Nutritional Strategies to Promote Bovine Oocyte Quality for In Vitro Embryo Production: Do They Really Work?

The ability of bovine oocytes to reach the blastocyst stage (i.e., embryo with around 150 cells in cattle) in vitro can be affected by technical (e.g., culture medium used) and physiological factors in oocyte donors (e.g., age, breed). As such, the nutritional status of oocyte donors plays a significant role in the efficiency of in vitro embryo production (IVEP), and several nutritional strategies have been investigated in cattle subjected to ovum pick-up (OPU). However, there is no clear consensus on the reliability of nutritional schemes to improve IVEP in cattle. Available evidence suggests that a moderate body condition score (i.e., 3 in a 1-5 scale) in cattle is compatible with a metabolic microenvironment in ovarian follicles that will promote embryo formation in vitro. The usefulness of fatty acid and micronutrient supplementation to improve IVEP in cattle is debatable with the current information available. Overall, the supply of maintenance nutritional requirements according to developmental and productive stage seems to be enough to provide bovine oocyte donors with a good chance of producing embryos in vitro. Future nutrition research in cattle using OPU-IVEP models needs to consider animal well-being aspects (i.e., stress caused by handling and sampling), which could affect the results.

The mammalian preimplantation embryo: Its role in the environmental programming of postnatal health and performance.

During formation of the preimplantation embryo several cellular and molecular milestones take place, making the few cells forming the early embryo vulnerable to environmental stressors than can impair epigenetic reprogramming and controls of gene expression. Although these molecular alterations can result in embryonic death, a significant developmental plasticity is present in the preimplantation embryo that promotes full-term pregnancy. Prenatal epigenetic modifications are inherited during mitosis and can perpetuate specific phenotypes during early postnatal development and adulthood. As such, the preimplantation phase is a developmental window where developmental programming can take place in response to the embryonic microenvironment present in vivo or in vitro. In this review, the relevance of the preimplantation embryo as a developmental stage where offspring health and performance can be programmed is discussed, with emphasis on malnutrition and assisted reproductive technologies; two major environmental insults with important implications for livestock production and human reproductive medicine.

Advanced maternal age perturbs mouse embryo development and alters the phenotype of derived embryonic stem cells.

Advanced maternal age (AMA) is known to reduce fertility, increases aneuploidy in oocytes and early embryos and leads to adverse developmental consequences which may associate with offspring lifetime health risks. However, investigating underlying effects of AMA on embryo developmental potential is confounded by the inherent senescence present in maternal body systems further affecting reproductive success. Here, we describe a new model for the analysis of early developmental mechanisms underlying AMA by the derivation and characterisation of mouse embryonic stem cell (mESC-like) lines from naturally conceived embryos. Young (7-8 weeks) and Old (7-8 months) C57BL/6 female mice were mated with young males. Preimplantation embryos from Old dams displayed developmental retardation in blastocyst morphogenesis. mESC lines established from these blastocysts using conventional techniques revealed differences in genetic, cellular and molecular criteria conserved over several passages in the standardised medium. mESCs from embryos from AMA dams displayed increased incidence of aneuploidy following Giemsa karyotyping compared with those from Young dams. Moreover, AMA caused an altered pattern of expression of pluripotency markers (Sox2, OCT4) in mESCs. AMA further diminished mESC survival and proliferation and reduced the expression of cell proliferation marker, Ki-67. These changes coincided with altered expression of the epigenetic marker, Dnmt3a and other developmental regulators in a sex-dependent manner. Collectively, our data demonstrate the feasibility to utilise mESCs to reveal developmental mechanisms underlying AMA in the absence of maternal senescence and with reduced animal use.

Analysis of the quality of anticoagulation with vitamin K antagonists in three clinical scenarios in Mexico.

INTRODUCTION: Vitamin K antagonists (VKA) are a therapeutic alternative in patients with venous thromboembolic disease; however, numerous factors affect their pharmacology. OBJECTIVE: To evaluate the quality of VKA anticoagulation at three different time periods in Mexico. METHODS: Prospective study, nested in patient cohorts at three different clinical scenarios between 2013 and 2019. Outpatients with indication for treatment with VKAs for at least 12 months were included. Patients were managed according to the criteria of the treating physician. RESULTS: Patient general characteristics were similar between groups, except for the VKA indication. The results of 4,148 patients and 38,548 INR assessments were analyzed. The times in therapeutic range during the three phases of the study and pooled data were significantly higher for the anticoagulation clinic. Only the number of patient visits was significantly associated with the results, unlike age, gender, and type of VKA. CONCLUSIONS: VKAs are widely used, but it is difficult for therapeutic goals to be achieved, especially in non-specialized clinical services. Creation of anticoagulation clinics is an urgent need for the Mexican health system.

