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The Future of Nursing 2020-2030 report identifies coalitions as a driving force for advancing health equity. Five coalitions provided insight into their accomplishments, lessons learned, and role in advancing health equity. The exemplar coalitions included Latinx Advocacy Team and Interdisciplinary Network for COVID-19, Black Coalition Against COVID, Camden Coalition, National Coalition of Ethnic Minority Nurse Associations, and The Future of Nursing: Campaign for Action. While all exemplar coalitions, credited relationship building and partnerships to their success, they used unique strategies for striving to meet their populations' needs, whether the needs arose from COVID-19, racial and/or ethnic disparities, socioeconomic disparities, or other barriers to health. Research and policy implications for coalitions are discussed. Nurses play a critical role in every highlighted coalition and in the national effort to make health and health care more equitable.

Informal caregivers encounter emotional distress, worsening personal health, and financial strain. The Medicaid 1915(c) Home and Community-Based Services (HCBS) waiver programs provide an array of services including support for caregivers.This policy analysis examined Medicaid waiver services offered to persons 65 and older among the 50 states and District of Columbia (DC).Data were obtained from Medicaid waiver applications for adults age 65 and older available at Medicaid.gov. Data elements included number of waiver programs and services for supporting caregivers. Descriptive statistics were applied.Forty-three states including DC (84%) offered a Medicaid waiver for older adults; seven states (14%) offer two waiver programs; eight states (16%) had no Medicaid waiver. Payment to a relative or legal guardian caregiver was the most common service offered in 39 (76%) states. Other services included in-home respite care and adult day health care (35 states; 67%), out-of-home respite care (32 states; 63%), skilled nursing (28 states; 55%), paid spousal caregivers (18 states; 35%), caregiver training (15 states; 29%), and adult day care for socialization (7 states, 14%).This study identifies wide variability in caregiver support across state-based Medicaid waivers. Future research should evaluate effectiveness of the waiver programs in supporting caregivers and inform evidence-based policy advocacy for supporting caregivers.

The catabolic pathway of autophagy is critical for pancreatic beta-cell function and is defective in established type 1 diabetes (T1D). However, it is unclear when and how this critical cell process becomes defective during diabetes pathogenesis. To study the nature of autophagy dysfunction in the context of autoimmune diabetes, we utilized intravital microscopy to study autophagic fluxin vivoin real time. We generated a custom AAV8- packaged mCherry-eGFP-LC3B biosensor driven by the insulin promoter for beta-cell-selective expression. For real time autophagic flux evaluation, fluorescent signal from eGFP and mCherry fluorophores was correlated in space and time to follow the process of autophagosome-lysosome fusion. We observed autophagic flux defects in the beta-cells of non-obese diabetic (NOD) mouse model of T1D prior to hyperglycemia onset that were less apparent in mice without a functional immune system. We also evaluated autophagic flux in human donor islets that were transplanted under the kidney capsule of immune incompetent mice. Collectively, we provide the first evaluation of autophagic fluxin vivoin 4D and demonstrate that autophagy defects precede hyperglycemia in NOD mice suggesting a potential causative role for these defects in beta-cell demise during T1D pathogenesis.

Metabolic dysfunction of β-cells has been implicated as a contributor to diabetes pathogenesis, and efforts are ongoing to optimize analytical techniques that evaluate islet metabolism. High-resolution respirometry offers sensitive measurements of the respiratory effects of metabolic substrates and customizable manipulation of electron transport chain components, though the delicate nature of islets can pose challenges to conventional analyses. An affordable and reliable option for respirometry is the Oroboros Oxygraph-2 K system, which utilizes a stir bar to circulate reagents around cells. While this technique may be suitable for individual cells or mitochondria, the continual force exerted by the stir bar can have damaging effects on islet integrity. Herein, we demonstrate the protective benefits of a novel 3D-printed islet stabilization device and highlight the destructive effects of conventional Oxygraph analysis on islet integrity. Islet containment did not inhibit cellular responses to metabolic modulatory drugs, as indicated by robust fluctuations in oxygen consumption rates. The average size of wild-type mouse islets was significantly reduced following a standard Mito Stress Test within Oxygraph chambers, with a clear disruption in islet morphology and viability. Alternatively, containment of the islets within the interior chamber of the islet stabilization device yielded preservation of both islet morphology and increased cell viability/survival after respirometry analysis. Collectively, our study introduces a new and easily accessible tool to improve conventional Oxygraph respirometry of pancreatic islets by preserving natural islet structure and function throughout metabolic analysis.

