Analytical validation of HER2DX genomic test for early-stage HER2-positive breast cancer.

BACKGROUND: HER2DX, a multianalyte genomic test, has been clinically validated to predict breast cancer recurrence risk (relapse risk score), the probability of achieving pathological complete response post-neoadjuvant therapy (pCR likelihood score), and individual ERBB2 messenger RNA (mRNA) expression levels in patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This study delves into the comprehensive analysis of HER2DX's analytical performance. MATERIALS AND METHODS: Precision and reproducibility of HER2DX risk, pCR, and ERBB2 mRNA scores were assessed within and between laboratories using formalin-fixed paraffin-embedded (FFPE) tumor tissues and purified RNA. Robustness was appraised by analyzing the impact of tumor cell content and protocol variations including different instruments, reagent lots, and different RNA extraction kits. Variability was evaluated across intratumor biopsies and genomic platforms [RNA sequencing (RNAseq) versus nCounter], and according to protocol variations. RESULTS: Precision analysis of 10 FFPE tumor samples yielded a maximal standard error of 0.94 across HER2DX scores (1-99 scale). High reproducibility of HER2DX scores across 29 FFPE tumors and 20 RNAs between laboratories was evident (correlation coefficients >0.98). The probability of identifying score differences >5 units was ≤5.2%. No significant variability emerged based on platform instruments, reagent lots, RNA extraction kits, or TagSet thaw/freeze cycles. Moreover, HER2DX displayed robustness at low tumor cell content (10%). Intratumor variability across 212 biopsies (106 tumors) was <4.0%. Concordance between HER2DX scores from 30 RNAs on RNAseq and nCounter platforms exceeded 90.0% (Cohen's κ coefficients >0.80). CONCLUSIONS: The HER2DX assay is highly reproducible and robust for the quantification of recurrence risk, pCR likelihood, and ERBB2 mRNA expression in early-stage HER2-positive breast cancer.

Identification of cell surface targets for CAR-T cell therapies and antibody-drug conjugates in breast cancer.

BACKGROUND: Two promising therapeutic strategies in oncology are chimeric antigen receptor-T cell (CAR-T) therapies and antibody-drug conjugates (ADCs). To be effective and safe, these immunotherapies require surface antigens to be sufficiently expressed in tumors and less or not expressed in normal tissues. To identify new targets for ADCs and CAR-T specifically targeting breast cancer (BC) molecular and pathology-based subtypes, we propose a novel in silico strategy based on multiple publicly available datasets and provide a comprehensive explanation of the workflow for a further implementation. METHODS: We carried out differential gene expression analyses on The Cancer Genome Atlas BC RNA-sequencing data to identify BC subtype-specific upregulated genes. To fully explain the proposed target-discovering methodology, as proof of concept, we selected the 200 most upregulated genes for each subtype and undertook a comprehensive analysis of their protein expression in BC and normal tissues through several publicly available databases to identify the potentially safest and viable targets. RESULTS: We identified 36 potentially suitable and subtype-specific tumor surface antigens (TSAs), including fibroblast growth factor receptor-4 (FGFR4), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), GDNF family receptor alpha 1 (GFRA1), integrin beta-6 (ITGB6) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We also identified 63 potential TSA pairs that might be appropriate for co-targeting strategies. Finally, we validated subtype specificity in a cohort of our patients, multiple BC cell lines and the METABRIC database. CONCLUSIONS: Overall, our in silico analysis provides a framework to identify novel and specific TSAs for the development of new CAR-T and antibody-based therapies in BC.

Immune microenvironment characterisation and dynamics during anti-HER2-based neoadjuvant treatment in HER2-positive breast cancer.

Despite their recognised role in HER2-positive (HER2+) breast cancer (BC), the composition, localisation and functional orientation of immune cells within tumour microenvironment, as well as its dynamics during anti-HER2 treatment, is largely unknown. We here investigate changes in tumour-immune contexture, as assessed by stromal tumour-infiltrating lymphocytes (sTILs) and by multiplexed spatial cellular phenotyping, during treatment with lapatinib-trastuzumab in HER2+ BC patients (PAMELA trial). Moreover, we evaluate the relationship of tumour-immune contexture with hormone receptor status, intrinsic subtype and immune-related gene expression. sTIL levels increase after 2 weeks of HER2 blockade in HR-negative disease and HER2-enriched subtype. This is linked to a concomitant increase in cell density of all four immune subpopulations (CD3+, CD4+, CD8+, Foxp3+). Moreover, immune contexture analysis showed that immune cells spatially interacting with tumour cells have the strongest association with response to anti-HER2 treatment. Subsequently, sTILs consistently decrease at the surgery in patients achieving pathologic complete response, whereas most residual tumours at surgery remain inflamed, possibly reflecting a progressive loss of function of T cells. Understanding the features of the resulting tumour immunosuppressive microenvironment has crucial implications for the design of new strategies to de-escalate or escalate systemic therapy in early-stage HER2+ BC.

