Identification of a therapeutic interfering particle-A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance.

Viral-deletion mutants that conditionally replicate and inhibit the wild-type virus (i.e., defective interfering particles, DIPs) have long been proposed as single-administration interventions with high genetic barriers to resistance. However, theories predict that robust, therapeutic DIPs (i.e., therapeutic interfering particles, TIPs) must conditionally spread between cells with R0 >1. Here, we report engineering of TIPs that conditionally replicate with SARS-CoV-2, exhibit R0 >1, and inhibit viral replication 10- to 100-fold. Inhibition occurs via competition for viral replication machinery, and a single administration of TIP RNA inhibits SARS-CoV-2 sustainably in continuous cultures. Strikingly, TIPs maintain efficacy against neutralization-resistant variants (e.g., B.1.351). In hamsters, both prophylactic and therapeutic intranasal administration of lipid-nanoparticle TIPs durably suppressed SARS-CoV-2 by 100-fold in the lungs, reduced pro-inflammatory cytokine expression, and prevented severe pulmonary edema. These data provide proof of concept for a class of single-administration antivirals that may circumvent current requirements to continually update medical countermeasures against new variants.

Towards reduction of preventable hospital readmission: Older people and family members' views on planned self-management of care at home.

AIMS AND OBJECTIVES: To reduce the likelihood of preventable readmissions, the aim was to investigate how older people (with their family members) managed their chronic health conditions at home following hospital discharge. The objectives explored older people and their family members' perspectives on how discharge plans assisted self-management of their chronic conditions, their recognition of deterioration and when to seek treatment/re-attend hospital. BACKGROUND: Chronic conditions have challenged older adults' self-management, particularly after hospital discharge and can impact on preventable readmission. Few studies have examined patients' and their family members' perspectives on the management of their conditions at home after hospitalisation. DESIGN: A qualitative exploratory design known as Interpretive Description was utilised. METHODS: Purposeful sampling involved 27 community-dwelling older adults; nineteen were discharged patients with one or more chronic health conditions. Eight nominated family members were also recruited to enhance understanding of the older persons' self-management at home. Interviews were undertaken and thematic data analysis followed the COREQ guidelines. RESULTS: Five themes emerged: (1) Post-Discharge Advice; (2) Managing at Home; (3) Recognition and Response to Deterioration; (4) Community Care and Support; and (5) The "Burden" on Others of Post-Discharge Care. CONCLUSION: Older people sought a clear plan for self-management at home prior to discharge. This plan should contain potential signs of deterioration and guidance on future action. We found that support given to older people from family and friends was critical to prevent readmission. In addition, their local General Practitioner and Pharmacist played an essential part in the support of their care. For some, social support services were also important. Nurse telephone follow-up in the week following discharge was mostly absent. However, this strategy would be strongly recommended. RELEVANCE TO CLINICAL PRACTICE: To mitigate against preventable readmission, we recommend the above strategies to assist the older person at home with self-management of their chronic conditions.

Optimized Curcumin, Pomegranate Extract, and Methylsulfonylmethane Reduce Acute, Systemic Inflammatory Response to a Half-marathon Race.

