Value Assessment Frameworks in Latin America: "Il buono, il brutto e il cattivo".

OBJECTIVES: Using a taxonomy previously developed, we assessed the strengths and limitations of available value assessment frameworks (VAF) in Latin America. METHODS: Systematic review of peer-reviewed journals, gray literature review, and surveys to ISPOR Latin America Industry Committee members were done to identify and select current VAF. Once selected, independent reviewers, organized by pairs, assessed each framework's input, methodology, and outputs. RESULTS: We assessed 7 of 9 VAF in the region, excluding 2 that were not currently in use. The review included 1 framework developed by a regional entity, and 6 country frameworks for either price assessment or to inform reimbursement. Most of these frameworks had a clear definition of the purpose (6 of 7) but could provide more details on the conceptual approach, including perspectives, methods for obtaining preferences, and the ability to incorporate multiple value dimensions (2 of 7). Most lacked information about inclusions/exclusions of elements included in the framework, and whether it assumes a base case comparator and how it is selected. The description of the evaluation of data sources and their scientific validity was inconsistently reported (3 of 7). Few included an assessment of the intervention's effect on total costs of treating a defined population (2 of 7), or a description of how uncertainty could be incorporated (3 of 7). Finally, potential conflicts of interest among those creating the framework are not sufficiently addressed (0 of 7). CONCLUSIONS: In the 7 frameworks assessed in Latin America, there are opportunities to improve dimensions, methods, and scope. Addressing these issues will strengthen these VAF for policy and clinical decision making.

[Molecular typing of Leishmania (Leishmania) amazonensis and species of the subgenus Viannia associated with cutaneous and mucosal leishmaniasis in Colombia: A concordance study].

INTRODUCTION: Multilocus enzyme electrophoresis (MLEE) is the reference standard for the characterization of Leishmania species. The test is restricted to specialized laboratories due to its technical complexity, cost, and time required to obtain results. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) is used to identify Leishmania species. OBJECTIVE: To establish the concordance between the two tests as identifying methods for circulating species in Colombia. MATERIALS AND METHODS: A total of 96 isolates from patients with cutaneous or mucosal leishmaniasis were selected and identified by MLEE and PCR-RFLP with miniexon and hsp70 as the molecular targets, which were used sequentially. Restriction enzymes HaeIII and BccI were similarly applied. Cohen's kappa coefficient and the 95% confidence interval (CI) were calculated. RESULTS: The kappa coefficient and the 95% CI between MLEE and PCR-RFLP displayed "very good" concordance with a coefficient of 0.98 (CI95%: 0.98 to 1.00). The identified species were Leishmania Viannia braziliensis, Leishmania Viannia panamensis, Leishmania Viannia guyanensis and Leishmania Leishmania amazonensis. A total of 80 of the 96 isolates were sequenced and the results obtained by PCR-RFLP were confirmed. CONCLUSION: Due to the concordance obtained between tests results with the amplification of the genes miniexon and hsp70, PCR-RFLP is proposed as an alternative for identifying circulating Leishmania species in Colombia.

Molecular typing of Leishmania (Leishmania) amazonensis and species of the subgenus Viannia associated with cutaneous and mucosal leishmaniasis in Colombia: A concordance study / Tipificación molecular de Leishmania (Leishmania) amazonensis y especies del subgénero Viannia asociadas a la leishmaniasis cutánea y la mucosa en Colombia: un estudio de concordancia

Resumen Introduction: Multilocus enzyme electrophoresis (MLEE) is the reference standard for the characterization of Leishmania species. The test is restricted to specialized laboratories due to its technical complexity, cost, and time required to obtain results. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) is used to identify Leishmania species. Objective: To establish the concordance between the two tests as identifying methods for circulating species in Colombia. Materials and methods: A total of 96 isolates from patients with cutaneous or mucosal leishmaniasis were selected and identified by MLEE and PCR-RFLP with miniexon and hsp70 as the molecular targets, which were used sequentially. Restriction enzymes HaeIII and BccI were similarly applied. Cohen's kappa coefficient and the 95% confidence interval (CI) were calculated. Results: The kappa coefficient and the 95% CI between MLEE and PCR-RFLP displayed "very good" concordance with a coefficient of 0.98 (CI95%: 0.98 to 1.00). The identified species were Leishmania Viannia braziliensis, Leishmania Viannia panamensis, Leishmania Viannia guyanensis and Leishmania Leishmania amazonensis. A total of 80 of the 96 isolates were sequenced and the results obtained by PCR-RFLP were confirmed. Conclusion: Due to the concordance obtained between tests results with the amplification of the genes miniexon and hsp70, PCR-RFLP is proposed as an alternative for identifying circulating Leishmania species in Colombia.

