A systematic review of the prevalence of late identified hearing loss in childhood.

OBJECTIVES: The objective of this systematic review was to assess the evidence about the prevalence of permanent hearing loss for children not identified from newborn hearing screening (NHS). DESIGN: Articles were grouped into three categories based on the methodological approach: (1) all participants received diagnostic testing, (2) otoacoustic emission (OAE) or pure tone screening was completed and those not passing were referred for a diagnostic test, and (3) data were retrieved from archival records. Study characteristics, prevalence, and contextual factors were synthesised and narratively described. STUDY SAMPLE: 30 peer-reviewed articles. RESULTS: Prevalence of permanent hearing loss per 1,000 children ranged from 0.32 to 77.87 (M = 7.30; SD = 16.87). Variations in the criteria for inclusion contributed to prevalence differences. Prevalence was higher when unilateral and milder degrees of hearing loss were included, and older children had higher prevalence (M = 13.71; SD = 23.21) than younger children (M = 1.57; SD = 0.86). CONCLUSION: There is scant research on prevalence of childhood hearing loss after NHS that utilised methods to accurately differentiate between permanent and temporary hearing loss. Rigorous research is needed on the prevalence of permanent childhood hearing loss to inform strategies for monitoring, identification, intervention, and management.

The stem rust effector protein AvrSr50 escapes Sr50 recognition by a substitution in a single surface-exposed residue.

Pathogen effectors are crucial players during plant colonisation and infection. Plant resistance mostly relies on effector recognition to activate defence responses. Understanding how effector proteins escape from plant surveillance is important for plant breeding and resistance deployment. Here we examined the role of genetic diversity of the stem rust (Puccinia graminis f. sp. tritici (Pgt)) AvrSr50 gene in determining recognition by the corresponding wheat Sr50 resistance gene. We solved the crystal structure of a natural variant of AvrSr50 and used site-directed mutagenesis and transient expression assays to dissect the molecular mechanisms explaining gain of virulence. We report that AvrSr50 can escape recognition by Sr50 through different mechanisms including DNA insertion, stop codon loss or by amino-acid variation involving a single substitution of the AvrSr50 surface-exposed residue Q121. We also report structural homology of AvrSr50 to cupin superfamily members and carbohydrate-binding modules indicating a potential role in binding sugar moieties. This study identifies key polymorphic sites present in AvrSr50 alleles from natural stem rust populations that play important roles to escape from Sr50 recognition. This constitutes an important step to better understand Pgt effector evolution and to monitor AvrSr50 variants in natural rust populations.

TLR expression in peripheral monocyte subsets of patients with idiopathic inflammatory myopathies: association with clinical and immunological features.

BACKGROUND: Monocytes and toll-like receptors (TLR) have been found in the inflammatory infiltrate of muscle biopsies in patients with idiopathic inflammatory myopathies (IIM), suggesting an important role of these cells in the pathogenesis of myositis. The monocyte subsets, their TLR expression in peripheral blood and their relationship with the clinical characteristics of patients with IIM has not been addressed. METHODS: We recruited 45 patients with IIM diagnosis and 15 age and sex-adjusted healthy controls. We assessed the disease activity and damage, performed a nailfold capillaroscopy and registered the cardio-pulmonary parameters from the medical charts. Monocyte subsets, their expression of TLR2 and TLR4 and the serum Th1/Th2/Th17 cytokines levels were evaluated by flow cytometry. We expressed quantitative variables as medians and interquartile ranges (IQR) or minimum and maximum (min-max). Differences between groups were assessed with Mann-Whitney U and the Kruskal-Wallis tests. Correlation between quantitative variables was assessed with Spearman Rho. RESULTS: Twenty-nine patients were women (64.4%) and 32 (71.1%) had dermatomyositis. In comparison to healthy controls, patients with active IIM had a higher percentage of intermediate monocytes and lower amounts of classical monocytes. Patients with IIM had a higher expression of TLR4 in all their monocyte subsets, regardless of disease activity and prednisone treatment. Serum IL-6 correlated with the TLR2 expression in every monocyte subset and the expression of TLR2 in intermediate monocytes was higher among patients with dysphagia. Subjects with nailfold capillaroscopy abnormalities had a higher amount of TLR2+ classical and non-classical monocytes and those with interstitial lung disease (ILD) had a higher percentage of TLR4+ non-classical monocytes. The classical and intermediate monocytes from patients with anti Mi2 antibodies had a higher expression of TLR4. The percentage of intermediate monocytes and the expression of TLR4 in all monocyte subsets showed a good diagnostic capacity in patients with IIM. CONCLUSION: Patients with IIM have a differential pool of monocyte subsets with an enhanced expression of TLR2 and TLR4, which correlates with disease activity and distinctive clinical features including dysphagia, ILD, vasculopathy, and pro-inflammatory cytokines. These immunological features might be useful as a potential diagnostic tool as well as novel disease activity biomarkers in IIM.

