Examining the role of dopamine in methylphenidate's effects on resting brain function.

The amplitude of low-frequency fluctuations (ALFF) and global functional connectivity density (gFCD) are fMRI (Functional MRI) metrics widely used to assess resting brain function. However, their differential sensitivity to stimulant-induced dopamine (DA) increases, including the rate of DA rise and the relationship between them, have not been investigated. Here we used, simultaneous PET-fMRI to examine the association between dynamic changes in striatal DA and brain activity as assessed by ALFF and gFCD, following placebo, intravenous (IV), or oral methylphenidate (MP) administration, using a within-subject double-blind placebo-controlled design. In putamen, MP significantly reduced D2/3 receptor availability and strongly reduced ALFF and increased gFCD in the brain for IV-MP (Cohen's d > 1.6) but less so for oral-MP (Cohen's d < 0.6). Enhanced gFCD was associated with both the level and the rate of striatal DA increases, whereas decreased ALFF was only associated with the level of DA increases. These findings suggest distinct representations of neurovascular activation with ALFF and gFCD by stimulant-induced DA increases with differential sensitivity to the rate and the level of DA increases. We also observed an inverse association between gFCD and ALFF that was markedly enhanced during IV-MP, which could reflect an increased contribution from MP's vasoactive properties.

A framework for understanding climate change impacts through non-compensatory intra- and interspecific climate change responses.

Understanding and predicting population responses to climate change is a crucial challenge. A key component of population responses to climate change are cases in which focal biological rates (e.g., population growth rates) change in response to climate change due to non-compensatory effects of changes in the underlying components (e.g., birth and death rates) determining the focal rates. We refer to these responses as non-compensatory climate change effects. As differential responses of biological rates to climate change have been documented in a variety of systems and arise at multiple levels of organization within and across species, non-compensatory effects may be nearly ubiquitous. Yet, how non-compensatory climate change responses combine and scale to influence the demographics of populations is often unclear and requires mapping them to the birth and death rates underlying population change. We provide a flexible framework for incorporating non-compensatory changes in upstream rates within and among species and mapping their consequences for additional downstream rates across scales to their eventual effects on population growth rates. Throughout, we provide specific examples and potential applications of the framework. We hope this framework helps to enhance our understanding of and unify research on population responses to climate change.

Biomechanical stimulation promotes blood vessel growth despite VEGFR-2 inhibition.

BACKGROUND: Angiogenesis, or the growth of new vasculature from existing blood vessels, is widely considered a primary hallmark of cancer progression. When a tumor is small, diffusion is sufficient to receive essential nutrients; however, as the tumor grows, a vascular supply is needed to deliver oxygen and nutrients into the increasing mass. Several anti-angiogenic cancer therapies target VEGF and the receptor VEGFR-2, which are major promoters of blood vessel development. Unfortunately, many of these cancer treatments fail to completely stop angiogenesis in the tumor microenvironment (TME). Since these therapies focus on the biochemical activation of VEGFR-2 via VEGF ligand binding, we propose that mechanical cues, particularly those found in the TME, may be a source of VEGFR-2 activation that promotes growth of blood vessel networks even in the presence of VEGF and VEGFR-2 inhibitors. RESULTS: In this paper, we analyzed phosphorylation patterns of VEGFR-2, particularly at Y1054/Y1059 and Y1214, stimulated via either VEGF or biomechanical stimulation in the form of tensile strains. Our results show prolonged and enhanced activation at both Y1054/Y1059 and Y1214 residues when endothelial cells were stimulated with strain, VEGF, or a combination of both. We also analyzed Src expression, which is downstream of VEGFR-2 and can be activated through strain or the presence of VEGF. Finally, we used fibrin gels and microfluidic devices as 3D microtissue models to simulate the TME. We determined that regions of mechanical strain promoted increased vessel growth, even with VEGFR-2 inhibition through SU5416. CONCLUSIONS: Overall, understanding both the effects that biomechanical and biochemical stimuli have on VEGFR-2 activation and angiogenesis is an important factor in developing effective anti-angiogenic therapies. This paper shows that VEGFR-2 can be mechanically activated through strain, which likely contributes to increased angiogenesis in the TME. These proof-of-concept studies show that small molecular inhibitors of VEGFR-2 do not fully prevent angiogenesis in 3D TME models when mechanical strains are introduced.