Abstract Introducción. La electroforesis de enzimas multilocus (Multilocus Enzyme Electrophoresis, MLEE) es el estándar de referencia para la tipificación de las especies de Leishmania. La prueba está restringida a laboratorios especializados por su complejidad técnica, sus costos y el tiempo necesario para obtener resultados. La PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) se utiliza para tipificar especies de Leishmania. Objetivo. Establecer la concordancia entre las dos pruebas como métodos de tipificación de las especies circulantes en Colombia. Materiales y métodos. Se seleccionaron 96 aislamientos de pacientes con leishmaniasis cutánea o mucocutánea y se tipificaron mediante MLEE y PCR-RFLP con los blancos moleculares miniexon y hsp70 usados en serie. Las enzimas de restricción aplicadas fueron la HaeIII y la BccI, respectivamente. Se calculó el coeficiente kappa y un intervalo de confianza (IC) de 95 %. Resultados. Se determinó que la concordancia fue "muy buena" al obtener un coeficiente de 0,98 (IC95%: 0,98-1,00). Las especies identificadas fueron: Leishmania Viannia braziliensis, L. (V.) panamensis, L. (V.) guyanensis y L. (L,) amazonensis. De los 96 aislamientos, 80 se enviaron a secuenciación y se confirmaron los resultados obtenidos mediante PCR-RFLP. Conclusión. Dada la concordancia obtenida con la PCR-RFLP amplificando los genes miniexon y hsp70, se propone esta prueba como alternativa para la tipificación de especies de Leishmania circulantes en Colombia.

Capacidades del talento humano para investigación en la Secretaría Distrital de Salud y las empresas sociales del Estado / Human Competencies Regarding Research at District Health Secretariat and State Social Enterprises / Capacidades do Talento Humano para a Pesquisa na Secretaria Distrital de Saúde e em Empresas Sociais do Estado

La generación de conocimiento aplicado a la resolución de problemas en salud es una necesidad inaplazable para impulsar los procesos de desarrollo competitivo en un país. Por eso, uno de los componentes esenciales dentro de los sistemas de ciencia, tecnología e innovación del mundo es el talento humano. En consecuencia, para fortalecer tales capacidades es necesario conocer suficientemente el estado actual. El objetivo del presente trabajo consiste en explorar las capacidades de investigación del talento humano de la Secretaría Distrital de Salud y la red adherida de empresas sociales del Estado. Esto se hizo a través de una metodología mixta donde se realizaron encuestas virtuales, revisiones del estado de los grupos de investigación en la plataforma ScienTI de Colciencias, grupos focales, y entrevistas para profundizar en una visión general y captar las ideas y estrategias probables de fortalecimiento. Los resultados mostraron un bajo porcentaje de servidorespúblicos y colaboradores con formación de alto nivel (< 6 %) y experiencia en investigación (27,9 %). Sin embargo, tienen un interés cada vez mayor por adherirse tanto al proceso de investigación (76,4 %) en cuanto a los grupos semillas de investigación (69,56 %). Igualmente, se identificaron ocho grupos de investigación dentro de esas instituciones, de los cuales cuatro fueron reconocidos y clasificados en la convocatoria 640-2013 de Colciencias. Estos hallazgos permitieron plantear algunas estrategias para el fortalecimiento de las capacidades para la investigación del talento humano desde la política, la gestión y la movilización del conocimiento institucional, siendo prioritaria la institucionalización de la investigación como eje de la misión en las organizaciones.