INTRODUCCIÓN: Los antagonista de la vitamina K (AVK) son una alternativa terapéutica en los pacientes con enfermedad tromboembólica venosa; sin embargo, numerosos factores afectan su farmacología. OBJETIVO: Evaluar la calidad de la anticoagulación AVK durante tres diferentes periodos en México. MÉTODOS: Estudio prospectivo, anidado en cohortes de pacientes en tres escenarios clínicos entre los años 2013-2019. Se incluyeron pacientes no hospitalizados con indicación para recibir AVK por al menos 12 meses, quienes fueron manejados de acuerdo con el criterio del médico tratante. RESULTADOS: Las características generales de los pacientes fueron similares entre los grupos, excepto por la indicación para usar los AVK. Se analizaron los resultados de 4148 pacientes y 38 548 evaluaciones de INR. Los tiempos en rango terapéutico durante las tres fases del estudio y los datos acumulados fueron significativamente mayores en la clínica de anticoagulación. Solo el número de visitas de control de los pacientes se asoció significativamente con los resultados, a diferencia de la edad, el sexo y el tipo de AVK. CONCLUSIONES: Los AVK se utilizan ampliamente, pero es difícil alcanzar la meta terapéutica, sobre todo en servicios clínicos no especializados. La creación de clínicas de anticoagulación es una necesidad urgente en el sistema mexicano de salud.

Análisis de la calidad de la anticoagulación con antagonistas de la vitamina K en tres escenarios clínicos en México / Analysis of the quality of anticoagulation with vitamin K antagonists in three clinical scenarios in Mexico

Resumen Introducción: Los antagonista de la vitamina K (AVK) son una alternativa terapéutica en los pacientes con enfermedad tromboembólica venosa; sin embargo, numerosos factores afectan su farmacología. Objetivo: Evaluar la calidad de la anticoagulación AVK durante tres diferentes periodos en México. Métodos: Estudio prospectivo, anidado en cohortes de pacientes en tres escenarios clínicos entre los años 2013-2019. Se incluyeron pacientes no hospitalizados con indicación para recibir AVK por al menos 12 meses, quienes fueron manejados de acuerdo con el criterio del médico tratante. Resultados: Las características generales de los pacientes fueron similares entre los grupos, excepto por la indicación para usar los AVK. Se analizaron los resultados de 4148 pacientes y 38 548 evaluaciones de INR. Los tiempos en rango terapéutico durante las tres fases del estudio y los datos acumulados fueron significativamente mayores en la clínica de anticoagulación. Solo el número de visitas de control de los pacientes se asoció significativamente con los resultados, a diferencia de la edad, el sexo y el tipo de AVK. Conclusiones: Los AVK se utilizan ampliamente, pero es difícil alcanzar la meta terapéutica, sobre todo en servicios clínicos no especializados. La creación de clínicas de anticoagulación es una necesidad urgente en el sistema mexicano de salud.

Abstract Introduction: Vitamin K antagonists (VKA) are a therapeutic alternative in patients with venous thromboembolic disease; however, numerous factors affect their pharmacology. Objective: To evaluate the quality of VKA anticoagulation at three different time periods in Mexico. Methods: Prospective study, nested in patient cohorts at three different clinical scenarios between 2013 and 2019. Outpatients with indication for treatment with VKAs for at least 12 months were included. Patients were managed according to the criteria of the treating physician. Results: Patient general characteristics were similar between groups, except for the VKA indication. The results of 4,148 patients and 38,548 INR assessments were analyzed. The times in therapeutic range during the three phases of the study and pooled data were significantly higher for the anticoagulation clinic. Only the number of patient visits was significantly associated with the results, unlike age, gender, and type of VKA. Conclusions: VKAs are widely used, but it is difficult for therapeutic goals to be achieved, especially in non-specialized clinical services. Creation of anticoagulation clinics is an urgent need for the Mexican health system.

The duration of embryo culture after mouse IVF differentially affects cardiovascular and metabolic health in male offspring.

