. However, female mice exposed to 50 or 200 cGy did not show object recognition. When fear memory was assessed in passive avoidance tests, sham-irradiated mice and mice irradiated with 25 cGy showed memory retention while mice exposed to 50 or 200 cGy did not. The effects of radiation passive avoidance memory retention were not sex-dependent. There was no effect of radiation on depressive-like behavior in the forced swim test. There was a trend toward an effect of radiation on BDNF levels in the cortex of males, but not for females, with higher levels in male mice irradiated with 50 cGy than sham-irradiated. Finally, sequential 6-ion irradiation impacted the composition of the gut microbiome in a sex-dependent fashion. Taxa were uncovered whose relative abundance in the gut was associated with the radiation dose received. Thus, exposure to sequential six-beam irradiation significantly affects behavioral and cognitive performance and the gut microbiome.

The hallmarks of Alzheimer's disease (AD) are the accumulation of Aβ plaques and neurofibrillary tangles composed of hyperphosphorylated tau. We developed sensitive cellular assays using human embryonic kidney-293T cells to quantify intracellular self-propagating conformers of Aβ in brain samples from patients with AD or other neurodegenerative diseases. Postmortem brain tissue from patients with AD had measurable amounts of pathological Aβ conformers. Individuals over 80 years of age had the lowest amounts of prion-like Aβ and phosphorylated tau. Unexpectedly, the longevity-dependent decrease in self-propagating tau conformers occurred in spite of increasing amounts of total insoluble tau. When corrected for the abundance of insoluble tau, the ability of postmortem AD brain homogenates to induce misfolded tau in the cellular assays showed an exponential decrease with longevity, with a half-life of about one decade over the age range of 37 to 99 years. Thus, our findings demonstrate an inverse correlation between longevity in patients with AD and the abundance of pathological tau conformers. Our cellular assays can be applied to patient selection for clinical studies and the development of new drugs and diagnostics for AD.

Subspecialty consultations are becoming highly prevalent in hospital medicine, due to an ageing population with multimorbid conditions and increasingly complex care needs, as well as medicolegal fears that lead to widespread defensive medical practices. Although timely subspecialty consultations in the appropriate clinical context have been found to improve clinical outcomes, there remains a significant proportion of specialty referrals in hospital medicine which are inappropriate, excessive, or do not add value to patient care. In this article, we sought to provide an overview of the common problems pertaining to excessive quantity and suboptimal quality of inpatient subspecialty consultations made in real-world practice and highlight their implications for healthcare financing and patient care. In addition, we discuss the underlying contributing factors that predispose to inappropriate use of the specialist referral system. Finally, we offer a practical, multitiered approach to help rationalize subspecialty consultations, through (i) a systematic model ('WISE' template) for individual referral-making, (ii) development of standardized healthcare institutional referral guidelines with routine clinical audits for quality control, (iii) adopting an integrated generalist care model, and (iv) incorporating training on effective referral-making in medical education. [ABSTRACT FROM AUTHOR]

The space radiation environment includes helium (⁴He) ions that may impact brain function. As little is known about the effects of exposures to ⁴He ions on the brain, we assessed the behavioral and cognitive performance of C57BL/6J × DBA2/J F1 (B6D2F1) mice three months following irradiation with ⁴He ions (250 MeV/n; linear energy transfer (LET) = 1.6 keV/μm; 0, 21, 42 or 168 cGy). Sham-irradiated mice and mice irradiated with 21 or 168 cGy showed novel object recognition, but mice irradiated with 42 cGy did not. In the passive avoidance test, mice received a slight foot shock in a dark compartment, and latency to re-enter that compartment was assessed 24 h later. Sham-irradiated mice and mice irradiated with 21 or 42 cGy showed a higher latency on Day 2 than Day 1, but the latency to enter the dark compartment in mice irradiated with 168 cGy was comparable on both days. ⁴He ion irradiation, at 42 and 168 cGy, reduced the levels of the dendritic marker microtubule-associated protein-2 (MAP-2) in the cortex. There was an effect of radiation on apolipoprotein E (apoE) levels in the hippocampus and cortex, with higher apoE levels in mice irradiated at 42 cGy than 168 cGy and a trend towards higher apoE levels in mice irradiated at 21 than 168 cGy. In addition, in the hippocampus, there was a trend towards a negative correlation between MAP-2 and apoE levels. While reduced levels of MAP-2 in the cortex might have contributed to the altered performance in the passive avoidance test, it does not seem sufficient to do so. The higher hippocampal and cortical apoE levels in mice irradiated at 42 than 168 cGy might have served as a compensatory protective response preserving their passive avoidance memory. Thus, there were no alterations in behavioral performance in the open filed or depressive-like behavior in the forced swim test, while cognitive impairments were seen in the object recognition and passive avoidance tests, but not in the contextual or cued fear conditioning tests. Taken together, the results indicate that some aspects of cognitive performance are altered in male mice exposed to ⁴He ions, but that the response is task-dependent. Furthermore, the sensitive doses can vary within each task in a non-linear fashion. This highlights the importance of assessing the cognitive and behavioral effects of charged particle exposure with a variety of assays and at multiple doses, given the possibility that lower doses may be more damaging due to the absence of induced compensatory mechanisms at higher doses.

