Practice What We Preach: Beginning a Journey to Embrace Patient-Centered Outcomes Research.

BACKGROUND: Patient-centered outcomes research seeks to answer patient-centered questions. The process includes varied locations and individuals throughout the care continuum to address individual differences and constraints in implementation and dissemination. PROBLEM: This paper intends to answer this question: do academic nurses practice what they preach by assisting patient-centered outcomes research and researchers through their engagement with patients, caregivers, and other community stakeholder partners in nursing research? APPROACH: This paper provides an overview of how academic nurses in a single institution (the University of Texas Medical Branch at Galveston School of Nursing) began to embrace patient-centered outcomes research. CONCLUSION: Whether academic nurses are practicing what they preach in terms of patient-centered outcomes research remains uncertain. More examples from academia are required to make that determination. Academic nurses worldwide have embarked on a steep learning curve to embrace patient-centered outcomes research. This journey will require patience and a systematic strategy.

As Births Diminish and Deaths Increase, Natural Decrease becomes More Widespread in Rural America.

Even before the onset of the Covid-19 pandemic, the U.S. population growth rate last year was the lowest in 100 years. And, from 2010 to 2019 nonmetropolitan America lost population for the first time in history. Diminished natural increase was a major contributor to this and also accelerated the incidence of natural decrease (more deaths than births), particularly in rural America. Deaths exceeded births in 46 percent of all U.S. counties-a near record high. Nearly 79 percent of these natural decrease counties were nonmetropolitan. This research uses recent data and a multivariate spatial regression model to update our understanding of the growing incidence of natural decrease in both rural and urban America. In light of the mortality increase and likely fertility declines stemming from the Covid-19 pandemic, these findings have significant implications for future nonmetropolitan demographic trends.

Metropolitan Reclassification and the Urbanization of Rural America.

We highlight the paradoxical implications of decadal reclassification of U.S. counties (and America's population) from nonmetropolitan to metropolitan status between 1960 and 2017. Using data from the U.S. Census Bureau, we show that the reclassification of U.S. counties has been a significant engine of metropolitan growth and nonmetropolitan decline. Over the study period, 753-or nearly 25% of all nonmetropolitan counties-were redefined by the Office of Management and Budget (OMB) as metropolitan, shifting nearly 70 million residents from nonmetropolitan to metropolitan America by 2017. All the growth since 1970 in the metropolitan share of the U.S. population came from reclassification rather than endogenous growth in existing metropolitan areas. Reclassification of nonmetropolitan counties also had implications for drawing appropriate inferences about rural poverty, population aging, education, and economic growth. The paradox is that these many nonmetropolitan "winners"-those experiencing population and economic growth-have, over successive decades, left behind many nonmetropolitan counties with limited prospects for growth. Our study provides cautionary lessons regarding the commonplace narrative of widespread rural decline and economic malaise but also highlights the interdependent demographic fates of metropolitan and nonmetropolitan counties.

The Influence of Human Demography on Land Cover Change in the Great Lakes States, USA.

The Great Lakes region contains productive agricultural and forest lands, but it is also highly urbanized, with 32 of its 52 million residents living in nine large metropolitan areas. Urbanization of undeveloped areas may adversely affect the productivity of agricultural and forest lands, and the provision of ecosystem services. We combine demographic and remote sensing data to evaluate land cover change in the region using a two-phase statistical modeling approach that predicts the incidence and extent of land cover change for each of the region's 10,579 county subdivisions. Observed patterns are spatially uneven, and the probability of land cover change is influenced by current land use, human habitation, industry, and demographic change. Pseudo R2 values varied from 0.053 to 0.338 for the first-phase logistic models predicting the presence of land cover change; second-stage beta models predicting the rate of change were more reliable, with pseudo R2 ranging from 0.225 to 0.675. Overall, changes from agriculture or greenspace to development were much more predictable than changes from agriculture to greenspace or vice versa, and demographic variables were much more important in models predicting change to development. Although models successfully predicted the general location of land cover change, and models from before the Great Recession were useful for predicting the location but not the amount of change during the recession, fine-grained prediction remained challenging. Understanding where future changes are most probable can inform planning and policy-making, which may reduce the impact of development on resource production, environmental health, and ecosystem services.

