Can primary health care mitigate the effects of economic crises on child health in Latin America? An integrated multicountry evaluation and forecasting analysis.

BACKGROUND: Latin American and Caribbean countries are dealing with the combined challenges of pandemic-induced socicoeconomic stress and increasing public debt, potentially leading to reductions in welfare and health-care services, including primary care. We aimed to evaluate the impact of primary health-care coverage on child mortality in Latin America over the past two decades and to forecast the potential effects of primary health-care mitigation during the current economic crisis. METHODS: This multicountry study integrated retrospective impact evaluations in Brazil, Colombia, Ecuador, and Mexico from 2000 to 2019 with forecasting models covering up to 2030. We estimated the impact of coverage of primary health care on mortality rates in children younger than 5 years (hereafter referred to as under-5 mortality) across different age groups and causes of death, adjusting for all relevant demographic, socioeconomic, and health-care factors, with fixed-effects multivariable negative binomial models in 5647 municipalities with an adequate quality of vital statistics. We also performed several sensitivity and triangulation analyses. We integrated previous longitudinal datasets with validated dynamic microsimulation models and projected trends in under-5 mortality rates under alternative policy response scenarios until 2030. FINDINGS: High primary health-care coverage was associated with substantial reductions in post-neonatal mortality rates (rate ratio [RR] 0·72, 95% CI 0·71-0·74), toddler (ie, aged between 1 year and <5 years) mortality rates (0·75, 0·73-0·76), and under-5 mortality rates (0·81, 0·80-0·82), preventing 305 890 (95% CI 251 826-360 517) deaths of children younger than 5 years over the period 2000-19. High primary health-care coverage was also associated with lower under-5 mortality rates from nutritional deficiencies (RR 0·55, 95% CI 0·52-0·58), anaemia (0·64, 0·57-0·72), vaccine-preventable and vaccine-sensitive conditions (0·70, 0·68-0·72), and infectious gastroenteritis (0·78, 0·73-0·84). Considering a scenario of moderate economic crisis, a mitigation response strategy implemented in the period 2020-30 that increases primary health-care coverage could reduce the under-5 mortality rate by up to 23% (RR 0·77, 95% CI 0·72-0·84) when compared with a fiscal austerity response, and this strategy would avoid 142 285 (95% CI 120 217-164 378) child deaths by 2030 in Brazil, Colombia, Ecuador, and Mexico. INTERPRETATION: The improvement in primary health-care coverage in Brazil, Colombia, Ecuador, and Mexico over the past two decades has substantially contributed to improving child survival. Expansion of primary health-care coverage should be considered an effective strategy to mitigate the health effects of the current economic crisis and to achieve Sustainable Development Goals related to child health. FUNDING: UK Medical Research Council. TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Disease-Agnostic Electronic Adherence Aid for Subcutaneous at-Home and Self-Administration Devices-The Lowest Common Denominator Based on a Cross-Indication Survey.

The value of connected devices and health apps with features such as adherence trackers, dosing reminders, and remote communication tools for users and healthcare providers has been assessed to support home-based subcutaneous administration. A comprehensive survey was conducted with 605 participants, including users and caregivers, from eight countries. Medical conditions encompassed ankylosing spondylitis, asthma, cerebral palsy, cluster headaches, Crohn's disease, hemophilia, lupus, migraine, multiple sclerosis, Parkinson's disease, plaque psoriasis, psoriatic arthritis, rheumatoid arthritis, spasticity, spondyloarthritis, and ulcerative colitis. Utilizing a maximum difference scaling methodology, the survey gauged participant preferences regarding specific attributes and features of connected drug delivery devices. Irrespective of demographic factors like age, gender, nationality, or the specific medical condition, the device's ability to verify a successful injection stood out as universally valued. The second and third most valued attributes pertained to temperature-related indicators or warnings. These features do not necessitate the use of a connected device and can be integrated into existing autoinjector platforms. The survey findings support the development of a universal adherence tool for at-home subcutaneous dosing, independent of a specific medical condition. This tool may be gradually improved with disease-specific features. Once established as a platform, manufacturers can launch any subcutaneous medication and later integrate real-world evidence for enhanced educational, treatment, and diagnostic capabilities. This approach is crucial for advancing connected adherence tools in decentralized healthcare, aligning with user and healthcare system needs while translating scientific innovation into practical solutions.

Evaluating social protection mitigation effects on HIV/AIDS and Tuberculosis through a mathematical modelling study.

The global economic downturn due to the COVID-19 pandemic, war in Ukraine, and worldwide inflation surge may have a profound impact on poverty-related infectious diseases, especially in low-and middle-income countries (LMICs). In this work, we developed mathematical models for HIV/AIDS and Tuberculosis (TB) in Brazil, one of the largest and most unequal LMICs, incorporating poverty rates and temporal dynamics to evaluate and forecast the impact of the increase in poverty due to the economic crisis, and estimate the mitigation effects of alternative poverty-reduction policies on the incidence and mortality from AIDS and TB up to 2030. Three main intervention scenarios were simulated-an economic crisis followed by the implementation of social protection policies with none, moderate, or strong coverage-evaluating the incidence and mortality from AIDS and TB. Without social protection policies to mitigate the impact of the economic crisis, the burden of HIV/AIDS and TB would be significantly larger over the next decade, being responsible in 2030 for an incidence 13% (95% CI 4-31%) and mortality 21% (95% CI 12-34%) higher for HIV/AIDS, and an incidence 16% (95% CI 10-25%) and mortality 22% (95% CI 15-31%) higher for TB, if compared with a scenario of moderate social protection. These differences would be significantly larger if compared with a scenario of strong social protection, resulting in more than 230,000 cases and 34,000 deaths from AIDS and TB averted over the next decade in Brazil. Using a comprehensive approach, that integrated economic forecasting with mathematical and epidemiological models, we were able to show the importance of implementing robust social protection policies to avert a significant increase in incidence and mortality from AIDS and TB during the current global economic downturn.

