Foxd1-dependent induction of a temporal retinal character is required for visual function.

Appropriate patterning of the retina during embryonic development is assumed to underlie the establishment of spatially localised specialisations that mediate the perception of specific visual features. For example, in zebrafish, an area involved in high acuity vision (HAA) is thought to be present in the ventro-temporal retina. Here, we show that the interplay of the transcription factor Rx3 with Fibroblast Growth Factor and Hedgehog signals initiates and restricts foxd1 expression to the prospective temporal retina, initiating naso-temporal regionalisation of the retina. Abrogation of Foxd1 results in the loss of temporal and expansion of nasal retinal character, and consequent absence of the HAA. These structural defects correlate with severe visual defects, as assessed in optokinetic and optomotor response assays. In contrast, optokinetic responses are unaffected in the opposite condition, in which nasal retinal character is lost at the expense of expanded temporal character. Our study indicates that the establishment of temporal retinal character during early retinal development is required for the specification of the HAA, and suggests a prominent role of the temporal retina in controlling specific visual functions.

Reading tea leaves worldwide: Decoupled drivers of initial litter decomposition mass-loss rate and stabilization.

The breakdown of plant material fuels soil functioning and biodiversity. Currently, process understanding of global decomposition patterns and the drivers of such patterns are hampered by the lack of coherent large-scale datasets. We buried 36,000 individual litterbags (tea bags) worldwide and found an overall negative correlation between initial mass-loss rates and stabilization factors of plant-derived carbon, using the Tea Bag Index (TBI). The stabilization factor quantifies the degree to which easy-to-degrade components accumulate during early-stage decomposition (e.g. by environmental limitations). However, agriculture and an interaction between moisture and temperature led to a decoupling between initial mass-loss rates and stabilization, notably in colder locations. Using TBI improved mass-loss estimates of natural litter compared to models that ignored stabilization. Ignoring the transformation of dead plant material to more recalcitrant substances during early-stage decomposition, and the environmental control of this transformation, could overestimate carbon losses during early decomposition in carbon cycle models.

Early-life external exposome in children 2-5 years old in Colombia.

Exposome studies are advancing in high-income countries to understand how multiple environmental exposures impact health. However, there is a significant research gap in low- and middle-income and tropical countries. We aimed to describe the spatiotemporal variation of the external exposome, its correlation structure between and within exposure groups, and its dimensionality. A one-year follow-up cohort study of 506 children under 5 in two cities in Colombia was conducted to evaluate asthma, acute respiratory infections, and DNA damage. We examined 48 environmental exposures during pregnancy and 168 during childhood in eight exposure groups, including atmospheric pollutants, natural spaces, meteorology, built environment, traffic, indoor exposure, and socioeconomic capital. The exposome was estimated using geographic information systems, remote sensing, spatiotemporal modeling, and questionnaires. The median age of children at study entry was 3.7 years (interquartile range: 2.9-4.3). Air pollution and natural spaces exposure decreased from pregnancy to childhood, while socioeconomic capital increased. The highest median correlations within exposure groups were observed in meteorology (r = 0.85), traffic (r = 0.83), and atmospheric pollutants (r = 0.64). Important correlations between variables from different exposure groups were found, such as atmospheric pollutants and meteorology (r = 0.76), natural spaces (r = -0.34), and the built environment (r = 0.53). Twenty principal components explained 70%, and 57 explained 95% of the total variance in the childhood exposome. Our findings show that there is an important spatiotemporal variation in the exposome of children under 5. This is the first characterization of the external exposome in urban areas of Latin America and highlights its complexity, but also the need to better characterize and understand the exposome in order to optimize its analysis and applications in local interventions aimed at improving the health conditions and well-being of the child population and contributing to environmental health decision-making.

Immunological and inflammatory effects of infectious diseases in circadian rhythm disruption and future therapeutic directions.

