Outcomes of Pediatric to Adult Health Care Transition Interventions: An Updated Systematic Review.

PROBLEM: A previous systematic review found that health care transition (HCT) interventions result in positive outcomes related to population health, patient experience of care, and utilization. Since its publication, new national statistics, updated professional guidance, and a growing body of published literature on HCT have prompted the need for an updated systematic review that aims to examine outcomes of the latest pediatric-to-adult HCT interventions. ELIGIBILITY CRITERIA: Eligible studies were published in English between May 2016 and December 2018, described HCT interventions for youth moving from pediatric to adult outpatient health care, quantitative in design, and peer-reviewed. SAMPLE: Nineteen articles from a literature search of CINAHL, OVID Medline, PubMed, Scopus, Web of Science were included in this review. RESULTS: All included studies examined youth with special health care needs. Most of the positive outcomes identified were related to population health, followed by improvements in utilization. All studies mentioned transfer assistance, most described transition planning supports, and almost half reported on integration into adult care. CONCLUSIONS: This review strengthens the evidence that a structured HCT process for youth with special health care needs can show improvements in adherence to care, disease-specific measures, quality of life, self-care skills, satisfaction with care, health care utilization, and HCT process of care. IMPLICATIONS: Future research studies should utilize interventions that incorporate all HCT components (planning, transfer, and integration) and assess provider experience of care as well as cost of care.

Effects of N-methyl-d-aspartate receptor (NMDAr) uncompetitive antagonists in a delay discounting paradigm using a concurrent-chains procedure.

Impulsive choice is often assessed in rodents using a delay discounting (DD) paradigm in which the delay to a large reinforcer (LR) increases across the session. This procedure allows one to test the effects of pharmacological manipulations within a single session. Because discounting is influenced by sensitivity to reinforcer magnitude (SRM) and sensitivity to delayed reinforcement (SDR), applying quantitative analyses (e.g., fitting hyperbolic function) is important for determining the precise behavioral mechanisms being altered following drug administration. One caveat to this approach is that observing increases in SMR/SDR can be difficult (e.g., most rats choose the LR when its delivery is immediate, whereas some rats may show exclusive preference for the small reinforcer [SR] when a delay on the LR is imposed). We utilized a variant of a concurrent-chains procedure in which rats (n = 8) could not show exclusive preference for either reinforcer, thus allowing one to observe increases/decreases in responding at each delay. The NMDAr antagonists MK-801 (0, 0.003, 0.01, 0.03 mg/kg), ketamine (0, 1.0, 5.0, 10.0 mg/kg), and memantine (0, 2.5, 5.0, 7.5 mg/kg) were administered following baseline training because this receptor has recently been implicated in DD. MK-801 (0.03 mg/kg) decreased SRM and SDR. Memantine (7.5 mg/kg) decreased SRM only. These results show that this variant of the concurrent-chains procedure can be used to study the effects of pharmacological manipulations on distinct aspects of DD.

Effects of N-methyl-D-aspartate receptor ligands on sensitivity to reinforcer magnitude and delayed reinforcement in a delay-discounting procedure.

RATIONALE: The N-methyl-D-aspartate (NMDA) receptor has been recently identified as an important mediator of impulsive choice, as assessed in delay discounting. Although discounting is independently influenced by sensitivity to reinforcer magnitude and delayed reinforcement, few studies have examined how NMDA receptor ligands differentially affect these parameters. OBJECTIVES: The current study examined the effects of various NMDA receptor ligands on sensitivity to reinforcer magnitude and delayed reinforcement in a delay-discounting procedure. METHODS: Following behavioral training, rats received treatments of the following NMDA receptor ligands: the uncompetitive antagonists ketamine (0, 1.0, 5.0, or 10.0 mg/kg; i.p.), MK-801 (0, 0.003, 0.01, or 0.03 mg/kg; s.c.), and memantine (0, 2.5, 5.0, or 10.0 mg/kg; i.p.), the competitive antagonist CGS 19755 (0, 5.0, 10.0, or 20.0 mg/kg; s.c.), the non-competitive NR2B subunit-selective antagonist ifenprodil (0, 1.0, 3.0, or 10.0 mg/kg; i.p), and the partial agonist D-cycloserine (0, 3.25, 15.0, or 30.0 mg/kg; s.c.). RESULTS: When an exponential model was used to describe discounting, CGS 19755 (5.0 mg/kg) increased impulsive choice without altering sensitivity to reinforcer magnitude. Conversely, ketamine (10.0 mg/kg), memantine (5.0 mg/kg), and ifenprodil (10.0 mg/kg) decreased sensitivity to reinforcer magnitude without altering impulsive choice. MK-801 and D-cycloserine did not alter delay-discounting performance, although two-way ANOVA analyses indicated D-cycloserine (15.0 mg/kg) decreased impulsive choice. CONCLUSIONS: The behavioral changes observed in delay discounting following administration of NMDA receptor antagonists do not always reflect an alteration in impulsive choice. These results emphasize the utility in employing quantitative methods to assess drug effects in delay discounting.

