A novel approach to the determination of clinical decision thresholds

Our objective was to determine the test and treatment thresholds for common acute primary care conditions. We presented 200 clinicians with a series of web-based clinical vignettes, describing patients with possible influenza, acute coronary syndrome (ACS), pneumonia, deep vein thrombosis (DVT) and urinary tract infection (UTI). We randomly varied the probability of disease and asked whether the clinician wanted to rule out disease, order tests or rule in disease. By randomly varying the probability, we obtained clinical decisions across a broad range of disease probabilities that we used to create threshold curves. For influenza, the test (4.5% vs 32%, p<0.001) and treatment (55% vs 68%, p=0.11) thresholds were lower for US compared with Swiss physicians. US physicians had somewhat higher test (3.8% vs 0.7%, p=0.107) and treatment (76% vs 58%, p=0.005) thresholds for ACS than Swiss physicians. For both groups, the range between test and treatment thresholds was greater for ACS than for influenza (which is sensible, given the consequences of incorrect diagnosis). For pneumonia, US physicians had a trend towards higher test thresholds and lower treatment thresholds (48% vs 64%, p=0.076) than Swiss physicians. The DVT and UTI scenarios did not provide easily interpretable data, perhaps due to poor wording of the vignettes. We have developed a novel approach for determining decision thresholds. We found important differences in thresholds for US and Swiss physicians that may be a function of differences in healthcare systems. Our results can also guide development of clinical decision rules and guidelines.

Evaluación de la formación del profesorado universitario novel

Durante el curso académico 2001-2002 se desarrolló en la Universidad de Barcelona el Curso de Postgrado 'Innovación en la Docencia Universitaria' dirigido al profesorado novel de la misma. Finalizado el programa se hacía imprescindible conocer su contribución a la mejora de la docencia del profesorado debutante. A través de este estudio se pretende, por tanto, identificar y valorar los cambios, transformaciones y mejoras acaecidas en la práctica docente del profesorado novel como consecuencia de su participación en el Postgrado. El presente trabajo recoge estos aspectos articulados en una evaluación diferida del impacto del Curso de Postgrado. El enfoque metodológico usado ha sido cualitativo-fenomenológico En lo que se refiere a los criterios de evaluación, dos han sido los utilizados en este estudio: la utilidad percibida por el profesorado y la transferibilidad del conocimiento elaborado en el curso.

A Novel Approach to Major Surgery: Tracking Its Pathophysiologic Footprints.

BACKGROUND: To study the 'metabolic profile' of different surgical procedures and correlate it with pertinent surgical details and postoperative complications. METHODS: We conducted a prospective pilot study of 70 patients, ten for each of the seven following groups: (1) laparoscopic cholecystectomy, (2) incisional hernia repair, (3) laparoscopic and (4) open colon surgery, (5) upper gastrointestinal, (6) hepatic, and (7) pancreatic resections. Biochemical assessment included white blood cell count (WBC), C-reactive protein (CRP), glucose, triglycerides (TG), albumin (Alb), and pre-albumin (Pre-Alb), from the day before surgery until 5 days thereafter. Biological markers were compared for major versus minor surgery groups, which were defined on a clinical basis. Univariable analysis was used to identify risk factors for postoperative complications and p < 0.05 was the significance threshold. RESULTS: Common findings in all surgery groups were the acute inflammatory response (↑: WBC, CRP, ↓: TG, Alb, pre-Alb). Using cut-off values of 240 min operative (OR) time and 300 ml estimated blood loss (EBL), laparoscopic cholecystectomy, incisional hernia repair, and laparoscopic colectomy could be distinguished from open colectomy, upper gastrointestinal, liver, and pancreas resections. In a biochemical level, increased CRP and reduced postoperative Alb levels were highly discriminative of all types of 'major surgery.' Significant risk factors for postoperative complications were age, male gender, malignancy, longer OR time, higher blood loss, high CRP, and low Alb levels. CONCLUSIONS: Biochemically, CRP and Alb levels can help quantify the magnitude of the surgical trauma, which is correlated with adverse outcomes.

Novel Roles of HCG/LH Signalling in the Mouse Mammary Gland and its Tumorigenesis.

