A Randomized, Double-Blind, Placebo-Controlled Trial (TAURCAT Study) of Citrate Lock Solution for Prevention of Endoluminal Central Venous Catheter Infection in Neutropenic Hematological Patients.

Infection of long-term central venous catheters (CVCs) remains a challenge in the clinical management of cancer patients. We aimed to determine whether a lock solution with taurolidine-citrate-heparin would be more effective than placebo for preventing nontunneled CVC infection in high-risk neutropenic hematologic patients. We performed a prospective, multicenter, randomized (1:1), double-blind, parallel, superiority, placebo-controlled trial involving 150 hematological patients with neutropenia carrying nontunneled CVCs who were assigned to receive CVC lock solution with taurolidine-citrate-heparin or heparin alone. The primary endpoint was bacterial colonization of the CVC hubs. Secondary endpoints were the incidence of catheter-related bloodstream infection (CRBSI), CVC removal, adverse events related to the lock solution, and the 30-day case fatality rate. CVC lock solution with taurolidine-citrate-heparin was associated with less colonization of the CVC hubs than that with placebo, with no statistically significant differences: 4.1%, versus 10.1% (relative risk [RR] = 0.41, 95% confidence interval [CI] = 0.11 to 1.52), with a cumulative incidence of 4.17 (95% CI = 0.87 to 11.70) and 10.14 (95% CI = 4.18 to 19.79), respectively. There were no significant differences regarding the secondary endpoints. Only three episodes of CRBSI occurred during the study period. No adverse events related to the administration of the lock solution occurred. In this trial involving high-risk patients carrying nontunneled CVCs, the use of taurolidine-citrate-heparin did not show a benefit over the use of placebo. Nevertheless, the safety of this prevention strategy and the trend toward less hub colonization in the taurolidine-citrate-heparin group raise the interest in assessing its efficacy in centers with higher rates of CRBSI. (This study has been registered in ISRCTN under identifier ISRCTN47102251.).

Escherichia coli "TatExpress" strains export several g/L human growth hormone to the periplasm by the Tat pathway.

Escherichia coli is a heavily used platform for the production of biotherapeutic and other high-value proteins, and a favored strategy is to export the protein of interest to the periplasm to simplify downstream processing and facilitate disulfide bond formation. The Sec pathway is the standard means of transporting the target protein but it is unable to transport complex or rapidly folding proteins because the Sec system can only transport proteins in an unfolded state. The Tat system also operates to transport proteins to the periplasm, and it has significant potential as an alternative means of recombinant protein production because it transports fully folded proteins. Here, we have tested the Tat system's full potential for the production of biotherapeutics for the first time using fed-batch fermentation. We expressed human growth hormone (hGH) with a Tat signal peptide in E. coli W3110 "TatExpress" strains that contain elevated levels of the Tat apparatus. This construct contained four amino acids from TorA at the hGH N-terminus as well as the initiation methionine from hGH, which is removed in vivo. We show that the protein is efficiently exported to the periplasm during extended fed-batch fermentation, to the extent that it is by far the most abundant protein in the periplasm. The protein was shown to be homogeneous, disulfide bonded, and active. The bioassay showed that the yields of purified periplasmic hGH are 5.4 g/L culture whereas an enzyme-linked immunosorbent assay gave a figure of 2.39 g/L. Separate analysis of a TorA signal peptide linked to hGH construct lacking any additional amino acids likewise showed efficient export to the periplasm, although yields were approximately two-fold lower.

Comparative proteome analysis in an Escherichia coli CyDisCo strain identifies stress responses related to protein production, oxidative stress and accumulation of misfolded protein.

