A Personalized Self-Management Rehabilitation System with an Intelligent Shoe for Stroke Survivors: A Realist Evaluation

Background: In the United Kingdom, stroke is the most significant cause of adult disability. Stroke survivors are frequently left with physical and psychological changes that can profoundly affect their functional ability, independence, and social participation. Research suggests that long-term, intense, task- and context-specific rehabilitation that is goal-oriented and environmentally enriched improves function, independence, and quality of life after a stroke. It is recommended that rehabilitation should continue until maximum recovery has been achieved. However, the increasing demand on services and financial constraints means that needs cannot be met through traditional face-to-face delivery of rehabilitation. Using a participatory design methodology, we developed an information communication technology–enhanced Personalized Self-Managed rehabilitation System (PSMrS) for stroke survivors with integrated insole sensor technology within an “intelligent shoe.”. The intervention model was based around a rehabilitation paradigm underpinned by theories of motor relearning and neuroplastic adaptation, motivational feedback, self-efficacy, and knowledge transfer. Objective: To understand the conditions under which this technology-based rehabilitation solution would most likely have an impact on the motor behavior of the user, what would work for whom, in what context, and how. We were interested in what aspects of the system would work best to facilitate the motor behavior change associated with self-managed rehabilitation and which user characteristics and circumstances of use could promote improved functional outcomes. Methods: We used a Realist Evaluation (RE) framework to evaluate the final prototype PSMrS with the assumption that the intervention consists of a series of configurations that include the Context of use, the underlying Mechanisms of change and the potential Outcomes or impacts (CMOs). We developed the CMOs from literature reviews and engagement with clinicians, users, and caregivers during a series of focus groups and home visits. These CMOs were then tested in five in-depth case studies with stroke survivors and their caregivers. Results: While two new propositions emerged, the second importantly related to the self-management aspects of the system. The study revealed that the system should also encourage independent use and the setting of personalized goals or activities. Conclusions: Information communication technology that purports to support the self-management of stroke rehabilitation should give significant consideration to the need for motivational feedback that provides quantitative, reliable, accurate, context-specific, and culturally sensitive information about the achievement of personalized goal-based activities

Dosimetric consequences of the shift towards computed tomography guided target definition and planning for breast conserving radiotherapy

Background: The shift from conventional two-dimensional (2D) to three-dimensional (3D)conformal target definition and dose-planning seems to have introduced volumetric as well as geometric changes. The purpose of this study was to compare coverage of computed tomography (CT)-based breast and boost planning target volumes (PTV), absolute volumes irradiated, and dose delivered to the organs at risk with conventional 2D and 3D-conformal breast conserving radiotherapy. Methods: Twenty-five patients with left-sided breast cancer were subject of CT-guided target definition and 3D-conformal dose-planning, and conventionally defined target volumes and treatment plans were reconstructed on the planning CT. Accumulated dose-distributions were calculated for the conventional and 3D-conformal dose-plans, taking into account a prescribed dose of 50 Gy for the breast plans and 16 Gy for the boost plans. Results: With conventional treatment plans, CT-based breast and boost PTVs received the intended dose in 78% and 32% of the patients, respectively, and smaller volumes received the prescribed breast and boost doses compared with 3D-conformal dose-planning. The mean lung dose, the volume of the lungs receiving > 20 Gy, the mean heart dose, and volume of the heart receiving > 30 Gy were significantly less with conventional treatment plans. Specific areas within the breast and boost PTVs systematically received a lower than intended dose with conventional treatment plans. Conclusion: The shift towards CT-guided target definition and planning as the golden standard for breast conserving radiotherapy has resulted in improved target coverage at the cost of larger irradiated volumes and an increased dose delivered to organs at risk. Tissue is now included into the breast and boost target volumes that was never explicitly defined or included with conventional treatment. Therefore, a coherent definition of the breast and boost target volumes is needed, based on clinical data confirming tumour control probability and normal tissue complication probability with the use of 3D-conformal radiotherapy

ADAM17 Deletion in Thymic Epithelial Cells Alters Aire Expression without Affecting T Cell Developmental Progression

Cellular interactions between thymocytes and thymic stromal cells are critical for normal T cell development. Thymic epithelial cells (TECs) are important stromal niche cells that provide essential growth factors, cytokines, and present self-antigens to developing thymocytes. The identification of genes that mediate cellular crosstalk in the thymus is ongoing. One candidate gene, Adam17, encodes a metalloprotease that functions by cleaving the ectodomain of several transmembrane proteins and regulates various developmental processes. In conventional Adam17 knockout mice, a non-cell autonomous role for ADAM17 in adult T cell development was reported, which strongly suggested that expression of ADAM17 in TECs was required for normal T cell development. However, knockdown of Adam17 results in multisystem developmental defects and perinatal lethality, which has made study of the role of Adam17 in specific cell types difficult. Here, we examined T cell and thymic epithelial cell development using a conditional knockout approach.We generated an Adam17 conditional knockout mouse in which floxed Adam17 is deleted specifically in TECs by Cre recombinase under the control of the Foxn1 promoter. Normal T cell lineage choice and development through the canonical αβ T cell stages was observed. Interestingly, Adam17 deficiency in TECs resulted in reduced expression of the transcription factor Aire. However, no alterations in the patterns of TEC phenotypic marker expression and thymus morphology were noted.In contrast to expectation, our data clearly shows that absence of Adam17 in TECs is dispensable for normal T cell development. Differentiation of TECs is also unaffected by loss of Adam17 based on phenotypic markers. Surprisingly, we have uncovered a novel genetic link between Adam17and Aire expression in vivo. The cell type in which ADAM17 mediates its non-cell autonomous impact and the mechanisms by which it regulates intrathymic T cell development remain to be identified

