Treatment rationale and study design for a phase III, double-blind, placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer.

BACKGROUND: To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed. METHODS/DESIGN: Approximately 900 patients will receive four cycles of induction chemotherapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 who have not progressed during induction therapy will randomly receive (in a 2:1 ratio) one of two double-blind maintenance regimens: pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive care (BSC) or placebo plus BSC. The primary objective is to compare PFS between treatment arms. Secondary objectives include a fully powered analysis of OS, objective tumor response rate, patient-reported outcomes, resource utilization, and toxicity. Tumor specimens for translational research will be obtained from consenting patients before induction treatment, with a second biopsy performed in eligible patients following the induction phase. DISCUSSION: Although using a drug as maintenance therapy that was not used in the induction regimen exposes patients to an agent with a different mechanism of action, evidence suggests that continued use of an agent present in the induction regimen as maintenance therapy enables the identification of patients most likely to benefit from maintenance treatment.

Andalusian Health Repository: Promoting the scientific health output among professionals and providing citizens with quality health information

The Andalusian Public Health System (Sistema Sanitario Público de Andalucía -SSPA) Repository is the open environment where all the scientific output generated by the SSPA professionals, resulting from their medical care, research and administrative activities, is comprehensively collected and managed. This repository possesses special features which determined its development: the SSPA organization and its purpose as a health institution, the specific sets of documents that it generates and the stakeholders involved in it. The repository uses DSpace 1.6.2, to which several changes were implemented in order to achieve the SSPA initial goals and requirements. The main changes were: the addition of specific qualifiers to the Metadata Dublin Core scheme, the modification of the submission form, the integration of the MeSH Thesaurus as controlled vocabulary and the optimization of the advanced search tool. Another key point during the setting up of the repository was the initial batch ingest of the documents.

Low intensity vs. self-guided internet-delivered psychotherapy for major depression: a multicenter, controlled, randomized study.

BACKGROUND Major depression will become the second most important cause of disability in 2020. Computerized cognitive-behaviour therapy could be an efficacious and cost-effective option for its treatment. No studies on cost-effectiveness of low intensity vs self-guided psychotherapy has been carried out. The aim of this study is to assess the efficacy of low intensity vs self-guided psychotherapy for major depression in the Spanish health system. METHODS The study is made up of 3 phases: 1.- Development of a computerized cognitive-behaviour therapy for depression tailored to Spanish health system. 2.- Multicenter controlled, randomized study: A sample (N=450 patients) with mild/moderate depression recruited in primary care. They should have internet availability at home, not receive any previous psychological treatment, and not suffer from any other severe somatic or psychological disorder. They will be allocated to one of 3 treatments: a) Low intensity Internet-delivered psychotherapy + improved treatment as usual (ITAU) by GP, b) Self-guided Internet-delivered psychotherapy + ITAU or c) ITAU. Patients will be diagnosed with MINI psychiatric interview. Main outcome variable will be Beck Depression Inventory. It will be also administered EuroQol 5D (quality of life) and Client Service Receipt Inventory (consume of health and social services). Patients will be assessed at baseline, 3 and 12 months. An intention to treat and a per protocol analysis will be performed. DISCUSSION The comparisons between low intensity and self-guided are infrequent, and also a comparative economic evaluation between them and compared with usual treatment in primary. The strength of the study is that it is a multicenter, randomized, controlled trial of low intensity and self-guided Internet-delivered psychotherapy for depression in primary care, being the treatment completely integrated in primary care setting. TRIAL REGISTRATION Clinical Trials NCT01611818.

HypatiaSalud. Institucional Repository for the Andalusian Public Health System, Spain

HypatiaSalud will be the freely accessible institutional repository for the Public Health System in Andalucía, Spain. Open access and new technologies have changed dramatically the environment in which research is being conducted and disseminated. Traditionally University has been the universal research provider, but at present time there are Government Organizations, as Public Health Systems, which are large-producers of research. Meanwhile most universities are running institutional repositories or have plans of setting up institutional repositories in the short-term, there are not many Government Organizations working on that direction. In this sense, HypatiaSalud represents an innovative initiative. Objectives: - Enhancing institutional efficiency, effectiveness and opportunities for knowledge exchange. -Expanding access and greater use of research findings to a much wider range of users increasing the visibility and reputation of Andalusian Public Health System. - Providing the foundation for effective gathering and long-term preservation of research output. Methodology. Phase I: Researching and learning from other institutional repositories. Phase II: Designing and planning the financial, organizational, legal and technical underlying issues. Phase III: Launching the service. Phase IV: Running the service. Outcomes. Bibliometrics: catalog of the research output of the Institution, in order to determine the conditions to include this scientific output in the Institutional Repository: direct deposit, deposit after a period of embargo, or closed access when publisher will not grant permission. Promote a mandate for the deposit of all peer-reviewed final drafts (postprints) for institutional record-keeping purposes. Access to that immediate postprint deposit in HypatiaSalud may be set immediately as ‘Open Access’ if copyright conditions allows; otherwise access can be set as ‘Closed Access’. International Standards application: HypatiaSalud will support OAI-PMH and DRIVER, to allow that central repositories could harvest its content or metadata. Development of human resources strategies in order to foster self-archiving through merit acknowledge and accreditation. Conclusions. It seems likely that setting up an Institutional Repository for the Public Health System in Andalucía would have substantial net benefits in the longer term for the Institution, despite the lag between the costs and realisation of benefits.