BACKGROUND: Circadian rhythm is characterised by daily variations in biological activity to align with the light and dark cycle. These diurnal variations, in turn, influence physiological functions such as blood pressure, temperature, and sleep-wake cycle. Though it is well established that the circadian pathway is linked to pro-inflammatory responses and circulating immune cells, its association with infectious diseases is widely unknown. OBJECTIVE: This comprehensive review aims to describe the association between circadian rhythm and host immune response to various kinds of infection. METHODS: We conducted a literature search in databases Pubmed/Medline and Science direct. Our paper includes a comprehensive analysis of findings from articles in English which was related to our hypothesis. FINDINGS: Molecular clocks determine circadian rhythm disruption in response to infection, influencing the host's response toward infection. Moreover, there is a complex interplay with intrinsic oscillators of pathogens and the influence of specific infectious processes on the CLOCK: BMAL1 pathway. Such mechanisms vary for bacterial and viral infections, both well studied in the literature. However, less is known about the association of parasitic infections and fungal pathogens with circadian rhythm modulation. CONCLUSION: It is shown that bidirectional relationships exist between circadian rhythm disruption and infectious process, which contains interplay between the host's and pathogens' circadian oscillator, immune response, and the influence of specific infectious. Further studies exploring the modulations of circadian rhythm and immunity can offer novel explanations of different susceptibilities to infection and can lead to therapeutic avenues in circadian immune modulation of infectious diseases.

Hydropeaking affects germination and establishment of riverbank vegetation.

Hydropeaking, defined as frequent and rapid variation in flow in regulated rivers with hydropower plants over a short period of time, usually sub-daily to weekly, alters hydraulic parameters such as water levels or flow velocity and exerts strong impacts on fluvial ecosystems. We evaluated the effects of hydropeaking on riverbank vegetation, specifically assessing the germination and establishment of seedlings and cuttings of plant species representing a variation in traits. We used seeds and seedlings and cuttings varying in size as phytometers, and transplanted them to riverbanks both above and below dams used for hydropower production in northern Sweden, selected to represent a gradient in hydropeaking intensity, and along a free-flowing reach. We also analyzed sub-daily water-level variables modified by hydropeaking to identify variables key in explaining the observed vegetation patterns. We found that plant responses to hydropeaking varied with species, with flood-intolerant species being the most strongly affected, as early as the germination stage. In contrast, seeds of flood-tolerant species managed to germinate and survive the early establishment phase, although strong erosive processes triggered by hydropeaking eventually caused most of them to fail. The fate of flood-intolerant species identifies germination as the most critical life-history stage. The depth and frequency of the inundation were the leading variables explaining plant responses, while the duration of shallow inundation explained little of the variation. The rise and fall rates of water levels were key in explaining variation in germination success. Based on the results, we propose restoration measures to enhance establishment of riparian plant communities while minimizing the impact on hydropower electricity production. Given the strong decrease in the germination of species intolerant to prolonged flooding with hydropeaking, planting of seedlings, preferably of large sizes, together with restrictions in the operation of the power plant during the establishment phase to enhance survival would be the best restoration option. Given the high probability of plant uprooting with hydropeaking, bank protection measures have the potential to increase riparian plant survival of all species, including flooding-tolerant species.

Opposing Shh and Fgf signals initiate nasotemporal patterning of the zebrafish retina.

The earliest known determinants of retinal nasotemporal identity are the transcriptional regulators Foxg1, which is expressed in the prospective nasal optic vesicle, and Foxd1, which is expressed in the prospective temporal optic vesicle. Previous work has shown that, in zebrafish, Fgf signals from the dorsal forebrain and olfactory primordia are required to specify nasal identity in the dorsal, prospective nasal, optic vesicle. Here, we show that Hh signalling from the ventral forebrain is required for specification of temporal identity in the ventral optic vesicle and is sufficient to induce temporal character when activated in the prospective nasal retina. Consequently, the evaginating optic vesicles become partitioned into prospective nasal and temporal domains by the opposing actions of Fgfs and Shh emanating from dorsal and ventral domains of the forebrain primordium. In absence of Fgf activity, foxd1 expression is established irrespective of levels of Hh signalling, indicating that the role of Shh in promoting foxd1 expression is only required in the presence of Fgf activity. Once the spatially complementary expression of foxd1 and foxg1 is established, the boundary between expression domains is maintained by mutual repression between Foxd1 and Foxg1.

Traits of riparian woody plants responding to hydrological and hydraulic conditions: a northern Swedish database.

