Impact of direct oral anticoagulant off-label doses on clinical outcomes of atrial fibrillation patients: A systematic review.

AIMS: Worldwide observational studies are evidencing discordance between guidelines and real-world practice regarding direct oral anticoagulant drug (DOAC) doses. This systematic review summarizes and evaluate DOACs use in real-world practice. METHODS: This review was performed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines searching PubMed (MEDLINE) and Medscape databases. RESULTS: Data from 75 studies showed that most of the patients treated with DOACs for stroke prevention in atrial fibrillation received doses in accordance to the guidelines. However, a significant number of patients received off-label doses (25-50% in most of the studies evaluated). DOAC overdosing was associated with increased all-cause mortality and worse bleeding events while underdosing was associated with increased cardiovascular hospitalization and, particularly for apixaban, with a nearly 5-fold increased risk of stroke. CONCLUSION: Patients prescribed with off-label DOAC doses did not receive the full benefit of anticoagulation and presented an increased risk of stroke, bleeding and/or adverse effects.

Wide dispersion of B chromosomes in Rhammatocerus brasiliensis (Orthoptera, Acrididae).

The grasshopper Rhammatocerus brasiliensis shows polymorphism of B chromosomes, but the magnitude of B-chromosome occurrence and the factors that may contribute to their dispersion in the species remain unknown thus far. The present study analyzed the occurrence and dispersion of B chromosomes in R. brasiliensis individuals from 21 populations widely distributed in the Brazilian Northeast. The genetic connectivity between 10 populations was verified through analysis of ISSR markers from 200 individuals. Of the 21 populations, 19 presented individuals with one B chromosome, three with two, and one with three B chromosomes. The B chromosome is of medium size and constitutive heterochromatin (CH) located in the pericentromeric region. A variant B chromosome was observed in three populations, similar in size to that of chromosome X, gap and CH, and located in the terminal region. B chromosome frequencies in different populations varied from 0% to 18,8%, mean 8,5%. The wide distribution of the B chromosome is likely a consequence of the positive gene flow among the analyzed populations. B-chromosome occurrence in populations of R. brasiliensis possibly follows the population genetic structure of the species and, owing to the existence of a variant, its origin may not be recent.

Possible origin of B chromosome in Dichotomius sericeus (Coleoptera).

B chromosomes have so far been described in about 80 species of Coleoptera, mainly using conventional staining analysis. In this study, 152 individuals of the dung beetle Dichotomius sericeus (Coleoptera), collected from three isolated geographical areas in the State of Pernambuco, Brazil, were analyzed to determine the frequency, prevalence, distribution, meiotic behavior, and possible B chromosome origin. The cytogenetic analysis consisted of conventional staining, C-banding, triple fluorochrome staining (CMA3/DA/DAPI), and fluorescent in situ hybridization using ribosomal DNAs (rDNAs) and H3 histone gene as probes, as well as microdissection and chromosome painting of the B chromosome. The B chromosomes were detected in all populations analyzed. Analysis revealed the heterochromatic nature and the presence of G+C-rich blocks and 18S rDNA on the B chromosome. FISH with DNA from microdissected B chromosome painted the entire extension of the B chromosome for all populations, besides the pericentromeric regions of all the autosomes, as well as the X chromosome. Finally, cross-hybridization in nine related species of Dichotomius using the microdissected B chromosome as probe did not reveal any hybridization signal. The results suggest an intraspecific and monophyletic origin for B chromosomes in D. sericeus, probably from the second or third autosomal pair.

Therapeutic Drug Monitoring of Amikacin in Neutropenic Oncology Patients.

