Strengths and Challenges of Implementing a Learning Collaborative in the Ryan White HIV/AIDS Program.

Learning collaboratives (LCs) are a popular tool for supporting collaboration and shared learning among health programs. Many variations of LCs have been reported in the literature. However, descriptions of key LC components and implementation lack standardization, making it hard to compare and contrast different LC approaches. To advance the field's understanding of how primary elements of LCs are implemented, we describe the implementation of an LC in the Ryan White HIV/AIDS Program using a recently established taxonomy of four primary elements of LCs-innovation, social systems, communication, and time. Additionally, we explain the strengths and challenges we encountered with regard to each of these elements when implementing this LC. We then offer recommendations to others on how to leverage LC facilitators and mitigate challenges in future projects. This information can guide other programs to replicate beneficial practices and avoid pitfalls in future LC projects.

A mathematical model to estimate the state-specific impact of the Health Resources and Services Administration's Ryan White HIV/AIDS Program.

BACKGROUND: Access to and engagement in high-quality HIV medical care and treatment is essential for ending the HIV epidemic. The Health Resources and Services Administration's (HRSA) Ryan White HIV/AIDS Program (RWHAP) plays a critical role in ensuring that people living with diagnosed HIV (PLWH) are linked to and consistently engaged in high quality care and receive HIV medication in a timely manner. State variation in HIV prevalence, the proportion of PLWH served by the RWHAP, and local health care environments could influence the state-specific impact of the RWHAP. This analysis sought to measure the state-specific impact of the RWHAP on the HIV service delivery system and health outcomes for PLWH, and presents template language to communicate this impact for state planning and stakeholder engagement. METHODS AND FINDINGS: The HRSA's HIV/AIDS Bureau (HAB) and the Centers for Disease Control and Prevention's Division of HIV/AIDS Prevention (CDC DHAP) have developed a mathematical model to estimate the state-specific impact of the RWHAP. This model was parameterized using RWHAP data, HIV surveillance data, an existing CDC model of HIV transmission and disease progression, and parameters from the literature. In this study, the model was used to analyze the hypothetical scenario of an absence of the RWHAP and to calculate the projected impact of this scenario on RWHAP clients, RWHAP-funded providers, mortality, new HIV cases, and costs compared with the current state inclusive of the RWHAP. To demonstrate the results of the model, we selected two states, representing high HIV prevalence and low HIV prevalence areas. These states serve to demonstrate the functionality of the model and how state-specific results can be translated into a state-specific impact statement using template language. CONCLUSIONS: In the example states presented, the RWHAP provides HIV care, treatment, and support services to a large proportion of PLWH in each state. The absence of the RWHAP in these states could result in substantially more deaths and HIV cases than currently observed, resulting in considerable lifetime HIV care and treatment costs associated with additional HIV cases. State-specific impact statements may be valuable in the development of state-level HIV prevention and care plans or for communications with planning bodies, state health department leadership, and other stakeholders. State-specific impact statements will be available to RWHAP Part B recipients upon request from HRSA's HIV/AIDS Bureau.

U.S. Centers for Disease Control and Prevention and Health Resources and Services Administration Initiatives to Address Disparate Rates of HIV Infection in the South.

The US South accounted for 51% of annual new HIV infections, 50% of undiagnosed infections and 45% of persons with HIV infection in 2016 while comprising 38% of the population. Myriad structural and contextual factors are associated with HIV-related disparities. This paper describes initiatives and strategies conducted by the Centers for Disease Control and Prevention and Health Resources and Services Administration to identify opportunities and activities addressing the disparity of HIV diagnoses in the South. Targeted HIV prevention and care efforts can change the trajectory of outcomes along the HIV care continuum and reduce HIV-related disparities in the South.

Extracellular glutamate exposure facilitates group I mGluR-mediated epileptogenesis in the hippocampus.