Abstract Chronic high-fat diet (HFD) consumption not only promotes obesity and insulin resistance, but also causes bone loss through mechanisms that are not well understood. Here, we fed wild-type CD-1 mice either chow or a HFD (43% of energy from fat) for 18 weeks; HFD-fed mice exhibited decreased trabecular volume (−28%) and cortical thickness (−14%) compared to chow-fed mice. In HFD-fed mice, bone loss was due to reduced bone formation and mineral apposition, without obvious effects on bone resorption. HFD feeding also increased skeletal expression of sclerostin and caused deterioration of the osteocyte lacunocanalicular network (LCN). In mice fed HFD, skeletal glucocorticoid signaling was activated relative to chow-fed mice, independent of serum corticosterone concentrations. We therefore examined whether skeletal glucocorticoid signaling was necessary for HFD-induced bone loss, using transgenic mice lacking glucocorticoid signaling in osteoblasts and osteocytes (HSD2OB/OCY-tg mice). In HSD2OB/OCY-tg mice, bone formation and mineral apposition rates were not suppressed by HFD, and bone loss was significantly attenuated. Interestingly, in HSD2OB/OCY-tg mice fed HFD, both Wnt signaling (less sclerostin induction, increased β-catenin expression) and glucose uptake were significantly increased, relative to diet- and genotype-matched controls. The osteocyte LCN remained intact in HFD-fed HSD2OB/OCY-tg mice. When fed a HFD, HSD2OB/OCY-tg mice also increased their energy expenditure and were protected against obesity, insulin resistance, and dyslipidemia. Therefore, glucocorticoid signaling in osteoblasts and osteocytes contributes to the suppression of bone formation in HFD-fed mice. Skeletal glucocorticoid signaling is also an important determinant of glucose uptake in bone, which influences the whole-body metabolic response to HFD.

Background: Although adult transplant centers are successfully transplanting organs from hepatitis C virus (HCV)‐infected donors with detectable viral load by nucleic acid testing (NAT+) into HCV‐negative recipients, this practice has not yet been adopted widely by the pediatric heart transplant community. Methods: We present a case series of four patients who received heart transplants from HCV NAT+ donors at a pediatric transplant center, including two pediatric patients < 18 years of age. Results: All recipients tolerated a 12‐week course of glecaprevir/pibrentasvir and achieved a sustained virologic response with no HCV or liver complications with over 1 year of follow‐up (range 1.4–2.5 years). All four have had good post‐heart transplant outcomes with normal graft function and good functional status without rejection or cardiac allograft vasculopathy at time of last follow‐up. Conclusions: This case series details the successful multidisciplinary implementation of a protocol to accept cardiac allografts from HCV NAT+ donors for transplantation into HCV negative recipients at our pediatric transplant center. With the limited donor pool in pediatrics and the morbidity associated with prolonged durations on the transplant waitlist, pediatric centers should consider utilizing organs from HCV NAT+ donors to broaden the donor pool. Future work should evaluate other organs beyond heart and optimal timing and duration of direct acting antiviral therapy. [ABSTRACT FROM AUTHOR]