Amikacin is the antibiotic of choice for the treatment of Gram-negative infections, namely, those in neutropenic oncology patients. No populational pharmacokinetic studies are currently available reporting amikacin pharmacokinetics in neutropenic oncology patients despite their specific pathophysiological features and treatments. A large-scale retrospective study was herein conducted to specifically investigate the effects that tumor diseases have on the pharmacokinetic parameters of amikacin and identify whether chemotherapy, the lag time between administration of chemotherapy and amikacin, age and renal function contribute to amikacin pharmacokinetics in neutropenic cancer patients. A total of 1180 pharmacokinetic analysis from 629 neutropenic patients were enrolled. The daily dose administered to oncology patients was higher than that administered to non-oncology patients (p < 0.0001). No statistical differences were found in amikacin concentrations, probably because drug clearance was increased in cancer patients (p < 0.0001). Chemotherapy influenced amikacin pharmacokinetics and drug clearance decreased as the lag time enhanced. The elderly group revealed no statistical differences between the doses administered to both the oncology groups, suggesting that the impact of ageing is stronger than chemotherapy. Our research suggests that cancer patients require higher initial doses of amikacin, as well as when chemotherapy is received less than 30 days before amikacin treatment has started.

Antifungals: From Pharmacokinetics to Clinical Practice.

The use of antifungal drugs started in the 1950s with polyenes nystatin, natamycin and amphotericin B-deoxycholate (AmB). Until the present day, AmB has been considered to be a hallmark in the treatment of invasive systemic fungal infections. Nevertheless, the success and the use of AmB were associated with severe adverse effects which stimulated the development of new antifungal drugs such as azoles, pyrimidine antimetabolite, mitotic inhibitors, allylamines and echinochandins. However, all of these drugs presented one or more limitations associated with adverse reactions, administration route and more recently the development of resistance. To worsen this scenario, there has been an increase in fungal infections, especially in invasive systemic fungal infections that are particularly difficult to diagnose and treat. In 2022, the World Health Organization (WHO) published the first fungal priority pathogens list, alerting people to the increased incidence of invasive systemic fungal infections and to the associated risk of mortality/morbidity. The report also emphasized the need to rationally use existing drugs and develop new drugs. In this review, we performed an overview of the history of antifungals and their classification, mechanism of action, pharmacokinetic/pharmacodynamic (PK/PD) characteristics and clinical applications. In parallel, we also addressed the contribution of fungi biology and genetics to the development of resistance to antifungal drugs. Considering that drug effectiveness also depends on the mammalian host, we provide an overview on the roles of therapeutic drug monitoring and pharmacogenomics as means to improve the outcome, prevent/reduce antifungal toxicity and prevent the emergence of antifungal resistance. Finally, we present the new antifungals and their main characteristics.

Influence of anthropic changes and environmental characteristics on the occurrence of Tegumentary Leishmaniasis in Montes Claros, Minas Gerais, Brazil, between 2012 and 2019.

This is an ecological study that investigated the influence of environmental, socioeconomic characteristics and changes in land use and cover on the occurrence of Tegumentary Leishmaniasis (TL) in the city of Montes Claros. The relationships between the number of cases of TL, which occurred between 2012 and 2019, in each census sector and the standardized covariates (Number of properties, altitude, Brazilian Deprivation Index, Normalized Difference Vegetation Index (NDVI), proportion of sector (PS) deforested, PS that underwent other anthropic alterations and unaltered PS) were evaluated with ecological Bayesian Models. Four multivariate models were constructed, with similar quality of adjustments, but Model 1 was the most parsimonious. Model 1 revealed that for each one-unit increase of standard deviation (SD) in the log of the number of properties, at the altitude and root of the deforested PS, corresponds to an increase of 44%, 34% and 24.5% in the number of cases of TL, respectively. The variable NDVI, included in models 3 and 4, was positively associated with the increase in the number of TL cases, being that for each one-unit increase in the NDVI was verified an increase of 21.3% and 20.2% respectively in the models. This study showed that the spatial distribution of TL cases in the city of Montes Claros occurs in a heterogeneous way and our findings support the hypothesis that socio-environmental characteristics and deforestation influence the occurrence of this disease in the studied area. Thus, these factors must be considered for the development of disease control strategies.

The Program for the Control of Visceral Leishmaniasis in Brazil: The Effect of the Systematic Euthanasia of Seropositive Dogs as a Single Control Action in Porteirinha, a Brazilian City with an Intense Transmission of Visceral Leishmaniasis.