20 kDa isoform of connexin-43 augments spatial reorganization of the brain endothelial junctional complex and lesion leakage in cerebral cavernous malformation type-3.

Cerebral cavernous malformation type-3 (CCM3) is a type of brain vascular malformation caused by mutations in programmed cell death protein-10 (PDCD10). It is characterized by early life occurrence of hemorrhagic stroke and profound blood-brain barrier defects. The pathogenic mechanisms responsible for microvascular hyperpermeability and lesion progression in CCM3 are still largely unknown. The current study examined brain endothelial barrier structural defects formed in the absence of CCM3 in vivo and in vitro that may lead to CCM3 lesion leakage. We found significant upregulation of a 20 kDa isoform of connexin 43 (GJA1-20 k) in brain endothelial cells (BEC) in both non-leaky and leaky lesions, as well as in an in vitro CCM3 knockdown model (CCM3KD-BEC). Morphological, biochemical, FRET, and FRAP analyses of CCM3KD-BEC found GJA1-20 k regulates full-length GJA1 biogenesis, prompting uncontrolled gap junction growth. Furthermore, by binding to a tight junction scaffolding protein, ZO-1, GJA1-20 k interferes with Cx43/ZO-1 interactions and gap junction/tight junction crosstalk, promoting ZO-1 dissociation from tight junction complexes and diminishing claudin-5/ZO-1 interaction. As a consequence, the tight junction complex is destabilized, allowing "replacement" of tight junctions with gap junctions leading to increased brain endothelial barrier permeability. Modifying cellular levels of GJA1-20 k rescued brain endothelial barrier integrity re-establishing the spatial organization of gap and tight junctional complexes. This study highlights generation of potential defects at the CCM3-affected brain endothelial barrier which may underlie prolonged vascular leakiness.

Ecogeography of group size suggests differences in drivers of sociality among cooperatively breeding fairywrens.

Cooperatively breeding species exhibit a range of social behaviours associated with different costs and benefits to group living, often in association with different environmental conditions. For example, recent phylogenetic studies have collectively shown that the evolution and distribution of cooperative breeding behaviour is related to the environment. However, little is known about how environmental variation may drive differences in social systems across populations within species, and how the relationship between environmental conditions and sociality may differ across species. Here, we examine variation in social group size along a steep environmental gradient for two congeneric cooperatively breeding species of fairywrens (Maluridae) and show that they exhibit opposing ecogeographic patterns. Purple-backed fairywrens, a species in which helpers increase group productivity, have larger groups in hot, dry environments and smaller groups in cool, wet environments. By contrast, superb fairywrens, a species with helpers that do not increase group productivity despite the presence of alloparental care, exhibit the opposite trend. We suggest differences in the costs and benefits of sociality contribute to these opposing ecogeographical patterns and demonstrate that comparisons of intraspecific patterns of social variation across species can provide insight into how ecology shapes social systems.

Sex differences in methylphenidate-induced dopamine increases in ventral striatum.

Sex differences in the prevalence of dopamine-related neuropsychiatric diseases and in the sensitivity to dopamine-boosting drugs such as stimulants is well recognized. Here we assessed whether there are sex differences in the brain dopamine system in humans that could contribute to these effects. We analyzed data from two independent [11C]raclopride PET brain imaging studies that measured methylphenidate-induced dopamine increases in the striatum using different routes of administration (Cohort A = oral 60 mg; Cohort B = intravenous 0.5 mg/kg; total n = 95; 65 male, 30 female), in blinded placebo-controlled designs. Females when compared to males reported stronger feeling of "drug effects" and showed significantly greater dopamine release in the ventral striatum (where nucleus accumbens is located) to both oral and intravenous methylphenidate. In contrast, there were no significant differences in methylphenidate-induced increases in dorsal striatum for either oral or intravenous administration nor were there differences in levels of methylphenidate in plasma. The greater dopamine increases with methylphenidate in ventral but not dorsal striatum in females compared to males suggests an enhanced sensitivity specific to the dopamine reward system that might underlie sex differences in the vulnerability to substance use disorders and to attention-deficit/hyperactivity disorder (ADHD).