STUDY QUESTION: Do the long-term health outcomes following IVF differ depending upon the duration of embryo culture before transfer? SUMMARY ANSWER: Using a mouse model, we demonstrate that in male but not female offspring, adverse cardiovascular (CV) health was more likely with prolonged culture to the blastocyst stage, but metabolic dysfunction was more likely if embryo transfer (ET) occurred at the early cleavage stage. WHAT IS KNOWN ALREADY: ART associate with increased risk of adverse CV and metabolic health in offspring, and these findings have been confirmed in animal models in the absence of parental infertility issues. It is unclear which specific ART treatments may cause these risks. There is increasing use of blastocyst, versus cleavage-stage, transfer in clinical ART which does not appear to impair perinatal health of children born, but the longer-term health implications are unknown. STUDY DESIGN, SIZE, DURATION: Five mouse groups were generated comprising: (i) natural mating (NM)-naturally mated, non-superovulated and undisturbed gestation; (ii) IV-ET-2Cell-in-vivo derived two-cell embryos collected from superovulated mothers, with immediate ET to recipients; (iii) IVF-ET-2Cell-IVF generated embryos, from oocytes from superovulated mothers, cultured to the two-cell stage before ET to recipients; (iv) IV-ET-BL-in-vivo derived blastocysts collected from superovulated mothers, with immediate ET to recipients; (v) IVF-ET-BL-IVF generated embryos, from oocytes from superovulated mothers, cultured to the blastocyst stage before ET to recipients. Both male and female offspring were analysed for growth, CV and metabolic markers of health. There were 8-13 litters generated for each group for analyses; postnatal data were analysed by multilevel random effects regression to take account of between-mother and within-mother variation and litter size. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: C57/BL6 female mice (3-4 weeks old) were used for oocyte production; CBA males for sperm with human tubal fluid medium were used for IVF. Embryos were transferred (ET) to MF1 pseudo-pregnant recipients at the two-cell stage or cultured in synthetic oviductal medium enriched with potassium medium to the blastocyst stage before ET. Control in-vivo embryos from C57BL6 × CBA matings were collected and immediately transferred at the two-cell or blastocyst stage. Postnatal assays included growth rate up to 27 weeks; systolic blood pressure (SBP) at 9, 15 and 21 weeks; lung and serum angiotensin-converting enzyme (ACE) activity at time of cull (27 weeks); glucose tolerance test (GTT; 27 weeks); basal glucose and insulin levels (27 weeks); and lipid accumulation in liver cryosections using Oil Red O imaging (27 weeks). MAIN RESULTS AND THE ROLE OF CHANCE: Blastocysts formed by IVF developed at a slower rate and comprised fewer cells that in-vivo generated blastocysts without culture (P < 0.05). Postnatal growth rate was increased in all four experimental treatments compared with NM group (P < 0.05). SBP, serum and lung ACE and heart/body weight were higher in IVF-ET-BL versus IVF-ET-2Cell males (P < 0.05) and higher than in other treatment groups, with SBP and lung ACE positively correlated (P < 0.05). Glucose handling (GTT AUC) was poorer and basal insulin levels were higher in IVF-ET-2Cell males than in IVF-ET-BL (P < 0.05) with the glucose:insulin ratio more negatively correlated with body weight in IVF-ET-2Cell males than in other groups. Liver/body weight and liver lipid droplet diameter and density in IVF-ET-2Cell males were higher than in IVF-ET-BL males (P < 0.05). IVF groups had poorer health characteristics than their in-vivo control groups, indicating that outcomes were not caused specifically by background techniques (superovulation, ET). No consistent health effects from duration of culture were identified in female offspring. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Results from experimental animal models cannot be extrapolated to humans. Nevertheless, they are valuable to develop conceptual models, in this case, in the absence of confounding parental infertility, in assessing the safety of ART manipulations. WIDER IMPLICATIONS OF THE FINDINGS: The study indicates that longer duration of embryo culture after IVF up to blastocyst before ET leads to increased dysfunction of CV health in males compared with IVF and shorter cleavage-stage ET. However, the metabolic health of male offspring was poorer after shorter versus longer culture duration. This distinction indicates that the origin of CV and metabolic health phenotypes after ART may be different. The poorer metabolic health of males after cleavage-stage ET coincides with embryonic genome activation occurring at the time of ET. STUDY FUNDING/COMPETING INTEREST(S): This work was supported through the European Union FP7-CP-FP Epihealth programme (278418) and FP7-PEOPLE-2012-ITN EpiHealthNet programme (317146) to T.P.F., the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/F007450/1) to T.P.F., and the Saudi government, University of Jeddah and King Abdulaziz University to A.A. The authors have no conflicts of interest to declare.

The role of CAPG in molecular communication between the embryo and the uterine endometrium: Is its function conserved in species with different implantation strategies?

During the preimplantation period of pregnancy in eutherian mammals, transcriptional and proteomic changes in the uterine endometrium are required to facilitate receptivity to an implanting blastocyst. These changes are mediated, in part, by proteins produced by the developing conceptus (inner cell mass and extraembryonic membranes). We hypothesized that this common process in early pregnancy in eutheria may be facilitated by highly conserved conceptus-derived proteins such as macrophage capping protein (CAPG). We propose that CAPG may share functionality in modifying the transcriptome of the endometrial epithelial cells to facilitate receptivity to implantation in species with different implantation strategies. A recombinant bovine form of CAPG (91% sequence identity between bovine and human) was produced and bovine endometrial epithelial (bEECs) and stromal (bESCs) and human endometrial epithelial cells (hEECs) were cultured for 24 hours with and without recombinant bovine CAPG (rbCAPG). RNA sequencing and quantitative real-time PCR analysis were used to assess the transcriptional response to rbCAPG (Control, vehicle, CAPG 10, 100, 1000 ng/mL: n = 3 biological replicates per treatment per species). Treatment of bEECs with CAPG resulted in alterations in the abundance of 1052 transcripts (629 increased and 423 decreased) compared to vehicle controls. Treatment of hEECs with bovine CAPG increased expression of transcripts previously known to interact with CAPG in different systems (CAPZB, CAPZA2, ADD1, and ADK) compared with vehicle controls (P < .05). In conclusion, we have demonstrated that CAPG, a highly conserved protein in eutherian mammals, elicits a transcriptional response in the endometrial epithelium in species with different implantation strategies that may contribute to pregnancy success.

Periconceptional environment and the developmental origins of disease

The concept emerging from Professor David Barker's seminal research on the developmental origins of later-life disease has progressed in many directions since it was first published. One critical question being when during gestation might environment alter the developmental programme with such enduring consequences. Here, we review the growing consensus from clinical and animal research that the period around conception, embracing gamete maturation and early embryogenesis might be the most vulnerable period. We focus on four types of environmental exposure shown to modify periconceptional reproduction and offspring development and health: maternal overnutrition and obesity; maternal undernutrition; paternal diet and health; and assisted reproductive technology. These conditions may act through diverse epigenetic, cellular and physiological mechanisms to alter gene expression and cellular signalling and function in the conceptus affecting offspring growth and metabolism leading to increased risk for cardiometabolic and neurological disease in later life.