Stimulation of group I mGluRs elicits several forms of translation-dependent neuronal plasticity including epileptogenesis. The translation process underlying plasticity induction is controlled by repressors including the fragile X mental retardation protein (FMRP). In the absence of FMRP-mediated repression, a condition that occurs in a mouse model (Fmr1(-/-)) of fragile X syndrome, group I mGluR-activated translation is exaggerated causing enhanced seizure propensity. We now show that glutamate exposure (10 µm for 30 min) reduced FMRP levels in wild-type mouse hippocampal slices. Downregulation of FMRP was dependent on group I mGluR activation and was blocked by a proteasome inhibitor (MG-132). Following glutamate exposure, synaptic stimulation induced prolonged epileptiform discharges with properties similar to those observed in Fmr1(-/-) preparations. In both cases, prolonged epileptiform discharges were blocked by group I mGluR antagonists (LY367385 + MPEP) and their induction was prevented by protein synthesis inhibitor (anisomycin). The results suggest that stimulation of group I mGluRs during glutamate exposure caused proteolysis of FMRP. Reduction of FMRP led to enhanced synaptic group I mGluR-mediated translation. Elevated translation facilitated the recruitment of group I mGluR-mediated prolonged epileptiform discharges.

Persistent receptor activity underlies group I mGluR-mediated cellular plasticity in CA3 neuron.

Plastic changes in cortical activities induced by group I metabotropic glutamate receptor (mGluR) stimulation include epileptogenesis, expressed in vitro as the conversion of normal neuronal activity to persistent, prolonged synchronized (ictal) discharges. At present, the mechanism that maintains group I mGluR-induced plasticity is not known. We examined this issue using hippocampal slices from guinea pigs and mice. Agonist [(S)-3,5-dihydroxyphenylglycine (DHPG), 30-50 µm)] stimulation of group I mGluRs induces persistent prolonged synchronized (ictal-like) discharges in CA3 that are associated with three identified excitatory cellular responses-suppression of spike afterhyperpolarizations, activation of a voltage-dependent cationic current, and increase in neuronal input resistance. Persistent prolonged synchronized discharges and the underlying excitatory cellular responses maintained following induction were reversibly blocked by mGluR1 antagonists [(S)-+-α-amino-4-carboxy-2-methylbenzeneacetic acid (LY 367385), 50, 100 µm; CPCCOEt (hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester, 100 µm], and to a lesser extent by the mGluR5 antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride, 50 µm]. Activation of persistent cellular responses to DHPG were unaffected by tetrodotoxin (0.5-1 µm) or perfusion with low Ca(2+)(0.2 mm)-Mn(2+)(0.5 mm) media-conditions that suppress endogenous glutamate release. The pharmacological profile of the blocking action of the group I mGluR antagonist MCPG [(RS)-α-methyl-4-carboxyphenylglycine, 50-500 µm] on persistent cellular responses was different from that on cellular responses directly activated by DHPG. These data indicate that transient stimulation of group I mGluRs alters receptor properties, rendering them persistently active in the absence of applied agonist or endogenous glutamate activation. Persistent receptor activities, primarily involving mGluR1, maintain excitatory cellular responses and emergent prolonged synchronized discharges.

Cellular plasticity for group I mGluR-mediated epileptogenesis.

Stimulation of group I metabotropic glutamate receptors (mGluRs) by the agonist (S)-dihydroxyphenylglycine in the hippocampus transforms normal neuronal activity into prolonged epileptiform discharges. The conversion is long lasting in that epileptiform discharges persist after washout of the inducing agonist and serves as a model of epileptogenesis. The group I mGluR model of epileptogenesis took on special significance because epilepsy associated with fragile X syndrome (FXS) may be caused by excessive group I mGluR signaling. At present, the plasticity mechanism underlying the group I mGluR-mediated epileptogenesis is unknown. I(mGluR(V)), a voltage-gated cationic current activated by group I mGluR agonists in CA3 pyramidal cells in the hippocampus, is a possible candidate. I(mGluR(V)) activation is associated with group I mGluR agonist-elicited epileptiform discharges. For I(mGluR(V)) to play a role in epileptogenesis, long-term activation of the current must occur after group I mGluR agonist exposure or synaptic stimulation. We observed that I(mGluR(V)), once induced by group I mGluR agonist stimulation in CA3 pyramidal cells, remained undiminished for hours after agonist washout. In slices prepared from FXS model mice, repeated stimulation of recurrent CA3 pyramidal cell synapses, effective in eliciting mGluR-mediated epileptiform discharges, also induced long-lasting I(mGluR(V)) in CA3 pyramidal cells. Similar to group I mGluR-mediated prolonged epileptiform discharges, persistent I(mGluR(V)) was no longer observed in preparations pretreated with inhibitors of tyrosine kinase, of extracellular signal-regulated kinase 1/2, or of mRNA protein synthesis. The results indicate that I(mGluR(V)) is an intrinsic plasticity mechanism associated with group I mGluR-mediated epileptogenesis.

