Estrategia para la gestión de las Investigaciones en Servicios y Sistemas de Salud. Villa Clara. 2017-2020 / Strategy for managing Investigations in Health Systems and Services. Villa Clara. 2017-2020

Introducción: Las Investigaciones en Servicios y Sistemas de Salud constituyen un componente esencial para lograr mayor eficiencia y efectividad del sistema de salud, sin embargo, su utilización es insuficiente. Objetivo: Desarrollar una estrategia para la gestión de las Investigaciones en Servicios y Sistemas de Salud. Métodos: Se realizó una intervención organizacional en la Dirección de Ciencia e Innovación Tecnológica de la Universidad de Ciencias Médicas de Villa Clara, desde el año 2017 hasta marzo de 2020. Participaron 52 directivos de Asistencia Médica Provincial, metodólogos, vicedirectores docentes y 46 profesionales que cursaron maestrías. La investigación se llevó a cabo en tres etapas: La primera, el diagnóstico organizacional para identificar las principales problemáticas en la gestión de los servicios, la segunda, dedicada a los talleres metodológicos sobre la Investigación en Servicios y Sistemas de Salud y la tercera, correspondió a la evaluación de los resultados mediante el registro de proyectos en este campo, y los aportes de las tesis de maestrías, respecto a la solución de los problemas identificados en los servicios de salud. Las técnicas utilizadas fueron: La observación, la entrevista, la revisión de documentos, el grupo focal y la lluvia de ideas. Resultados: Se identificaron 221 proyectos de investigación en este campo, y la ejecución y evaluación de 46 tesis de maestrías, con resultados satisfactorios en la solución de las problemáticas de salud estudiadas. Conclusiones: La estrategia desarrollada posibilitó la gestión de proyectos de investigación en Servicios y Sistemas de Salud, y la ejecución de tesis de maestrías para solucionar problemas prioritarios.

Introduction: investigations in Health Systems and Services constitute an essential component to achieve greater efficiency and effectiveness; however, its use is still insufficient. Objective: to develop a strategy for managing investigations in Health Systems and Services. Methods: an organizational intervention was carried out in the Directorate of Science and Technological Innovation at the University of Medical Sciences of Villa Clara, from 2017 to March 2020. Fifty-two managers of the Provincial Medical Assistance, methodologists, teaching vice-directors and forty-six professionals who took master's degrees participated. The investigation was carried out in three stages; the first, referring to the organizational diagnosis to identify the main problems in the management of services; the second, dedicated to methodological workshops on Investigations in Health Systems and Services and the third ones, corresponded to the evaluation of the results, through the registration of projects in this field and the contributions of the master's theses, regarding the solution of the identified problems. Observation, interview, document review, focus group and brainstorming were the techniques used. Results: a number of 221 research projects were identified in this field, as well as the execution and evaluation of 46 master's theses, with satisfactory results in the solution of the health problems studied. Conclusions: the developed strategy made possible the management of research projects in Health Systems and Services, and the execution of master's theses to solve priority problems.

Interpopulational variation and ontogenetic shift in the venom composition of Lataste's viper (Vipera latastei, Boscá 1878) from northern Portugal.