Sprawling and diverse: The changing U.S. population and implications for public lands in the 21st Century.

Public lands are typically established in recognition of their unique ecological value, yet both ecological and social values of public lands change over time, along with human distribution and land use. These transformations are evident even in developed countries with long histories of public land management, such as the United States. The 20th Century saw dramatic changes in the American population, in distribution and in racial and ethnic diversity, leading to new challenges and new roles for public lands. Our goal with this paper is to review changing demographics and implications for terrestrial protected areas in the U.S. We overview the fundamentals of population change and data, review past trends in population change and housing growth and their impacts on public lands, and then analyze the most recent decade of demographic change (2000-2010) relative to public lands. Discussions of demographic change and public lands commonly focus on the rural West, but we show that the South is also experiencing substantial change in rural areas with public lands, including Hispanic population growth. We identify those places, rural and urban, where demographic change (2000-2010), including diversification and housing growth, coincide with public lands. Understanding the current trends and long-term demographic context for recent changes in populations can help land managers and conservation scientists mitigate the effects of residential development near public lands, serve a more diverse population, and anticipate future population changes.

The relocation bump: Memories of middle adulthood are organized around residential moves.

The lifetime temporal distribution of older adults' autobiographical memories peaks during the transitional period of late adolescence and early adulthood, a phenomenon known as the reminiscence bump. This age-specific memory enhancement suggests that transitions may provide a more general organizing structure for autobiographical memory. To test this hypothesis, we examined how older adults' memories of events that occurred between the ages of 40 and 60 were distributed around residential relocations occurring within this same time frame. The temporal distribution of memories showed a marked relocation bump around the age of the most important residential move. Although previous research has focused on the negative effects of relocation, the current findings suggest that transitions could have a positive effect on autobiographical memory. (PsycINFO Database Record

Moving Toward Integration? Effects of Migration on Ethnoracial Segregation Across the Rural-Urban Continuum.

This study analyzes the impact of migration on ethnoracial segregation among U.S. counties. Using county-level net migration estimates by age, race, and Hispanic origin from 1990-2000 and 2000-2010, we estimate migration's impact on segregation by age and across space. Overall, migration served to integrate ethnoracial groups in both decades, whereas differences in natural population change (increase/decrease) would have increased segregation. Age differences, however, are stark. Net migration of the population under age 40 reduced segregation, while net migration of people over age 60 further segregated people. Migration up and down the rural-urban continuum (including suburbanization among people of color) did most to decrease segregation, while interregional migration had only a small impact. People of color tended to move toward more predominantly white counties and regions at all ages. Migration among white young adults (aged 20-39) also decreased segregation. Whites aged 40 and older, however, showed tendencies toward white flight. Moderate spatial variation suggests that segregation is diminishing the most in suburban and fringe areas of several metropolitan areas in the Northeast and Midwest, while parts of the South, Southwest, and Appalachia show little evidence of integration.

Migration signatures across the decades: Net migration by age in U.S. counties, 1950-2010.

BACKGROUND: Migration is the primary population redistribution process in the United States. Selective migration by age, race/ethnic group, and spatial location governs population integration, affects community and economic development, contributes to land use change, and structures service needs. OBJECTIVE: Delineate historical net migration patterns by age, race/ethnic, and rural-urban dimensions for United States counties. METHODS: Net migration rates by age for all US counties are aggregated from 1950-2010, summarized by rural-urban location and compared to explore differential race/ethnic patterns of age-specific net migration over time. RESULTS: We identify distinct age-specific net migration 'signatures' that are consistent over time within county types, but different by rural-urban location and race/ethnic group. There is evidence of moderate population deconcentration and diminished racial segregation between 1990 and 2010. This includes a net outflow of Blacks from large urban core counties to suburban and smaller metropolitan counties, continued Hispanic deconcentration, and a slowdown in White counterurbanization. CONCLUSIONS: This paper contributes to a fuller understanding of the complex patterns of migration that have redistributed the U.S. population over the past six decades. It documents the variability in county age-specific net migration patterns both temporally and spatially, as well as the longitudinal consistency in migration signatures among county types and race/ethnic groups.

