Influence of the number of daily pills and doses on adherence to antiretroviral treatment: a 7-year study

[EN] What is known and objective: Antiretroviral treatment (ART) is hampered by complicated regimens, high pill burden, drug–drug interactions, and frequent short- and long-term adverse effects, leading to decreased adherence. Over recent years, considerable effort has been directed at developing regimens that are less burdening. We undertook a 7-year retrospective study of the records of 264 HIV-infected subjects enrolled in a pharmaceutical care programme to document the progress made and to study the influence of the number of ART pills and doses on the level of treatment adherence. Methods: Antiretroviral dispensing records were analysed for the number of pills and doses administered and the ART adherence rate estimated. Results and discussion: In 2005, the patients took a mean of 6 2 pills daily (CI 95%: 5 9–6 6), and 92 9% of them were on a twice-a-day (BID) dosage regimen. By 2012, the mean number of pills was reduced to 4 1 (CI 95%: 3 8–4 4), and only 50 9% were on a BID regimen. No statistically significant relation was observed between number of daily pills and doses and ART adherence reached by the patients in any of the analyses performed. What is new and conclusions: There has been a continuous reduction in the number of pills and doses of antiretrovirals taken by individual patients over the last 7 years due largely to the introduction of improved treatments and regimens. More daily pills or doses was not associated with worse ART adherence in our pharmaceutical care programme

The CRISPR/Cas9 system efficiently reverts the tumorigenic ability of BCR/ABL in vitro and in a xenograft model of chronic myeloid leukemia

[EN]CRISPR/Cas9 technology was used to abrogate p210 oncoprotein expression in the Boff-p210 cell line, a pro-B line derived from interlukin-3-dependent Baf/3, that shows IL-3-independence arising from the constitutive expression of BCR-ABL p210. Using this approach, pools of Boff-p210-edited cells and single edited cell-derived clones were obtained and functionally studied in vitro. The loss of p210 expression in Boff-p210 cells resulted in the loss of ability to grow in the absence of IL-3, as the Baf/3 parental line, showing significantly increased apoptosis levels. Notably, in a single edited cell-derived clone carrying a frame-shift mutation that prevents p210 oncoprotein expression, the effects were even more drastic, resulting in cell death. These edited cells were injected subcutaneously in immunosuppressed mice and tumor growth was followed for three weeks. BCR/ABL-edited cells developed smaller tumors than those originating from unedited Boff-p210 parental cells. Interestingly, the single edited cell-derived clone was unable to develop tumors, similar to what is observed with the parental Baf/3 cell line. CRISPR/Cas9 genomic editing technology allows the ablation of the BCR/ ABL fusion gene, causing an absence of oncoprotein expression, and blocking its tumorigenic effects in vitro and in the in vivo xenograft model of CML. The future application of this approach in in vivo models of CML will allow us to more accurately assess the value of CRISPR/Cas9 technology as a new therapeutic tool that overcomes resistance to the usual treatments for CML patients

Miradas colectivas del departamento del Tolima, Huila y Putumayo, municipios del Líbano, Pitalito y Puerto Asís

Este documento, expresa de manera concreta las diferentes situaciones o problemáticas tratadas en las comunidades abordadas a través del Diplomado en Desarrollo Humano y Familia por el grupo 91 y las cuales fueron identificadas con la aplicación del Diagnóstico Social Participativo (DSP), tales como la Falta de Unión Comunitaria en el barrio Santa Rosa Bajo (Líbano, Tolima); Incidencia de pautas de crianza en el desarrollo integral de los NNA- Niños, Niñas y Adolescentes- de la comunidad del barrio el Jardín, (Puerto Asís, Putumayo); Factores psicosociales que inciden en la pérdida o la falta de comunicación en las familias de la comunidad del Barrio el Vergel (Neiva, Huila); Modelos de crianza inadecuados en el barrio el Salado (Ibagué-Tolima); y Factores Psicosociales que inciden el consumo de sustancias Psicoactivas en la Institución Educativa Criollo de Pitalito (Pitalito, Huila). Por tanto, también se presenta la ubicación de cada comunidad intervenida, así como la situación identificada (problemática comunitaria) por los estudiantes del grupo 91, a través de un mapa situacional de cada departamento; y posteriormente, la descripción y análisis de las diferentes propuestas de acompañamiento elaboradas para cada una de las comunidades.This document expresses in a concrete way the different situations or problems dealt with in the communities addressed through the Diploma in Human and Family Development by group 91 and which were identified with the application of Participative Social Diagnosis (DSP), such as the lack Of Community Union in the Santa Rosa Bajo neighborhood (Lebanon, Tolima); Incidence of child-rearing patterns in the integral development of the children and adolescents of the neighborhood of El Jardín, (Puerto Asís, Putumayo); Psychosocial factors that affect the loss or lack of communication in the families of the community of Barrio el Vergel (Neiva, Huila); Inadequate breeding models in the El Salado neighborhood (Ibagué-Tolima); And Psychosocial Factors that influence the consumption of psychoactive substances in the Criollo Educational Institution of Pitalito (Pitalito, Huila). Therefore, it is also presented the location of each community involved, as well as the situation identified (community problem) by the students of group 91, through a situational map of each department; And later, the description and analysis of the different proposals of accompaniment elaborated for each one of the communities