BACKGROUND: Porteirinha is endemic for visceral leishmaniasis (VL), with intense disease transmission of the disease. We evaluated the impact of canine euthanasia as a single control measure on the incidence of VL in humans and canines. METHODS: A prospective observational cohort study was carried out over four years (1998-2002) in 8 of the 12 neighborhoods of the city. The dynamics of canine visceral leishmaniasis (CVL) transmission were evaluated for 2 years, before beginning the screening-culling intervention. The comparative morbidity index (CMI) was used to stratify areas with the greatest risk of CVL, and the spatial distribution of human and canine VL cases was compared using univariate and bivariate K-functions. RESULTS: Human cases conglomerated in three neighborhoods. Spatial clusters were detected for CVL in 1998, 2000, and 2001, but not in 1999, when greater spatial dispersion occurred. The screening and culling intervention reduced the number of human VL cases and decreased the incidence of CVL, mainly in neighborhoods with a high CMI. CONCLUSIONS: The systematic euthanasia of seropositive dogs was shown to be an effective control action of the Program for Control of Visceral Leishmaniasis (PCLV) in Brazil. The fundamental role of domestic dogs in the epidemiological chain of VL was reaffirmed.

[Medication Reconciliation During Admission to an Internal Medicine Department: A Pilot Study]. / Reconciliação Terapêutica na Admissão de um Serviço de Medicina Interna: Estudo-Piloto.

INTRODUCTION: The purpose of medication reconciliation is to promote patient safety by reducing medication errors and adverse events due to medication discrepancies in transition of care. The aim of this pilot study of medication reconciliation at the time of hospital admission was to identify the necessary resources for its implementation in clinical practice. MATERIAL AND METHODS: Pilot study with 100 patients admitted to an Internal Medicine department between October and December 2019, aged 18 and over, and chronically taking at least one medicine. The best possible medication history was obtained systematically, with subsequent identification, classification and resolution of the discrepancies. RESULTS: The study sample, in general characterized by polypharmacy and by having multiple long-term conditions, presented a mean age of 77.04 ± 13.74 years, being 67.0% male. Overall, 791 discrepancies were identified. Intentional discrepancies were 95.7% and 50.9% of them were documented. The difficulties encountered were mainly related with the access and quality of therapeutic information and communication problems between different healthcare professionals. The key priority resources that were identified were related with the process, tools, and personnel categories. CONCLUSION: The data revealed weaknesses in the clinical records available at the primary/hospital care interface. Optimization of data sources, standardization and informatization of the process, multidisciplinary approach and definition of priority groups were identified as opportunities for optimization.

Introdução: A reconciliação terapêutica visa promover a segurança do doente por meio da redução de erros de medicação e eventos adversos decorrentes de discrepâncias de medicação na transição de cuidados. Foi nosso objetivo realizar um estudo-piloto de reconciliação terapêutica no momento da admissão hospitalar para, a partir dele, identificarmos os recursos necessários para a sua implementação na prática clínica.Material e Métodos: Estudo-piloto com 100 doentes admitidos num serviço de Medicina Interna entre outubro e dezembro de 2019, com mais de 18 anos e a tomar cronicamente pelo menos um medicamento. A melhor história farmacoterapêutica possível foi obtida sistematicamente, com posterior identificação, classificação e resolução das discrepâncias.Resultados: A amostra em estudo, em geral polimedicada e com múltiplas morbilidades, apresentou uma média de idades de 77,04 ± 13,74 anos, sendo 67,0% do sexo masculino. Foram identificadas 791 discrepâncias e as intencionais (95,7%) estavam documentadas em 50,9% das situações. As dificuldades encontradas relacionaram-se principalmente com o acesso e a qualidade da informação terapêutica e com a dificuldade de comunicação entre os diversos profissionais de saúde. Os principais recursos prioritários identificados relacionaram-se com as categorias de processo, ferramentas e pessoal.Conclusão: Os dados revelaram fragilidades nos registos clínicos disponíveis na interface dos cuidados primários/hospitalares. A otimização das fontes de dados, normalização e informatização do processo, atuação multidisciplinar e definição de grupos prioritários foram identificadas como oportunidades de otimização.