α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor activation protects against phencyclidine-induced caspase-3 activity by activating voltage-gated calcium channels.

Phencyclidine (PCP) is a noncompetitive, open channel blocker of the N-methyl-D-aspartate (NMDA) receptor-ion channel complex. When administered to immature animals, it is known to cause apoptotic neurodegeneration in several regions, and this is followed by olanzapine-sensitive, schizophrenia-like behaviors in late adolescence and adulthood. Clarification of its mechanism of action could yield data that would help to inform the treatment of schizophrenia. In our initial experiments, we found that α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) inhibited PCP-induced apoptosis in organotypic neonatal rat brain slices in a concentration-dependent and 6-cyano-7-nitroquinoxaline-2,3-dione-sensitive manner. Calcium signaling pathways are widely implicated in apoptosis, and PCP prevents calcium influx through NMDA receptor channels. We therefore hypothesized that AMPA could protect against this effect by activation of voltage-dependent calcium channels (VDCCs). In support of this hypothesis, pretreatment with the calcium channel blocker cadmium chloride eliminated AMPA-mediated protection against PCP. Furthermore, the L-type VDCC inhibitor nifedipine (10 µM) fully abrogated the effects of AMPA, suggesting that L-type VDCCs are required for AMPA-mediated protection against PCP-induced neurotoxicity. Whereas the P/Q-type inhibitor ω-agatoxin TK (200 nM) reduced AMPA protection by 51.7%, the N-type VDCC inhibitor ω-conotoxin (2 µM) had no effect. Decreased AMPA-mediated protection following cotreatment with K252a, a TrkB inhibitor, suggests that brain-derived neurotrophic factor signaling plays an important role. By analogy, these results suggest that activation of L-type, and to a lesser extent P/Q-type, VDCCs might be advantageous in treating conditions associated with diminished NMDAergic activity during early development.

The role of inflammation in brain cancer.

Malignant brain tumors are among the most lethal of human tumors, with limited treatment options currently available. A complex array of recurrent genetic and epigenetic changes has been observed in gliomas that collectively result in derangements of common cell signaling pathways controlling cell survival, proliferation, and invasion. One important determinant of gene expression is DNA methylation status, and emerging studies have revealed the importance of a recently identified demethylation pathway involving 5-hydroxymethylcytosine (5hmC). Diminished levels of the modified base 5hmC is a uniform finding in glioma cell lines and patient samples, suggesting a common defect in epigenetic reprogramming. Within the tumor microenvironment, infiltrating immune cells increase oxidative DNA damage, likely promoting both genetic and epigenetic changes that occur during glioma evolution. In this environment, glioma cells are selected that utilize multiple metabolic changes, including changes in the metabolism of the amino acids glutamate, tryptophan, and arginine. Whereas altered metabolism can promote the destruction of normal tissues, glioma cells exploit these changes to promote tumor cell survival and to suppress adaptive immune responses. Further understanding of these metabolic changes could reveal new strategies that would selectively disadvantage tumor cells and redirect host antitumor responses toward eradication of these lethal tumors.

A combined bioinformatics and chemoinformatics approach for developing asymmetric bivalent AMPA receptor positive allosteric modulators as neuroprotective agents.

PAMs new in town! An effective, combined bioinformatics and chemoinformatics approach was applied to the design of novel asymmetric bivalent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators (PAMs) with marked potency in vitro and efficacy in vivo for preventing neuroapoptosis. The novel chemotype could provide pharmacological probes and potential therapeutic agents for glutamatergic hypofunction and its related neurological and psychiatric disorders.

Prefrontal dopaminergic and enkephalinergic synaptic accommodation in HIV-associated neurocognitive disorders and encephalitis.

