In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting.

In vitro, ACE2 translocates to the nucleus to induce SARS-CoV-2 replication. Here, using digital spatial profiling of lung tissues from SARS-CoV-2-infected golden Syrian hamsters, we show that a specific and selective peptide inhibitor of nuclear ACE2 (NACE2i) inhibits viral replication two days after SARS-CoV-2 infection. Moreover, the peptide also prevents inflammation and macrophage infiltration, and increases NK cell infiltration in bronchioles. NACE2i treatment increases the levels of the active histone mark, H3K27ac, restores host translation in infected hamster bronchiolar cells, and leads to an enrichment in methylated ACE2 in hamster bronchioles and lung macrophages, a signature associated with virus protection. In addition, ACE2 methylation is increased in myeloid cells from vaccinated patients and associated with reduced SARS-CoV-2 spike protein expression in monocytes from individuals who have recovered from infection. This protective epigenetic scarring of ACE2 is associated with a reduced latent viral reservoir in monocytes/macrophages and enhanced immune protection against SARS-CoV-2. Nuclear ACE2 may represent a therapeutic target independent of the variant and strain of viruses that use the ACE2 receptor for host cell entry.

Using item response theory to develop and refine patient-reported outcome measures.

There is a long tradition of incorporating patient-reported outcomes (PROs) into nursing research and practice. Classical Test Theory (CTT) has been the traditional approach used to develop and refine PROs. Item response theory (IRT) offers promise for addressing measurement problems that have been difficult to solve using CTT. This paper presents foundational concepts in IRT to illustrate how it can be used to improve the development and refinement of PRO measures, with emphasis on interpreting key IRT parameters.

Landscape of Epidermal Growth Factor Receptor Heterodimers in Brain Metastases.

HER2+ breast cancer patients have an elevated risk of developing brain metastases (BM), despite adjuvant HER2-targeted therapy. The mechanisms underpinning this reduced intracranial efficacy are unclear. We optimised the in situ proximity ligation assay (PLA) for detection of the high-affinity neuregulin-1 receptor, HER2-HER3 (a key target of pertuzumab), in archival tissue samples and developed a pipeline for high throughput extraction of PLA data from fluorescent microscope image files. Applying this to a large BM sample cohort (n = 159) showed that BM from breast, ovarian, lung and kidney cancers have higher HER2-HER3 levels than other primary tumour types (melanoma, colorectal and prostate cancers). HER2 status, and tumour cell membrane expression of pHER2(Y1221/1222) and pHER3(Y1222) were positively, but not exclusively, associated with HER2-HER3 frequency. In an independent cohort (n = 78), BM had significantly higher HER2-HER3 levels than matching primary tumours (p = 0.0002). For patients who had two craniotomy procedures, HER2-HER3 dimer levels were lower in the consecutive lesion (n = 7; p = 0.006). We also investigated the effects of trastuzumab and pertuzumab on five different heterodimers in vitro: HER2-EGFR, HER2-HER4, HER2-HER3, HER3-HER4, HER3-EGFR. Treatment significantly altered the absolute frequencies of individual complexes in SKBr3 and/or MDA-MB-361 cells, but in the presence of neuregulin-1, the overall distribution was not markedly altered, with HER2-HER3 and HER2-HER4 remaining predominant. Together, these findings suggest that markers of HER2 and HER3 expression are not always indicative of dimerization, and that pertuzumab may be less effective at reducing HER2-HER3 dimerization in the context of excess neuregulin.

Characterization of Immune Cell Subsets of Tumor Infiltrating Lymphocytes in Brain Metastases.

The heterogeneity of tumor infiltrating lymphocytes (TILs) is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune-cell subsets in brain metastasis tissues to test immunosuppressive routes involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune-cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and IBA-1, and analyzed an average of 15,000 cells per sample. Classifying tumors as either high (>30%) or low (<30%) TILs, we found that increased TILs density correlated with survival. Phenotyping these TILs we found tumors with low TILs had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p < 0.01) as well as in their microenvironment (p < 0.001). Contrastingly, the tumors with high TILs displayed higher levels of microglia, as measured by IBA-1 expression. Low TILs-tumors displayed CD8+ T-cells that co-express VISTA (p < 0.01) significantly more compared to high TILs group, where CD8+cells significantly co-express IBA-11 (p < 0.05). These results were supported by RNA analysis of a publicly available, independent cohort. Our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.

