Role of 3.0 T multiparametric MRI in local staging in prostate cancer and clinical implications for radiation oncology.

PURPOSE: To evaluate the accuracy of preoperative 3T multiparametric magnetic resonance imaging (3TmMRI) for local staging of prostate cancer and its influence on the decision to change the clinical target volume (CTV), total dose and hormonal therapy when treating prostate cancer patients with radiotherapy. METHODS: From 2009 to 2013, 150 patients, who had confirmed prostate cancer and underwent a 3TmMRI before treatment with radical prostatectomy or radical radiation therapy, were included. Radiation therapy treatment (CTV, total dose and hormonal therapy) was initially determined on the basis of the clinical information, and radiation therapy plan was reevaluated after 3TmMRI review. The value of preoperative 3TmMRI in local staging and in the decision of radiotherapy treatment according to NCCN risk classification was analyzed. RESULTS: 3TmMRI performed correct, over- and under staging in 78.7 % (37/47), 6.3 % (3/47), 14.8 % patients (7/47), respectively. 3TmMRI identified 6 cT2a, 7 cT2b, 28 cT2c, 3 cT3a, 3 cT3b tumors. At final pathology, 5 tumors were classified as pT2a, 5 as pT2b, 30 as pT2c, 4 as pT3a, 3 as pT3b. After reviewing the MRI reports, the initial radiotherapy and hormonal therapy plan was changed in 33.9 % patients (35/103). CONCLUSIONS: In our group of patients, 3TmMRI has been a reliable technique providing an optimal staging for prostate cancer. Its routine use could induce important changes in radiation therapy treatments in a significant number of such patients. However, more additional studies are needed to clarify this issue.

Maternal care interacts with prenatal stress in altering sexual dimorphism in male rats.

The present study analyzes the interaction between prenatal stress and mother's behavior on brain, hormonal, and behavioral development of male offspring in rats. It extends to males our previous findings, in females, that maternal care can alter behavioral dimorphism that becomes evident in the neonates when they mature. Experiment 1 compares the maternal behavior of foster mothers toward cross-fostered pups versus mothers rearing their own litters. Experiment 2 ascertains the induced "maternal" behavior of the male pups, derived from Experiment 1 when they reached maturity. The most striking effect was that the males non-exposed to the stress as fetuses and raised by stressed foster mothers showed the highest levels of "maternal" behavior of all the groups (i.e., induction of maternal behavior and retrieving behavior), not differing from the control, unstressed, female groups. Furthermore, those males showed significantly fewer olfactory bulb mitral cells than the control males that were non-stressed as fetuses and raised by their own non-stressed mothers. They also presented the lowest levels of plasma testosterone of all the male groups. The present findings provide evidence that prenatal environmental stress can "demasculinize" the behavior, brain anatomy and hormone secretion in the male fetuses expressed when they reach maturity. Moreover, the nature of the maternal care received by neonates can affect the behavior and physiology that they express at maturity.

Systematic review and meta-analysis of vagus nerve stimulation in the treatment of depression: variable results based on study designs.

PURPOSE: To determine the efficacy of vagus nerve stimulation (VNS) for treatment of depression. METHODS: We conducted a systematic review and meta-analysis of analytical studies. Efficacy was evaluated according to severity of illness and percentage of responders. RESULTS: We identified 687 references. Of these, 14 met the selection criteria and were included in the review. The meta-analysis of efficacy for uncontrolled studies showed a significant reduction in scores at the Hamilton Depression Rating Scale endpoint, and the percentage of responders was 31.8% ([23.2% to 41.8%], P<0.001). However, the randomised control trial which covered a sample of 235 patients with depression, reported no statistically significant differences between the active intervention and placebo groups (OR=1.61 [95%CI 0.72 to 3.62]; P=0.25). To study the cause of this heterogeneity, a meta-regression was performed. The adjusted coefficient of determination (R2(Adj)) was 0.84, which implies that an 84% variation in effect size across the studies was explained by baseline severity of depression (P<0.0001). CONCLUSION: Currently, insufficient data are available to describe VNS as effective in the treatment of depression. In addition, it cannot be ruled out that the positive results observed in the uncontrolled studies might have been mainly due to a placebo effect.