Current and Projected Mortality and Hospitalization Rates Associated With Conditional Cash Transfer, Social Pension, and Primary Health Care Programs in Brazil, 2000-2030.

Importance: The health outcomes of increased poverty and inequalities in low- and middle-income countries (LMICs) have been substantially amplified as a consequence of converging multiple crises. Brazil has some of the world's largest conditional cash transfer (Programa Bolsa Família [PBF]), social pension (Beneficio de Prestacão Continuada [BPC]), and primary health care (Estratégia de Saúde da Família [ESF]) programs that could act as mitigating interventions during the current polycrisis era of increasing poverty, slow or contracting economic growth, and conflicts. Objective: To evaluate the combined association of the Brazilian conditional cash transfer, social pension, and primary health care programs with the reduction of morbidity and mortality over the last 2 decades and forecast their potential mitigation of the current global polycrisis and beyond. Design, Setting, and Participants: This cohort study used a longitudinal ecological design with multivariable negative binomial regression models (adjusted for relevant socioeconomic, demographic, and health care variables) integrating the retrospective analysis from 2000 to 2019, with dynamic microsimulation models to forecast potential child mortality scenarios up to 2030. Participants included a cohort of 2548 Brazilian municipalities from 2004 to 2019, projected from 2020 to 2030. Data analysis was performed from September 2022 to February 2023. Exposure: PBF coverage of the target population (those who were poorest) was categorized into 4 levels: low (0%-29.9%), intermediate (30.0%-69.9%), high (70.0%-99.9%), and consolidated (≥100%). ESF coverage was categorized as null (0), low (0.1%-29.9%), intermediate (30.0%-69.9%), and consolidated (70.0%-100%). BPC coverage was categorized by terciles. Main outcomes and measures: Age-standardized, all-cause mortality and hospitalization rates calculated for the entire population and by age group (<5 years, 5-29 years, 30-69 years, and ≥70 years). Results: Among the 2548 Brazilian municipalities studied from 2004 to 2019, the mean (SD) age-standardized mortality rate decreased by 16.64% (from 6.73 [1.14] to 5.61 [0.94] deaths per 1000 population). Consolidated coverages of social welfare programs studied were all associated with reductions in overall mortality rates (PBF: rate ratio [RR], 0.95 [95% CI, 0.94-0.96]; ESF: RR, 0.93 [95% CI, 0.93-0.94]; BPC: RR, 0.91 [95% CI, 0.91-0.92]), having all together prevented an estimated 1 462 626 (95% CI, 1 332 128-1 596 924) deaths over the period 2004 to 2019. The results were higher on mortality for the group younger than age 5 years (PBF: RR, 0.87 [95% CI, 0.85-0.90]; ESF: RR, 0.89 [95% CI, 0.87-0.93]; BPC: RR, 0.84 [95% CI, 0.82-0.86]), on mortality for the group aged 70 years and older, and on hospitalizations. Considering a shorter scenario of economic crisis, a mitigation strategy that will increase the coverage of PBF, BPC, and ESF to proportionally cover the newly poor and at-risk individuals was projected to avert 1 305 359 (95% CI, 1 163 659-1 449 256) deaths and 6 593 224 (95% CI, 5 534 591-7 651 327) hospitalizations up to 2030, compared with fiscal austerity scenarios that would reduce the coverage of these interventions. Conclusions and relevance: This cohort study's results suggest that combined expansion of conditional cash transfers, social pensions, and primary health care should be considered a viable strategy to mitigate the adverse health outcomes of the current global polycrisis in LMICs, whereas the implementation of fiscal austerity measures could result in large numbers of preventable deaths.

A Mathematical Model for the Impact of 3HP and Social Programme Implementation on the Incidence and Mortality of Tuberculosis: Study in Brazil.

In this paper, we presented a mathematical model for tuberculosis with treatment for latent tuberculosis cases and incorporated social implementations based on the impact they will have on tuberculosis incidence, cure, and recovery. We incorporated two variables containing the accumulated deaths and active cases into the model in order to study the incidence and mortality rate per year with the data reported by the model. Our objective is to study the impact of social program implementations and therapies on latent tuberculosis in particular the use of once-weekly isoniazid-rifapentine for 12 weeks (3HP). The computational experimentation was performed with data from Brazil and for model calibration, we used the Markov Chain Monte Carlo method (MCMC) with a Bayesian approach. We studied the effect of increasing the coverage of social programs, the Bolsa Familia Programme (BFP) and the Family Health Strategy (FHS) and the implementation of the 3HP as a substitution therapy for two rates of diagnosis and treatment of latent at 1% and 5%. Based of the data obtained by the model in the period 2023-2035, the FHS reported better results than BFP in the case of social implementations and 3HP with a higher rate of diagnosis and treatment of latent in the reduction of incidence and mortality rate and in cases and deaths avoided. With the objective of linking the social and biomedical implementations, we constructed two different scenarios with the rate of diagnosis and treatment. We verified with results reported by the model that with the social implementations studied and the 3HP with the highest rate of diagnosis and treatment of latent, the best results were obtained in comparison with the other independent and joint implementations. A reduction of the incidence by 36.54% with respect to the model with the current strategies and coverage was achieved, and a greater number of cases and deaths from tuberculosis was avoided.

