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Introduction: The use of psychotropic drugs in children and adolescents is widespread but associated with suboptimal treatment effects. Therapeutic drug monitoring (TDM) can improve safety of psychotropic drugs in children and adolescents but is not routinely performed. A major reason is that the relationship between drug concentrations and effects is not well known. Areas covered: This systematic review evaluated studies assessing the relationship between psychotropic drug concentrations and clinical outcomes in children and adolescents, including antipsychotics, psychostimulants, alpha-agonists, antidepressants, and mood-stabilizers. PRISMA guidelines were used and a quality assessment of the retrieved studies was performed. Sixty-seven eligible studies involving 24 psychotropic drugs were identified from 9,298 records. The findings were generally heterogeneous and the majority of all retrieved studies were not of sufficient quality. For 11 psychotropic drugs, a relationship between drug concentrations and side-effects and/or effectiveness was evidenced in reasonably reported and executed studies, but these findings were barely replicated. Expert opinion: In order to better support routine TDM in child- and adolescent psychiatry, future work must improve in aspects of study design, execution and reporting to demonstrate drug concentration-effect relationships. The quality criteria proposed in this work can guide future TDM research. Systematic review protocol and registration PROSPERO CRD42018084159.

Introduction Chile has an incipient policy regarding humanized birth practices. Obstetric violence is becoming an issue in the public discussion, as brought up by women. Despite this advancement, no initiatives were observed to overcome the conflict. Questions arise from the different points of view of the main stakeholders involved. These questions help identify strategies contributing to the development of health policies that consider influencing actors. Objectives To identify stakeholders' perceptions of humanized care in childbirth and obstetric violence. Methods We conducted a scoping review that included articles and analysis of texts reflecting the scientific communities' point of view. We included statements from governmental, social, professional, and political actors as expressed in institutional websites. Moreover, we performed a qualitative inductive, thematic content analysis. Results We included seventy documents. The scientific community is visualized as aligned with ministerial recommendations for personalized childbirth. Several researchers analyze the difficulties for its improvement due to the historical, socio-cultural, and economic construction of the predominantly biomedical model for birthing. Convergence is observed among the scientific community and other stakeholders in recognition of humanized birth benefits and the need to overcome institutional obstacles within the health sector. However, the progress of the proposed change is slow, and health professionals' resistance to address women's complaints towards obstetric violence and claim of quality care is observed. This discussion finds its reflection in a parliamentary discussion. Conclusions The stakeholders' analysis reflects areas of conflict and consensus, as well as the diverse interacting dimensions that hinder the advance of humanized care in childbirth. This broad analysis strategy contributes to identifying critical aspects to be addressed in the development of integral and effective health policies.

International audience; Post-transplantation lymphoproliferative disorder (PTLD) is a severe complication in organ transplant recipients. The use of T lymphocyte-depleting antibodies (TLDAb), especially rabbit TLDAb, contributes to PTLD, and the V158F polymorphism of Fc gamma receptor IIIA (FcγRIIIA) also named CD16A could affect the concentration–effect relationship of TLDAb. We therefore investigated the association of this polymorphism with PTLD in kidney transplant recipients. We characterized the V158F polymorphism in two case–control cohorts (discovery, n = 196; validation, n = 222). Then, we evaluated the binding of rabbit IgG to human FcγRIIIA-158V and FcγRIIIA-158F. The V158F polymorphism was not linked to PTLD in the overall cohorts, but risk of PTLD was increased in VV homozygous recipients receiving TLDAb compared with F carriers in both cohorts, especially in recipients receiving TLDAb without muromonab (discovery HR = 2.22 [1.03–4.76], P = 0.043, validation HR = 1.75 [1.01–3.13], P = 0.049). In vitro, we found that the binding of rabbit IgG to human NK-cell FcγRIIIA was increased when cells expressed the 158-V versus the 158-F allotype. While the 158-V allotype of human FcγRIIIA binds rabbit immunoglobulin-G with higher affinity, the risk of PTLD was increased in homozygous VV kidney transplant recipients receiving polyclonal TLDAb.