BACKGROUND: The Twin-arginine translocation (Tat) pathway of Escherichia coli has great potential for the export of biopharmaceuticals to the periplasm due to its ability to transport folded proteins, and its proofreading mechanism that allows correctly folded proteins to translocate. Coupling the Tat-dependent protein secretion with the formation of disulfide bonds in the cytoplasm of E. coli CyDisCo provides a powerful platform for the production of industrially challenging proteins. In this study, we investigated the effects on the E. coli cells of exporting a folded substrate (scFv) to the periplasm using a Tat signal peptide, and the effects of expressing an export-incompetent misfolded variant. RESULTS: Cell growth is decreased when either the correctly folded or misfolded scFv is expressed with a Tat signal peptide. However, only the production of misfolded scFv leads to cell aggregation and formation of inclusion bodies. The comprehensive proteomic analysis revealed that both conditions, recombinant protein overexpression and misfolded protein accumulation, lead to downregulation of membrane transporters responsible for protein folding and insertion into the membrane while upregulating the production of chaperones and proteases involved in removing aggregates. These conditions also differentially affect the production of transcription factors and proteins involved in DNA replication. The most distinct stress response observed was the cell aggregation caused by elevated levels of antigen 43. Finally, Tat-dependent secretion causes an increase in tatA expression only after induction of protein expression, while the subsequent post-induction analysis revealed lower tatA and tatB expression levels, which correlate with lowered TatA and TatB protein abundance. CONCLUSIONS: The study identified characteristic changes occurring as a result of the production of both a folded and a misfolded protein, but also highlights an exclusive unfolded stress response. Countering and compensating for these changes may result in higher yields of pharmaceutically relevant proteins exported to the periplasm.

Vitamin D: Effect on Haematopoiesis and Immune System and Clinical Applications.

Vitamin D is a steroid-like hormone which acts by binding to vitamin D receptor (VDR). It plays a main role in the calcium homeostasis and metabolism. In addition, vitamin D display other important effects called "non-classical actions." Among them, vitamin D regulates immune cells function and hematopoietic cells differentiation and proliferation. Based on these effects, it is currently being evaluated for the treatment of hematologic malignancies. In addition, vitamin D levels have been correlated with patients' outcome after allogeneic stem cell transplantation, where it might regulate immune response and, accordingly, might influence the risk of graft-versus-host disease. Here, we present recent advances regarding its clinical applications both in the treatment of hematologic malignancies and in the transplant setting.

Emerging BCR/ABL1 Mutations Under Treatment with Tyrosine Kinase Inhibitors in Paediatric Acute Lymphoblastic Leukaemia.

We report on the emergence and clinical relevance of an unusual BCR-ABL1 kinase domain mutational status in a 2-year-old female with p210-BCR-ABL Philadelphia chromosome-positive acute lymphoblastic leukaemia. We detected three BCR-ABL1 clones determined by the presence of the E255V, D276G and F317L mutations. We point out the usefulness of searching for mutated populations that survive tyrosine-kinase inhibitor therapy and the role of their clonal selection over time in relation to therapeutic intervention.

Intimate partner violence in older women in Spain: prevalence, health consequences, and service utilization.

The purpose of this study is to estimate the prevalence of lifetime intimate partner violence (IPV) in older women and to analyze its effect on women's health and Healthcare Services utilization. Women aged 55 years and over (1,676) randomly sampled from Primary Healthcare Services around Spain were included. Lifetime IPV prevalence, types, and duration were calculated. Descriptive and multivariate procedures using logistic and multiple lineal regression models were used. Of the women studied, 29.4% experienced IPV with an average duration of 21 years. Regardless of the type of IPV experienced, abused women showed significantly poorer health and higher healthcare services utilization compared to women who had never been abused. The high prevalence detected long standing duration, negative health impact, and high healthcare services utilization, calling attention to a need for increased efforts aimed at addressing IPV in older women.

Dynamic secondary electron emission in rough composite materials.

The interaction of ionizing radiation with matter is of critical importance in numerous areas of science and technology like space and vacuum technology and even medicine and biotechnology. Secondary electron emission is a consequence of electron irradiation on materials. We achieve extremely low secondary electron emission yield values smaller than 0.2, even up to incident electron energies ~1 keV, due to an undocumented synergy between neighbouring metal and dielectric domains in composite samples. To investigate this experimental discovery, we propose a simple 3D model where the dielectric and metallic domains are arranged in parallel and interleaved. The proposed surface profile has a triangular shape to model the surface roughness. We obtain a continuous equation to describe the electric field that arises between grounded conductors and charged dielectrics domains. The calculated trajectories of secondary electrons in this 3D geometry are used to predict dynamic secondary emission yield, which strongly depends on the charge accumulated in the dielectric domains. This research paves the way to design new materials of low secondary emission yield, addressing the technological problem not yet resolved to inhibit the electron avalanche in RF equipment that limit their maximum working power.