Background/Aims Nocardiosis is a rare infectious disease caused by the aerobic bacteria genus Nocardia and can cause severe suppurative disease affecting virtually any organ. It tends to affect the immunocompromised, making rheumatology patients a particular risk group for this infection. It is not normal human flora and is found in soil, decaying vegetable matter and aquatic environments. It can become airborne and the most common means of entry is thought to be dust inhalation. Methods Our patient is a 75-year-old woman with giant cell arteritis (GCA) treated with prednisolone, SC methotrexate and tocilizumab (started 4 months before her acute illness). Symptoms began with a fall in the garden sustaining a nasty laceration to her leg and an injury to her back worsening some chronic lower back pain (X-rays did not show any fracture). Over the next 5 weeks due to a productive cough and sweats she was prescribed oral antibiotics with no improvement. She was then admitted to hospital due to an acute increase in the severity of her lower back pain alongside a change in character to a burning pain. Her presenting CRP was 32, likely due to having held tocilizumab due to a presumed chest infection. MRI showed a collection in the right erector spinae muscle extending from C7 to the iliac crest and another large collection in the right thigh. A mass in the left sub-mammary area led to a chest CT that showed a chest wall abscess alongside a spiculated lesion in the lung, and further nodular changes. Peripheral blood cultures were negative and eventually draining of the erector spinae abscess led to culture of Nocardiosis nova. Imipenam and Septrin were given as per sensitivities. Unfortunately, our patient has had a difficult clinical course. During her hospital stay she has had possible DRESS syndrome/Septrin-induced liver injury alongside drug induced neutropaenia and lymphopaenia and a possible stroke (this was thought less likely to represent CNS Nocardiosis). Results Her rheumatology management initially involved stopping her DMARDs however due to flares in symptoms her doses of prednisolone have been up and down. It has been difficult to separate symptoms that may be due to cervical spine collections and a possible CNS lesion from GCA symptoms. Conclusion This case demonstrates the need to thoroughly investigate immunosuppressed patients when they are not responding as expected to antibiotics or present with atypical symptoms. It also demonstrates the importance of obtaining a microbiological diagnosis. Cellular immunity is generally thought to be key in preventing Nocardia dissemination however in our patient’s case she was only taking 2.5mg prednisolone when admitted. This is one of only a few case reports of patients developing Nocardia infection whilst on tocilizumab. Disclosure R.J. Crowder: None. H. Mills: None. O. Savanovic-Abel: None. J. King: None. O. Moore: None. M. Perry: None. S. Hewagamage: None. M. Gunathilaka: None.

Supplementary Table 1 from PIK3CA and PIK3CB Inhibition Produce Synthetic Lethality when Combined with Estrogen Deprivation in Estrogen Receptor–Positive Breast Cancer

Supplementary Methods and Materials from PIK3CA and PIK3CB Inhibition Produce Synthetic Lethality when Combined with Estrogen Deprivation in Estrogen Receptor–Positive Breast Cancer

Several phosphoinositide 3-kinase (PI3K) catalytic subunit inhibitors are currently in clinical trial. We therefore sought to examine relationships between pharmacologic inhibition and somatic mutations in PI3K catalytic subunits in estrogen receptor (ER)–positive breast cancer, in which these mutations are particularly common. RNA interference (RNAi) was used to determine the effect of selective inhibition of PI3K catalytic subunits, p110α and p110β, in ER+ breast cancer cells harboring either mutation (PIK3CA) or gene amplification (PIK3CB). p110α RNAi inhibited growth and promoted apoptosis in all tested ER+ breast cancer cells under estrogen deprived-conditions, whereas p110β RNAi only affected cells harboring PIK3CB amplification. Moreover, dual p110α/p110β inhibition potentiated these effects. In addition, treatment with the clinical-grade PI3K catalytic subunit inhibitor BEZ235 also promoted apoptosis in ER+ breast cancer cells. Importantly, estradiol suppressed apoptosis induced by both gene knockdowns and BEZ235 treatment. Our results suggest that PI3K inhibitors should target both p110α and p110β catalytic subunits, whether wild-type or mutant, and be combined with endocrine therapy for maximal efficacy when treating ER+ breast cancer. [Cancer Res 2009;69(9):3955–62]

Romantic heartbreak is common, affects all genders, and does not spare the adolescent or adult. While some recover and experience growth beyond their pre-break-up state, others do not fully recover. What are the factors that facilitate or impede recovery? Could there be restoration for heartbreak? These are some questions that this study set out to explore. Using a phenomenological lens, eight Caucasian adult females who self-reported as experiencing heartbreak from heterosexual and same sex relationships were interviewed. Emerging themes from transcribed and coded interviews included relational evolution, decline, end, rumination, and recovery. While each relational phase transitioned to the next, the path of rumination influenced participants’ level of recovery. Results indicated that participants who exhibited productive rumination eventually achieved a state of mental and spiritual renewal. Several implications are discussed, including how counselors may help to facilitate productive client rumination and renewal post heartbreak.