The main goal of this study was to create a database that ultimately serves further studies on riparian vegetation and flow response guilds in the boreal region and on transferability of results across different regions. To achieve this aim, we compiled traits for all woody riparian species in northern Sweden which, directly or indirectly, underlie their responses to hydrological and hydraulic conditions, between October 2012 and April 2015. Consulted sources of information were diverse, ranging from scientific to informative and whose accuracy might or might not be verified. They were focused on particular or several traits and species from concrete areas to a worldwide perspective. Sources were characterized by different degrees of accessibility and showed a wide variety of descriptions, categorical and ordinal classifications, and numerical information for each trait. Our effort was to synthesize information for each trait from all sources into the common frame of our own database, following own defined criteria so that comparisons between species are congruent. Therefore, this data set is unique in that it comprehensively combines and homogenizes morphological, phenological, reproductive, and ecological data for 59 woody, riparian, boreal species and from 118 sources of information, that would otherwise be scattered and hardly available.

Volatile composition of Pedro Ximénez and Muscat sweet Sherry wines from sun and chamber dried grapes: a feasible alternative to the traditional sun-drying.

Sweet Sherry wines from Pedro Ximénez and Muscat sun and chamber-dried grapes during vintages 2009 and 2010 were aged in American oak wood for 12 months. Their volatile content was periodically analyzed using SBSE-GC-MS. Cluster analysis and principal component analysis demonstrated that the volatile compounds considered can be used to detect grape variety and vintage. Principal component analysis for each grape variety, clearly differentiated aging time and vintage. Drying type was the least significant factor. Sweet wines produced using chamber driers were from Pedro Ximénez and Muscat grapes provides similar in volatile constituents as those produced by traditional process.

The differences in plant invasion in two types of shorelines under flow regulation of the Three Gorges Reservoir.

Riparian zones, crucial for linking fluvial and terrestrial habitats, are among the most diverse ecosystems. However, they are intensively invaded by alien plants, particularly in dam-regulated rivers. Therefore, understanding the mechanisms underlying plant invasion in dam-regulated river systems has become increasingly important, given that over two-thirds of global rivers are artificially regulated. Regulated rivers may flood upland areas or pristine riparian zones, resulting in shorelines developed from pre-upland and pre-riparian areas. However, differences in invasion intensities, adaptive strategies of invasive plants, and native species' resistance (namely the diversity-invasibility relationship) across these shorelines are unclear. To address these uncertainties, we performed field investigations in the Three Gorges Reservoir (TGR) on the upper Yangtze River, where both pre-upland and pre-riparian shorelines are present. Our findings indicate that pre-upland shorelines are more intensively invaded, showing higher relative richness and cover of invasive species. Invasive plants in this area displayed more conservative resource strategies and greater drought tolerance, exhibiting lower community-weighted mean (CWM) specific leaf area, higher CWM leaf dry mass content, and larger CWM seed mass. Pre-upland shorelines' invasibility decreased as the richness and cover of native species increased, a trend not observed in pre-riparian shorelines. The observed variations in plant invasion between the two shoreline types are primarily driven by differences in resident plant presence, soil moisture levels, and hydrological disturbances. This study provides valuable insights for policymakers and practitioners involved in managing invasive plants in regulated river ecosystems.

Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial.

BACKGROUND: The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL. METHODS: Patients with relapsed or refractory MCL who had received one to four previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at MD Anderson Cancer Center. In phase 1, to identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1-21 of each 28-day cycle. 375 mg/m(2) intravenous rituximab was also administered in four weekly doses during cycle 1 only. In phase 2, patients received rituximab plus the MTD of lenalidomide, following the same cycles as for phase 1. Treatment in both phases continued until disease progression, stem-cell transplantation, or severe toxicity. The primary efficacy endpoint was overall response (complete or partial response). The secondary efficacy endpoint was survival. We used the Kaplan-Meier method to estimate response duration, progression-free survival, and overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00294632. FINDINGS: 52 patients were enrolled between Feb 10, 2006 and July 30, 2009, 14 in phase 1 and 44 (including six patients who received the MTD of lenalidomide in the phase 1 portion) in phase 2. The MTD was 20 mg lenalidomide. One patient who was treated with 25 mg lenalidomide developed a grade 4 non-neutropenic infection and died. In the phase 2 portion of the study, grade 3-4 haematological toxicities included neutropenia (29 patients), lymphopenia (16 patients), leucopenia (13 patients), and thrombocytopenia (ten patients). There were only two episodes of febrile neutropenia. Among 44 patients in phase 2, 25 (57%) had an overall response: 16 (36%) had a complete response and nine (20%) had a partial response. The median response duration was 18·9 months (95% CI 17·0 months to not reached [NR]). The median progression-free survival was 11·1 months (95% CI 8·3 to 24·9 months), and the median overall survival was 24·3 months (19·8 months to NR). Five of 14 patients who had received bortezomib treatment before enrolment achieved an overall response. INTERPRETATION: Oral lenalidomide plus rituximab is well tolerated and effective for patients with relapsed or refractory MCL. FUNDING: Celgene.

