Interface of Clinical Nurse Specialist Practice and Healthcare Technology.

PURPOSE: This article demonstrates the leadership role of the clinical nurse specialist in developing and implementing healthcare technology across the continuum of care. DESCRIPTION: Three virtual nursing practices-facilitated self-care, remote patient monitoring, and virtual acute care nursing-illustrate how the clinical nurse specialist is well suited to transform traditional practice models to ones that use healthcare technology effectively. These 3 practices use interactive healthcare technology to gather patient data and allow communication and coordination with the healthcare team to meet patient-specific needs. OUTCOME: Use of healthcare technology in virtual nursing practices led to early care team intervention, optimized care team processes, proactive patient outreach, timely access to care, and reduction in healthcare-associated errors and near-miss events. CONCLUSION: Clinical nurse specialists are well positioned to develop innovative, effective, accessible, and high-quality virtual nursing practices. Integrating healthcare technology with nursing practice augments care for various patients, ranging from those with low illness severity in the outpatient setting to acutely ill patients in the inpatient hospital environment.

Development and acceptability of a mobile health application integrated with the electronic heath record for treatment of chronic insomnia disorder.

STUDY OBJECTIVES: To describe the development and feasibility of a cognitive behavioral therapy for insomnia (CBT-I) program delivered via personal digital devices and fully integrated with the electronic health record (EHR). METHODS: A multidisciplinary team of clinicians and members of our Center for Digital Health collaborated to develop a Chronic Insomnia Interactive Care Plan (ChI-ICP), an application that provides personalized and just in time education and promotes self-management using CBT-I concepts, and is activated from and fully integrated into the EHR. Following development, we evaluated patient engagement and workflows, assessed changes to provider workload, and examined outcomes on measures of insomnia during a pilot deployment of the application. RESULTS: A total of 222 patients were enrolled and 179 engaged with the plan during the 3-month pilot program. Enrolled patients generated an average of 3.9 ± 2.3 In Basket messages, most being automated notifications related to noncompletion of assigned tasks, while only a few were related to patients requesting additional training or help with insomnia. Sleep efficiency improved from baseline until the completion of the program from 74.5% ± 16.7% to 87.6% ± 10.8% (P = .001), and the Insomnia Severity Index improved from 14.9 ± 5.22 to 11.6 ± 4.80 (P = .006). CONCLUSIONS: In this pilot implementation of an integrated ChI-ICP, patient engagement was favorable, workflows and workload were not significantly burdensome for the care teams, and initial evaluation of efficacy was favorable. This provides evidence for an application that is a scalable method to assist patients with chronic insomnia and future work should assess its efficacy in controlled trials. CITATION: Morgenthaler TI, Kolla BP, Anderson SE, et al. Development and acceptability of a mobile health application integrated with the electronic heath record for treatment of chronic insomnia disorder. J Clin Sleep Med. 2022;18(12):2785-2792.

Mice with humanized immune system as novel models to study HIV-associated pulmonary hypertension.

People living with HIV and who receive antiretroviral therapy have a significantly improved lifespan, compared to the early days without therapy. Unfortunately, persisting viral replication in the lungs sustains chronic inflammation, which may cause pulmonary vascular dysfunction and ultimate life-threatening Pulmonary Hypertension (PH). The mechanisms involved in the progression of HIV and PH remain unclear. The study of HIV-PH is limited due to the lack of tractable animal models that recapitulate infection and pathobiological aspects of PH. On one hand, mice with humanized immune systems (hu-mice) are highly relevant to HIV research but their suitability for HIV-PH research deserves investigation. On another hand, the Hypoxia-Sugen is a well-established model for experimental PH that combines hypoxia with the VEGF antagonist SU5416. To test the suitability of hu-mice, we combined HIV with either SU5416 or hypoxia. Using right heart catheterization, we found that combining HIV+SU5416 exacerbated PH. HIV infection increases human pro-inflammatory cytokines in the lungs, compared to uninfected mice. Histopathological examinations showed pulmonary vascular inflammation with arterial muscularization in HIV-PH. We also found an increase in endothelial-monocyte activating polypeptide II (EMAP II) when combining HIV+SU5416. Therefore, combinations of HIV with SU5416 or hypoxia recapitulate PH in hu-mice, creating well-suited models for infectious mechanistic pulmonary vascular research in small animals.