Far-reaching cellular consequences of tat deletion in Escherichia coli revealed by comprehensive proteome analyses.

In Escherichia coli, the Twin-arginine translocation (Tat) pathway secretes a set of folded proteins with important physiological functions to the periplasm and outer membrane. The loss of Tat secretion impairs outer membrane integrity and leads to decreased cell growth. Only recently, the Tat pathway has gained more attention due to its essential role in bacterial virulence and applications in the production of fully folded heterologous proteins. In this study, we investigated the influence of the deletion of all active Tat pathway components on the E. coli cells. The comprehensive proteomic analysis revealed activation of several stress responses and experimentally confirmed the dependence of certain proteins on the Tat system for export. We observed that a tat deletion triggers protein aggregation, membrane vesiculation, synthesis of colanic acid and biofilm formation. Furthermore, the mislocalization of Tat-dependent proteins disturbs iron and molybdenum homeostasis and impairs the cell envelope integrity. The results show that the functional Tat pathway is important for the physiological stability and that its dysfunction leads to a series of severe changes in E. coli cells.

Immediate Effects of Dasatinib on the Migration and Redistribution of Naïve and Memory Lymphocytes Associated With Lymphocytosis in Chronic Myeloid Leukemia Patients.

Introduction: Dasatinib is a dual SRC/ABL tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML) that is known to have unique immunomodulatory effects. In particular, dasatinib intake typically causes lymphocytosis, which has been linked to better clinical response. Since the underlying mechanisms are unknown and SRC family kinases are involved in many cell motility processes, we hypothesized that the movement and migration of lymphocytes is modulated by dasatinib. Patients, Materials and Methods: Peripheral blood samples from CML patients treated with second-line dasatinib were collected before and 2 h after the first dasatinib intake, and follow-up samples from the same patients 3 and 6 months after the start of therapy. The migratory capacity and phenotype of lymphocytes and differential blood counts before and after drug intake were compared for all study time-points. Results: We report here for the first time that dasatinib intake is associated with inhibition of peripheral blood T-cell migration toward the homeostatic chemokines CCL19 and CCL21, which control the trafficking toward secondary lymphoid organs, mainly the lymph nodes. Accordingly, the proportion of lymphocytes in blood expressing CCR7, the chemokine receptor for both CCL19 and CCL21, decreased after the intake including both naïve CD45RA+ and central memory CD45RO+ T-cells. Similarly, naïve B-cells diminished with dasatinib. Finally, such changes in the migratory patterns did not occur in those patients whose lymphocyte counts remained unchanged after taking the drug. Discussion: We, therefore, conclude that lymphocytosis induced by dasatinib reflects a pronounced redistribution of naïve and memory populations of all lymphocyte subsets including CD4+ and CD8+ T-cells and B-cells.

A framework to analyse gender bias in epidemiological research.

The design and analysis of research may cause systematic gender dependent errors to be produced in results because of gender insensitivity or androcentrism. Gender bias in research could be defined as a systematically erroneous gender dependent approach related to social construct, which incorrectly regards women and men as similar/different. Most gender bias can be found in the context of discovery (development of hypotheses), but it has also been found in the context of justification (methodological process), which must be improved. In fact, one of the main effects of gender bias in research is partial or incorrect knowledge in the results, which are systematically different from the real values. This paper discusses some forms of conceptual and methodological bias that may affect women's health. It proposes a framework to analyse gender bias in the design and analysis of research carried out on women's and men's health problems, and on specific women's health issues. Using examples, the framework aims to show the different theoretical perspectives in a social or clinical research context where forms of selection, measurement and confounding bias are produced as a result of gender insensitivity. Finally, this paper underlines the importance of re-examining results so that they may be reinterpreted to produce new gender based knowledge.

The incorporation of comorbidities in the prognostication of patients with lower-risk myelodysplastic syndrome.