Aging is a physiological process accompanied by cognitive decline, principally in memory and executive functions. Alterations in the connectivity of the default mode network (DMN) have been found to participate in cognitive decline, as well as in several neurocognitive disorders. The DMN has antisynchronic activity with attentional networks (task-positive networks (TPN)), which are critical to executive function and memory. Findings pointing to the regulation of the DMN via activation of TPN suggest that it can be used as a strategy for neuroprotection. Meditation is a noninvasive and nonpharmacological technique proven to increase meta-awareness, a cognitive ability which involves the control of both networks. In this review, we discuss the possibility of facilitating healthy aging through the regulation of networks through meditation. We propose that by practicing specific types of meditation, cognitive decline could be slowed, promoting a healthy lifestyle, which may enhance the quality of life for the elderly.

Aim: To investigate the potential influence of variants in genes involved in the calcineurin pathway on the efficacy and toxicity of calcineurin inhibitors in renal transplantation. Materials & methods: Twenty-three polymorphisms in thirteen genes were tested in 381 renal transplant recipients receiving ciclosporin (n = 221) or tacrolimus (n = 160) and mycophenolate mofetil. Data were collected prospectively over the first year post-transplantation. Results: Multivariate survival analyses revealed no genetic associations with biopsy proven acute graft rejection and serious infections. Donor–recipient Cytomegalovirus mismatch was the only variable associated with serious infection. Conclusion: This large exploratory study casts doubts on the potential interest of genetic biomarkers related to CNI pharmacodynamics but associations with other phenotypes in transplantation deserve further studies.

The modulation of the immune system following solid organ transplantation has made considerable progress with new immunosuppressive regimens and has considerably improved rejections rates. The improvement in long-term allograft survival is, however, modest. A complex network of cytokines, chemokines, adhesion, activation and co-stimulatory molecules are the frontline contributors to allograft rejection, which in turn determines the evolution of graft function and its long-term survival. Polymorphisms in these genes influence protein levels and presumably their signaling effects. In this review, we present a relevant panel of candidate genes related to the immune system in the context of solid organ transplantation; we discuss the most convincing reports of genetic associations with outcomes in renal transplantation and highlight the most promising loci among the vast body of literature.

The placenta is a transitory organ, located between the mother and the foetus, which supports intrauterine life. This organ has nutritional, endocrine and immunologic functions to support foetal development. Several factors are related to the correct functioning of the placenta including foetal and maternal blood flow, appropriate nutrients, expression and function of receptors and transporters, and the morphology of the placenta itself. Placental morphology is crucial for understanding the pathophysiology of the organ as represents the physical structure where nutrient exchange occurs. In pathologies of pregnancy such as diabetes mellitus in humans and animal models, several changes in the placental morphology occur, related mainly with placental size, hypervascularization, higher branching capillaries of the villi and increased glycogen deposits among others. Gestational diabetes mellitus is associated with modifications in the structure of the human placenta including changes in the surface area and volume, as well as histological changes including an increased volume of intervillous space and terminal villi, syncytiotrophoblast number, fibrinoid areas, and glycogen deposits. These modifications may result in functional changes in this organ thus limiting the wellbeing of the developing foetus. This review gives an overview of recurrent morphological changes at macroscopic and histological levels seen in the placenta from gestational diabetes in humans and animal models. This article is part of a Special Issue entitled: Membrane Transporters and Receptors in Pregnancy Metabolic Complications edited by Luis Sobrevia.