UNLABELLED: Changes in synapse structure occur in frontal neocortex with HIV encephalitis (HIVE) and may contribute to HIV-associated neurocognitive disorders (HAND). A postmortem survey was conducted to determine if mRNAs involved in synaptic transmission are perturbed in dorsolateral prefrontal cortex (DLPFC) in subjects with HIVE or HAND. Expression of the opioid neurotransmitter preproenkephalin mRNA (PENK) was significantly decreased in a sampling of 446 brain specimens from HIV-1 infected people compared to 67 HIV negative subjects. Decreased DLPFC PENK was most evident in subjects with HIVE and/or increased expression of interferon regulatory factor 1 mRNA (IRF1). Type 2 dopamine receptor mRNA (DRD2L) was decreased significantly, but not in the same set of subjects with PENK dysregulation. DRD2L downregulation occurred primarily in the subjects without HIVE or neurocognitive impairment. Subjects with neurocognitive impairment often failed to significantly downregulate DRD2L and had abnormally high IRF1 expression. CONCLUSION: Dysregulation of synaptic preproenkephalin and DRD2L in frontal neocortex can occur with and without neurocognitive impairment in HIV-infected people. Downregulation of DRD2L in the prefrontal cortex was associated with more favorable neuropsychological and neuropathological outcomes; the failure to downregulate DRD2L was significantly less favorable. PENK downregulation was related neuropathologically to HIVE, but was not related to neuropsychological outcome independently. Emulating endogenous synaptic plasticity pharmacodynamically could enhance synaptic accommodation and improve neuropsychological and neuropathological outcomes in HIV/AIDS.

Hispanic Assimilation and Fertility in New Destinations.

This paper evaluates comparative patterns of fertility in new Hispanic destinations and established gateways using pooled cross-sectional data from the 2005-2009 microdata files of the American Community Survey. Changing Hispanic fertility provides a useful indicator of cultural incorporation. Analyses show that high fertility among Hispanics has been driven in part by the Mexican-origin and other new immigrant populations (e.g., noncitizens, those with poor English language skills, etc.). However, high fertility rates among Hispanics - and Mexican-origin Hispanics in particular - cannot be explained entirely by socio-demographic characteristics that place them at higher risk of fertility. For 2005-2009, Hispanic fertility rates were 48 percent higher than fertility among whites; they were roughly 25 percent higher after accounting for differences in key social characteristics, such as age, nativity, county of origin, and education. Contrary to most previous findings of spatial assimilation among in-migrants, fertility rates among Hispanics in new destinations exceeded fertility in established gateways by 18 percent. In the multivariate analyses, Hispanics in new destinations were roughly 10 percent more likely to have had a child in the past year than those living in established gateways. Results are consistent with sub-cultural explanations of Hispanic fertility and raise new questions about the spatial patterning of assimilation and the formation of ethnic enclaves outside traditional settlement areas.

Brain-derived neurotrophic factor prevents phencyclidine-induced apoptosis in developing brain by parallel activation of both the ERK and PI-3K/Akt pathways.

Phencyclidine is an N-methyl d-aspartate receptor (NMDAR) blocker that has been reported to induce neuronal apoptosis during development and schizophrenia-like behaviors in rats later in life. Brain-derived neurotrophic factor (BDNF) has been shown to prevent neuronal death caused by NMDAR blockade, but the precise mechanism is unknown. This study examined the role of the phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways in BDNF protection of PCP-induced apoptosis in corticostriatal organotypic cultures. It was observed that BDNF inhibited PCP-induced apoptosis in a concentration-dependent fashion. BDNF effectively prevented PCP-induced inhibition of the ERK and PI-3K/Akt pathways and suppressed GSK-3beta activation. Blockade of either PI-3K/Akt or ERK activation abolished BDNF protection. Western blot analysis revealed that the PI-3K inhibitor LY294002 prevented the stimulating effect of BDNF on the PI-3K/Akt pathway, but had no effect on the ERK pathway. Similarly, the ERK inhibitor PD98059 prevented the stimulating effect of BDNF on the ERK pathway, but not the PI-3K/Akt pathway. Co-application of LY294002 and PD98059 had no additional effect on BDNF-evoked activation of Akt or ERK. However, concurrent exposure to PD98059 and LY294002 caused much greater inhibition of BDNF-evoked phosphorylation of GSK-3beta at serine 9 than did LY294002 alone. Finally, either BDNF or GSK-3beta inhibition prevented PCP-induced suppression of cyclic-AMP response element binding protein (CREB) phosphorylation. These data demonstrate that the protective effect of BDNF against PCP-induced apoptosis is mediated by parallel activation of the PI-3K/Akt and ERK pathways, most likely involves inhibition of GSK-3beta and activation of CREB.