Marek's Disease Virus Telomeric Integration Profiles of Neoplastic Host Tissues Reveal Unbiased Chromosomal Selection and Loss of Cellular Diversity during Tumorigenesis.

The avian α-herpesvirus known as Marek's disease virus (MDV) linearly integrates its genomic DNA into host telomeres during infection. The resulting disease, Marek's disease (MD), is characterized by virally-induced lymphomas with high mortality. The temporal dynamics of MDV-positive (MDV+) transformed cells and expansion of MD lymphomas remain targets for further understanding. It also remains to be determined whether specific host chromosomal sites of MDV telomere integration confer an advantage to MDV-transformed cells during tumorigenesis. We applied MDV-specific fluorescence in situ hybridization (MDV FISH) to investigate virus-host cytogenomic interactions within and among a total of 37 gonad lymphomas and neoplastic splenic samples in birds infected with virulent MDV. We also determined single-cell, chromosome-specific MDV integration profiles within and among transformed tissue samples, including multiple samples from the same bird. Most mitotically-dividing cells within neoplastic samples had the cytogenomic phenotype of 'MDV telomere-integrated only', and tissue-specific, temporal changes in phenotype frequencies were detected. Transformed cell populations composing gonad lymphomas exhibited significantly lower diversity, in terms of heterogeneity of MDV integration profiles, at the latest stages of tumorigenesis (>50 days post-infection (dpi)). We further report high interindividual and lower intraindividual variation in MDV integration profiles of lymphoma cells. There was no evidence of integration hotspots into a specific host chromosome(s). Collectively, our data suggests that very few transformed MDV+ T cell populations present earlier in MDV-induced lymphomas (32-50 dpi), survive, and expand to become the dominant clonal population in more advanced MD lymphomas (51-62 dpi) and establish metastatic lymphomas.

One-step generation of a targeted knock-in calf using the CRISPR-Cas9 system in bovine zygotes.

BACKGROUND: The homologous recombination (HR) pathway is largely inactive in early embryos prior to the first cell division, making it difficult to achieve targeted gene knock-ins. The homology-mediated end joining (HMEJ)-based strategy has been shown to increase knock-in efficiency relative to HR, non-homologous end joining (NHEJ), and microhomology-mediated end joining (MMEJ) strategies in non-dividing cells. RESULTS: By introducing gRNA/Cas9 ribonucleoprotein complex and a HMEJ-based donor template with 1 kb homology arms flanked by the H11 safe harbor locus gRNA target site, knock-in rates of 40% of a 5.1 kb bovine sex-determining region Y (SRY)-green fluorescent protein (GFP) template were achieved in Bos taurus zygotes. Embryos that developed to the blastocyst stage were screened for GFP, and nine were transferred to recipient cows resulting in a live phenotypically normal bull calf. Genomic analyses revealed no wildtype sequence at the H11 target site, but rather a 26 bp insertion allele, and a complex 38 kb knock-in allele with seven copies of the SRY-GFP template and a single copy of the donor plasmid backbone. An additional minor 18 kb allele was detected that looks to be a derivative of the 38 kb allele resulting from the deletion of an inverted repeat of four copies of the SRY-GFP template. CONCLUSION: The allelic heterogeneity in this biallelic knock-in calf appears to have resulted from a combination of homology directed repair, homology independent targeted insertion by blunt-end ligation, NHEJ, and rearrangement following editing of the gRNA target site in the donor template. This study illustrates the potential to produce targeted gene knock-in animals by direct cytoplasmic injection of bovine embryos with gRNA/Cas9, although further optimization is required to ensure a precise single-copy gene integration event.