Lataste's viper (Vipera latastei) is a venomous European viper endemic to the Iberian Peninsula, recognised as medically important by the World Health Organization. To date, no comprehensive characterisation of this species' venom has been reported. Here, we analysed the venoms of juvenile and adult specimens of V. latastei from two environmentally different populations from northern Portugal. Using bottom-up venomics, we produced six venom proteomes (three per population) from vipers belonging to both age classes (i.e., two juveniles and four adults), and RP-HPLC profiles of 54 venoms collected from wild specimens. Venoms from juveniles and adults differed in their chromatographic profiles and relative abundances of their toxins, suggesting the occurrence of ontogenetic changes in venom composition. Specifically, snake venom metalloproteinase (SVMP) was the most abundant toxin family in juvenile venoms, while snake venom serine proteinases (SVSPs), phospholipases A2 (PLA2s), and C-type lectin-like (CTLs) proteins were the main toxins comprising adult venoms. The RP-HPLC venom profiles were found to vary significantly between the two sampled localities, indicating geographic variability. Furthermore, the presence/absence of certain peaks in the venom chromatographic profiles appeared to be significantly correlated also to factors like body size and sex of the vipers. Our findings show that V. latastei venom is a variable phenotype. The intraspecific differences we detected in its composition likely mirror changes in the feeding ecology of this species, taking place during different life stages and under different environmental pressures. SIGNIFICANCE: Lataste's viper (Vipera latastei) is a medically important viper endemic to the Iberian Peninsula, inhabiting different habitats and undergoing a marked ontogenetic dietary shift. In the current study, we report the first proteomic analysis of V. latastei venom from two environmentally different localities in northern Portugal. Our bottom-up venomic analyses show that snake venom serine proteinases (SVSPs), phospholipases A2 (PLA2s), and C-type lectin-like (CTLs) proteins are the major components of adult V. latastei venom. The comparative analysis of young and adult venoms suggests the occurrence of ontogenetic shift in toxin abundances, with snake venom metalloproteinases (SVMPs) being the predominant toxins in juvenile venoms. Moreover, geographic venom variation between the two studied populations is also detected, with our statistical analyses suggesting that factors like body size and sex of the vipers are possibly at play in its determination. Our work represents the first assessment of the composition of V. latastei venom, and the first step towards a better understanding of the drivers behind its variability.

Dagestan blunt-nosed viper, Macrovipera lebetina obtusa (Dwigubsky, 1832), venom. Venomics, antivenomics, and neutralization assays of the lethal and toxic venom activities by anti-Macrovipera lebetina turanica and anti-Vipera berus berus antivenoms.

We have applied a combination of venomics, in vivo neutralization assays, and in vitro third-generation antivenomics analysis to assess the preclinical efficacy of the monospecific anti-Macrovipera lebetina turanica (anti-Mlt) antivenom manufactured by Uzbiopharm® (Uzbekistan) and the monospecific anti-Vipera berus berus antivenom from Microgen® (Russia) against the venom of Dagestan blunt-nosed viper, Macrovipera lebetina obtusa (Mlo). Despite their low content of homologous (anti-Mlt, 5-10%) or para-specific (anti-Vbb, 4-9%) F(ab')2 antibody fragments against M. l. obtusa venom toxins, both antivenoms efficiently recognized most components of the complex venom proteome's arsenal, which is made up of toxins derived from 11 different gene families and neutralized, albeit at different doses, key toxic effects of M. l. obtusa venom, i.e., in vivo lethal and hemorrhagic effects in a murine model, and in vitro phospholipase A2, proteolytic and coagulant activities. The calculated lethality neutralization potencies for Uzbiopharm® anti-Mlt and anti-Vbb Microgen® antivenoms were 1.46 and 1.77 mg/mL, indicating that 1 mL of Uzbiopharm® and Microgen® antivenoms may protect mice from 41 to 50 LD50s of Mlo venom, respectively. The remarkable degree of conservation of immunogenic determinants between species of the clades of European and Oriental viper, which evolved geographically segregated since the early Miocene, suggests an eventual window of opportunity for the treatment of envenomings by Eurasian snakes. Clearly, the rational use of heterologous antivenoms requires establishing their para-specificity landscapes. This paper illustrates the analytical power of combining in vitro and in vivo preclinical quantitative assays toward this goal.

Third-generation antivenomics analysis of the preclinical efficacy of Bothrofav® antivenom towards Bothrops lanceolatus venom.

Bothrops lanceolatus inflicts severe envenomings in the Lesser Caribbean island of Martinique. Bothrofav®, a monospecific antivenom against B. lanceolatus venom, has proven highly effective at the preclinical and clinical levels. Here, we report a detailed third-generation antivenomics quantitative analysis of Bothrofav®. With the exception of poorly-immunogenic peptides, Bothrofav® immunocaptured all the major protein components. These results, along with previous preclinical and clinical observations, underscore the high neutralizing efficacy of the antivenom against B. lanceolatus venom.