Integrating Metalib and SFX into the BV-SSPA

Introduction To guarantee the success of a virtual library it is essential that all users can access all the library resources independently of the user’s location. Achieving this goal in the Andalusian Public Health System has been a particularly difficult task, due to it is made up of 10 research centers and 95.000 health-care professionals. Aims Since the BV-SSPA started three years ago, one of its mayor aims has been to provide remote access to all its resources in this complex scenario, as well as facilitate the access to the virtual library to both professionals and citizens. IP access was guaranteed because health-care professionals could access everything from their workplaces thanks to the intranet, but it was restricted when they were not there. The BV-SSPA solved this problem by installing a federated authentication and authorization system called PAPI and a PAPI rewriting proxy. After three years the BV-SSPA has met a new challenge: adapting its federated access system to Metalib and SFX, specifically the access management module PDS had to be connected with the existing PAPI system. This new challenge came along with the introduction of a new metasearcher and link resolver. Material and Methods Initially there were three independent systems: • A Metalib and SFX PDS module, • A federated authentication and authorization system: PAPI. • A PAPI Rewriting Proxy. The chosen solution went through the reutilization of the existing software. To achieve this goal, a PHP connector between these applications was developed and several modules in the PDS configuration were modified. On the other hand, providing a simplified access to Metalib has been solved using Xerxes and integrating it in a Drupal website. Results Thanks to this connector the BV-SSPA was able to get all its users remotely accessing its new metasearcher without changing the way they used to validate, or without having to remember a new username and password. Futhermore, thanks to Xerxes, it is possible to use Metalib from a simple interface and without having to leave the BV-SSPA website to go its native interface.

Integración de la Biblioteca Virtual del Sistema Sanitario Público de Andalucía en la política científica de la Consejería de Salud y Bienestar Social

Capítulo incluido en parte III del Congreso: Indicadores cuantitativos y cualitativos para el análisis de la colaboración científica

Rationale and design of a randomized, double-blind, placebo controlled multicenter trial to study efficacy, security, and long term effects of intermittent repeated levosimendan administration in patients with advanced heart failure: LAICA study.

BACKGROUND Advanced heart failure (HF) is associated with high morbidity and mortality; it represents a major burden for the health system. Episodes of acute decompensation requiring frequent and prolonged hospitalizations account for most HF-related expenditure. Inotropic drugs are frequently used during hospitalization, but rarely in out-patients. The LAICA clinical trial aims to evaluate the effectiveness and safety of monthly levosimendan infusion in patients with advanced HF to reduce the incidence of hospital admissions for acute HF decompensation. METHODS The LAICA study is a multicenter, prospective, randomized, double-blind, placebo-controlled, parallel group trial. It aims to recruit 213 out-patients, randomized to receive either a 24-h infusion of levosimendan at 0.1 μg/kg/min dose, without a loading dose, every 30 days, or placebo. RESULTS The main objective is to assess the incidence of admission for acute HF worsening during 12 months. Secondarily, the trial will assess the effect of intermittent levosimendan on other variables, including the time in days from randomization to first admission for acute HF worsening, mortality and serious adverse events. CONCLUSIONS The LAICA trial results could allow confirmation of the usefulness of intermittent levosimendan infusion in reducing the rate of hospitalization for HF worsening in advanced HF outpatients.

Telehealth system (e-CUIDATE) to improve quality of life in breast cancer survivors: rationale and study protocol for a randomized clinical trial.