Identification of the Regulatory Logic Controlling Salmonella Pathoadaptation by the SsrA-SsrB Two-Component System

Sequence data from the past decade has laid bare the significance of horizontal gene transfer in creating genetic diversity in the bacterial world. Regulatory evolution, in which non-coding DNA is mutated to create new regulatory nodes, also contributes to this diversity to allow niche adaptation and the evolution of pathogenesis. To survive in the host environment, Salmonella enterica uses a type III secretion system and effector proteins, which are activated by the SsrA-SsrB two-component system in response to the host environment. To better understand the phenomenon of regulatory evolution in S. enterica, we defined the SsrB regulon and asked how this transcription factor interacts with the cis-regulatory region of target genes. Using ChIP-on-chip, cDNA hybridization, and comparative genomics analyses, we describe the SsrB-dependent regulon of ancestral and horizontally acquired genes. Further, we used a genetic screen and computational analyses integrating experimental data from S. enterica and sequence data from an orthologous regulatory system in the insect endosymbiont, Sodalis glossinidius, to identify the conserved yet flexible palindrome sequence that defines DNA recognition by SsrB. Mutational analysis of a representative promoter validated this palindrome as the minimal architecture needed for regulatory input by SsrB. These data provide a high-resolution map of a regulatory network and the underlying logic enabling pathogen adaptation to a host

Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes

Resting memory CD4+ T-cells harboring latent HIV proviruses represent a critical barrier to viral eradication. Histone deacetylase inhibitors (HDACis), such as suberanilohydroxamic acid (SAHA), romidepsin, and panobinostat have been shown to induce HIV expression in these resting cells. Recently, it has been demonstrated that the low levels of viral gene expression induced by a candidate HDACi may be insufficient to cause the death of infected cells by viral cytopathic effects, necessitating their elimination by immune effectors, such as cytotoxic T-lymphocytes (CTL). Here, we study the impact of three HDACis in clinical development on T-cell effector functions. We report two modes of HDACi-induced functional impairment: i) the rapid suppression of cytokine production from viable T-cells induced by all three HDACis ii) the selective death of activated T-cells occurring at later time-points following transient exposures to romidepsin or, to a lesser extent, panobinostat. As a net result of these factors, HDACis impaired CTL-mediated IFN-γ production, as well as the elimination of HIV-infected or peptide-pulsed target cells, both in liquid culture and in collagen matrices. Romidepsin exerted greater inhibition of antiviral function than SAHA or panobinostat over the dose ranges tested. These data suggest that treatment with HDACis to mobilize the latent reservoir could have unintended negative impacts on the effector functions of CTL. This could influence the effectiveness of HDACi-based eradication strategies, by impairing elimination of infected cells, and is a critical consideration for trials where therapeutic interruptions are being contemplated, given the importance of CTL in containing rebound viremia

Soluble and Cell-Associated Insulin Receptor Dysfunction Correlates with Severity of HAND in HIV-Infected Women

Blood sugar metabolism abnormalities have been identified in HIV-infected individuals and associated with HIV-associated neurocognitive disorders (HAND). These abnormalities may occur as a result of chronic HIV infection, long-term use of combined antiretroviral treatment (CART), aging, genetic predisposition, or a combination of these factors, and may increase morbidity and mortality in this population.To determine if changes in soluble and cell-associated insulin receptor (IR) levels, IR substrate-1 (IRS-1) levels, and IRS-1 tyrosine phosphorylation are associated with the presence and severity of HAND in a cohort of HIV-seropositive women.This is a retrospective cross-sectional study using patient database information and stored samples from 34 HIV-seropositive women and 10 controls without history of diabetes from the Hispanic-Latino Longitudinal Cohort of Women. Soluble IR subunits [sIR, ectodomain (α) and full-length or intact (αβ)] were assayed in plasma and CSF samples by ELISA. Membrane IR levels, IRS-1 levels, and IRS-1 tyrosine phosphorylation were analyzed in CSF white cell pellets (WCP) using flow cytometry. HIV-seropositive women had significantly increased levels of intact or full-length sIR in plasma (p<0.001) and CSF (p<0.005) relative to controls. Stratified by HAND, increased levels of full-length sIR in plasma were associated with the presence (p<0.001) and severity (p<0.005) of HAND. A significant decrease in IRS-1 tyrosine-phosphorylation in the WCP was also associated with the presence (p<0.02) and severity (p<0.02) of HAND.This study provides evidence that IR secretion is increased in HIV-seropositive women, and increased IR secretion is associated with cognitive impairment in these women. Thus, IR dysfunction may have a role in the progression of HAND and could represent a biomarker for the presence and severity of HAND