Toxin-resolved antivenomics-guided assessment of the immunorecognition landscape of antivenoms.

Snakebite envenoming represents a major issue in rural areas of tropical and subtropical regions across sub-Saharan Africa, South to Southeast Asia, Latin America and Oceania. Antivenoms constitute the only scientifically validated therapy for snakebite envenomings, provided they are safe, effective, affordable, accessible and administered appropriately. However, the lack of financial incentives in a technology that has remained relatively unchanged for more than a century, has contributed to some manufacturers leaving the market and others downscaling production or increasing the prices, leading to a decline in the availability and accessibility for these life-saving antidotes to millions of rural poor most at risk from snakebites in low income countries. The shortage of antivenoms can be significantly alleviated by optimizing the use of current antivenoms (through the assessment of their specific and paraspecific efficacy against the different medically relevant homologous and heterologous snake venoms) and by generating novel polyspecific antivenoms exhibiting broad clinical spectrum and wide geographic distribution range. Research on venoms has been continuously enhanced by advances in technology. Particularly, the last decade has witnessed the development of omics strategies for unravelling the toxin composition of venoms ("venomics") and to assess the immunorecognition profile of antivenoms ("antivenomics"). Here, we review recent developments and reflect on near future innovations that promise to revolutionize the mutually enlightening relationship between evolutionary and translational venomics.

Third Generation Antivenomics: Pushing the Limits of the In Vitro Preclinical Assessment of Antivenoms.

Second generation antivenomics is a translational venomics approach designed to complement in vivo preclinical neutralization assays. It provides qualitative and quantitative information on the set of homologous and heterologous venom proteins presenting antivenom-recognized epitopes and those exhibiting impaired immunoreactivity. In a situation of worrying antivenom shortage in many tropical and sub-tropical regions with high snakebite mortality and morbidity rates, such knowledge has the potential to facilitate the optimal deployment of currently existing antivenoms and to aid in the rational design of novel broad specificity antidotes. The aim of the present work was to expand the analytical capability of the immunoaffinity second-generation antivenomics platform, endowing it with the ability to determine the maximal binding capacity of an antivenom toward the different toxins present in a venom, and to quantify the fraction of venom-specific antibodies present in a given antivenom. The application of this new platform, termed third generation (3G) antivenomics, in the preclinical evaluation of antivenoms is illustrated in this paper for the case of antivenom EchiTAb-Plus-ICP® reactivity towards the toxins of homologous (B. arietans) and heterologous (N. melanoleuca) venoms.

Proteomic analysis of venom variability and ontogeny across the arboreal palm-pitvipers (genus Bothriechis).

