Molecular organization of the human serotonin transporter at the air/water interface

AbstractThe serotonin transporter (SERT) is the target of several important antidepressant and psychostimulant drugs. It has been shown that under defined conditions, the transporter spread at the air/water interface was able to bind its specific ligands. In this paper, the interfacial organization of the protein has been assessed from dynamic surface pressure and ellipsometric measurements. For areas comprising between 10 400 and 7100 Å2/molecule, ellipsometric measurements reveal an important change in the thickness of the SERT film. This change was attributed to the reorientation of the transporter molecules from a horizontal to their natural predictive transmembrane orientation. The thickness of the SERT film at 7100 Å2/molecule was found to be approximately equal to 84 Å and coincided well with the theoretical value estimated from the calculations based on the dimensions of α-helices containing membrane proteins. These data suggest that the three-dimensional arrangement of the SERT may be represented as a box with lengths dz=83–85 Å and dy or dx=41–47 Å

Reducing the burden of hypoglycaemia in people with diabetes through increased understanding:design of the Hypoglycaemia Redefining Solutions for Better Lives (Hypo-RESOLVE) project

Background Hypoglycaemia is the most frequent complication of treatment with insulin or insulin secretagogues in people with diabetes. Severe hypoglycaemia, i.e. an event requiring external help because of cognitive dysfunction, is associated with a higher risk of adverse cardiovascular outcomes and all‐cause mortality, but underlying mechanism(s) are poorly understood. There is also a gap in the understanding of the clinical, psychological and health economic impact of ‘non‐severe’ hypoglycaemia and the glucose level below which hypoglycaemia causes harm. Aim To increase understanding of hypoglycaemia by addressing the above issues over a 4‐year period. Methods Hypo‐RESOLVE is structured across eight work packages, each with a distinct focus. We will construct a large, sustainable database including hypoglycaemia data from >100 clinical trials to examine predictors of hypoglycaemia and establish glucose threshold(s) below which hypoglycaemia constitutes a risk for adverse biomedical and psychological outcomes, and increases healthcare costs. We will also investigate the mechanism(s) underlying the antecedents and consequences of hypoglycaemia, the significance of glucose sensor‐detected hypoglycaemia, the impact of hypoglycaemia in families, and the costs of hypoglycaemia for healthcare systems. Results The outcomes of Hypo‐RESOLVE will inform evidence‐based definitions regarding the classification of hypoglycaemia in diabetes for use in daily clinical practice, future clinical trials and as a benchmark for comparing glucose‐lowering interventions and strategies across trials. Stakeholders will be engaged to achieve broadly adopted agreement. Conclusion Hypo‐RESOLVE will advance our understanding and refine the classification of hypoglycaemia, with the ultimate aim being to alleviate the burden and consequences of hypoglycaemia in people with diabetes

Competencias Investigativas del Docente Construidas durante la Formación Universitaria

The university at this time, is the ideal context for encounters and exchange of knowledge, mediated by outgoing logics and worldviews, seeking their belief and social significance. This scientific article is based on the positivist paradigm, with a quantitative approach. Its general objective is to create methodological principles concerning the investigative competences of the teacher, built during their university education. Supported by theoretical references such as those of Gallardo (2003); Ordóñez (2017), among others. The methodology is descriptive, supported by a field design, where a study will be applied for teachers assigned to the University of Los Andes, University Nucleus "Rafael Rangel" (ULA-NURR), Trujillo State. In accordance with the approaches investigated in the article, it is concluded that it is expected that students at the time of producing knowledge in the research process are able to establish relationships of connection between theory and practice. In addition, in the performance of its investigative actions the student must acquire new knowledge for an efficient development of the investigative competences and thus be able to generate scientific productions in favor of the society of the environment to which they belong.La universidad en este momento, se constituye como el contexto propicio para encuentros e intercambio de saberes, mediados por lógicas y cosmovisiones salientes, que buscan su creencia y significación social. Este artículo científico es sustentado en el paradigma positivista, con enfoque cuantitativo. Tiene como objetivo general, crear principios metodológicos referentes a las competencias investigativas del docente, construidas durante su formación universitaria. Apoyada con referentes teóricos como los de Gallardo (2003); Ordóñez (2017), entre otros. La metodología es de tipo descriptiva, apoyada en un diseño de campo, donde se aplicará un estudio para docentes adscritos a la Universidad de Los Andes, Núcleo Universitario “Rafael Rangel” (ULA-NURR), estado Trujillo. De acuerdo con los planteamientos investigados en el artículo, se concluye que es de esperar que los estudiantes al momento de producir conocimiento en el proceso investigativo sean capaces de establecer relaciones de conexión entre teoría y práctica. Además, en el desempeño de su accionar investigador el estudiante deberá adquirir nuevos conocimientos para un eficiente desarrollo de las competencias investigativas y así puedan generar producciones científicas en pro de la sociedad del entorno al que pertenezcan