Characterization of the platelet phenotype caused by a germline RUNX1 Variant in a CRISPR/Cas9-generated murine model

RUNX1-related disorder (RUNX1-RD) is caused by germline variants affecting the RUNX1 gene. This rare, heterogeneous disorder has no specific clinical or laboratory phenotype, making genetic diagnosis necessary. Although international recommendations have been established to classify the pathogenicity of variants, identifying the causative alteration remains a challenge in RUNX1-RD. Murine models may be useful not only for definitively settling the controversy about the pathogenicity of certain RUNX1 variants, but also for elucidating the mechanisms of molecular pathogenesis. Therefore, we developed a knock-in murine model, using the CRISPR/Cas9 system, carrying the RUNX1 p.Leu43Ser variant (mimicking human p.Leu56Ser) to study its pathogenic potential and mechanisms of platelet dysfunction. A total number of 75 mice were generated; 25 per genotype (RUNX1WT/WT, RUNX1WT/L43S, and RUNX1L43S/L43S). Platelet phenotype was assessed by flow cytometry and confocal microscopy. On average, RUNX1L43S/L43S and RUNX1WT/L43S mice had a significantly longer tail-bleeding time than RUNX1WT/WT mice, indicating the variant's involvement in hemostasis. However, only homozygous mice displayed mild thrombocytopenia. RUNX1L43S/L43S and RUNX1WT/L43S displayed impaired agonist-induced spreading and α-granule release, with no differences in δ-granule secretion. Levels of integrin αIIbβ3 activation, fibrinogen binding, and aggregation were significantly lower in platelets from RUNX1L43S/L43S and RUNX1WT/L43S using phorbol 12-myristate 13-acetate (PMA), adenosine diphosphate (ADP), and high thrombin doses. Lower levels of PKC phosphorylation in RUNX1L43S/L43S and RUNX1WT/L43S suggested that the PKC-signaling pathway was impaired. Overall, we demonstrated the deleterious effect of the RUNX1 p.Leu56Ser variant in mice via the impairment of integrin αIIbβ3 activation, aggregation, α-granule secretion, and platelet spreading, mimicking the phenotype associated with RUNX1 variants in the clinical setting.This work was partially supported by grants from Instituto de Salud Carlos III (ISCIII) and Feder (PI17/01311, PI17/01966, and CB15/00055), Fundación Séneca (19873/GERM/15), Gerencia Regional de Salud (GRS 2061A/19 and 1647/A/17), Fundación Mutua Madrileña (FMM, AP172142019), and Sociedad Española de Trombosis y Hemostasia (SETH-FETH; Premio López Borrasca 2019 and Ayuda a Grupos de Trabajo en Patología Hemorrágica 2019). The authors' research on IPDs is conducted in accordance with the aims of the Functional and Molecular Characterization of Patients with Inherited Platelet Disorders Project, which is supported by the Hemorrhagic Diathesis Working Group of the Spanish Society of Thrombosis and Haemostasis. A.M.-Q., C.F.-I., and L.H.-C. were supported by predoctoral grants from the Junta de Castilla y León, Spain. E.V. was supported by the predoctoral grant from the University of Salamanca, Spain. IG-T and RB were supported by "Contratos postdoctorales Programa II) from the University of Salamanca, Spain

3D Printed Porous Polyamide Macrocapsule Combined with Alginate Microcapsules for Safer Cell-Based Therapies