[Correction to the article "Medication Reconciliation During Admission to an Internal Medicine Department: A Pilot Study", Published as Ahead of Print on Acta Med Port 2022.] / Errata ao artigo "Reconciliação Terapêutica na Admissão de um Serviço de Medicina Interna: Estudo-Piloto", Publicado em Ahead of Print em Acta Med Port 2022.

Na página 9, Figura 2 onde se lê:73,53%Deverá ler-se:76,48%Artigo publicado com erros: https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/16892.

Impact of vector control actions in the abundance of Lutzomyia longipalpis in Montes Claros, Brazil.

Visceral leishmaniasis (VL) is endemic to many states in Brazil. To prevent further expansion of the disease, the Brazilian Ministry of Health adopted integrated measures through the Program of Surveillance and Control of Visceral Leishmaniasis (PSCVL), whose actions include the diagnosis and euthanasia of seropositive dogs (the main domestic reservoirs), the use of residual insecticides, environmental management (EM) to control vector population (mainly Lutzomyia longipalpis phlebotomine), rigorous epidemiological surveillance, and health education. The present study was conducted in areas with recent moderate VL transmission to evaluate the efficacy of vector control activities. The systematic capture of phlebotomine was performed for three consecutive days per month, from August 2015 to July 2017. The number of specimens captured was taken as a representative of the monthly insect population. A total of 38,055 phlebotomine specimens were captured and identified at the species level. Lu. longipalpis was consistently found to be the predominant species (97.7%) each month. In the first year of the study, no intervention was performed. In the second year, two cycles of chemical spraying, EM, or a combination of both were performed before and after the rainy season. All interventions, either individually or in combination, reduced the abundance of Lu. longipalpis in the study area.

American Tegumentary Leishmaniasis in an endemic municipality in the North of Minas Gerais State: spatial analysis and socio-environmental factors.

American Tegumentary Leishmaniasis (ATL) is endemic in the municipality of Montes Claros, Minas Gerais State. The use of geotechnology such as spatial statistics and remote sensing has contributed to a better understanding of the eco-epidemiology of diseases, and consequently a better definition of control strategies. This study aimed to analyze the spatial distribution of probable sites of cases of ATL infection (2007-2011) in the municipality of Montes Claros and to identify related socio-environmental factors. Data on ATL cases notification were obtained from the Municipal Health Department of Montes Claros. The annual incidence of ATL in the municipality was calculated and the probable sites of infection were georeferenced. Crude Rate and the Local Empirical Bayesian Rate were calculated with census sectors considered as the unit of analysis. The Normalized Difference Vegetation Index (NDVI) was calculated from LANDSAT 5 TM images. The spatial association between the crude rate of ATL and the NDVI of the census tracts was evaluated using the Local Bivariate of Moran I. The socio-environmental aspects of household structures were assessed based on a structured questionnaire. The incidence of ATL in the evaluated period ranged from 6.2 to 16.6 cases/100,000 inhabitants. The highest rates of ATL occurrence were found in the census sectors located in the rural area and in the peripheral census sectors in the city. Through the Empirical Bayes Smoothed Rate map, it was found that in the peripheral areas of the city, the rates of ATL occurrence were lower than in the rural area and their values decreased as they approach the city center. Local Bivariate of Moran I showed a positive correlation between NDVI and crude ATL rates, with significant high-high clusters observed in the rural area and in the census sectors in the Western peripheral area of the city that have experienced an urban expansion concomitant to the period investigated. In most homes of people affected by the disease, there were domestic animals and organic matter in the peridomicile. In addition, a high percentage of individuals affected by ATL reported the presence of rodents circulating near their homes. In conclusion, it is possible that the disorderly expansion process in the city of Montes Claros favored the establishment of the ATL periurban and urban transmission cycle. These regions deserve special attention from health surveillance to combat this zoonosis.