Digitalization and real-time control to mitigate environmental impacts along rivers: Focus on artificial barriers, hydropower systems and European priorities.

Hydropower globally represents the main source of renewable energy, and provides several benefits, e.g., water storage and flexibility; on the other hand, it may cause significant impacts on the environment. Hence sustainable hydropower needs to achieve a balance between electricity generation, impacts on ecosystems and benefits on society, supporting the achievement of the Green Deal targets. The implementation of digital, information, communication and control (DICC) technologies is emerging as an effective strategy to support such a trade-off, especially in the European Union (EU), fostering both the green and the digital transitions. In this study, we show how DICC can foster the environmental integration of hydropower into the Earth spheres, with focus on the hydrosphere (e.g., on water quality and quantity, hydropeaking mitigation, environmental flow control), biosphere (e.g., improvement of riparian vegetation, fish habitat and migration), atmosphere (reduction of methane emissions and evaporation from reservoirs), lithosphere (better sediment management, reduction of seepages), and on the anthroposphere (e.g., reduction of pollution associated to combined sewer overflows, chemicals, plastics and microplastics). With reference to the abovementioned Earth spheres, the main DICC applications, case studies, challenges, Technology Readiness Level (TRL), benefits and limitations, and transversal benefits for energy generation and predictive Operation and Maintenance (O&M), are discussed. The priorities for the European Union are highlighted. Although the paper focuses primarly on hydropower, analogous considerations are valid for any artificial barrier, water reservoir and civil structure which interferes with freshwater systems.

Comparison of the Diagnostic Performance of Five Clinical Questionnaires for Chronic Obstructive Pulmonary Disease.

Background: Chronic obstructive pulmonary disease (COPD) remains one of the most prevalent pathologies in the world and is among the leading causes of mortality and morbidity, partially due to underdiagnosis. The use of clinical questionnaires to identify high-risk individuals to take them to further diagnostic procedures has emerged as a strategy to address this problem. Objective: To compare the performance of the COULD IT BE COPD, CDQ, COPD-PS, LFQ, and PUMA questionnaires for COPD diagnosis. Methods: A cross-sectional study was carried out on subjects who underwent spirometry in the third-level center. Data were collected between January 2015 and March 2020. Bivariate analysis was performed between the study variables and the presence of COPD. The area under the receiver operating characteristics curve (AUC-ROC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) for each questionnaire were calculated. The AUC-ROCs were compared with the DeLong test, considering a p value <0.05 statistically significant. Results: 681 subjects met the inclusion criteria and were taken to the final analysis. The prevalence of COPD was 27.5% (187/681). The mean age of the subjects was 65.9 years (SD ± 11.79); 46.3% (315/681) were female, and 83.6% (569/681) reported respiratory symptoms. Statistically significant relationship was found for COPD diagnosis with male sex, older age, respiratory symptoms, and exposure to wood smoke (p value <0.05). The AUC-ROCs of the questionnaires were between 0.581 and 0.681. The COULD IT BE COPD questionnaire had a lower discriminatory capacity AUC-ROC of 0.581, concerning the other scores (DeLong test, p = 0.0002). Conclusion: The CDQ, COPD-PS, LFQ, PUMA, and COULD IT BE COPD questionnaires have acceptable performance for the diagnosis of COPD together with low sensitivity and specificity. Therefore, its use must be complemented with other diagnostic tests or techniques such as pulmonary function tests.

Trapped between drowning and desiccation: Riverine plants under hydropeaking.

