Search

Background: The molecules that provide access to activated T cells in the CNS, including chemokines, have been considered to be a crucial step in the pathogenesis of multiple sclerosis (MS).Aims: In this study, we investigated serial serum chemokine levels in patients with relapsing-remitting MS over 1 year and the association of these chemokine levels with treatment regimens, lesions on MRI and patients' characteristics.Methods: Serum CXCL9, CXCL10, CCL2, CCL4 and CCL5 levels were evaluated using ELISA every 2 months for a year in 28 healthy controls and 28 MS patients during their treatment with interferon (IFN)-β. Patients underwent MRI and were evaluated using the Expanded Disability Status Scale (EDSS) at the first and final evaluations.Results: CXCL10 serum levels were higher in MS patients compared with controls, were positively correlated with T2 lesions on MRI and were slightly increased during relapses. Treatment with IFNβ-1a or IFNβ-1b was associated with increased CXCL10 levels when evaluated more than 36 hours after subcutaneous injection. The CXCL9 levels were higher after MS relapse. There was significant variability in CCL4 and CCL5 levels in the serial evaluations, associated with gender and treatment. CCL2 levels were higher in treated MS patients than healthy controls, particularly among those patients with a stable form of the disease.Conclusion: Serum is a feasible resource for searching for an immunological marker in MS. Peripheral chemokine levels correlated in different ways with IFNβ therapy and with disease and patient characteristics.Clinical Trial Registration Number: ISRCTN45526724. [ABSTRACT FROM AUTHOR]

Background: The study of the endotoxin tolerance phenomenon in light of the recently defined roles of mast cells and toll-like receptors as essential components of the innate immune response and as orchestrators of acquired immunity may reveal potentially useful mechanisms of immunomodulation of infectious and allergic inflammatory responses, such as sepsis or asthma. Here we evaluated the phenomenon of direct tolerance of endotoxins, as well as the induction of cross-tolerance and synergism by stimulation with toll-like receptor-2 (TLR2) and FcepsilonR1 agonists, in murine mast cells prestimulated with lipopolysaccharide (LPS). Additionally, we evaluated some stimulatory and inhibitory signaling molecules potentially involved in these phenomena.Methods: MC/9 cells and primary bone marrow-derived mast cells obtained from C57BL/6 and TLR4-/- knock-out mice were sensitized to DNP-HSA (antigen) by incubation with DNP-IgE and were prestimulated with LPS for 18 hr prior to stimulation. Cultures were stimulated with LPS or Pam3Cys-Ser-(Lys)4 3HCl (P3C), a TLR2 agonist, individually or in combination with antigen. The production of IL-6 and TNFalpha, the phosphorylation of NFkappaB and p38 MAPK, and the expression of TLR4 and SOCS-1 and -3 were analyzed.Results: We found that production of TNFalpha and IL-6 in murine mast cells that have been pretreated with LPS and challenged with TLR4 (LPS) or -2 (P3C) agonists was reduced, phenomena described as endotoxin tolerance (LPS) and cross-tolerance (P3C), respectively. The expression of TLR4 was not affected by LPS pretreatment. Our results show that the FcepsilonR1 agonist DNP-HSA (antigen) interacts synergistically with LPS or P3C to markedly enhance production of cytokines (TNFalpha and IL-6). This synergistic effect with LPS and P3C was also attenuated by LPS pretreatment and was mediated by TLR4. These results may be attributed to the reduction in phosphorylation of the mitogen-activated protein kinase (MAPK), p38, and the transcription factor NFkappaB, as well as to an increase in the expression of the suppressors of cytokine signaling (SOCS)-1 and -3 proteins in LPS-pretreated mast cells.Conclusions: These findings can be explored with respect to the modulation of inflammatory responses associated with infectious and allergic processes in future studies. [ABSTRACT FROM AUTHOR]

The African planthopper Leptodelphax maculigera (Hemiptera: Delphacidae) has been recently reported in many places in Brazil in association with maize. Its occurrence in maize production fields in Brazil has brought concerns to the corn production chain regarding the possibility of this planthopper to be a vector for maize bushy stunt phytoplasma (MBSP), corn stunt spiroplasma ( Spiroplasma kunkelii ), maize rayado fino virus (MRFV), and maize striate mosaic virus (MSMV). The phytoplasma and spiroplasma, which are bacteria belonging to the class Mollicutes, and the two viruses are associated with the corn stunt disease complex. Given the presence of the African planthopper species and the corn stunt complex in Brazil, we further investigated the abundance of this planthopper species in the State of Santa Catarina, Brazil, and whether the planthopper can carry the four pathogens. We inspected 12 maize production fields in different municipalities in the state for 20 weeks, using two yellow sticky traps for each maize field. The sticky traps were replaced weekly. A total of 130 specimens of L. maculigera were captured, with a great discrepancy in quantity among locations and weeks. We detected the mollicute MBSP and the viruses MRFV and MSMV in L. maculigera , whereas S. kunkelii was absent in the assessed African planthopper samples. The molecular detection of the phytoplasma and the viruses in field-collected African planthoppers is strong evidence that this insect species has the ability to acquire those pathogens through feeding from the phloem of diseased maize plants. Nonetheless, transmission capacity needs to be experimentally proven to assert L. maculigera as a vector for the corn-stunting pathogens., Competing Interests: The author(s) declare no conflict of interest.

Brazil's private health insurance market is the second largest in the world, behind only the United States, making it a valuable source of real-world evidence. This paper documents how physicians' inpatient reimbursement fees vary in the country and explores the relationship between these fees and the market share of health providers and health insurance companies. We implement a fixed-effects panel regression and take advantage of an unprecedented database that contains national administrative records of inpatient procedures paid by health insurance companies in 2016. We find a positive correlation between reimbursement for ICU procedures and provider market share. Conversely, we observe a negative correlation with insurers' market share. Additionally, we document substantial variation in procedure prices, both across and within Brazilian states, and observe that more competitive markets in Brazil tend to have higher population and GDP levels. Overall, our research enhances our understanding of the price setting dynamics of physician reimbursement fees in the context of a developing country. The insights gained from this study can assist policymakers in formulating appropriate regulations to ensure appropriate access to healthcare services., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Scorpionism is a public health problem, especially in tropical regions. In Brazil, the prevalence of envenomation by scorpions is high, and the average national lethality is around 0.16 percent. The Tityus serrulatus scorpion is the primary species of medical importance. However, objective tools to predict and define the severity of these envenomations are lacking., Materials and Methods: This was an observational study conducted among patients aged 0-19 years with scorpionism. Patients were admitted to a reference hospital between December 2020 and May 2022. Point-of-care ultrasound was performed within 24 hours of the scorpion sting., Results: Forty-nine patients were included, with a median age of 3.6 (interquartile range 2.3-5.3) years and a predominance of females (51 percent). Fifteen patients (30.6 percent) presented major life-threatening signs, 32 (65.3 percent) minor systemic manifestations, and two (4.1 percent) only local manifestations. Left ventricular dysfunction was identified in 13 patients (26.5 percent). Ten patients (20.4 percent) presented pattern B (visualization of three or more B lines in the evaluated quadrant) in at least one lung window. The sensitivity and specificity of cardiac and pulmonary ultrasound to identify the most severely ill patients were 86 percent and 94 percent, respectively., Discussion: The changes found on point-of-care ultrasound were associated with life-threatening signs. All patients with class III envenomation were referred to the intensive care unit, showing the importance of early identification of this subgroup. The main limitations were the small sample size and the fact that admission to intensive care was not based on systematic criteria., Conclusions: Point-of-care ultrasound is able to identify early signs of pulmonary congestion and heart failure in scorpionism. It can be useful for the objective selection of patients who are at a higher risk of complications and death and who require intensive support; it may also be valuable for periodic reassessments. Point-of-care ultrasound is a valuable tool for identifying and monitoring severe cases of scorpionism.