Activation of dopamine D1 receptors blocks phencyclidine-induced neurotoxicity by enhancing N-methyl-D-aspartate receptor-mediated synaptic strength.

Early postnatal blockade of NMDA receptors by phencyclidine (PCP) causes cortical apoptosis in animals. This is associated with the development of schizophrenia-like behaviors in rats later in life. Recent studies show that the mechanism involves a loss of neurotrophic support from the phosphoinositol-3 kinase/Akt pathway, which is normally maintained by synaptic NMDA receptor activation. Here we report that activation of dopamine D1 receptors (D1R) with dihydrexidine (DHX) prevents PCP-induced neurotoxicity in cortical neurons by enhancing the efficacy of NMDAergic synapses. DHX increases serine phosphorylation of the NR1 subunit through protein kinase A activation and tyrosine phosphorylation of the NR2B subunit via Src kinase. DHX enhances recruitment of NR1 and NR2B, but not NR2A, into synapses. DHX also facilitated the synaptic response in cortical slices and this was blocked by an NR2B antagonist. DHX pre-treatment of rat pups prior to PCP on postnatal days 7, 9 and 11 inhibited PCP-induced caspase-3 activation on PN11 and deficits in pre-pulse inhibition of acoustic startle measured on PN 26-28. In summary, these data demonstrate that PCP-induced deficits in NMDA receptor function, neurotoxicity and subsequent behavioral deficits may be prevented by D1R activation in the cortex and further, it is suggested that D1R activation may be beneficial in treating schizophrenia.

Atypical anti-schizophrenic drugs prevent changes in cortical N-methyl-D-aspartate receptors and behavior following sub-chronic phencyclidine administration in developing rat pups.

We sought to determine the relationship between phencyclidine (PCP)-induced alterations in behavior and NMDAR expression in the cortex by examining the effect of anti-schizophrenic drug treatment on both. Sprague-Dawley rat pups were pretreated with risperidone or olanzapine prior to treatment with PCP on postnatal day 7 (PN7) or sub-chronically on PN7, 9, and 11. Pre-pulse inhibition (PPI) of acoustic startle was measured on PN24-26 and following a challenge dose of 4 mg/kg PCP, locomotor activity was measured on PN28-35. PCP treatment on PN7 did not cause a deficit in PPI, but did cause locomotor sensitization. This was prevented by both antipsychotics. PCP treatment on PN7 caused an up-regulation of NR1 and NR2B, which was not affected by either anti-schizophrenic drug. PCP treatment on PN7, 9, and 11 caused a deficit in PPI and a sensitized locomotor response to PCP challenge as well as an up-regulation of NR1 and NR2A, all of which were prevented by both atypical anti-schizophrenic drugs. These data support the hypothesis that sub-chronic, but not single injection PCP treatment in developing rats results in behavioral alterations that are sensitive to antipsychotic drugs and these behavioral changes observed could be related to up-regulation of cortical NR1/NR2A receptors.

Lithium protection of phencyclidine-induced neurotoxicity in developing brain: the role of phosphatidylinositol-3 kinase/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathways.

Phencyclidine (PCP) and other N-methyl-D-aspartate (NMDA) receptor antagonists have been shown to be neurotoxic to developing brains and to result in schizophrenia-like behaviors later in development. Prevention of both effects by antischizophrenic drugs suggests the validity of PCP neurodevelopmental toxicity as a heuristic model of schizophrenia. Lithium is used for the treatment of bipolar and schizoaffective disorders and has recently been shown to have neuroprotective properties. The present study used organotypic corticostriatal slices taken from postnatal day 2 rat pups to investigate the protective effect of lithium and the role of the phosphatidylinositol-3 kinase (PI-3K)/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways in PCP-induced cell death. Lithium pretreatment dose-dependently reduced PCP-induced caspase-3 activation and DNA fragmentation in layers II to IV of the cortex. PCP elicited time-dependent inhibition of the MEK/ERK and PI-3K/Akt pathways, as indicated by dephosphorylation of ERK1/2 and Akt. The proapoptotic factor glycogen synthase kinase (GSK)-3beta was also dephosphorylated at serine 9 and thus activated. Lithium prevented PCP-induced inhibition of the two pathways and activation of GSK-3beta. Furthermore, blocking either PI-3K/Akt or MEK/ERK pathway abolished the protective effect of lithium, whereas inhibiting GSK-3beta activity mimicked the protective effect of lithium. However, no cross-talk between the two pathways was found. Finally, specific GSK-3beta inhibition did not prevent PCP-induced dephosphorylation of Akt and ERK. These data strongly suggest that the protective effect of lithium against PCP-induced neuroapoptosis is mediated through independent stimulation of the PI-3K/Akt and ERK pathways and suppression of GSK-3beta activity.