Hydropeaking is part of hydropower production. The discontinuous release of turbined water during hydropeaking generates sudden rise and falls of the water levels, as well as extended droughts. These artificial flow fluctuations impose challenging growing conditions for riverine vegetation. In order to identify vulnerable/resistant plant species to hydropeaking and to evaluate the impact of contrasting hydropeaking scenarios (simplified (i.e., sudden deep floods, frequent soil saturation and drought) and real-life, power plant-induced scenarios), we measured germination, survival, and morphological and physiological attributes of a selection of 14 plant species commonly found along riparian areas. Species were subject to different hydropeaking scenarios during three months (vegetative period) in the field and in a greenhouse. Half of the species performed worse under hydropeaking in comparison to the control (e.g., less germination and biomass, lower growth rates, reduced stem and root length, physiological stress) but none of the tested hydropeaking scenarios was clearly more disruptive than others. Betula pubescens, Alnus incana and Filipendula ulmifolia showed the largest vulnerability to hydropeaking, while other species (e.g., Carex acuta) were resistant to it. Both in the field and in the greenhouse, plants in perturbed scenarios accumulated more 13C than in the control scenario indicating limited capacity to perform 13C isotope discrimination and evidencing plant physiological stress. The highest 13C abundances were found under drought or flooding conditions in the greenhouse, and under the highest hydropeaking intensities in the field (e.g., Betula pubescens). Our results suggest that any hydropeaking scheme can be equally detrimental in terms of plant performance. Hydropeaking schemes that combine periods of severe drought with long and frequent flooding episodes may create a hostile environment for riverine species. Further research on "hydropeaking-tolerant" plant traits is key to draw the boundaries beyond which riverine species can germinate, grow and complete their life cycle under hydropeaking.

Hypermucoviscous Klebsiella pneumoniae invasive syndrome in a patient with diabetes without liver abscess.

Klebsiella pneumoniae is part of the human gastrointestinal microbiota. It is also a well-known cause of community and nosocomial infections, involving mainly the lung and urinary tract. An invasive syndrome with liver abscess due to a new hypervirulent strain of K. pneumoniae was recently described. Several cases have been reported, mainly in Asia. Here, we show a case of a patient with an extrahepatic involvement affecting the lung and prostate.

Endemic Burkitt's lymphoma as a polymicrobial disease: new insights on the interaction between Plasmodium falciparum and Epstein-Barr virus.

Despite the well-established relationship between endemic Plasmodium falciparum malaria and Epstein-Barr virus (EBV) infection in the genesis of endemic Burkitt's lymphoma (eBL), very little research has examined the interaction between these two pathogens. eBL, the most prevalent childhood cancer in equatorial Africa where malaria is holoendemic, is a high-grade B cell lymphoma characterized by a c-myc translocation and the consistent presence of EBV. After primary infection, EBV establishes a life-long persistent infection characterized by virus shedding into saliva. African children are infected early in life and most have sero-converted by 3 years of age while sero-conversion tends to occur later in developed countries. Acute and chronic malaria infections profoundly affect the B cell compartment, inducing polyclonal activation, hyper-gammaglobulinemia and a dramatic increase in the levels of circulating EBV. In this review we present and discuss recent data suggesting a molecular link between the parasite, the B cell and EBV and provide evidence that adds to the concept of polymicrobial disease pathogenesis in eBL. Following the observation of EBV reactivation in children living in malaria endemic areas and its relationship with acute malaria infection, we identified the cystein-rich inter-domain region 1 alpha (CIDR1 alpha) of the Plasmodium falciparum membrane protein 1 as a polyclonal B cell activator. CIDR1 alpha increases B cell survival and preferentially activates the memory compartment where EBV is known to persist. Analysis of the mechanisms of interaction between CIDR1 alpha and EBV in the context of B cells demonstrated that CIDR1 alpha induces virus production in the EBV-infected B cell line Akata and in latently infected primary B cells derived from the peripheral blood of healthy carriers and children with eBL. This is the first demonstration that EBV can be reactivated directly by another pathogen. Our results suggest that P. falciparum antigens such as PfEMP1 can directly induce EBV reactivation during malaria infections. The increased viral load and the concomitant polyclonal B cell activation with enhanced B cell survival may augment the risk of eBL development in children living in malaria-endemic areas.

Can vegetation provide shelter to cyprinid species under hydropeaking?