Context: Endurance running places substantial physiological strain on the body, which can develop into chronic inflammation and overuse injuries, negatively affecting subsequent training and performance. A recent study found that dietary polyphenols and methlysulfonylmethane (MSM) can reduce systemic inflammation and oxidative stress without adverse side effects. Objective: The purpose was to identify a set of candidate protein and RNA biomarkers that are associated with improved outcomes related to inflammation and muscle injury, when athletes used 3 proprietary supplements both prior to and during early recovery from a half-marathon race. Design: The study was an open-label pilot study. Setting: The study was field based, with sample analysis conducted in the Applied Physiology Laboratory in the Department of Kinesiology, Health Promotion and Recreation at the University of North Texas in Denton, Texas. Participants: Participants were 15 young, exercise-trained men and women. Intervention: The intervention group consumed 1000 mg/d of a proprietary 50-50 mix of optimized curcumin and pomegranate extract for 26 days. The group also consumed 500 mg/d of a proprietary MSM for the same period. Three days prior to and one day after a race, the daily dosage was doubled. The control group received no supplements. Outcome Measures: Venous blood samples were collected at pre-race and at 4h and 24h after running a half-marathon race. The research team evaluated results for target proteins that have been associated with inflammation and muscle injury in the scientific literature. The team also performed an analysis of RNA biomarkers. Results: At the 4h and 24h time points, a significant treatment-response was observed that included increases in proteins: (1) osteonectin/SPARC-osteonectin/secreted protein acidic and rich in cysteine and (2) BDNF-brain-derived neurotrophic factor. At the same points, the study also found increased RNA: (1) PACER-P50-associated COX-2 extragenic RNA, (2) PTGES-prostaglandin E synthase, (3) MYD88-innate immune signal transduction adaptor MYD88, (4) TNFS14-tumor necrosis factor (TNF) superfamily member 14, (5) THRIL-TNF and heterogeneous nuclear ribonucleoprotein L (HNRNPL)-related immunoregulatory long noncoding RNA, (6) TRAF6-TNF receptor associated factor 6, (7) CX3CL1-C-X3-C motif chemokine ligand 1, (8) MALAT1-metastasis-associated lung adenocarcinoma transcript 1, and (9) LINC00305-long intergenic nonprotein coding RNA 305. Conclusions: The combination of polyphenol and MSM supplementation resulted in a systemic response that may translate to an accelerated rate of muscle recovery, allowing participants return to exercise and normal activities more quickly. This pilot study is the foundation for a larger investigation in the research team's laboratory.

Sitters as a Patient Safety Strategy to Reduce Hospital Falls: A Systematic Review.

Background: Bedside "sitters" are often used for patients at high risk for falls, but they are expensive and their effectiveness is unclear. Purpose: To review evidence about the effect of sitters and alternatives to sitters on patient falls in acute care hospitals. Data Sources: PubMed searches to 8 October 2019, other databases from inception to December 2018, citation searches on key articles, and a Google search (22 October 2019). Study Selection: English-language studies of any design that assessed the effect of adding sitters to usual care or compared alternatives to sitters (for example, video monitors or "close observation units") for adult patients on general wards of acute care hospitals and reported falls as a primary outcome. Data Extraction: Dual-reviewer extraction of study data and risk of bias; single reviewer with group discussion for GRADE (Grading of Recommendations Assessment, Development and Evaluation) certainty of evidence. Data Synthesis: Of 20 studies meeting inclusion criteria, 2 added sitters to usual care and 18 compared alternatives to sitters. There were no randomized trials, 11 time-series studies, 1 retrospective quasi-experimental study, and 8 pre-post studies. All studies had at least 1 methodological limitation. Two studies provided very-low-certainty evidence that adding sitters reduced falls. Eight studies provided moderate-certainty evidence that interventions that included video monitoring reduced sitter use and either did not affect or reduced the number of falls. Very-low-certainty evidence suggested that interventions that included nurse assessment tools (3 studies) or a close observation unit (2 studies) were effective alternatives to sitters. Limitation: No studies had low risk of bias, publication bias is likely, and studies may have been missed. Conclusion: Despite a compelling rationale, evidence is scant that adding sitters to usual care reduces falls. Primary Funding Source: Veterans Affairs Quality Enhancement Research Initiative. (PROSPERO: CRD42019127424).

Effect of exercise in a desert environment on physiological and subjective measures.

Green exercise is beneficial to emotional and physiological measures, however, the US has large desert areas. We aimed to determine if exercise in a desert (brown) environment extends similar benefits to green. Participants (N = 10) completed baseline measures (PRE), 30-min seated rest (SIT), and 30-min self-paced walking (WALK) in: indoor, outdoor urban, green, and two brown environments. Heart rate (HR), blood pressure (BP), and measures of stress, comfort, and calm were obtained. After SIT, HR was elevated in urban vs green (p = 0.05). Systolic BP was lower after SIT compared to PRE and WALK (p = 0.05). Brown and green returned greater comfort and calm scores (p = 0.001). Stress was lower following WALK than PRE and SIT (p < 0.01). Comfort and calm were greatest in natural environments, and exercise significantly reduced perceived stress. Taken together, these data provide evidence that exercise in a desert environment is just a beneficial as the exercise performed in a green environment. Abbreviations: ANCOVA: analysis of covariance; ANOVA: analysis of variance; AU: arbitrary units; BP: blood pressure; BSL: below sea level; DBP: diastolic blood pressure; HR: heart rate; PRE: baseline measurement; PS: perceived stress; SBP: systolic blood pressure; SIT: measurement following 30-min seated rest; WALK: measurement following 30-min self-paced walking.