Generating knowledge to solve health problems is a pressing need to boost the competitive development processes of a country. For this reason, human talent is one of the vital constituents of the world's science, technology and innovation systems. Therefore, in order to strengthen such abilities, it is necessary to know the current state of the art. The goal of this study is exploring research competencies of the human talent at District Health Department and their networked State Social Enterprises. This was possible through a mixed methodology where we carried out virtual surveys, status checks of the research groups in Colciencias ScienTI platform, focus group, and interviews to deepen into a general overview and catching insights and probable strengthening strategies. Results showed a low percentage of public servants and collaborators with high-level training (< 6 %) and research experience (27,9 %). Nonetheless, there is an increasing interest to carry out both the research process (76,4 %) and research seedlings (69,56 %). In addition, we could identify eight research groups within these institutions, of which four recognized and classified at call 640-2013 by Colciencias. These findings allowed us to propose some strategies to strength research competencies by human talent taking into account policies, management and involvement where institutionalization of research activities may be a cornerstone for organizations.

A geração de conhecimento aplicada a resolução de problemáticas em saúde é uma necessidade inadiável para impulsar os processos de desenvolvimento competitivo num pais. Por isso, um dos componentes essenciais dentro dos sistemas de ciência, tecnologia e inovação do mundo é o talento humano. Em consequência, para fortalecer tais capacidades é preciso conhecer grandemente o estado atual. O intuito do presente trabalho consiste em explorar as capacidades de pesquisa do talento humano da Secretaria Distrital de Saúde e a rede aderida de Empresas Sociais do Estado. Isso foi feito através de uma metodologia mista onde foram efetuadas enquetes virtuais, revisões do estado dos grupos de pesquisa na plataforma ScienTI de Colciencias, grupo focal, e entrevistas para afundar no panorama geral e capturar as percepções e possíveis estratégias de fortalecimento. Os resultados mostraram um baixo porcentagem de servidores públicos e colaboradores com formação de alto nível (< 6 %) e experiência em pesquisa (27,9 %). No entanto, tem um interesse cada vez maior por se aderir tanto ao processo de pesquisa (76,4 %) quanto aos grupos sementes de pesquisa (69,56 %). Igualmente, foram identificados 8 grupos de pesquisa no interior dessas instituições, dos quais 4 foram reconhecidos e classificados na convocatória 640-2013 de Colciencias. Esses achados permitiram plantear algumas estratégias para o fortalecimento das capacidades para a pesquisa do talento humano desde a política, a gestão e a mobilização do conhecimento institucional, sendo prioritária a institucionalização da pesquisa como eixo da missão nas organizações.

Polymerase chain reaction-miniexon: a promising diagnostic method for mucocutaneous leishmaniasis.

BACKGROUND: Mucocutaneous leishmaniasis is a chronic disease caused mainly by Leishmania species that belong to Viannia subgenus. It affects upper respiratory airways and may lead to deformity, dysphagia, and even death in severe cases. Diagnosis is a challenge because clinical and histopathologic changes are easily confused with other diseases, and conventional methods for parasite identification and culture have a low sensitivity. Molecular methods have been used in the last two decades. In 2007, we published a validation study using internal transcript spacers and kinetoplast DNA as molecular targets with satisfactory results. In this research, we tested miniexon gene as the target. METHODS: Mucosal tissue samples from 60 Colombian patients with clinical signs of mucocutaneous leishmaniasis were included. A composite reference standard defined 30 cases and 30 controls. Two blind observers performed patient classification and test application independently. Miniexon gene amplification generated: 226-230 bp fragment for subgenus Viannia; 308 bp fragment for L. amazonensis; 340 bp fragment for L. mexicana; and 418 bp fragment for L. infantum-chagasi. RESULTS: Polymerase chain reaction (PCR) sensitivity for fresh samples was 87.5% (95% confidence interval [CI] 72.2-100), specificity, 95% (95% CI 83.0-100), and positive likelihood ratio was 17.5 (95% CI 2.58-118.93), similar to results obtained with paraffin-embedded samples. Agreement between observers was 96% (kappa = 0.912; 95% CI 0.815-1.000) for both subgenus Viannia and Leishmania. CONCLUSIONS: We consider PCR-miniexon as a diagnostic method of first choice for mucocutaneous leishmaniasis due to its excellent diagnostic performance and its ability to discriminate between Leishmania and Viannia subgenera as well as between species belonging to Leishmania subgenus.

