General unknown screening procedure for the characterization of human drug metabolites: application to loratadine phase I metabolism.

This article describes the application of a recently developed general unknown screening (GUS) strategy based on LC coupled to a hybrid linear IT-triple quadrupole mass spectrometer (LC-MS/MS-LIT) for the simultaneous detection and identification of drug metabolites following in vitro incubation with human liver microsomes. The histamine H1 receptor antagonist loratadine was chosen as a model compound to demonstrate the interest of such approach, because of its previously described complex and extensive metabolism. Detection and mass spectral characterization were based on data-dependent acquisition, switching between a survey scan acquired in the ion-trapping Q3 scan mode with dynamic subtraction of background noise, and a dependent scan in the ion-trapping product ion scan mode of automatically selected parent ions. In addition, the MS(3) mode was used in a second step to confirm the structure of a few fragment ions. The sensitivity of the ion-trapping modes combined with the selectivity of the triple quadrupole modes allowed, with only one injection, the detection and identification of 17 phase I metabolites of loratadine. The GUS procedure used in this study may be applicable as a generic technique for the characterization of drug metabolites after in vitro incubation, as well as probably in vivo experiments.

Effects of motive-oriented therapeutic relationship in a ten-session general psychiatric treatment of borderline personality disorder: a randomized controlled trial.

Background: Motive-oriented therapeutic relationship (MOTR) was postulated to be a particularly helpful therapeutic ingredient in the early treatment phase of patients with personality disorders, in particular with borderline personality disorder (BPD). The present randomized controlled study using an add-on design is the first study to test this assumption in a 10-session general psychiatric treatment with patients presenting with BPD on symptom reduction and therapeutic alliance. Methods: A total of 85 patients were randomized. They were either allocated to a manual-based short variant of the general psychiatric management (GPM) treatment (in 10 sessions) or to the same treatment where MOTR was deliberately added to the treatment. Treatment attrition and integrity analyses yielded satisfactory results. Results: The results of the intent-to-treat analyses suggested a global efficacy of MOTR, in the sense of an additional reduction of general problems, i.e. symptoms, interpersonal and social problems (F1, 73 = 7.25, p < 0.05). However, they also showed that MOTR did not yield an additional reduction of specific borderline symptoms. It was also shown that a stronger therapeutic alliance, as assessed by the therapist, developed in MOTR treatments compared to GPM (Z55 = 0.99, p < 0.04). Conclusions: These results suggest that adding MOTR to psychiatric and psychotherapeutic treatments of BPD is promising. Moreover, the findings shed additional light on the perspective of shortening treatments for patients presenting with BPD. © 2014 S. Karger AG, Basel.

Apocrypha Hiberniae. I. Evangelia infantiae

In 1927 M. R. James published Latin Infancy Gospels, identified by him in two related but not identical manuscripts (one the British Library Arundel 404; the other from Hereford), together with a parallel text from the Irish manuscript known as the Leabhar Breac. Later researches brought to light more manuscripts of this Latin work, and also of the Irish text. James recognized that his apocryphal Latin Infancy text was compiled from a combination of the Protevangelium of James and a hitherto unknown text which he named "The Source". Recent research has identified a full Latin translation of the Protevangelium of James. A hitherto unrecognized Irish Infancy Narrative has also been identified in the Dublin manuscript known as the Liber Flavus Fergusiorum. A deep study of this related tradition was called for. This has been carried out over the past ten years by an Irish team in conjunction with Professor Daniel Kaestli and AELAC. The fruits of this labour are published in these two volumes. Volume 13 has a general introduction with a historical sketch of New Testament apocrypha in Ireland and a history of research on the subject. This is followed by a comparison of the Infancy Narratives in the Leabhar Breac and the Liber Flavus Fergusiorum. There are special introductions to these Infancy texts, followed by critical editions of the Irish texts, accompanied by English translations and rich annotation. Next there is similar treatment of the Irish versified Narrative (from ca. 700) of the Childhood Deeds of Jesus (commonly known as the Infancy Narrative (or Gospel) of Thomas. There is then (in volume 14, but with continuous pagination) the edition and translation of an Irish thirteenth-century poem with elements from Infancy Narratives, and both Latin and Irish texts on the wonders at Christ's birth, accompanied by translations and notes. The edition of the Irish material is followed by a critical edition of the full Arundel and Hereford forms of the Infancy Narrative (here referred to as the "J Compilation"), together with a detailed study of all the questions relating to this work. The volume concludes with a critical edition (by Rita Beyers) of the Latin text of the Protevangelium of James, accompanied by a detailed study of the work.. The work contains a detailed study of the Latin translations of the Protevangelium of James and the transmission of this work in the West. The "J Compilation" (a combination of the Protevangelium and texts of Pseudo-Matthew) can be traced back in manuscript transmission to ca. 800,and must have originated some time earlier. Behind it stands an earlier "I ("I" for Irish) Compilation" without influence from Pseudo-Matthew, the form found in the Irish witnesses. It is argued that M. R. James's "Source" may be of Judaeo-Christian origin and may really be the Gospel of the Nazoreans. Among the indexes there is a list of all the Irish words found in the texts. This edition of the Irish and related Latin texts is a major contribution to the study of the apocryphal Infancy Narratives. It should also be of particular interest to Celtic scholars, to students of Irish ecclesiastical learning, and in general to all medievalists.