Determinación de las características funcionales de los nódulos tiroideos mediante imágenes de medicina nuclear en pacientes que acudieron al Instituto de Investigaciones en Ciencias de la Salud - UNA, en el periodo 2016-2019 / Determination of the functional characteristics of thyroid nodules through nuclear medicine images in patients, who attended the Instituto de Investigaciones en Ciencias de la Salud - UNA, in the period 2016-2019

nuclear permiten visualizar la estructura y función de un órgano, tejido, hueso o sistema dentro del cuerpo, entre ellos la glándula tiroidea, la cual puede presentar un nódulo tiroideo y este es importante diagnosticar por su potencial malignidad. Objetivo: Determinar las características funcionales de los nódulos tiroideos en 183 pacientes que asistieron al Servicio de Medicina Nuclear del Instituto de Investigaciones en Ciencias de la Salud - UNA durante el período de noviembre del 2016 - noviembre del 2019. Metodología: Fue utilizada la gammacámara SPECT doble cabezal, siguiendo protocolo estandarizado, con administración de pertecnetato de sodio. Resultados: Se observó que la gran mayoría de los pacientes corresponden al sexo femenino 89%, así como que el 64% provienen de la capital y del departamento central; las patologías detectadas corresponden a bocio en 82%, 15% a nódulos (hipercaptantes, hipocaptantes y autónomos) y casos particulares de tiroiditis, tiroides ectópica y adenoma tóxico. La medicina nuclear está directamente involucrada tanto en el diagnóstico como en el tratamiento de la enfermedad tiroidea, por lo que se requiere una comprensión de la fisiopatología y el manejo de los trastornos de la tiroides, de manera a que las políticas de salud pública sean implementadas para el fortalecimiento de la lucha contra estas enfermedades. Conclusión: El trabajo de investigación realizado comprobó que un mayoritario porcentaje de participantes de sexo femenino (89%), con enfermedades tiroideas asistieron al IICS/UNA, y que la frecuencia de bocio entre la totalidad de pacientes que participaron de este estudio fué de 151/183 (82%), los pacientes provenían en su mayoría de hospitales de referencia del departamento Central y coinciden con la localización geográfica de los domicilios de los pacientes, quienes provenían principalmente del mismo departamento Central 118/183 (64%), no obstante también participaron del trabajo de investigación pacientes provenientes de otros departamentos del país. Palabras claves: Diagnóstico, medicina nuclear, tiroides, tecnología nuclear en salud, SPECT

Introduction: The images obtained by nuclear medicine allow to visualize the structure and function of an organ, tissue, bone or system inside the body, including the thyroid gland, which can present a thyroid nodule and this is important to diagnose for its potential malignancy. Objective: To determine the functional characteristics of the thyroid nodules were determined in 183 patients, who attended the Nuclear Medicine Service at the Instituto de Investigaciones en Ciencias de la Salud during the period of November 2016 - November 2019. Methodology: It was used the dual head SPECT gamma camera following a standardized protocol with administration of sodium pertechnetate. Result: It was observed that most of the patients corresponded to the female sex 89 %, as well as that 64% came from the capital and the central department. The pathologies detected corresponded to goiter in 82%, 15% to nodules (hypercaptant, hypocaptant and autonoms) and particular cases of thyroiditis, ectopic thyroid and toxic adenoma. Nuclear medicine is directly involved both in the diagnosis and in the treatment of thyroid disease, therefore it requires an understanding of the pathophysiology and management of thyroid disorders in order that public health policies are implemented for strengthening the fight against these diseases. Conclusion: The research carried out showed that a majority percentage of female participants (89%), with thyroid diseases attended IICS / UNA, and the frequency of goiter among all patients who participated in this study was 151/183 ( 82%), the patients mostly they came the reference hospitals in the Central department and coincide with the geographic location of the patients' homes, who tested mainly from the same Central department 118/183 (64%), also participate in the research work patients from other departments of the country. Keywords: Diagnosis, nuclear medicine, thyroid, health technology, SPECT.

De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2-week letrozole: results of the PerELISA neoadjuvant study.