Las Prácticas Profesionales como Escenario de Aprendizaje para Desarrollar Procesos Cognitivos de Alto Nivel

The aim of this essay is to analyze the high level cognitive processes that intervene in the teaching of students of professional practices. The study was addressed, where the essayist includes theories of interest analyzed in a referential, practical and reflective manner on the subject. Making use of the analytical knowledge proposed by Carr and Kemmis (1986); and Tallaferro (2006). In a conclusive way, it is highlighted: professional practices as a learning space come to allow acquiring and developing skills in the profession based on "know-how" and must be done throughout the career to achieve the desired scope; Negative compendiums are observed more than positive ones, diminishing expectations in the later work as a teacher, the teacher transmits more information, than effective empowerment in cognitive terms, able to admit students to highlight cognitive difficulties and solve problems, in the everydayness.El ensayo mostrado presenta como objetivo, analizar los procesos cognitivos de alto nivel, que intervienen en la enseñanza de los estudiantes de prácticas profesionales. El estudio fue abordado, donde el ensayista incluye teorías de interés analizadas de forma referencial, práctica y reflexiva sobre el tema. Haciendo uso de los conocimientos analíticos planteados por Carr y Kemmis (1986); y Tallaferro (2006). De manera conclusiva, se resalta: las prácticas profesionales como espacio de aprendizaje llegan a permitir adquirir y desarrollar habilidades en la profesión sustentadas en el “saber hacer” y debe hacerse durante toda la carrera para lograr el alcance deseado; se observan más los compendios negativos que los positivos, disminuyendo expectativas en el posterior trabajo como enseñante, el profesor transmite más información, que el potenciamiento eficaz en los términos cognitivos, capaces de admitir en los estudiantes el resaltar dificultades cognitivas y resolver problemas, en la cotidianidad

The cost of treating diabetic ketoacidosis in the UK: a national survey of hospital resource use

Aims: Diabetic ketoacidosis (DKA) is a commonly encountered metabolic emergency. In 2014 a national survey was conducted looking at the management of DKA in adult patients across the UK. The survey reported the clinical management of individual patients as well as institutional factors that teams felt were important in helping to deliver that care. However, costs of treating DKA were not reported. Methods: We used a ‘bottom up’ approach to cost analysis to determine the total expense associated with treating DKA in a mixed population sample. The data were derived from the source data from the national UK survey of 283 individual patients collected via questionnaires sent to hospitals across the country. Results: Because the initial survey collection tool was not designed with a health economic model in mind, several assumptions were made when analysing the data. The mean and median time in hospital was 5.6 and 2.7 days, respectively. Based on the individual patient data and using the Joint British Diabetes Societies Inpatient Care Group guidelines, the cost analysis shows that for this cohort, the average cost for an episode of DKA was £2064 per patient (95% CI: £1800, 2563). Conclusion: Despite relatively short stays in hospital, costs for managing episodes of DKA in adults were relatively high. Assumptions made in calculations did not take into account prolonged hospital stay due to co-morbidities nor costs incurred as a loss of productivity. Therefore the actual costs to the healthcare system and society in general are likely to be substantially higher

The Real-World Observational Prospective Study of Health Outcomes with Dulaglutide and Liraglutide in Type 2 Diabetes Patients (TROPHIES): Baseline Patient-Reported Outcomes