Breast cancer is the most common cancer in women, and its development is intimately related to hormonal factors, but how hormones affect breast physiology and tumorigenesis is not sufficiently known. Pregnancy elicits long-term protection from breast cancer, but during the first ten years after pregnancy, breast cancer risk is increased. In previous studies, there has been conflicting data on the role of human chorionic gonadotropin (HCG) and the functionality of its receptor in extragonadal tissues. The aim of this study was to elucidate the role of chronically elevated HCG in mouse physiology. We have created a transgenic (TG) mouse model that overexpresses HCG. HCG is similar to lutenizing hormone (LH), but is secreted almost solely by the placenta during pregnancy. HCG and LH both bind to the LH receptor (LHR). In the current study, mammary gland tumors were observed in HCG TG mice. We elucidated the role of HCG in mammary gland signalling and the effects of LHR mediated signalling in mouse mammary gland gene expression. We also studied the effects of HCG in human breast epithelial cell cultures. Several endocrine disturbances were observed in HCGβ TG female mice, resulting in precocious puberty, infertility, obesity and pituitary and mammary gland tumors. The histology of the mammary gland tumors of HCGβ TG females resembled those observed in mouse models with activated Wnt/β-catenin signalling pathway. Wnts are involved in stem cell regulation and tumorigenesis, and are hormonally regulated in the mammary gland. We observed activated β-catenin signalling and elevated expression of Wnt5b and Wnt7b in TG tumors and mammary glands. Furthermore, we discovered that HCG directly regulates the expression of Wnt5b and Wnt7b in the mouse mammary gland. Pharmacological treatment with HCG also caused upregulation of several Wnt-pathway target genes in ovariectomized wild type (WT) mice in the presence of physiological concentrations of estradiol and progesterone. In addition, differential expression of several metabolic genes was observed, suggesting that HCG affects adipocyte function or glucose metabolism. When WT mice were transplanted with LHR deficient or wild type WT mammary epithelium, differential expression of several genes affecting the Wnt-signalling pathway was observed in microarray analysis. Diminished expression of several genes associated with LHR function in other tissues, such as the ovary, was observed in mammary glands deficient of epithelial LHR. In cultured human mammary epithelial cells HCG upregulated the expression of WNT5B, WNT7B similar to mouse, suggesting that the observations found are relevant in human physiology. These studies suggest that HCG/LHR signalling affects gene expression in non-gonadal tissues, and that Wnt-signalling is regulated by HCG/LH in human and mouse mammary glands.

A novel set of DIP-STR markers for improved analysis of challenging DNA mixtures.

Currently available molecular biology tools allow forensic scientists to characterize DNA evidence found at crime scenes for a large variety of samples, including those of limited quantity and quality, and achieve high levels of individualization. Yet, standard forensic markers provide limited or no results when applied to mixed DNA samples where the contributors are present in very different proportions (unbalanced DNA mixtures). This becomes an issue mostly for the analysis of trace samples collected on the victim or from touched objects. To this end, we recently proposed an innovative type of genetic marker, named DIP-STR that relies on pairing deletion/insertion polymorphisms (DIP) with standard short tandem repeats (STR). This novel compound marker allows detection of the minor DNA contributor in a DNA mixture of any gender and cellular origin with unprecedented resolution (beyond a DNA ratio of 1:1000). To provide a novel analytical tool useful in practice to common forensic laboratories, this article describes the first set of 10 DIP-STR markers selected according to forensic technical standards. The novel DIP-STR regions are short (between 146 and 271 bp), include only highly polymorphic tri-, tetra- and pentanucleotide tandem repeats and are located on different chromosomes or chromosomal arms to provide statistically independent results. This novel set of DIP-STR can target the amplification of 0.03-0.1 ng of DNA when mixed with a 1000-fold excess of major DNA. DIP-STR relative allele frequencies are estimated based on a survey of 103 Swiss individuals. Finally, this study provides an estimate of the occurrence of informative alleles and a calculation of the corresponding random match probability of the detected minor DIP-STR genotype assessed across 10,506 pairwise conceptual mixtures.

Switzerland as a "fractured" nation

This article deals with Swiss nationalism and Swiss nation-building. Its main thesis is that Switzerland cannot accurately be described as either a nation or a non-nation but is something in between, and could thus best be characterised as a 'fractured' nation. Switzerland has experienced some powerful nationalist moments, from the creation of the Swiss state in 1848 to the last few decades. Yet this recurrent nationalism among the Swiss, considered alongside their more traditional reluctance to consider themselves a nation, make Switzerland a peculiar object: a 'fractured' nation. This flawed process of nation-building in turn reveals some basic characteristics of all nations - inherent artificiality, and the tremendous efforts undertaken to hide it. Switzerland could be considered an unfinished, incomplete nation, and this is precisely why its study can be interesting for scholars of nations and nationalism.