Bothriechis is a genus of eleven currently recognized slender and arboreal venomous snakes, commonly called palm-pitvipers that range from southern Mexico to northern South America. Despite dietary studies suggesting that palm-pitvipers are generalists with an ontogenetic shift toward endothermic prey, venom proteomic analyses have revealed remarkable divergence between the venoms of the Costa Rican species, B. lateralis, B. schlegelii, B. supraciliaris, and B. nigroviridis. To achieve a more complete picture of the venomic landscape across Bothriechis, the venom proteomes of biodiversity of the northern Middle American highland palm-pitvipers, B. thalassinus, B. aurifer, and B. bicolor from Guatemala, B. marchi from Honduras, and neonate Costa Rican B. lateralis and B. schlegelii, were investigated. B. thalassinus and B. aurifer venoms are comprised by similar toxin arsenals dominated by SVMPs (33-39% of the venom proteome), CTLs (11-16%), BPP-like molecules (10-13%), and CRISPs (5-10%), and are characterized by the absence of PLA2 proteins. Conversely, the predominant (35%) components of B. bicolor are D49-PLA2 molecules. The venom proteome of B. marchi is similar to B. aurifer and B. thalassinus in that it is rich in SVMPs and BPPs, but also contains appreciable amounts (14.3%) of PLA2s. The major toxin family found in the venoms of both neonate B. lateralis and B. schlegelii, is serine proteinase (SVSP), comprising about 20% of their toxin arsenals. The venom of neonate B. schlegelii is the only palm-pitviper venom where relative high amounts of Kunitz-type (6.3%) and γPLA2 (5.2%) inhibitors have been identified. Despite notable differences between their proteomes, neonate venoms are more similar to each other than to adults of their respective species. However, the ontogenetic changes taking place in the venom of B. lateralis strongly differ from those that occur in the venom of B. schlegelii. Thus, the ontogenetic change in B. lateralis produces a SVMP-rich venom, whereas in B. schlegelii the age-dependent compositional shift generates a PLA2-rich venom. Overall, genus-wide venomics illustrate the high evolvability of palm-pitviper venoms. The integration of the pattern of venom variation across Bothriechis into a phylogenetic and biogeographic framework may lay the foundation for assessing, in future studies, the evolutionary path that led to the present-day variability of the venoms of palm-pitvipers. SIGNIFICANCE: Bothriechis represents a monophyletic basal genus of eleven arboreal palm-pitvipers that range from southern Mexico to northern South America. Despite palm-pitvipers' putative status as diet generalists, previous proteomic analyses have revealed remarkable divergence between the venoms of Costa Rican species, B. lateralis, B. schlegelii, B. supraciliaris, and B. nigroviridis. Our current proteomic study of Guatemalan species, B. thalassinus, B. aurifer, and B. bicolor, Honduran B. marchi, and neonate B. lateralis and B. schlegelii from Costa Rica was undertaken to deepen our understanding of the evolutionary pattern of venom proteome diversity across Bothriechis. Ancestral characters are often, but not always, preserved in an organism's development. Venoms of neonate B. lateralis and B. schlegelii are more similar to each other than to adults of their respective species, suggesting that the high evolvability of palm-pitviper venoms may represent an inherent feature of Bothriechis common ancestor. Our genus-wide data identified four nodes of venom phenotype differentiation across the phylogeny of Bothriechis. Integrated into a phylogenetic and biogeographic framework, the pattern of venom variation across Bothriechis may lay the groundwork to establish whether divergence was driven by selection for efficient resource exploitation in arboreal 'islands', thereby contributing to the ecological speciation of the genus.

Preclinical evaluation of three polyspecific antivenoms against the venom of Echis ocellatus: Neutralization of toxic activities and antivenomics.

Snakebite envenoming has a heavy burden in the public health in sub-Saharan Africa. The viperid species Echis ocellatus (carpet viper or saw-scaled viper) is the medically most important snake in the savannahs of western sub-Saharan Africa. Several antivenoms are being distributed and used in this region for the treatment of envenomings by E. ocellatus, but the preclinical efficacy of some of these antivenoms has not been assessed. The present study evaluated the preclinical efficacy against E. ocellatus venom of three polyspecific antivenoms: (a) Snake Venom Antiserum (Pan Africa), manufactured by Premium Serums and Vaccines (India); (b) Snake Venom Antiserum (Africa), manufactured by VINS Bioproducts (India); and (c) Antivipmyn(®) Africa, manufactured by Instituto Bioclon (Mexico). Antivenomics analysis revealed the ability of the three antivenoms to immunocapture the majority of components of the venoms of E. ocellatus from Cameroon, Nigeria and Mali, although their maximal immunocapturing capability varied. Bioclon and Premium Serums antivenoms were effective in the neutralization of lethal, hemorrhagic and in vitro coagulant activities of the venom of E. ocellatus from Cameroon, albeit with different potencies. VINS antivenom neutralized hemorrhagic activity of this venom, but failed to neutralize lethality at the highest antivenom dose tested, and had a low neutralizing efficacy against in vitro coagulant effect.