Dimensions of Community Assets for Health. A Systematised Review and Meta-Synthesis.

Since Aaron Antonovsky's salutogenesis theory and Morgan and Ziglio's health assets model were first proposed, there has been a growing concern to define the resources available to the individual and the community to maintain or improve health and well-being. The aim of the present study was to identify the dimensions that characterise community assets for health. To this end, we conducted a systematised review with a meta-synthesis and content analysis of research or projects involving asset mapping in the community. Articles that met our eligibility criteria were: (1) based on the salutogenic approach and (2) described an assets mapping process and among their results, explained what, how and why particular community assets for health had been selected. The search included primary studies in the published and grey literature which were selected from websites and electronic databases (Web of Science, MEDLINE, Scopus, EBSCOhost, Dialnet, SciELO). Of the 607 records examined by a single reviewer, 34 were included in the content analysis and 14 in the qualitative synthesis. Using an inductive process, we identified 14 dimensions with 24 categories, for which in-depth literature reviews were then carried out to define specific indicators and items. These dimensions were: utility, intention, previous use, accessibility ("circumstances-opportunity-affordability"), proximity-walkability, connectivity, intelligibility (visibility, transparency), identity (uniqueness, appropriability, attachment), design (configuration, functionality, comfort), safety (objective/subjective), diversity, the dimension of public and private, and sustainability (which includes maintenance, profitability or economic sustainability, environmental sustainability, centrality-participation and equity-inclusiveness).

Association between Life Skills and Academic Performance in Adolescents in the Autonomous Community of Aragon (Spain).

BACKGROUND: Learning and socio-emotional development is promoted through the creation and nurturing of an optimal school climate. This study aims to analyze the relationship between life skills and academic performance in a large sample of adolescents from the autonomous community of Aragón (Spain). METHODS: A cross-sectional study was conducted on the life skills and academic performance of a sample of 7th and 8th grade middle school students during the academic year 2018-2019. A sample of 43 middle schools were randomly selected; the final sample comprised 1745 students. The following data were collected through an anonymized, previously validated questionnaire: sociodemographic variables, social skills, self-efficacy, affective balance, and academic performance. RESULTS: We found a statistically significant association between life skills and academic performance (p < 0.001) in our sample. We also observed significant gender differences in life skills, with boys obtaining higher scores in cognitive skills and affective balance, and with girls achieving higher scores in social skills. CONCLUSION: We argue that life skills should be integrated into educational policies in order to improve the academic performance and health outcomes of students.

Development of a Diabetes-Focused Print Health Literacy Scale Using the Rapid Estimate of Adult Literacy in Medicine Model.

BACKGROUND: A diabetes mellitus (DM)-specific health literacy (HL) measure that focuses on both oral and print HL is needed in clinical and research settings. OBJECTIVE: The present study developed a psychometrically sound DM-specific HL instrument that measures oral and print HL. METHODS: We developed the measure in three steps. First, we reviewed clinical guidelines and conducted focus groups with experts to generate items. Next, we conducted a psychometric evaluation of the scale in three language versions (English, Spanish, and Korean). Lastly, we identified and removed items with potential cultural bias and duplicate functions to produce shorter versions of the scale, using item response theory (IRT). KEY RESULTS: We initially developed an 82-item DM-specific oral HL scale using the Rapid Estimate of Adult Literacy in Medicine (DM-REALM) model. To improve the clinical utility of the DM-REALM, we created shorter forms, a 40-item and 20-item version, and evaluated them by using IRT. All DM-REALM versions had high Cronbach alphas (.985, .974, and .945, respectively) and yielded sufficient convergent validity by positive correlations with existing functional HL scale (r = .49, p < .001), education (r = .14, p = .14 to r = .54, p < .001), and DM knowledge (r = .04, p = .70 to r = .36, p < .001). DM-REALM also demonstrated adequate sensitivity as an intervention evaluation tool that captures the changes induced by an intervention. CONCLUSIONS: All forms of the DM-REALM tool were reliable, valid, and clinically useful measures of HL in the context of DM care. Both researchers and clinicians can use this tool to assess DM-specific HL across multiple racial and ethnic populations. [HLRP: Health Literacy Research and Practice. 2020;4(4):e237-e249.] PLAIN LANGUAGE SUMMARY: This article reported the process and findings of a newly developed health literacy scale for people with diabetes mellitus using three different language versions. Both long and short versions of the scale demonstrated adequate validity and reliability.