Maternal care counteracts behavioral effects of prenatal environmental stress in female rats.

There is extensive evidence in rats that prenatal environmental stress (PES) exposure and early postnatal altered maternal care, as a consequence of stress during gestation, can detrimentally affect the brain and behavioral development of the offspring. In order to separate the effect of PES on the fetuses from that on the behavior of the mother, in the present study, we used a cross-fostering procedure in which PES-fetuses were raised by non-stressed mothers and non PES-fetuses were raised by stressed mothers. In Experiment 1, non-stressed mothers showed significantly more maternal behavior than stressed mothers. In Experiment 2, when the female offspring from Experiment 1 reached maturity, they were tested for: (1) induced maternal behavior (MB), (2) plasma levels of corticosterone (Cpd B), progesterone (P), and estradiol (E(2)), (3) number of accessory olfactory bulb (AOB) mitral cells, and (4) c-fos expression measured in AOB and medial preoptic area (MPOA) neurons. We replicated our previous findings that the PES group reared by their own stressed mothers, when adult, attacked the young, expressed disorganized MB and showed altered Cpd B, P and E(2) levels, plus a male-like neuro-morphological pattern in the AOB, by comparison with the non-PES group, reared by their own non-stressed mothers. By contrast, when adult, the PES group reared by non-stressed mothers showed hormonal and morphological neuronal alterations, but they displayed appropriate (full) MB. The non-PES group raised by stressed mothers also showed altered hormone levels, but showed full MB and no morphological neuronal changes. Significant differences in the AOB and MPOA c-fos activity, related to whether or not MB was expressed, were found in the non-PES groups, but not in the PES group reared by non-stressed mothers. To our knowledge, this is the first study to document that adequate maternal care, early in development, can shape the subsequent expression of induced MB, overcoming neuro-morphological and hormonal alterations that are produced by prenatal environmental stress. We conclude that maternal care during early postnatal development can counteract detrimental effects of prenatal environmental stress, exerting long-lasting effects that modulate the behavioral phenotype of the offspring.

Curso de introducción a la investigación clínica. Capítulo 7: Estadística: Estadística Descriptiva y Estadística Inferencial / Introduction course to clinical research. Chapter 7: Statistics: descriptive and inferential statistics

La estadística estudia los métodos científicos para recoger, organizar, resumir y analizar datos, permite obtener conclusiones válidas y tomar decisiones razonables basadas en el análisis. La estadística es, por tanto, la ciencia que recoge, clasifica y analiza la información que se presenta habitualmente mediante datos agregados que permiten que las observaciones puedan cuantificarse, medirse, estimarse y compararse utilizando medidas de tendencia central, medidas de distribución, métodos gráficos, etc. La estadística aplicada trata sobre cómo y cuándo utilizar los procedimientos matemáticos (estadística matemática) y cómo interpretar los resultados que se obtienen. Así, la bioestadística es la rama de la estadística que enseña y ayuda a investigar en todas las áreas de las ciencias de la vida donde la variabilidad es la regla. Se divide en dos grandes ramas, la bioestadística descriptiva y la bioestadística analítica o inferencial. La estadística descriptiva resume la información contenida en los datos recogidos y la estadística inferencial demuestra asociaciones y permite hacer comparaciones entre características observadas

Statistics is the study of the scientific methods for collecting, organizing, summarizing, and analyzing data; it makes it possible to reach valid conclusions and make reasonable decisions on the basis of the analysis. Statistics is, therefore, the science of gathering, classifying, and analyzing information that is usually presented through aggregated data that enable observations to be quantified, measured, estimated, and compared using measurements of central tendency, measurements of distribution, graphical methods... Applied statistics deals with how and when to use the mathematical procedures (mathematical statistics) and how to interpret the results that are obtained using these procedures. Likewise, biostatistics is the branch of statistics that teaches and helps the investigator to carry out research in all of the different branches of the life sciences where variability is the rule. Biostatistics can be divided into two main areas: descriptive biostatistics and analytical or inferential statistics. Descriptive statistics summarizes the information contained in the data collected and inferential statistics demonstrates associations and makes it possible to make comparisons among the characteristics observed