A scoping review of new implementations of interprofessional bedside rounding models to improve teamwork, care, and outcomes in hospitals.

Poor communication within healthcare teams occurs commonly, contributing to inefficiency, medical errors, conflict, and other adverse outcomes. Interprofessional bedside rounds (IBR) are a promising model that brings two or more health professions together with patients and families as part of a consistent, team-based routine to share information and collaboratively arrive at a daily plan of care. The purpose of this systematic scoping review was to investigate the breadth and quality of IBR literature to identify and describe gaps and opportunities for future research. We followed an adapted Arksey and O'Malley Framework and PRISMA scoping review guidelines. PubMed, CINAHL, PsycINFO, and Embase were systematically searched for key IBR words and concepts through June 2020. Seventy-nine articles met inclusion criteria and underwent data abstraction. Study quality was assessed using the Mixed Methods Assessment Tool. Publications in this field have increased since 2014, and the majority of studies reported positive impacts of IBR implementation across an array of team, patient, and care quality/delivery outcomes. Despite the preponderance of positive findings, great heterogeneity, and a reliance on quantitative non-randomized study designs remain in the extant research. A growing number of interventions to improve safety, quality, and care experiences in hospital settings focus on redesigning daily inpatient rounds. Limited information on IBR characteristics and implementation strategies coupled with widespread variation in terminology, study quality, and design create challenges in assessing the effectiveness of models of rounds and optimal implementation strategies. This scoping review highlights the need for additional studies of rounding models, implementation strategies, and outcomes that facilitate comparative research.

Combining single molecule counting with bead-based multiplexing to quantify biological inflammation time course following skeletal muscle injury.

Bead-based analysis methods allow for the exploration of a variety of complex biological processes. In particular, these techniques can be applied to better understand how peripheral muscle injury contributes to systemic inflammation. Understanding how these two processes affect one another can give additional insight concerning how changes in inflammation effect readiness to perform in exercise and work environments. The present method sought to combine the strengths of bead-based multiplexing with the precision and low-end detection of single molecule counting (SMC) methods. We used performance of an extreme aerobic exercise session (i.e. half-marathon race) to cause a defined quantity of lower body muscle injury and a systemic inflammatory response lasting up to 24 h. Using a high-sensitivity, multiplex assay (Milliplex; Millipore-Sigma) we were able to identify 9 of 21 cytokines that were significantly elevated at either 4 or 24 h post half-marathon performance. Despite the known role of IL-1ß, IL-6, and TNF-α in the pro-inflammatory response, they did not appear to change based on the multiplex analysis. We thus, conducted further analysis using an SMC assay and found increases in IL-1ß, IL-6, and TNF-α at 4 h compared to 24 h post exercise. This method approach demonstrates how combining two common, bead-based protein assays can increase the amount of meaningful biological information that can be collected. We anticipate that this approach will be useful in a variety of inflammation-associated disease states.

Combined bead-based multiplex detection of RNA and protein biomarkers: Implications for understanding the time course of skeletal muscle injury and repair.

Biological response to skeletal muscle injury time course is generally classified as initial (elevated within first 4-h), delayed (elevated at 24-h), and/or prolonged (elevated at 4-h and sustained to 24-h). Accurate description of this process requires the ability to measure a robust set of RNA and protein biomarkers, yet such an approach is not common and not always feasible. This method proposes a novel experimental approach that focuses on the use of bead-based multiplex detection to measure mRNA, lncRNA, cytokines, soluble cytokine receptors, and myokines at 4-h and 24-h post muscle injury. We used an extreme aerobic exercise session (half-marathon race) to create a consistent muscle injury stimulus via oxidative stress and eccentric contractions. Venous blood samples were analyzed to determine the change in 90 targets. Specifically, we identified 14 mRNA, 2 lncRNA, 4 cytokines, and 5 myokines that had only an initial response (change at 4-h). We identified 2 mRNA, 2 cytokines, 13 soluble cytokine receptors, and 1 myokine that had only a delayed response (change at 24-h). Finally, we identified 18 mRNA, 4 lncRNA, 6 myokines and 15 cytokines that had a prolonged response (change at 4-h and sustained at 24-h). We found 4 targets to be undetectable or having no response relative to muscle injury recovery. These findings demonstrate the interplay between RNA and protein biomarkers in response to skeletal muscle injury. This novel experimental application of bead-based multiplexing is applicable to a variety of clinical models that involve muscle injury and/or wasting.