Chronic medical diseases, evaluated by several comorbidities indexes have been reported to influence on overall survival in patients with myelodysplastic syndrome (MDS). However, these studies included patients with lower and higher-risk disease by IPSS. This study retrospectively evaluates the role of comorbidities (evaluated by the MDS comorbidity index; MDS-CI) together with clinical parameters in a series of 232 patients with LR-MDS (defined as either an IPSS score of low/intermediate-1 and favorable cytogenetic categories by IPSS-R). In multivariate analysis, together with age >75 years, diabetes requiring therapy and hemoglobin <10 g/dL; the incorporation of comorbidities by the MDS-CI (HR = 2.5; p< 0.0001) were independently associated to the probability of nonleukemic death (NLD). The combination of these variables allowed development of a model, which categorizes patients in three different groups with significantly different probability of NLD overtime (p< 0.001). This integrated score confirms the importance of comorbidities at diagnosis of patients with LR-MDS.

Immunomodulatory Effect of Vitamin D after Allogeneic Stem Cell Transplantation: Results of a Prospective Multicenter Clinical Trial.

PURPOSE: We describe the results of a prospective multicenter phase I/II trial evaluating the impact of the use of vitamin D (VitD) from day -5 to +100 on the outcome of patients undergoing allogeneic transplantation (EudraCT: 2010-023279-25; ClinicalTrials.gov: NCT02600988). EXPERIMENTAL DESIGN: A total of 150 patients were included in three consecutive cohorts of 50 patients each group: control group (CG, not receive VitD); low-dose group (LdD, received 1,000 IU VitD daily); and high-dose group (HdD, 5,000 IU VitD daily). We measured levels of VitD, cytokines, and immune subpopulations after transplantation. RESULTS: No significant differences were observed in terms of cumulative incidence of overall and grades 2-4 acute GVHD in terms of relapse, nonrelapse mortality, and overall survival. However, a significantly lower cumulative incidence of both overall and moderate plus severe chronic GVHD (cGVHD) at 1 year was observed in LdD (37.5% and 19.5%, respectively) and HdD (42.4% and 27%, respectively) as compared with CG (67.5% and 44.7%, respectively; P < 0.05). In multivariable analysis, treatment with VitD significantly decreased the risk of both overall (for LdD: HR = 0.31, P = 0.002; for HdD: HR = 0.36, P = 0.006) and moderate plus severe cGVHD (for LdD: HR = 0.22, P = 0.001; for HdD: HR = 0.33, P = 0.01). VitD modified the immune response, decreasing the number of B cells and naïve CD8 T cells, with a lower expression of CD40L. CONCLUSIONS: This is the first prospective trial that analyzes the effect of VitD postransplant. We observed a significantly lower incidence of cGVHD among patients receiving VitD. Interestingly, VitD modified the immune response after allo-SCT. Clin Cancer Res; 22(23); 5673-81. ©2016 AACR.

Do all people with schizophrenia receive the same benefit from different family intervention programs?

The study evaluated baseline characteristics that could be used to predict the outcome of family intervention in schizophrenia and focussed on identifying the subgroups of patients who were more likely to respond to one therapeutic modality than another. We conducted a controlled trial in which participants were assigned at random to either a Behavioral Family Intervention Group or a Relatives' Group. Patients in one catchment area, having suffered one psychotic relapse within the previous year and living with their families, were assessed by an independent evaluator at baseline and 12 months later. Some clinical and family factors such as the duration of illness, number of hospital admissions and relatives' level of psychological distress can predict the differential outcome of either type of family intervention modality. The results suggested that the short-term illness group requires more intensive and personal intervention, while the long-term illness group needs more continuous support. Our results should be confirmed in a larger sample before clinical recommendations can be made.

Overexpression of GYS1, MIF, and MYC is associated with adverse outcome and poor response to azacitidine in myelodysplastic syndromes and acute myeloid leukemia.

BACKGROUND: The prognosis of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) is very heterogeneous. PATIENTS AND METHODS: We analyzed the prognostic value of several genes in a cohort of 85 MDS and AML patients. RESULTS: Overexpression of glycogen synthase 1 and macrophage migration inhibitory factor genes had an adverse outcome in multivariate analysis (P = .003 and P < .001, respectively). Furthermore, the higher expression of myelocytomatosis oncogene was associated with a lower response to azacitidine (P = .03). CONCLUSION: In the current study we identified a specific gene expression profile as prognostic factors for response to azacitidine and survival in MDS and AML.