Curso de introducción a la investigación clínica. Capítulo 5: Selección de la muestra: técnicas de muestreo y tamaño muestral / Introduction course to clinical research. Chapter 5: Sample selection: sampling techniques and sample size

Para realizar un proyecto de investigación debemos obtener datos de la población objetivo, que se define como el conjunto de elementos del cual se quiere conocer cierto aspecto. En algunos estudios cada elemento de la población puede ser medido realmente, lo cual es posible solamente si la población no es muy numerosa y si todos los elementos son accesibles. Pero lo habitual es que el estudio completo de la población sea inviable, ya que el trabajo empírico necesario es costoso e implica mucho tiempo y recursos. Para obtener resultados confiables no es necesario obtener los datos de todos los elementos poblacionales, es suficiente recoger las variables de un subconjunto de elementos denominado muestra. El estudio tendrá la validez y la fiabilidad necesarias si este subconjunto es representativo de la población objetivo y los resultados obtenidos son extrapolables a la misma. Existen distintas técnicas o procedimientos para seleccionar la muestra, dependiendo del tiempo, de los recursos económicos y de la naturaleza de los elementos poblacionales. El conjunto de estas técnicas se denomina muestreo. En el diseño del estudio se debe definir el tamaño muestral necesario; su cálculo está relacionado con ciertos problemas que estudia la Inferencia Estadística y que permitirán extraer conclusiones científicamente válidas a la población

To carry out a research project it is necessary to obtain data from the target population, which is defined as the set of elements about which we aim to find out a certain aspect. In some studies, this aspect can be directly measured in each element of the population; however, this is only possible if the population is not very large and if all of the elements are accessible. In the vast majority of cases, it is not viable to study the entire population because the empirical work necessary is expensive and involves much time and resources. To obtain reliable results, it is not necessary to obtain all of the data from all of the elements of the population; it is sufficient to collect the variables in a subgroup of elements called the sample. Unless this subgroup is representative of the target population, the results of the study cannot be extrapolated and will not be valid or reliable for the target population as a whole. There are different techniques or procedures to select the sample, depending on the time and financial resources available, as well as the nature of the elements of the population. This set of techniques is called sampling. When designing a study, it is necessary to define the necessary sample size, which involves certain problems studied by Inferential Statistics and will enable scientifically valid conclusions to be reached regarding the population

Curso de introducción a la investigación clínica. Capítulo 4: El ensayo clínico. Metodología de calidad y bioética / Introduction course to clinical research. Chapter 4: The clinical trial. Quality and bioethical methodology

Los estudios analíticos permiten estudiar y verificar hipótesis causales, y los ensayos clínicos, en particular, aportan el mayor nivel de evidencia en la comprobación de estas hipótesis. Un ensayo clínico aleatorio (ECA) es un experimento planificado en el que, de forma prospectiva, se comparan dos o más intervenciones preventivas, curativas o rehabilitadoras, que son asignadas de forma individualizada y aleatoria a un grupo de pacientes para estudiar el efecto de estas intervenciones en el hombre. Para su realización es necesario tener en cuenta una serie de aspectos metodológicos, como la elección de la muestra de sujetos a partir de unos adecuados criterios de selección, asignación aleatoria de los sujetos a los diferentes grupos de intervención, elección del grupo control, enmascaramiento o cegamiento de algunos o todos los sujetos que intervienen en el estudio, y descripción de pérdidas y abandonos para un correcto análisis de los datos. Las características de este tipo de estudios, realizados sobre humanos, implican la necesidad del cumplimiento de unos requisitos éticos y legales que protejan a los participantes, motivo por el cual es imprescindible la obtención de un consentimiento informado, así como el informe favorable de un Comité Ético de Investigación Clínica para su realización

Analytic studies make it possible to study and verify causal hypotheses and clinical studies, specifically contribute the greatest level of evidence in the verification of these hypothesis. A randomized clinical trial (RCT) is a planned experiment in which two or more preventive, curative or rehabilitating interventions, assigned in an individualized and random way to a group of patients to study the effect of these interventions in man, are compared. To do so, a series of methodological aspects must be taken into account, such as the choice of the subject sample based on adequate screening criteria, random allotment of the subjects to the different intervention groups, choice of the control group, masking or blinding of some or all the subjects participating in the study and description of losses and drop-outs for correct analysis of the data. The characteristics of the type of study, conducted in humans, imply the need for the fulfillment of some ethical and legal requirements that protect the participants, reason why it is essential to obtain an informed consent and favorable report from the Ethics Committee for its conduction