A novel study that focuses on the capacity of vegetation to provide shelter for fish species under hydropeaking regimes is presented. Two artificial patches mimicking the structure and density of Carex sp. mats were installed in an experimental flume to test whether submerged plants can offer flow refuge to two cyprinid species, Luciobarbus bocagei and Pseudochondrostoma polylepis, under baseflow and hydropeaking scenarios. Local flow fields were characterized using a Lateral Line Probe (LLP) and an Acoustic Doppler Velocimeter (ADV) and 33 h of video analysis were viewed to report, on a per-second basis, fish use of 1) patches with plants, 2) patches upstream and 3) downstream from vegetation and 4) patches without vegetation. Data on flow fields and fish patch use were integrated and analyzed to assess whether plants favored fish sheltering behavior. Vegetation created hydraulically stable areas suitable for fish to shelter, triggering changes in fish patch use. Although both species sheltered under hydropeaking, L. bocagei presented a stronger preference than P. polylepis for vegetated patches and areas downstream from plants, taking advantage of sheltered regions more frequently. P. polylepis weaker search for shelter could be related to species-specific factors and territorial behavior interferences rather than to fish performance relative to flume hydraulic conditions. Despite a weaker response, some P. polylepis individuals used patches downstream from plants more during the second half of the hydropeaking trials. A trade-off between reducing swimming effort and territoriality might explain this response. Results indicate that vegetation can help to counterbalance the impact of hydropeaking on fish while providing river functioning benefits. Evaluating fish sheltering to a wide set of river plants and patch designs on a species-by-species basis would help targeting vegetation-based actions for restoring hydropeaking rivers.

Functional Diversity of Riparian Woody Vegetation Is Less Affected by River Regulation in the Mediterranean Than Boreal Region.

River regulation may filter out riparian plants often resulting in reduced functional diversity, i.e., in the range of functions that organisms have in communities and ecosystems. There is, however, little empirical evidence about the magnitude of such reductions in different regions. We investigated the functional diversity patterns of riparian woody vegetation to streamflow regulation in boreal Sweden and Mediterranean Portugal using nine plant functional traits and field data from 109 sampling sites. We evaluated changes in mean plant functional traits as well as in indices of multidimensional functional traits, i.e., functional richness (FRic) and functional redundancy (FRed) within regions and between free-flowing and regulated river reaches. We found that regulation significantly reduced functional diversity in Sweden but not in Portugal. In Sweden, the increased magnitude of variations in water flow and water level in summer, the prolonged duration of extreme hydrological events, the increased frequency of high-water pulses, and the rate of change in water conditions were the likely main drivers of functional diversity change. Small riparian plant species with tiny leaves, poorly lignified stems, and shallow root systems were consistently associated with regulated sites in the boreal region. In Portugal, the similar functional diversity values for free-flowing and regulated rivers likely stem from the smaller streamflow alterations by regulation combined with the species legacy adaptations to the Mediterranean natural hydrological regimes. We conclude that streamflow regulation may reduce the functional diversity of riparian woody vegetation, but the magnitude of these effects will vary depending on the adaptations of the local flora and the patterns of streamflow disturbances. Our study provides insights into functional diversity patterns of riparian woody vegetation affected by regulation in contrasting biomes and encourages further studies of the functional diversity thresholds for maintaining ecosystems.

[Implementation research of primary health care in Paraguay in three periods of government: political, technical and social dimensions at the subnational level.] / Implementación de la Atención Primaria de Salud en Paraguay en tres periodos de gobierno: dimensiones políticas, sociales y técnicas observadas en el nivel subnacional.

OBJECTIVE: The study hopes to contribute to the analysis of political, technical and social dimensions and sub-dimensions that affect the processes of adjustments to the health system model based on the renewed PHC (Primary Health Care) strategy, at the regional (meso) and local levels. (micro), levels where problems and obstacles are externalized and institutional capacity gaps are verified, in contexts of changes in political leadership, which put their sustainability at risk. The observation included three government periods (2008-2012, 2012- 2013 and 2013-2018), in two departments of Paraguay (Misiones -rural- and Central -urban-). METHODS: Qualitative research on the implementation of public health policy in Paraguay, aimed at promoting improvements in health services in specific contexts, through case studies, complemented with a documentary review. It explores macro, meso, and micro health processes, disaggregated in their political, social, and technical dimensions, to trace the PHC management profile over time. Directors, managers, and professionals in the field of health with experience, commitment, adherence, and prior knowledge were interviewed, using a priori analysis categories. The data and selection of discursive fragments were processed with the Atlas Ti software and auxiliary matrices in Excel. RESULTS: Social changes and health outcomes are perceived in the study regions, despite financial restrictions and no flexibility of public spending on health attributed to the leadership and individual performance of health workers, which establish differences in terms of empowerment, cohesion and commitment in the development of the strategies outlined by the technical teams and decision-makers responsible for the implementation of policy lines in primary health care. CONCLUSIONS: There are technological limitations, asymmetries of the information subsystems that translate into management weaknesses, as well as little community participation in the design and evaluation of health plans. Coordination weaknesses and improvement plans were detected in operating units of the regional networks, as well as. different training modalities. The availability of specialists in family medicine is low.