BACKGROUND: In human epidermal growth factor receptor 2 (HER2+) breast cancers, neoadjuvant trials of chemotherapy plus anti-HER2 treatment consistently showed lower pathologic complete response (pCR) rates in hormone receptor (HR) positive versus negative tumors. The PerELISA study was aimed to evaluate the efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HR+/HER2+ breast cancer patients selected on the basis of Ki67 inhibition after 2-week letrozole. PATIENTS AND METHODS: PerELISA is a phase II, multicentric study for postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received 2-week letrozole, and then underwent re-biopsy for Ki67 evaluation. Patients classified as molecular responders (Ki67 relative reduction >20% from baseline) continued letrozole and started trastuzumab-pertuzumab for five cycles. Patients classified as molecular non-responders started weekly paclitaxel for 13 weeks combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR. According to a two-stage Simon's design, to reject the null hypothesis, at least 8/43 pCR had to be documented. RESULTS: Sixty-four patients were enrolled, 44 were classified as molecular responders. All these patients completed the assigned treatment with letrozole-trastuzumab-pertuzumab and underwent surgery. A pCR was observed in 9/44 cases (20.5%, 95% confidence interval 11.1% to 34.5%). Among molecular non-responders, 16/17 completed treatment and underwent surgery, with pCR observed in 81.3% of the cases. PAM50 intrinsic subtype was significantly associated with Ki67 response and pCR. Among molecular responders, the pCR rate was significantly higher in HER2-enriched than in other subtypes (45.5% versus 13.8%, P = 0.042). CONCLUSIONS: The primary end point of the study was met, by reaching the pre-specified pCRs. In patients selected using Ki67 reduction after short-term letrozole exposure, a meaningful pCR rate can be achieved without chemotherapy. PAM50 intrinsic subtyping further refines our ability to identify a subset of patients for whom chemotherapy might be spared. EUDRACT NUMBER: 2013-002662-40. CLINICALTRIALS.GOV IDENTIFIER: NCT02411344.

Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types.

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

Effect of magnetic ion exchange (MIEX®) on removal of emerging organic contaminants.

In this study, the removal of nine emerging organic contaminants was investigated by using anion exchange resins. The selected compounds were carbamazepine, atrazine, simazine, estrone, bisphenol A, methylparaben, ethylparaben, propylparaben and butylparaben. Two different magnetic anionic exchanger resins were tested: MIEX® DOC and MIEX® GOLD. The optimal resin dose (40 mL/L) and contact time (20 min) had been previously determined. Once these optimum parameters were set, the effect of the initial concentration of contaminants on the removal efficiency of the contaminants by the resins was studied. The study was carried out using mono and multicomponent systems, with distilled water and natural waters, to which contaminants had been previously added, in order to evaluate the competitive and matrix effects. Results showed that the average removal percentages obtained with the MIEX® DOC resin were: 51%, 61%, 68% and 80% for methyl-, ethyl-, propyl-, and butylparaben, respectively. For bisphenol A the result was similar, i.e., 66%, whereas for the rest of the compounds studied, removal efficiencies lower than 15% were obtained. The MIEX® GOLD resin achieved lower elimination rates than the MIEX® DOC resin in all cases.

A predictive model of pathologic response based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer treated with chemo-free dual HER2 blockade.

Background: The presence of stromal tumor-infiltrating lymphocytes (TILs) is associated with increased pathologic complete response (pCR) and improved outcomes in HER2-positive early-breast cancer (BC) treated with anti-HER2-based chemotherapy. In the absence of chemotherapy, the association of TILs with pCR following anti-HER2 therapy-only is largely unknown. Patients and methods: The PAMELA neoadjuvant trial treated 151 women with HER2-positive BC with lapatinib and trastuzumab [and hormonal therapy if hormone receptor (HR)-positive] for 18 weeks. Percentage of TILs and tumor cellularity were determined at baseline (N = 148) and at day 15 (D15) of treatment (N = 134). Associations of TILs and tumor cellularity with pCR in the breast were evaluated. A combined score based on tumor cellularity and TILs (CelTIL) measured at D15 was derived in PAMELA, and validated in D15 samples from 65 patients with HER2-positive disease recruited in the LPT109096 neoadjuvant trial, where anti-HER2 therapy-only was administer for 2 weeks, then standard chemotherapy was added for 24 weeks. Results: In PAMELA, baseline and D15 TILs were significantly associated with pCR in univariate analysis. In multivariable analysis, D15 TILs, but not baseline TILs, were significantly associated with pCR. At D15, TILs and tumor cellularity were found independently associated with pCR. A combined score (CelTIL) taking into account both variables was derived. CelTIL at D15 as a continuous variable was significantly associated with pCR, and patients with CelTIL-low and CelTIL-high scores had a pCR rate of 0% and 33%, respectively. In LPT109096, CelTIL at D15 was found associated with pCR both as a continuous variable and as group categories using a pre-defined cut-off (75.0% versus 33.3%). Conclusions: On-treatment TILs, but not baseline TILs, are independently associated with response following anti-HER2 therapy-only. A combined score of TILs and tumor cellularity measured at D15 provides independent predictive information upon completion of neoadjuvant anti-HER2-based therapy. Clinical trial number: NCT01973660.