Investigating regional excess mortality during 2020 COVID-19 pandemic in selected Latin American countries.

In this paper, we measure the effect of the 2020 COVID-19 pandemic wave at the national and subnational levels in selected Latin American countries that were most affected: Brazil, Chile, Ecuador, Guatemala, Mexico, and Peru. We used publicly available monthly mortality data to measure the impacts of the pandemic using excess mortality for each country and its regions. We compare the mortality, at national and regional levels, in 2020 to the mortality levels of recent trends and provide estimates of the impact of mortality on life expectancy at birth. Our findings indicate that from April 2020 on, mortality exceeded its usual monthly levels in multiple areas of each country. In Mexico and Peru, excess mortality was spreading through many areas by the end of the second half of 2020. To a lesser extent, we observed a similar pattern in Brazil, Chile, and Ecuador. We also found that as the pandemic progressed, excess mortality became more visible in areas with poorer socioeconomic and sanitary conditions. This excess mortality has reduced life expectancy across these countries by 2-10 years. Despite the lack of reliable information on COVID-19 mortality, excess mortality is a useful indicator for measuring the effects of the coronavirus pandemic, especially in the context of Latin American countries, where there is still a lack of good information on causes of death in their vital registration systems. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41118-021-00139-1.

CCL3, CCL5, IL-15, IL-1Ra and VEGF compose a reliable algorithm to discriminate classes of adverse events following 17DD-YF primary vaccination according to cause-specific definitions.

In the present study, a range of serum biomarkers were quantified in suspected cases of adverse events following YF immunization (YEL-AEFI) to propose a reliable laboratorial algorithm to discriminate confirmed YEL-AEFI ("A1" class) from cases with other illnesses ("C" class). Our findings demonstrated that increased levels of CXCL8, CCL2, CXCL10, IL-1ß, IL-6 and TNF-α were observed in YEL-AEFI ("A1" and "C" classes) as compared to primary vaccines without YEL-AEFI [PV(day 3-28)] and reference range (RR) controls. Notably, increased levels of CCL3, CCL4, CCL2, CCL5, IL-1ß, IL-15, IL-1Ra and G-CSF were found in "A1" as compared to "C" class. Venn diagrams analysis allowed the pre-selection of biomarkers for further analysis of performance indices. Data demonstrated that CCL3, CCL5, IL-15 and IL-1Ra presented high global accuracy (AUC = 1.00) to discriminate "A1" from "C". Decision tree was proposed with a reliable algorithm to discriminate YEL-AEFI cases according to cause-specific definitions with outstanding overall accuracy (91%). CCL3, CCL5, IL-15 and IL-1Ra appears as root attributes to identify "A1" followed by VEGF as branch nodes to discriminate Wild Type YFV infection ("C(WT-YFV)") from cases with other illnesses ("C*"). Together, these results demonstrated the applicability of serum biomarker measurements as putative parameters towards the establishment of accurate laboratorial tools for complementary differential diagnosis of YEL-AEFI cases.

Enantioselective assay for therapeutic drug monitoring of eslicarbazepine acetate: no interference with carbamazepine and its metabolites.