The combined effect of social pensions and cash transfers on child mortality: evaluating the last two decades in Brazil and projecting their mitigating effect during the global economic crisis.

Background: The world is currently experiencing multiple economic crises due to the COVID-19 pandemic, war in Ukraine, and inflation surge, which disproportionately affect children, especially in low- and middle-income countries (LMICs). We evaluated if the expansion of Social Assistance, represented by Social Pensions (SP) and Conditional Cash Transfers (CCT), could reduce infant and child mortality, and mitigate excess deaths among children in Brazil, one of the LMICs most affected by these economic crises. Methods: We conducted a retrospective impact evaluation in a cohort of Brazilian municipalities from 2004 to 2019 using multivariable fixed-effects negative binomial models, adjusted for relevant demographic, social, and economic factors, to estimate the effects of the SP and CCT on infant and child mortality. To verify the robustness of the results, we conducted several sensitivity and triangulation analyses, including difference-in-difference with propensity-score matching. These results were incorporated into dynamic microsimulation models to generate projections to 2030 of various economic crises and Social Assistance scenarios. Findings: Consolidated coverage of SP was associated with significant reductions in infant and child mortality rates, with a rate ratio (RR) of 0.843 (95% CI: 0.826-0.861) and 0.840 (95% CI: 0.824-0.856), respectively. Similarly, CCT consolidated coverages showed RRs of 0.868 (95% CI: 0.842-0.849) and 0.874 (95% CI: 0.850-0.899) for infant and child mortality, respectively. The higher the degree of poverty in the municipalities, the stronger the impact of CCT on reducing child mortality. Given the current economic crisis, a mitigation strategy that will increase the coverage of SP and CCT could avert 148,736 (95% CI: 127,148-170,706) child deaths up to 2030, compared with fiscal austerity measures. Interpretation: SP and CCT programs could strongly reduce child mortality in LMICs, and their expansion should be considered as an effective strategy to mitigate the impact of the current multiple global economic crises. Funding: Bill & Melinda Gates Foundation, Grant_Number:INV-027961. Medical Research Council(MRC-UKRI),Grant_Number:MC_PC_MR/T023678/1.

Understanding the social determinants of child mortality in Latin America over the last two decades: a machine learning approach.

The reduction of child mortality rates remains a significant global public health challenge, particularly in regions with high levels of inequality such as Latin America. We used machine learning (ML) algorithms to explore the relationship between social determinants and child under-5 mortality rates (U5MR) in Brazil, Ecuador, and Mexico over two decades. We created a municipal-level cohort from 2000 to 2019 and trained a random forest model (RF) to estimate the relative importance of social determinants in predicting U5MR. We conducted a sensitivity analysis training two more ML models and presenting the mean square error, root mean square error, and median absolute deviation. Our findings indicate that poverty, illiteracy, and the Gini index were the most important variables for predicting U5MR according to the RF. Furthermore, non-linear relationships were found mainly for Gini index and U5MR. Our study suggests that long-term public policies to reduce U5MR in Latin America should focus on reducing poverty, illiteracy, and socioeconomic inequalities. This research provides important insights into the relationships between social determinants and child mortality rates in Latin America. The use of ML algorithms, combined with large longitudinal data, allowed us to evaluate the effects of social determinants on health more carefully than traditional models.

Use of Intralesional and Perilesional Human Recombinant Epidermal Growth Factor (hrEGF) in the Local Treatment of Venous Ulcer - Review Article - Expert Recommendation.

Venous Ulcers (VU) represent 60-80% of all leg ulcers and are the final stage of the disease secondary to venous hypertension or valve insufficiency. Conventional treatment that focuses on its etiological factors continues to be the gold standard; however, 30% of ulcers do not heal with this treatment; thus, it has been seen that the use of growth factor can be used as an adjuvant for this pathology. A literature review was carried out to evaluate the evidence from systematic reviews, meta-analyses, case studies, and quantitative studies that respond to the objective of this analysis review in the different databases with specific inclusion criteria with publications between 2002 and 2022, initially finding the topical application of the factor and later, more recently, the intralesional and perilesional application, the latter being an alternative treatment for this type of pathology and generating some recommendations for using the Factor.