National and Gender Measurement Invariance of the Utrecht-Management of Identity Commitments Scale (U-MICS) : A 10-Nation Study With University Students

The purpose of this study was to examine the psychometric properties of the Utrecht-Management of Identity Commitments Scale (U-MICS), a self-report measure aimed at assessing identity processes of commitment, in-depth exploration, and reconsideration of commitment. We tested its factor structure in university students from a large array of cultural contexts, including 10 nations located in Europe (i.e., Italy, the Netherlands, Poland, Portugal, Romania, and Switzerland), Middle East (i.e., Turkey), and Asia (i.e., China, Japan, and Taiwan). Furthermore, we tested national and gender measurement invariance. Participants were 6,118 (63.2% females) university students aged from 18 to 25 years (Mage = 20.91 years). Results indicated that the three-factor structure of the U-MICS fitted well in the total sample, in each national group, and in gender groups. Furthermore, national and gender measurement invariance were established. Thus, the U-MICS can be fruitfully applied to study identity in university students from various Western and non-Western contexts.

Combining niche modelling and landscape genetics to study local adaptation: A novel approach illustrated using alpine plants

Understanding the factors that shape adaptive genetic variation across species niches has become of paramount importance in evolutionary ecology, especially to understand how adaptation to changing climate affects the geographic range of species. The distribution of adaptive alleles in the ecological niche is determined by the emergence of novel mutations, their fitness consequences and gene flow that connects populations across species niches. Striking demographical differences and source sink dynamics of populations between the centre and the margin of the niche can play a major role in the emergence and spread of adaptive alleles. Although some theoretical predictions have long been proposed, the origin and distribution of adaptive alleles within species niches remain untested. In this paper, we propose and discuss a novel empirical approach that combines landscape genetics with species niche modelling, to test whether alleles that confer local adaptation are more likely to occur in either marginal or central populations of species niches. We illustrate this new approach by using a published data set of 21 alpine plant species genotyped with a total of 2483 amplified fragment length polymorphisms (AFLP), distributed over more than 1733 sampling sites across the Alps. Based on the assumption that alleles that were statistically associated with environmental variables were adaptive, we found that adaptive alleles in the margin of a species niche were also present in the niche centre, which suggests that adaptation originates in the niche centre. These findings corroborate models of species range evolution, in which the centre of the niche contributes to the emergence of novel adaptive alleles, which diffuse towards niche margins and facilitate niche and range expansion through subsequent local adaptation. Although these results need to be confirmed via fitness measurements in natural populations and functionally characterised genetic sequences, this study provides a first step towards understanding how adaptive genetic variation emerges and shapes species niches and geographic ranges along environmental gradients.

Identification of the regions involved in phonological assembly using a novel paradigm.

Here we adopt a novel strategy to investigate phonological assembly. Participants performed a visual lexical decision task in English in which the letters in words and letterstrings were delivered either sequentially (promoting phonological assembly) or simultaneously (not promoting phonological assembly). A region of interest analysis confirmed that regions previously associated with phonological assembly, in studies contrasting different word types (e.g. words versus pseudowords), were also identified using our novel task that controls for a number of confounding variables. Specifically, the left pars opercularis, the superior part of the ventral precentral gyrus and the supramarginal gyrus were all recruited more during sequential delivery than simultaneous delivery, even when various psycholinguistic characteristics of the stimuli were controlled. This suggests that sequential delivery of orthographic stimuli is a useful tool to explore how readers, with various levels of proficiency, use sublexical phonological processing during visual word recognition.

Infrastructure and nation building: The regulation and financing of network transportation infrastructures in Spain (1720-2010)

This paper analyzes Spanish infrastructure policy since the early 1700s: Road building in the eighteenth century, railway creation and expansion in the nineteenth, motorway expansion in the twentieth, and high speed rail development in the twenty-first. The analysis reveals a long-term pattern, in which infrastructure policy in Spain has been driven not by the requirements of commerce and economic activity, but rather by the desire to centralize transportation around the country’s political capital.

In Vivo Profiling and Distribution of Known and Novel Phase I and Phase II Metabolites of Efavirenz in Plasma, Urine, and Cerebrospinal Fluid.