[Gender and mental health in a changing world]. / Género y salud mental en un mundo cambiante.

It is well established that human psychological development, violence and sexual abuse, the experience of reproduction and parenting, as well as psychopathology and psychiatric morbidity are different for men and women, both in quality and quantity. In this chapter some of these differences, including disability and the use of services in the Spanish population are described and analysed. Whether there is a need for a new discipline to study psychiatric illness and psychiatric treatment from the point of view of gender is discussed. There has been a deep process of transformation of gender roles in our society. In our opinion this calls for new research efforts aimed at estimating the rates of prevalence and associated risk factors in men and women at present. The results of such research will probably lead to the formulation of new and more relevant hypotheses, and to the development of new research strategies and more valid and reliable measuring instruments.

Variables motivacionales y cognitivas predictivas del rendimiento en estudiantes universitarios de ciencias de la salud / Cognitive and Motivational Predictive Variables Associated with Performance in University Students of Health Sciences

Introducción: La motivación, el aprendizaje y la ejecución, presentan una relación recíproca según las últimas investigaciones en aprendizaje autorregulado. La motivación influye en el aprendizaje, los estudiantes organizan y elaboran mejor los materiales, se esfuerzan más, piden ayuda con más frecuencia y en definitiva están más comprometidos con la tarea académica. Por otro lado, la ejecución y lo que los estudiantes aprenden y realizan, puede, a su vez, aumentar o disminuir la motivación, a través de variables como la autoeficacia. Objetivo: Identificar qué variables motivacionales y cognitivas predicen el rendimiento académico y como lo hacen. Métodos: Se realizó un estudio descriptivo e inferencial con una muestra de 508 estudiantes de ciencias de la salud pertenecientes a dos universidades privadas españolas, a la que se evalúa a través del Motivated Strategies For Learning Questionnaire, la utilización de estrategias cognitivas, metacognitivas, de gestión de recursos y motivacionales; después, se realizó un modelo de regresión, tomando estas estrategias como variables independientes y el rendimiento medido a través de las notas de los estudiantes como variable dependiente. Resultados: La autoeficacia para el rendimiento fue la variable que mejor predijo el rendimiento académico en los estudiantes universitarios de la muestra. Otras variables que también se relacionaron con el rendimiento fueron la gestión del tiempo y el lugar, la búsqueda de ayuda y la meta de autoensalzamiento. Conclusiones: Los resultados académicos dependen de los métodos de evaluación, del uso de estrategias cognitivas, metacognitivas, y motivacionales adecuadas al contexto instruccional, y de una mejor gestión de los recursos de aprendizaje. Estos hallazgos nos orientan a los docentes a proponer intervenciones educativas dirigidas a aumentar el uso de estrategias motivacionales y de aprendizaje en estudiantes universitarios(AU)

Introduction: Motivation, learning and practice have a reciprocal relationship, according to latest research in self-regulated learning. Motivation influences learning, students organize and elaborate materials better, make greater effort, ask for help more frequently, and ultimately are more committed to the academic task. On the other hand, the execution and what students learn and do in practice, can in turn increase or decrease motivation, through variables such as self-efficacy. Objective: To establish what motivational and cognitive variables predict academic performance and how they do it. Methods: A descriptive and inferential study was carried out with a sample of 508 students of health sciences belonging to two Spanish private universities, which are evaluated, through an adapted Motivated Strategies for Learning Questionnaire, their usage of cognitive and metacognitive strategies, and others for resource management and associated with motivation. Later, we elaborated a regression model, taking these strategies as independent variables and the performance measured through the student's grades as a dependent variable. Results: Self-efficacy for performance was the variable that best predicted academic performance in the university students that made up the sample. Other variables that were also related to performance were the management of time and place, the search for help, and the goal of self-praise. Conclusions: The academic results depend on the evaluation methods, the use of cognitive, metacognitive, and motivational strategies appropriate to the instructional context, and on better management of learning resources. These findings guide teachers to propose educational interventions aimed at increasing the use of motivational and learning strategies in university students(AU)

Afrontamiento de la muerte en estudiantes de Ciencias de la Salud / Coping with death by students of Health Sciences