Aprendizaje automático aplicado a la predicción de diabetes mellitus, utilizando información socioeconómica y ambiental de usuarios del sistema de salud

Objetivo: Se propuso aplicar modelos basados en técnicas de aprendizaje automático como apoyo para el diagnóstico temprano de la diabetes mellitus, utilizando variables de datos ambientales, sociales, económicos y sanitarios, sin la dependencia de la toma de muestras clínicas. Metodología: Se utilizaron datos de 10 889 usuarios afiliados al régimen subsidiado de salud de la zona suroccidental en Colombia, diagnosticados con hipertensión y agrupados en usuarios sin (74,3 %) y con (25,7 %) diabetes mellitus. Se entrenaron modelos supervisados utilizando k vecinos más cercanos, árboles de decisión y bosques aleatorios, así como modelos basados en ensambles, aplicados a la base de datos antes y después de balancear el número de casos en cada grupo de diagnóstico. Se evalúo el rendimiento de los algoritmos mediante la división de la base de datos en datos de entreno y de prueba (70/30, respectivamente), y se utilizaron métricas de exactitud, sensibilidad, especificidad y área bajo la curva. Resultados: Los valores de sensibilidad aumentaron considerablemente al utilizar datos balanceados, pasando de valores máximos del 17,1 % (datos sin balancear) a valores de hasta 57,4 % (datos balanceados). El valor más alto de área bajo la curva (0,61) fue obtenido con los modelos de ensambles, al aplicar un balance en el número de datos por cada grupo y al codificar las variables categóricas. Las variables de mayor peso estuvieron asociadas con aspectos hereditarios (24,65 %) y con el grupo étnico (5.59 %), además de la dificultad visual, el bajo consumo de agua, una dieta baja en frutas y verduras, y el consumo de sal y azúcar. Conclusiones: Aunque los modelos predictivos, utilizando información socioeconómica y ambiental de las personas, surgen como una herramienta para el diagnóstico temprano de la diabetes mellitus, estos aún deben ser mejorados en su capacidad predictiva.

Objective: The objective was to apply models based on machine learning techniques to support the early diagnosis of diabetes mellitus, using environmental, social, economic and health data variables, without dependence on clinical sample collection. Methodology: Data from 10,889 users affiliated with the subsidized health system in the southwestern area of Colombia, diagnosed with hypertension and grouped into users without (74.3%) and with (25.7%) diabetes mellitus, were used. Supervised models were trained using k-nearest neighbors, decision trees, and random forests, as well as ensemble-based models, applied to the database before and after balancing the number of cases in each diagnostic group. The performance of the algorithms was evaluated by dividing the database into training and test data (70/30, respectively), and metrics of accuracy, sensitivity, specificity, and area under the curve were used. Results: Sensitivity values increased significantly when using balanced data, going from maximum values of 17.1% (unbalanced data) to values as high as 57.4% (balanced data). The highest value of area under the curve (0.61) was obtained with the ensemble models, by applying a balance in the amount of data for each group and by coding the categorical variables. The variables with the greatest weight were associated with hereditary aspects (24.65%) and with the ethnic group (5.59%), in addition to visual difficulty, low water consumption, a diet low in fruits and vegetables, and the consumption of salt and sugar. Conclusions: Although predictive models, using people's socioeconomic and environmental information, emerge as a tool for the early diagnosis of diabetes mellitus, their predictive capacity still needs to be improved.

Objetivo: Propôs-se aplicar modelos baseados em técnicas de aprendizagem automática como apoio para o diagnóstico precoce da diabetes mellitus, utilizando variáveis de dados ambientais, sociais, econômicos e sanitários, sem a dependência da coleta de amostras clínicas. Metodologia: Usaram-se dados de 10.889 usuários filiados ao regime subsidiado de saúde da zona sudoeste da Colômbia, diagnosticados com hipertensão e agrupados em usuários sem (74,3%) e com (25,7%) diabetes mellitus. Foram treinados modelos supervisionados utilizando k vizinhos mais próximos, árvores de decisão e florestas aleatórias, assim como modelos baseados em montagens, aplicados à base de dados antes de depois de equilibrar o número de casos em cada grupo de diagnóstico. Avaliou-se o desempenho dos algoritmos por meio da divisão da base de dados de treino e teste (70/30, respectivamente), e utilizaram-se métricas de exatidão, sensibilidade, especificidade e área sob a curva. Resultados: Os valores de sensibilidade aumentaram de maneira significativa ao utilizar dados equilibrados, passando de valores máximos de 17,1% (dados sem equilibrar) a valores de até 57,4% (dados equilibrados). O valor mais elevado de área sob a curva (0,61) foi obtido com os modelos de montagens, ao aplicar um balanço no número de dados por cada grupo e codificar as variáveis categóricas. As variáveis de maior peso estiveram associadas com fatores hereditários (24,65%) e com o grupo étnico (5,59%), além da dificuldade visual, o baixo consumo de água, um regime baixo em frutas e vegetais e o consumo de sal e açúcar. Conclusões: Embora os modelos preditivos, utilizando informação socioeconômica e ambiental das pessoas, surgem como uma ferramenta para o diagnóstico precoce da diabetes mellitus, ainda devem ser melhorados em sua capacidade preditiva.

Evaluation and Forecasting Analysis of the Association of Conditional Cash Transfer With Child Mortality in Latin America, 2000-2030.