Carceral Citizenship as Strength: Formerly Incarcerated Activists, Civic Engagement and Criminal Justice Transformation.

During the era of mass incarceration, a history of felony convictions and imprisonment imposes legal and extra-legal sanctions that strip individuals of rights-what Miller and Alexander (2016) call "carceral citizenship." Despite the wide-reaching structural constraints that accompany the identity of being formerly incarcerated, many individuals enact their agency with civic engagement to reshape boundaries around individual and collective identity. Building from past convict criminology research (e.g., Ross and Richards 2003), we address the gap of including formerly incarcerated people into policymaking and community organizing around penal system reform. We offer expanded conceptualization of "carceral citizenship" and provide a framework for the transformation of practices that constitute carceral systems. As Goodman and colleagues (2017) demonstrate, the reformation of penal systems is not simply a result of the mechanical swing of a pendulum. Instead, the ongoing contestation between different stakeholders shapes criminal justice. Borrowing foundational theoretical concepts from multiple critical criminology perspectives, we frame the role of "carceral citizenship" within the transformation of the penal system reform.

HIV X4 Variants Increase Arachidonate 5-Lipoxygenase in the Pulmonary Microenvironment and are associated with Pulmonary Arterial Hypertension.

Pulmonary Arterial Hypertension (PAH) is overrepresented in People Living with Human Immunodeficiency Virus (PLWH). HIV protein gp120 plays a key role in the pathogenesis of HIV-PAH. Genetic changes in HIV gp120 determine viral interactions with chemokine receptors; specifically, HIV-X4 viruses interact with CXCR4 while HIV-R5 interact with CCR5 co-receptors. Herein, we leveraged banked samples from patients enrolled in the NIH Lung HIV studies and used bioinformatic analyses to investigate whether signature sequences in HIV-gp120 that predict tropism also predict PAH. Further biological assays were conducted in pulmonary endothelial cells in vitro and in HIV-transgenic rats. We found that significantly more persons living with HIV-PAH harbor HIV-X4 variants. Multiple HIV models showed that recombinant gp120-X4 as well as infectious HIV-X4 remarkably increase arachidonate 5-lipoxygenase (ALOX5) expression. ALOX5 is essential for the production of leukotrienes; we confirmed that leukotriene levels are increased in bronchoalveolar lavage fluid of HIV-infected patients. This is the first report associating HIV-gp120 genotype to a pulmonary disease phenotype, as we uncovered X4 viruses as potential agents in the pathophysiology of HIV-PAH. Altogether, our results allude to the supplementation of antiretroviral therapy with ALOX5 antagonists to rescue patients with HIV-X4 variants from fatal PAH.

Vaccination and Host Marek's Disease-Resistance Genotype Significantly Reduce Oncogenic Gallid alphaherpesvirus 2 Telomere Integration in Host Birds.

Marek's disease (MD) is an infectious disease characterized by lymphomas and high mortality in susceptible chickens. The causative and ubiquitous alpha-herpesvirus known as MD virus (MDV) integrates into host telomeres during early infection through latency, known to be an important phase for oncogenic transformation. Herein, we sought to determine the influence of vaccination and host genetics on the temporal dynamics of MDV-host genome interactions. We studied integration profiles using 2 MD vaccines that vary in protective efficacy in 2 genetic lines that differ in MD resistance/susceptibility. Virus integration of both oncogenic MDV and vaccine strains was observed in both MD susceptible and resistant birds, however, the lines differed in their dynamic telomere-integration profiles. Notably, the resistant host genotype exhibited a smaller percentage of replicating cells with the virus telomere-integrated only phenotype as compared to the susceptible genotype. Vaccination with Rispens, the most protective MD vaccine, also reduced the establishment of the virus telomere-integrated only phenotype, suggesting a significant role of the phenotype in MD lymphoma development. The effect of Rispens vaccination was most dramatic in the susceptible genotype. These results suggest important connections between vaccinal immunity, MDV telomere integration, virus-induced oncogenesis, and virus-host genome interactions in the context of host genetics and disease susceptibility.