Exploiting Genetic Interference for Antiviral Therapy.

Rapidly evolving viruses are a major threat to human health. Such viruses are often highly pathogenic (e.g., influenza virus, HIV, Ebola virus) and routinely circumvent therapeutic intervention through mutational escape. Error-prone genome replication generates heterogeneous viral populations that rapidly adapt to new selection pressures, leading to resistance that emerges with treatment. However, population heterogeneity bears a cost: when multiple viral variants replicate within a cell, they can potentially interfere with each other, lowering viral fitness. This genetic interference can be exploited for antiviral strategies, either by taking advantage of a virus's inherent genetic diversity or through generating de novo interference by engineering a competing genome. Here, we discuss two such antiviral strategies, dominant drug targeting and therapeutic interfering particles. Both strategies harness the power of genetic interference to surmount two particularly vexing obstacles-the evolution of drug resistance and targeting therapy to high-risk populations-both of which impede treatment in resource-poor settings.

Impact of Experience Corps® Participation on Children's Academic Achievement and School Behavior.

This article reports on the impact of the Experience Corps® (EC) Baltimore program, an intergenerational, school-based program aimed at improving academic achievement and reducing disruptive school behavior in urban, elementary school students in Kindergarten through third grade (K-3). Teams of adult volunteers aged 60 and older were placed in public schools, serving 15 h or more per week, to perform meaningful and important roles to improve the educational outcomes of children and the health and well-being of volunteers. Findings indicate no significant impact of the EC program on standardized reading or mathematical achievement test scores among children in grades 1-3 exposed to the program. K-1st grade students in EC schools had fewer principal office referrals compared to K-1st grade students in matched control schools during their second year in the EC program; second graders in EC schools had fewer suspensions and expulsions than second graders in non-EC schools during their first year in the EC program. In general, both boys and girls appeared to benefit from the EC program in school behavior. The results suggest that a volunteer engagement program for older adults can be modestly effective for improving selective aspects of classroom behavior among elementary school students in under-resourced, urban schools, but there were no significant improvements in academic achievement. More work is needed to identify individual- and school-level factors that may help account for these results.

A mixed methods thematic review: Health-related decision-making by the older person.

AIMS AND OBJECTIVES: To undertake a mixed methods thematic literature review that explored how elderly adults approached decision-making in regard to their health care following discharge. BACKGROUND: A critical time for appropriate health decisions occurs during hospital discharge planning with nursing staff. However, little is known how the 89% of elderly living at home make decisions regarding their health care. Research into older adults' management of chronic conditions emerges as an important step to potentially encourage symptom monitoring, prevent missed care and detect deterioration. All should reduce the risk of hospital re-admission. DESIGN: A mixed methods thematic literature review was undertaken. The structure followed the PRISMA reporting guidelines for systematic reviews recommended by the EQUATOR network. METHODS: PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Scopus online databases were searched using keywords, inclusion and exclusion criteria. References drawn from relevant publications, identified by experts and published between 1995 and 2017 were also considered. Twenty-five qualitative, quantitative and mixed methods studies and reviews were critically appraised (CASP 2013) before inclusion in the review. Analysis of each study's findings was undertaken using Braun and Clarke's (2006) steps to identify major themes and sub-themes. RESULTS: Four main themes associated with health-related decision-making in the elderly were identified: "the importance of maintaining independence," "decision making style," "management of conditions at home" and "discharge planning." CONCLUSION: Health care decision preferences in the elderly emerged as highly complex and influenced by multiple factors. Development of a tool to assess these components has been recommended. RELEVANCE TO CLINICAL PRACTICE: Nurses play a vital role in exploring and understanding the influence that maintaining independence has with each patient. This understanding provides an initial step toward development of a tool to assist collaboration between patients and healthcare professionals involved in their care.

Transient Thresholding: A Mechanism Enabling Noncooperative Transcriptional Circuitry to Form a Switch.

