Assessment of the quality of the vital registration system for under-5 mortality in Yucatan, Mexico.

INTRODUCTION: Vital registration is an important element in health information systems which can inform policy and strengthen health systems. Mexico has a well-functioning vital registration system; however, there is still room for improvement, especially for deaths of children under 5. This study assesses the quality of the vital registration system in capturing deaths and evaluates the quality of cause of death certification in under-5 deaths in Yucatan, Mexico. METHODS: We collected information on under-5 deaths that occurred in 2015 and 2016 in Yucatan, Mexico. We calculated the Vital Statistics Performance Index (VSPI) to have a general assessment of the vital registration performance. We examined the agreement between vital registration records and medical records at the individual and population levels using the chance-corrected concordance (CCC) and cause-specific mortality fraction (CSMF) accuracy as quality metrics. RESULTS: We identified 966 records from the vital registry for all under-5 deaths, and 390 were linked to medical records of deaths occurring at public hospitals. The Yucatan vital registration system captured 94.8% of the expected under-5 deaths, with an overall VSPI score of 87.2%. Concordance between underlying cause of death listed in the vital registry and the cause determined by the medical record review varied substantially across causes, with a mean overall chance-corrected concordance across causes of 6.9% for neonates and 46.9% for children. Children had the highest concordance for digestive diseases, and neonates had the highest concordance for meningitis/sepsis. At the population level, the CSMF accuracy for identifying the underlying cause listed was 35.3% for neonates and 67.7% for children. CONCLUSIONS: Although the vital registration system has overall good performance, there are still problems in information about causes of death for children under 5 that are related mostly to certification of the causes of death. The accuracy of information can vary substantially across age groups and causes, with causes reported for neonates being generally less reliable than those for older children. Results highlight the need to implement strategies to improve the certification of causes of death in this population.

Astrocytic C-X-C motif chemokine ligand-1 mediates ß-amyloid-induced synaptotoxicity.

BACKGROUND: Pathological interactions between ß-amyloid (Aß) and tau drive synapse loss and cognitive decline in Alzheimer's disease (AD). Reactive astrocytes, displaying altered functions, are also a prominent feature of AD brain. This large and heterogeneous population of cells are increasingly recognised as contributing to early phases of disease. However, the contribution of astrocytes to Aß-induced synaptotoxicity in AD is not well understood. METHODS: We stimulated mouse and human astrocytes with conditioned medium containing concentrations and species of human Aß that mimic those in human AD brain. Medium from stimulated astrocytes was collected and immunodepleted of Aß before being added to naïve rodent or human neuron cultures. A cytokine, identified in unbiased screens of stimulated astrocyte media and in postmortem human AD brain lysates was also applied to neurons, including those pre-treated with a chemokine receptor antagonist. Tau mislocalisation, synaptic markers and dendritic spine numbers were measured in cultured neurons and organotypic brain slice cultures. RESULTS: We found that conditioned medium from stimulated astrocytes induces exaggerated synaptotoxicity that is recapitulated following spiking of neuron culture medium with recombinant C-X-C motif chemokine ligand-1 (CXCL1), a chemokine upregulated in AD brain. Antagonism of neuronal C-X-C motif chemokine receptor 2 (CXCR2) prevented synaptotoxicity in response to CXCL1 and Aß-stimulated astrocyte secretions. CONCLUSIONS: Our data indicate that astrocytes exacerbate the synaptotoxic effects of Aß via interactions of astrocytic CXCL1 and neuronal CXCR2 receptors, highlighting this chemokine-receptor pair as a novel target for therapeutic intervention in AD.

Factors associated with delays in the search for care in under-5 deaths in Yucatán, Mexico / Factores asociados con demoras en la búsqueda de atención en muertes de menores de cinco años en Yucatán, México

Abstract: Objective: We examined delays during the search for care and associations with mother, child, or health services characteristics, and with symptoms reported prior to death. Materials and methods: Cross-sectional study comprising household interviews with 252 caregivers of children under-5 who died in the state of Yucatán, Mexico, during 2015-2016. We evaluated the three main delays: 1) time to identify symptoms and start search for care, 2) transport time to health facility, and 3) wait time at health facility. Results: Children faced important delays including a mean time to start the search for care of 4.1 days. The mean transport time to the first facility was longer for children enrolled in Seguro Popular and there were longer wait times at public facilities, especially among children who also experienced longer travel time Conclusions: Providing resources to enable caregivers to access health services in a timely manner may reduce delays in seeking care.

Resumen: Objetivo: Analizar las demoras en la búsqueda de atención y su asociación con características de la madre, del niño y los servicios de salud, así como con los síntomas reportados antes de la defunción. Material y métodos: Diseño transversal con entrevistas a 252 cuidadores que se encargaron de niños menores de cinco años que fallecieron en el estado de Yucatán, México, durante 2015-2016. Se evaluaron tres demoras: 1) tiempo en identificar la complicación e iniciar el proceso de búsqueda; 2) tiempo de transporte; y 3) tiempo de espera en la unidad de salud. Resultados: Los niños enfrentaron demoras importantes en la búsqueda de atención. La media de tiempo para iniciar la búsqueda de atención fue de 4.1 días. La media de tiempo de transporte a la primera unidad de atención fue mayor para niños inscritos en el Seguro Popular y hubo tiempos de espera más largos en unidades de salud del sector público, especialmente entre niños que tuvieron tiempos de transporte largos. Conclusión: Proporcionar recursos que permitan a los cuidadores acceder a los servicios de salud de manera oportuna puede reducir las demoras en la búsqueda de atención.