Origins of lifetime health around the time of conception: causes and consequences.

Parental environmental factors, including diet, body composition, metabolism, and stress, affect the health and chronic disease risk of people throughout their lives, as captured in the Developmental Origins of Health and Disease concept. Research across the epidemiological, clinical, and basic science fields has identified the period around conception as being crucial for the processes mediating parental influences on the health of the next generation. During this time, from the maturation of gametes through to early embryonic development, parental lifestyle can adversely influence long-term risks of offspring cardiovascular, metabolic, immune, and neurological morbidities, often termed developmental programming. We review periconceptional induction of disease risk from four broad exposures: maternal overnutrition and obesity; maternal undernutrition; related paternal factors; and the use of assisted reproductive treatment. Studies in both humans and animal models have demonstrated the underlying biological mechanisms, including epigenetic, cellular, physiological, and metabolic processes. We also present a meta-analysis of mouse paternal and maternal protein undernutrition that suggests distinct parental periconceptional contributions to postnatal outcomes. We propose that the evidence for periconceptional effects on lifetime health is now so compelling that it calls for new guidance on parental preparation for pregnancy, beginning before conception, to protect the health of offspring.

Insulin and branched-chain amino acid depletion during mouse preimplantation embryo culture programmes body weight gain and raised blood pressure during early postnatal life.

Mouse maternal low protein diet exclusively during preimplantation development (Emb-LPD) is sufficient to programme altered growth and cardiovascular dysfunction in offspring. Here, we use an in vitro model comprising preimplantation culture in medium depleted in insulin and branched-chain amino acids (BCAA), two proposed embryo programming inductive factors from Emb-LPD studies, to examine the consequences for blastocyst organisation and, after embryo transfer (ET), postnatal disease origin. Two-cell embryos were cultured to blastocyst stage in defined KSOM medium supplemented with four combinations of insulin and BCAA concentrations. Control medium contained serum insulin and uterine luminal fluid amino acid concentrations (including BCAA) found in control mothers from the maternal diet model (N-insulin+N-bcaa). Experimental medium (three groups) contained 50% reduction in insulin and/or BCAA (L-insulin+N-bcaa, N-insulin+L-bcaa, and L-insulin+N-bcaa). Lineage-specific cell numbers of resultant blastocysts were not affected by treatment. Following ET, a combined depletion of insulin and BCAA during embryo culture induced a non sex-specific increase in birth weight and weight gain during early postnatal life. Furthermore, male offspring displayed relative hypertension and female offspring reduced heart/body weight, both characteristics of Emb-LPD offspring. Combined depletion of metabolites also resulted in a strong positive correlation between body weight and glucose metabolism that was absent in the control group. Our results support the notion that composition of preimplantation culture medium can programme development and associate with disease origin affecting postnatal growth and cardiovascular phenotypes and implicate two important nutritional mediators in the inductive mechanism. Our data also have implications for human assisted reproductive treatment (ART) practice.

[Public health impact of a remote diagnosis system implemented in regional and district hospitals in Paraguay]. / Impacto en la salud pública del sistema de telediagnóstico implementado en Paraguay.

OBJECTIVE: Determine the viability of a remote diagnosis system implemented to provide health care to remote and scattered populations in Paraguay. METHODS: The study was conducted in all regional and general hospitals in Paraguay, and in the main district hospitals in the country's 18 health regions. Clinical data, tomographic images, sonography, and electrocardiograms (ECGs) of patients who needed a diagnosis by a specialized physician were entered into the system. This information was sent to specialists in diagnostic imaging and in cardiology for remote diagnosis and the report was then forwarded to the hospitals connected to the system. The cost-benefit and impact of the remote diagnosis tool was analyzed from the perspective of the National Health System. RESULTS: Between January 2014 and May 2015, a total of 34 096 remote diagnoses were made in 25 hospitals in the Ministry of Health's telemedicine system. The average unit cost of remote diagnosis was US$2.6 per ECG, tomography, and sonography, while the unit cost of "face-to-face" diagnosis was US$11.8 per ECG, US$68.6 per tomography, and US$21.5 per sonography. As a result of remote diagnosis, unit costs were 4.5 times lower for ECGs; 26.4 times lower for tomography, and 8.3 times lower for sonography. In monetary terms, implementation of the remote diagnosis system during the 16 months of the study led to average savings of US$2 420 037. CONCLUSION: Paraguay has a remote diagnosis system for electrocardiography, tomography, and sonography, using low-cost information and communications technologies (ICTs) based on free software that is scalable to other types of remote diagnostic studies of interest for public health. Implementation of remote diagnosis helped to strengthen the integrated network of health services and programs, enabling professionals to optimize their time and productivity, while improving quality, increasing access and equity, and reducing costs.