Crowdsourcing biocuration: The Community Assessment of Community Annotation with Ontologies (CACAO).

Experimental data about gene functions curated from the primary literature have enormous value for research scientists in understanding biology. Using the Gene Ontology (GO), manual curation by experts has provided an important resource for studying gene function, especially within model organisms. Unprecedented expansion of the scientific literature and validation of the predicted proteins have increased both data value and the challenges of keeping pace. Capturing literature-based functional annotations is limited by the ability of biocurators to handle the massive and rapidly growing scientific literature. Within the community-oriented wiki framework for GO annotation called the Gene Ontology Normal Usage Tracking System (GONUTS), we describe an approach to expand biocuration through crowdsourcing with undergraduates. This multiplies the number of high-quality annotations in international databases, enriches our coverage of the literature on normal gene function, and pushes the field in new directions. From an intercollegiate competition judged by experienced biocurators, Community Assessment of Community Annotation with Ontologies (CACAO), we have contributed nearly 5,000 literature-based annotations. Many of those annotations are to organisms not currently well-represented within GO. Over a 10-year history, our community contributors have spurred changes to the ontology not traditionally covered by professional biocurators. The CACAO principle of relying on community members to participate in and shape the future of biocuration in GO is a powerful and scalable model used to promote the scientific enterprise. It also provides undergraduate students with a unique and enriching introduction to critical reading of primary literature and acquisition of marketable skills.

Effects of Device Limitations on Acquisition of the /t/-/k/ Contrast in Children With Cochlear Implants.

OBJECTIVES: The present study investigated how development of the /t/-/k/ contrast is affected by the unique perceptual constraints imposed on young children using cochlear implants (CIs). We hypothesized that children with CIs would demonstrate unique patterns of speech acquisition due to device limitations, rather than straightforward delays due to a lack of auditory input in the first year of life before implantation. This study focused on the contrast between /t/ and /k/ because it is acquired early in the sequence of development, requires less advanced motor control than later-acquired place contrasts, is differentiated by spectral cues (which are particularly degraded when processed by CIs), and is not easily differentiated by visual cues alone. Furthermore, perceptual confusability between /t/ and /k/ may be exacerbated in front-vowel contexts, where the spectral energy for /k/ is shifted to higher frequencies, creating more spectral overlap with /t/. DESIGN: Children with CIs (n = 26; ages 31 to 66 mo) who received implants around their first birthdays were matched to peers with normal hearing (NH). Children participated in a picture-prompted auditory word-repetition task that included over 30 tokens of word-initial /t/ and /k/ consonants. Tokens were balanced across front-vowel and back-vowel contexts to assess the effects of coarticulation. Productions were transcribed and coded for accuracy as well as the types of errors produced (manner of articulation, voicing, or place of articulation errors). Centroid frequency was also calculated for /t/ and /k/ tokens that were produced correctly. Mixed-effects models were used to compare accuracy, types of errors, and centroid frequencies across groups, target consonants, and vowel contexts. RESULTS: Children with CIs produced /t/ and /k/ less accurately than their peers in both front- and back-vowel contexts. Children with CIs produced /t/ and /k/ with equal accuracy, and /k/ was produced less accurately in front-vowel contexts than in back-vowel contexts. When they produced errors, children with CIs were more likely to produce manner errors and less likely to produce voicing errors than children with NH. Centroid frequencies for /t/ and /k/ were similar across groups, except for /k/ in front-vowel contexts: children with NH produced /k/ in front-vowel contexts with higher centroid frequency than children with CIs, and they produced /k/ and /t/ with equal centroid frequencies in front-vowel contexts. CONCLUSIONS: Children with CIs not only produced /t/ and /k/ less accurately than peers with NH, they also demonstrated idiosyncratic patterns of acquisition, likely resulting from receiving degraded and distorted spectral information critical for differentiating /t/ and /k/. Speech-language pathologists should consider perceptual confusability of consonants (and their allophonic variations) during their assessment and treatment of this unique population of children.