Importance: Latin America has implemented the world's largest and most consolidated conditional cash transfer (CCT) programs during the last 2 decades. As a consequence of the COVID-19 pandemic, poverty rates have markedly increased, and a large number of newly low-income individuals, especially children, have been left unprotected. Objective: To evaluate the association of CCT programs with child health in Latin American countries during the last 2 decades and forecast child mortality trends up to 2030 according to CCT alternative implementation options. Design, Setting, and Participants: This cohort study used a multicountry, longitudinal, ecological design with multivariable negative binomial regression models, which were adjusted for all relevant demographic, socioeconomic, and health care variables, integrating the retrospective impact evaluations from January 1, 2000, to December 31, 2019, with dynamic microsimulation models to forecast potential child mortality scenarios up to 2030. The study cohort included 4882 municipalities from Brazil, Ecuador, and Mexico with adequate quality of civil registration and vital statistics according to a validated multidimensional criterion. Data analysis was performed from September 2022 to February 2023. Exposure: Conditional cash transfer coverage of the target (lowest-income) population categorized into 4 levels: low (0%-29.9%), intermediate (30.0%-69.9%), high (70.0%-99.9%), and consolidated (≥100%). Main Outcomes and Measures: The main outcomes were mortality rates for those younger than 5 years and hospitalization rates (per 1000 live births), overall and by poverty-related causes (diarrheal, malnutrition, tuberculosis, malaria, lower respiratory tract infections, and HIV/AIDS), and the mortality rates for those younger than 5 years by age groups, namely, neonatal (0-28 days), postneonatal (28 days to 1 year), infant (<1 year), and toddler (1-4 years). Results: The retrospective analysis included 4882 municipalities. During the study period of January 1, 2000, to December 31, 2019, mortality in Brazil, Ecuador, and Mexico decreased by 7.8% in children and 6.5% in infants, and an increase in coverage of CCT programs of 76.8% was observed in these Latin American countries. Conditional cash transfer programs were associated with significant reductions of mortality rates in those younger than 5 years (rate ratio [RR], 0.76; 95% CI, 0.75-0.76), having prevented 738 919 (95% CI, 695 641-782 104) child deaths during this period. The association of highest coverage of CCT programs was stronger with poverty-related diseases, such as malnutrition (RR, 0.33; 95% CI, 0.31-0.35), diarrhea (RR, 0.41; 95% CI, 0.40-0.43), lower respiratory tract infections (RR, 0.66, 95% CI, 0.65-0.68), malaria (RR, 0.76; 95% CI, 0.63-0.93), tuberculosis (RR, 0.62; 95% CI, 0.48-0.79), and HIV/AIDS (RR, 0.32; 95% CI, 0.28-0.37). Several sensitivity and triangulation analyses confirmed the robustness of the results. Considering a scenario of moderate economic crisis, a mitigation strategy that will increase the coverage of CCTs to protect those newly in poverty could reduce the mortality rate for those younger than 5 years by up to 17% (RR, 0.83; 95% CI, 0.80-0.85) and prevent 153 601 (95% CI, 127 441-180 600) child deaths by 2030 in Brazil, Ecuador, and Mexico. Conclusions and Relevance: The results of this cohort study suggest that the expansion of CCT programs could strongly reduce childhood hospitalization and mortality in Latin America and should be considered an effective strategy to mitigate the health impact of the current global economic crisis in low- and middle-income countries.

Renal Sympathetic Hyperactivity in Diabetes Is Modulated by 5-HT1D Receptor Activation via NO Pathway.

Renal vasculature, which is highly innervated by sympathetic fibers, contributes to cardiovascular homeostasis. This renal sympathetic outflow is inhibited by 5-HT in normoglycaemic rats. Considering that diabetes induces cardiovascular complications, we aimed to determine whether diabetic state modifies noradrenergic input at renal level and its serotonergic modulation in rats. Alloxan diabetic rats were anaesthetized (pentobarbital; 60 mg/kg i.p.) and prepared for in situ autoperfusion of the left kidney to continuously measure systemic blood pressure (SBP), heart rate (HR), and renal perfusion pressure (RPP). Electrical stimulation of renal sympathetic outflow induces frequency-dependent increases (Δ) in RPP (23.9 ± 2.1, 59.5 ± 1.9, and 80.5 ± 3.5 mm Hg at 2, 4, and 6 Hz, respectively), which were higher than in normoglycaemic rats, without modifying HR or SBP. Intraarterial bolus of 5-HT and 5-CT (5-HT1/5/7 agonist) reduced electrically induced ΔRPP. Only L-694,247 (5-HT1D agonist) reproduced 5-CT inhibition on sympathetic-induced vasoconstrictions, whereas it did not modify exogenous noradrenaline-induced ΔRPP. 5-CT inhibition was exclusively abolished by i.v. bolus of LY310762 (5-HT1D antagonist). An inhibitor of guanylyl cyclase, ODQ (i.v.), completely reversed the L-694,247 inhibitory effect. In conclusion, diabetes induces an enhancement in sympathetic-induced vasopressor responses at the renal level. Prejunctional 5-HT1D receptors, via the nitric oxide pathway, inhibit noradrenergic-induced vasoconstrictions in diabetic rats.

Effect of a conditional cash transfer programme on AIDS incidence, hospitalisations, and mortality in Brazil: a longitudinal ecological study.