Venomic Analysis of the Poorly Studied Desert Coral Snake, Micrurus tschudii tschudii, Supports the 3FTx/PLA2 Dichotomy across Micrurus Venoms.

The venom proteome of the poorly studied desert coral snake Micrurus tschudii tschudii was unveiled using a venomic approach, which identified ≥38 proteins belonging to only four snake venom protein families. The three-finger toxins (3FTxs) constitute, both in number of isoforms (~30) and total abundance (93.6% of the venom proteome), the major protein family of the desert coral snake venom. Phospholipases A2 (PLA2s; seven isoforms, 4.1% of the venom proteome), 1-3 Kunitz-type proteins (1.6%), and 1-2 l-amino acid oxidases (LAO, 0.7%) complete the toxin arsenal of M. t. tschudii. Our results add to the growing evidence that the occurrence of two divergent venom phenotypes, i.e., 3FTx- and PLA2-predominant venom proteomes, may constitute a general trend across the cladogenesis of Micrurus. The occurrence of a similar pattern of venom phenotypic variability among true sea snake (Hydrophiinae) venoms suggests that the 3FTx/PLA2 dichotomy may be widely distributed among Elapidae venoms.

Caracterización del infarto cerebral de etiología aterotrombótica, del territorio carotídeo según tomografía computarizada / Characterization of atherothrombotic stroke, in carotid region as computed tomography

Introducción: la causa más frecuente de enfermedad cerebrovascular isquémica en Cuba es el infarto cerebral de etiología aterotrombótica, que a su vez es más frecuente en el territorio anterior del encéfalo. Objetivo: caracterizar el infarto cerebral aterotrombótico reciente del territorio carotídeo, según la tomografía computarizada. Métodos: estudio descriptivo y transversal en 42 pacientes con diagnóstico clínico de infarto cerebral aterotrombótico de territorio carotídeo, a los que se les realizó tomografía de cráneo. Resultados: la presencia de infarto cerebral de origen aterotrombótico del territorio carotídeo se incrementó con la edad del paciente, alcanzó su pico máximo en los hipertensos mayores de 70 años, con mayor frecuencia en el sexo masculino. El territorio vascular más afectado fue el de la arteria cerebral media en 38 (90,5 %) enfermos, en 23 (54,7 %) pacientes hubo infartos medianos y se observó con mayor frecuencia, 24 (57,2 %) sujetos, la ausencia de infarto antiguo en el territorio anterior del cerebro. Conclusiones: el infarto cerebral aterotrombótico reciente, del territorio carotídeo, se caracteriza por la presencia de infartos medianos que afectan con mayoría casi exclusiva el territorio de la arteria cerebral media con ausencia de la enfermedad cerebrovascular antigua asociada.

Introduction: the most common cause of ischemic stroke in Cuba is atherothrombotic stroke, which, in turn, is more common in the former region of the brain. Objective: to characterize the recent atherothrombotic stroke in the carotid region, according to CT scan. Methods: a descriptive study in 42 patients with clinical diagnosis of atherothrombotic stroke in the carotid region, who underwent cranial CT. Results: the presence of atherothrombotic stroke in the carotid region increased with age. It peaked in hypertensive patients older than 70, and it is much frequently in males. The middle cerebral artery was the most affected in the vascular region in 38 (90.5 %) patients, 23 (54.7 %) patients had middle heart attacks, the absence of previous infarction in the brain anterior region was much frequently observed in 24 (57.2 %) subjects. Conclusions: the recent atherothrombotic stroke in the carotid region is characterized by the presence of middle heart attacks affecting almost exclusively the majority the middle cerebral artery region with absence of previous cerebrovascular disease associated.