In experimental studies, researchers apply an intervention to a group of study participants and analyze the effects over a future or prospective timeline. The prospective nature of these types of studies allows for the determination of causal relationships, but the interventions they are based on require rigorous bioethical evaluation, approval from an ethics committee, and registration of the study protocol prior to implementation. Experimental research includes clinical and preclinical testing of a novel intervention or therapy at different phases of development. The main objective of clinical trials is to evaluate an interventions efficacy and safety. Conventional clinical trials are blinded, randomized, and controlled, meaning that participants are randomly assigned to either the study intervention group or a comparator (a control group exposed to a placebo intervention or another non-placebo or active interventionor not exposed to any intervention) to reduce selection and confounding biases, and researchers are also unaware of the type of intervention being applied. Intention-to-treat analysis (inclusion of all originally randomized subjects) should be done to avoid the effects of attrition (dropout) and crossover (variance in the exposure or treatment over time). A quasi-experimental design and external controls may also be used. Metrics used to measure the magnitude of effects include relative risk, absolute and relative risk reductions, and numbers needed to treat and harm. Confounding factors are controlled by randomization. Other types of bias to consider are selection, performance, detection, and reporting. This review is the fifth of a methodological series on general concepts in biostatistics and clinical epidemiology developed by the Chair of Scientific Research Methodology at the School of Medicine, University of Valparaíso, Chile. It describes general theoretical concepts related to randomized clinical trials and other experimental studies in humans, including fundamental elements, historical development, bioethical issues, structure, design, association measures, biases, and reporting guidelines. Factors that should be considered in the execution and evaluation of a clinical trial are also covered.En los estudios experimentales, el investigador aplica una intervención sobre los participantes, por lo que su eje temporal es prospectivo. Estas características permiten probar relaciones causales, pero implican una rigurosa evaluación bioética y una inscripción previa del protocolo de estudio. Entre las investigaciones experimentales se encuentran los estudios preclínicos y diversos ensayos con objetivos distintos según la fase de desarrollo en que se encuentre. Entre ellos se incluyen los ensayos clínicos, cuyo objetivo principal es evaluar la eficacia y la seguridad de alguna intervención o terapia. El diseño convencional de ensayo clínico es aleatorizado controlado enmascarado, donde se asigna aleatoriamente a los participantes a una intervención y a sus comparadores (otra intervención, placebo o nada); lo que permite controlar el sesgo de selección y el de confusión. Asimismo, los participantes y los investigadores no conocen la intervención que fue asignada. El análisis de sus resultados debe considerar a todos los sujetos originalmente aleatorizados, lo que se conoce como análisis por intención de tratar. Otros tipos de estudios experimentales incluyen los estudios cuasiexperimentales y los estudios experimentales con controles externos. Las medidas de magnitud del efecto utilizadas son el riesgo relativo, las reducciones absolutas y relativas de riesgo y los números necesarios a tratar y dañar. Si bien los factores de confusión son controlados por el proceso de aleatorización, otros sesgos que hay que considerar son los de selección, desarrollo, detección, desgaste y reporte. En este artículo, se abordan los conceptos teóricos generales sobre los estudios experimentales en seres humanos, fundamentalmente sobre los ensayos clínicos aleatorizados, considerando sus elementos fundamentales, desarrollo histórico, aspectos bioéticos, construcción, variantes en el diseño, medidas de asociación, sesgos y pautas de reporte. Finalmente, se sintetizan algunas consideraciones que siempre hay que tener en mente durante la ejecución y la evaluación de un ensayo clínico. Esta revisión es la quinta entrega de una serie metodológica sobre conceptos generales en bioestadística y epidemiologia clínica desarrollada por la Cátedra de Metodología de la Investigación Científica de la Escuela de Medicina de la Universidad de Valparaíso, Chile.