Cobertura Universal de Servicios Diagnósticos a través de la Telemedicina / Universal Coverage of Diagnostic Services through Telemedicine

Con la Telemedicina pueden desarrollarse sistemas de telediagnóstico ventajosos para mejorar la atención de la salud de poblaciones remotas que no tienen acceso a especialistas. Este estudio realizado por la Unidad de Telemedicina del Ministerio de Salud Pública y Bienestar Social (MSPBS) en colaboración con el Dpto. de Ingeniería Biomédica e Imágenes del Instituto de Investigaciones en Ciencias (IICS-UNA) y la Universidad del País Vasco (UPV/EHU) sirvió para evaluar la utilidad de un sistema de telediagnóstico para la cobertura universal en la salud pública. Para el efecto se analizaron los resultados obtenidos por el sistema de telediagnóstico implementado en 56 hospitales del MSPBS. En dicho sentido se analizaron 293.142 diagnósticos remotos realizados entre enero del 2014 y septiembre de 2017. Del total, el 37,29 % (109.311) correspondieron a estudios de tomografía, 61,44 % (180.108) a electrocardiografía (ECG), 1,26 % (3.704) a electroencefalografía (EEG) y 0,01 % (19) a ecografía. No se observaron diferencias significativas entre el diagnóstico remoto y el diagnóstico "cara a cara". Con el diagnostico remoto se logró una reducción del coste que supone un beneficio importante para cada ciudadano del interior del país. Los resultados obtenidos evidencian que la telemedicina puede contribuir para mejorar significativamente la cobertura universal de los servicios diagnósticos y programas de salud, maximizando el tiempo del profesional y su productividad, aumentando el acceso y la equidad, y disminuyendo los costos. Sin embargo antes de realizar su implementación sistemática se deberá realizar una contextualización con el perfil epidemiológico regional. Palabras claves: Telemedicina; Cobertura Universal; Telediagnóstico; TICs en Salud; Innovación Tecnológica.

Through the telemedicine, advantageous telediagnostic systems can be developed to improve the health care of remote populations that don`t have access to specialists. This study was carried out by the Telemedicine Unit of the Ministry of Public Health and Social Welfare (MSPBS) in collaboration with the Department of Biomedical Engineering and Imaging of the Health Science Research Institute (IICS-UNA) and the University of the Basque Country (UPV / EHU) to evaluate the utility of a telediagnostic system for universal coverage in public health. For this purpose, the results obtained by the telediagnosis system implemented in 56 MSPBS hospitals were analyzed. In that sense, 293,142 remote diagnoses were performed between January 2014 and September 2017. Of the total, 37.29% (109,311) corresponded to tomography studies, 61.44% (180.108) to electrocardiography (ECG), 1.26% (3,704) to electroencephalography (EEG) and 0.01% (19) to ultrasound. There were no significant differences between the remote and the "face to face" diagnosis. With the remote diagnosis a reduction of the cost was obtained, that supposes an important benefit for each citizen of the interior of the country. The results show that the telemedicine can contribute to improve significantly the universal coverage of diagnostic services and health programs, maximizing professional time and productivity, increasing access and equity, and reducing costs. However, before carrying out its systematic implementation, a contextualization with the regional epidemiological profile must be performed. Key words: Telemedicine; Universal Coverage; Telediagnosis; ICT in Health; Technological Innovation.

Costo-Beneficio de un Sistema de Telediagnóstico para Hospitales Regionales y Distritales del Paraguay / Cost-Effectiveness of a Remote Telediagnostic System for Regional and District Hospitals in Paraguay

En el contexto de una evaluación económica y tecnológica de las alternativas metodológicas que facilite un sistema de cobertura universal y el uso eficiente de los recursos disponibles en la salud pública, existen argumentos de costo-beneficio para que un sistema de telediagnóstico sea considerado ventajoso en los países en vías de desarrollo como una herramienta para mejorar la atención de la salud de poblaciones remotas que no tienen acceso a los especialistas. Este estudio observacional y descriptivo realizado por la Unidad de Telemedicina del Ministerio de Salud Pública y Bienestar Social (MSPBS) en colaboración con el Dpto. de Ingeniería Biomédica e Imágenes del Instituto de Investigaciones en Ciencias de la Salud de la Universidad Nacional de Asunción (IICS-UNA) y la Universidad del País Vasco (UPV/EHU) sirvió como un proyecto piloto para evaluar el costo-beneficio de un sistema de telediagnóstico en la salud pública. Para el efecto fueron analizados los resultados obtenidos en un proyecto piloto de telediagnóstico implementado en 25 hospitales regionales y distritales del MSPBS. En dicho sentido, en el marco del proyecto piloto fueron realizados 34.096 diagnósticos remotos entre enero del 2014 y mayo de 2015 a través del sistema. Del total de telediagnósticos realizados, el 38,0 % (12.966) correspondieron a estudios de tomografía, 61,1 % (21.111) a electrocardiografía (ECG) y 0,1 % (19) a ecografía. Se observó una diferencia importante en el coste de diagnóstico remoto en relación al diagnóstico "cara a cara", en el análisis se incorporaron los costos de implantación y mantenimiento de la TIC para el diagnóstico remoto y los costos de transporte, alimentación y oportunidad para el diagnóstico "cara a cara". La reducción del coste a través del diagnóstico remoto fue de 4,5 veces para ECG, 26,4 veces para tomografía y de 8,3 veces para ecografía, lo que supone un beneficio importante para cada ciudadano del interior del país toda vez que el coste promedio de diagnóstico remoto para cada hospital sea igual o inferior al coste total del diagnóstico cara a cara. Los resultados obtenidos en este estudio contribuirán en forma significativa al fortalecimiento de la cobertura universal de servicios diagnósticos, capacidad de innovación y aseguramiento de la sostenibilidad económica del sistema de telediagnóstico público. Además ayudará a mejorar sustancialmente la capacidad resolutiva local de los hospitales regionales y distritales en el interior del país. Sin embargo, antes de recomendar su utilización masiva se deberá analizar los costos para su implementación y la sostenibilidad técnico-económica del sistema acorde a los recursos disponibles. Palabras claves: Telediagnóstico, Telesalud, Telemedicina, TICs en salud, Telemática en salud.