Introduction: Although patient-reported outcome (PRO) measures provide important information beyond clinical data, studies that assess the PROs of type 2 diabetes mellitus (T2DM) patients initiating injectable glucose-lowering medications in routine clinical practice are limited. We describe the perspectives of patients based on a diversified panel of generic and disease-specific PRO measures at the time of enrollment (baseline) in the TROPHIES study. Methods: TROPHIES is a 24-month prospective observational study performed in France, Germany, and Italy in patients with T2DM who initiated their first injectable glucose-lowering medication with once-weekly dulaglutide or once-daily liraglutide. To better understand the perspectives of these patients regarding their overall health, treatment satisfaction, and quality of life and work, the patients’ responses to the following questionnaires were collected at baseline before they initiated treatment with dulaglutide or liraglutide: EQ-5D-5L (scale: 0–1), EQ-VAS (visual analog scale: 0–100), Impact of Weight on Self-Perceptions Questionnaire (IW-SP; scale: 0–100), Diabetes Treatment Satisfaction Questionnaire Status (DTSQs; scale: 0–36), and Diabetes Productivity Measure (DPM; scale: 0–100). Analyses were descriptive in nature, with higher scores reflecting better outcomes. Results: Data from patients at the time of enrollment were analyzed. At baseline, patients initiating dulaglutide (N = 1130) or liraglutide (N = 1051) rated their quality of life in terms of mean EQ-5D-5L index as 0.84 and 0.83, and in terms of mean EQ-VAS as 67.5 and 67.5, respectively. The mean baseline scores in patients initiating dulaglutide or liraglutide were 59.8 and 61.3 for IW-SP, 24.6 and 25.8 for DTSQs, 78.6 and 79.5 for DPM Life Productivity, and 87.5 and 86.8 for DPM Work Productivity, respectively. Conclusion: The information from this varied panel of PRO instruments collected at baseline complements clinical outcomes data

The Real-World Observational Prospective Study of Health Outcomes with Dulaglutide and Liraglutide in Type 2 Diabetes Patients (TROPHIES): Design and Baseline Characteristics

Introduction: The TROPHIES observational study enrolled patients with type 2 diabetes mellitus (T2DM) initiating their first injectable treatment with the glucagon-like peptide 1 receptor agonists (GLP-1 RAs) dulaglutide or liraglutide. This manuscript focuses on the study design, baseline characteristics of the enrolled population, and factors associated with GLP-1 RA choice. Methods: TROPHIES is a prospective, observational, 24-month study conducted in France, Germany, and Italy. Inclusion criteria include adult patients with T2DM, naïve to injectable antihyperglycemic treatments, initiating dulaglutide or liraglutide per routine clinical practice. The primary outcome is the duration of treatment on dulaglutide or liraglutide without a significant treatment change. Results: The analysis included 2181 patients (dulaglutide, 1130; liraglutide, 1051) (cutoff date May 15, 2019). The population was 56% male with mean [standard deviation (SD)] patient characteristics at baseline as follows: age, 59.2 (11.0) years; body mass index (BMI), 33.9 (6.6) kg/m2; T2DM duration, 8.5 (6.9) years; and glycated hemoglobin (HbA1c), 8.2 (1.3)%. Between-cohort demographic and clinical characteristics were balanced. The mean (SD) HbA1c and BMI values for French, German, and Italian patients were, respectively, 8.6 (1.4)%, 8.2 (1.4)%, 8.0 (0.8)%; 33.3 (6.1) kg/m2, 36.0 (7.2) kg/m2, and 32.6 (5.9) kg/m2. Conclusion: This study analysis at baseline provides an opportunity to evaluate between-country differences in baseline HbA1c, weight, macrovascular complications, and factors driving GLP-1 RA selection for patients with T2DM in daily practice

Development of a new health-related quality of life measure for people with diabetes who experience hypoglycaemia:the Hypo-RESOLVE QoL