Observational studies evaluate variables of interest in a sample or a population, without intervening in them. They can be descriptive if they focus on the description of variables, or analytical when comparison between groups is made to establish associations through statistical inference. Cross-sectional studies and ecologicalalso called correlationalstudies are two observational methodological designs. Cross-sectional studies collect the data of the exposure variable and the outcome at the same time, to describe characteristics of the sample or to study associations. Ecological studies describe and analyze correlations among different variables, and the unit of analysis is aggregated data from multiple individuals. In both types of studies, associations of interest for biomedical research can be established, but no causal relationships should be inferred. This is the second of a methodological series of articles on general concepts in biostatistics and clinical epidemiology developed by the Chair of Scientific Research Methodology at the School of Medicine, University of Valparaíso, Chile. In this review, we address general theoretical concepts about cross-sectional and ecological studies, including applications, measures of association, advantages, disadvantages, and reporting guidelines. Finally, we discuss some concepts about observational designs relevant to undergraduate and graduate students of health sciences.Los estudios observacionales analizan las variables de interés en la muestra o en la población, sin intervenir en ellas. Pueden ser meramente descriptivos si se focalizan en la descripción de las variables, o analíticos, en el caso de presentar grupos de comparación para establecer asociaciones mediante la inferencia estadística. Los estudios transversales y los estudios ecológicos, también llamados correlacionales, son dos diseños metodológicos observacionales. Los estudios transversales recogen los datos de la variable exposición y desenlace en un mismo momento, para describir sus características y eventualmente estudiar asociaciones. Los estudios ecológicos describen y analizan las correlaciones entre distintas variables, pero su unidad de análisis corresponde a datos agregados de múltiples individuos. En ambos casos no puede inferirse una relación causal, pero sí pueden establecerse asociaciones de gran interés para la investigación biomédica. Esta revisión es la segunda entrega de una serie metodológica sobre conceptos generales en bioestadística y epidemiología clínica desarrollada por la Cátedra de Metodología de la Investigación Científica de la Escuela de Medicina de la Universidad de Valparaíso, Chile. En este artículo se abordan conceptos teóricos generales sobre estudios transversales y estudios ecológicos, considerando sus aplicaciones, medidas de asociación, ventajas, desventajas y reporte. Finalmente, se discuten algunos conceptos de relevancia sobre diseños observacionales para los estudiantes de pre y posgrado de ciencias de la salud.

Interindividual variability in immunosuppressive drug responses might be partly explained by genetic variants in proteins involved in the immune response or associated with IS pharmacodynamics. On a general basis, the pharmacogenetics of drug target proteins is less known and understood than that of proteins involved in drug disposition pathways. The aim of this review is to facilitate research related to the pharmacodynamics of the main immunosuppressive drugs used in solid organ transplantation. We elaborated a quality of evidence grading system based on a literature review and identified ‘highly recommended’, ‘recommended’ or ‘potential’ candidates for further research. It is likely that a number of additional rare variants might further explain drug response phenotypes in transplantation, and particularly the most severe ones. The advent of next-generation sequencing will help to identify those variants.

Voriconazole (VCZ) use is limited by its narrow therapeutic range and significant interpatient variability in exposure. This study aimed to assess (i) the impact of CYP2C19 genotype on VCZ exposure and (ii) the doses required to achieve the therapeutic range in adult patients with invasive fungal infections (IFIs). Therapeutic drug monitoring (TDM) of VCZ, based on trough concentration measurement, and CYP2C19 genotyping were used to guide VCZ dosing in Caucasian patients with IFIs. The two common polymorphisms in Caucasians (CYP2C19*2 and *17), associated with decreased or increased CYP2C19 activity, respectively, were correlated with the daily VCZ dose, pharmacokinetic parameters and concentration-to-dose ratio. In total, 111 trough concentration measurements from 35 genotyped patients were analysed using linear mixed-effect models. The mean VCZ doses required to achieve target concentrations were significantly higher in CYP2C19*17 carriers compared with CYP2C19*1/*1 individuals (P

International audience; Post-transplant lymphoproliferative disorders (PTLDs) represent a serious complication in solid organ transplantation and are the first cause of cancer related mortality in this population. Pre-transplant Epstein Barr Virus seronegativity and receipt of T cell depleting agents for induction or severe/refractory rejection are known risk factors, but they primarily impact early occurring disease. On the other hand, late occurring disease, which has typically not correlated with the above or other specific risk factors, has recently been shown to be associated with older recipient age and prolonged receipt of calcineurin inhibitors. Furthermore, recent data has contributed to and, in some instances shed light on, previous debate concerning the role of viruses other than EBV and the level of HLA mismatches as risk factors for PTLD. Gene association studies focusing on key cytokines and their receptors have identified several polymorphisms that may prove useful to identify patients at risk, with distinction for early and late occurring disease. Determining the influence of individual maintenance immunosuppressive agents on lymphomagenesis has been limited by the complexity of the multi-drug regimens used and absence of measures of drug exposure and time-dependent covariates in multivariable analyses. Biomarkers that measure the extent of immunosupression may have a role in avoiding PTLD, and other post-transplant complications.