Objectives: The objective of this study was to identify Brazil's most critical garbage codes (GCs) reclassified to Chagas disease (ChD) in mortality data and their proportions. We also estimated the potential impact of misclassification on the number of deaths attributed to ChD., Study Design: Population-based descriptive study., Methods: We used the Mortality Information System (SIM; in Portuguese) data before and after routine GC investigation in 2015-2019 to evaluate ChD deaths detected among them. We identified priority GCs, which contributed more than 0.1 % to the percentage of total ChD deaths registered. Spearman's correlation was used to evaluate the association between the reclassification of priority GCs and ChD prevalence. Then, we applied the GC correction factors to estimate the number of deaths attributed to ChD., Results: 22,154 deaths were reported as ChD in the study period. Among them, 1004 deaths originally listed as priority GCs were deaths reclassified to ChD after an investigation in the SIM final database. Unspecific cardiomyopathy (10.2 %), unspecific heart diseases (4.7 %), and heart failure (2.8 %) were GCs with the highest proportions of reclassification to ChD in Brazil. Higher ChD prevalence at the state level was associated with a higher proportion of GC deaths reclassified as ChD. When applying correction factors identified after investigation, we estimated an increase of 26.4 % in registered ChD deaths, mostly in states with higher endemicity., Conclusions: GCs might conceal deaths due to ChD, particularly in Brazil's states with higher endemicity. The approach suggested in this study may offer an alternative method for estimating ChD-related deaths in endemic countries., (Copyright © 2023 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Chagas disease (ChD), a Neglected Tropical Disease, has witnessed a transformative epidemiological landscape characterized by a trend of reduction in prevalence, shifting modes of transmission, urbanization, and globalization. Historically a vector-borne disease in rural areas of Latin America, effective control measures have reduced the incidence in many countries, leading to a demographic shift where most affected individuals are now adults. However, challenges persist in regions like the Gran Chaco, and emerging oral transmission in the Amazon basin adds complexity. Urbanization and migration from rural to urban areas and to non-endemic countries, especially in Europe and the US, have redefined the disease's reach. These changing patterns contribute to uncertainties in estimating ChD prevalence, exacerbated by the lack of recent data, scarcity of surveys, and reliance on outdated models. Besides, ChD's lifelong natural history, marked by acute and chronic phases, introduces complexities in diagnosis, particularly in non-endemic regions where healthcare provider awareness is low. The temporal dissociation of infection and clinical manifestations, coupled with underreporting, has rendered ChD invisible in health statistics. Deaths attributed to ChD cardiomyopathy often go unrecognized, camouflaged under alternative causes. Understanding these challenges, the RAISE project aims to reassess the burden of ChD and ChD cardiomyopathy. The project is a collaborative effort of the World Heart Federation, Novartis Global Health, the University of Washington's Institute for Health Metrics and Evaluation, and a team of specialists coordinated by Brazil's Federal University of Minas Gerais. Employing a multidimensional strategy, the project seeks to refine estimates of ChD-related deaths, conduct systematic reviews on seroprevalence and prevalence of clinical forms, enhance existing modeling frameworks, and calculate the global economic burden, considering healthcare expenditures and service access. The RAISE project aspires to bridge knowledge gaps, raise awareness, and inform evidence-based health policies and research initiatives, positioning ChD prominently on the global health agenda., Competing Interests: Dr Demacq, Dr Quijano, and Dr Geissbühler are Novartis employees and have some stocks of the company., (Copyright: © 2024 The Author(s).)