Threshold generation in fate-selection circuits is often achieved through deterministic bistability, which requires cooperativity (i.e., nonlinear activation) and associated hysteresis. However, the Tat positive-feedback loop that controls HIV's fate decision between replication and proviral latency lacks self-cooperativity and deterministic bistability. Absent cooperativity, it is unclear how HIV can temporarily remain in an off-state long enough for the kinetically slower epigenetic silencing mechanisms to act-expression fluctuations should rapidly trigger active positive feedback and replication, precluding establishment of latency. Here, using flow cytometry and single-cell imaging, we find that the Tat circuit exhibits a transient activation threshold. This threshold largely disappears after ∼40 h-accounting for the lack of deterministic bistability-and promoter activation shortens the lifetime of this transient threshold. Continuous differential equation models do not recapitulate this phenomenon. However, chemical reaction (master equation) models where the transcriptional transactivator and promoter toggle between inactive and active states can recapitulate the phenomenon because they intrinsically create a single-molecule threshold transiently requiring excess molecules in the inactive state to achieve at least one molecule (rather than a continuous fractional value) in the active state. Given the widespread nature of promoter toggling and transcription factor modifications, transient thresholds may be a general feature of inducible promoters.

The association of adverse childhood experiences with mid-life depressive symptoms and quality of life among incarcerated males: exploring multiple mediation.

OBJECTIVES: To explore the association of experiencing death, trauma, and abuse during childhood with depressive symptoms and quality of life at mid-life among incarcerated men and to understand how current social support and coping strategies mediate the impact of childhood trauma histories on mental health. METHODS: Study participants were 192 male inmates in a maximum security prison. Participants completed measures of adverse childhood experiences related to death, trauma, and abuse, and depressive symptoms and quality of life. Data were analyzed using multiple mediation modeling. RESULTS: Men who reported having experienced adverse childhood experiences reported more depressive symptoms and lower quality of life than their counterparts. The results showed that in models both unadjusted and adjusted for age, race, education, number of years served, and whether the inmate had a life sentence, the association between adverse childhood experiences and quality of life were partially explained by the total of the indirect effects (point estimate = -.5052; CI.95 = -1.0364, -.0429 and point estimate = -.7792; CI.95 = -1.6369, -.0381), primarily via social support. However, the associations between adverse childhood experiences and depressive symptoms were not explained by social support and coping. CONCLUSION: Adverse childhood experiences are associated with deleterious mental health effects in later life. Social support and coping partially mediate the association between adverse childhood experiences and quality of life. The high prevalence of childhood trauma among aging prison inmates warrants attention to increasing social support mechanisms to improve mental health.

Increases in lifestyle activities as a result of experience Corps® participation.

Experience Corps® (EC) was designed to simultaneously increase cognitive, social, and physical activity through high-intensity volunteerism in elementary school classrooms. It is, therefore, highly likely that EC participation may alter pre-existing patterns of lifestyle activity. This study examined the impact of "real-world" volunteer engagement on the frequency of participation in various lifestyle activities over a 2-year period. Specifically, we examined intervention-related changes on reported activity levels at 12 and 24 months post-baseline using Intention-to-Treat (ITT) and Complier Average Causal Effect (CACE) analyses, which account for the amount of program exposure. ITT analyses indicated that, compared to the control group, EC participants reported modest increases (approximately half a day/month) in overall activity level, especially in intellectual and physical activities 12 months post-baseline. Increases in activity were not found at the 24-month assessment. CACE models revealed similar findings for overall activity as well as for intellectual and physical activities at 12 months. Additionally, CACE findings suggested modest increases in social activity at 12 months and in intellectual and passive activities at 24 months post-baseline. This community-based, health promotion intervention has the potential to impact lifestyle activity, which may lead to long-term increases in activity and to other positive cognitive, physical, and psychosocial health outcomes.

Impact of Experience Corps(®) participation on school climate.

We examined the impact of the Experience Corps(®) (EC) program on school climate within Baltimore City public elementary schools. In this program, teams of older adult volunteers were placed in high intensity (>15 h per week), meaningful roles in public elementary schools, to improve the educational outcomes of children as well as the health and well-being of volunteers. During the first year of EC participation, school climate was perceived more favorably among staff and students in EC schools as compared to those in comparison schools. However, with a few notable exceptions, perceived school climate did not differ for staff or students in intervention and comparison schools during the second year of exposure to the EC program. These findings suggest that perceptions of school climate may be altered by introducing a new program into elementary schools; however, research examining how perceptions of school climate are impacted over a longer period is warranted.