In the context of an assessment of alternative economic and technological methods that would facilitate a universal health coverage system and the effcient use of available resources in public health, there is debate about the cost-effectiveness and advantages of a remote telediagnostic system in developing countries as a tool to improve healthcare for remote populations without access to specialists. This observational and descriptive study by the Telemedicine Unit of the Ministry of Public Health and Social Welfare (MSPBS) in collaboration with the Dept. Of Biomedical Engineering and Imaging Research of the Institute in Health Sciences of the National University of Asuncion (IICS -A) and the University of the Basque Country (UPV / EHU) served as a pilot project to assess the cost-effectiveness of a system of remote telediagnostics in public health. For this purpose, we analyzed the results of a telediagnosis pilot project implemented in 25 regional and district MSPBS hospitals MSPBS. During the pilot project timeframe, 34,096 remote telediagnoses were made between January 2014 and May 2015 throughout the system. Of the total remote telediagnoses performed, 38.0% (12,966) were of tomography studies, 61.1% (21,111) were of electrocardiography (ECG) and 0.1% (19) were ultrasound interpretations. A signifcant difference was observed in the cost of remote telediagnosis compared to"face to face" diagnosis; the analysis included implementation and maintenance costs of information technology for remote telediagnoses vs. transportation costs, meals and access options for "face to face" diagnoses. The cost reduction via remote diagnosis was 4.5 times for ECG, 26.4 times for CT scans and 8.3 times for ultrasound, which would be a major beneft for patients living in remote areas of the country, since the average cost for remote telediagnosis at each hospital is equal to or less than the total cost of "fact to face" diagnosis. The results obtained in this study are a signifcant contribution to providing universal coverage for diagnostic services, improve the capacity to innovate in the public health system and reassure policymakers regarding the economic sustainability of a public health remote telediagnosis system. It will also help to substantially improve the resolution ability of regional and district hospitals in the countryside. However, before recommending its extensive use, the implementation costs, as well as the technical and economic sustainability considering local resource availability, should be analyzed. Keywords: Remote diagnostics, telehealth, telemedicine, health information technology, health Telematics.

Perspectivas de un Sistema de Telemedicina en la Salud Pública del Paraguay. Estudio Piloto / Perspectives on a Telemedicine System in Public Health in Paraguay. A Pilot Study

En el contexto de una cobertura universal y el uso eficiente de los recursos disponibles en la salud pública que deben estar orientados hacia una mayor equidad en la prestación de servicios, mayor preocupación por la efectividad y utilidad de las tecnologías para la salud, existe una perspectiva favorable para que la telemedicina sea considerada en los países industrializados y en vías de desarrollo como una herramienta para mejorar la atención de la salud de poblaciones remotas que no tienen acceso a los especialistas. Este estudio observacional y descriptivo realizado por la Unidad de Telemedicina del Ministerio de Salud Pública y Bienestar Social (MSPBS) en colaboración con el Dpto. de Ingeniería Biomédica e Imágenes del Instituto de Investigaciones en Ciencias de la Salud de la Universidad Nacional de Asunción (IICSUNA) y la Universidad del País Vasco (UPV/EHU) sirvió como un proyecto piloto para evaluar las potencialidades de un sistema de telemedicina en la salud pública. Para el efecto fueron analizados los resultados preliminares de un proyecto piloto de telediagnóstico implementado en algunos hospitales regionales y distritales del MSPBS. En dicho sentido, en el marco del proyecto piloto fueron realizados 15968 diagnósticos remotos entre enero y noviembre de 2014 a través del sistema. Del total de telediagnósticos realizados, el 43,9 % (7008) correspondieron a estudios de tomografía, 56,0 % (8941) a electrocardiografía (ECG) y 0,1 % (19) a ecografía. Las dificultades observadas se relacionaron: al recurso humano (capacitación de asistente técnico, reticencia a aceptar totalmente el telediagnóstico como una nueva herramienta) y el tecnológico (identificación de las señales disponibles, baja velocidad de la red interna y los modelos de aplicación referidos a standalone o web). Los resultados obtenidos a través de este estudio piloto son de vital importancia para la formulación de metodologías prácticas y viables para la implantación de un sistema de telemedicina que ayudará a mejorar sustancialmente la capacidad resolutiva local de los centros asistenciales a las poblaciones remotas y dispersas e intercambiar con mayor efectividad informaciones clínicas, administrativas y de capacitación del personal. Este estudio piloto basado en las tecnologías disponibles, las experiencias previas propias y foráneas muestra las potencialidades de un sistema de telemedicina en la salud pública. Pero, antes de recomendar su utilización masiva se deberá realizar un estudio exhaustivo y pormenorizado de los sistemas de salud, los costos para su implementación y la sustentabilidad del sistema acorde a las metodologías vigentes. Palabras claves: Telemedicina, Telesalud, Teleeducación, Telecuidado, Telemática en salud.