As add-on therapy, phase III clinical trials of eslicarbazepine acetate (ESL) conducted in patients with refractory partial-onset seizures have shown good efficacy, safety, and tolerability, even in patients taking carbamazepine (CBZ) at baseline (approximately 60% of the enrolled patients). Thus, considering the pharmacological disadvantages of CBZ and the similar efficacy spectrum of CBZ and ESL, switching to ESL may be successful in many patients. As ESL is a prodrug almost instantaneously converted to S-licarbazepine (S-Lic; approximately 95%), an interest in therapeutic drug monitoring (TDM) of S-Lic is likely to develop in the future. This study investigated the plasma concentrations of S-Lic and R-licarbazepine (R-Lic) enantiomers in patients under CBZ long-term treatment to assess the potential interference of CBZ or its metabolites in the enantioselective TDM of ESL (using S-Lic concentrations). A chiral high-performance liquid chromatography assay with ultraviolet detection (HPLC-UV) previously developed and validated by our research group was used. Twenty-four patients admitted to the Coimbra University Hospital and supposedly receiving CBZ long-term treatment were identified. Blood samples were collected from patients and serum CBZ concentrations were measured by the usual TDM protocol. Aliquots of plasma from such patients were also submitted to a chiral HPLC-UV analysis. The bioanalytical data indicated that S-Lic and R-Lic were not present at detectable concentrations in plasma samples of the CBZ-treated patients. The chromatograms generated by the analysis of patient plasma samples, when compared with those obtained from blank plasma samples spiked with S-Lic and R-Lic, clearly showed the absence of interferences at the retention times of both Lic enantiomers. These data support the usefulness of the chiral HPLC-UV method used for the enantioselective TDM of ESL (using S-Lic) for programs in which switching from CBZ to ESL is implemented.

Development, validation and application of a new HPLC-DAD method for simultaneous quantification of apixaban, dabigatran, edoxaban and rivaroxaban in human plasma.

Direct oral anticoagulants (DOACs) have been commonly used for the treatment of venous thromboembolism and for the prevention of stroke in patients with atrial fibrillation. Despite not being initially recommended, monitoring DOACs plasma concentrations is now recognized as essential in emergency situations and in special populations. Moreover, the inter-individual variability found in real studies as well as the high reported non-adherence are corroborating the importance of determining the individual relationship between administered doses, plasma concentrations and pharmacological effects. Therefore, accurate but user-friendly bioanalytical techniques are required to monitor DOACs plasma concentrations in routine clinical practice and phase IV clinical trials. Herein, a fast and simple high performance liquid chromatography (HPLC) method coupled to diode array detection (DAD) was developed, validated and applied to quantify the four currently marketed DOACs (apixaban, edoxaban, dabigatran and rivaroxaban). Sample preparation was performed by solid phase extraction followed by evaporation and concentration of the analytes. Chromatographic separation was accomplished within 6 min on a reversed-phase column (octadecyl-silica packing material; 55 mm × 4 mm, 3 µm particle size), applying a mobile phase composed of an aqueous solution of formic acid (0.1 %, v/v) and acetonitrile, pumped with a gradient elution at 30 °C. The proposed method was linear (r2 ≥ 0.993) within the concentration ranges of 0.017-5.28 µg mL-1, 0.066-5.28 µg mL-1, 0.033-5.28 µg mL-1 and 0.017-5.28 µg mL-1 for apixaban, dabigatran, edoxaban and rivaroxaban, respectively, all of them including the expected range of therapeutic concentrations. Overall, intra- and inter-day trueness of quality control samples, including at the lower limit of quantification (LLOQ), varied between -12.98 to 5.79 %, while imprecision was lower than 16.43 %, supporting that the method is accurate and precise in accordance to international guidelines. Recovery and stability were also assessed and allowed the method to be applied in clinical practice, during therapeutic drug monitoring.

Effectiveness of insecticide-impregnated collars for the control of canine visceral leishmaniasis.