Recognition of the Magnaporthe oryzae Effector AVR-Pia by the Decoy Domain of the Rice NLR Immune Receptor RGA5.

Nucleotide binding domain and leucine-rich repeat proteins (NLRs) are important receptors in plant immunity that allow recognition of pathogen effectors. The rice (Oryza sativa) NLR RGA5 recognizes the Magnaporthe oryzae effector AVR-Pia through direct interaction. Here, we gained detailed insights into the molecular and structural bases of AVR-Pia-RGA5 interaction and the role of the RATX1 decoy domain of RGA5. NMR titration combined with in vitro and in vivo protein-protein interaction analyses identified the AVR-Pia interaction surface that binds to the RATX1 domain. Structure-informed AVR-Pia mutants showed that, although AVR-Pia associates with additional sites in RGA5, binding to the RATX1 domain is necessary for pathogen recognition but can be of moderate affinity. Therefore, RGA5-mediated resistance is highly resilient to mutations in the effector. We propose a model that explains such robust effector recognition as a consequence, and an advantage, of the combination of integrated decoy domains with additional independent effector-NLR interactions.

High relative abundance of firmicutes and increased TNF-α levels correlate with obesity in children.

OBJECTIVE: To investigate the correlation among pro- or anti-inflammatory cytokines and the two main gut microbiota phyla in obese children. MATERIALS AND METHODS: Anthropometric data were obtained from 890 children under 14 years old to determine the degree of obesity. Serum cytokine concentration was measured by ELISA. Relative abundance of gut microbiota in feces was evaluated by quantitative RealTime PCR assays. RESULTS: Anthropometric and biochemical parameters were statistically higher in overweigth/ obese children (OW/O) than in lean (NW), Increased TNF-α levels were found in obese children that also have a high relative abundance of Firmicutes. CONCLUSIONS: Obese children have a high relative abundance of Firmicutes that correlates with increased levels of TNF-α. This is the first study that shows a relation between Firmicute abundance and TNF-α serum concentration in obese children.

Targeting the Cytochrome bc1 Complex of Leishmania Parasites for Discovery of Novel Drugs.

Endochin-like quinolones (ELQs) are potent and specific inhibitors of cytochrome bc1 from Plasmodium falciparum and Toxoplasma gondii and show promise for novel antiparasitic drug development. To determine whether the mitochondrial electron transport chain of Leishmania parasites could be targeted similarly for drug development, we investigated the activity of 134 structurally diverse ELQs. A cohort of ELQs was selectively toxic to amastigotes of Leishmania mexicana and L. donovani, with 50% inhibitory concentrations (IC50s) in the low micromolar range, but the structurally similar hydroxynaphthoquinone buparvaquone was by far the most potent inhibitor of electron transport, ATP production, and intracellular amastigote growth. Cytochrome bc1 is thus a promising target for novel antileishmanial drugs, and further improvements on the buparvaquone scaffold are warranted for development of enhanced therapeutics.

Polymorphisms in the LPL and CETP Genes and Haplotype in the ESR1 Gene Are Associated with Metabolic Syndrome in Women from Southwestern Mexico.

Metabolic syndrome (MetS) is a combination of metabolic disorders associated with an increased risk for cardiovascular disease (CVD). Studies in women reported associations between polymorphisms in ESR1, LPL and CETP genes and MetS. Our aim was to evaluate the association between variants in ESR1, LPL and CETP genes with MetS and its components. Four hundred and eighty women were analyzed, anthropometric features and biochemical profiles were evaluated, and genotyping was performed by real-time PCR. We found an association with elevated glucose levels (odds ratio (OR) = 2.9; p = 0.013) in carrying the AA genotype of rs1884051 in the ESR1 gene compared with the GG genotype, and the CC genotype of rs328 in the LPL gene was associated with MetS compared to the CG or GG genotype (OR = 2.8; p = 0.04). Moreover, the GA genotype of rs708272 in the CETP gene is associated with MetS compared to the GG or AA genotype (OR = 1.8; p = 0.006). In addition the ACTCCG haplotype in the ESR1 gene is associated with a decrease in the risk of MetS (OR = 0.02; p < 0.001). In conclusion, our results show the involvement of the variants of ESR1, LPL and CETP genes in metabolic events related to MetS or some of its features.