In the context of universal coverage and the efficient use of available resources in public health which should be directed towards greater equity in the provision of services, greater concern for the effectiveness and usefulness of health technologies, there is a favorable opportunity to develop telemedicine in both developing and industrialized countries as a tool to improve health care in remote locations without access to specialists. This observational and descriptive study, performed by the Telemedicine Unit of the Ministry of Public Health and Social Welfare (MOHSW) in collaboration with the Dept. Of Biomedical Engineering & Imaging Research Institute in Health Sciences of the National University of Asunción (IICS-UNA) and the University of the Basque Country (UPV / EHU) served as a pilot project to evaluate the potential of a telemedicine system in public health. For these purposes, we analyzed preliminary results of a pilot project using telemedicine for diagnosis implemented in some remote regional and district hospitals MSPBS. During the pilot project time period, 15968 remote diagnostics were conducted between January and November 2014 using the system. Of all remote diagnostics modalities performed, 43.9% (7008) corresponded to tomography studies, 56.0% (8941) to electrocardiography (ECG) and 0.1% (19) to ultrasound studies. The observed difficulties were: human resources (training of technical assistants, reluctance to fully accept remote diagnostics as a new tool) and technological (difficult identification of signals available, low-speed internet network and computer applications that were "standalone" or web-based). The results obtained from this pilot study are vital for the development of practical and workable methodologies for the implementation of a telemedicine system that will help to substantially improve local response capacity of health facilities to remote and dispersed populations and to more effectively exchange clinical information, and train administrative and staff personnel. This pilot study, which was based on available technology and previous experiences in other countries, shows the potential of a telemedicine system in public health. But, before recommending its widespread use there will need to be a thorough and detailed study of health systems, costs for implementation and sustainability of the system using current methodologies. Keywords: Telemedicine, Telehealth, Tele-education, telecare, Telematics health

Síntomas residuales en el anciano con depresión / Residual symptoms in elderly patients with depression

Objectives. Buscar síntomas residuales en pacientes mayores de 65 años diagnosticados de depresión. Averiguar si existen más síntomas residuales en relación a la comorbilidad física y la hiperfrecuentación. Material y método. Estudio observacional, transversal, aleatorizado y multicéntrico. La muestra se obtuvo de 3 cupos de Atención Primaria de 3C.S. urbanos (población aproximada 5.200 habitantes). Se seleccionó a pacientes mayores de 65 años con diagnóstico de depresión, que hubieran recibido más de 3 meses de tratamiento. Se administraron cuestionarios mediante entrevista personal que incluyen variables universales, tiempo de evolución y de tratamiento, recurrencias, comorbilidad, síntomas residuales, Escala de Yesavage, EQ-5D y EVA. Resultados. de 100 registros estudiados, encontramos un 99% con presencia de síntomas residuales. El 22% presentaba 4 síntomas (de los 10 preguntados). El síntoma más frecuente fue tristeza (68%) seguida de dolor (55%) y pérdida de energía (55%). Conclusiones. Prevalencia de depresión encontrada en nuestro estudio fue 13,8%. El 99% presenta algún síntoma residual. Los pacientes que viven en pareja y los varones (realizan más actividades de ocio) presentan menor número de síntomas residuales. No se halló relación entre presencia de comorbilidad e hiperfrecuentación con mayor número de síntomas residuales. La mayoría de los pacientes padecen una depresión crónica (> 2 años). El 18% se encuentra a tratamiento exclusivamente con benzodiacepinas (AU)

Objectives. To look for residual symptoms in patients older than 65 years diagnosed with depression, and to find out if there are more residual symptoms in relation to physical comorbidity and the number of visits made to a Primary Care Centre. Methods. A descriptive, randomised and cross-sectional multicentre study, with a sample of patients attending 3 urban Health Primary Care Centres. Patients older than 65 years with a diagnosis of depression and who had received more than 3 months treatment were selected. Data was collected by means of questionnaires during personal interviews, which included universal data, time of onset, treatment recurrence, comorbidity, and residual symptoms. The Yesavage questionnaire, EQ-5D and VAS were also used. Results. Of 100 patients studied, 99% had residual symptoms, with 22% with 4 symptoms (from 10 asked). The most frequent symptom was the sadness (68%), followed by pain (55%), and loss of energy (55%). Conclusions. The prevalence of depression found in our study was 13.8%, and a 99% had at least one residual symptom. Patients who lived as a couple and men (who performed more recreational activities) had a lower number of residual symptoms. No relationship was found between comorbidity and frequent use of Primary Care Centres with a higher number of residuals symptoms. The majority of patients suffered chronic depression (> 2 years). Benzodiazepines only were used as treatment in 18% of the patients (AU)

Segmentation of time series with long-range fractal correlations.