Factors associated with delays in the search for care in under-5 deaths in Yucatán, Mexico.

OBJECTIVE: We examined delays during the search for care and associations with mother, child, or health services characteristics, and with symptoms reported prior to death. MATERIALS AND METHODS: Cross-sectional study compris-ing household interviews with 252 caregivers of children under-5 who died in the state of Yucatán, Mexico, during 2015-2016. We evaluated the three main delays: 1) time to identify symptoms and start search for care, 2) transport time to health facility, and 3) wait time at health facility. RESULTS: Children faced important delays including a mean time to start the search for care of 4.1 days. The mean transport time to the first facility was longer for children enrolled in Seguro Popular and there were longer wait times at public facilities, especially among children who also experienced longer travel time. CONCLUSIONS: Providing resources to enable caregiv-ers to access health services in a timely manner may reduce delays in seeking care.

Identification of an amino-terminus determinant critical for ryanodine receptor/Ca2+ release channel function.

AIMS: The cardiac ryanodine receptor (RyR2), which mediates intracellular Ca2+ release to trigger cardiomyocyte contraction, participates in development of acquired and inherited arrhythmogenic cardiac disease. This study was undertaken to characterize the network of inter- and intra-subunit interactions regulating the activity of the RyR2 homotetramer. METHODS AND RESULTS: We use mutational investigations combined with biochemical assays to identify the peptide sequence bridging the ß8 with ß9 strand as the primary determinant mediating RyR2 N-terminus self-association. The negatively charged side chains of two aspartate residues (D179 and D180) within the ß8-ß9 loop are crucial for the N-terminal inter-subunit interaction. We also show that the RyR2 N-terminus domain interacts with the C-terminal channel pore region in a Ca2+-independent manner. The ß8-ß9 loop is required for efficient RyR2 subunit oligomerization but it is dispensable for N-terminus interaction with C-terminus. Deletion of the ß8-ß9 sequence produces unstable tetrameric channels with subdued intracellular Ca2+ mobilization implicating a role for this domain in channel opening. The arrhythmia-linked R176Q mutation within the ß8-ß9 loop decreases N-terminus tetramerization but does not affect RyR2 subunit tetramerization or the N-terminus interaction with C-terminus. RyR2R176Q is a characteristic hypersensitive channel displaying enhanced intracellular Ca2+ mobilization suggesting an additional role for the ß8-ß9 domain in channel closing. CONCLUSION: These results suggest that efficient N-terminus inter-subunit communication mediated by the ß8-ß9 loop may constitute a primary regulatory mechanism for both RyR2 channel activation and suppression.

Astrocytes in Tauopathies.

Tauopathies are a group of neurodegenerative diseases characterized by the progressive accumulation across the brain of hyperphosphorylated aggregates of the microtubule-associated protein tau that vary in isoform composition, structural conformation and localization. Tau aggregates are most commonly deposited within neurons but can show differential association with astrocytes, depending on the disease. Astrocytes, the most abundant neural cells in the brain, play a major role in synapse and neuronal function, and are a key component of the glymphatic system and blood brain barrier. However, their contribution to tauopathy progression is not fully understood. Here we present a brief overview of the association of tau with astrocytes in tauopathies. We discuss findings that support a role for astrocytes in the uptake and spread of pathological tau, and we describe how alterations to astrocyte phenotype in tauopathies may cause functional alterations that impedes their ability to support neurons and/or cause neurotoxicity. The research reviewed here further highlights the importance of considering non-neuronal cells in neurodegeneration and suggests that astrocyte-directed targets that may have utility for therapeutic intervention in tauopathies.

The novel adenosine A2a receptor antagonist ST1535 potentiates the effects of a threshold dose of L-DOPA in MPTP treated common marmosets.

Adenosine A(2a) receptor antagonists may represent a novel non-dopaminergic approach to the treatment of Parkinson's disease. However, there is little information available on their ability to reverse motor deficits in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP)-treated primates. We have studied the effects of the novel A(2a) receptor antagonist 2-butyl-9-methyl-8-(2H-1,2,3-triazol 2-yl)-9 H-purin-6-ylamine (ST1535) alone and in combination with l-3, 4-dihydroxyphenylalanine (L-DOPA) in MPTP-treated common marmosets. ST1535 (10, 20 and 40 mg/kg, p.o.) when administered alone to MPTP-treated common marmosets produced a dose related increase in locomotor motor activity and tended to reverse motor disability. Treatment with a threshold dose of L-DOPA (2.5 mg/kg, p.o.) produced an increase in locomotor activity and again tended to reverse motor disability. When L-DOPA (2.5 mg/kg, p.o.) was administered in combination with ST1535 (20 mg/kg, p.o.), there was an enhancement in the intensity and duration of the effect of L-DOPA (2.5 mg/kg, p.o.) in reversing motor deficits as shown by both a further increase in locomotor activity and reversal of motor disability. The combination of L-DOPA (2.5 mg/kg, p.o.) plus ST1535 (20 mg/kg, p.o.) significantly increased "on time" in these animals. These data substantiate the evidence that adenosine A(2a) receptor antagonists are able to reverse motor deficits in a highly predictive model of clinical efficacy in Parkinson's disease. The data suggests that ST1535 will be an effective anti-parkinsonian agent in combination with L-DOPA and allow a reduction in l-DOPA usage in the treatment of Parkinson's disease.