Applied Research in Clinical Audiology with Spanish Speakers in the United States: A Scoping Review.

BACKGROUND: The Hispanic population is growing, and Spanish is the second most spoken language in the United States. When individuals experience a hearing problem, culturally and linguistically responsive services represent an important part of person-centered care, contributing to wellbeing and intervention outcomes. PURPOSE: The purpose was to identify research in clinical audiology conducted with Spanish speakers to illuminate gaps and inform future research. RESEARCH DESIGN: A scoping literature review. DATA COLLECTION AND ANALYSIS: A database search was completed in January 2022. Included research was conducted in clinical audiology, had Spanish-speaking deaf or hard-of-hearing (DHH) adults/parents of a DHH child in the United States, Spanish language data collection, and published in English in a peer-reviewed journal. Studies were categorized by the area of audiology and a narrative description provided. RESULTS: The search identified 655 articles. Following screening, 11 studies met the inclusion criteria and 1 article was identified from the reference lists of included articles for a total 12 articles. The articles were published between 1997 and 2021. Most studies were conducted with adults and a few were with parents of DHH children. Research was conducted in four areas: hearing loss experiences, hearing aid experiences, hearing screening, and communication. CONCLUSIONS: There is limited research with Spanish-speaking DHH individuals and parents of DHH children. There is an urgent need for future research to inform culturally and linguistically responsive clinical practice, and to provide evidence-based interventions for effective hearing health care management.

Extensive immune receptor repertoire diversity in disease-resistant rice landraces.

Plants have powerful defense mechanisms and extensive immune receptor repertoires, yet crop monocultures are prone to epidemic diseases. Rice (Oryza sativa) is susceptible to many diseases, such as rice blast caused by Magnaporthe oryzae. Varietal resistance of rice to blast relies on intracellular nucleotide binding, leucine-rich repeat (NLR) receptors that recognize specific pathogen molecules and trigger immune responses. In the Yuanyang terraces in southwest China, rice landraces rarely show severe losses to disease whereas commercial inbred lines show pronounced field susceptibility. Here, we investigate within-landrace NLR sequence diversity of nine rice landraces and eleven modern varieties using complexity reduction techniques. We find that NLRs display high sequence diversity in landraces, consistent with balancing selection, and that balancing selection at NLRs is more pervasive in landraces than modern varieties. Notably, modern varieties lack many ancient NLR haplotypes that are retained in some landraces. Our study emphasizes the value of standing genetic variation that is maintained in farmer landraces as a resource to make modern crops and agroecosystems less prone to disease. The conservation of landraces is, therefore, crucial for ensuring food security in the face of dynamic biotic and abiotic threats.

Assessing pyrethroid resistance in Aedes aegypti from Cordoba Colombia: Implications of kdr mutations.

Resistance to insecticides is one of the great challenges that vector control programs must face. The constant use of pyrethroid-type insecticides worldwide has caused selection pressure in populations of the Aedes aegypti vector, which has promoted the emergence of resistant populations. The resistance mechanism to pyrethroid insecticides most studied to date is target-site mutations that desensitize the voltage-gated sodium channel (VGSC) of the insect to the action of pyrethroids. In the present study, susceptibility to the pyrethroid insecticides permethrin, lambda-cyhalothrin, and deltamethrin was evaluated in fourteen populations from the department of Córdoba, Colombia. The CDC bottle bioassay and WHO tube methods were used. Additionally, the frequencies of the F1534C, V1016I, and V410L mutations were determined, and the association of resistance with the tri-locus haplotypes was examined. The results varied between the two techniques used, with resistance to permethrin observed in thirteen of the fourteen populations, resistance to lambda-cyhalothrin in two populations, and susceptibility to deltamethrin in all the populations under study with the CDC method. In contrast, the WHO method showed resistance to the three insecticides evaluated in all populations. The frequencies of the mutated alleles ranged from 0.05-0.43 for 1016I, 0.94-1.0 for 1534C, and 0.01-0.59 for 410L. The triple homozygous mutant CIL haplotype was associated with resistance to all three pyrethroids evaluated with the WHO bioassay, while with the CDC bioassay, it was only associated with resistance to permethrin. This study highlights the importance of implementing systematic monitoring of kdr mutations, allowing resistance management strategies to be dynamically adjusted to achieve effective control of Aedes aegypti.