Visceral leishmaniasis is a neglected tropical disease widely distributed worldwide. In Brazil, the control measures adopted in the last decades have not been able to prevent the spread of the disease. This study aimed to evaluate the effectiveness of a population-based intervention using 4% deltamethrin-impregnated dog collars on the incidence of canine visceral leishmaniasis. A community intervention study was carried out in two areas of the city of Montes Claros, State of Minas Gerais, Brazil. In the control area, the preventive measures recommended by the Brazilian Program for Surveillance and Control of Visceral Leishmaniasis were implemented (culling of infected dogs and vector control with residual insecticides). In the intervention area, deltamethrin-impregnated collars were fit to domiciled dogs, in addition to the above mentioned preventive measures. At the beginning of the study, a census survey was carried out among domiciled dogs to detect the prevalence of L. infantum infection. Dogs found seronegative at recruitment were longitudinally followed-up to evaluate the incidence of infection. Monitoring of canine infection (control and intervention areas) and replacement of collars (intervention area) occurred through sequential surveys at 12, 18, and 24 months after the initial survey. At each survey, dogs were tested, and the owner answered a questionnaire about the general characteristics of the animal. Multilevel logistic regression models were used to test the effect of collars on the risk of canine infection, with households considered as aggregation units. Associations were expressed as odds ratios (OR) and respective 95% confidence intervals (95%CI). The prevalence of infection in the initial survey was 9.7% and 9.9% in the intervention and control areas, respectively (p = 0.732). Among a total of 20,477 dogs participating in the study, 9,770 were seronegative at recruitment. The cumulative incidence of infection was 4.1% in the intervention area and 7.9% in the control area (p < 0.001). In the multivariable analysis, the risk of infection was 52% lower in the intervention area as compared to the control area (OR = 0.48, 95%CI:0.39-0.59), after adjusting for the number of dogs in the house, period of recruitment, time of dog ownership, and age, sex, length of fur and breed. The use of 4% deltamethrin-impregnated dog collars was effective in reducing the incidence of canine leishmaniasis. Cost-effectiveness studies are recommended before the incorporation of collars in the arsenal of control measures of the Brazilian Program for Surveillance and Control of Visceral Leishmaniasis.

Cost-effectiveness of a canine visceral leishmaniasis control program in Brazil based on insecticide-impregnated collars.

INTRODUCTION: The use of insecticide-impregnated dog collars is a potentially useful tool for the control of visceral leishmaniasis. The objective of the present study was to perform a cost-effectiveness analysis of a program based on insecticide-impregnated collars compared to traditional visceral leishmaniasis control strategies used in Brazil. METHODS: A cost-effectiveness analysis was performed from the perspective of the Unified Health System, using data from the Visceral Leishmaniasis Control Program implemented in the municipality of Montes Claros, Minas Gerais. The direct costs of the three control strategies, which were 1) canine infection screening + sacrifice, 2) residual chemical control of the vector, and 3) insecticide-impregnated dog collars (Scalibor®), were evaluated over the two-year study period. RESULTS: The total cost of the program in the area subjected to the traditional control strategies (strategies 1 and 2; control area) was R$ 1,551,699.80, and in the area subjected to all three control strategies (intervention area), it was R$ 1,898,190.16. The collar program was considered highly cost-effective at preventing canine visceral leishmaniasis (incremental cost-effectiveness ratio of approximately R$ 578 per avoided dog sacrifice). CONCLUSIONS: These results provide support for the decision by the Brazilian Ministry of Health in 2019 to provide insecticide-impregnated collars for the control of canine visceral leishmaniasis in a pilot project.

Historical sedimentary deposition and flux of PAHs, PCBs and DDTs in sediment cores from the western Adriatic Sea.

The sources and depositional history of polycyclic aromatic hydrocarbons (PAHs) and organochlorine compounds (OCs) over the last century were investigated in sediment cores from the North Adriatic Sea (Po River prodelta) and the South-Western Adriatic Margin (SWAM). Contaminant concentrations were higher in the Po River prodelta. ∑16PAHs ranged from 193 to 533 ng g-1, ∑5PCBs ranged from 0.9 to 5.2 ng g-1 and ∑DDTs (p,p'-DDD + p,p'-DDE) ranged from 0.1 to 2.5 ng g-1. In the SWAM, ∑PAHs ranged from 11 to 74 ng g-1 while ∑PCB and ∑DDT concentrations were close to the MQL. Accordingly, contaminant fluxes were much higher in the northern (mean values of 152 ±â€¯31 ng cm2 y-1 and 0.70 ±â€¯0.35 ng cm2 y-1 for PAHs and OCs, respectively) than in the southern Adriatic (2.62 ±â€¯0.9 ng cm2 y-1 and 0.03 ±â€¯0.02 ng cm2 y-1 for PAHs and OCs, respectively). The historical deposition of PAHs seemed to be influenced by the historical socioeconomic development and by changes in the composition of fossil fuel consumption (from petroleum derivatives to natural gas) in Italy from the end of the 19th century to the present. Similarly, vertical variations in DDT concentrations matched its historical use and consumption in Italy, which started around in the mid-late 1940s to fight typhus during the II World War. Contaminant concentrations detected in sediments does not seem to pose ecotoxicological risk for marine organisms in the Adriatic Sea.