Aims/hypothesis Pancreatic beta cells are subjected to exogenous damaging factors such as proinflammatory cytokines or excess glucose that can cause accumulation of damage-inducing reactive oxygen species during the pathogenesis of diabetes. We and others have shown that beta cell autophagy can reduce reactive oxygen species to protect against apoptosis. While impaired islet autophagy has been demonstrated in human type 2 diabetes, it is unknown if islet autophagy is perturbed in the pathogenesis of type 1 diabetes. We hypothesised that beta cell autophagy is dysfunctional in type 1 diabetes, and that there is a progressive loss during early diabetes development. Methods Pancreases were collected from chloroquine-injected and non-injected non-obese diabetes-resistant (NOR) and non-obese diabetic (NOD) mice. Age- and BMI-matched pancreas tissue sections from human organ donors (N = 34) were obtained from the Network for Pancreatic Organ Donors with Diabetes (nPOD). Tissue sections were stained with antibodies against proinsulin or insulin (beta cell markers), microtubule-associated protein 1 light chain 3 A/B (LC3A/B; autophagosome marker), lysosomal-associated membrane protein 1 (LAMP1; lysosome marker) and p62 (autophagy adaptor). Images collected on a scanning laser confocal microscope were analysed with CellProfiler and ImageJ. Secondary lysosomes and telolysosomes were assessed in electron micrographs of human pancreatic tissue sections (n = 12), and energy dispersive x-ray analysis was performed to assess distribution of elements (n = 5). Results We observed increased autophagosome numbers in islets of diabetic NOD mice (p = 0.008) and increased p62 in islets of both non-diabetic and diabetic NOD mice (p p p p = 0.003) and non-diabetic NOD mice (p p p p p = 0.002). Conclusions/interpretation We provide evidence of islet macroautophagy/crinophagy impairment in human type 1 diabetes. We also document accumulation of telolysosomes with peripheral nitrogen in beta cells of autoantibody-positive donors, demonstrating altered lysosome content that may be associated with lysosome dysfunction before clinical hyperglycaemia. Similar macroautophagy impairments are present in the NOD mouse model of type 1 diabetes. Graphical abstract

Objective Adult polyglucosan body disease (APBD) is an adult‐onset neurological variant of glycogen storage disease type IV. APBD is caused by recessive mutations in the glycogen branching enzyme gene, and the consequent accumulation of poorly branched glycogen aggregates called polyglucosan bodies in the nervous system. There are presently no treatments for APBD. Here, we test whether downregulation of glycogen synthesis is therapeutic in a mouse model of the disease. Methods We characterized the effects of knocking out two pro‐glycogenic proteins in an APBD mouse model. APBD mice were crossed with mice deficient in glycogen synthase (GYS1), or mice deficient in protein phosphatase 1 regulatory subunit 3C (PPP1R3C), a protein involved in the activation of GYS1. Phenotypic and histological parameters were analyzed and glycogen was quantified. Results APBD mice deficient in GYS1 or PPP1R3C demonstrated improvements in life span, morphology, and behavioral assays of neuromuscular function. Histological analysis revealed a reduction in polyglucosan body accumulation and of astro‐ and micro‐gliosis in the brains of GYS1‐ and PPP1R3C‐deficient APBD mice. Brain glycogen quantification confirmed the reduction in abnormal glycogen accumulation. Analysis of skeletal muscle, heart, and liver found that GYS1 deficiency reduced polyglucosan body accumulation in all three tissues and PPP1R3C knockout reduced skeletal muscle polyglucosan bodies. Interpretation GYS1 and PPP1R3C are effective therapeutic targets in the APBD mouse model. These findings represent a critical step toward the development of a treatment for APBD and potentially other glycogen storage disease type IV patients.

Volatility, and the uncertainty it creates, has long been recognized as a factor in economic decision making. Since hiring occurs before shocks to productivity are realized, firms’ investment in ne...