Cross-Sectional Detection of Acute HIV Infection: Timing of Transmission, Inflammation and Antiretroviral Therapy

BACKGROUND: Acute HIV infection (AHI) is a critical phase of infection when irreparable damage to the immune system occurs and subjects are very infectious. We studied subjects with AHI prospectively to develop better treatment and public health interventions. METHODS: Cross-sectional screening was employed to detect HIV RNA positive, antibody negative subjects. Date of HIV acquisition was estimated from clinical history and correlated with sequence diversity assessed by single genome amplification (SGA). Twenty-two cytokines/chemokines were measured from enrollment through week 24. RESULTS: Thirty-seven AHI subjects were studied. In 7 participants with limited exposure windows, the median exposure to HIV occurred 14 days before symptom onset. Lack of viral sequence diversification confirmed the short duration of infection. Transmission dates estimated by SGA/sequencing using molecular clock models correlated with transmission dates estimated by symptom onset in individuals infected with single HIV variants (mean of 28 versus 33 days). Only 10 of 22 cytokines/chemokines were significantly elevated among AHI participants at enrollment compared to uninfected controls, and only 4 participants remained seronegative at enrollment. DISCUSSION: The results emphasize the difficulty in recruiting subjects early in AHI. Viral sequence diversity proved accurate in estimating time of infection. Regardless of aggressive screening, peak viremia and inflammation occurred before enrollment and potential intervention. Given the personal and public health importance, improved AHI detection is urgently needed

Widespread Endogenization of Genome Sequences of Non-Retroviral RNA Viruses into Plant Genomes

Non-retroviral RNA virus sequences (NRVSs) have been found in the chromosomes of vertebrates and fungi, but not plants. Here we report similarly endogenized NRVSs derived from plus-, negative-, and double-stranded RNA viruses in plant chromosomes. These sequences were found by searching public genomic sequence databases, and, importantly, most NRVSs were subsequently detected by direct molecular analyses of plant DNAs. The most widespread NRVSs were related to the coat protein (CP) genes of the family Partitiviridae which have bisegmented dsRNA genomes, and included plant- and fungus-infecting members. The CP of a novel fungal virus (Rosellinia necatrix partitivirus 2, RnPV2) had the greatest sequence similarity to Arabidopsis thaliana ILR2, which is thought to regulate the activities of the phytohormone auxin, indole-3-acetic acid (IAA). Furthermore, partitivirus CP-like sequences much more closely related to plant partitiviruses than to RnPV2 were identified in a wide range of plant species. In addition, the nucleocapsid protein genes of cytorhabdoviruses and varicosaviruses were found in species of over 9 plant families, including Brassicaceae and Solanaceae. A replicase-like sequence of a betaflexivirus was identified in the cucumber genome. The pattern of occurrence of NRVSs and the phylogenetic analyses of NRVSs and related viruses indicate that multiple independent integrations into many plant lineages may have occurred. For example, one of the NRVSs was retained in Ar. thaliana but not in Ar. lyrata or other related Camelina species, whereas another NRVS displayed the reverse pattern. Our study has shown that single- and double-stranded RNA viral sequences are widespread in plant genomes, and shows the potential of genome integrated NRVSs to contribute to resolve unclear phylogenetic relationships of plant species

A Conserved Developmental Patterning Network Produces Quantitatively Different Output in Multiple Species of Drosophila

Differences in the level, timing, or location of gene expression can contribute to alternative phenotypes at the molecular and organismal level. Understanding the origins of expression differences is complicated by the fact that organismal morphology and gene regulatory networks could potentially vary even between closely related species. To assess the scope of such changes, we used high-resolution imaging methods to measure mRNA expression in blastoderm embryos of Drosophila yakuba and Drosophila pseudoobscura and assembled these data into cellular resolution atlases, where expression levels for 13 genes in the segmentation network are averaged into species-specific, cellular resolution morphological frameworks. We demonstrate that the blastoderm embryos of these species differ in their morphology in terms of size, shape, and number of nuclei. We present an approach to compare cellular gene expression patterns between species, while accounting for varying embryo morphology, and apply it to our data and an equivalent dataset for Drosophila melanogaster. Our analysis reveals that all individual genes differ quantitatively in their spatio-temporal expression patterns between these species, primarily in terms of their relative position and dynamics. Despite many small quantitative differences, cellular gene expression profiles for the whole set of genes examined are largely similar. This suggests that cell types at this stage of development are conserved, though they can differ in their relative position by up to 3–4 cell widths and in their relative proportion between species by as much as 5-fold. Quantitative differences in the dynamics and relative level of a subset of genes between corresponding cell types may reflect altered regulatory functions between species. Our results emphasize that transcriptional networks can diverge over short evolutionary timescales and that even small changes can lead to distinct output in terms of the placement and number of equivalent cells