Impact of the Baltimore Experience Corps Trial on cortical and hippocampal volumes.

INTRODUCTION: There is a substantial interest in identifying interventions that can protect and buffer older adults from atrophy in the cortex and particularly, the hippocampus, a region important to memory. We report the 2-year effects of a randomized controlled trial of an intergenerational social health promotion program on older men's and women's brain volumes. METHODS: The Brain Health Study simultaneously enrolled, evaluated, and randomized 111 men and women (58 interventions; 53 controls) within the Baltimore Experience Corps Trial to evaluate the intervention impact on biomarkers of brain health at baseline and annual follow-ups during the 2-year trial exposure. RESULTS: Intention-to-treat analyses on cortical and hippocampal volumes for full and sex-stratified samples revealed program-specific increases in volumes that reached significance in men only (P's ≤ .04). Although men in the control arm exhibited age-related declines for 2 years, men in the Experience Corps arm showed a 0.7% to 1.6% increase in brain volumes. Women also exhibited modest intervention-specific gains of 0.3% to 0.54% by the second year of exposure that contrasted with declines of about 1% among women in the control group. DISCUSSION: These findings showed that purposeful activity embedded within a social health promotion program halted and, in men, reversed declines in brain volume in regions vulnerable to dementia. CLINICAL TRIAL REGISTRATION: NCT0038.

Bcl-2 proteins and autophagy regulate mitochondrial dynamics during programmed cell death in the Drosophila ovary.

The Bcl-2 family has been shown to regulate mitochondrial dynamics during cell death in mammals and C. elegans, but evidence for this in Drosophila has been elusive. Here, we investigate the regulation of mitochondrial dynamics during germline cell death in the Drosophila melanogaster ovary. We find that mitochondria undergo a series of events during the progression of cell death, with remodeling, cluster formation and uptake of clusters by somatic follicle cells. These mitochondrial dynamics are dependent on caspases, the Bcl-2 family, the mitochondrial fission and fusion machinery, and the autophagy machinery. Furthermore, Bcl-2 family mutants show a striking defect in cell death in the ovary. These data indicate that a mitochondrial pathway is a major mechanism for activation of cell death in Drosophila oogenesis.

Examining functional and social determinants of depression in community-dwelling older adults: implications for practice.

Coping with declining health, physical illnesses and complex medical regimens, which are all too common among many older adults, requires significant lifestyle changes and causes increasing self-management demands. Depression occurs in community-dwelling older adults as both demands and losses increase, but this problem is drastically underestimated and under-recognized. Depressive symptoms are often attributed to physical illnesses and thus overlooked, resulting in lack of appropriate treatment and diminished quality of life. The purpose of this study is to assess prevalence of depressive symptoms in community-dwelling older adults with high levels of co-morbidity and to identify correlates of depression. In this sample of 533 homebound older adults screened (76.1% female, 71.8% white, mean age 78.5 years) who were screened using the Geriatric Depression Scale (SF), 35.9% scored greater than 5. Decreased satisfaction with family support (p << 0.001) and functional status (p ≤ 0.001) and increased loneliness (p < 0.001) were significant independent predictors of depression status in this sample; thus, these factors should be considered when planning care.

Effects of a graduate-level interprofessional education program on adult nurse practitioner student and internal medicine resident physician attitudes towards interprofessional care.

This article describes the development, implementation and evaluation of a longitudinal interprofessional education (IPE) experience for adult nurse practitioner students and internal medicine residents. This experience focused on providing care for complex community based patients during clinic and home visits, preceded by didactic learning that emphasized understanding one another's professional roles and education, teamwork and conflict management. Evaluation demonstrated significant improvements in attitudes and beliefs associated with professional role, respect among health professions' disciplines and conflict management. Results with regards to attitudes towards IPE and interprofessional practice, and valuing teamwork training were mixed. In particular, the curricular intervention did not change participants'self-reported skill in communication and did not affect attitudes and beliefs towards effects of interprofessional education on patient outcomes.