Signaling mechanisms underlying group I mGluR-induced persistent AHP suppression in CA3 hippocampal neurons.

Activation of group I metabotropic glutamate receptors (mGluRs) leads to a concerted modulation of spike afterpotentials in guinea pig hippocampal neurons including a suppression of both medium and slow afterhyperpolarizations (AHPs). Suppression of AHPs may be long-lasting, in that it persists after washout of the agonist. Here, we show that persistent AHP suppression differs from short-term, transient suppression in that distinct and additional signaling processes are required to render the suppression persistent. Persistent AHP suppression followed DHPG application for 30 min, but not DHPG application for 5 min. Persistent AHP suppression was temperature dependent, occurring at 30-31 degrees C, but not at 25-26 degrees C. Preincubation of slices in inhibitors of protein synthesis (cycloheximide or anisomycin) prevented the persistent suppression of AHPs by DHPG. Similarly, preincubation of slices in an inhibitor of p38 MAP kinase (SB 203580) prevented persistent AHP suppression. In contrast, a blocker of p42/44 MAP kinase activation (PD 98059) had no effect on persistent AHP suppression. Additionally, we show that the mGluR5 antagonist MPEP, but not the mGluR1 antagonist LY 367385, prevented DHPG-induced persistent AHP suppression. Thus persistent AHP suppression by DHPG in hippocampal neurons requires activation of mGluR5. In addition, activation of p38 MAP kinase signaling and protein synthesis are required to impart persistence to the DHPG-activated AHP suppression.

Gap junctions on hippocampal mossy fiber axons demonstrated by thin-section electron microscopy and freeze fracture replica immunogold labeling.

Gap junctions have been postulated to exist between the axons of excitatory cortical neurons based on electrophysiological, modeling, and dye-coupling data. Here, we provide ultrastructural evidence for axoaxonic gap junctions in dentate granule cells. Using combined confocal laser scanning microscopy, thin-section transmission electron microscopy, and grid-mapped freeze-fracture replica immunogold labeling, 10 close appositions revealing axoaxonic gap junctions ( approximately 30-70 nm in diameter) were found between pairs of mossy fiber axons ( approximately 100-200 nm in diameter) in the stratum lucidum of the CA3b field of the rat ventral hippocampus, and one axonal gap junction ( approximately 100 connexons) was found on a mossy fiber axon in the CA3c field of the rat dorsal hippocampus. Immunogold labeling with two sizes of gold beads revealed that connexin36 was present in that axonal gap junction. These ultrastructural data support computer modeling and in vitro electrophysiological data suggesting that axoaxonic gap junctions play an important role in the generation of very fast (>70 Hz) network oscillations and in the hypersynchronous electrical activity of epilepsy.

Modulation of afterpotentials and firing pattern in guinea pig CA3 neurones by group I metabotropic glutamate receptors.