How many bytes does it take? A content analysis of cyber issues in couple and family therapy journals.

In the fifteen years since the explosion of the Internet, using cyber technology for work and social functions has exponentially increased. Yet, questions around how to manage such changes remain elusive in family therapy literature. In this investigation, we conducted a content analysis to determine to what extent marriage/couple and family therapy (M/CFT) journals have responded to the integration of the Internet in couple and family life. We found 79 of 13,274 articles across seventeen journals focused on the Internet in some capacity. Implications for clinical practice, training, and future research are discussed.

Translational imaging studies of cortical spreading depression in experimental models for migraine aura.

This perspective discusses cortical spreading depression (CSD) phenomena and their translational significance for human migraine aura and the peri-infarct events following cerebral ischemia and injury. They begin with interstitial K(+) release and accumulation following neuronal stimulation, and a buffering astrocytic K(+) influx and remote liberation propagating waves of neuronal hyperexcitability and depression. Diffusion-weighted echoplanar MRI demonstrates CSD features in gyrencephalic brains recapitulating human migraine aura, spatial and temporal features of single primary events and multiple secondary events, their stimulus dependence, pharmacological properties, and their relationship to blood oxygenation level-dependent signals and late cerebrovascular changes. The article finally explores prospects for physiological studies of CSD gaining fuller insights both into mechanisms underlying the pathology of the corresponding human condition and possible approaches to management.

Inosine promotes recovery of skilled motor function in a model of focal brain injury.

Recovery of function following traumatic brain injury (TBI) is partly through neuronal plasticity. However plasticity is limited in the adult CNS compared with young animals. In order to test whether treatments that enhance CNS plasticity might improve functional recovery after TBI, a new rat head injury model was developed, in which a computer-controlled impactor produced full thickness lesions of the forelimb region of the sensorimotor cortex. Behavioural deficits were seen in several sensorimotor tasks, most of which recovered spontaneously by 21 days. However, skilled paw reaching behaviour, a task that requires corticospinal function, was only approximately 40% recovered by 28 days. In order to promote plasticity inosine was infused into the lateral ventricles for 28 days. This treatment produced an almost complete recovery of skilled paw reaching ability, associated with sprouting of the uninjured corticospinal axons across the midline into the territory of the lesioned pathway. In the cervical spinal cord the number of corticospinal axons originating from the uninjured cortex that innervated the contralateral cervical cord was five times that of controls, and in the red nucleus the number of contralaterally projecting axons was four times control values. Inosine treatment did not affect recovery in unskilled behavioural tasks, most of which recovered to normal levels by 28 days without treatment. Animals were placed in an enriched environment as an alternative method to promote plasticity. This resulted in more rapid recovery in several tasks including skilled paw function, but by 28 days normally housed animals had caught up to the same level of improvement.

Quantal self-assembly of polymer layers in polypeptide multilayer nanofilms.

Simple molecular models predict key aspects of the "microscopic" assembly behavior of various peptide systems in the fabrication of multilayer films. Such films show substantial differences in density for different peptide systems. The data suggest that exponential film growth is possible in the absence of polymer diffusion and that "macroscopic" assembly behavior is more a function of peptide-peptide interactions than peptide sequence alone.

Physiological studies of cortical spreading depression.

