The endocannabinoid N-arachidonoyl dopamine is critical for hyperalgesia induced by chronic sleep disruption.

Chronic pain is highly prevalent and is linked to a broad range of comorbidities, including sleep disorders. Epidemiological and clinical evidence suggests that chronic sleep disruption (CSD) leads to heightened pain sensitivity, referred to as CSD-induced hyperalgesia. However, the underlying mechanisms are unclear. The thalamic reticular nucleus (TRN) has unique integrative functions in sensory processing, attention/arousal and sleep spindle generation. We report that the TRN played an important role in CSD-induced hyperalgesia in mice, through its projections to the ventroposterior region of the thalamus. Metabolomics revealed that the level of N-arachidonoyl dopamine (NADA), an endocannabinoid, was decreased in the TRN after CSD. Using a recently developed CB1 receptor (cannabinoid receptor 1) activity sensor with spatiotemporal resolution, CB1 receptor activity in the TRN was found to be decreased after CSD. Moreover, CSD-induced hyperalgesia was attenuated by local NADA administration to the TRN. Taken together, these results suggest that TRN NADA signaling is critical for CSD-induced hyperalgesia.

AAV-mediated expression of a new conformational anti-aggregated α-synuclein antibody prolongs survival in a genetic model of α-synucleinopathies.

Prion-like transmission of pathology in α-synucleinopathies like Parkinson's disease or multiple system atrophy is increasingly recognized as one potential mechanism to address disease progression. Active and passive immunotherapies targeting insoluble, aggregated α-synuclein are already being actively explored in the clinic with mixed outcomes so far. Here, we report the identification of 306C7B3, a highly selective, aggregate-specific α-synuclein antibody with picomolar affinity devoid of binding to the monomeric, physiologic protein. 306C7B3 binding is Ser129-phosphorylation independent and shows high affinity to several different aggregated α-synuclein polymorphs, increasing the likelihood that it can also bind to the pathological seeds assumed to drive disease progression in patients. In support of this, highly selective binding to pathological aggregates in postmortem brains of MSA patients was demonstrated, with no staining in samples from other human neurodegenerative diseases. To achieve CNS exposure of 306C7B3, an adeno-associated virus (AAV) based approach driving expression of the secreted antibody within the brain of (Thy-1)-[A30P]-hα-synuclein mice was used. Widespread central transduction after intrastriatal inoculation was ensured by using the AAV2HBKO serotype, with transduction being spread to areas far away from the inoculation site. Treatment of (Thy-1)-[A30P]-hα-synuclein mice at the age of 12 months demonstrated significantly increased survival, with 306C7B3 concentration reaching 3.9 nM in the cerebrospinal fluid. These results suggest that AAV-mediated expression of 306C7B3, targeting extracellular, presumably disease-propagating aggregates of α-synuclein, has great potential as a disease-modifying therapy for α-synucleinopathies as it ensures CNS exposure of the antibody, thereby mitigating the selective permeability of the blood-brain barrier.

BI-Y, an Neuropilin-1 Antagonist, Enhances Revascularization and Prevents Vascular Endothelial Growth Factor-A Induced Retinal Hyperpermeability in Rodent Models of Retinopathies.

Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults. Despite an established standard of care for advanced forms of DR, some patients continue to lose vision after treatment. This may be due to the development of diabetic macular ischemia (DMI), which has no approved treatment. Neuropilin-1 (Nrp-1) is a coreceptor with two ligand-binding domains, with semaphorin-3A (Sema3A) binding to the A-domain and vascular endothelial growth factor-A (VEGF-A) binding to the B-domain. Sema3A directs a subset of neuronal growth cones as well as blood vessel growth by repulsion; when bound to Nrp-1, VEGF-A mediates vascular permeability and angiogenesis. Modulating Nrp-1 could therefore address multiple complications arising from DR, such as diabetic macular edema (DME) and DMI. BI-Y is a monoclonal antibody that binds to the Nrp-1 A-domain, antagonizing the effects of the ligand Sema3A and inhibiting VEGF-A-induced vascular permeability. This series of in vitro and in vivo studies examined the binding kinetics of BI-Y to Nrp-1 with and without VEGF-A165, the effect of BI-Y on Sema3A-induced cytoskeletal collapse, the effect of BI-Y on VEGF- A165-induced angiogenesis, neovascularization, cell integrity loss and permeability, and retinal revascularization. The data show that BI-Y binds to Nrp-1 and inhibits Sema3A-induced cytoskeletal collapse in vitro, may enhance revascularization of ischemic areas in an oxygen-induced retinopathy mouse model, and prevents VEGF-A-induced retinal hyperpermeability in rats. However, BI-Y does not interfere with VEGF-A-dependent choroidal neovascularization. These results support further investigation of BI-Y as a potential treatment for DMI and DME. SIGNIFICANCE STATEMENT: Diabetic macular ischemia (DMI) is a complication of diabetic retinopathy (DR) with no approved pharmacological treatment. Diabetic macular edema (DME) commonly co-occurs with DMI in patients with DR. This series of preclinical studies in mouse and rat models shows that neuropilin-1 antagonist BI-Y may enhance the revascularization of ischemic areas and prevents vascular endothelial growth factor-A (VEGF-A)-induced retinal hyperpermeability without affecting VEGF-A-dependent choroidal neovascularization; thus, BI-Y may be of interest as a potential treatment for patients with DR.

Evaluating the impact of broadband access and internet use in a small underserved rural community.

Having adequate access to the internet at home enhances quality-of-life for households and facilitates economic and social opportunities. Despite increased investment in response to the COVID-19 pandemic, millions of households in the rural United States still lack adequate access to high-speed internet. In this study, we evaluate a wireless broadband network deployed in Turney, a small, underserved rural community in northwest Missouri. In addition to collecting survey data before and after this internet intervention, we collected pre-treatment and post-treatment survey data from comparison communities to serve as a control group. Due to technical constraints, some of Turney's interested participants could not connect to the network, creating an additional comparison group. These comparisons suggest two primary findings, (1) changes in using the internet for employment, education, and health could not be directly attributed to the internet intervention, and (2) the internet intervention was associated with benefits stemming from the ability to use multiple devices at once. This study has implications for the design of future broadband evaluation studies, particularly those examining underserved rather than unserved communities. Recommendations for identifying appropriate outcome variables, executing recruitment strategies, and selecting the timing of surveys are made.

Sema3A Antibody BI-X Prevents Cell Permeability and Cytoskeletal Collapse in HRMECs and Increases Tip Cell Density in Mouse Oxygen-Induced Retinopathy.

Purpose: Semaphorin 3A (Sema3A) is an axonal guidance molecule that inhibits angiogenesis by vasorepulsion and blocks revascularization in the ischemic retina. BI-X is an intravitreal anti-Sema3A agent under clinical investigation in patients with proliferative diabetic retinopathy (PDR) and diabetic macular ischemia (DMI). Methods: Surface plasmon resonance was used to determine binding affinity of BI-X to human and murine Sema3A. In vitro, human retinal microvascular endothelial cells (HRMECs) were used to assess effects of BI-X on cell permeability and cytoskeletal collapse induced by Sema3A. In vivo, intravitreal BI-X or an anti-trinitrophenol control antibody was administered in both eyes in mice with oxygen-induced retinopathy (OIR). Retinal flat mounts were prepared, and avascular area and tip cell density were determined using confocal laser-scanning microscopy. Results: Dissociation constants for BI-X binding to human and murine Sema3A were 29 pM and 27 pM, respectively. In vitro, BI-X prevented HRMEC permeability and cytoskeletal collapse induced by Sema3A. In vivo, BI-X increased tip cell density by 33% (P < 0.001) and reduced avascular area by 12% (not significant). A significant negative correlation was evident between avascular area and tip cell density (r2 = 0.4205, P < 0.0001). Conclusions: BI-X binds to human Sema3A with picomolar affinity and prevents cell permeability and cytoskeletal collapse in HRMECs. BI-X also enhances revascularization in mice with OIR. Translational Relevance: BI-X is a potent inhibitor of human Sema3A that improves revascularization in a murine model of OIR; BI-X is currently being investigated in patients with laser-treated PDR and DMI.