Introducción: La muerte es un proceso que está presente en la vida. Los estudiantes de Ciencias de la Salud están especialmente expuestos al mismo, así como al hecho de estar presentes y acompañar en el proceso de morir a los pacientes. Objetivos: Conocer los niveles de afrontamiento ante la muerte en estudiantes de Ciencias de la Salud. Conocer la influencia de otras variables tales como el género, edad, año académico, religión y experiencias previas ante la muerte en relación al afrontamiento de la muerte. Métodos: Se llevó a cabo un estudio descriptivo de corte transversal. La muestra estuvo compuesta por 227 estudiantes de la Universidad Alfonso X el Sabio (Madrid-España). Para medir el afrontamiento de la muerte se utilizó la Escala Bugen de Afrontamiento de la Muerte-EBAM. Resultados: Los estudiantes de enfermería presentaron mayores niveles de afrontamiento de la muerte que los estudiantes de farmacia y Actividad Física y Deporte. La prueba de Chi Cuadrado mostró que existía relación entre la titulación cursada y el nivel de afrontamiento de la muerte (p< 0,01). La t de student también constató que no existían diferencias estadísticamente significativas al considerar el Afrontamiento de la muerte y haber tenido experiencias previas con moribundos (p< 0,01). No se constató influencia del género, edad, año académico y religión con el nivel de afrontamiento. Conclusiones: De este estudio se deduce la necesidad de incluir en los planes formativos asignaturas que traten el proceso de la muerte de manera que se puedan manejar de forma adecuada aspectos psicológico-emocionales del profesional, cuestión que repercutirá en el aumento de la calidad asistencial(AU)

Introduction: Death is a process that is present in life. Health science students are particularly exposed to it, as well as to the fact of being present and accompanying dying patients in such process. Objectives: To know the levels of coping with death in students of health sciences. To know the influence of other variables such as gender, age, academic year, religion and previous experiences with death in association to coping with death. Methods: A descriptive, cross-sectional study was carried out. The sample consisted of 227 students from Alfonso X el Sabio University in Madrid, Spain. For measuring coping of death, Bugen's Coping with Death Scale was used. Results: Nursing students showed higher levels of coping with death than Pharmacy or Physical Activity and Sport students. The chi-square test showed a relation between the degree completed and the level of coping with death (p< 0,01). The Student's t-test also showed no statistically significant differences when considering coping with death together with having previous experiences with dying (p< 0,01). No influence of gender, age, academic year and religion was found in association with the level of coping. Conclusions: This study shows the need to include, in the syllabuses, subjects that treat the process of death, so that psychological-emotional aspects of the professional can be handled appropriately, as it is an issue that will have an impact on the increase in the quality of healthcare(AU)

Support groups and cardiac rehabilitation: effects of partner participation on anxiety and depression.

This study analyzes the effect on levels of patient anxiety and depression of a partner joining a cardiac rehabilitation program support group, also taking into account the sex of the patient. The study was undertaken using a two-group comparison design with pre-and post-test measures in non-equivalent groups. The sample comprised patients in the cardiac rehabilitation program (CRP) at the Ramón y Cajal Hospital, Madrid (Spain). Analysis of covariance (ANCOVA) showed direct effects of sex and partner participation in support groups on the anxiety trait. Similarly, interaction effects were observed between the sex variable and partner participation. These results indicate the pertinence of designing separate groups for patients and partners.

Patterns of infection in patients with myelodysplastic syndromes and acute myeloid leukemia receiving azacitidine as salvage therapy. Implications for primary antifungal prophylaxis.

Incidence, etiology, and outcome of infectious episodes in patients with myeloid neoplasms receiving azacitidine are uncertain, with no prospective data available in this group of patients. The aim of the current study was to analyze the incidence and factors related to the probability of infection in a cohort of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) treated with azacitidine who did not receive any type of antimicrobial prophylaxis. Significantly, the group of patients who received prior intensive chemotherapy had more infectious episodes (P = 10(-4)), and particularly, invasive aspergillosis (P = .015), than patients who received frontline azacitidine. Primary antifungal prophylaxis might be recommended in MDS and AML patients receiving azacitidine as salvage therapy after intensive regimens.