Autophagic degradation is a dynamic recycling process that contributes to cellular homeostasis and mitigation of cellular stress. While there are multiple forms of -phagic degradation processes, a common endpoint is the final degradation step in the lumen of the acidic lysosomes. Post-mitotic cells, including beta cells, can accumulate tertiary lysosomes called telolysosomes which contain oxidized proteins and lipids that are not completely digested. We recently found that autophagy is impaired in the beta cells of individuals with T1D and also in islets of diabetic NOD mice. We also observed a significant increase in the number of autophagosomes, and telolysosomes in the beta cells of autoantibody positive organ donors when compared to nondiabetic organ donors. We now also find a 1.5-fold increase in the number of telolysosomes in the alpha cells of autoantibody positive donors when compared to nondiabetic organ donors (p=0.03). This was mirrored by our previous observation of globally increased lysosome numbers across the islets of pre-diabetic NOD mice, suggesting that these lysosomes may be dysfunctional. To test this, we performed a lysosomal enzyme activity assay to analyze the lysosomal cysteine protease Cathepsin H (a T1D susceptibility locus). Interestingly, we found that the activity of Cathepsin H was increased by ~2-fold in islets of pre-diabetic NOD mice when compared to NOR controls (p=0.02). Taken together, these data suggest a compensatory hyperactivation of the lysosomal enzyme Cathepsin H in the islets of pre-diabetic NOD mice, potentially as a mechanism to rid the cell of degradation-resistant oxidized proteins and lipids whose accumulation in lysosomes might lead to the presence of telolysosomes. Disclosure C. Muralidharan: None. J. Crowder: None. A. K. Linnemann: None. Funding Network for Pancreatic Organ Donors with Diabetes (nPOD; RRID:SCR_014641); JDRF (nPOD: 5-SRA-2018-557-Q-R); The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D053)

β-cells are highly metabolic and vulnerable to a variety of exogenous stressors, many of which elicit the generation of reactive oxygen species (ROS). Endogenous adaptive responses can restore homeostasis after excessive ROS elevation. If the endogenous adaptive response fails, ROS accumulation can cause damage to DNA, proteins, and organelles, ultimately leading to apoptosis. A wealth of evidence supports that ROS accumulation contributes to β-cell dysfunction and destruction during diabetes development. These findings suggest that stimulating the antioxidant response could prevent or treat diabetes. However, limitations exist in that persistent systemic activation of the antioxidant response can perturb the normal second messenger function of ROS, and that exogenous antioxidants have poor bioavailability and lack specificity. To overcome these obstacles, we developed β-cell targeted nanoparticles to selectively deliver antioxidants to β-cells. We conjugated modified Exendin-4 (Ex4) to an amphiphilic polymer, allowing us to generate lipid nanoparticles to deliver small hydrophobic compounds to GLP-1R expressing cells. We assessed β-cell targeting of our nanoparticles using isolated islets from mice expressing tdTomato selectively in the β-cell. Isolated islets were treated with nanoparticles containing a lipid intercalating dye, DiO, and we observed selective DiO accumulation in tdTomato positive cells. We also performed in vivo imaging of live mice injected with targeted or non-targeted nanoparticles containing a near-IR lipid intercalating dye. These experiments demonstrated selective retention of targeted nanoparticles both systemically and in the pancreata of animals 1 hour after tail vein injection. Collectively, we provide evidence that Ex4 coated micelles are selective to β-cells. Future experiments will explore this targeted approach to deliver drugs to stimulate the antioxidant response and reduce β-cell apoptosis under diabetogenic conditions. Disclosure A. Novak: None. T. Nallan chakravarthula: None. J. Crowder: None. N. J. Alves: None. J. Broichhagen: None. D. Hodson: None. A. Bedwell: None. A. K. Linnemann: None.

