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Addressing missed opportunities for vaccination requires a nuanced and context-specific approach. The five-step P-Process provides a robust framework to develop a clearly defined strategy that addresses social and behavioral drivers, integrates into existing health delivery systems, and facilitates collaboration with local experts. This approach allows teams to design, implement, monitor, and evaluate strategies to address public health issues. However, its specific application in vaccination communication programs remains relatively underexplored and under-documented. Our team designed a multi-pronged communication intervention aimed at enhancing vaccine uptake among hospitalized children in two tertiary hospitals in India and Nigeria. In the Inquiry stage, we conducted in-depth interviews with caregivers of hospitalized children to assess barriers to vaccination in a hospital setting. In the Strategic Development stage, we developed a blueprint for activities, identifying target audiences and communication channels and developing implementation plans. During the Create and Test stage, we brought together a range of stakeholders to co-develop a communication intervention through human-centered design workshops, after which we piloted the materials in both hospitals. We then Mobilized and Monitored progress of the activities to identify potential gaps that our materials did not initially address. Lastly, in the Evaluate and Evolve stage, we conducted in-depth interviews with healthcare workers and caregivers to measure outcomes and assess the impact on caregivers' decisions to vaccinate their hospitalized children. By following the P-Process for the design, caregivers reported that many of their concerns about vaccines were alleviated, and HCWs reported that they were able to communicate with caregivers more effectively about vaccination. By harnessing the power of the P-Process, researchers can forge a context-specific path towards impactful vaccination communication interventions, one step at a time.
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Global health research has traditionally been rooted in colonialism, with some investigators in high-income countries leading and managing research and investigators in low- and middle-income countries serving as implementing partners. The Community Health Worker-Led Intervention for Vaccine Information and Confidence (CIVIC) Project, conducted in India and led jointly by India- and US-based investigators, leveraged web-based platforms to facilitate a more horizontal, inclusive, and balanced approach to partnerships between researchers and the community. Using web-based platforms to conduct research was found to be an effective strategy to engage researchers at all levels and combat systemic barriers associated with in-person activities such as power, economic, social, and gender dynamics. Connecting online for research meetings created a more equitable environment for community members to engage meaningfully with research. Further, by conducting research through web-based platforms, we found that we were able to strengthen the diversity of participants, provide a space for more marginalized groups to speak up, and minimize logistical barriers to attendance. Harnessing web-based approaches in research provides a pathway toward opportunities to promote equity and contribute to the decolonization of global health spaces.
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Agentes Comunitarios de Salud , Salud Global , Humanos , Renta , India , InternetRESUMEN
BACKGROUND: Although immunization is one of the most successful public health interventions, vaccine hesitancy and the COVID-19 pandemic have strained health systems, contributing to global reductions in immunization coverage. Existing literature suggests that involving community members in vaccine interventions has been beneficial, but efforts to facilitate community ownership to motivate vaccine acceptance have been limited. METHODS: Our research leveraged community-based participatory research to closely involve the community from conception to implementation of an intervention to facilitate vaccine acceptance in Mewat District in Haryana, an area in India with extremely low vaccination coverage. Through the development of a community accountability board, baseline data collection on vaccination barriers and facilitators, and two human-centered design workshops, our team co-created a six-pronged intervention with community leaders and community health workers. This intervention included involving religious leaders in vaccine discussions, creating pamphlets of local vaccine champions for dissemination to parent and child caregivers, creating short videos of local leaders advocating for vaccines, implementing communication training exercises for community health workers, and implementing strategies to strengthen coordination between health workers and supervisors. RESULTS: Post-intervention data suggested parents and child caregivers had improvements in knowledge of the purpose of vaccines and side effects of vaccines. They noted that the involvement of religious leaders was beneficial, they were more willing to travel to vaccinate their children, and they had fewer non-logistical reasons to refuse vaccination services. Interviews with community leaders and community health workers who were involved in the creation of the intervention suggested that they experienced higher levels of ownership, they were better equipped to address community concerns, and that vaccine misinformation decreased in the post-intervention period. CONCLUSION: Through this unique intervention to strengthen vaccine uptake that incorporated the needs, interests, and expertise of local community members, we developed a community-driven approach to strengthen vaccine acceptance in a population with low uptake. This comprehensive approach is essential to amplify local voices, identify local concerns and advocates, and leverage bottom-up strategies to co-design successful interventions to facilitate long-term change.