Activation of group I metabotropic glutamate receptors (mGluRs) alters the firing patterns of individual CA3 pyramidal cells in guinea pig hippocampal slices. Following addition of the selective group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) to the bathing solution, pyramidal cells initially firing regular, single action potentials switched to firing in brief bursts. This change in firing pattern resulted from modulation by mGluRs of three afterpotentials. The medium and slow afterhyperpolarizations (m and sAHPs) were blocked by mGluR activation. In addition, a voltage-dependent after depolarization (ADP) was induced. Recordings from mutant mice lacking phospholipase C(beta1) (PLC(beta1)) showed that mGluR block of the mAHP, as well as induction of the ADP, depended on the phosphoinositide hydrolysis pathway. Block of the sAHP, however, was partly spared in the absence of PLC(beta1). Optical recordings of post spike intracellular Ca(2+) rises showed that mGluR block of the AHP was not mediated by alterations of action potential-associated Ca(2+) increases (Ca(2+) transients). The mGluR induction of an ADP was also independent of any changes in the Ca(2+) transient. The mGluR-induced change in the firing pattern of hippocampal pyramidal cells is thus the result of multiple mechanisms, including suppression of both m and sAHPs and activation of an ADP, that act together to produce a specific excitatory effect, namely an increased likelihood that a single action potential will lead immediately to one or more following action potentials.

Trends and responsiveness in national resource allocation for needed HIV services: a five year (1996-2000) analysis.

A recent study conducted by the Institute of Medicine concluded that there are approximately 1,200 to 1,400 avoidable deaths per year in the U.S. among people living with HIV (PLWH) who do not have health insurance (Institute of Medicine, 2002). The Ryan White Comprehensive AIDS Resources Emergency (CARE) Act was passed by the U.S. Congress in 1990 to provide funding for community-based HIV care services for uninsured and underinsured PLWH--the only Federal program to provide such funding. There is substantial local autonomy in the allocation of CARE Act funds, with planning processes that take place in both States and metropolitan areas. The purpose of this study is to examine trends in the allocation of such funds from 1996 through 2000, the first five years during which effective antiretroviral medications were available for HIV. The study also considers whether these trends were responsive to the evolving modalities of care and the service needs of a changing population of PLWH.

Delivering HIV services to vulnerable populations: an evaluation and research agenda.

In May 2000, the HIV/AIDS Bureau of the Health Resources and Services Administration convened HIV experts from throughout the country to identify new and emerging areas of research needed to guide policy and programmatic decisions on HIV service delivery to vulnerable populations. This article describes the process used to develop an evaluation/research agenda, discusses key findings and recommendations of the conference, and proposes a set of principles to guide the design and conduct of future investigations. Conference participants identified nine major evaluation/research themes that span the continuum of HIV behavioral prevention services and treatment. They recommended focusing future research on questions relevant to populations experiencing rapid rates of increase in HIV infection (for example, women, people of color, and adolescents and young adults) and considering explanatory factors at multiple levels of analysis (individual, clinician, organization, service delivery system, and environment).

Activation of group I mGluRs elicits different responses in murine CA1 and CA3 pyramidal cells.

The group I metabotropic glutamate receptor agonist DHPG has been shown to produce two major effects on CA3 pyramidal cells at rest: a reduction in the background conductance and an activation of a voltage-gated inward current (I(mGluR(V))). Both effects contribute to depolarising CA3 pyramidal cells and the latter has been implicated in eliciting prolonged epileptiform population bursts. We observed that DHPG-induced depolarisation was smaller in CA1 pyramidal cells than in CA3 cells. Voltage clamp studies revealed that while DHPG elicited I(mGluR(V)) in CA3 pyramidal cells, such a response was absent in CA1 pyramidal cells. Both mGluR1 and mGluR5 have been localised in CA3 pyramidal cells, whereas only mGluR5 has been detected in CA1 pyramidal cells. Using mGluR1 knockout mice, we evaluated whether the absence of an I(mGluR(V)) response can be correlated with the absence of mGluR1. In these experiments, DHPG failed to elicit I(mGluR(V)) in CA3 pyramidal cells. This suggests that the smaller depolarising effects of DHPG on wild-type CA1 pyramidal cells is caused, at least in part, by the absence of I(mGluR(V)) in these cells and that the difference in the responses of CA1 and CA3 cells may be attributable to the lack of mGluR1 in CA1 pyramidal cells.