The role of Akt-GSK-3beta signaling and synaptic strength in phencyclidine-induced neurodegeneration.

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) can induce positive and negative symptoms of schizophrenia in humans and related effects in rodents. PCP treatment of developing rats induces apoptotic neurodegeneration and behavioral deficits later in life that mimic some symptoms of schizophrenia. The precise mechanism of PCP-induced neural degeneration is unknown. This study used selective antagonists, siRNA, and Western analysis to investigate the role of the Akt-glycogen synthase kinase-3beta (GSK-3beta) pathway in PCP-induced neuronal apoptosis in both neuronal culture and postnatal day 7 rats. PCP administration in vivo and in vitro reduced the phosphorylation of Akt Ser427 and GSK-3beta Ser9, decreasing Akt activity and increasing GSK-3beta activity. The alteration of Akt-GSK-3beta signaling parallels the temporal profile of caspase-3 activation by PCP. Reducing GSK-3beta activity by application of selective inhibitors or depletion of GSK-3beta by siRNA attenuates caspase-3 activity and blocks PCP-induced neurotoxicity. Moreover, increasing synaptic strength by either activation of L-type calcium channels with BAY K8644 or potentiation of synaptic NMDA receptors with either a low concentration of NMDA or bicuculline plus 4-aminopyridine completely blocks PCP-induced cell death by increasing Akt phosphorylation. These neuroprotective effects are associated with activation of phosphoinositide-3-kinase-Akt signaling, and to a lesser extent, the MAPK signaling pathway. Overall, these data suggest that PCP-induced hypofunction of synaptic NMDA receptors impairs the Akt-GSK-3beta cascade, which is necessary for neuronal survival during development, and that interference with this cascade by PCP or natural factors may contribute to neural pathologies, perhaps including schizophrenia.

Postnatal phencyclidine administration selectively reduces adult cortical parvalbumin-containing interneurons.

Transient postnatal NMDA receptor blockade by phencyclidine (PCP), ketamine, or MK-801 induces developmental neuroapoptosis and adult behavioral deficits, which resemble abnormal human behaviors typically present in schizophrenia. This study tested the hypothesis that PCP-induced developmental apoptosis causes a specific deficit of GABAergic interneurons containing parvalbumin (PV), calretinin (CR), or calbindin (CB). Young adult (PND56) rats that were given a single dose of PCP (10 mg/kg) on PND7 exhibited no densitometric change of either CR or CB neurons in any brain region studied, but demonstrated a selective deficit of PV-containing neurons in the superficial layers (II-IV) of the primary somatosensory (S1), motor (M), and retrosplenial cortices, but not in the striatum (CPu) or hippocampus. Further, CR and CB neurons, which were expressed at the time of PCP administration, showed no colocalization with cellular markers of apoptosis (terminal dUTP nick-end labeling (TUNEL) of broken DNA or cleaved caspase-3), indicating that CR- and CB-containing neurons were protected from the toxic effect of PCP and survived into adulthood. This suggests that the deletion of PV neurons occurred during development, but cleaved caspase-3 showed no colocalization with BrdU, a specific marker of S-phase proliferation. These data suggest that the loss of PV-containing neurons was not due to an effect of PCP on proliferating neurons, but rather an effect on post-mitotic neurons. The developmental dependence and neuronal specificity of this effect of PCP provides further evidence that this model may be valuable in exploring the pathophysiology of schizophrenia.