Aims/hypothesisPancreatic beta cells are highly metabolic secretory cells that are subjected to exogenous damaging factors such as proinflammatory cytokines or excess glucose that can cause accumulation of damage-inducing reactive oxygen species (ROS) during the pathogenesis of diabetes. We and others have shown that beta cell autophagy can reduce ROS to protect against apoptosis both in vitro and in vivo. While impaired islet autophagy has been demonstrated in human type 2 diabetes, it is unknown if islet autophagy is perturbed in the pathogenesis of type 1 diabetes. We hypothesized that beta cell autophagy is dysfunctional in type 1 diabetes, and that there is a progressive loss during early diabetes development.MethodsMouse pancreata were collected from chloroquine injected and non-injected NOR, nondiabetic NOD, and diabetic NOD mice. Age and BMI-matched pancreas tissue sections from human organ donors (n=34) were obtained from the Network for Pancreatic Organ Donors with Diabetes (nPOD). To assess autophagic flux, we injected the mice with chloroquine to inhibit the final stages of autophagy. We analyzed tissues for markers of autophagy via immunofluorescence analysis. Tissue sections were stained with antibodies against proinsulin or insulin (beta cell markers), LC3A/B (autophagosome marker), Lamp1 (lysosome marker), and p62 (autophagy adaptor protein and marker for autophagic flux). Images were collected on a scanning laser confocal microscope then analyzed with CellProfiler and ImageJ. Secondary lysosomes and telolysosomes (formerly called lipofuscin bodies, residual bodies or tertiary lysosomes) were analyzed in electron micrographs of pancreatic tissue sections from human organ donors (nPOD; n=12) deposited in www.nanotomy.org/OA/nPOD. Energy Dispersive X-ray (EDX) analysis was also performed on these tissues to analyze distribution of elements such as nitrogen, phosphorus, and osmium in secondary lysosomes and telolysosomes of nondiabetic and autoantibody positive donor tissues (n=5).ResultsWe observed increased autophagosome numbers in islets of diabetic NOD mice (p=0.0077) and increased p62 in islets of both nondiabetic and diabetic NOD mice (pConclusions/interpretationCollectively, we provide evidence of impairment in the final degradation stages of islet macroautophagy and crinophagy in human type 1 diabetes. We also document an accumulation of telolysosomes with nitrogen accumulation at their periphery in the beta cells of autoantibody positive donors. This demonstrates clear differences in the lysosome contents of autoantibody positive donors that may be associated with lysosome dysfunction prior to clinical hyperglycemia. We observe similar impairments in macroautophagy in the diabetic NOD mouse, a model of type 1 diabetes, suggesting that this mouse model can be appropriately used to study the pathogenesis of autophagy/crinophagy loss and how it relates to disease initiation and progression. Considering these data in the context of what is known regarding the cell-protective effects of islet autophagy, we suggest targeting beta cell autophagy pathways as an approach to reduce apoptosis in individuals at risk for type 1 diabetes development.Research in contextWhat is already known about this subject?Autophagy confers a cytoprotective role in the beta cell.Autophagy is reduced in type 2 diabetes.Autophagy in the context of type 1 diabetes is unexplored.What is the key question?Is autophagy reduced during the pathogenesis of human type 1 diabetes?What are the new findings?We provide evidence of reduced autophagy and crinophagy in human type 1 diabetes.These data are supported by observations of reduced autophagy in a mouse model of autoimmune diabetes.How might this impact on clinical practice in the foreseeable future?This study provides evidence that autophagy is impaired in human type 1 diabetes. Prior studies have shown that loss of autophagy in the islet is associated with increased beta cell apoptosis, therefore we propose that therapeutic targeting of autophagy pathways may reduce beta cell death in type 1 diabetes development.

Autophagy is a dynamic recycling mechanism that maintains beta cell homeostasis, whereas the related process of crinophagy also plays a specific role in insulin granule regulation. Impairment of autophagy and crinophagy have been implicated in beta cell death and dysfunction in the context of type 2 diabetes; however, there is currently no literature describing beta cell autophagy in type 1 diabetes pathogenesis. Therefore, we set out to determine if beta cell autophagy and crinophagy are impaired in the context of type 1 diabetes. We utilized immunofluorescent staining of LC3 (autophagosome marker), Lamp1 (lysosome marker), and proinsulin to analyze pancreatic islet autophagy and crinophagy in the NOD (non-obese diabetic) mouse model of type 1 diabetes as well as in human pancreas tissue obtained from the network for Pancreatic Organ donors with Diabetes (nPOD). We observed evidence of reduced macroautophagy in the residual proinsulin-positive islet cells of human donors with type 1 diabetescompared to controls, as measured by significantly reduced autophagosome:lysosome colocalization (p=0.034). Similarly, there was a trend towards reduced autophagosome:lysosome colocalization in islets of diabetic NOD mice compared to nondiabetic NOR mice (p=0.08). We also observed significantly reduced colocalization of proinsulin with lysosomes in the proinsulin positive cells from human donors with type 1 diabetes in comparison to both controls without diabetes (p=0.0014) and autoantibody positive donors (p= 0.0278), as well as in diabetic NOD vs. nondiabetic NOR mice (p=0.0121), suggesting that crinophagy is also reduced as a function of type 1 diabetes. Collectively, we provide evidence that macroautophagy and crinophagy are reduced in the context of type 1 diabetes. Considering these data in the context of what is known regarding the cell-protective effects of islet autophagy, we suggest targeting beta cell autophagy pathways as an approach to reduce apoptosis in individuals at risk for type 1 diabetes development. Disclosure C. Muralidharan: None. M. Marasco: Employee; Spouse/Partner; Eli Lilly and Company. J. Crowder: Employee; Spouse/Partner; Eli Lilly and Company. A.M. Conteh: None. A.K. Linnemann: None.