Segmentation is a standard method of data analysis to identify change-points dividing a nonstationary time series into homogeneous segments. However, for long-range fractal correlated series, most of the segmentation techniques detect spurious change-points which are simply due to the heterogeneities induced by the correlations and not to real nonstationarities. To avoid this oversegmentation, we present a segmentation algorithm which takes as a reference for homogeneity, instead of a random i.i.d. series, a correlated series modeled by a fractional noise with the same degree of correlations as the series to be segmented. We apply our algorithm to artificial series with long-range correlations and show that it systematically detects only the change-points produced by real nonstationarities and not those created by the correlations of the signal. Further, we apply the method to the sequence of the long arm of human chromosome 21, which is known to have long-range fractal correlations. We obtain only three segments that clearly correspond to the three regions of different G + C composition revealed by means of a multi-scale wavelet plot. Similar results have been obtained when segmenting all human chromosome sequences, showing the existence of previously unknown huge compositional superstructures in the human genome.

[Residual symptoms in elderly patients with depression]. / Síntomas residuales en el anciano con depresión.

OBJECTIVES: To look for residual symptoms in patients older than 65 years diagnosed with depression, and to find out if there are more residual symptoms in relation to physical comorbidity and the number of visits made to a Primary Care Centre. METHODS: A descriptive, randomised and cross-sectional multicentre study, with a sample of patients attending 3 urban Health Primary Care Centres. Patients older than 65 years with a diagnosis of depression and who had received more than 3 months treatment were selected. Data was collected by means of questionnaires during personal interviews, which included universal data, time of onset, treatment recurrence, comorbidity, and residual symptoms. The Yesavage questionnaire, EQ-5D and VAS were also used. RESULTS: Of 100 patients studied, 99% had residual symptoms, with 22% with 4 symptoms (from 10 asked). The most frequent symptom was the sadness (68%), followed by pain (55%), and loss of energy (55%). CONCLUSIONS: The prevalence of depression found in our study was 13.8%, and a 99% had at least one residual symptom. Patients who lived as a couple and men (who performed more recreational activities) had a lower number of residual symptoms. No relationship was found between comorbidity and frequent use of Primary Care Centres with a higher number of residuals symptoms. The majority of patients suffered chronic depression (> 2 years). Benzodiazepines only were used as treatment in 18% of the patients.

High-level organization of isochores into gigantic superstructures in the human genome.

Human DNA shows a complex structure with compositional features at many scales; the isochores--long DNA segments (~105 bp) of relatively homogeneous guanine-cytosine (G + C) content--are the largest well-documented and well-analyzed compositional structures. However, we report here on the existence of a high-level compositional organization of isochores in the human genome. By using a segmentation algorithm incorporating the long-range correlations existing in human DNA, we find that every chromosome is composed of a few huge segments (~ 107 bp) of relatively homogeneous G + C content, which become the largest compositional organization of the genome. Finally, we show evidence of the biological relevance of these superstructures, pointing to a large-scale functional organization of the human genome.

Sistema de vigilancia epidemiológica comunitaria bonis: estado actualy proyecciones futuras / Community epidemiological surveillance system bonis: current status and future projections

El sistema actual de vigilancia epidemiológica en la zona del Centro de Ayuda Mutua y Salud para Todos (CAMSAT) del Bañado Sur, de Asunción, se basa en la búsqueda rutinaria de posibles casos febriles mediante visitas domiciliarias, realizadas por las agentes comunitarias adscritas a la Unidad de Salud Familiar (USF). Cada una de las diezagentes comunitarias de CAMSAT tiene asignada 150 hogares, y los resultados de susvisitas domiciliarias quedan recogidos en planillas que se reportan mediante medios tradicionales (papel, correo interno, fax, etc.) a la DGVS del Ministerio de Salud. La consecuencia de este modo de trabajo es que muchas veces las acciones de bloqueo de la transmisión llegan tarde con el coste social y económico que ello significa. El sistema Bonis introduce la telefonía móvil como elemento catalizador para transformar la búsqueda rutinaria de posibles casos febriles en una acción proactiva, y también la utilización de tecnologías web y bases de datos para el registro de pacientes y su correspondiente seguimiento por el personal sanitario. La utilización de estas tecnologíasde la información y comunicación (TICs) transforman el sistema de vigilancia epidemiológica en un caso de estudio de e-Salud en Paraguay. Se describe el estado actual y proyecciones futuras del sistema de vigilancia epidemiológica comunitaria “Bonis”,que utiliza las TICs para prevenir, alertar, supervisar y controlar la expansión de síndromes febriles en un área de influencia del Hospital Barrio Obrero (HBO), en la Unidad de Atención Primaria en Salud del Centro de Ayuda Mutua y Salud para Todos, Asunción,Paraguay.