["Good life is to be in peace and harmony with everything around us": a qualitative study on good living among the Kankuamo Indigenous people of Colombia]. / "Buen vivir es estar en paz y armonía con todo lo que nos rodea": estudio cualitativo sobre el buen vivir en el pueblo indígena Kankuamo de Colombia.

The Kankuamo people are one of the 102 native peoples of Colombia, who are developing strategies for individual and collective health self-management. This article aims to investigate, identify and analyze, collaboratively and interculturally, the factors that influence the well-being of the Kankuamo people, using the Capabilities Approach proposed by Amartya Sen. To this end, three focus groups were conducted with the participation of 37 people from the 15 communities of the Kankuamo reservation. The transcripts were analyzed by means of a thematic analysis. Three central themes for the well-being of the Kankuamo emerged from the focus groups: (i) harmony between nature and human beings, (ii) social coexistence and (iii) self-determination. These themes reflect the fundamental principles and values that guide the community towards a good life, expansion of their capabilities, harmony and holistic development. The results suggest that material aspects play a secondary role in the Kankuamo community's concept of good life, and confirm that it is fundamental to consider a collective vision of capabilities, not only individual ones, in indigenous contexts. Studies such as this one can contribute to the development of more contextually appropriate approaches to assess and measure the quality of life and well-being of Indigenous communities, including the Kankuamo people.

El pueblo Kankuamo es uno de los 102 pueblos originarios de Colombia, que se encuentran en el proceso de desarrollo de estrategias para la autogestión de salud individual y colectiva. Este artículo tiene como objetivo investigar, identificar y analizar, de forma colaborativa e intercultural, los factores que influyen en el bienestar del pueblo Kankuamo, utilizando el Enfoque de Capacidades propuesto por Amartya Sen. Con este fin, se llevaron a cabo tres grupos focales con la participación de 37 personas de las 15 comunidades del resguardo Kankuamo. Las transcripciones fueron analizadas mediante un análisis temático. De los grupos focales surgieron tres temas centrales para el bienestar de los Kankuamo: (i) armonía entre la naturaleza y los seres humanos, (ii) convivencia social y (iii) autodeterminación. Estos temas reflejan los principios y valores fundamentales que guían a la comunidad hacia el bienestar, la expansión de sus capacidades, la armonía y el desarrollo integral. Los resultados sugieren que los aspectos materiales desempeñan un papel secundario en el concepto de bienestar de la comunidad Kankuamo, y además confirman que es fundamental considerar una visión colectiva de capacidades, no solo individuales, en contextos indígenas. Estudios como este pueden contribuir al desarrollo de enfoques más contextualmente apropiados para evaluar y medir la calidad de vida y el bienestar de las comunidades indígenas, incluyendo el pueblo Kankuamo.

O povo Kankuamo é um dos 102 povos indígenas da Colômbia que estão em processo de desenvolvimento de estratégias para a autogestão da saúde individual e coletiva. Este artigo tem como objetivo investigar, identificar e analisar, de forma colaborativa e intercultural, os fatores que influenciam o bem-estar do povo Kankuamo, usando a Abordagem de Capacidades proposta por Amartya Sen. Para isso, foram realizados três grupos focais com a participação de 37 pessoas das 15 comunidades da reserva Kankuamo. Análise temática foi usada nas transcrições. Três temas centrais para o bem-estar dos Kankuamo emergiram dos grupos focais: (i) harmonia entre a natureza e os seres humanos, (ii) coexistência social e (iii) autodeterminação. Esses temas refletem os princípios e valores fundamentais que orientam a comunidade para o bem-estar, a expansão de suas capacidades, a harmonia e o desenvolvimento integral. Os resultados sugerem que os aspectos materiais desempenham um papel secundário no conceito de bem-estar da comunidade Kankuamo e confirmam ainda que é essencial considerar uma visão coletiva das capacidades, e não apenas individual, em contextos indígenas. Estudos como este podem contribuir para o desenvolvimento de abordagens mais adequadas ao contexto para avaliar e medir a qualidade de vida e o bem-estar das comunidades indígenas, incluindo o povo Kankuamo.

Medical Imagery: Cytomegalovirus sialadenitis in a patient with B-cell acute lymphoblastic leukemia.