Detection of Metalloproteases and Cysteine Proteases RNA Transcripts of Leishmania (Leishmania) infantum in Ear Edge Skin of Naturally Infected Dogs.

Leishmania spp. proteases have been proposed as virulence factors contributing to adaptive success these parasites to the mammalian hosts. Since these enzymes are poorly studied in naturally infected dogs, this work aims to show the differences in metalloprotease and cysteine proteases gene expression in ear edge skin of dogs naturally infected by Leishmania (Leishmania) infantum. A cohort of dogs (n = 20) naturally infected by L. (L.) infantum was clinically classified as asymptomatic, oligosymptomatic, and polysymptomatic and the parasite load range estimated. The analysis of proteases expression by RT-PCR in the ear edge skin was also assessed, suggesting more transcripts of proteases in cDNA samples from polysymptomatic dogs than oligosymptomatic and asymptomatic ones. Metalloprotease RT-PCR assays yielded products (202 bp) in all assessed cDNA dog samples. In contrast, cysteine proteases transcripts (227 bp) had shown to be better detected in cDNA samples of polysymptomatic dogs, compared with cDNA samples from asymptomatic and oligosymptomatic dogs. Predictive in silico assays suggested that secondary structures of metalloproteasee mRNAs can be more stable than cysteine proteases at the skin temperature of dogs. Evidence is presented that during natural infection of dogs by L. (L.) infantum, this parasite produces transcripts of metalloprotease and cysteine protease RNA in the skin from asymptomatic, oligosymptomatic, and polysymptomatic dogs.

Dogs with divergent serology for visceral leishmaniasis as sources of Leishmania infection for Lutzomyia longipalpis phlebotomine sand flies - an observational study in an endemic area in Brazil.

Visceral leishmaniasis (VL) is a neglected tropical disease, caused by Leishmania (Kinetoplastida, Trypanosomatidae) species. In Brazil, the transmission of this parasite essentially occurs through the bite of Lutzomyia longipalpis (Diptera: Psychodidae: Phlebotominae) previously infected with Leishmania infantum. Aiming at preventing VL expansion over the country, integrated control actions have been implemented through a Visceral Leishmaniasis Surveillance and Control Program (VLSCP). Among the actions currently adopted by the program, the screening-culling of seropositive dogs for canine VL (CVL) is particularly polemic. Dogs with negative or divergent serology for CVL remain in their owner's domicile and are monitored by public health agents. In the present study, we determined the prevalence of CVL and analyzed the implementation of the VLSCP screening-culling action, in an area in Brazil where there has been a recent expansion of VL. Canine census surveys were conducted semiannually for two years (Aug/2015 to Feb/2017). Serological diagnosis of CVL was performed in accordance with current VLSCP protocol: immunochromatography (TR-DPP) followed by enzyme-linked immunosorbent assay (ELISA EIE). 6,667 dogs were serologically screened for CVL, of which 567 (8.5%) were positive in both tests and 641 (9.6%) had divergent results. A variable percentage (6.3% to 65.4%) of the dogs in the latter group became positive within nine months from the first result. Xenodiagnosis was conducted in canine samples belonging to any of the three possible serological statuses for CVL-positive, divergent or negative. Leishmania spp. DNA was detected in Lu. longipalpis that fed on 50.0% (5/10) of dogs with positive serology and on 29.4% (5/17) of dogs with divergent serological status for CVL. Therefore, dogs with divergent serology for CVL may be as Leishmania-infective to Lu. longipalpis as seropositive ones. Even with the adoption of euthanasia for seropositive dogs, part of the canine population will continue to serve as a source of Leishmania infection for phlebotomine sand flies.