Pathways that mitigate cellular stress are critical for pancreatic beta cell function and survival. We have reported that the cytokine interleukin-6 (IL-6) coordinately activates two such pathways, autophagy and the antioxidant response, resulting in decreased oxidative stress and increased beta cell survival under diabetogenic conditions. Our investigation of this protective effect of IL-6 on the beta cells subsequently revealed that members of the IL-6 family of cytokines stimulated the mitochondrial translocation of NRF2, the central antioxidant regulator. This was surprising since NRF2 is well-characterized as a transcription factor. Under these conditions, we also observe translocation of another transcription factor, STAT3, to the mitochondria, consistent with previously published observations. Here, we present data to validate these findings in the islet in vivo and investigate the downstream events associated with NRF2 mitochondrial translocation. We used a mouse model where animals were intraperitoneally injected with either IL-6 or another IL-6 family member, leukemia inhibitory factor (LIF), and pancreata were collected at 30 minutes post-injection. We then used immunofluorescence analysis of paraffin tissue sections. We observed that both IL-6 and LIF rapidly elicit a reduction in the autophagy receptor p62 both in the cytosol and at the mitochondria when compared to saline-injected mice. This suggests that both global autophagy and selective mitophagy are stimulated in the beta cell by both IL-6 and LIF. Furthermore, as both IL-6 and LIF selectively stimulate mitochondrial but not nuclear translocation of NRF2, our data suggests that NRF2 may play a role in the stimulation of mitophagy by IL-6 family cytokines. Further studies investigating the requirement of NRF2 for beta cell mitophagy under conditions of beta cell stress response will shed light on this novel pathway of the cellular antioxidant response. Disclosure M. Marasco: Employee; Spouse/Partner; Eli Lilly and Company. Z. Akbar: None. J. Crowder: Employee; Spouse/Partner; Eli Lilly and Company. A. Novak: None. C. Muralidharan: None. M. Arvin: None. A.K. Linnemann: None. Funding National Institutes of Health (T32DK064466-16, R03DK115990)

The Neo-Fisher hypothesis is the idea, first suggested by Jim Bullard (FRB St. Louis Rev 92(5):339–352, 2010) and then thrown into the public debate by John Cochrane on his blog (http://johnhcochrane.blogspot.com/), that trend inflation can be increased by increasing the nominal policy rate. The reasoning is that the Fisher relation must hold in the long run, so given a constant steady-state real rate of interest, raising the nominal interest rate will eventually lead to a higher inflation rate. Cochrane (Do Higher Interest Rates Raise or Lower Inflation? Hoover Institution, 2016) demonstrates that this Neo-Fisher result is consistent with virtually all dynamic general equilibrium macroeconomic models, like the new Keynesian and DGSE models employed by policymakers. The implication of the hypothesis is that an increase in expected (trend) inflation can be caused by an increase in nominal interest rates. An empirical analysis using US data reveals that, contrary to the Neo-Fisherian hypothesis, trend inflation causes nominal interest rates.

Small nucleolar RNAs (snoRNAs) are noncoding RNAs that guide chemical modifications of structural RNAs. Whereas snoRNAs primarily localize in the nucleolus, where their canonical function is to target nascent ribosomal RNAs for 2′-O-methylation, recent studies provide evidence that snoRNAs traffic out of the nucleus. Furthermore, RNA-Seq data indicate that extracellular vesicles released from cells contain snoRNAs. However, it is not known whether snoRNA secretion is regulated or whether secreted snoRNAs are functional. Here, we show that inflammation stimulates secretion of Rpl13a snoRNAs U32a (SNORD32a), U33 (SNORD33), U34 (SNORD34), and U35a (SNORD35a) from cultured macrophages, in mice, and in human subjects. Secreted snoRNAs co-fractionate with extracellular vesicles and are taken up by recipient cells. In a murine parabiosis model, we demonstrate that snoRNAs travel through the circulation to function in distant tissues. These findings support a previously unappreciated link between inflammation and snoRNA secretion in mice and humans and uncover a potential role for secreted snoRNAs in cell–cell communication.