Aims/hypothesis: Valid and reliable patient-reported outcome measures are vital for assessing disease impact, responsiveness to healthcare and the cost-effectiveness of interventions. A recent review has questioned the ability of existing measures to assess hypoglycaemia-related impacts on health-related quality of life for people with diabetes. This mixed-methods project was designed to produce a novel health-related quality of life patient-reported outcome measure in hypoglycaemia: the Hypo-RESOLVE QoL.Methods: Three studies were conducted with people with diabetes who experience hypoglycaemia. In Stage 1, a comprehensive health-related quality of life framework for hypoglycaemia was elicited from semi-structured interviews (N=31). In Stage 2, the content validity and acceptability of draft measure content were tested via three waves of cognitive debriefing interviews (N=70 people with diabetes; N=14 clinicians). In Stage 3, revised measure content was administered alongside existing generic and diabetes-related measures in a large cross-sectional observational survey to assess psychometric performance (N=1246). The final measure was developed using multiple evidence sources, incorporating stakeholder engagement.Results: A novel conceptual model of hypoglycaemia-related health-related quality of life was generated, featuring 19 themes, organised by physical, social and psychological aspects. From a draft version of 76 items, a final 14-item measure was produced with satisfactory structural (χ2=472.27, df=74, p<0.001; comparative fit index =0.943; root mean square error of approximation =0.069) and convergent validity with related constructs (r=0.46–0.59), internal consistency (α=0.91) and test–retest reliability (intraclass correlation coefficient =0.87).Conclusions/interpretation: The Hypo-RESOLVE QoL is a rigorously developed patient-reported outcome measure assessing the health-related quality of life impacts of hypoglycaemia. The Hypo-RESOLVE QoL has demonstrable validity and reliability and has value for use in clinical decision-making and as a clinical trial endpoint

Development of a new health-related quality of life measure for people with diabetes who experience hypoglycaemia:the Hypo-RESOLVE QoL

Aims/hypothesis: Valid and reliable patient-reported outcome measures are vital for assessing disease impact, responsiveness to healthcare and the cost-effectiveness of interventions. A recent review has questioned the ability of existing measures to assess hypoglycaemia-related impacts on health-related quality of life for people with diabetes. This mixed-methods project was designed to produce a novel health-related quality of life patient-reported outcome measure in hypoglycaemia: the Hypo-RESOLVE QoL.Methods: Three studies were conducted with people with diabetes who experience hypoglycaemia. In Stage 1, a comprehensive health-related quality of life framework for hypoglycaemia was elicited from semi-structured interviews (N=31). In Stage 2, the content validity and acceptability of draft measure content were tested via three waves of cognitive debriefing interviews (N=70 people with diabetes; N=14 clinicians). In Stage 3, revised measure content was administered alongside existing generic and diabetes-related measures in a large cross-sectional observational survey to assess psychometric performance (N=1246). The final measure was developed using multiple evidence sources, incorporating stakeholder engagement.Results: A novel conceptual model of hypoglycaemia-related health-related quality of life was generated, featuring 19 themes, organised by physical, social and psychological aspects. From a draft version of 76 items, a final 14-item measure was produced with satisfactory structural (χ2=472.27, df=74, p<0.001; comparative fit index =0.943; root mean square error of approximation =0.069) and convergent validity with related constructs (r=0.46–0.59), internal consistency (α=0.91) and test–retest reliability (intraclass correlation coefficient =0.87).Conclusions/interpretation: The Hypo-RESOLVE QoL is a rigorously developed patient-reported outcome measure assessing the health-related quality of life impacts of hypoglycaemia. The Hypo-RESOLVE QoL has demonstrable validity and reliability and has value for use in clinical decision-making and as a clinical trial endpoint

Safety Outcomes and Near-Adult Height Gain of Growth Hormone-Treated Children with SHOX Deficiency: Data from an Observational Study and a Clinical Trial

Background/Aims: To assess auxological and safety data for growth hormone (GH)-Treated children with SHOX deficiency. Methods: Data were examined for GH-Treated SHOX-deficient children (n = 521) from the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). For patients with near-Adult height information, GeNeSIS results (n = 90) were compared with a clinical trial (n = 28) of SHOX-deficient patients. Near-Adult height was expressed as standard deviation score (SDS) for chronological age, potentially increasing the observed effect of treatment. Results: Most SHOX-deficient patients in GeNeSIS had diagnoses of Leri-Weill syndrome (n = 292) or non-syndromic short stature (n = 228). For GeNeSIS patients with near-Adult height data, mean age at GH treatment start was 11.0 years, treatment duration 4.4 years, and height SDS gain 0.83 (95% confidence interval 0.49-1.17). Respective ages, GH treatment durations and height SDS gains for GeNeSIS patients prepubertal at baseline (n = 42) were 9.2 years, 6.0 years and 1.19 (0.76-1.62), and for the clinical trial cohort they were 9.2 years, 6.0 years and 1.25 (0.92-1.58). No new GH-related safety concerns were identified. Conclusion: Patients with SHOX deficiency who had started GH treatment before puberty in routine clinical practice had a similar height gain to that of patients in the clinical trial on which approval for the indication was based, with no new safety concerns