BACKGROUND: One of the biggest challenges of the response to the AIDS epidemic is to reach the poorest people. In 2004, Brazil implemented one of the world's largest conditional cash transfer programmes, the Bolsa Família Programme (BFP). We aimed to evaluate the effect of BFP coverage on AIDS incidence, hospitalisations, and mortality in Brazil. METHODS: In this longitudinal ecological study, we developed a conceptual framework linking key mechanisms of BFP effects on AIDS indicators and used ecological panel data from 5507 Brazilian municipalities over the period of 2004-18. We used government sources to calculate municipal-level AIDS incidence, hospitalisation, and mortality rates, and used multivariable regressions analyses of panel data with fixed-effects negative binomial models to estimate the effect of BFP coverage, which was classified as low (0-29%), intermediate (30-69%), and high (≥70%), on AIDS indicators, while adjusting for all relevant demographic, socioeconomic, and health-care covariates at the municipal level. FINDINGS: Between 2004 and 2018, in the municipalities under study, 601 977 new cases of AIDS were notified, of which 376 772 (62·6%) were in males older than 14 years, 212 465 (35·3%) were in females older than 14 years, and 12 740 (2·1%) were in children aged 14 years or younger. 533 624 HIV/AIDS-related hospitalisations, and 176 868 AIDS-related deaths had been notified. High BFP coverage was associated with reductions in incidence rate ratios of 5·1% (95% CI 0·9-9·1) for AIDS incidence, 14·3% (7·7-20·5) for HIV/AIDS hospitalisations, and 12·0% (5·2-18·4) for AIDS mortality. The effect of the BFP on AIDS indicators was more pronounced in municipalities with higher AIDS endemicity levels, with reductions in incidence rate ratios of 12·7% (95% CI 5·4-19·4) for AIDS incidence, 21·1% (10·7-30·2) for HIV/AIDS hospitalisations, and 14·7% (3·2-24·9) for AIDS-related mortality, and reductions in AIDS incidence of 14·6% (5·9-22·5) in females older than 14 years, 9·7% (1·4-17·3) in males older than 14 years, and 24·5% (0·5-42·7) in children aged 14 years or younger. INTERPRETATION: The effect of BFP coverage on AIDS indicators in Brazil could be explained by the reduction of households' poverty and by BFP health-related conditionalities. The protection of the most vulnerable populations through conditional cash transfers could contribute to the reduction of AIDS burden in low-income and middle-income countries. FUNDING: US National Institute of Allergy and Infectious Diseases, National Institutes of Health. TRANSLATION: For the Portugese translation of the abstract see Supplementary Materials section.

CRISPR/Cas9-Directed Gene Trap Constitutes a Selection System for Corrected BCR/ABL Leukemic Cells in CML.

Chronic myeloid leukaemia (CML) is a haematological neoplasm driven by the BCR/ABL fusion oncogene. The monogenic aspect of the disease and the feasibility of ex vivo therapies in haematological disorders make CML an excellent candidate for gene therapy strategies. The ability to abolish any coding sequence by CRISPR-Cas9 nucleases offers a powerful therapeutic opportunity to CML patients. However, a definitive cure can only be achieved when only CRISPR-edited cells are selected. A gene-trapping approach combined with CRISPR technology would be an ideal approach to ensure this. Here, we developed a CRISPR-Trap strategy that efficiently inserts a donor gene trap (SA-CMV-Venus) cassette into the BCR/ABL-specific fusion point in the CML K562 human cell line. The trapping cassette interrupts the oncogene coding sequence and expresses a reporter gene that enables the selection of edited cells. Quantitative mRNA expression analyses showed significantly higher level of expression of the BCR/Venus allele coupled with a drastically lower level of BCR/ABL expression in Venus+ cell fractions. Functional in vitro experiments showed cell proliferation arrest and apoptosis in selected Venus+ cells. Finally, xenograft experiments with the selected Venus+ cells showed a large reduction in tumour growth, thereby demonstrating a therapeutic benefit in vivo. This study represents proof of concept for the therapeutic potential of a CRISPR-Trap system as a novel strategy for gene elimination in haematological neoplasms.

Curación de úlceras venosas crónicas inducida con un hidrogel de aloe vera, sorbitol, alantoína y glicerol.

OBJETIVO: Evaluar la eficacia de un hidrogel compuesto con aloe vera, sorbitol, alantoína y glicerol, y estudiar clínicamente los niveles de interleucina 6 (IL-6) para el tratamiento de úlceras venosas (UV). MÉTODO: Se realizó un ensayo clínico no aleatorizado de un solo brazo en 10 sujetos. Cada sujeto fue tratado con el hidrogel durante ocho semanas. Tras completar el período de seguimiento, se realizó una evaluación final de las puntuaciones clínicas y moleculares de cada paciente, que se comparó con los datos iniciales. RESULTADOS: Los pacientes tratados con el hidrogel presentaron una reducción media del área de la UV de -1,12 cm5 (±2,53), reducción media del volumen de -1,47 cm6 (±3,43) y valor medio de IL-6 perilesional de -1,81 pg/mL (±8,07). También, se encontró una reducción media de la puntuación de la gravedad clínica venosa (VCSSr) de -9,3 (±2,62) y de la puntuación del dolor en la escala visual analógica (VAS) de -5,5 (±2,22). CONCLUSIÓN: La IL-6 es un indicador molecular útil para la vigilancia de la cicatrización de heridas. El tratamiento con un hidrogel a base de aloe vera, sorbitol y alantoína favorece la cicatrización de la herida, mejora la calidad de vida y reduce los niveles de dolor de la UV. CONFLICTO DE INTERÉS: El investigador principal, Dr Jorge Ulloa, declara recepción de recursos para investigación por parte de Humany Care. Este proyecto fue financiado por Humany Care.

Curación de úlceras venosas crónicas inducida con un hidrogel de aloe vera, sorbitol, alantoína y glicerol.