OBJETIVO: El estudio espera contribuir al análisis de dimensiones y subdimensiones políticas, técnicas y sociales que repercuten en los procesos de ajustes al modelo de sistema de salud basado en la estrategia renovada de APS (Atención Primaria de Salud), a nivel regional (meso) y local (micro), niveles donde se exteriorizan los problemas, obstáculos y se constatan las brechas de capacidad institucional, en contextos de cambios de conducción política, que ponen en riesgo su sostenibilidad, La observación incluyo tres periodos de gobierno (2008-2012, 2012-2013 y 2013-2018), en dos departamentos de Paraguay (Misiones -rural- y Central -urbano-). METODOS: Se realizó una investigación cualitativa sobre la implementación de políticas públicas de salud, basada en estudios de caso en contextos específicos, complementada con revisión documental. Se exploraron procesos sanitarios macro, meso y micro, desagregados en dimensiones políticas, sociales y técnicas, para poder trazar el perfil de gestión de la APS en el nivel subnacional en tres periodos de gestión de gobierno. Se entrevistó a directores, gerentes y profesionales sanitarios, con experiencia, compromiso, adherencia y conocimiento previo, utilizando categorías de análisis seleccionadas a priori. Los datos y selección de fragmentos discursivos fueron procesados con el software Atlas Ti y hojas de cálculo en Excel. RESULTADOS: A pesar de las restricciones financieras y la nula flexibilidad del gasto público, se declararon resultados positivos en salud en las regiones en estudio, atribuidas al liderazgo, el empoderamiento, el desempeño individual, la cohesión de los equipos de salud y el compromiso en el desarrollo de las estrategias delineadas, todo ello en el marco de implementación de las políticas de APS. Se constataron asimetrías y limitaciones tecnológicas de los subsistemas de información, traducidas en debilidades de gestión. Se consideró incipiente la participación comunitaria en el diseño y evaluación de planes de salud. Persistían debilidades de coordinación para la continuidad de los cuidados. Se desarrollaron diferentes modelos de capacitación en los diferentes niveles. Fue insuficiente la dotación de médicos de familia. CONCLUSIONES: Los vínculos entre los objetivos de implementación de las líneas de políticas de Atención Primaria de salud, los procesos decisorios y la sostenibilidad administrativa han permanecido frágiles durante los sucesivos cambios de gobierno.

A molecular link between malaria and Epstein-Barr virus reactivation.

Although malaria and Epstein-Barr (EBV) infection are recognized cofactors in the genesis of endemic Burkitt lymphoma (BL), their relative contribution is not understood. BL, the most common paediatric cancer in equatorial Africa, is a high-grade B cell lymphoma characterized by c-myc translocation. EBV is a ubiquitous B lymphotropic virus that persists in a latent state after primary infection, and in Africa, most children have sero-converted by 3 y of age. Malaria infection profoundly affects the B cell compartment, inducing polyclonal activation and hyper-gammaglobulinemia. We recently identified the cystein-rich inter-domain region 1alpha (CIDR1alpha) of the Plasmodium falciparum membrane protein 1 as a polyclonal B cell activator that preferentially activates the memory compartment, where EBV is known to persist. Here, we have addressed the mechanisms of interaction between CIDR1alpha and EBV in the context of B cells. We show that CIDR1alpha binds to the EBV-positive B cell line Akata and increases the number of cells switching to the viral lytic cycle as measured by green fluorescent protein (GFP) expression driven by a lytic promoter. The virus production in CIDR1alpha-exposed cultures was directly proportional to the number of GFP-positive Akata cells (lytic EBV) and to the increased expression of the EBV lytic promoter BZLF1. Furthermore, CIDR1alpha stimulated the production of EBV in peripheral blood mononuclear cells derived from healthy donors and children with BL. Our results suggest that P. falciparum antigens such as CIDR1alpha can directly induce EBV reactivation during malaria infection that may increase the risk of BL development for children living in malaria-endemic areas. To our knowledge, this is the first report to show that a microbial protein can drive a latently infected B cell into EBV replication.