Impacto en la salud pública del sistema de telediagnóstico implementado en Paraguay / Public health impact of a remote diagnosis system implemented in regional and district hospitals in Paraguay / Impacto sobre a saúde pública do sistema de teledi¬agnóstico implementado em hospitais regionais e dis¬tritais do Paraguai

Objetivo. Determinar la viabilidad y puesta en marcha de un sistema de telediagnóstico para dar asistencia sanitaria a poblaciones remotas y dispersas del Paraguay. Métodos. El estudio fue realizado en todos los hospitales regionales, generales y principales hospitales distritales de las 18 regiones sanitarias del Paraguay. En el sistema se registraron los datos clínicos y las imágenes tomográficas, ecográficas y trazados electrocardiográficos del paciente que precisaba de un diagnóstico por parte de un médico especialista. Esta información se transmitió a los especialistas en imagenología y en cardiología para su diagnóstico remoto y posterior envío del informe a los hospitales conectados al sistema. Se analizó el costo-beneficio e impacto de la herramienta de telediagnóstico desde la perspectiva del Sistema Nacional de Salud. Resultados. Entre enero de 2014 y mayo de 2015 se realizaron 34 096 telediagnósticos distribuidos en 25 hospitales a través del Sistema de Telemedicina del Ministerio de Salud. El costo unitario promedio del diagnóstico remoto fue de USD 2,6 (dólares estadounidenses) para electrocardiograma (ECG), tomografía y ecografía, mientras que el costo unitario para el diagnóstico “cara a cara” fue de UDS 11,8 para ECG; USD 68,6 para tomografía y USD 21,5 para ecografía. La reducción del costo mediante el diagnóstico remoto fue de 4,5 veces para ECG; 26,4 veces para tomografía y de 8,3 veces para ecografía. En términos monetarios, la implementación del sistema de telediagnóstico, durante los 16 meses del estudio, significó un ahorro promedio de USD 2 420 037. Conclusión. Paraguay cuenta con un sistema de telediagnóstico para electrocardiografía, tomografía y ecografía aplicando las tecnologías de la información y comunicación (TIC) de bajo costo, basadas en software libre y escalable a otros tipos de estudios diagnósticos a distancia; de interés para la salud pública. Con una aplicación práctica del telediagnóstico, se contribuyó al fortalecimiento de la red integrada de servicios y programas de salud, lo que permitió maximizar el tiempo del profesional y su productividad, mejorar la calidad, aumentar el acceso y la equidad, y disminuir los costos.

Objective. Determine the viability of a remote diagnosis system implemented to provide health care to remote and scattered populations in Paraguay. Methods. The study was conducted in all regional and general hospitals in Paraguay, and in the main district hospitals in the country’s 18 health regions. Clinical data, tomographic images, sonography, and electrocardiograms (ECGs) of patients who needed a diagnosis by a specialized physician were entered into the system. This information was sent to specialists in diagnostic imaging and in cardiology for remote diagnosis and the report was then forwarded to the hospitals connected to the system. The cost-benefit and impact of the remote diagnosis tool was analyzed from the perspective of the National Health System. Results. Between January 2014 and May 2015, a total of 34 096 remote diagnoses were made in 25 hospitals in the Ministry of Health’s telemedicine system. The average unit cost of remote diagnosis was US$2.6 per ECG, tomography, and sonography, while the unit cost of “face-to-face” diagnosis was US$11.8 per ECG, US$68.6 per tomography, and US$21.5 per sonography. As a result of remote diagnosis, unit costs were 4.5 times lower for ECGs; 26.4 times lower for tomography, and 8.3 times lower for sonography. In monetary terms, implementation of the remote diagnosis system during the 16 months of the study led to average savings of US$2 420 037. Conclusion. Paraguay has a remote diagnosis system for electrocardiography, tomography, and sonography, using low-cost information and communications technologies (ICTs) based on free software that is scalable to other types of remote diagnostic studies of interest for public health. Implementation of remote diagnosis helped to strengthen the integrated network of health services and programs, enabling professionals to optimize their time and productivity, while improving quality, increasing access and equity, and reducing costs.

Objetivo. Avaliar a viabilidade e a implementação de um sistema de telediagnóstico destinado a oferecer assistência de saúde a populações remotas e dispersas do Paraguai. Métodos. O estudo foi realizado em todos os hospitais regionais e gerais e nos principais hospitais distritais das 18 regiões sanitárias do Paraguai. Foram registrados no sistema os dados clínicos, as imagens tomográficas e ecográficas e os traçados eletrocardiográficos de pacientes que precisavam de um diagnóstico por parte de um médico especialista. Estas informações foram transmitidas a especialistas em diagnóstico por imagem e cardiologia para que fizessem o diagnóstico remoto e enviassem então os laudos aos hospitais conectados ao sistema. Analisou-se a relação custo- benefício e o impacto da ferramenta de telediagnóstico da perspectiva do Sistema Nacional de Saúde. Resultados. Entre janeiro de 2014 e maio de 2015, foram realizados 34.096 telediagnósticos em 25 hospitais através do Sistema de Telemedicina do Ministério da Saúde. O custo unitário médio do diagnóstico remoto foi de US$ 2,6 (dólares americanos) para eletrocardiografia (ECG), tomografia e ecografia, enquanto que o custo unitário para o diagnóstico presencial foi de US$ 11,8 para ECG, US$ 68,6 para tomografia e US$ 21,5 para ecografia. A redução do custo pelo uso do diagnóstico remoto foi de 4,5 vezes para ECG, 26,4 vezes para tomografia e 8,3 vezes para ecografia. Em termos monetários, a implementação do sistema de telediagnóstico, ao longo dos 16 meses do estudo, representou uma economia média de US$ 2.420.037. Conclusão. O Paraguai conta com um sistema de telediagnóstico para eletrocardiografia, tomografia e ecografia que utiliza tecnologias da informação e comunicação (TIC) de baixo custo, baseadas em software livre e ampliáveis a outros tipos de exames diagnósticos à distância que são de interesse para a saúde pública. A aplicação prática do telediagnóstico contribuiu para o fortalecimento da rede integrada de serviços e programas de saúde, o que permitiu maximizar o tempo dos profissionais e sua produtividade, melhorar a qualidade, aumentar o acesso e a equidade e reduzir os custos.