Cáncer de piel no melanoma: de la patología a la tutela / Nonmelanoma skin cancer: pathology guardianship

El manuscrito hace una revisión sobre cáncer de piel no melanoma desde diferentes aristas del problema: iniciando en aspectos de conceptualización de la patología, pasando por la descripción de los trámites y costos que debe afrontar un paciente que requiere atención al presentar un diagnóstico presuntivo de cáncer de piel no melanoma en el actual Sistema General de Seguridad Social en Salud colombiano. Adicionalmente, se describien las barreras de acceso y negaciones de servicios, acotando el caso con resultados de una Empresa Promotora de Salud con sede en Bogotá y finalizando en la tutela como tabla de salvación para exigir un derecho fundamental, el derecho a la salud. En Colombia un paciente con cáncer de piel no melanoma diariamente batalla no solo contra su enfermedad sino contra una estructura compleja que supera el resorte del sistema de salud y trasciende a los componentes político, social y económico del país. Lo anterior constituye un círculo vicioso que requiere con urgencia de una intervención profunda a diferentes escalas y que supera el alcance de la reforma del sistema de salud colombiano. Para superar las dificultades documentadas en el acceso real, efectivo y de calidad de los colombianos que sufren de cáncer de piel no melanoma a los servicios de salud se requiere de un compromiso decidido y de acciones concretas.

The manuscript is a review of non-melanoma skin cancer (NSC) from different angles of the problem: starting in conceptualizing aspects of the disease through the description of the procedures and the cost that a patient who requires attention when presenting presumptive NSC diagnosis must face in the current General System of Social Security in Colombian Health. Additionally, barriers to access and denial of services are explained by mentioning the results of a case-based EPS in Bogotá which ending in guardianship as a lifeline to demand the fundamental right to health. In Colombia, a patient with NSC daily struggles not only against the disease but also with a complex structure that overcomes the rein of the health system and transcends political, social and economic components of the country. This is considered as a vicious circle which urgently requires a deep intervention at different scales and which exceeds the scope of the reform of the Colombian health . A strong commitment and concrete actions are required to overcome the difficulties documented in the real, effective and quality access of the Colombians who are suffering from NSC to health services.

Miltefosine and antimonial drug susceptibility of Leishmania Viannia species and populations in regions of high transmission in Colombia.

BACKGROUND: Pentavalent antimonials have been the first line treatment for dermal leishmaniasis in Colombia for over 30 years. Miltefosine is administered as second line treatment since 2005. The susceptibility of circulating populations of Leishmania to these drugs is unknown despite clinical evidence supporting the emergence of resistance. METHODOLOGY/PRINCIPAL FINDINGS: In vitro susceptibility was determined for intracellular amastigotes of 245 clinical strains of the most prevalent Leishmania Viannia species in Colombia to miltefosine (HePC) and/or meglumine antimoniate (Sb(V)); 163, (80%) were evaluated for both drugs. Additionally, susceptibility to Sb(V) was examined in two cohorts of 85 L. V. panamensis strains isolated between 1980-1989 and 2000-2009 in the municipality of Tumaco. Susceptibility to each drug differed among strains of the same species and between species. Whereas 68% of L. V. braziliensis strains presented in vitro resistance to HePC, 69% were sensitive to Sb(V). Resistance to HePC and Sb(V) occurred respectively, in 20% y 21% of L. panamensis strains. Only 3% of L. V. guyanensis were resistant to HePC, and none to Sb(V). Drug susceptibility differed between geographic regions and time periods. Subpopulations having disparate susceptibility to Sb(V) were discerned among L. V. panamensis strains isolated during 1980-1990 in Tumaco where resistant strains belonged to zymodeme 2.3, and sensitive strains to zymodeme 2.2. CONCLUSIONS/SIGNIFICANCE: Large scale evaluation of clinical strains of Leishmania Viannia species demonstrated species, population, geographic, and epidemiologic differences in susceptibility to meglumine antimoniate and miltefosine, and provided baseline information for monitoring susceptibility to these drugs. Sensitive and resistant clinical strains within each species, and zymodeme as a proxy marker of antimony susceptibility for L. V. panamensis, will be useful in deciphering factors involved in susceptibility and the distribution of sensitive and resistant populations.