Background and Hypothesis: Glycogen is a highly branched polymer of glucose and is an important form of energy storage in mammals. The brain is able to form glycogen in astrocytes and neurons via glycogen synthase and branching enzyme. Once formed, brain glycogen functions as the only stored energy source for these cells. Various physiological roles for brain glycogen have been hypothesized, including memory consolidation and sleep regulation, as well as a protective role during various physiological stressors, such as hypoglycemia and hypoxia. For instance, rat brain glycogen levels were decreased 10 minutes after vaginal birth, but not after a C-section. This suggested that cerebral hypoxia experienced during vaginal birth induced the utilization of brain glycogen to minimize neurodegeneration during the hypoxic event. Symptoms of hypoxia can range from tachycardia, tachypnea, shortness of breath, and diaphoresis to confusion, loss of motor coordination and cognitive function, neurodegeneration, and brain death. The many causes of hypoxia include lungs diseases (COPD, pneumonia, pulmonary edema), CNS depressants (opiates), heart problems (CHF), anemia, and obstructive sleep apnea (OSA). We hypothesized that the lack of brain glycogen would cause a noticeable detrimental effect to the survival time and physiologic functions of mice exposed to acute hypoxia. Experimental Design or Project Methods: We subjected mice, with or without glycogen synthase disrupted in the brain, to carbon dioxide- or nitrogen-induced hypoxia and monitored effects on brain glycogen levels, behavior, and survival time. Results: We found that mice lacking brain glycogen exhibited the characteristic physiologic responses to hypoxia, but expired ~50% sooner than mice with brain glycogen. Conclusion and Potential Impact: These results provide evidence that brain glycogen is imperative in responding to hypoxic events. Further, these findings suggest that brain glycogen may protect patients with OSA against other comorbidities, especially neurodegeneration and cognitive impairment.

Doctor of Nursing Practice (DNP) students need to be effective health policy leaders and contribute their expertise to legislative discussions. Nursing faculty have unique opportunities to prepare future DNP health policy leaders through legislative experiential learning opportunities. Yet, the creation of legislative fellowships can seem challenging. This article describes a state legislative fellowship based on Kolb's experiential learning theory and explores ways faculty can support DNP student preparation.

Objective: This study aims to develop and validate the Family Management Scale for Children with Asthma (FMSCA) in China context. Methods: Based on the Family Management Style Framework (FMSF) model, an original 89 items were generated from literature review and interviews with 15 caregivers of children with asthma. The preliminary scale was refined to 82 items through two rounds of experts’ evaluation and a pilot study, then administered to 329 caregivers of children with asthma for testing between April and July 2013. Item analysis and exploratory factor analysis were performed to screen the items, reliability and validity analysis were tested using psychometric techniques (internal consistency, split-half reliability, test-retest reliability, content validity, and construct validity). Confirmatory factor analysis was adopted to further evaluate the construct validity of the scale in an additional 600 children with asthma and their parents from August 2014 to December 2015. Results: A final 57-item FMSCA from 8 subscales (children identity, view of condition, management mindset, parental mutuality, parenting philosophy, management approach, family focus, and future expectation) were generated. The excellent internal consistency (Cronbach’s α = 0.918), very good split-half reliability (r = 0.802, p r = 0.857, p r range = 0.513–0.865, P r range = 0.195–0.604, p r range = 0.408–0.876, p Conclusions: The study demonstrates FMSCA can serve as a valid and reliable measure of family management level for Chinese children with asthma.

Numerous randomized controlled trials (RCTs) with the goal of improving caregiver Quality of Life (QoL) that reflect health and well-being have been conducted. However, it is unclear what type of intervention is most effective. Moreover, participant and intervention characteristics were rarely examined in the studies of caregiver QoL. The aims of this meta-analyses were to (1) evaluate the effectiveness of different types of interventions on the QoL of caregivers of individuals with dementia, and (2) explore participant and intervention characteristics that influence interventions’ effect. A systematic search of MEDLINE, CINAHL, PsycINFO, and Cochrane Library electronic databases was conducted to find RCTs published from 2005 to 2017. A total of 28 RCTs were included. Multicomponent interventions with 898 participants (Hedges G = 0.491; 95% CI = [0.220, 0.762]; p

Small nucleolar RNAs (snoRNAs) are noncoding RNAs that guide chemical modifications of structural RNAs. Whereas snoRNAs primarily localize in the nucleolus, where their canonical function is to target nascent ribosomal RNAs for 2′-O-methylation, recent studies provide evidence that snoRNAs traffic out of the nucleus. Furthermore, RNA-Seq data indicate that extracellular vesicles released from cells contain snoRNAs. However, it is not known whether snoRNA secretion is regulated or whether secreted snoRNAs are functional. Here, we show that inflammation stimulates secretion of Rpl13a snoRNAs U32a (SNORD32a), U33 (SNORD33), U34 (SNORD34), and U35a (SNORD35a) from cultured macrophages, in mice, and in human subjects. Secreted snoRNAs co-fractionate with extracellular vesicles and are taken up by recipient cells. In a murine parabiosis model, we demonstrate that snoRNAs travel through the circulation to function in distant tissues. These findings support a previously unappreciated link between inflammation and snoRNA secretion in mice and humans and uncover a potential role for secreted snoRNAs in cell–cell communication.