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BACKGROUND: Peripheral nerve interfaces have emerged as alternative solutions for a variety of therapeutic and performance improvement applications. The Defense Advanced Research Projects Agency (DARPA) has widely invested in these interfaces to provide motor control and sensory feedback to prosthetic limbs, identify non-pharmacological interventions to treat disease, and facilitate neuromodulation to accelerate learning or improve performance on cognitive, sensory, or motor tasks. In this commentary, we highlight some of the design considerations for optimizing peripheral nerve interfaces depending on the application space. We also discuss the ethical considerations that accompany these advances.
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Miembros Artificiales , Retroalimentación Sensorial , Nervios Periféricos , PrescripcionesRESUMEN
Ejaculation is controlled by coordinated and rhythmic contractions of bulbospongiosus (BSM) and ischiocavernosus muscles. Motoneurons that innervate and control BSM contractions are located in the dorsomedial portion of the ventral horn in the L(5-6) spinal cord termed the dorsomedial (DM) nucleus. We characterized intrinsic properties of DM motoneurons as well as synaptic inputs from the dorsal gray commissure (DGC). Electrical stimulation of DGC fibers elicited fast inhibitory and excitatory responses. In the presence of glutamate receptor antagonists, both fast GABAergic as well as glycinergic inhibitory postsynaptic potentials (IPSPs) were recorded. No slow GABA(B)-mediated inhibition was evident. In the presence of GABA(A) and glycine receptor antagonists, DGC stimulation elicited fast glutamatergic excitatory responses that were blocked by application of CNQX. Importantly, a slow depolarization (timescale of seconds) was routinely observed that sufficiently depolarized the DM motoneurons to fire "bursts" of action potentials. This slow depolarization was elicited by a range of stimulus train frequencies and was insensitive to glutamate receptor antagonists (CNQX and d-APV). The slow depolarization was accompanied by an increase in membrane resistance with an extrapolated reversal potential near the K(+) Nernst potential. It was mediated by the combination of the block of a depolarization-activated K(+) current and the activation of a QX-314-sensitive cation current. These results demonstrate that fast synaptic responses in DM motoneurons are mediated primarily by glutamate, GABA, and glycine receptors. In addition, slow nonglutamatergic excitatory postsynaptic potentials (EPSPs), generated through DGC stimulation, can elicit burstlike responses in these neurons.
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Eyaculación/fisiología , Neuronas Motoras/fisiología , Músculo Esquelético/inervación , Médula Espinal/fisiología , Sinapsis/fisiología , 2-Amino-5-fosfonovalerato/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Estimulación Eléctrica , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/fisiología , Masculino , Neuronas Motoras/efectos de los fármacos , Músculo Esquelético/fisiología , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Médula Espinal/efectos de los fármacos , Sinapsis/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
GABAergic dysfunction is implicated in hippocampal deficits of the Ts65Dn mouse model of Down syndrome (DS). Since Ts65Dn mice overexpress G-protein coupled inward-rectifying potassium (GIRK2) containing channels, we sought to evaluate whether increased GABAergic function disrupts the functioning of hippocampal circuitry. After confirming that GABA(B)/GIRK current density is significantly elevated in Ts65Dn CA1 pyramidal neurons, we compared monosynaptic inhibitory inputs in CA1 pyramidal neurons in response to proximal (stratum radiatum; SR) and distal (stratum lacunosum moleculare; SLM) stimulation of diploid and Ts65Dn acute hippocampal slices. Synaptic GABA(B) and GABA(A) mediated currents evoked by SR stimulation were generally unaffected in Ts65Dn CA1 neurons. However, the GABA(B)/GABA(A) ratios evoked by stimulation within the SLM of Ts65Dn hippocampus were significantly larger in magnitude, consistent with increased GABA(B)/GIRK currents after SLM stimulation. These results indicate that GIRK overexpression in Ts65Dn has functional consequences which affect the balance between GABA(B) and GABA(A) inhibition of CA1 pyramidal neurons, most likely in a pathway specific manner, and may contribute to cognitive deficits reported in these mice.