Well-designed math apps can foster children's numeracy development. Although parents are interested in using math apps for their children, the quantity and variability in quality of apps can make app selection challenging. As such, it is important to know how parents evaluate numeracy content in math apps for their children. This study investigated parents' evaluations of four numeracy apps of varying quality. Forty-five parents of 3- to 6-year-old children explored each app for three minutes on their own device and rated each on 17 early numeracy skills. Parents were conservative in their ratings of numeracy skills. Likelihood of downloading apps ranged from 24.4% to 73%. If the first app viewed was of the highest quality, it influenced their subsequent ratings suggesting that parents could be using it as a benchmark. Individual differences affected numeracy ratings, such that parents high in both math teaching confidence and/or anxiety rated the apps more favourably than parents low in those traits. Parents experienced some challenges in identifying better content and design features and individual differences contributed to this. Outcomes also suggest practical supports such as providing parents with a "good" referent may aid app selection. Impact Summary: Prior State of Knowledge: Well-designed numeracy apps can have positive effects on children's academic abilities but many apps available are of poor quality. Despite interest in choosing math apps, it is unknown how parents evaluate numeracy features in their children's math apps. Novel Contributions: Parentsevaluated numeracy content in math apps for children. Parent ratings of numeracy content were compared with ratings by trained coders. The impact of parental anxiety and confidence on ratings and parental math app selection was examined. Practical Implications: Parentsprovided conservative evaluations of numeracy content. Individual differences in math anxiety and teaching confidence indicates parental supports may be needed. Presenting a good or bad app first impacted ratings suggesting a potential tool for supporting parents' app decisions. [ABSTRACT FROM AUTHOR]

Attempts to model inherited human prion disorders such as familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) disease, and fatal familial insomnia (FFI) using genetically modified mice have produced disappointing results. We recently demonstrated that transgenic (Tg) mice expressing wild-type bank vole prion protein (BVPrP) containing isoleucine at polymorphic codon 109 develop a spontaneous neurodegenerative disorder that exhibits many of the hallmarks of prion disease. To determine if mutations causing inherited human prion disease alter this phenotype, we generated Tg mice expressing BVPrP containing the D178N mutation, which causes FFI; the E200K mutation, which causes familial CJD; or an anchorless PrP mutation similar to mutations that cause GSS. Modest expression levels of mutant BVPrP resulted in highly penetrant spontaneous disease in Tg mice, with mean ages of disease onset ranging from ~120 to ~560 days. The brains of spontaneously ill mice exhibited prominent features of prion disease-specific neuropathology that were unique to each mutation and distinct from Tg mice expressing wild-type BVPrP. An ~8-kDa proteinase K-resistant PrP fragment was found in the brains of spontaneously ill Tg mice expressing either wild-type or mutant BVPrP. The spontaneously formed mutant BVPrP prions were transmissible to Tg mice expressing wild-type or mutant BVPrP as well as to Tg mice expressing mouse PrP. Thus, Tg mice expressing mutant BVPrP exhibit many of the hallmarks of heritable prion disorders in humans including spontaneous disease, protease-resistant PrP, and prion infectivity.

The Monty Hall Dilemma (MHD) is a classic brain teaser thateven mathematicians appear to consistently answerincorrectly, and when the correct solution is presented peopleremain unconvinced. We examined how convincing werethree solution types: a simple statement of the solution, aguided diagram solution, or simulated trials. Participants weregiven the MHD, followed by one of the three types ofsolutions, then we measured their level of conviction andtheir numeracy, Cognitive Reflection (CR), Need forCognition (NFC), and Openness. Overall, both guideddiagrams and simulated trials led to higher convictioncompared to a simple solution statement. Higher numeracyand higher CR were associated with lower conviction afterthe simple solution; furthermore higher numeracy tended tohelp more in the simulation condition, whereas higher CRhelped more in the guided condition. Therefore thepersuasiveness of a solution depended both on its nature andcharacteristics of individual reasoners.

An increasing number of studies argues that self-propagating protein conformations (i.e., prions) feature in the pathogenesis of several common neurodegenerative diseases. Mounting evidence contends that aggregates of the amyloid-β (Aβ) peptide become self-propagating in Alzheimer's disease (AD) patients. An important characteristic of prions is their ability to replicate distinct strains, the biological information for which is enciphered within different conformations of protein aggregates. To investigate whether distinct strains of Aβ prions can be discerned in AD patients, we performed transmission studies in susceptible transgenic mice using brain homogenates from sporadic or heritable (Arctic and Swedish) AD cases. Mice inoculated with the Arctic AD sample exhibited a pathology that could be distinguished from mice inoculated with the Swedish or sporadic AD samples, which was judged by differential accumulation of Aβ isoforms and the morphology of cerebrovascular Aβ deposition. Unlike Swedish AD- or sporadic AD-inoculated animals, Arctic AD-inoculated mice, like Arctic AD patients, displayed a prominent Aβ38-containing cerebral amyloid angiopathy. The divergent transmission behavior of the Arctic AD sample compared with the Swedish and sporadic AD samples was maintained during second passage in mice, showing that Aβ strains are serially transmissible. We conclude that at least two distinct strains of Aβ prions can be discerned in the brains of AD patients and that strain fidelity was preserved on serial passage in mice. Our results provide a potential explanation for the clinical and pathological heterogeneity observed in AD patients.