Background: In 2018, the National Health System released the 'Guide to reducing long hospital stays' to stimulate improvement and decrease length of stay (LOS) in England hospitals. The SAFER patient flow bundle and Red2Green tool were described as strategies to be implemented in inpatient wards to reduce discharge delays., Objective: To verify if implementing the SAFER patient flow bundle and Red2Green days tool is associated with LOS reduction in the internal medicine unit (IMU) wards of a university hospital in Brazil., Methods: In this pre post study, we compared the LOS of patients discharged from the IMU wards in 2019, during the implementation of the SAFER bundle and Red2Green tool, to the LOS of patients discharged in the same period in 2018. The Diagnosis-Related Group Brazil algorithm compared groups according to complexity and resource requirements. In-hospital mortality, readmission rates, the number of hospital acquired conditions and the number and causes of inappropriate hospital days were also evaluated., Results: Two hundred and eight internal medicine patients were discharged in 2018, and 252 were discharged in 2019. The median hospital LOS was significantly lower during the intervention period (14.2 days (IQR, 8-23) vs 19 days (IQR, 12-32); p<0.001). In-hospital mortality, 30-day mortality, readmission in 30 days and the number of hospital acquired conditions were the same between groups. Of the 3350 patient days analysed, 1482 (44.2%) were classified as green and 1868 (55.8%) as red. The lack of senior review was the most frequent cause of a red day (42.4%)., Conclusion: The SAFER patient flow bundle and Red2Green days tool implementation were associated with a significant decrease in hospital LOS in a university hospital IMU ward. There is a considerable improvement opportunity for hospital LOS reduction by changing the multidisciplinary team's attitude during patient hospitalisation using these strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Chagas disease (CD) is a neglected disease affecting millions worldwide, yet little is known about its economic burden. This systematic review is part of RAISE project, a broader study that aims to estimate the global prevalence, mortality, and health and economic burden attributable to chronic CD and Chronic Chagas cardiomyopathy. The objective of this study was to assess the main costs associated with the treatment of CD in both endemic and non-endemic countries., Methods: An electronic search of the Medline, Lilacs, and Embase databases was conducted until 31st, 2022, to identify and select economic studies that evaluated treatment costs of CD. No restrictions on place or language were made. Complete or partial economic analyses were included., Results: Fifteen studies were included, with two-thirds referring to endemic countries. The most commonly investigated cost components were inpatient care, exams, surgeries, consultation, drugs, and pacemakers. However, significant heterogeneity in the estimation methods and presentation of data was observed, highlighting the absence of standardization in the measurement methods and cost components. The most common component analyzed using the same metric was hospitalization. The mean annual hospital cost per patient ranges from $25.47 purchasing power parity US dollars (PPP-USD) to $18,823.74 PPP-USD, and the median value was $324.44 PPP-USD. The lifetime hospital cost per patient varies from $209,44 PPP-USD for general care to $14,351.68 PPP-USD for patients with heart failure., Discussion: Despite the limitations of the included studies, this study is the first systematic review of the costs of CD treatment. The findings underscore the importance of standardizing the measurement methods and cost components for estimating the economic burden of CD and improving the comparability of cost components magnitude and cost composition analysis. Finally, assessing the economic burden is essential for public policies designed to eliminate CD, given the continued neglect of this disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Andrade et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To evaluate the results of a program that offered access to HbA1c POC tests for the glycemic control of patients with diabetes in small and poor municipalities of Minas Gerais, Brazil., Methods: Using a before and after study, we compared four groups: patients submitted to (i) POC tests; (ii) conventional tests; (iii) both tests; and (iv) neither test. The analysis considered three periods: before the program; before the pandemic; and during the pandemic. A cost comparison was conducted under the societal perspective and a cost-parity model was designed., Results: 1349 patients previously diagnosed with diabetes were included in the analysis. The rate of consultations and the rate of HbA1c testing were significantly different between all periods and groups. Group iii had a much higher consultation and testing rate. The costs were around 89.45 PPP-USD for POC tests and between 32.44 and 54.66 PPP-USD for conventional tests. Cost-parity analysis suggests that the technology would be acceptable if the annual number of tests was between 247 and 771., Conclusion: Using POC devices improved access to HbA1c testing but not glycemic control. Even in small towns, the number of tests necessary to achieve cost-parity is low enough to enable their incorporation into the public health system., Competing Interests: Conflicts of interest The authors declare to have no conflicts of interest that could jeopardize this study., (Copyright © 2023 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Objectives: This study aims to compare the strategies fludarabine, cyclophosphamide, and rituximab and fludarabine and cyclophosphamide for the treatment of chronic lymphocytic leukemia in Brazil., Methods: A three-states clock-reset semi-Markovian model was constructed in R. The time horizon of the analysis was 15 years and monthly cycles were used. Transition probabilities were derived from the survival curves of the CLL-8 study. Other probabilities were also derived from the medical literature. Costs included in the model referred to the application of injectable drugs, prescription cost, cost of treating adverse events, and costs of supportive care. The model was evaluated by microsimulation. To determine the study result, multiple cost-effectiveness threshold values were used., Results: In the main analysis, an incremental cost-effectiveness ratio of 19 029.38 PPP-US dollars (USD)/quality-adjusted life-year (QALY) (41 141.52 Brazilian real/QALY) was observed. In 1.8% of the iterations, fludarabine and cyclophosphamide was considered dominant over fludarabine, cyclophosphamide, and rituximab. It can be shown that at 1 gross domestic product (GDP) per capita/QALY, 36.1% of the iterations would consider the technology cost-effective. At 2 GDP per capita/QALY, this number rises to 82.1%. At 50 000 USD/QALY, 92.8% of the iterations would suggest the technology to be cost-effective. In terms of some threshold accepted or proposed around the world, the technology would be considered cost-effective at 50 000 USD/QALY, 3 GDP per capita/QALY, and 2 GDP per capita/QALY. It would not be cost-effective at 1 GDP per capita/QALY or the opportunity costs threshold., Conclusion: It can be considered that rituximab is cost-effective for the treatment of chronic lymphocytic leukemia in Brazil., (Copyright © 2023 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: Quantifying disease costs is critical for policymakers to set priorities, allocate resources, select control and prevention strategies, and evaluate the cost-effectiveness of interventions. Although malaria carries a very large disease burden, the availability of comprehensive and comparable estimates of malaria costs across endemic countries is scarce., Methods: A literature review to summarize methodologies utilized to estimate malaria treatment costs was conducted to identify gaps in knowledge., Results: Only 45 publications met the inclusion criteria. They utilize different methods, include distinct cost components, have varied geographical coverage (a country vs a city), include different periods in the analysis, and focus on specific parasite types or population groups (e.g., pregnant women)., Conclusions: Cost estimates currently available are not comparable, hindering broad statements on the costs of malaria, and constraining advocacy efforts towards investment in malaria control and elimination, particularly with the finance and development sectors of the government., (© 2022. The Author(s).)

Background: Colorectal cancer (CRC) has a high mortality rate and can develop in either colitis-dependent (colitis-associated (CA)-CRC) or colitis-independent (sporadic (s)CRC) manner. There has been a significant debate about whether mast cells (MCs) promote or inhibit the development of CRC. Herein we investigated MC activity throughout the multistepped development of CRC in both human patients and animal models., Methods: We analyzed human patient matched samples of healthy colon vs CRC tissue alongside conducting a The Cancer Genome Atlas-based immunogenomic analysis and multiple experiments employing genetically engineered mouse (GEM) models., Results: Analyzing human CRC samples revealed that MCs can be active or inactive in this disease. An activated MC population decreased the number of tumor-residing CD8 T cells. In mice, MC deficiency decreased the development of CA-CRC lesions, while it increased the density of tumor-based CD8 infiltration. Furthermore, co-culture experiments revealed that tumor-primed MCs promote apoptosis in CRC cells. In MC-deficient mice, we found that MCs inhibited the development of sCRC lesions. Further exploration of this with several GEM models confirmed that different immune responses alter and are altered by MC activity, which directly alters colon tumorigenesis. Since rescuing MC activity with bone marrow transplantation in MC-deficient mice or pharmacologically inhibiting MC effects impacts the development of sCRC lesions, we explored its therapeutic potential against CRC. MC activity promoted CRC cell engraftment by inhibiting CD8+ cell infiltration in tumors, pharmacologically blocking it inhibits the ability of allograft tumors to develop. This therapeutic strategy potentiated the cytotoxic activity of fluorouracil chemotherapy., Conclusion: Therefore, we suggest that MCs have a dual role throughout CRC development and are potential druggable targets against this disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The joint provision of efficient and equitable healthcare service delivery is a critical factor in improving social welfare. However, healthcare services pose a particular challenge when balancing healthcare provider efficiency and equity. Typically characterized by economies of scale and scope, inpatient care involves a wide variety of medical care that usually demands a broad range of health professional expertise and technological complexity to ensure health care quality. This study analyzes the current spatial organization of the Brazilian general hospitals and their respective flow of patients to identify the possible benefits of closing inefficient hospitals. We studied how inpatient care referrals may be reallocated without increasing access inequities following the potential closure of inefficient public hospitals. We used data from the Brazilian Hospital Information System of the Brazilian Unified National Health System (SIH/SUS) and the Brazilian National Register of Health Establishments (CNES). The smallest and least efficient hospitals were selected as units for potential closure, conditioned on an optimization criterion that minimizes patient travel distances to the nearest efficient hospital. Our results show that there is room for hospital resource reorganization in Brazil without compromising health care access equity.