Impacto en la salud pública del sistema de telediagnóstico implementado en Paraguay / Public health impact of a remote diagnosis system implemented in regional and district hospitals in Paraguay / Impacto sobre a saúde pública do sistema de telediagnóstico implementado em hospitais regionais e distritais do Paraguai

RESUMEN Objetivo Determinar la viabilidad y puesta en marcha de un sistema de telediagnóstico para dar asistencia sanitaria a poblaciones remotas y dispersas del Paraguay. Métodos El estudio fue realizado en todos los hospitales regionales, generales y principales hospitales distritales de las 18 regiones sanitarias del Paraguay. En el sistema se registraron los datos clínicos y las imágenes tomográficas, ecográficas y trazados electrocardiográficos del paciente que precisaba de un diagnóstico por parte de un médico especialista. Esta información se transmitió a los especialistas en imagenología y en cardiología para su diagnóstico remoto y posterior envío del informe a los hospitales conectados al sistema. Se analizó el costo-beneficio e impacto de la herramienta de telediagnóstico desde la perspectiva del Sistema Nacional de Salud. Resultados Entre enero de 2014 y mayo de 2015 se realizaron 34 096 telediagnósticos distribuidos en 25 hospitales a través del Sistema de Telemedicina del Ministerio de Salud. El costo unitario promedio del diagnóstico remoto fue de USD 2,6 (dólares estadounidenses) para electrocardiograma (ECG), tomografía y ecografía, mientras que el costo unitario para el diagnóstico “cara a cara” fue de UDS 11,8 para ECG; USD 68,6 para tomografía y USD 21,5 para ecografía. La reducción del costo mediante el diagnóstico remoto fue de 4,5 veces para ECG; 26,4 veces para tomografía y de 8,3 veces para ecografía. En términos monetarios, la implementación del sistema de telediagnóstico, durante los 16 meses del estudio, significó un ahorro promedio de USD 2 420 037. Conclusión Paraguay cuenta con un sistema de telediagnóstico para electrocardiografía, tomografía y ecografía aplicando las tecnologías de la información y comunicación (TIC) de bajo costo, basadas en software libre y escalable a otros tipos de estudios diagnósticos a distancia; de interés para la salud pública. Con una aplicación práctica del telediagnóstico, se contribuyó al fortalecimiento de la red integrada de servicios y programas de salud, lo que permitió maximizar el tiempo del profesional y su productividad, mejorar la calidad, aumentar el acceso y la equidad, y disminuir los costos.

ABSTRACT Objective Determine the viability of a remote diagnosis system implemented to provide health care to remote and scattered populations in Paraguay. Methods The study was conducted in all regional and general hospitals in Paraguay, and in the main district hospitals in the country’s 18 health regions. Clinical data, tomographic images, sonography, and electrocardiograms (ECGs) of patients who needed a diagnosis by a specialized physician were entered into the system. This information was sent to specialists in diagnostic imaging and in cardiology for remote diagnosis and the report was then forwarded to the hospitals connected to the system. The cost-benefit and impact of the remote diagnosis tool was analyzed from the perspective of the National Health System. Results Between January 2014 and May 2015, a total of 34 096 remote diagnoses were made in 25 hospitals in the Ministry of Health’s telemedicine system. The average unit cost of remote diagnosis was US$2.6 per ECG, tomography, and sonography, while the unit cost of “face-to-face” diagnosis was US$11.8 per ECG, US$68.6 per tomography, and US$21.5 per sonography. As a result of remote diagnosis, unit costs were 4.5 times lower for ECGs; 26.4 times lower for tomography, and 8.3 times lower for sonography. In monetary terms, implementation of the remote diagnosis system during the 16 months of the study led to average savings of US$2 420 037. Conclusion Paraguay has a remote diagnosis system for electrocardiography, tomography, and sonography, using low-cost information and communications technologies (ICTs) based on free software that is scalable to other types of remote diagnostic studies of interest for public health. Implementation of remote diagnosis helped to strengthen the integrated network of health services and programs, enabling professionals to optimize their time and productivity, while improving quality, increasing access and equity, and reducing costs.