Broadband adoption and availability: Impacts on rural employment during COVID-19.

Amidst COVID-19-related stay-at-home orders, the economy moved largely online and broadband internet became more important than ever. This paper explores the relationship between broadband and employment rates during April and May 2020 in rural U.S. counties. We use two broadband dimensions: infrastructure availability rates and household adoption rates. We use a two-stage least squares approach to address endogeneity and control for socioeconomic, demographic, and pandemic-related factors. Results show broadband availability and wired broadband adoption both had significant, positive impacts on the employment rate. Our findings suggest both broadband adoption and availability may be associated with economic benefits in rural America.

Remodeling Interprofessional Collaboration Through a Nurse-for-a-Day Shadowing Program for Medical Residents.

BACKGROUND: Evidence reflects that effective collaboration leads to improved care quality, patient satisfaction, nurse and physician retention, as well as decreased length of stay, readmissions, and costs. While interprofessional collaboration is widely accepted as the gold standard for health care, room for improvement exists within the nurse-physician relationship. PURPOSE: To evaluate the impact of a shadowing experience on nursing and resident perceptions of communication and collaboration through a shared clinical experience in providing direct patient care. METHODS: From 2016 to 2020, the Internal Medicine Residency Training Program and Medical-Surgical Nursing Department collaborated to pair all internal medicine residents with a nurse preceptor for a 12-hour shift, where participants worked side-by-side in providing patient care. A total of 148 residents and 75 nurse preceptors participated in the study and were provided with a checklist of nursing activities as a guideline. Both residents and nurses completed a questionnaire regarding the shadowing experience utilizing a 5-point Likert scale, with questions focusing on collaboration and communication, program value, and impact on practice. RESULTS: The study found increases in resident communication with nurses from pre-intervention to post-intervention, as well as enjoyment of collaboration with nurses and understanding of the nurse's role. Residents believed that the program should be included for all residents at the beginning of their training; similarly, nurses advocated for the program, believing that the program would improve physician-nurse communication and collaboration. CONCLUSION: Interprofessional training through a Nurse-for-a-Day Program may strengthen nurse-resident relations by cultivating understanding essential for effective collaboration through mutual role understanding.

Effect of cell microenvironment on the drug sensitivity of hepatocellular cancer cells.

The native hepatocellular cancer (HCC) microenvironment is characterized by more hypoxic, hypoglycemic, and acidic conditions than those used in standard cell culture. This study aimed to investigate whether HCC cells cultured in more native conditions have an altered phenotype and drug sensitivity compared to those cultured in standard conditions. Six HCC cell lines were cultured in "standard" (21% O2, 25 mM glucose) or more "native" (1% O2, 5 mM glucose, 10 mM lactate) conditions. Cells were assessed for growth rates, cell cycle distribution, relevant metabolite and protein levels, genome-wide gene expression, mitochondrial DNA sequence and sensitivity to relevant drugs. Many differences in cellular and molecular phenotypes and drug sensitivity were observed between the cells. HCC cells cultured in native conditions had slower doubling times, increased HK2 and GLUT, lower PHDA and ATP levels, and mutations in mitochondrial DNA. Thirty-one genes, including the hypoxia-associated NDRG1, were differentially expressed between the cells. HCC patients in The Cancer Genome Atlas (TCGA) with tumors with a high score based on these 31 genes had a poorer prognosis than those with a low score (p = 0.002). From 90 comparisons of drug sensitivity, increased resistance and sensitivity for cells cultured in native conditions was observed in 14 (16%) and 8 (9%) comparisons respectively. In conclusion, cells cultured in more native conditions can have a more glycolytic and aggressive phenotype and varied drug sensitivity to those cultured in standard conditions, and may provide new insights to understanding tumor biology and drug development.

Attitudes and Perceptions Toward Healthcare Technology Adoption Among Older Adults in Singapore: A Qualitative Study.