Effects of Group I metabotropic glutamate receptor antagonists on sensitivity to reinforcer magnitude and delayed reinforcement in a delay-discounting task in rats: Contribution of delay presentation order.

Metabotropic glutamate receptor 1 (mGluR1) blockade has been shown to decrease impulsive choice, as measured in delay discounting. However, several variables are known to influence an animal's discounting, including sensitivity to delayed reinforcement and sensitivity to reinforcer magnitude. The goal of this experiment was to determine the effects of mGluR1, as well as mGluR5, antagonism on these parameters. Forty Sprague Dawley rats were trained in delay discounting, in which consistently choosing a small, immediate reward reflects impulsive choice. For half of the rats, the delay to the large reinforcer increased across blocks of trials, whereas the delay decreased across the session for half of the rats. Following training, half of the rats received injections of the mGluR1 antagonist JNJ 16259685 (JNJ; 0, 0.1, 0.3, or 1.0mg/kg; i.p), and half received injections of the mGluR5 antagonist MPEP (0, 1.0, 3.0, or 10.0mg/kg; i.p.). Administration of JNJ increased sensitivity to delayed reinforcement (i.e., promoted impulsive choice), regardless of which schedule was used. However, the order in which delays were presented modulated the effects of JNJ on sensitivity to reinforcer magnitude. Specifically, JNJ decreased sensitivity to reinforcer magnitude in rats trained on the descending schedule only. MPEP did not alter sensitivity to reinforcer magnitude or sensitivity to delayed reinforcement. These results show that mGluR1 is an important mediator of impulsive choice, and they provide further evidence that delay order presentation is an important variable that influences drug effects in delay discounting.

Effects of NMDA receptor antagonists on probability discounting depend on the order of probability presentation.

Risky decision making can be measured using a probability-discounting procedure, in which animals choose between a small, certain reinforcer and a large, uncertain reinforcer. Recent evidence has identified glutamate as a mediator of risky decision making, as blocking the N-methyl-d-aspartate (NMDA) receptor with MK-801 increases preference for a large, uncertain reinforcer. Because the order in which probabilities associated with the large reinforcer can modulate the effects of drugs on choice, the current study determined if NMDA receptor ligands alter probability discounting using ascending and descending schedules. Sixteen rats were trained in a probability-discounting procedure in which the odds against obtaining the large reinforcer increased (n=8) or decreased (n=8) across blocks of trials. Following behavioral training, rats received treatments of the NMDA receptor ligands MK-801 (uncompetitive antagonist; 0, 0.003, 0.01, or 0.03mg/kg), ketamine (uncompetitive antagonist; 0, 1.0, 5.0, or 10.0mg/kg), and ifenprodil (NR2B-selective non-competitive antagonist; 0, 1.0, 3.0, or 10.0mg/kg). Results showed discounting was steeper (indicating increased risk aversion) for rats on an ascending schedule relative to rats on the descending schedule. Furthermore, the effects of MK-801, ketamine, and ifenprodil on discounting were dependent on the schedule used. Specifically, the highest dose of each drug decreased risk taking in rats in the descending schedule, but only MK-801 (0.03mg/kg) increased risk taking in rats on an ascending schedule. These results show that probability presentation order modulates the effects of NMDA receptor ligands on risky decision making.

Religiosity in a hemodialysis population and its relationship to satisfaction with medical care, satisfaction with life, and adherence.

BACKGROUND: The religious beliefs and spirituality of patients on hemodialysis (HD) therapy have not been studied extensively. Studies of the dialysis population seem to indicate that religion may be associated with increased patient satisfaction with life and increased levels of social support. METHODS: Using multiple religiosity scales and scales to assess patient satisfaction with life and social support, we studied the relationship between religiosity and medical and/or social factors and adherence to treatment in 74 HD patients. RESULTS: High scores on the Intrinsic Religiosity Scale were associated strongly with high scores on the Satisfaction With Life Scale, whereas age and high Organizational Religious Activity Scale scores were associated strongly with high scores on the Satisfaction With Medical Care Scale. Older age was associated strongly with increased adherence. No relationship existed between religiosity and adherence in our population. CONCLUSION: Religious beliefs are related strongly to measures of satisfaction with life, whereas religious behaviors are related to satisfaction with medical care. Age is the single most important demographic factor associated with adherence. Because of the complex nature of religiosity, additional investigation is in order.

Activated extracellular signal-regulated kinases are necessary and sufficient to initiate tubulogenesis in renal tubular MDCK strain I cell cysts.