OBJETIVO: Evaluar la eficacia de un hidrogel compuesto con aloe vera, sorbitol, alantoína y glicerol, y estudiar clínicamente los niveles de interleucina 6 (IL-6) para el tratamiento de úlceras venosas (UV). MÉTODO: Se realizó un ensayo clínico no aleatorizado de un solo brazo en 10 sujetos. Cada sujeto fue tratado con el hidrogel durante ocho semanas. Tras completar el período de seguimiento, se realizó una evaluación final de las puntuaciones clínicas y moleculares de cada paciente, que se comparó con los datos iniciales. RESULTADOS: Los pacientes tratados con el hidrogel presentaron una reducción media del área de la UV de -1,12 cm5 (±2,53), reducción media del volumen de -1,47 cm6 (±3,43) y valor medio de IL-6 perilesional de -1,81 pg/mL (±8,07). También, se encontró una reducción media de la puntuación de la gravedad clínica venosa (VCSSr) de -9,3 (±2,62) y de la puntuación del dolor en la escala visual analógica (VAS) de -5,5 (±2,22). CONCLUSIÓN: La IL-6 es un indicador molecular útil para la vigilancia de la cicatrización de heridas. El tratamiento con un hidrogel a base de aloe vera, sorbitol y alantoína favorece la cicatrización de la herida, mejora la calidad de vida y reduce los niveles de dolor de la UV. CONFLICTO DE INTERÉS: El investigador principal, Dr Jorge Ulloa, declara recepción de recursos para investigación por parte de Humany Care. Este proyecto fue financiado por Humany Care.

Estudio Descriptivo: Cumplimiento del estándar de estimación de la edad gestacional en la atención prenatal en un hospital general en Ecuador / Descriptive Study: Compliance of the standards for estimating gestational age during prenatal care in a general hospital in Ecuador.

INTRODUCCIÓN: La datación gestacional es un requisito crítico en la toma de decisiones durante el embarazo; la Organización Mundial de Salud recomienda realizar el primer estudio ecográfico antes de la semana 24 de gestación. La edad gestacional también se puede estimar en función de la historia menstrual. El objetivo del presente estudio fue describir la taza de cumplimiento del estándar de estimación de la edad gestacional en un hospital general en la ciudad de Machala, Ecuador. MATERIALES Y MÉTODOS: El presente es un estudio observacional, descriptivo, trasversal, cuyo universo fueron las pacientes embarazadas que acudieron a consulta prenatal al Hospital General de Machala, El Oro-Ecuador, entre abril del 2017 y marzo del 2020. Se estudió a la totalidad del universo. Se recopilaron datos de las variables: edad, paridad, FUM, edad menstrual, ecografía temprana, datación gestacional confiable. RESULTADOS: El 47.9% de la muestra tuvo entre 18 y 29 años de edad. El 83.33% (195/234) pacientes cumplieron con el registro de semanas de amenorrea. El 75.21% (176/234), de pacientes cumplieron con la recomendación de una ecografía temprana, a las 24 semanas o menos. El 1.28% no tuvo ningún de los métodos de datación gestacional. El 64%(n=149) de la muestra se le realizó la primera ecografía hasta la semana 20 de gestación. De las 140 pacientes que cumplen con tener tanto datación gestacional por FUM confiable y ecografía, en 31/140 pacientes (22.1%) no se pudo confirmar la edad gestacional dada por el tiempo de amenorrea, con la ecografía temprana. CONCLUSIÓN: Concluimos que la datación gestacional obtenida por semanas de amenorrea, se registró en el 83.33% de las pacientes, que califica como un cumplimiento regular. Se realizó ecografía temprana, a las ≤ 24 semanas, como recomienda la OMS en el 75% de las pacientes, que califica como un cumplimiento pobre.(au)

BACKGROUND: Gestational dating is an important requirement for decision-making during pregnancy; the World Health Organization recommends making the first ultrasound before week 24. Gestational age can also be estimated based on menstrual history. The aim of this study was to describe the rate of compliance of the standards for estimating gestational age in a general hospital in Machala, Ecuador. METHODS: This is an observational, descriptive, cross-sectional study; the universe was the total of pregnant women who attended for prenatal care to Hospital General Machala, El Oro- Ecuador, between April 2017 and March 2020. The entire universe was studied. We collected data for the variables: age, parity, last menstrual period( LMP), menstrual age, early ultrasound, reliable gestational dating. RESULTS: 47.9% of the sample was 18 to 29 years old. 83.33% (195/234) patients complied with the weeks of amenorrhea registry. 75.21% (176/234) of patients complied with the recommendation of an early ultrasound, at 24 weeks or less. 1.28% did not have any method of gestational dating. 64% (n=149) of the sample underwent the first ultrasound until week 20. Of 140 patients who complied with having both gestational dating by reliable LMP and ultrasound, in 31/140 (22.1%) the gestational age given by LMP could not be confirmed with early ultrasound. CONCLUSION: We concluded that gestational dating obtained by weeks of amenorrhea was registered n 83.33% of the patients, this rate qualifies as regular compliance. An early ultrasound was performed, at ≤ 24 weeks, as recommended by WHO, in 75% of the patients, this rate qualifies as poor compliance.(au)