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Región CA1 Hipocampal/fisiología , Modelos Animales de Enfermedad , Síndrome de Down/fisiopatología , Potenciales Postsinápticos Inhibidores/fisiología , Inhibición Neural/genética , Animales , Síndrome de Down/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/biosíntesis , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Transgénicos , Técnicas de Cultivo de Órganos , Receptores de GABA-A/fisiología , Receptores de GABA-B/fisiología , Transducción de Señal/genéticaRESUMEN
The conventional view of neurons is that synaptic inputs are integrated on a timescale of milliseconds to seconds in the dendrites, with action potential initiation occurring in the axon initial segment. We found a much slower form of integration that leads to action potential initiation in the distal axon, well beyond the initial segment. In a subset of rodent hippocampal and neocortical interneurons, hundreds of spikes, evoked over minutes, resulted in persistent firing that lasted for a similar duration. Although axonal action potential firing was required to trigger persistent firing, somatic depolarization was not. In paired recordings, persistent firing was not restricted to the stimulated neuron; it could also be produced in the unstimulated cell. Thus, these interneurons can slowly integrate spiking, share the output across a coupled network of axons and respond with persistent firing even in the absence of input to the soma or dendrites.
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Potenciales de Acción/fisiología , Axones/fisiología , Hipocampo/fisiología , Interneuronas/fisiología , Animales , Corteza Cerebral/fisiología , Dendritas/fisiología , Ratones , Ratones Transgénicos , Red Nerviosa/fisiología , Técnicas de Placa-Clamp , Sinapsis/fisiologíaRESUMEN
Down syndrome (DS) results from the presence of an extra copy of genes on the long-arm of chromosome 21. Aberrant expression of these trisomic genes leads to widespread neurological changes that vary in their severity. However, how the presence of extra genes affects the physiological and behavioral phenotypes associated with DS is not well understood. The most likely cause of the complex DS phenotypes is the overexpression of dosage-sensitive genes. However, other factors, such as the complex interactions between gene products as proteins and noncoding RNAs, certainly play significant roles contributing to the spectrum of severity. Here we will review evidence regarding how the overexpression of one particular gene encoding for G-protein-activated inward rectifying potassium type 2 (GIRK2) channel subunit and its coupling to GABA(B) receptors may contribute to a range of mental and functional disabilities in DS.
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Síndrome de Down/metabolismo , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Receptores de GABA-B/metabolismo , Transducción de Señal , Animales , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/metabolismo , Síndrome de Down/complicaciones , Síndrome de Down/patología , Hipocampo/metabolismo , Hipocampo/patología , HumanosRESUMEN
Over-inhibition is thought to be one of the underlying causes of the cognitive deficits in Ts65Dn mice, the most widely used model of Down syndrome. We found a direct link between gene triplication and defects in neuron production during embryonic development. These neurogenesis defects led to an imbalance between excitatory and inhibitory neurons and to increased inhibitory drive in the Ts65Dn forebrain. We discovered that Olig1 and Olig2, two genes that are triplicated in Down syndrome and in Ts65Dn mice, were overexpressed in the Ts65Dn forebrain. To test the hypothesis that Olig triplication causes the neurological phenotype, we used a genetic approach to normalize the dosage of these two genes and thereby rescued the inhibitory neuron phenotype in the Ts65Dn brain. These data identify seminal alterations during brain development and suggest a mechanistic relationship between triplicated genes and these brain abnormalities in the Ts65Dn mouse.