Cell microencapsulation is an attractive strategy for cell-based therapies that allows the implantation of genetically engineered cells and the continuous delivery of de novo produced therapeutic products. However, the establishment of a way to retrieve the implanted encapsulated cells in case the treatment needs to be halted or when cells need to be renewed is still a big challenge. The combination of micro and macroencapsulation approaches could provide the requirements to achieve a proper immunoisolation, while maintaining the cells localized into the body. We present the development and characterization of a porous implantable macrocapsule device for the loading of microencapsulated cells. The device was fabricated in polyamide by selective laser sintering (SLS), with controlled porosity defined by the design and the sintering conditions. Two types of microencapsulated cells were tested in order to evaluate the suitability of this device; erythropoietin (EPO) producing C2C12 myoblasts and Vascular Endothelial Growth Factor (VEGF) producing BHK fibroblasts. Results showed that, even if the metabolic activity of these cells decreased over time, the levels of therapeutic protein that were produced and, importantly, released to the media were stable.This work was done under the BIOPAN project (CIBER-BBN). Authors wish to thank the intellectual and technical assistance from the ICTS "NANBIOSIS", more specifically by the Drug Formulation Unit (U10) and the Micro-Nano Technology Unit (U8) of the CIBER in Bioengineering, Biomaterials & Nanomedicine (CIBERBBN). Also, they thank the support to research on cell microencapsulation from the University of the Basque Country UPV/EHU (EHUA 16/06) and the Basque Country Government (Grupos Consolidados, No ref: IT907-16). The authors acknowledge the financial support from the Ministerio de Economia y Competitividad (MINECO) (Spain) through Ramon y Cajal program (RYC-2013-14479). This work has made use of the Spanish ICTS Network MICRONANOFABS partially supported by MINECO

Uso de hidroxicloroquina en pacientes COVID ambulatorios: evaluación de interacciones y riesgo cardiaco

Objetivo: La hidroxicloroquina fue ampliamente utilizada al inicio de la pandemia de COVID-19 fuera de ficha técnica y con poca evidencia de eficacia. El objetivo de nuestro trabajo fue identificar interacciones entre hidroxicloroquina y otros fármacos con riesgo conocido de prolongar el intervalo QT, así como factores de riesgo asociados con el inicio de Torsade de Pointes, en pacientes no hospitalizados diagnosticados de COVID-19. Método: La población de estudio fueron pacientes procedentes de dos áreas de salud. Se consideró toda la medicación que tuvieran prescrita. Las interacciones se analizaron con la herramienta Medsafety Scan®. Se realizó encuesta al médico de referencia. El análisis estadístico se realizó con el programa IBM® SPSS® statistics version 20. Resultados: El número medio de fármacos con capacidad de prolongar el intervalo QT por paciente, incluyendo la hidroxicloroquina fue de 2,8. Se encontraron interacciones en el 93,2% de los pacientes. La mayoría de los pacientes estaban afectados por al menos 2 interacciones, aunque en pacientes institucionalizados un alto porcentaje tenía hasta 4. La interacción más repetida fue hidroxicloroquina-antibióticos (en 85% de ellos), fundamentalmente debido al uso de azitromicina con hidroxicloroquina, hidroxicloroquina-antiácidos (38%) y hidroxicloroquina-antidepresivos (23%). La encuesta muestra que 15,3% de los pacientes tuvieron algún efecto adverso asociado con la hidroxicloroquina. Conclusiones: Los pacientes no hospitalizados fueron expuestos a un alto porcentaje de interacciones entre hidroxicloroquina y otros fármacos con la capacidad de prolongar el intervalo QT. Ante una eficacia no claramente demostrada para la hidroxicloroquina, los pacientes estuvieron expuestos a un posible riesgo innecesario

Uso de hidroxicloroquina en pacientes COVID ambulatorios: evaluación de interacciones y riesgo cardiaco