Qualitative Analysis by Experts of the Essential Elements of the Nursing Practice Environments Proposed by the TOP10 Questionnaire of Assessment of Environments in Primary Health Care.

Background: A short TOP10 scale based on the Practice Environment Scale-Nursing Work Index questionnaire measures the characteristics of nursing work environments. Positive environments result in better quality care and health outcomes. Objective: To identify a small number of core elements that would facilitate more effective interventions by nurse managers, and compare them with the essential elements proposed by the TOP10. Method: Qualitative research by a nominal group of eight experts. The content analysis was combined with descriptive data. Results: Ten most important items were selected and analyzed by the expert group. A high level of consensus in four items (2, 15, 20, 31) and an acceptable consensus in five items was reached (6, 11, 14, 18, 26). The tenth item in the top ten was selected from content analysis (19). The expert group agreed 90% with the elements selected as essential to the TOP10. Conclusion: The expert group achieved a high level of consensus that supports 90% of the essential elements of primary care settings proposed by the TOP10 questionnaire. Organizational changes implemented by managers to improve working environments must be prioritized following our results, so care delivery and health outcomes can be further improved.

Descriptive Study of Children's Nutritional Status and Identification of Community-Level Nursing Diagnoses in a School Community in Africa.

Effectively responding to children's nutritional status and eating behaviors in Mozambique requires a community-based care approach grounded in sound nursing research that is evidence-based. The Community Assessment, Intervention, and Empowerment Model (MAIEC) is a nursing theoretical model that is based upon clinical decision-making for community health nurses using communities as a unit of care. We used the MAIEC to identify a community-based nursing diagnosis to address children's nutritional status and eating behaviors in Mozambique. OBJECTIVES: (1) to conduct a descriptive study of children's nutritional status and eating behaviors in a school community in Mavalane, Mozambique, and (2) to identify a community-based nursing diagnosis using the MAIEC clinical decision-making matrix in the same school community. METHOD: a cross-sectional, quantitative study was conducted to assess the nutritional status of children using anthropometric data, including brachial perimeter and the tricipital skinfold, and standard deviation for the relation of weight-height, in a sample of 227 children. To assess community management of the problem and identify a community-based nursing diagnosis, we surveyed 176 parents/guardians and 49 education professionals, using a questionnaire based on the MAIEC clinical decision matrix as a reference. RESULTS: malnutrition was identified in more than half of the children (51.3%). We also identified a community-based nursing diagnosis of impaired community management related to the promotion of child health and healthy eating evidenced by the lack of community leadership, participation, and processing among more than 70% of the community members (parents/guardians and education professionals). CONCLUSION: a nursing diagnosis and diagnostic criteria for nutritional status and community management were identified. The need to intervene using a multidisciplinary public health approach is imperative, with the school community as the unit of care. In addition, reliable anthropometric data were identified as important criteria to complement the nursing diagnosis and guide future public health interventions.

Applying Computer Adaptive Testing Methods to Suicide Risk Screening in the Emergency Department.