Claudin-1-Dependent Destabilization of the Blood-Brain Barrier in Chronic Stroke.

Recent evidence suggests that blood-brain barrier (BBB) recovery and reestablishment of BBB impermeability after stroke is incomplete. This could influence stroke recovery, increase the risk of repeat stroke, and be a solid substrate for developing vascular dementia. Although accumulating evidence has defined morphological alterations and underlying mechanisms of tight junction (TJ) changes during BBB breakdown in acute stroke, very little is known about the type of alterations and mechanisms in BBB "leakage" found subacutely or chronically. The current study examined BBB structural alterations during the "BBB leakage" associated with the chronic phase of stroke in male mice and both genders of humans. We found significant upregulation of claudin-1 mRNA and protein, a nonspecific claudin for blood vessels, and downregulation in claudin-5 expression. Morphological and biochemical as well as fluorescence resonance energy transfer and fluorescence recovery after photobleaching analysis of postischemic brain endothelial cells and cells overexpressing claudin-1 indicated that newly synthesized claudin-1 was present on the cell membrane (∼45%), was incorporated into the TJ complex with established interaction with zonula occludens-1 (ZO-1), and was building homophilic cis- and trans-interactions. The appearance of claudin-1 in the TJ complex reduced claudin-5 strands (homophilic claudin-5 cis- and trans-interactions) and claudin-5/ZO-1 interaction affecting claudin-5 incorporation into the TJ complex. Moreover, claudin-1 induction was associated with an endothelial proinflammatory phenotype. Targeting claudin-1 with a specific C1C2 peptide improved brain endothelial barrier permeability and functional recovery in chronic stroke condition. This study highlights a potential "defect" in postischemic barrier formation that may underlie prolonged vessel leakiness.SIGNIFICANCE STATEMENT Although rarely expressed at the normal blood-brain barrier (BBB), claudin-1 is expressed in pathological conditions. Analyzing poststroke human and mouse blood microvessels we have identified that claudin-1 is highly expressed in leaky brain microvessels. Our results reveal that claudin-1 is incorporated in BBB tight junction complex, impeding BBB recovery and causing BBB leakiness during poststroke recovery. Targeting claudin-1 with a claudin-1 peptide improves brain endothelial barrier permeability and consequently functional neurological recovery after stroke.

Communities of practice in Alberta Health Services: advancing a learning organisation.

BACKGROUND: In 2009, Alberta Health Services (AHS) became Canada's first and largest fully integrated healthcare system, involving the amalgamation of nine regional health authorities and three provincial services. Within AHS, communities of practice (CoPs) meet regularly to learn from one another and to find ways to improve service quality. This qualitative study examined CoPs as an applied practice of a learning organisation along with their potential influence in a healthcare system by exploring the perspectives of CoP participants. METHODS: A collective case study method was used to enable the examination of a cross-section of cases in the study organisation. Semi-structured interviews were conducted with 31 participants representing 28 distinct CoPs. Using Senge's framework of a learning organisation, CoP influences associated with team learning and organisational change were explored. RESULTS: CoPs in AHS were described as diverse in practice domains, focus, membership boundaries, attendance and sphere of influence. Using small-scale resource investments, CoPs provided members with opportunities for meaningful interactions, the capacity to build information pathways, and enhanced abilities to address needs at the point of care and service delivery. Overall, CoPs delivered a sophisticated array of engagement and knowledge-sharing activities perceived as supportive of organisational change, systems thinking, and the team learning practice critical to a learning organisation. CONCLUSION: CoPs enable the diverse wealth of knowledge embedded in people, local conditions and special circumstances to flow from practice domain groups to programme and service areas, and into the larger system where it can effect organisational change. This research highlights the potential of CoPs to influence practice and broad-scale change more directly than previously understood or reported in the literature. As such, this study suggests that CoPs have the potential to influence and advance widespread systems change in Canadian healthcare.

Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure.

Familial cerebral cavernous malformations type III (fCCM3) is a disease of the cerebrovascular system caused by loss-of-function mutations in ccm3 that result in dilated capillary beds that are susceptible to hemorrhage. Before hemorrhage, fCCM3 lesions are characterized by a hyperpermeable blood-brain barrier (BBB), the key pathologic feature of fCCM3. We demonstrate that connexin 43 (Cx43), a gap junction (GJ) protein that is incorporated into the BBB junction complex, is up-regulated in lesions of a murine model of fCCM3. Small interfering RNA-mediated ccm3 knockdown (CCM3KD) in brain endothelial cells in vitro increased Cx43 protein expression, GJ plaque size, GJ intracellular communication (GJIC), and barrier permeability. CCM3KD hyperpermeability was rescued by GAP27, a peptide gap junction and hemichannel inhibitor of Cx43 GJIC. Tight junction (TJ) protein, zonula occludens 1 (ZO-1), accumulated at Cx43 GJs in CCM3KD cells and displayed fragmented staining at TJs. The GAP27-mediated inhibition of Cx43 GJs in CCM3KD cells restored ZO-1 to TJ structures and reduced plaque accumulation at Cx43 GJs. The TJ protein, Claudin-5, was also fragmented at TJs in CCM3KD cells, and GAP27 treatment lengthened TJ-associated fragments and increased Claudin 5-Claudin 5 transinteraction. Overall, we demonstrate that Cx43 GJs are aberrantly increased in fCCM3 and regulate barrier permeability by a TJ-dependent mechanism.-Johnson, A. M., Roach, J. P., Hu, A., Stamatovic, S. M., Zochowski, M. R., Keep, R. F., Andjelkovic, A. V. Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure.

Quantifying robustness of the /t/-/k/ contrast using a single, static spectral feature.

Dynamic spectral shape features accurately classify /t/ and /k/ productions across speakers and contexts. This paper shows that word-initial /t/ and /k/ tokens produced by 21 adults can be differentiated using a single, static spectral feature when spectral energy concentration is considered relative to expectations within a given speaker and vowel context. Centroid and peak frequency-calculated from both acoustic and psychoacoustic spectra-were compared to determine whether one feature could reliably differentiate /t/ and /k/, and, if so, which feature best differentiated them. Centroid frequency from both acoustic and psychoacoustic spectra accurately classified productions of /t/ and /k/.

Multiple hypotheses explain variation in extra-pair paternity at different levels in a single bird family.

Extra-pair paternity (EPP), where offspring are sired by a male other than the social male, varies enormously both within and among species. Trying to explain this variation has proved difficult because the majority of the interspecific variation is phylogenetically based. Ideally, variation in EPP should be investigated in closely related species, but clades with sufficient variation are rare. We present a comprehensive multifactorial test to explain variation in EPP among individuals in 20 populations of nine species over 89 years from a single bird family (Maluridae). Females had higher EPP in the presence of more helpers, more neighbours or if paired incestuously. Furthermore, higher EPP occurred in years with many incestuous pairs, populations with many helpers and species with high male density or in which males provide less care. Altogether, these variables accounted for 48% of the total and 89% of the interspecific and interpopulation variation in EPP. These findings indicate why consistent patterns in EPP have been so challenging to detect and suggest that a single predictor is unlikely to account for the enormous variation in EPP across levels of analysis. Nevertheless, it also shows that existing hypotheses can explain the variation in EPP well and that the density of males in particular is a good predictor to explain variation in EPP among species when a large part of the confounding effect of phylogeny is excluded.

Decreasing Peripherally Inserted Central Catheter Use With Ultrasound-Guided Peripheral Intravenous Lines: A Quality Improvement Project in the Acute Care Setting.