The current system of epidemiologic surveillance in the area of Mutual Aid Centre and Health for All (CAMSAT in Spanish) in the “Bañado Sur” in Asuncion is based on routine screening of possible febrile cases through home visits made by community agents fromthe Primary Health Care Unit (USF in Spanish). Each of the ten community agents are assigned to 150 households and the results of these home visits are recorded on sheets that are reported through traditional means (paper, internal mail, fax, etc.) to the DGVSof the Ministry of Health. The consequence of this working system is that often the blocking actions arrive late with the social and economic costs that this implies. The Bonis system uses the mobile phone as a catalyst to transform the routine screening ofpotential feverish cases in a proactive action and the web technology and databases for patient records and appropriate follow-up by health personnel. The use of theseinformation and communication technologies of (ICTs) transforms the Epidemiological Surveillance System in a study case of e-Health in Paraguay. This document describes the current status and future projections of the community epidemiological surveillancesystem Bonis which uses Information and Communication Technologies (ICTs) to prevent, warn, monitor and control the spread of febrile syndromes in a catchment area of Barrio Obrero Hospital (HBO), Unit of Primary Health Care Center Mutual Aid and Health for All, Asuncion, Paraguay.

Telemedicina: metas y aplicaciones / Telemedicine: fine and applicability

La atención sanitaria ha ido variando en las últimas décadas, pasando de una asistenciaenfocada a la enfermedad, a una atención dirigida al ciudadano, más global dondeconceptos como calidad, costes, equidad y continuidad cobran nuevos valores. El enfoquede atención no es sólo tratar cuando la enfermedad llega, sino crear y promover hábitossaludables de vida y prevención de la enfermedad. En la actualidad las tecnologías deinformación y comunicación se han combinado para dar lugar a la telemedicina a fin debrindar asistencia médica a quien la requiera en sitios distantes, se incluye dentro de estecampo a la educación para la salud, salud pública y comunitaria, el desarrollo deprogramas de salud y de prevención, estudios epidemiológicos entre otros. Así mismo, laamplia utilización de Internet ha contribuido a masificar el uso de estos servicios, es asícomo ha nacido un nuevo término conocido como “e-health”, el cual acuña cualquierpráctica de la telemedicina usando esta red. En este artículo se desea incorporarinformación sobre esta disciplina que se encuentra entre medicina y tecnología, la mismapuede proveer un apoyo importante pero su aprovechamiento dependerá de losdiferentes actores envueltos en la implementación.

Implementación de un Sistema de Telemedicina/Telesalud en el Institutode Investigaciones en Ciencias de la Salud (IICS). Estudio Piloto / Implementation of a Telemedicine/Telehealth system at the Institute of

Los procesos de reforma del sector salud orientados hacia una mayor equidad en laprestación de servicios, mayor preocupación por la efectividad y utilidad de lastecnologías para la salud, han contribuido para que la telemedicina sea considerada en lospaíses industrializados y en vías de desarrollo como una herramienta para mejorar laatención de la salud de poblaciones remotas que no tienen acceso a los especialistas. Esteestudio observacional y descriptivo realizado por el Dpto. de Ingeniería Biomédica eImágenes, con el apoyo de la División de Informática del IICS y el Centro Nacional deComputación de la UNA para relevar y analizar las imágenes de 294 pacientes e informestransmitidos por las áreas de ecografía, medicina nuclear y electrocardiografía, incluidosen el proyecto piloto. De los cuales, 254 (86,4 por ciento) correspondieron al servicio de MedicinaNuclear (Centellografía) y completan el grupo los estudios por imágenes ecográficas yelectrocardiográficas. El 49 por ciento fueron gammagrafía de tiroides, 22 por ciento gammagrafías óseas,habiéndose realizado también renogramas isotópicos, gammagrafía hepática, ecografíasde tiroides, abdominales. El tiempo empleado en todo el proceso desde el ingreso delpaciente hasta el informe medico varió en un promedio de 107 a 123 minutos según tipode estudio solicitado.

Level statistics of words: finding keywords in literary texts and symbolic sequences.

Using a generalization of the level statistics analysis of quantum disordered systems, we present an approach able to extract automatically keywords in literary texts. Our approach takes into account not only the frequencies of the words present in the text but also their spatial distribution along the text, and is based on the fact that relevant words are significantly clustered (i.e., they self-attract each other), while irrelevant words are distributed randomly in the text. Since a reference corpus is not needed, our approach is especially suitable for single documents for which no a priori information is available. In addition, we show that our method works also in generic symbolic sequences (continuous texts without spaces), thus suggesting its general applicability.

Identifying characteristic scales in the human genome.

The scale-free, long-range correlations detected in DNA sequences contrast with characteristic lengths of genomic elements, being particularly incompatible with the isochores (long, homogeneous DNA segments). By computing the local behavior of the scaling exponent alpha of detrended fluctuation analysis (DFA), we discriminate between sequences with and without true scaling, and we find that no single scaling exists in the human genome. Instead, human chromosomes show a common compositional structure with two characteristic scales, the large one corresponding to the isochores and the other to small and medium scale genomic elements.