Cytomegalovirus (CMV) can cause a broad range of diseases, with severity depending on immune status, comorbidities, and age. Initial CMV infection usually occurs in childhood and is typically asymptomatic, leading to lifelong latency. In immunocompromised patients, CMV can affect multiple organs, but salivary gland infections are rare. This study presents a case of a 66-year-old woman with B-cell acute lymphoblastic leukemia who developed swelling and pain in the right preauricular region during pre-transplant consolidation therapy. Despite a recent bone marrow biopsy indicating morphological remission and a flow cytometry analysis detecting only 0.04 % B lymphoblasts, she exhibited these symptoms. A CT scan revealed enlargement, hyperdensity, and enhancement of the right parotid glands, with accompanying subcutaneous edema. A biopsy of the right parotid gland showed a dense interstitial lymphoplasmacytic infiltrate with numerous Cowdry bodies and smaller granular cytoplasmic inclusions, all testing positive for CMV immunohistochemistry. The findings confirm the diagnosis of CMV sialadenitis in an immunocompromised patient. This case underscores the importance of considering CMV infections in similar clinical scenarios, particularly in patients with compromised immune systems.

Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents.

Leishmaniasis is a neglected tropical disease that is estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered and developed a natural product-inspired tambjamine chemotype, known to be effective against Plasmodium spp, as a novel class of antileishmanial agents. Herein, we report in vitro and in vivo antileishmanial activities, detailed structure-activity relationships, and metabolic/pharmacokinetic profiles of a large library of tambjamines. A number of tambjamines exhibited excellent potency against both Leishmania mexicana and Leishmania donovani parasites with good safety and metabolic profiles. Notably, tambjamine 110 offered excellent potency and provided partial protection to leishmania-infected mice at 40 and/or 60 mg/kg/10 days of oral treatment. This study presents the first account of antileishmanial activity in the tambjamine family and paves the way for the generation of new oral antileishmanial drugs.

[Cutaneous leishmaniasis and multidermatomic herpes zoster]. / Leishmaniasis cutánea y herpes zoster multidermatómico.

Standard treatment of leishmaniasis consists of n-metilglucamine, meglumine antimoniate, which can trigger side effects such as general malaise, renal and hepatic impairment, and cardiac arrhythmias. Infrequently, reactivations of varicella-zoster virus infections have been reported. This paper describes a patient with cutaneous leishmaniasis in treatment with meglumine and herpes zoster multiplex. After ruling out other possible causes of immunosuppression, an acyclovir therapy was initiated.

Population-specific facial traits and diagnosis accuracy of genetic and rare diseases in an admixed Colombian population.

Up to 40% of rare disorders (RD) present facial dysmorphologies, and visual assessment is commonly used for clinical diagnosis. Quantitative approaches are more objective, but mostly rely on European descent populations, disregarding diverse population ancestry. Here, we assessed the facial phenotypes of Down (DS), Morquio (MS), Noonan (NS) and Neurofibromatosis type 1 (NF1) syndromes in a Latino-American population, recording the coordinates of 18 landmarks in 2D images from 79 controls and 51 patients. We quantified facial differences using Euclidean Distance Matrix Analysis, and assessed the diagnostic accuracy of Face2Gene, an automatic deep-learning algorithm. Individuals diagnosed with DS and MS presented severe phenotypes, with 58.2% and 65.4% of significantly different facial traits. The phenotype was milder in NS (47.7%) and non-significant in NF1 (11.4%). Each syndrome presented a characteristic dysmorphology pattern, supporting the diagnostic potential of facial biomarkers. However, population-specific traits were detected in the Colombian population. Diagnostic accuracy was 100% in DS, moderate in NS (66.7%) but lower in comparison to a European population (100%), and below 10% in MS and NF1. Moreover, admixed individuals showed lower facial gestalt similarities. Our results underscore that incorporating populations with Amerindian, African and European ancestry is crucial to improve diagnostic methods of rare disorders.

Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides.

Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure-activity and structure-property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.

Trypanosoma cruzi: experimental parasitism in the central nervous system of albino mice.