Embolización superselectiva de angiomiolipoma renal: presentación de un caso / Overselective embolization of renal angiomyolipoma: a case presentation

INTRODUCCION: Los angiomiolipomas renales son tumores benignos infrecuentes. Tanto la observación periódica como el tratamiento quirúrgico y la embolización arterial selectiva son modalidades válidas para el manejo de dichas lesiones, teniendo en cuenta su tamaño y la sintomatología del paciente en cuestión. OBJETIVOS: Presentar un caso de angiomiolipoma renal, así como el tratamiento utilizado. PRESENTACION DEL CASO: Paciente masculino de 65 años de edad, quien asistió a consulta por dolor lumbo-abdominal intenso del lado derecho. En el ultrasonido se constato imagen tumoral hiperecogénica con densidad grasa en la cara anterior y parte media del riñón derecho. La lesión fue corroborada mediante tomografía axial computarizada, y presentaba las características típicas del angiomiolipoma, con aproximadamente siete centímetros de diámetro. Se realizó la embolización superselectiva mediante una técnica mixta de gelfoam y alcohol absoluto. El paciente no presentó ninguna complicación. Se ha mantenido asintomático y en la evolución tomográfica, realizada a los seis meses de la embolización, se constató la disminución del tamaño de la lesión y de su porción angiomiogénica. CONCLUSIONES: La embolización superselectiva de los angiomiolipomas renales sintomáticos constituye una opción de tratamiento electivo segura y mínimamente invasiva, que permite la conservación de la unidad renal

INTRODUCTION: The renal angiomyolipomas are uncommon benign tumors. As much the periodical observation like a surgical treatment as the selective arterial embolization are valid modalities for the management of such lesions, taking into account its size and the symptoms of patient as regards. OBJECTIVES: To present a case of renal angiomyolipoma, as well as the treatment applied. CASE PRESENTATION: A male patient aged 65 who came to consultation due to intensive lumboabdominal pain in right side. In ultrasound (US) it was possible to verify a hyperechogenic tumor image with fat density in the anterior face and in the middle part of right kidney. The lesion was corroborated by computed axial tomography with the typical features of an angiomyolipoma of approximately seven centimeters of diameter. A Overselective embolization was carried out by means of a mixed technique of Gelfoam and absolute alcohol. There was not complication and the patient has remained asymptomatic and in the tomography course carried out at 6 months of embolization, there was a decrease in the lesion size and of its angiomyogenic. CONCLUSIONS: The Overselective embolization of symptomatic renal angiomyolipomas is a safe and minimally invasive option of the elective treatment allowing the conservation of renal unit

Aneurismas de la arteria comunicante anterior: complicaciones de la vía subfrontal interhemisférica / Aneurisms of the anterior communicating artery: complications of the subfrontal interhemispheral tract

Se realizó un análisis retrospectivo en una muestra de 15 pacientes operados de aneurisma de la arteria comunicante anterior por vía interhemisférica subfrontal, en el Instituto Superior de Medicina Militar ôDr. Luis Díaz Sotoö, entre los meses de enero 1990 y diciembre 1998. Existió apertura del seno frontal en 5 casos. Las complicaciones transoperatorias más frecuentes fueron: ruptura aneurismática y lesión de los nervios olfatorios en 3 pacientes cada una. Las complicaciones posoperatorias inmediatas fueron: anosmia en 8 pacientes, hemiparesia en 2 enfermos y fístula de líquido cefalorraquídeo en 1 paciente. Entre las complicaciones tardías se encontraron trastornos de la conducta, memoria o bradipsiquia en 4 enfermos, sinusitis con mucocele en 2 casos. En 3 de los pacientes a quienes se les realizó clipaje temporal aparecieron trastornos de conducta y en 2 hemiparesia. A 3 enfermos en los que se demostró la presencia de un infarto cerebral posoperatorio, se les había realizado clipaje temporal y en uno de ellos existió ruptura aneurismática. No se consideró que el desenlace estuviera influido por el tiempo quirúrgico. Las conclusiones de este análisis hacen pensar que esta es una vía de abordaje factible desde el punto de vista quirúrgico, pero con un porcentaje de complicaciones importantes que deben tenerse en cuenta