RESUMO Objetivo Avaliar a viabilidade e a implementação de um sistema de telediagnóstico destinado a oferecer assistência de saúde a populações remotas e dispersas do Paraguai. Métodos O estudo foi realizado em todos os hospitais regionais e gerais e nos principais hospitais distritais das 18 regiões sanitárias do Paraguai. Foram registrados no sistema os dados clínicos, as imagens tomográficas e ecográficas e os traçados eletrocardiográficos de pacientes que precisavam de um diagnóstico por parte de um médico especialista. Estas informações foram transmitidas a especialistas em diagnóstico por imagem e cardiologia para que fizessem o diagnóstico remoto e enviassem então os laudos aos hospitais conectados ao sistema. Analisou-se a relação custo-benefício e o impacto da ferramenta de telediagnóstico da perspectiva do Sistema Nacional de Saúde. Resultados Entre janeiro de 2014 e maio de 2015, foram realizados 34.096 telediagnósticos em 25 hospitais através do Sistema de Telemedicina do Ministério da Saúde. O custo unitário médio do diagnóstico remoto foi de US$ 2,6 (dólares americanos) para eletrocardiografia (ECG), tomografia e ecografia, enquanto que o custo unitário para o diagnóstico presencial foi de US$ 11,8 para ECG, US$ 68,6 para tomografia e US$ 21,5 para ecografia. A redução do custo pelo uso do diagnóstico remoto foi de 4,5 vezes para ECG, 26,4 vezes para tomografia e 8,3 vezes para ecografia. Em termos monetários, a implementação do sistema de telediagnóstico, ao longo dos 16 meses do estudo, representou uma economia média de US$ 2.420.037. Conclusão O Paraguai conta com um sistema de telediagnóstico para eletrocardiografia, tomografia e ecografia que utiliza tecnologias da informação e comunicação (TIC) de baixo custo, baseadas em software livre e ampliáveis a outros tipos de exames diagnósticos à distância que são de interesse para a saúde pública. A aplicação prática do telediagnóstico contribuiu para o fortalecimento da rede integrada de serviços e programas de saúde, o que permitiu maximizar o tempo dos profissionais e sua produtividade, melhorar a qualidade, aumentar o acesso e a equidade e reduzir os custos.

Innovación tecnológica en servicios diagnósticos públicos del Paraguay / Technological innovations in public diagnostic services of Paraguay

A través de innovaciones tecnológicas basadas enlas tecnologías de la información y comunicación(TIC) pueden desarrollarse sistemas de telediagnósticoventajosos para mejorar la atención de lasalud de poblaciones remotas que no tienen accesoa los médicos especialistas. Este estudio realizadopor la Unidad de Telemedicina del Ministeriode Salud Pública y Bienestar Social (MSPBS) encolaboración con el Dpto. de Ingeniería Biomédicae Imágenes del Instituto de Investigaciones enCiencias de la Salud de la Universidad Nacional deAsunción (IICS-UNA) y la Universidad del PaísVasco (UPV/EHU) sirvió para evaluar la utilidadde un sistema de telediagnóstico en la salud pú-blica. Fueron analizados los resultados obtenidospor el sistema de telediagnóstico de 54 hospitalesregionales, distritales, especializados y centros desalud del MSPBS. Fueron realizados 182.406 diagnósticosremotos de enero del 2014 a noviembrede 2016 a través del sistema. Del total, el 37,32% (68.085) correspondieron a estudios de tomografía,62,00 % (113.059) a electrocardiografía(ECG), 0,68 % (1243) a electroencefalografía(EEG) y 0,01 % (19) a ecografía. Se observó unadiferencia importante en el coste de diagnóstico remotoen relación al diagnóstico “cara a cara”, enel análisis se incorporaron los costos de implantacióny mantenimiento de la TIC para el diagnósticoremoto y los costos de transporte, alimentación yoportunidad para el diagnóstico “cara a cara”. Lareducción del coste a través del diagnóstico remoto supone un beneficio importante para cada ciudadanodel interior del país toda vez que el costepromedio de diagnóstico remoto para cada hospitalsea igual o inferior al coste total del diagnósticocara a cara...

Through based on information and communicationtechnologies (ICT), advantageous telediagnosticsystems can be developed to improve the healthcare of remote populations that do not have accessto specialist doctors. This study was carried outby the Telemedicine Unit of the Ministry of PublicHealth and Social Welfare (MSPBS – acronym inspanish) in collaboration with the Department of Biomedical Engineering and Medical Imaging ofthe Institute of Research in Health Sciences of theNational University of Asunción (IICS-UNA acronymin spanish) and the University of the BasqueCountry (UPV / EHU acronym in spanish) servedto evaluate the utility of a telediagnostic system inpublic health. The results obtained by the telediagnosticsystem of 54 regional, district, specializedhospitals and health centers of the MoH (MSPBS)were analyzed. A total of 18.406 remote diagnoseswere performed from January 2014 to November2016 through the system. Of the total, 37.32%(68,085) corresponded to tomography studies(CT), 62.00% (113.059) to electrocardiography(ECG), 0.68% (1243) to electroencephalography(EEG) and 0.01% (19) to ultrasound. A significantdifference was observed in the cost of remote diagnosisin relation to the “face-to-face” diagnosis,in the analysis the costs of implementation andmaintenance of the ICT for the remote diagnosisand transport, feeding and opportunity costs forthe diagnosis “face to face” diagnosis,in the analysis the costs of implementation andmaintenance of the ICT for the remote diagnosisand transport, feeding and opportunity costs forthe diagnosis “face to face” were incorporatedinto the analysis. Reducing costs through remotediagnosis is an important benefit for every citizenof the interior of the country, since the average costof remote diagnosis for each hospital is equal toor less than the total cost of face-to-face diagnosis...