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Encefalopatías/genética , Encéfalo/anomalías , Síndrome de Down/genética , Proteínas del Tejido Nervioso/genética , Animales , Western Blotting , Encéfalo/citología , Encéfalo/embriología , Encefalopatías/fisiopatología , Modelos Animales de Enfermedad , Desarrollo Embrionario/genética , Inmunohistoquímica , Hibridación in Situ , Potenciales Postsinápticos Inhibidores/fisiología , Ratones , Microscopía Confocal , Neuronas/citología , Factor de Transcripción 2 de los Oligodendrocitos , Técnicas de Placa-Clamp , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Down syndrome (DS) is the leading non-heritable cause of mental retardation and is due to the effects of an extra chromosome 21. Mouse models of DS have been developed which parallel many of the cognitive and behavioral deficits of DS individuals. Of these, Ts65Dn mice show abnormal hippocampal properties including learning and memory deficits, altered synaptic plasticity and irregular dendritic spines. We assessed synaptic function of cultured postnatal Ts65Dn hippocampal neurons through examination of spontaneous miniature excitatory post-synaptic currents (mEPSCs) and compared them to those from diploid neurons. Averaged amplitudes and frequency of mEPSC events were similar to diploid suggesting presynaptic function is not overtly disrupted in Ts65Dn hippocampal neurons. However, both averaged decay and rise times (10-90% of peak) were significantly faster (approximately 20% for both rise and decay) in Ts65Dn neurons compared to diploid. The distribution of both decay and rise times, indicates global scaling of all percentile groups and is independent of amplitude suggesting normal electrotonic filtering in spite of abnormal expression of GIRK2 channel in Ts65Dn mouse. Western blot analysis suggests overexpression of GluR4 subunit of AMPA receptors which may contribute to faster mEPSC in Ts65Dn neurons. Intrinsic synaptic properties influenced by genetics or epigenetics factors in Ts65Dn postnatal cultured neurons are therefore disrupted and may contribute to the cognitive deficits associated with DS.
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Potenciales Postsinápticos Excitadores/fisiología , Hipocampo/citología , Neuronas/fisiología , Animales , Animales Recién Nacidos , Células Cultivadas , Modelos Animales de Enfermedad , Síndrome de Down/genética , Síndrome de Down/patología , Potenciales Postsinápticos Excitadores/genética , Regulación de la Expresión Génica/genética , Humanos , Ratones , Ratones Transgénicos , Técnicas de Placa-Clamp/métodos , Tiempo de Reacción/fisiología , Tiempo de Reacción/efectos de la radiación , Receptores AMPA/metabolismoRESUMEN
Down syndrome (DS) is the most common nonheritable cause of mental retardation. DS is the result of the presence of an extra chromosome 21 and its phenotype may be a consequence of overexpressed genes from that chromosome. One such gene is Kcnj6/Girk2, which encodes the G-protein-coupled inward rectifying potassium channel subunit 2 (GIRK2). We have recently shown that the DS mouse model, Ts65Dn, overexpresses GIRK2 throughout the brain and in particular the hippocampus. Here we report that this overexpression leads to a significant increase ( approximately 2-fold) in GABA(B)-mediated GIRK current in primary cultured hippocampal neurons. The dose response curves for peak and steady-state GIRK current density is significantly shifted left toward lower concentrations of baclofen in Ts65Dn neurons compared with diploid controls, consistent with increased functional expression of GIRK channels. Stationary fluctuation analysis of baclofen-induced GIRK current from Ts65Dn neurons indicated no significant change in single-channel conductance compared with diploid. However, significant increases in GIRK channel density was found in Ts65Dn neurons. In normalized baclofen-induced GIRK current and GIRK current kinetics no difference was found between diploid and Ts65Dn neurons, which suggests unimpaired mechanisms of interaction between GIRK channel and GABA(B) receptor. These results indicate that increased expression of GIRK2 containing channels have functional consequences that likely affect the balance between excitatory and inhibitory neuronal transmission.