Curso de introducción a la Investigación Clínica. Capítulo 3: La investigación a partir de la observación. Estudios descriptivos. Estudios analíticos / Introduction course to Clinical Research. Chapter 3: Research based on observation. Descriptive studies. Analytic studies

El diseño de un estudio consiste en un conjunto de procedimientos, métodos y técnicas mediante las cuales el investigador selecciona la variable respuesta, define los criterios de selección de la población en estudio, calcula el número de sujetos necesarios en la(s) muestra(s) y selecciona las variables que deben medirse, con el objetivo de estimar la magnitud del efecto o de la respuesta observada, controlar los factores de confusión e interpretar los resultados. La elección del tipo de diseño dependerá fundamentalmente del objetivo del estudio, de las hipótesis planteadas y de los recursos de los que disponga el grupo de investigación. Los estudios descriptivos permiten analizar cómo son y cómo se manifiestan los fenómenos de salud y permiten al investigador detallar las características más importantes de la enfermedad o del evento en estudio. Por el contrario, los estudios analíticos pretenden encontrar las causas que ocasionan esos fenómenos y estudian la relación entre diferentes variables, generalmente entre una causa y un efecto

The design of the study consists in a combination of procedures, methods and techniques by which the investigator selects the response variable, defines study population selection criteria, calculates the number of subjects needed in this sample(s) and selects the variables that should be measured in order to estimate the magnitude of the effect or of the response observed, to control confounding factors and interpret the results. The choice of the type of design will basically depend on the study objectives, and the hypotheses proposed and on the resources that the research group has. Descriptive studies make it possible to analyze how the health phenomena are manifested and what they are and make it possible for the investigator to detail the most important characteristics of the disease or event under study. On the contrary, analytic studies aim to find the causes of these phenomena and studied the relationship between different variables, generally between a cause and effect

Capítulo 1: Formulación de la pregunta de investigación / Chapter 1: Formulating the research question

La investigación clínica o aplicada, es un proceso cuyo objetivo es resolver cuestiones planteadas en cada una de las etapas del proceso asistencial para poder mejorar tanto la práctica clínica diaria, como la calidad de la atención prestada a los pacientes. El punto de partida de todo proceso de investigación es el planteamiento de una incertidumbre, que toma forma mediante la formulación de una pregunta de investigación. Ésta permitirá el desarrollo de una estrategia científica y un protocolo de trabajo que nos conducirán a resolver nuestra incertidumbre inicial. Las cuestiones suelen surgir en tres escenarios principales: para sustituir o mejorar actuaciones o intervenciones de la práctica asistencial diaria, ante la existencia de lagunas de conocimiento, o en el campo de la docencia. Para formular una pregunta correctamente es necesario que reúna una serie de características en cuanto a estructura y a contenido; debe estar correctamente operativizada, de tal modo que en su estructura ha de contener la información necesaria que permita definir y diferenciar el tipo de pacientes y/ o patología a estudiar, la intervención que vamos a realizar, si se trata de un estudio de intervención y las medidas de resultado que deseamos conocer. Para la obtención de resultados útiles es deseable, además, reunir las características de factibilidad, interés, novedad y relevancia. Una pregunta bien formulada ayudará al desarrollo de otras etapas del proceso de investigación, y además, facilitará la obtención de resultados ajustados a nuestra cuestión inicial y el posterior manejo de éstos, tanto para la realización de investigaciones secundarias, como para satisfacer adecuadamente las necesidades individuales de conocimiento