Cortical spreading depression (CSD) produces propagating waves of transient neuronal hyperexcitability followed by depression. CSD is initiated by K+ release following neuronal firing or electrical, mechanical or chemical stimuli. A triphasic (30-50 s) cortical potential transient accompanies localized transmembrane redistributions of K+, glutamate, Ca2+, Na+, Cl- and H+. Accumulated K+ in the restricted interstitial space can cause both further neuronal depolarisation and inward movement of K+ into astrocytes that buffers this increased extracellular K+ concentration ([K+])o. However, astrocyte interconnections may then propagate the CSD wave by K+ liberation through an opening of remote K+ channels by volume, Ca2+ or N-methyl-D-aspartate receptor activation. Changes in cerebral blood volume and in apparent water diffusion co-efficient (ADC) accompanying CSD were first studied using magnetic resonance imaging (MRI) in whole lissencephalic brains. Diffusion-weighted echoplanar imaging in gyrencephalic brains went on to demonstrate CSD features that paralleled classical migraine aura. The ADC activity persisted minutes/hours post KCl stimulus. Pixelwise analyses distinguished single primary events and multiple, spatially restricted, slower propagating, secondary events whose detailed features varied with the nature of the originating stimulus. These ADC changes varied reciprocally with T2*-weighted (i.e. referring to spin-spin relaxation times) waveforms reflecting local blood flow. There followed prolonged decreases in cerebral blood flow culminating in late cerebrovascular changes blocked by the antimigraine agent sumatriptan. CSD phenomena have possible translational significance for human migraine aura and other cerebral pathologies such as the peri-infarct depolarisation events that follow ischaemia and brain injury.

Cortical spreading depression in the feline brain following sustained and transient stimuli studied using diffusion-weighted imaging.

Cortical spreading depression (CSD) was induced by transient (10 min) applications of KCl in agar upon the cortical surface of alpha-chloralose anaesthetised cats. Its features were compared with CSD resulting from sustained applications of crystalline KCl through a mapping of the apparent diffusion coefficient (ADC) using diffusion-weighted echo planar imaging (DWI) over a poststimulus period of 60-100 min. Individual CSD events were computationally detected with the aid of Savitzky-Golay smoothing applied to critically sampled data derived from regions of interest (ROIs) made up of 2 x 2 pixel matrices. The latter were consistently placed at three selected sites on the suprasylvian gyrus (SG) and six sites on the marginal gyrus (MG). The CSD events thus detected were then quantitatively characterised for each ROI using the original time series. Both stimuli consistently elicited similar spreading patterns of initial, primary CSD events that propagated over the SG and marginal MG and were restricted to the hemispheres on which the stimuli were applied. There followed secondary events over smaller extents of cortical surface. Sustained stimuli elicited primary and secondary CSD events with similar amplitudes of ADC deflection that were distributed around a single mean. The ADC deflections were also conserved in peak amplitude throughout the course of their propagation. The initial primary event showed a poststimulus latency of 1.1 +/- 0.1 min. Successive secondary events followed at longer, but uniform, time intervals of around 10 min. Primary and secondary CSDs showed significantly different velocities of conduction (3.32 +/- 0.43 mm min(-1) vs. 2.11 +/- 0.21 mm min(-1), respectively; n = 5) across the cerebral hemisphere. In contrast, transient stimuli produced significantly fewer numbers of CSD events (3.8 +/- 0.5 events per animal, n = 5) than did sustained stimuli (7.4 +/- 0.5 events per animal, mean +/- S.E.M., n = 5, P = 0.002). The peak ADC deflection of their primary CSD events declined by approximately 30 % as they propagated from their initiation site to the interhemispheric boundary. The primary CSD event following a transient stimulus showed a latency of 1.4 +/- 0.1 min. It was followed by successive and smaller secondary ADC deflections that were separated by progressively longer time intervals. Conduction velocities of secondary events were similar to those of primary events. Conduction velocities of both primary and secondary events were slower than their counterparts following a sustained stimulus. ADC changes associated with CSD thus persist at times well after stimulus withdrawal and vary markedly with the nature of the initiating stimulus even in brain regions remote from the stimulus site.