Background: Medical adhesives are used to affix components to the skin. They are part of procedures performed by medical specialties because of their participation as constituents of different products, such as tapes, dressings, and electrodes., Aim: This study aims to assess the prevalence of, and factors associated with, the development of medical adhesive-related skin injuries (MARSIs) in patients treated with medical tapes in the neonatology department of a large teaching hospital in Brazil., Study Design: Cohort study., Methods: All premature newborns (gestational age from 28 to <37 weeks) admitted in the neonatal intensive care unit of a teaching hospital, from March to August 2019, were followed up. Neonate skin condition was assessed based on the Neonatal Skin Condition Scale (NSCS). Data analyses were conducted in R software., Results: In total, 46 premature newborns were included in the study; 552 evaluations were performed-mean of 11.7 per patient. Most neonates (n = 41; 89.1%) used adhesive tapes, either paper tape (n = 37; 80.4%) or transparent film dressing (n = 34; 73.9%). Newborns' face and head were the most affected body regions (n = 125; 50.2%). Eight patients had MARSIs (19.5% of patients who used tape). NSCS scores (P value <.001) and the adopted warming system (P value = .01302) were associated with the occurrence of MARSIs. Incubators seem to be a protective factor for MARSI (OR = 0.048; IC95% = 0.0008-0.75; P value = .013)., Conclusion: Adhesive tapes in premature newborns should be considered a risk factor for injuries. Although NSCS showed mild-to-moderate impairment and lesion severity was low, this event is relatively frequent in neonatal units., Relevance to Clinical Practice: Awareness of the risk associated with adhesive tape application and removal in newborns allow health services to better address the problem by enforcing good practices, elaborating better protocols, qualifying the health care professionals, and potentially selecting softer tapes for neonates., (© 2021 British Association of Critical Care Nurses.)

Introduction: To describe and understand the attitudes, cultural knowledge, and therapeutic practices of the Misak people concerning rheumatoid arthritis (RA), inscribed in an emergent culturally sensitive healthcare model along with the indigenous community and health professionals, following a respectful and empathic relational contact approach to the inter-ethnic encounter., Methods: A qualitative study that used ethnographic methods using observation techniques and in-depth interviews was carried out in the Misak community, Colombia, by a multidisciplinary team (rheumatology, physiotherapy, and anthropology). A thematic analysis based around the concept of explanatory models (EMs) was carried out., Results: Researchers interviewed 20 patients with RA, 12 traditional healers, and 5 health professionals. The following themes were identified: (1) the traditional healers are allowed to practice only if the community recognizes their vocation; (2) two types of EM were observed: Misak community EM related to conception of RA and its treatment, shared by patients and the traditional healers; and biomedical EM. The interaction of the two types is still a healthcare challenge that requires articulating to achieve better clinical outcomes for patients., Conclusion: The EMs of RA care identified in the Misak community are focused on both the patients and the traditional healers. However, this predominant EM and the biomedical EM of RA care need to be brought closer together to contribute to the construction of a unifying model of a culturally sensitive care.

Pollution incidents cause transient water quality alterations during the passage of contaminants' plume along watercourses, with plume passage period and contaminants' concentrations modelled by advection-dispersion equations. Despite being transient, water quality alterations can impose many impacts on the streamwater ecosystem services. This study proposes two frameworks based on Habitat Equivalency Analysis to be applied during assessments of streamwaters' pollution incidents and respective compensation panoramas: (1) Streamwater interim loss framework, to calculate interim loss debits caused by transient alterations in the streamwater quality; (2) Total credit framework, to calculate streamwater credits generated by improvements in selected watercourse's streamwater quality, produced by wastewater treatment plants in this study. The amount of credits calculated in the selected watercourses assists in the proposal of suitable compensatory remediation projects to offset interim losses. Frameworks' calculations are founded on IVA, a water quality index for protection of aquatic life and aquatic communities. Frameworks' calculations depend on three parameters: IVA, watercourses fluxes and the present value multiplier. The frameworks were calculated in ΔIVAxL, unit defined by multiplying sensed alterations in streamwater quality (as ΔIVA) and streamwater flux, in liters (L). The frameworks were applied to two major streamwater pollution incidents in Brazil, caused by the dam collapses of Mariana and Brumadinho, suggesting suitable compensatory remediations' projects for the respective streamwater interim losses. Depending on the selected project, Brumadinho compensation period varied from 2 to 5 years, with estimated costs in the 2020 Int.$ 5.7-18.7M range; Mariana compensation period varied from 8 to 20 years, with estimated costs in the 2020 Int.$ 16.7-58.1M range. Based on Brumadinho compensatory remediation projects, an average water pollution environmental damage value per interim loss was calculated, 1.17E-4 2020 Int.$/ΔIVAxL, which might be useful in comparing streamwater pollution evaluations around the world., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Emergency medicine (EM) in Brazil has achieved critical steps toward its development in the last decades including its official recognition as a specialty in 2016. In this article, we worked in collaboration with the Brazilian Association of Emergency Medicine (ABRAMEDE) to describe three main aspects of EM in Brazil: (1) brief historical perspective; (2) current status; and (3) future challenges., Main Text: In Brazil, the first EM residency program was created in 1996. Only 20 years later, the specialty was officially recognized by national regulatory bodies. Prior to recognition, there were only 2 residency programs. Since then, 52 new programs were initiated. Brazil has now 54 residency programs in 16 of the 27 federative units. As of December 2020, 192 physicians have been board certified as emergency physicians in Brazil. The shortage of formal EM-trained physicians is still significant and at this point it is not feasible to have all Brazilian emergency care units and EDs staffed only with formally trained emergency physicians. Three future challenges were identified including the recognition of EM specialists in the house of Medicine, the need of creating a reliable training curriculum despite highly heterogeneous emergency care practice across the country, and the importance of fostering the development of academic EM as a way to build a strong research agenda and therefore increase the knowledge about the epidemiology and organization of emergency care., Conclusion: Although EM in Brazil has accomplished key steps toward its development, there are several obstacles before it becomes a solid medical specialty. Its continuous development will depend on special attention to key challenges involving recognition, reliability, and research., (© 2021. The Author(s).)