Clinical or applied research is a procedure whose objective is to resolve questions established on each one of the stages of the care procedure to be able to improve both the daily clinical practice and quality of care given to the patients. The starting point of all research procedures is the statement of an uncertainty that is formed by formulating a research question. This allows for the development of a scientific strategy and work protocol that will lead us to solve our initial uncertainty. The questions generally arise on three main scenarios: to substitute or improve actions or interventions of the daily care practice when there are knowledge gaps or in the teaching field. To formulate a question correctly, a series of characteristics on structure and content must be gathered. The question should be correctly made operative so that its structure should contain the information necessary to make it possible to define and differentiate the type of patients and/or disease to be studied, the intervention that we are going to conduct if this is an intervention study and the measurements of the outcome that we want to know. To obtain useful results it is also desirable to gather the characteristics of feasibility, interest, novelty and relevance. A well-formulated question will help to develop other research procedure stages and will also facilitate the obtaining of results adapted to our initial question and the subsequent management of these results for both the conduction of secondary investigations and to adequately satisfy the individuals needs of knowledge

Olanzapine orally-disintegrating tablet in severe psychotic agitation: a naturalistic study.

INTRODUCTION: This study was conducted to determine effectiveness and safety of olanzapine in patients with severe agitation. METHOD: A naturalistic, open-label study in 80 acutely agitated psychotic patients visited in our psychiatric emergency department. Patients received either a 20-mg olanzapine orally-disintegrating tablet or conventional treatment depending on attending psychiatrist's preference. Efficacy was assessed by the Excitement Component of the Positive and Negative Syndrome Scale (PANSS-EC), the Agitation-Calmness Evaluation Scale (ACES) and pragmatic variables (second pharmacological intervention and need for physical restraints). RESULTS: 60 % patients completed a 6 hour trial. Both groups showed a significant reduction in mean PANSS-EC score. The olanzapine-treated group showed statistically significant improvements: PANSS-EC (F=122.9; df=2.4; p=0.000), ACES (F=68.2; df=2.8; p=0.000). Treatment was well-tolerated and no serious side-effects were observed. CONCLUSIONS: In this naturalistic study in patients with severe agitation, 20-mg oral olanzapine was effective, rapid and safe.

Transcranial magnetic stimulation for the treatment of obsessive-compulsive disorder.

BACKGROUND: Transcranial magnetic stimulation (TMS) was introduced as a neurophysiological technique in 1985 when Anthony Barker and his team developed a compact machine that permitted non-invasive stimulation of the cerebral cortex (Barker 1985). Since its introduction, TMS has been used to evaluate the motor system, to study the function of several cerebral regions, and for the pathophysiology of several neuropsychiatric illnesses. In addition, it has been suggested that TMS might have therapeutic potential. Some controlled studies have evaluated the effects of repetitive TMS (rTMS) in patients with obsessive-compulsive disorder (OCD). Greenberg (Greenberg 1997) observed that a single session of right prefrontal cortex stimulation produced a significant decrease in compulsive urges in OCD patients lasting over eight hours. Other studies have reported transitory improvements in mood but there are no observations for changes in anxiety or obsessions. OBJECTIVES: To develop a systematic review on the clinical efficacy and safety of transcranial magnetic stimulation from randomised controlled trials in the treatment of obsessive-compulsive disorder. SEARCH STRATEGY: An electronic search was performed including the Cochrane Collaboration Depression, Anxiety and Neurosis Review Group trials register (last searched June, 2002), the Cochrane Controlled Trials Register (Issue 2, 2002), MEDLINE (1966-2002), EMBASE (1974-2002), PsycLIT (1980-2002), and bibliographies from reviewed articles. SELECTION CRITERIA: Randomised controlled trials assessing the therapeutic efficacy and safety of transcranial magnetic stimulation for obsessive-compulsive disorder. DATA COLLECTION AND ANALYSIS: All reviewers independently extracted the information and verified it by cross-checking. Disagreements were resolved through discussion. MAIN RESULTS: Three trials were included in the review and only two contained data in a suitable form for quantitative analysis. It was not possible to pool any results for a meta-analysis. No difference was seen between rTMS and sham TMS using the Yale-Brown Obsessive-Compulsive Scale or the Hamilton Depression Rating Scale for all time periods analysed. REVIEWER'S CONCLUSIONS: There are currently insufficient data from randomised controlled trials to draw any conclusions about the efficacy of transcranial magnetic stimulation in the treatment of obsessive-compulsive disorder.