Smart Nation is a key initiative of Singapore to move toward digitalization of its industries including healthcare. The complex negotiations of aging amid Smart Nation are addressed in this paper, where we study the challenges faced to adapt the elderly for the digital revolution while ensuring dignified aging. While the healthcare industry accelerates its study and use of health technologies to improve diagnostics, treatment, and the quality of life of those in the aging category, the elderly socially construct these technological insertions that challenge the dominant understandings of what these technologies can do for their health outcomes. The study reveals re-constructions of these technological insertions through the voice of the elderly in their negotiations with health technologies in their everyday lives. Here, narratives reveal key themes that proliferate technology negotiation as barriers to everyday lived experiences.

Prophylactic anticoagulation in patients with glioblastoma or brain metastases and atrial fibrillation: an increased risk for intracranial hemorrhage?

PURPOSE: Patients with glioblastoma (GBM) or brain metastases (MET) and atrial fibrillation (AF) might be at an increased risk of intracranial hemorrhage (ICH) due to anticoagulation (AC). Our aim was to assess this risk. METHODS: Our institution's database (from 2005 to 2017) was screened for patients with GBM or MET and AF with an indication for AC according to their CHA2DS2VASc stroke risk score (≥ 2). Required follow-up was at least 3 months. AC was either performed with heparins, phenprocoumon or non-Vitamin K antagonist oral anticoagulants. Applying the propensity score approach, patient cohorts (matched according to primary tumor, age, sex) were generated (GBM [or MET] with AF ± AC, GBM [or MET] without AF/AC, no GBM [or MET] but AF on AC). ICH was defined as clinical deterioration caused by new blood on imaging. A log rank test was performed to compare the risk for ICH between the three groups. RESULTS: In total, 104 patients were identified of which 49 with GBM (37% on AC) and 37 with MET (46% on AC) were successfully matched. Median follow up was 8.6 and 7.2 months, respectively. ICH occurred in 10.2% of GBM + AF and 12.2% GBM-AF, whereas 8% of patients with AF on AC suffered ICH (p = 0.076). 13.5% of patients with MET + AF had ICHs, in the controls it was 16% for MET-AF and 8% for AF on AC (p = 0.11). CONCLUSION: AC did not seem to influence the incidence of ICH in patients with glioblastoma or brain metastases within follow up of just under 9 months.

Ocular and systemic pharmacokinetics of BI-X, a nanobody targeting VEGF and Ang-2, after intravitreal dosing in cynomolgus monkeys - Evidence for half-life extension by albumin.

Half-life extension strategies to reduce the intravitreal dosing frequency of biomolecules for the treatment of retinal neovascular diseases are attracting increasing interest. This study investigated ocular and systemic pharmacokinetics of the trivalent nanobody BI-X (with affinity to VEGF, Ang-2 and human albumin) in cynomolgus monkeys after intravitreal injection. BI-X concentrations were measured in serial samples of plasma, vitreous humor, aqueous humor and retina. Ocular pharmacokinetics of BI-X exhibited two phases. Initially up to 2-4 weeks after dosing, BI-X concentrations in vitreal, aqueous humor and retina declined with half-lives of around 3 days, which is comparable to macromolecules with a similar molecular weight. Thereafter, only vitreal concentrations were measurable, with a terminal half-life of 13.2 days, which is considerably longer than expected based on the BI-X molecular weight or hydrodynamic radius. It is hypothesized that binding of BI-X to low levels of intraocular albumin resulted in this half-life extension. BI-X was detectable in plasma up to 10 weeks post-dosing. Plasma pharmacokinetics of BI-X exhibited a similar biphasic disposition profile to the vitreous body, with a terminal half-life of 11.8 days, thus reflecting input kinetics from the eye. In conclusion, an important half-life extension principle based on vitreal albumin binding could be confirmed in a primate model, and the data obtained can potentially be translated to humans taking into account the differing vitreal albumin concentrations.

Multisystem effects of COVID-19: a concise review for practitioners.