CRISPR-Cas9 Technology as a Tool to Target Gene Drivers in Cancer: Proof of Concept and New Opportunities to Treat Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is a hematopoietic malignancy produced by a unique oncogenic event involving the constitutively active tyrosine-kinase (TK) BCR/ABL1. TK inhibitors (TKI) changed its prognosis and natural history. Unfortunately, ABL1 remains unaffected by TKIs. Leukemic stem cells (LSCs) remain, and resistant mutations arise during treatment. To address this problem, we have designed a therapeutic CRISPR-Cas9 deletion system targeting BCR/ABL1. The system was efficiently electroporated to cell lines, LSCs from a CML murine model, and LSCs from CML patients at diagnosis, generating a specific ABL1 null mutation at high efficiency and allowing the edited leukemic cells to be detected and tracked. The CRISPR-Cas9 deletion system triggered cell proliferation arrest and apoptosis in murine and human CML cell lines. Patient and murine-derived xenografts with CRISPR-edited LSCs in NOD SCID gamma niches revealed that normal multipotency and repopulation ability of CRISPR edited LSCs were fully restored. Normal hematopoiesis was restored, avoiding myeloid bias. To the best of our knowledge, we show for the first time how a CRISPR-Cas9 deletion system efficiently interrupts BCR/ABL1 oncogene in primary LSCs to bestow a therapeutic benefit. This study is a proof of concept for genome editing in all those diseases, like CML, sustained by a single oncogenic event, opening up new therapeutic opportunities.

Biological significance of monoallelic and biallelic BIRC3 loss in del(11q) chronic lymphocytic leukemia progression.

BIRC3 is monoallelically deleted in up to 80% of chronic lymphocytic leukemia (CLL) cases harboring del(11q). In addition, truncating mutations in the remaining allele of this gene can lead to BIRC3 biallelic inactivation, which has been shown to be a marker for reduced survival in CLL. Nevertheless, the biological mechanisms by which these lesions could contribute to del(11q) CLL pathogenesis and progression are partially unexplored. We implemented the CRISPR/Cas9-editing system to generate isogenic CLL cell lines harboring del(11q) and/or BIRC3 mutations, modeling monoallelic and biallelic BIRC3 loss. Our results reveal that monoallelic BIRC3 deletion in del(11q) cells promotes non-canonical NF-κB signaling activation via RelB-p52 nuclear translocation, being these effects allelic dose-dependent and therefore further enhanced in del(11q) cells with biallelic BIRC3 loss. Moreover, we demonstrate ex vivo in primary cells that del(11q) cases including BIRC3 within their deleted region show evidence of non-canonical NF-κB activation which correlates with high BCL2 levels and enhanced sensitivity to venetoclax. Furthermore, our results show that BIRC3 mutations in del(11q) cells promote clonal advantage in vitro and accelerate leukemic progression in an in vivo xenograft model. Altogether, this work highlights the biological bases underlying disease progression of del(11q) CLL patients harboring BIRC3 deletion and mutation.

A phenolic-rich extract from Ugni molinae berries reduces abnormal protein aggregation in a cellular model of Huntington's disease.

Accumulation of misfolded proteins in the brain is a common hallmark of most age-related neurodegenerative diseases. Previous studies from our group identified the presence of anti-inflammatory and antioxidant compounds in leaves derived from the Chilean berry Ugni molinae (murtilla), in addition to show a potent anti-aggregation activity in models of Alzheimer´s disease. However, possible beneficial effects of berry extracts of murtilla was not investigated. Here we evaluated the efficacy of fruit extracts from different genotypes of Chilean-native U. molinae on reducing protein aggregation using cellular models of Huntington´s disease and assess the correlation with their chemical composition. Berry extraction was performed by exhaustive maceration with increasing-polarity solvents. An unbiased automatic microscopy platform was used for cytotoxicity and protein aggregation studies in HEK293 cells using polyglutamine-EGFP fusion proteins, followed by secondary validation using biochemical assays. Phenolic-rich extracts from murtilla berries of the 19-1 genotype (ETE 19-1) significantly reduced polyglutamine peptide aggregation levels, correlating with the modulation in the expression levels of autophagy-related proteins. Using LC-MS and molecular network analysis we correlated the presence of flavonoids, phenolic acids, and ellagitannins with the protective effects of ETE 19-1 effects on protein aggregation. Overall, our results indicate the presence of bioactive components in ethanolic extracts from U. molinae berries that reduce the load of protein aggregates in living cells.

Changes in the Organosulfur and Polyphenol Compound Profiles of Black and Fresh Onion during Simulated Gastrointestinal Digestion.

This study aims to determine the changes in, and bioaccessibility of, polyphenols and organosulfur compounds (OSCs) during the simulated gastrointestinal digestion of black onion, a novel product derived from fresh onion by a combination of heat and humidity treatment, and to compare it with its fresh counterpart. Fresh and black onions were subjected to in-vitro gastrointestinal digestion, and their polyphenol and OSC profiles were determined by ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS). Although to a lesser extent than in the fresh onion, the phenolic compounds in the black variety remained stable during the digestion process, presenting a higher bioaccessibility index (BI) with recovery corresponding to 41.1%, compared with that of fresh onion (23.5%). As for OSCs, apart from being more stable after the digestion process, with a BI of 83%, significantly higher quantities (21 times higher) were found in black onion than in fresh onion, suggesting that the black onion production process has a positive effect on the OSC content. Gallic acid, quercetin, isorhamnetin, and ɣ-glutamyl-S-(1-propenyl)-L-cysteine sulfoxide were the most bioaccessible compounds in fresh onion, while isorhamnetin, quercetin-diglucoside, ɣ-glutamyl-S-methyl-L-cysteine sulfoxide and methionine sulfoxide were found in black onion. These results indicate that OSCs and polyphenols are more bioaccessible in black onion than in fresh onion, indicating a positive effect of the processing treatment.