A classic in vitro model of renal cyst and tubule formation utilizes the Madin-Darby canine kidney (MDCK) cell line, of which two strains exist. Most cyst and tubule formation studies that utilized MDCK cells have been performed with MDCK strain II cells. MDCK strain II cells form hollow cysts in a three-dimensional collagen matrix over 10 days and tubulate in response to hepatocyte growth factor, which increases levels of active (phosphorylated) ERK1/2. In this study, we demonstrate that MDCK strain I cells also form cysts when grown in a collagen matrix; however, MDCK strain I cell cysts spontaneously initiate the primary steps in tubulogenesis. Analysis of time-lapse microscopy of both MDCK strain I and strain II cell cysts during the initial stages of tubulogenesis demonstrates a highly dynamic process with cellular extensions and retractions occurring rapidly and continuously. MDCK strain I cell cysts can spontaneously initiate tubulogenesis mainly because of relatively higher levels of active ERK in MDCK strain I, compared with strain II, cells. The presence of either of two distinct inhibitors of ERK activation (UO126 and PD09059) prevents tubulogenesis from occurring spontaneously in MDCK strain I cell cysts and, in response to hepatocyte growth factor, in strain II cell cysts. The difference between MDCK strain I and strain II cell lines is likely explained by differing embryological origins, with strain I cells being of collecting duct, and hence ureteric bud, origin. Ureteric bud cells also have high levels of active ERK and spontaneously tubulate in our in vitro collagen gel system, with tubulogenesis inhibited by UO126 and PD09059. These results suggest that a seminal event in kidney development may be the activation of ERK in the mesonephric duct/ureteric bud cells destined to form the collecting tubules.

The Rho family of small GTPases is involved in epithelial cystogenesis and tubulogenesis.

BACKGROUND: Epithelial cyst and tubule formation represent critical processes for the development of many mammalian organs and involve transient, highly choreographed changes in cell polarity. The Rho family of small GTPases, whose prototypes are RhoA, Rac1, and Cdc42, regulate many biologic processes, including cell polarization and morphogenesis. The exocyst is a conserved eight-subunit protein complex involved in the biogenesis of polarity; in yeast, it is a downstream effector for several Rho family proteins, and, in mammals, plays a central role in cystogenesis and tubulogenesis. METHODS: Inducible cell lines expressing mutant forms of RhoA, Rac1, and Cdc42 and an in vitro model of cystogenesis and tubulogenesis were used to examine the effects of Rho family proteins on cyst and tubule formation. A series of pulse-chase assays, using basolateral, apical, and secretory proteins, were performed to examine the synthesis and membrane trafficking profile of the various Rho family mutant proteins. RESULTS: We show that expression of mutant RhoA, Rac1, and Cdc42 proteins all result in abnormal cyst and tubule formation. Furthermore, with respect to cystogenesis and tubulogenesis, the phenotypic effects of expressing each mutant Rho family protein are different. Specifically, cyst and, therefore, tubule formation is completely inhibited in the presence of constitutively active RhoA and tubulogenesis is inhibited in the presence of dominant negative Rac1. Reversal of cyst polarity is seen in the presence of dominant negative RhoA, dominant negative Rac1, and both dominant negative and constitutively active Cdc42. The series of synthesis and delivery assays, using basolateral, apical, and secretory proteins, revealed that Rho family mutant proteins display an exocyst-like trafficking profile. CONCLUSION: The differential effects suggest that RhoA, Rac1, and Cdc42 all act to control cyst and tubule formation and may act in concert to control these higher-order processes. The exocyst-like membrane trafficking profile displayed by the Rho family mutant proteins raises the possibility that Rho family proteins interact, either directly or indirectly, with the exocyst to control cyst and tubule formation.

The exocyst localizes to the primary cilium in MDCK cells.

Primary cilia play a role in the maintenance of tubular epithelial differentiation and ciliary dysfunction can result in abnormal cyst formation, such as occurs in autosomal dominant polycystic kidney disease (ADPKD). We previously showed that the exocyst, an eight-protein complex involved in the biogenesis of polarity from yeast to mammals, is centrally involved in cyst formation [Mol. Biol. Cell. 11 (2000) 4259]. Here we show that the exocyst complex localizes to the primary cilium in Madin-Darby canine kidney (MDCK) tubular epithelial cells. We further show that the exocyst is overexpressed in both cell lines and primary cell cultures of ADPKD origin, suggesting that the exocyst may be involved in the pathogenesis of ADPKD.

Gene expression alterations during HGF-induced dedifferentiation of a renal tubular epithelial cell line (MDCK) using a novel canine DNA microarray.

Hepatocyte growth factor (HGF) elicits a broad spectrum of biological activities, including epithelial cell dedifferentiation. One of the most widely used and best-studied polarized epithelial cell lines is the Madin-Darby canine kidney (MDCK) cell line. Here, we describe and validate the early response of polarized monolayers of MDCK cells stimulated with recombinant HGF using a novel canine DNA microarray designed to query 12,473 gene sequences. In our survey, eight genes previously implicated in the HGF signaling pathway were differentially regulated, demonstrating that the system was responsive to HGF. Also identified were 117 genes not previously known to be involved in the HGF pathway. The results were confirmed by real-time PCR or Western blot analysis for 38 genes. Of particular interest were the large number of differentially regulated genes encoding small GTPases, proteins involved in endoplasmic reticulum translation, proteins involved in the cytoskeleton, the extracellular matrix, and the hematopoietic and prostaglandin systems.