Efavirenz (EFV) is principally metabolized by CYP2B6 to 8-hydroxy-efavirenz (8OH-EFV) and to a lesser extent by CYP2A6 to 7-hydroxy-efavirenz (7OH-EFV). So far, most metabolite profile analyses have been restricted to 8OH-EFV, 7OH-EFV, and EFV-N-glucuronide, even though these metabolites represent a minor percentage of EFV metabolites present in vivo. We have performed a quantitative phase I and II metabolite profile analysis by tandem mass spectrometry of plasma, cerebrospinal fluid (CSF), and urine samples in 71 human immunodeficiency virus patients taking efavirenz, prior to and after enzymatic (glucuronidase and sulfatase) hydrolysis. We have shown that phase II metabolites constitute the major part of the known circulating efavirenz species in humans. The 8OH-EFV-glucuronide (gln) and 8OH-EFV-sulfate (identified for the first time) in humans were found to be 64- and 7-fold higher than the parent 8OH-EFV, respectively. In individuals (n = 67) genotyped for CYP2B6, 2A6, and CYP3A metabolic pathways, 8OH-EFV/EFV ratios in plasma were an index of CYP2B6 phenotypic activity (P < 0.0001), which was also reflected by phase II metabolites 8OH-EFV-glucuronide/EFV and 8OH-EFV-sulfate/EFV ratios. Neither EFV nor 8OH-EFV, nor any other considered metabolites in plasma were associated with an increased risk of central nervous system (CNS) toxicity. In CSF, 8OH-EFV levels were not influenced by CYP2B6 genotypes and did not predict CNS toxicity. The phase II metabolites 8OH-EFV-gln, 8OH-EFV-sulfate, and 7OH-EFV-gln were present in CSF at 2- to 9-fold higher concentrations than 8OH-EFV. The potential contribution of known and previously unreported EFV metabolites in CSF to the neuropsychological effects of efavirenz needs to be further examined in larger cohort studies.

Ultra-high Field (7 T) MRI and a Novel Robust Segmentation of Thalamic Nuclei on DWI for Gamma Knife Surgery Purposes: The Targeting of the Ventrointermediate Nucleus

Introduction: Gamma Knife surgery (GKS) is a noninvasive neurosurgical stereotactic procedure, increasingly used as an alternative to open functional procedures. This includes the targeting of the ventrointermediate nucleus of the thalamus (e.g., Vim) for tremor. Objective: To enhance anatomic imaging for Vim GKS using high-field (7 T) MRI and Diffusion Weighted Imaging (DWI). Methods: Five young healthy subjects and two patients were scanned both on 3 and 7 T MRI. The protocol was the same in all cases, and included: T1-weighted (T1w) and DWI at 3T; susceptibility weighted images (SWI) at 7T for the visualization of thalamic subparts. SWI was further integrated into the Gamma Plan Software® (LGP, Elekta Instruments, AB, Sweden) and co-registered with 3T images. A simulation of targeting of the Vim was done using the quadrilatere of Guyot. Furthermore, a correlation with the position of the found target on SWI and also on DWI (after clustering of the different thalamic nuclei) was performed. Results: For the 5 healthy subjects, there was a good correlation between the position of the Vim on SWI, DWI and the GKS targeting. For the patients, on the pretherapeutic acquisitions, SWI helped in positioning the target. For posttherapeutic sequences, SWI supposed position of the Vim matched the corresponding contrast enhancement seen at follow-up MRI. Additionally, on the patient's follow-up T1w images, we could observe a small area of contrast-enhancement corresponding to the target used in GKS (e.g., Vim), which belongs to the Ventral-Lateral-Ventral (VLV) nuclei group. Our clustering method resulted in seven thalamic groups. Conclusion: The use of SWI provided us with a superior resolution and an improved image contrast within the central gray matter, enabling us to directly visualize the Vim. We additionally propose a novel robust method for segmenting the thalamus in seven anatomical groups based on DWI. The localization of the GKS target on the follow-up T1w images, as well as the position of the Vim on 7 T, have been used as a gold standard for the validation of VLV cluster's emplacement. The contrast enhancement corresponding to the targeted area was always localized inside the expected cluster, providing strong evidence of the VLV segmentation accuracy. The anatomical correlation between the direct visualization on 7T and the current targeting methods on 3T (e.g., quadrilatere of Guyot, histological atlases, DWI) seems to show a very good anatomical matching.