Objectives: In 2015, a dam collapsed at Samarco iron ore mine in the municipality of Mariana, Brazil, and contaminated more than 600 km of watercourses and destroyed almost 1600 acres of vegetation. Nineteen people died and more than 600 families lost their homes. This study aimed to estimate health-related quality of life (HRQoL) losses owing to this disaster., Methods: We collected data from a probabilistic sample of 459 individuals aged 15 years or older. Household face-to-face interviews were conducted in December 2018. Pre-event data were not available for this population, so respondents were asked to evaluate at present and in retrospect their health status using EQ-5D-3L. The Minas Gerais societal value sets for EQ-5D-3L health preferences, estimated in 2011, were used to calculate utility losses. The health loss estimation from EQ-5D will form the basis for the calculation of compensation payments for the victims., Results: Approximately 74% of the study population suffered some HRQoL loss. On average, EQ-5D index values decreased from 0.95 to 0.76. The greatest effects were observed for the anxiety/depression dimension, followed by pain/discomfort. Before the tragedy, the proportion of individuals with severe anxiety/depression and pain/discomfort was equal to 1% rising to 23% and 11%, respectively., Conclusions: Catastrophic losses owing to the Samarco disaster were found. The EQ-5D-3L instrument showed feasibility and sensitiveness to measure HRQoL losses owing to a negative health shock in a low-income Brazilian population., (Copyright © 2021 ISPOR--The professional society for health economics and outcomes research. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to analyze, in vitro, the reduction of Enterococcus faecalis in root canals of primary teeth after final irrigation and photodynamic therapy (PDT) use. Twenty primary molars were contaminated with Enterococcus faecalis. The teeth were randomly distributed into four groups according to the irrigation solutions and PDT use: G1 (Saline solution and no PDT use), G2 (17 % EDTA and no PDT use), G3 (Saline solution and PDT use) and G4 (17 % EDTA and PDT use). For PDT, 0.005 % toluidine blue was chosen as the photosensitizer, which was inserted in the canals with sterile paper cones. Bacterial counts were performed with a BHI test in blood agar plate, where bacteria were collected inside the canal for 30 s using sterile paper cones. The collection took place before and after the irrigation and PDT protocols. The samples were diluted, spread onto a blood agar plate and then incubated at 37 °C for 24 h. There was a reduction of the microbiota from the irrigation solutions before and after the final irrigation for all groups. It was observed a statistically significant reduction (p < 0,05) when PDT was used (97.6 % at the saline solution and 89.8 % at the 17 % EDTA) when compared to the groups with no PDT use. Our data demonstrated that PDT, according to the parameters used, increased the disinfection performance of the solutions tested in the root canals of primary teeth., (Copyright © 2021 Elsevier B.V. All rights reserved.)

One of the highest incidences of illegal drug products is related to phosphodiesterase-5 inhibitors, used in treatment of erectile dysfunction, including those containing sildenafil citrate and tadalafil. In this context, comprehensive evaluation of the quality of genuine and illegal medicines was performed. A simple and rapid ultra-high performance liquid chromatography (UHPLC-UV) method to quantify sildenafil and tadalafil in the presence of six degradation products was developed and validated. Sildenafil and tadalafil were submitted to forced degradation. The separation was carried out on a Kinetex C18 (50 × 2.1 mm; 1.7 μm) column with mobile phase composed of acetonitrile and aqueous triethylamine solution. The calibration curves were linear in the range of 14-126 μg mL-1 for sildenafil citrate and 4-36 μg mL-1 for tadalafil and the method proved to be selective, precise, accurate and robust. Sildenafil degraded in oxidative media, whereas tadalafil degraded in acidic, alkaline and oxidative environment. The chemical structures and the mechanisms for the formation of the main degradation products were proposed by UHPLC coupled to tandem mass spectrometry. The UHPLC-UV method was applied in the pharmaceutical analysis of genuine and seized medicines. Some of them did not meet quality standards, mainly due to contents below specifications and the large variation on contents between units within a batch., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This paper assesses the economic efficiency of Brazilian general hospitals that provide inpatient care for the Unified Health System (SUS). We combined data envelopment analysis (DEA) and spatial analysis to identify predominant clusters, measure hospital inefficiency and analyze the spatial pattern of inefficiency throughout the country. Our findings pointed to a high level of hospital inefficiency, mostly associated with small size and distributed across all Brazilian states. Many of these hospitals could increase production and reduce inputs to achieve higher efficiency standards. These findings suggest room for optimization, but inequalities in access and the matching of demand and supply must be carefully considered in any attempt to reorganize the hospital system in Brazil.

This study aims to analyze the pressure on the Brazilian health system from the additional demand created by COVID-19. The authors performed a series of simulations to estimate the demand for hospital beds (health micro-regions) as well as to ICU beds, and mechanical ventilators (health macro-regions) under different scenarios of intensity (infection rates equivalent to 0.01, 0.1, and 1 case por 100 inhabitants) and time horizons (1, 3, and 6 months). The results reveal a critical situation in the system for meeting this potential demand, with numerous health micro-regions and macro-regions operating beyond their capacity, compromising the care for patients, especially those with more severe symptoms. The study presents three relevant messages. First, it is necessary to slow the spread of COVID-19 in the Brazilian population, allowing more time for the reorganization of the supply and relieve the pressure on the health system. Second, the expansion of the number of available beds will be the key. Even if the private sector helps offset the deficit, the combined supply from the two sectors (public and private) would be insufficient in various macro-regions. The construction of field hospitals is important, both in places with a history of "hospital deserts" and in those already pressured by demand. The third message involves the regionalized organization of health services, whose design may be adequate in situations of routine demand, but which suffer additional challenges during pandemics, especially if patients have to travel long distances to receive care.

Background: The rational use of antibiotics is one of the main strategies to limit the development of bacterial resistance. We therefore sought to evaluate the effectiveness of a C-reactive protein-based protocol in reducing antibiotic treatment time in critically ill patients., Methods: A randomized, open-label, controlled clinical trial conducted in two intensive care units of a university hospital in Brazil. Critically ill infected adult patients were randomly allocated to (i) intervention to receive antibiotics guided by daily monitoring of CRP levels and (ii) control to receive antibiotics according to the best practices for rational use of antibiotics., Results: One hundred thirty patients were included in the CRP (n = 64) and control (n = 66) groups. In the intention-to-treat analysis, the median duration of antibiotic therapy for the index infectious episode was 7.0 (5.0-8.8) days in the CRP and 7.0 (7.0-11.3) days in the control (p = 0.011) groups. A significant difference in the treatment time between the two groups was identified in the curve of cumulative suspension of antibiotics, with less exposure in the CRP group only for the index infection episode (p = 0.007). In the per protocol analysis, involving 59 patients in each group, the median duration of antibiotic treatment was 6.0 (5.0-8.0) days for the CRP and 7.0 (7.0-10.0) days for the control (p = 0.011) groups. There was no between-group difference regarding the total days of antibiotic exposure and antibiotic-free days., Conclusions: Daily monitoring of CRP levels may allow early interruption of antibiotic therapy in a higher proportion of patients, without an effect on total antibiotic consumption. The clinical and microbiological relevance of this finding remains to be demonstrated., Trial Registry: ClinicalTrials.gov Identifier: NCT02987790. Registered 09 December 2016.