Purpose: Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains first-line therapy for the management of estrogen receptor (ESR1)–positive breast cancer. However, ESR1 mutations or other ligand-independent ESR1 activation mechanisms limit the duration of response. The clinical efficacy of fulvestrant, a selective estrogen receptor downregulator (SERD) that competitively inhibits agonist binding to ESR1 and triggers receptor downregulation, has confirmed that ESR1 frequently remains engaged in endocrine therapy–resistant cancers. We evaluated the activity of a new class of selective estrogen receptor modulators (SERM)/SERD hybrids (SSH) that downregulate ESR1 in relevant models of endocrine-resistant breast cancer. Building on the observation that concurrent inhibition of ESR1 and the cyclin-dependent kinases 4 and 6 (CDK4/6) significantly increased progression-free survival in advanced patients, we explored the activity of different SERD– or SSH–CDK4/6 inhibitor combinations in models of endocrine therapy–resistant ESR1+ breast cancer. Experimental Design: SERDs, SSHs, and the CDK4/6 inhibitor palbociclib were evaluated as single agents or in combination in established cellular and animal models of endocrine therapy–resistant ESR1+ breast cancer. Results: The combination of palbociclib with a SERD or an SSH was shown to effectively inhibit the growth of MCF7 cell or ESR1-mutant patient-derived tumor xenografts. In tamoxifen-resistant MCF7 xenografts, the palbociclib/SERD or SSH combination resulted in an increased duration of response as compared with either drug alone. Conclusions: A SERD– or SSH–palbociclib combination has therapeutic potential in breast tumors resistant to endocrine therapies or those expressing ESR1 mutations. Clin Cancer Res; 21(22); 5121–30. ©2015 AACR. See related commentary by DeMichele and Chodosh, p. 4999

Few studies have focused on asthma self-management in African American adolescents, a group with high rates of the disease. This study examined factors associated with asthma self-management in 133 African Americans aged 14-16 years including gender, asthma impairment, prior asthma education, cognitive and emotional illness representations. Twenty-five percent of the variance in asthma self-management was explained by having attended an asthma education program, perceiving more asthma consequences (illness consequences), and reporting greater understanding of asthma as an illness (illness coherence). Findings suggest that these variables may be important targets of interventions to improve asthma self-management in African American middle adolescents.

Using active learning strategies, educators facilitate nurses' ability to convey messages to nonhealth care audiences about important policy issues. In this article, mock interviews are described as an active learning approach to develop important communication skills for nurses. J Contin Educ Nurs. 2016;47(2):58–60.

Conserved homologues of the Hrd1 ubiquitin ligase target for degradation proteins that persistently or aberrantly engage the endoplasmic reticulum translocon, including mammalian apolipoprotein B (apoB; the major protein component of low-density lipoproteins) and the artificial yeast proteinDeg1-Sec62. A complete understanding of the molecular mechanism by which translocon-associated proteins are recognized and degraded may inform the development of therapeutic strategies for cholesterol-related pathologies. Both apoB andDeg1-Sec62 are extensively post-translationally modified. Mass spectrometry of a variant ofDeg1-Sec62 revealed that the protein is acetylated at the N-terminal methionine and two internal lysine residues. N-terminal and internal acetylation regulates the degradation of a variety of unstable proteins. However, preventing N-terminal and internal acetylation had no detectable consequence for Hrd1-mediated proteolysis ofDeg1-Sec62. Our data highlight the importance of empirically validating the role of post-translational modifications and sequence motifs on protein degradation, even when such elements have previously been demonstrated sufficient to destine other proteins for destruction.

Persistent deviations of exchange rates from equilibrium values may lead to inefficient resource allocations internationally. Such persistence is well documented and represents a challenge for policy makers. If the source of the persistent deviations is real then effective policy interventions are limited. However, effective policy responses are possible when deviations are caused by nominal or market-structure shocks. The appropriate policy response depends on the cause of the disequilibrium. In this study I use a structural vector autoregression to identify the shocks responsible for purchasing power parity (PPP) deviations for 12 US dollar exchange rates. I find that aggregate demand shocks are not the primary cause of PPP deviations. Real shocks and foreign exchange shocks are much more important. Foreign exchange shocks dominate exchange rate behaviour. This suggests a policy response with greater focus on the foreign exchange market and the degree to which persistent PPP deviations represent compensation for risk-bearing or a form of micro-structure inefficiency.