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Encéfalo/metabolismo , Síndrome de Down/metabolismo , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Receptores de GABA-B/metabolismo , Transmisión Sináptica/genética , Animales , Animales Recién Nacidos , Baclofeno/farmacología , Encéfalo/fisiopatología , Membrana Celular/efectos de los fármacos , Membrana Celular/genética , Membrana Celular/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Síndrome de Down/genética , Síndrome de Down/fisiopatología , Potenciales Postsinápticos Excitadores/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Agonistas del GABA/farmacología , Potenciales Postsinápticos Inhibidores/genética , Ratones , Ratones Mutantes Neurológicos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Técnicas de Placa-Clamp , Potasio/metabolismo , Receptores de GABA-B/genética , Trisomía/genética , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The Ts65Dn mouse model of Down syndrome (DS) has an extra segment of chromosome (Chr.) 16 exhibits abnormal behavior, synaptic plasticity and altered function of several signaling molecules. We have further investigated signaling pathways that may be responsible for the impaired hippocampal plasticity in the Ts65Dn mouse. Here we report that calcium/calmodulin-dependent protein kinase II (CaMKII), phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulated kinase (ERK), protein kinase A (PKA) and protein kinase C (PKC), all of which have been shown to be involved in synaptic plasticity, are altered in the Ts65Dn hippocampus. We found that the phosphorylation of CaMKII and protein kinase Akt was increased, whereas ERK was decreased. Activities of PKA and PKC were decreased. Furthermore, abnormal PKC activity and an absence of the increase in Akt phosphorylation were demonstrated in the Ts65Dn hippocampus after high-frequency stimulation that induces long-term potentiation. Our findings suggest that abnormal synaptic plasticity in the Ts65Dn hippocampus is the result of compensatory alterations involving the glutamate receptor subunit GluR1 in either one or more of these signaling cascades caused by the expression of genes located on the extra segment of Chr. 16.
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Síndrome de Down/fisiopatología , Hipocampo/fisiología , Plasticidad Neuronal/fisiología , Transducción de Señal/fisiología , Animales , Western Blotting , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Proteínas Quinasas Dependientes de Calcio-Calmodulina/fisiología , AMP Cíclico/fisiología , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Estimulación Eléctrica , Electrofisiología , Potenciales Postsinápticos Excitadores/fisiología , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/fisiología , Fosfatidilinositol 3-Quinasas/fisiología , Proteína Quinasa C/fisiología , Receptor Cross-Talk/fisiología , Receptores AMPA/fisiología , Receptores de N-Metil-D-Aspartato/efectos de los fármacosRESUMEN
Ts65Dn, a mouse model of Down syndrome (DS), demonstrates abnormal hippocampal synaptic plasticity and behavioral abnormalities related to spatial learning and memory. The molecular mechanisms leading to these impairments have not been identified. In this study, we focused on the G-protein-activated inwardly rectifying potassium channel 2 (GIRK2) gene that is highly expressed in the hippocampus region. We studied the expression pattern of GIRK subunits in Ts65Dn and found that GIRK2 was overexpressed in all analyzed Ts65Dn brain regions. Interestingly, elevated levels of GIRK2 protein in the Ts65Dn hippocampus and frontal cortex correlated with elevated levels of GIRK1 protein. This suggests that heteromeric GIRK1-GIRK2 channels are overexpressed in Ts65Dn hippocampus and frontal cortex, which could impair excitatory input and modulate spike frequency and synaptic kinetics in the affected regions. All GIRK2 splicing isoforms examined were expressed at higher levels in the Ts65Dn in comparison to the diploid hippocampus. The pattern of GIRK2 expression in the Ts65Dn mouse brain revealed by in situ hybridization and immunohistochemistry was similar to that previously reported in the rodent brain. However, in the Ts65Dn mouse a strong immunofluorescent staining of GIRK2 was detected in the lacunosum molecular layer of the CA3 area of the hippocampus. In addition, tyrosine hydroxylase containing dopaminergic neurons that coexpress GIRK2 were more numerous in the substantia nigra compacta and ventral tegmental area in the Ts65Dn compared to diploid controls. In summary, the regional localization and the increased brain levels coupled with known function of the GIRK channel may suggest an important contribution of GIRK2 containing channels to Ts65Dn and thus to DS neurophysiological phenotypes.