Cell signalling during blastocyst morphogenesis.

Blastocyst morphogenesis is prepared for even before fertilisation. Information stored within parental gametes can influence both maternal and embryonic gene expression programmes after egg activation at fertilisation. A complex network of intrinsic, cell-cell mediated and extrinsic, embryo-environment signalling mechanisms operates throughout cleavage, compaction and cavitation. These signalling events not only ensure developmental progression, cell differentiation and lineage allocation to inner cell mass (embryo proper) and trophectoderm (future extraembryonic lineages) but also provide a degree of developmental plasticity ensuring survival in prevailing conditions by adaptive responses. Indeed, many cellular functions including differentiation, metabolism, gene expression and gene expression regulation are subject to plasticity with short- or long-term consequences even into adult life. The interplay between intrinsic and extrinsic signals impacting on blastocyst morphogenesis is becoming clearer. This has been best studied in the mouse which will be the focus of this chapter but translational significance to human and domestic animal embryology will be a focus in future years.

Impacto de la sobrenutrición materna sobre el periodo de periconcepción / Impact of maternal overnutrition on the periconceptional period

La sobrenutrición puede ocasionar obesidad. La obesidad materna puede afectar la fertilidad no solo a través de la anovulación, sino también por medio de efectos directos en ovocitos y en embriones en la fase de preimplantación, indicando que el periodo de periconcepción es sensible a condiciones de sobrenutrición. El periodo de periconcepción abarca desde la foliculogénesis hasta el momento de la implantación. Estudios en modelos animales indican que ovocitos derivados de hembras obesas usualmente muestran una talla pequeña y anormalidades mitocondriales. Estas perturbaciones son probablemente inducidas a través de alteraciones en los componentes del fluido folicular ovárico. La evidencia experimental también indica que la obesidad puede afectar el microambiente en oviductos y útero, lo cual conlleva al desarrollo de embriones en la fase de preimplantación con un número reducido de células y con una regulación ascendente de genes proinflamatorios. Sin embargo, se necesita más investigación para una caracterización a fondo de los efectos de la obesidad materna durante el periodo de periconcepción

Overnutrition may lead to obesity. Maternal obesity may affect fertility not only via anovulation, but also through direct effects on oocytes and preimplantation embryos, indicating that the periconceptional period is sensitive to conditions of overnutrition. The periconceptional period includes from folliculogenesis to implantation. Animal model studies suggest that oocytes derived from obese females usually have a small size and mitochondrial abnormalities. These disruptions are probably induced by changes in the components of the ovarian follicular fluid. Experimental evidence also suggests that obesity may affect the microenvironment in oviducts and uterus, resulting in development of preimplantation embryos with reduced cell numbers and up-regulation of proinflammatory genes. However, further research is needed for in-depth characterization of the effects of maternal obesity during the periconceptional period

Do little embryos make big decisions? How maternal dietary protein restriction can permanently change an embryo's potential, affecting adult health.

Periconceptional environment may influence embryo development, ultimately affecting adult health. Here, we review the rodent model of maternal low-protein diet specifically during the preimplantation period (Emb-LPD) with normal nutrition during subsequent gestation and postnatally. This model, studied mainly in the mouse, leads to cardiovascular, metabolic and behavioural disease in adult offspring, with females more susceptible. We evaluate the sequence of events from diet administration that may lead to adult disease. Emb-LPD changes maternal serum and/or uterine fluid metabolite composition, notably with reduced insulin and branched-chain amino acids. This is sensed by blastocysts through reduced mammalian target of rapamycin complex 1 signalling. Embryos respond by permanently changing the pattern of development of their extra-embryonic lineages, trophectoderm and primitive endoderm, to enhance maternal nutrient retrieval during subsequent gestation. These compensatory changes include stimulation in proliferation, endocytosis and cellular motility, and epigenetic mechanisms underlying them are being identified. Collectively, these responses act to protect fetal growth and likely contribute to offspring competitive fitness. However, the resulting growth adversely affects long-term health because perinatal weight positively correlates with adult disease risk. We argue that periconception environmental responses reflect developmental plasticity and 'decisions' made by embryos to optimise their own development, but with lasting consequences.

[Impact of maternal overnutrition on the periconceptional period]. / Impacto de la sobrenutrición materna sobre el periodo de periconcepción.

Overnutrition may lead to obesity. Maternal obesity may affect fertility not only via anovulation, but also through direct effects on oocytes and preimplantation embryos, indicating that the periconceptional period is sensitive to conditions of overnutrition. The periconceptional period includes from folliculogenesis to implantation. Animal model studies suggest that oocytes derived from obese females usually have a small size and mitochondrial abnormalities. These disruptions are probably induced by changes in the components of the ovarian follicular fluid. Experimental evidence also suggests that obesity may affect the microenvironment in oviducts and uterus, resulting in development of preimplantation embryos with reduced cell numbers and up-regulation of proinflammatory genes. However, further research is needed for in-depth characterization of the effects of maternal obesity during the periconceptional period.