OBJECTIVE: Combine test theory with technology to develop brief, reliable suicide risk measures in the emergency department. METHODS: A computer adaptive test for suicide risk was built using the Beck Scale for Suicide Ideation and tested among the emergency department population. Data were analyzed from a sample of 1,350 patients in several Massachusetts emergency departments. The test was built as outlined by the National Institutes of Health Patient-Reported Outcomes Measurement Information System. RESULTS: Of 1,350 patients, 74 (5%) scored above the cutoff of BSS > 2. Item 2, "Wish to die", was the most informative item. When using only Item 2, 20% (n = 15/74) of at-risk patients and 3% (n = 40/1,276) of not-at-risk patients were misclassified. Patients were classified after four items with computer adaptive testing trait estimates highly comparable to those of the full scale. The precision rule model did not reduce the scale. CONCLUSIONS: This study models the creation of a computer adaptive test for suicide ideation and marks the start of the development of computer adaptive tests as a novel suicide risk screening tool in the emergency department. Computer adaptive tests hold promise for revolutionizing behavioral health screening by addressing barriers including time and knowledge deficits.

Motivating people to sustain healthy lifestyles using persuasive technology: A pilot study of Korean Americans with prediabetes and type 2 diabetes.

OBJECTIVE: To test the efficacy of a hybrid model of the self-help intervention program (hSHIP), which combines a mobile version of SHIP (mSHIP) and personal coaching, to address unique cultural and motivational factors for optimal self-management of type 2 diabetes and prediabetes among Korean Americans (KAs). METHODS: A single-group feasibility study design was used. The hSHIP utilizes texts and motivational counseling based on well-tested intervention content for KAs. To facilitate the dissemination of hSHIP, we developed a web application adopting the principles of persuasive technology to motivate behavior changes. RESULTS: Feasibility assessment found that hSHIP was well accepted by both participants and community health workers who delivered the intervention. An average of 1.3% A1C reduction (from 7.8% to 6.5%) was achieved by KAs with diabetes (n = 165), 51.5% of whom lowered their A1C below 6.5% in 6-months. No one with prediabetes (n = 50) progressed to diabetes. Other clinical outcomes (e.g., weight, depression, and blood pressure) also improved significantly; 41.2% were able to reduce or discontinue antidiabetic drugs. CONCLUSION: The feasibility and initial efficacy of hSHIP were demonstrated. PRACTICE IMPLICATION: This hybrid diabetes self-management model is a viable tool for traditionally underserved groups with diabetes or prediabetes.

The State of the Science of Health Literacy Measurement.

Advancing health literacy (HL) research requires high-quality HL measures. This chapter provides an overview of the state of the science of HL measurement: where the field started, currently is, and should be going. It is divided into eight key sections looking at (1) the history of HL measurement, (2) the relationship between HL definitions and measurement, (3) the HL conceptual domains most and least frequently measured, (4) the methods used to validate HL measures, (5) the characteristics of the participants in the measurement validation studies, (6) the practical considerations related to administering HL measures, (7) the advantages and disadvantages of using objective versus subjective HL measures, and (8) future directions for HL measurement. Based on the material presented in this chapter, the following conclusions can be drawn. First, there is an enormous proliferation of HL measures and this growth presents both opportunities and challenges for the field. Second, to move the field forward, there is an urgent need to better align HL measurement with definitions of HL. Third, some HL domains, such as numeracy, are measured more often than others, such as speaking and listening. Consequently, it is important to think about novel mechanisms to measure HL domains that are rarely measured. Fourth, HL measures are most often developed, validated, and refined using classical measurement approaches. However, strong empirical and practical rationales suggest making an assertive shift toward using modern measurement approaches. Fifth, most HL measures are not well validated for use in minority populations; consequently, future validation studies should be mindful of validation samples. Sixth, HL measures can be administered using multiple modes, most frequently via paper-and-pencil surveys. Identifying which mode of administration is most suitable requires reflecting on the underlying measurement purpose and the characteristics of the participants being measured. These considerations should also be made when deciding between a subjective versus objective HL measure. Cumulatively, this chapter provides tools to help readers select and use the most appropriate measures of HL for their needs. It also provides rationale and strategies for moving the science of HL measurement forward.