An ultrasound-guided peripheral intravenous (UGPIV) quality improvement project occurred in an 849-bed tertiary care hospital with a goal to reduce the use of central lines, in particular, peripherally inserted central catheters (PICCs). Since implementation, PICCs have decreased by 46.7% overall, and 59 nurses in-hospital are competent in placing UGPIVs. Placement of UGPIVs by the bedside nurse is a key initiative in decreasing PICC use and, potentially, infections.

The Protein Interactome of Mycobacteriophage Giles Predicts Functions for Unknown Proteins.

UNLABELLED: Mycobacteriophages are viruses that infect mycobacterial hosts and are prevalent in the environment. Nearly 700 mycobacteriophage genomes have been completely sequenced, revealing considerable diversity and genetic novelty. Here, we have determined the protein complement of mycobacteriophage Giles by mass spectrometry and mapped its genome-wide protein interactome to help elucidate the roles of its 77 predicted proteins, 50% of which have no known function. About 22,000 individual yeast two-hybrid (Y2H) tests with four different Y2H vectors, followed by filtering and retest screens, resulted in 324 reproducible protein-protein interactions, including 171 (136 nonredundant) high-confidence interactions. The complete set of high-confidence interactions among Giles proteins reveals new mechanistic details and predicts functions for unknown proteins. The Giles interactome is the first for any mycobacteriophage and one of just five known phage interactomes so far. Our results will help in understanding mycobacteriophage biology and aid in development of new genetic and therapeutic tools to understand Mycobacterium tuberculosis. IMPORTANCE: Mycobacterium tuberculosis causes over 9 million new cases of tuberculosis each year. Mycobacteriophages, viruses of mycobacterial hosts, hold considerable potential to understand phage diversity, evolution, and mycobacterial biology, aiding in the development of therapeutic tools to control mycobacterial infections. The mycobacteriophage Giles protein-protein interaction network allows us to predict functions for unknown proteins and shed light on major biological processes in phage biology. For example, Giles gp76, a protein of unknown function, is found to associate with phage packaging and maturation. The functions of mycobacteriophage-derived proteins may suggest novel therapeutic approaches for tuberculosis. Our ORFeome clone set of Giles proteins and the interactome data will be useful resources for phage interactomics.

Chemical Analysis of Drug Biocrystals: A Role for Counterion Transport Pathways in Intracellular Drug Disposition.

In mammals, highly lipophilic small molecule chemical agents can accumulate as inclusions within resident tissue macrophages. In this context, we characterized the biodistribution, chemical composition, and structure of crystal-like drug inclusions (CLDIs) formed by clofazimine (CFZ), a weakly basic lipophilic drug. With prolonged oral dosing, CFZ exhibited a significant partitioning with respect to serum and fat due to massive bioaccumulation and crystallization in the liver and spleen. The NMR, Raman, and powder X-ray diffraction (p-XRD) spectra of CLDIs isolated from the spleens of CFZ-treated mice matched the spectra of pure, CFZ hydrochloride crystals (CFZ-HCl). Elemental analysis revealed a 237-fold increase in chlorine content in CLDIs compared to untreated tissue samples and a 5-fold increase in chlorine content compared to CFZ-HCl, suggesting that the formation of CLDIs occurs through a chloride mediated crystallization mechanism. Single crystal analysis revealed that CFZ-HCl crystals had a densely packed orthorhombic lattice configuration. In vitro, CFZ-HCl formed at a pH of 4-5 only if chloride ions were present at sufficiently high concentrations (>50:1 Cl(-)/CFZ), indicating that intracellular chloride transport mechanisms play a key role in the formation of CLDIs. While microscopy and pharmacokinetic analyses clearly revealed crystallization and intracellular accumulation of the drug in vivo, the chemical and structural characterization of CLDIs implicates a concentrative, chloride transport mechanism, paralleling and thermodynamically stabilizing the massive bioaccumulation of a weakly basic drug.

Complete genome sequences of mycobacteriophages Ageofdapage, Aubs, BABullseye, CheetoDust, ShaboiShabazz, and TomBrady.