While COVID-19 has primarily been characterized by the respiratory impact of viral pneumonia, it affects every organ system and carries a high consequent risk of death in critically ill patients. Higher sequential organ failure assessment (SOFA) scores have been associated with increased mortality in patients critically ill patients with COVID-19. It is important that clinicians managing critically ill COVID-19 patients be aware of the multisystem impact of the disease so that care can be focused on the prevention of end-organ injuries to potentially improve clinical outcomes. We review the multisystem complications of COVID-19 and associated treatment strategies to improve the care of critically ill COVID-19 patients.

Ultrasound Teleguidance to Reduce Healthcare Worker Exposure to Coronavirus Disease 2019.

The global spread of coronavirus disease 2019 has accelerated the adoption of technologies that facilitate patient care while reducing viral spread. We illustrate a proof of concept application of teleguidance to ultrasound-guided bedside procedures as an example of an innovative solution that has been used at our institution to maximize patient and provider safety.

VHH antibody targeting the chemokine receptor CX3CR1 inhibits progression of atherosclerosis.

CX3CR1 has been identified as a highly attractive target for several therapeutic interventions. Despite this potential, no potent antagonists, either small molecule or monoclonal antibody, have been identified. Here we describe the lead finding and engineering approach that lead to the identification of BI 655088, a potent biotherapeutic antagonist to CX3CR1. BI 655088 is a potent CX3CR1 antagonist that, upon therapeutic dosing, significantly inhibits plaque progression in the standard mouse model of atherosclerosis. BI 655088 represents a novel and highly selective biotherapeutic that could reduce inflammation in the atherosclerotic plaque when added to standard of care treatment including statins, which could result in a significant decrease in atherothrombotic events in patients with existing cardiovascular disease.

Exploring the research culture in the health information management profession in Australia.

BACKGROUND: Research is an important activity that informs knowledge and practice. The research culture within the Australian Health Information Management (HIM) profession has not been previously reported. OBJECTIVE: This study explored the perceptions of HIM practitioners about research in their role to establish if there is a research culture in the Australian HIM profession. METHOD: An online survey was distributed to the HIM community using a snowball recruitment strategy. RESULTS: Of the 149 respondents, more than half (54%) identified they possessed research skills from prior education, whilst 40% considered they had a strong knowledgebase in conducting research. However, only a quarter of respondents indicated that they should undertake research in their role. Barriers to undertaking research included recognition, organisational support and time. DISCUSSION: The findings from this study reflected other studies within clinical workforces. The lack of recognition and support to incorporate research into practitioner roles has implications for the profession and its body of knowledge. CONCLUSION: Advocating for research to be incorporated into practitioner roles is required to inform knowledge and practice. Increased professional development opportunities may create a stronger research culture within the HIM profession in Australia and strengthen the position of the profession within health.

Leadership development in health information management (HIM): literature review.

PURPOSE: The health information management (HIM) profession lacks clarity around leadership and leadership development. To date, little empirical research exists on this topic, and it is unclear if broader approaches for healthcare leadership are suitable. This paper aims to explore which the leadership styles are relevant to the HIM profession. The findings were also used to inform a discussion on how HIM professionals could develop these leadership styles. DESIGN/METHODOLOGY/APPROACH: Through a systematic scoping literature review, deductive thematic analysis was undertaken to extrapolate common themes around this style of leadership based on transversal competency domains that reflect twenty-first century skills (i.e. critical thinking and innovation, interpersonal, intrapersonal and global citizenship) (Bernard, Watch and Ryan, 2016; UNESCO, 2015 ). This approach enabled the findings to be discussed from a leadership development perspective. FINDINGS: Analysis of the literature revealed that a relational leadership style through a team-based approach is required. Literature studies on how to develop leadership competencies were not found. RESEARCH LIMITATIONS/IMPLICATIONS: Future policy and research implications include the need for research on transversal competencies to determine if they can shape HIM leadership development. PRACTICAL IMPLICATIONS: This leadership style and competencies proposed are relevant across many occupations and may have broader applications for leadership research, education and development. ORIGINALITY/VALUE: This paper defines the style of leadership required in the HIM profession and identifies a succinct set of contemporary competencies to inform the development of this type of leadership.