OBJECTIVE To characterize the organization of Brazilian general hospitals that provide services to the Unified Health System using indicators that describe the main dimensions of hospital care. METHODS A 2015 cross-sectional observational study, comprising the range of general hospitals that serve the Unified Health System. We constructed the hospital indicators from two national administrative databases: the National Registry of Health Facilities and the Hospital Information System of the Unified Health System. The indicators include the main dimensions associated with hospital care: public-private mix, production, production factors, performance, quality, case-mix and geographic coverage. Latent class analysis of indicators with bootstrapping was used to identify hospital profiles. RESULTS We identified three profiles, with hospital size being the variable with the highest degree of belonging. Small hospitals show low occupancy rates (21.36%) and high participation of hospitalizations that could have been solved with outpatient care, besides attending only medium complexity cases. They receive few non-residents, indicating that they are mainly dedicated to the local population. Medium-sized hospitals are more similar to small-sized ones: about 100% of the visits are of medium complexity, low occupancy rate (45.81%), high rate of hospitalizations for primary care sensitive conditions (17.10%) and relative importance in the healthcare provision of non-residents (26%). Large hospitals provide high complexity care, have an average occupancy rate of 64.73% and show greater geographical coverage. CONCLUSIONS The indicators point to three hospital profiles, characterized mainly by the production scale. Small hospitals show low performance, suggesting the need to reorganize hospital care provision, especially at the municipal level. The set of proposed indicators includes the main dimensions of hospital care, providing a tool that can help to plan and continuously monitor the hospital network of the Unified Health System.

Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) are inflammatory diseases with different bone remodeling patterns. Fibroblast-like synoviocytes (FLS) are cells involved in the transition from an acute and reparable phase to a chronic and persistent stage in these diseases. The distinction of joint phenotypes involves inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-17, and IL-22 directly or through key signaling pathways such as Wnt. To evaluate the role of FLS as the source of Wnt antagonists (sFRP3/FRZB and Dkk1) in the synovia, levels of TNF- α, IL-17, IL-22, Dkk1, and sFRP3 were measured by ELISA directly in the synovial fluid of patients with RA, PsA, or AS. Dkk1 and sFRP3 were also measured in the FLS culture supernatants after different inflammatory stimulus. sFRP3 and Dkk1 are constitutively expressed by FLS. IL-22 and sFRP3 were positively correlated (r=0.76; P<0.01) in synovial fluid. The stimulation of FLS with IL-22, but not TNF-alpha and IL-17, increased the production of sFRP3. No stimulus altered the basal expression of Dkk1. These results showed, for the first time, the ability of IL-22 to increase the expression of sFRP3/FRZB by human FLS in both in vitro and ex vivo models. This finding linked IL-22 to local inhibition of Wnt signaling and possibly to blockade of osteogenesis. Furthermore, FLS presented as a source of this inhibitor in synovial fluid, assigning to this cell a bone injury mechanism.

Background: Only a small share of new drugs is truly innovative; 85% to 90% of all new health technologies have little or no advantage over existing therapeutic alternatives. Health economic evaluations can be used to induce acceptable prices for new technologies through threshold pricing., Objective: This work discusses a cost-effectiveness threshold (λ) to be applied to the price regulation of substitute technologies., Methods: Considering that substitute technologies add only small marginal benefits in terms of innovation or ethical considerations to the system, it does not make sense to allow a loss of efficiency to list them. It has been postulated that the threshold calculated from opportunity costs (κ) represents its maximum possible value and that there must be a threshold (β) that maximizes consumer surplus. For a substitute technology to be listed, the cost of treatment associated with it must be lower than the cost of treatment of the incumbent technology added to the difference in effectiveness priced at the threshold., Results: There is no reason for us to believe that the oligopolistic pharmaceutical market is currently charging prices at the cost of production. That way, the cost-effectiveness ratio of the incumbent technology, when lower than κ, is shown through a deductive process to be a plausible estimate for λ that fulfills the objective of maximizing consumer benefit, granting producers a part of the combined surplus to stimulate research and development; that is, it would be between β and κ., Conclusion: In conclusion, the price of substitute technologies should be limited by the cost-effectiveness ratio of the incumbent technology., (Copyright © 2019 ISPOR--The professional society for health economics and outcomes research. Published by Elsevier Inc. All rights reserved.)

In 1988, the Brazilian Constitution defined health as a universal right and a state responsibility. Progress towards universal health coverage in Brazil has been achieved through a unified health system (Sistema Único de Saúde [SUS]), created in 1990. With successes and setbacks in the implementation of health programmes and the organisation of its health system, Brazil has achieved nearly universal access to health-care services for the population. The trajectory of the development and expansion of the SUS offers valuable lessons on how to scale universal health coverage in a highly unequal country with relatively low resources allocated to health-care services by the government compared with that in middle-income and high-income countries. Analysis of the past 30 years since the inception of the SUS shows that innovations extend beyond the development of new models of care and highlights the importance of establishing political, legal, organisational, and management-related structures, with clearly defined roles for both the federal and local governments in the governance, planning, financing, and provision of health-care services. The expansion of the SUS has allowed Brazil to rapidly address the changing health needs of the population, with dramatic upscaling of health service coverage in just three decades. However, despite its successes, analysis of future scenarios suggests the urgent need to address lingering geographical inequalities, insufficient funding, and suboptimal private sector-public sector collaboration. Fiscal policies implemented in 2016 ushered in austerity measures that, alongside the new environmental, educational, and health policies of the Brazilian government, could reverse the hard-earned achievements of the SUS and threaten its sustainability and ability to fulfil its constitutional mandate of providing health care for all., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Rheumatoid arthritis is a risk factor for early mortality due to cardiovascular disease. Interleukin-33 appears to protect against the development of atherosclerosis. The purpose of this study was to investigate the relationship between serum levels of interleukin-33 and its soluble receptor with the presence of subclinical carotid atherosclerosis in rheumatoid arthritis patients., Methods: Rheumatoid arthritis patients without atherosclerotic disease were subjected to clinical and laboratory assessments, including carotid ultrasound. Interleukin-33 and its soluble receptor serum levels were measured by ELISA., Results: 102 patients were included. The prevalence of carotid plaques was 23.5% and the median intima-media thickness was 0.7 mm. The median interleukin-33 and its soluble receptor concentration was 69.1 and 469.8 pg/ml. No association was found between serum interleukin-33 or its soluble receptor and intima-media thickness or plaque occurrence. Each 0.1 mm increase of intima-media thickness raised the odds of plaque occurrence by 5.3-fold, and each additional year of rheumatoid arthritis duration increased the odds of plaque occurrence by 6%. Each additional year in patients age and each one-point increase in the Framingham Risk Score were associated with a 0.004 mm and 0.012 mm increase in intima-media thickness. Methotrexate use was associated with a 0.07 mm reduction in intima-media thickness., Conclusions: Interleukin-33 and its soluble receptor were not associated with subclinical atherosclerosis. Traditional risk factors for atherosclerosis and rheumatoid arthritis duration were associated with intima-media thickness and plaque occurrence; methotrexate use was associated with a lower intima-media thickness.