We report genome sequences of six mycobacteriophages. Each virus was isolated from a soil sample and belongs to the siphovirus morphology. Genomes are 41,901-60,613 bp in length, contain between 62 and 103 protein-coding genes, with up to 40% of those genes having a predicted function.

The prognostic effect of mechanical, ultrastructural, and ECM signatures in glioblastoma core and rim.

Glioblastoma (GBM) is a highly invasive, aggressive brain cancer that carries a median survival of 15 months and is resistant to standard therapeutics. Recent studies have demonstrated that intratumoral heterogeneity plays a critical role in promoting resistance by mediating tumor adaptation through microenvironmental cues. GBM can be separated into two distinct regions-a core and a rim, which are thought to drive specific aspects of tumor evolution. These differences in tumor progression are regulated by the diverse biomolecular and biophysical signals in these regions, but the acellular biophysical characteristics remain poorly described. This study investigates the mechanical and ultrastructural characteristics of the tumor extracellular matrix (ECM) in patient-matched GBM core and rim tissues. Seven patient-matched tumor core and rim samples and one non-neoplastic control were analyzed using atomic force microscopy, scanning electron microscopy, and immunofluorescence imaging to quantify mechanical, ultrastructural, and ECM composition changes. The results reveal significant differences in biophysical parameters between GBM core, rim, and non-neoplastic tissues. The GBM core is stiffer, denser, and is rich in ECM proteins hyaluronic acid and tenascin-C when compared to tumor rim and non-neoplastic tissues. These alterations are intimately related and have prognostic effect with stiff, dense tissue correlating with longer progression-free survival. These findings reveal new insights into the spatial heterogeneity of biophysical parameters in the GBM tumor microenvironment and identify a set of characteristics that may correlate with patient prognosis. In the long term, these characteristics may aid in the development of strategies to combat therapeutic resistance.

Translating a motivational interviewing intervention for childhood cancer survivors into an eHealth tool: A user-centered design process.

Childhood cancer survivors have a higher risk of developing cardiomyopathy than members of the general population. Screening echocardiograms can facilitate early detection and treatment of cardiomyopathy. Furthermore, motivational interviewing can increase uptake of cardiac screening. However, such approaches are time- and resource-intensive, which limits their reach to the survivors who need them. We describe how we utilized a user-centered design process to translate an in-person motivational interviewing intervention into an eHealth tool to improve cardiac screening among childhood cancer survivors. We used an iterative, three-phase, user-centered design approach: (i) setting the stage (convening advisory boards and reviewing the original intervention), (ii) content programming and development (writing and programming intervention text and flow), and (iii) intervention testing (research team testing and cognitive interviews.) For cognitive interviews, participants were recruited via institutional participant registries and medical records. Data were analyzed using rapid qualitative analysis. During Phase 1, we identified survivor and provider advisors and outlined elements of the in-person intervention to change for the eHealth tool. During Phases 2 and 3, advisors recommended several modifications that guided the final intervention content and flow. Examples include: acknowledging potential hesitation or apprehension surrounding medical screenings, addressing barriers and facilitators to obtaining screening, and improving the tool's usability and appeal. In Phase 3, cognitive interview participants suggested additional refinements to the intervention language. This translation process shows that continued in-depth engagement of community advisors and iterative testing can improve the applicability of an eHealth to survivors' lived experiences and social contexts.

Childhood cancer survivors have a higher-than-average risk for developing heart damage compared to the general population. One-on-one interviews aimed at educating survivors about the importance of screening for heart damage can increase engagement in screening, but these programs are often too resource-intensive to be made available to large groups of survivors. Programs delivered using digital technology, like websites and smartphone apps, can be a more accessible alternative. In this article, we describe how we translated an in-person counseling program into a digital tool. We convened advisors who were childhood cancer survivors and healthcare providers to review the tool throughout the three-phase translation process: (i) setting the stage (convening advisory boards and reviewing original intervention), (ii) content programming and development (writing, and programming intervention text and flow), and (iii) intervention testing (research team testing and cognitive interviews.). Our translation process shows that continuously engaging with advisory boards and testing apps with participants can improve health programs in line with communities' diverse perspectives.