Human macrophage response to L. (Viannia) panamensis: microarray evidence for an early inflammatory response.

BACKGROUND: Previous findings indicate that susceptibility to Leishmania (Viannia) panamensis infection of monocyte-derived macrophages from patients and asymptomatically infected individuals were associated with the adaptive immune response and clinical outcome. METHODOLOGY/PRINCIPAL FINDINGS: To understand the basis for this difference we examined differential gene expression of human monocyte-derived macrophages following exposure to L. (V.) panamensis. Gene activation profiles were determined using macrophages from healthy volunteers cultured with or without stationary phase promastigotes of L. (V.) panamensis. Significant changes in expression (>1.5-fold change; p<0.05; up- or down-regulated) were identified at 0.5, 4 and 24 hours. mRNA abundance profiles varied over time, with the highest level of activation occurring at earlier time points (0.5 and 4 hrs). In contrast to observations for other Leishmania species, most significantly changed mRNAs were up- rather than down-regulated, especially at early time points. Up-regulated transcripts over the first 24 hours belonged to pathways involving eicosanoid metabolism, oxidative stress, activation of PKC through G protein coupled receptors, or mechanism of gene regulation by peroxisome proliferators via PPARα. Additionally, a marked activation of Toll-receptor mediated pathways was observed. Comparison with published microarray data from macrophages infected with L. (Leishmania) chagasi indicate differences in the regulation of genes involved in signaling, motility and the immune response. CONCLUSIONS: Results show that the early (0.5 to 24 hours) human monocyte-derived macrophage response to L. (Viannia) panamensis is not quiescent, in contrast to published reports examining later response times (48-96 hours). Early macrophage responses are important for the developing cellular response at the site of infection. The kinetics and the mRNA abundance profiles induced by L. (Viannia) panamensis illustrate the dynamics of these interactions and the distinct biologic responses to different Leishmania species from the outset of infection within their primary host cell.

Novel approach to in vitro drug susceptibility assessment of clinical strains of Leishmania spp.

Resistance to antimonial drugs has been documented in Leishmania isolates transmitted in South America, Europe, and Asia. The frequency and distribution of resistance to these and other antileishmanial drugs are unknown. Technical constraints have limited the assessment of drug susceptibility of clinical strains of Leishmania. Susceptibility of experimentally selected lines and 130 clinical strains of Leishmania panamensis, L. braziliensis, and L. guyanensis to meglumine antimoniate and miltefosine was determined on the basis of parasite burden and percentage of infected U-937 human macrophages. Reductions of infection at single predefined concentrations of meglumine antimoniate and miltefosine and 50% effective doses (ED(50)s) were measured and correlated. The effects of 34°C and 37°C incubation temperatures and different parasite-to-host cell ratios on drug susceptibility were evaluated at 5, 10, and 20 parasites/cell. Reduction of the intracellular burden of Leishmania amastigotes in U-937 cells exposed to the predefined concentrations of meglumine antimoniate or miltefosine discriminated sensitive and experimentally derived resistant Leishmania populations and was significantly correlated with ED(50) values of clinical strains (for meglumine antimoniate, ρ = -0.926 and P < 0.001; for miltefosine, ρ = -0.906 and P < 0.001). Incubation at 37°C significantly inhibited parasite growth compared to that at 34°C in the absence of antileishmanial drugs and resulted in a significantly lower ED(50) in the presence of drugs. Susceptibility assessment was not altered by the parasite-to-cell ratio over the range evaluated. In conclusion, measurement of the reduction of parasite burden at a single predetermined drug concentration under standardized conditions provides an efficient and reliable strategy for susceptibility evaluation and monitoring of clinical strains of Leishmania.