Trypanosoma cruzi causes a pan-infection, Chagas disease, in American mammals through fecal transmission by triatomine insects, resulting in an acute phase parasitemia with intracellularity mainly in the myocells and cells of the central nervous system (CNS).The parasites, due to the immune response, then decrease in number, characteristic of the life-long chronicity of the disease. We infected a mouse model with isolates obtained from reservoirs and vectors from rural and urban endemic areas in Venezuela. Intracellular proliferation and differentiation of the parasite in astrocytes, microglia, neurons, endothelial cells of the piarachnoid, cells of the Purkinje layer, and spinal ganglion cells, as well as extracellularly in the neuropil, were evaluated during the acute phase. Damages were identified as meningoencephalitis, astrocytosis, reactive microglia, acute neuronal degeneration by central chromatolysis, endothelial cell hyperplasia, edema of the neuropil, and satellitosis. This is the first time that satellitosis has been reported from a mammal infected with T. cruzi. Intracellular T. cruzi and inflammatory infiltrates were found in cardiac and skeletal myocytes and liver cells. No parasitism or alterations to the CNS were observed in the chronic mice, although they did show myocarditis and myocitis with extensive infiltrates. Our results are discussed in relation to hypotheses that deny the importance of the presence of tissue parasites versus the direct relationship between these and the damages produced during the chronic phase of Chagas disease. We also review the mechanisms proposed as responsible for the nervous phase of this parasitosis.

Intervention Research to Increase Pediatric Hearing Device Use: A Scoping Review.

PURPOSE: This study is a scoping review examining interventions to increase hearing device use for children. METHOD: Online databases were used to identify peer-reviewed journal articles published prior to November 1, 2021, yielding 1,288 after duplications were removed. Four articles met the inclusion criteria after articles were screened by title name and abstract and subsequent full-text screening of six articles. A qualitative analysis was conducted to identify features of the intervention studies related to the participants, design, intervention, key findings, and limitations. RESULTS: The included studies were published between 1982 and 2021, and in all four studies, the children used hearing aids. All four of the studies used a longitudinal design to address hearing aid use problems, with the timeframe ranging from approximately 1 month to 6 months and had variable success in increasing use time. None of the studies included a protocol, such as counseling skills, for addressing internal challenges that interfere with hearing aid use. CONCLUSIONS: Review of the limited research in this area found variable effectiveness for the interventions studied. There is an urgent need for research in this area to inform clinical practice and provide evidence-based interventions to address malleable factors that interfere with audibility for children who use hearing devices.

The burden of the most common rheumatic disease in Colombia.

BACKGROUND: Estimating the burden of rheumatic diseases (RDs) requires proper evaluation of its lethal and nonlethal consequences. In Colombia, it is possible to find local data and Global Burden of Disease (GBD) reports that collect information from varied contexts and apply complex statistical models, but no on-site estimations are available. METHODS: This was a descriptive study on the burden of RD based on occurrence and mortality data in the general population during 2015, including information and prevalence estimations from the Community Oriented Program for the Control of Rheumatic Diseases (COPCORD) study. Disability-adjusted life years (DALYs) were estimated by combining measures of years of life lost (YLL) and years lived with disability (YLDs). For disability weight estimations among cases, different COPCORD responses were mapped using flowcharts to show the severity distribution according to GBD. All model parameters and results were validated through an expert consensus panel. RESULTS: Low back pain (LBP) was the RD with the greatest burden of disease, costing 606.05 (95% CI 502.76-716.58) DALYs per 100,000 inhabitants, followed by osteoarthritis (292.11; 95% CI 205.76-386.85) and rheumatoid arthritis (192.46, 95% CI 109.7-239.69). CONCLUSIONS: The burden of RD is as high in Colombia as in other countries of the region. The results offer an interesting tool for optimizing healthcare system design as well as for planning the distribution of human and economic resources to achieve early diagnosis and adequate care of these diseases.

Purine restriction induces pronounced translational upregulation of the NT1 adenosine/pyrimidine nucleoside transporter in Leishmania major.

Leishmania and other parasitic protozoa are unable to synthesize purines de novo and are reliant upon purine nucleoside and nucleobase transporters to import preformed purines from their hosts. To study the roles of the four purine permeases NT1-NT4 in Leishmania major, null mutants in each transporter gene were prepared and the effect of each gene deletion on purine uptake was monitored. Deletion of the NT3 purine nucleobase transporter gene or both NT3 and the NT2 nucleoside transporter gene resulted in pronounced upregulation of adenosine and uridine uptake mediated by the NT1 permease and also induced up to a 200-fold enhancement in the level of the NT1 protein but not mRNA. A similar level of upregulation of NT1 was achieved in wild-type promastigotes that were transferred to medium deficient in purines. Pulse labelling and treatment of cells with the translation inhibitor cycloheximide revealed that control of NT1 expression occurs primarily at the level of translation and not protein turnover. These observations imply the existence of a translational control mechanism that enhances the ability of Leishmania parasites to import essential purines when they are present at limiting concentrations.