Objetivo: La hidroxicloroquina fue ampliamente utilizada al inicio de la pandemia de COVID-19 fuera de ficha técnica y con poca evidencia de eficacia. El objetivo de nuestro trabajo fue identificar interacciones entre hidroxicloroquina y otros fármacos con riesgo conocido de prolongar el intervalo QT, así como factores de riesgo asociados con el inicio de Torsade de Pointes, en pacientes no hospitalizados diagnosticados de COVID-19. Método: La población de estudio fueron pacientes procedentes de dos áreas de salud. Se consideró toda la medicación que tuvieran prescrita. Las interacciones se analizaron con la herramienta Medsafety Scan®. Se realizó encuesta al médico de referencia. El análisis estadístico se realizó con el programa IBM® SPSS® statistics version 20. Resultados: El número medio de fármacos con capacidad de prolongar el intervalo QT por paciente, incluyendo la hidroxicloroquina fue de 2,8. Se encontraron interacciones en el 93,2% de los pacientes. La mayoría de los pacientes estaban afectados por al menos 2 interacciones, aunque en pacientes institucionalizados un alto porcentaje tenía hasta 4. La interacción más repetida fue hidroxicloroquina-antibióticos (en 85% de ellos), fundamentalmente debido al uso de azitromicina con hidroxicloroquina, hidroxicloroquina-antiácidos (38%) y hidroxicloroquina-antidepresivos (23%). La encuesta muestra que 15,3% de los pacientes tuvieron algún efecto adverso asociado con la hidroxicloroquina. Conclusiones: Los pacientes no hospitalizados fueron expuestos a un alto porcentaje de interacciones entre hidroxicloroquina y otros fármacos con la capacidad de prolongar el intervalo QT. Ante una eficacia no claramente demostrada para la hidroxicloroquina, los pacientes estuvieron expuestos a un posible riesgo innecesario

Use of maraviroc in patients with undetectable viral load: efficacy, tolerance and predictors of viral response in MARAVIROC-cohort study

Introduction: No controlled clinical trials had studied the role of maraviroc (MRV) in fully suppressed patients [1]. Methods and Materials: MRV-cohort is an observational, retrospective, multicentric (27 sites) large cohort study of patients starting MRV in clinical practice under different circumstances, with at least 48 weeks of follow-up. For the present analysis we selected all those patients starting with an HIV-RNAB50 copies/mL. Demographics, baseline CD4 cell count, past history of antiretroviral treatment (ART), tropism, reasons for MRV use, MRV based therapy and change/end of MRV use were assessed. Paired analysis of lipid, hepatic and kidney profile changes and univariate and multivariate analyses of HIV-RNAB50 copies/mL at 48 weeks were explored. Results: We included 247 out of 667 subjects from the entire cohort. At study entry, their median age was 47 years, 23% were women, 31% MSM, 49% had CDC category C, median CD4 counts were 468 cells/mm3 , 46% were HCV and 4.5% AgHBs. Tropism information was available in 197 (94% R5). Median length of prior ARTV was 10.7 years, with exposure to a median of three drug families. Main reasons for prescribing MRV were: toxicity 38%, inmunodiscordance 23%, simplification 19% and admission in a clinical trial 10.4%. MRV based therapies used were MRV2NRTIs 9%, MRVPI 46%, MRVPIother 40% and MRVother 5%. At 48 weeks, 23% of patients had changed or finished MRV therapy due to toxicity 2.4%, virological failure 2%, immunological failure 1.2%, simplification 3,2%, trial requirement 9.7%, medical decision 2.8%, treatment suspension 1.2% and unknown 0.4%. At 48 weeks, no significant changes were observed in lipid, hepatic or kidney profiles, and 85% of patients remained with HIV-RNAB50 copies/mL. Focusing on viral response univariate and multivariate models did not show any significant baseline variable explaining viral failure. Conclusions: In clinical practice MRV was used, mostly in R5 positive patients, with adequate efficacy and tolerance, but important number of patients changed due to non-clinical reasons. In this scenario neither reason for use of MRV nor MRVbased therapy explained viral failure

Nanoteknologiaren aplikazioak garu-minbizian

Nanoterapiak aukera berri asko ireki ditu garun minbizien tratamendu eta diagnostikoan. Nanogarraiatzaileen erabilerak, tumore ingurura molekula konplexuen zuzentzea eta sistemikoki administratutako farmakoen iragana muga hematoentzefalikotik zehar baimentzen du. Kapsularatzen badira, farmakoek batez besteko bizitza luzeagoa dute organismoan, eta gainera efektu kaltegarriak jaitsi egiten dira. Nanogarraiatzaile hauen erabilgarritasuna dela eta, tumoreen aurka zuzendutako askapensistemak garatu dira, eta horre la terapia genikoan, antigiogenikoan eta termoterapian erab iltzen hasi dira. Lan honetan, nanoteknologiaren azken ikerketak, aplikazioak eta erronkak garun minbizian azalduko ditugu