Objectives: The objective of the study was to compare the production of metalloproteinases (MMP)-1, -3 and interleukin (IL)-6 by fibroblast-like synoviocytes (FLS) derived from synovial fluid (FD-FLS), and FLS derived from synovial tissue (TD-FLS) of patients with primary osteoarthritis (OA). The more accessible FD-FLS could facilitate the study of the role of these cells in OA pathophysiology., Methods: MMP-1, MMP-3, and IL-6 levels were measured in the supernatant culture at baseline and 22 hours after stimulation with TNF-α and IL-1 β., Results: There was no difference at baseline between MMP-1, MMP-3 and IL-6 production by FD-FLS and TDFLS. Analogous to baseline, stimulation of FD-FLS and TD-FLS with IL-1β and TNF-α did not result in difference on MMP-3 and IL-6 production. However, TD-FLS produced more MMP-1 than FD-FLS after stimulation with IL-1β (p=0.01). Additionally, there was a positive correlation for production of MMP-1, MMP-3 and IL-6 between FD-FLS and TD-FLS (r=0.40 and p<0.0008; r=0.66 and p<0.0001; r=0.76 and p<0.0001, respectively). Supporting this statistical significant positive correlation, the Bland-Altman plotting, showed a homogeneous distribution of the values and low mean disagreement rates between all results of FD-FLS and TD-FLS (23.1%, 56.8% and 48.1%, respectively)., Conclusions: Our data demonstrated functional similarity between FD-FLS and TD-FLS and support the use of a more accessible source of FLS for the study of the pathogenesis of joint destruction and therapeutic targets in primary OA.

Objective: To address the implementation of the Lab for Innovation in Chronic Conditions in Santo Antonio do Monte, indicating the main challenges and lessons of a new chronic condition model., Methods: This is an observational study based on two sources of data: 1) two cross-sectional household surveys, 2013 (2012 as reference year) and 2015 (2014 as reference year), representative for the entire population and four target groups (pregnant women; children under two years old; individuals with hypertension and diabetes); medical records of individuals who self-reported having hypertension or diabetes in the household survey of 2013. A descriptive statistics analysis was performed., Results: The main findings showed that the public health system is the main provider of health services, mainly primary care, in Santo Antonio do Monte. Besides, the implementation of Lab for Innovation in Chronic Conditions showed the importance of building a Primary Health Care network in small municipalities., Conclusions: Community health agents and health managers played a fundamental role in the Primary Health Care network. The case study of Santo Antonio do Monte poses some challenges and lessons that clarify future interventions on building a Primary Health Care network that is essential to provide an adequate and longitudinal care to chronic conditions.

Objectives: To assess the measurement equivalence of the original paper version of an adapted tablet version of the EuroQol five-dimensional questionnaire (EQ-5D)., Methods: A randomly selected sample of 509 individuals aged 18 to 64 years from the general population responded to the EQ-5D at two time points separated by a minimum interval of 24 hours and were allocated to one of the following groups: test-retest group (tablet-tablet) or crossover group (paper-tablet and tablet-paper). Agreement between methods was determined using the intraclass correlation coefficient (ICC) and the κ coefficient., Results: In the crossover group, the following ICC values were obtained: 0.76 (confidence interval [CI] 0.58-0.89) for EQ-5D scores and 0.77 (CI 0.68-0.84) for visual analogue scale in subjects responding first to the tablet version; 0.83 (CI 0.75-0.89) for EQ-5D scores and 0.75 (CI 0.67-0.85) for visual analogue scale in subjects responding first to the paper version. In the test-retest group, the ICC was 0.85 (CI 0.73-0.91) for EQ-5D scores and 0.79 (CI 0.66-0.87) for visual analogue scale. The κ values were higher than 0.69 in this group. The internal consistencies of the paper and tablet methods were similar., Conclusions: The paper and tablet versions of the EQ-5D are equivalent. Test-retest and crossover agreement was high and the acceptability of the methods was similar among individuals., (Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

There is a constant need to improve antiretrovirals against HIV since therapy is limited by cost, side effects and the emergence of drug resistance. Kudzu is a climbing vine from which the root extract (Pueraria lobata), rich in isoflavones and saponins, has long been used in traditional Chinese medicine for a variety of purposes, from weight loss to alcoholism prevention. Here we show that Kudzu root extract significantly inhibits HIV-1 entry into cell lines, primary human CD4 + T lymphocytes and macrophages, without cell-associated toxicity. Specifically, Kudzu inhibits the initial attachment of the viral particle to the cell surface, a mechanism that depends on the envelope glycoprotein gp120 but is independent from the HIV-1 cell receptor CD4 and co-receptors CXCR4/CCR5. This activity seems selective to lentiviruses since Kudzu inhibits HIV-2 and simian immunodeficiency virus, but does not interfere with Hepatitis C, Influenza, Zika Brazil and adenovirus infection. Importantly, depending on the dose, Kudzu can act synergistically or additively with the current antiretroviral cocktails against HIV-1 and can block   viruses resistant to the fusion inhibitor Enfuvirtide. Together our results highlight Kudzu's root extract value as a supplement to current antiretroviral therapy against HIV.

Family Health Strategy, the primary health care program in Brazil, has been scaled up throughout the country, but its expansion has been heterogeneous across municipalities. We investigate if there are unique municipal characteristics that can explain the timing of uptake and the pattern of expansion of the Family Health Strategy from years 1998 to 2012. We categorized municipalities in six groups based on the relative speed of the Family Health Strategy uptake and the pattern of Family Health Strategy coverage expansion. We assembled data for 11 indicators for years 2000 and 2010, for 5,507 municipalities, and assessed differences in indicators across the six groups, which we mapped to examine spatial heterogeneities. Important factors differentiating early and late adopters of the Family Health Strategy were supply of doctors and population density. Sustained coverage expansion was related mainly to population size, marginal benefits of the program and doctors' supply. The uptake was widespread nationwide with no distinct patterns among regions, but highly heterogeneous at the state and municipal level. The Brazilian experience of expanding primary health care offers three lessons in relation to factors influencing diffusion of primary health care. First, the funding mechanism is critical for program implementation, and must be accompanied by ways to support the supply of primary care physicians in low density areas. Second, in more developed and bigger areas the main challenge is lack of incentives to pursue universal coverage, especially due to the availability of private insurance. Third, population size is a crucial element to guarantee coverage sustainability over time., Competing Interests: The authors have declared that no competing interests exist.