Coping measurement: Creating short form of Coping and Adaptation Processing Scale using item response theory and patients dealing with chronic and acute health conditions.

PURPOSE: The purpose of this study was to enhance the CAPS tool by clarifying the concept of coping, using item response theory (IRT) to shorten and assess the metric equivalence of the scale, and testing the preliminary validity of the resulting shortened scale. METHODS: A descriptive design of participants from different ethnic backgrounds was employed (USA n = 347 and Panama n = 327). To select items for the shortened CAPS, a well-established multi-step process grounded in IRT was used. Further, a coping ladder was created to approximate the a priori perceived location/difficulty of each item along the coping trait scale. Items for the shortened scale were selected based on considerations central to the middle range theory of coping and adaptation processing and the results of the item calibration and model testing. RESULTS: A total of 15 items were selected. The selected items were well distributed on the coping ladder and all basic subconcepts of the middle range theory were included. Further the sum of the DIF size for the selected short form items is − 0.01, so the overall bias of the total score is minimal. Finally, concurrent and divergent validity of the new scale was demonstrated in two separate correlational studies. CONCLUSION: The 15-item Coping and Adaptation Processing Scale (CAPS)--Short-Form can be a practical tool to effectively and efficiently measure coping and adaptation in both practice and research for people dealing with both chronic and acute health conditions.

Flux of signalling endosomes undergoing axonal retrograde transport is encoded by presynaptic activity and TrkB.

Axonal retrograde transport of signalling endosomes from the nerve terminal to the soma underpins survival. As each signalling endosome carries a quantal amount of activated receptors, we hypothesized that it is the frequency of endosomes reaching the soma that determines the scale of the trophic signal. Here we show that upregulating synaptic activity markedly increased the flux of plasma membrane-derived retrograde endosomes (labelled using cholera toxin subunit-B: CTB) in hippocampal neurons cultured in microfluidic devices, and live Drosophila larval motor neurons. Electron and super-resolution microscopy analyses revealed that the fast-moving sub-diffraction-limited CTB carriers contained the TrkB neurotrophin receptor, transiently activated by synaptic activity in a BDNF-independent manner. Pharmacological and genetic inhibition of TrkB activation selectively prevented the coupling between synaptic activity and the retrograde flux of signalling endosomes. TrkB activity therefore controls the encoding of synaptic activity experienced by nerve terminals, digitalized as the flux of retrogradely transported signalling endosomes.

Botulinum neurotoxin type-A enters a non-recycling pool of synaptic vesicles.

Neuronal communication relies on synaptic vesicles undergoing regulated exocytosis and recycling for multiple rounds of fusion. Whether all synaptic vesicles have identical protein content has been challenged, suggesting that their recycling ability may differ greatly. Botulinum neurotoxin type-A (BoNT/A) is a highly potent neurotoxin that is internalized in synaptic vesicles at motor nerve terminals and induces flaccid paralysis. Recently, BoNT/A was also shown to undergo retrograde transport, suggesting it might enter a specific pool of synaptic vesicles with a retrograde trafficking fate. Using high-resolution microscopy techniques including electron microscopy and single molecule imaging, we found that the BoNT/A binding domain is internalized within a subset of vesicles that only partially co-localize with cholera toxin B-subunit and have markedly reduced VAMP2 immunoreactivity. Synaptic vesicles loaded with pHrodo-BoNT/A-Hc exhibited a significantly reduced ability to fuse with the plasma membrane in mouse hippocampal nerve terminals when compared with pHrodo-dextran-containing synaptic vesicles and pHrodo-labeled anti-GFP nanobodies bound to VAMP2-pHluorin or vGlut-pHluorin. Similar results were also obtained at the amphibian neuromuscular junction. These results reveal that BoNT/A is internalized in a subpopulation of synaptic vesicles that are not destined to recycle, highlighting the existence of significant molecular and functional heterogeneity between synaptic vesicles.