BACKGROUND Breast cancer survivors suffer physical impairment after oncology treatment. This impairment reduces quality of life (QoL) and increase the prevalence of handicaps associated to unhealthy lifestyle (for example, decreased aerobic capacity and strength, weight gain, and fatigue). Recent work has shown that exercise adapted to individual characteristics of patients is related to improved overall and disease-free survival. Nowadays, technological support using telerehabilitation systems is a promising strategy with great advantage of a quick and efficient contact with the health professional. It is not known the role of telerehabilitation through therapeutic exercise as a support tool to implement an active lifestyle which has been shown as an effective resource to improve fitness and reduce musculoskeletal disorders of these women. METHODS / DESIGN This study will use a two-arm, assessor blinded, parallel randomized controlled trial design. People will be eligible if: their diagnosis is of stages I, II, or IIIA breast cancer; they are without chronic disease or orthopedic issues that would interfere with ability to participate in a physical activity program; they had access to the Internet and basic knowledge of computer use or living with a relative who has this knowledge; they had completed adjuvant therapy except for hormone therapy and not have a history of cancer recurrence; and they have an interest in improving lifestyle. Participants will be randomized into e-CUIDATE or usual care groups. E-CUIDATE give participants access to a range of contents: planning exercise arranged in series with breathing exercises, mobility, strength, and stretching. All of these exercises will be assigned to women in the telerehabilitation group according to perceived needs. The control group will be asked to maintain their usual routine. Study endpoints will be assessed after 8 weeks (immediate effects) and after 6 months. The primary outcome will be QoL measured by The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 version 3.0 and breast module called The European Organization for Research and Treatment of Cancer Breast Cancer-Specific Quality of Life questionnaire. The secondary outcomes: pain (algometry, Visual Analogue Scale, Brief Pain Inventory short form); body composition; physical measurement (abdominal test, handgrip strength, back muscle strength, and multiple sit-to-stand test); cardiorespiratory fitness (International Fitness Scale, 6-minute walk test, International Physical Activity Questionnaire-Short Form); fatigue (Piper Fatigue Scale and Borg Fatigue Scale); anxiety and depression (Hospital Anxiety and Depression Scale); cognitive function (Trail Making Test and Auditory Consonant Trigram); accelerometry; lymphedema; and anthropometric perimeters. DISCUSSION This study investigates the feasibility and effectiveness of a telerehabilitation system during adjuvant treatment of patients with breast cancer. If this treatment option is effective, telehealth systems could offer a choice of supportive care to cancer patients during the survivorship phase. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01801527.

Use of Two-Part Regression Calibration Model to Correct for Measurement Error in Episodically Consumed Foods in a Single-Replicate Study Design: EPIC Case Study.

In epidemiologic studies, measurement error in dietary variables often attenuates association between dietary intake and disease occurrence. To adjust for the attenuation caused by error in dietary intake, regression calibration is commonly used. To apply regression calibration, unbiased reference measurements are required. Short-term reference measurements for foods that are not consumed daily contain excess zeroes that pose challenges in the calibration model. We adapted two-part regression calibration model, initially developed for multiple replicates of reference measurements per individual to a single-replicate setting. We showed how to handle excess zero reference measurements by two-step modeling approach, how to explore heteroscedasticity in the consumed amount with variance-mean graph, how to explore nonlinearity with the generalized additive modeling (GAM) and the empirical logit approaches, and how to select covariates in the calibration model. The performance of two-part calibration model was compared with the one-part counterpart. We used vegetable intake and mortality data from European Prospective Investigation on Cancer and Nutrition (EPIC) study. In the EPIC, reference measurements were taken with 24-hour recalls. For each of the three vegetable subgroups assessed separately, correcting for error with an appropriately specified two-part calibration model resulted in about three fold increase in the strength of association with all-cause mortality, as measured by the log hazard ratio. Further found is that the standard way of including covariates in the calibration model can lead to over fitting the two-part calibration model. Moreover, the extent of adjusting for error is influenced by the number and forms of covariates in the calibration model. For episodically consumed foods, we advise researchers to pay special attention to response distribution, nonlinearity, and covariate inclusion in specifying the calibration model.

Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury.

BACKGROUND & AIMS Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI. METHODS We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL). RESULTS Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity. CONCLUSIONS When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.

Revisión de los trabajos publicados sobre promoción de la salud en jóvenes españoles.

The objective of this study is to review the health promotion interventions on spanish youths published in Spanish in the 1995-2000 period and to describe them in accordance with the scope within which they have been carried out, the topics addressed, the methodology, the evaluation design used and the results obtained. Two hundred and fourteen intervention were identified. Illegal drugs were the topic on which the largest number of interventions were focused (29.8%), followed by alcohol (15.9%), the risk-related sexual behaviours (14.6%) and leisure time (12.6%). The activities carried out most often were: participation-based educational methods (30.7%), explanatory education methods (11.5%) and the preparation of educational materials (11%). In 80.8% of the cases, some evaluation of the health promotion activities was found. The type of evaluation employed most often was the process evaluation (73.7%), and the medium-long term results evaluation being those employed the least (2.2%). The evaluation methodologies used most often were questionnaires (28.2%). A combination of qualitative and quantitative methods was employed in 13.2% of the cases. The four interventions in which the medium-long term impact was gauged had the purpose of preventing and reducing cigarette smoking and/or drinking and or marijuana smoking, all of these initiatives achieving a reduction in cigarette smoking. In conclusion, it seems necessary to improve the design of the evaluations of the health promotion initiatives addressed to young people in Spain and to increase the dissemination of the same by way of their publication.