Background: Trypanosoma cruzi (T. cruzi) infects millions of Latin Americans each year and can induce chagasic megacolon. Little is known about how serotonin (5-HT) modulates this condition. Aim We investigated whether 5-HT synthesis alters T. cruzi infection in the colon., Materials and Methods: Forty-eight paraffin-embedded samples from normal colon and chagasic megacolon were histopathologically analyzed (173/2009). Tryptophan hydroxylase 1 (Tph1) knockout (KO) mice and c-Kit W-sh mice underwent T. cruzi infection together with their wild-type counterparts. Also, mice underwent different drug treatments (16.1.1064.60.3)., Results: In both humans and experimental mouse models, the serotonergic system was activated by T. cruzi infection (p < 0.05). While treating Tph1KO mice with 5-HT did not significantly increase parasitemia in the colon (p > 0.05), rescuing its synthesis promoted trypanosomiasis (p < 0.01). T. cruzi-related 5-HT release (p < 0.05) seemed not only to increase inflammatory signaling, but also to enlarge the pericryptal macrophage and mast cell populations (p < 0.01). Knocking out mast cells reduced trypanosomiasis (p < 0.01), although it did not further alter the neuroendocrine cell number and Tph1 expression (p > 0.05). Further experimentation revealed that pharmacologically inhibiting mast cell activity reduced colonic infection (p < 0.01). A similar finding was achieved when 5-HT synthesis was blocked in c-Kit W-sh mice (p > 0.05). However, inhibiting mast cell activity in Tph1KO mice increased colonic trypanosomiasis (p < 0.01)., Conclusion: We show that mast cells may modulate the T. cruzi-related increase of 5-HT synthesis in the intestinal colon.

Universal Health Coverage (UHC) is one of the United Nations Sustainable Development Goals (SDGs). Achieving UHC will require strong health systems to promote and deliver equitable and integrated healthcare services through primary healthcare (PHC). In Brazil, the Family Health Strategy (FHS) delivers PHC through the public health system. Created in 1994, the FHS covered almost 123 million individuals (63% of the Brazilian population) by 2015. The FHS has been associated with many health improvements, but gaps in coverage still remain. This article examines factors associated with the implementation and expansion of the FHS across 5419 Brazilian municipalities from 1998 to 2012. The proportion of the municipal population covered by the FHS over time was assessed using a longitudinal multilevel model for change that accounted for variables covering eight domains: economic development, healthcare supply, healthcare needs/access, availability of other sources of healthcare, political context, geographical isolation, regional characteristics and population size. Data were obtained from multiple publicly available sources. During the 15-year study period, national coverage of the FHS increased from 4.4% to 54%, with 58% of the municipalities having population coverage of 95% or more, and municipalities that had not adopted the programme decreased from 86.4% to 4.9%. The increase in FHS uptake and coverage was not homogenous across municipalities, and was positively associated with small population size, low population density, low coverage of private health insurance, low level of economic development, alignment of the political party of the Mayor and the state Governor, and availability of healthcare supply. Efforts to expand the FHS coverage will need to focus on increasing the availability of health personnel, devising financial incentives for municipalities to uptake/expand the FHS and devising new policies that encompass both private and public sectors.

Background: Studies have shown that omega-3 fatty acids reduce the concentrations of eicosanoids, cytokines, chemokines, C-reactive protein (CRP) and other inflammatory mediators., Objective: To investigate the effects of omega-3 fatty acids on circulating levels of inflammatory mediators and biochemical markers in women with systemic lupus erythematosus (SLE)., Methods: Experimental clinical study (clinical trial: NCT02524795); 49 women with SLE (ACR1982/1997) were randomized: 22 to the omega-3 group (daily intake of 1080mg EPA+200mg DHA, for 12 weeks) and 27 to the control group. The inflammatory mediators and biochemical markers at T0 and T1 in omega-3 group were compared using Wilcoxon test. U-Mann-Whitney test was used to compare variations of measured variables [ΔV=pre-treatment (T0)-post-treatment (T1) concentrations] between groups. p<0.05 was considered significant., Results: The median (interquartile range - IQR) of age was 37 (29-48) years old, of disease duration was 7 (4-13) years, and of SLEDAI-2K was 1 (0-2). The median (IQR) of variation in CRP levels between the two groups showed a decrease in omega-3 group while there was an increase in control group (p=0.008). The serum concentrations of IL-6 and IL-10, leptin and adiponectin did not change after a 12 week treatment., Conclusions: Supplementation with omega-3 had no impact on serum concentrations of IL-6, IL-10, leptin and adiponectin in women with SLE and low disease activity. There was a significant decrease of CRP levels as well as evidence that omega-3 may impact total and LDL-cholesterol., (Copyright © 2016. Published by Elsevier Editora Ltda.)

During the course of Chagas disease, infectious forms of Trypanosoma cruzi are occasionally liberated from parasitized heart cells. Studies performed with tissue culture trypomastigotes (TCTs, Dm28c strain) demonstrated that these parasites evoke neutrophil/CXCR2-dependent microvascular leakage by activating innate sentinel cells via toll-like receptor 2 (TLR2). Upon plasma extravasation, proteolytically derived kinins and C5a stimulate immunoprotective Th1 responses via cross-talk between bradykinin B2 receptors (B2Rs) and C5aR. Awareness that TCTs invade cardiovascular cells in vitro via interdependent activation of B2R and endothelin receptors [endothelin A receptor (ET A R)/endothelin B receptor (ET B R)] led us to hypothesize that T. cruzi might reciprocally benefit from the formation of infection-associated edema via activation of kallikrein-kinin system (KKS). Using intravital microscopy, here we first examined the functional interplay between mast cells (MCs) and the KKS by topically exposing the hamster cheek pouch (HCP) tissues to dextran sulfate (DXS), a potent "contact" activator of the KKS. Surprisingly, although DXS was inert for at least 30 min, a subtle MC-driven leakage resulted in factor XII (FXII)-dependent activation of the KKS, which then amplified inflammation via generation of bradykinin (BK). Guided by this mechanistic insight, we next exposed TCTs to "leaky" HCP-forged by low dose histamine application-and found that the proinflammatory phenotype of TCTs was boosted by BK generated via the MC/KKS pathway. Measurements of footpad edema in MC-deficient mice linked TCT-evoked inflammation to MC degranulation (upstream) and FXII-mediated generation of BK (downstream). We then inoculated TCTs intracardiacally in mice and found a striking decrease of parasite DNA (quantitative polymerase chain reaction; 3 d.p.i.) in the heart of MC-deficient mutant mice. Moreover, the intracardiac parasite load was significantly reduced in WT mice pretreated with (i) cromoglycate (MC stabilizer) (ii) infestin-4, a specific inhibitor of FXIIa (iii) HOE-140 (specific antagonist of B2R), and (iv) bosentan, a non-selective antagonist of ET A R/ET B R. Notably, histopathology of heart tissues from mice pretreated with these G protein-coupled receptors blockers revealed that myocarditis and heart fibrosis (30 d.p.i.) was markedly and redundantly attenuated. Collectively, our study suggests that inflammatory edema propagated via activation of the MC/KKS pathway fuels intracardiac parasitism by generating infection-stimulatory peptides (BK and endothelins) in the edematous heart tissues.