Comparison of the clientele of an anonymous HIV test centre and persons tested in the general population.

This study compares the clientele of a Swiss anonymous test centre with the general population tested. Information was obtained through similar questionnaires submitted to two samples of HIV-tested people aged from 17 to 45 years: the first administered in the context of a general population telephone survey (n = 245) and the second completed during face-to-face interviews of the clientele of an anonymous test centre (n = 250). The test centre sample has higher proportions of younger and single people. Attenders for anonymous testing were more likely to have acquired a new regular partner during the year preceding the interview (48.0% versus 14.4%). These differences remain when controlling for age and gender. Decision to test comes mostly from the respondent's own initiative, but suggestion from a doctor is more frequent in the general population (23.8% versus 0.8%), whereas suggestion from partner or friends is more frequent in the anonymous centre (44.4% versus 3.0%). The anonymous test centre clientele is not different from the general population tested except for the relational situation and origin of decision for testing. The test centre has become a place where the general population finds a response to a situation-specific need for HIV testing.

Overlapping, additive and counterregulatory effects of type II and I interferons on myeloid dendritic cell functions.

Dendritic cells (DCs) are central player in immunity by bridging the innate and adaptive arms of the immune system (IS). Interferons (IFNs) are one of the most important factors that regulate both innate and adaptive immunity too. Thus, the understanding of how type II and I IFNs modulate the immune-regulatory properties of DCs is a central issue in immunology. In this paper, we will address this point in the light of the most recent literature, also highlighting the controversial data reported in the field. According to the wide literature available, type II as well as type I IFNs appear, at the same time, to collaborate, to induce additive effects or overlapping functions, as well as to counterregulate each one's effects on DC biology and, in general, the immune response. The knowledge of these effects has important therapeutic implications in the treatment of infectious/autoimmune diseases and cancer and indicates strategies for using IFNs as vaccine adjuvants and in DC-based immune therapeutic approaches.

Distinguishing general concepts from individuals: an automatic coarse-grained classifier

Named entity recognizers are unable to distinguish if a term is a general concept as "scientist" or an individual as "Einstein". In this paper we explore the possibility to reach this goal combining two basic approaches: (i) Super Sense Tagging (SST) and (ii) YAGO. Thanks to these two powerful tools we could automatically create a corpus set in order to train the SuperSense Tagger. The general F1 is over 76% and the model is publicly available.

Advance directives and the impact of timing. A qualitative study with Swiss general practitioners.

PRINCIPLES: Advance directives are seen as an important tool for documenting the wishes of patients who are no longer competent to make decisions in regards to their medical care. Due to their nature, approaching the subject of advance directives with a patient can be difficult for both the medical care provider and the patient. This paper focuses on general practitioners' perspectives regarding the timing at which this discussion should take place, as well as the advantages and disadvantages of the different moments. METHODS: In 2013, 23 semi-structured face-to-face interviews were performed with Swiss general practitioners. Interviews were analysed using qualitative content analysis. RESULTS: In our sample, 23 general practitioners provided different options that they felt were appropriate moments: either (a) when the patient is still healthy, (b) when illness becomes predominant, or (c) when a patient has been transferred to a long-term care facility. Furthermore, general practitioners reported uncertainty and discomfort regarding initiating the discussion. CONCLUSION: The distinct approaches, perspectives and rationales show that there is no well-defined or "right" moment. However, participants often associated advance directives with death. This link caused discomfort and uncertainty, which led to hesitation and delay on the part of general practitioners. Therefore we recommend further training on how to professionally initiate a conversation about advance directives. Furthermore, based on our results and experience, we recommend an early approach with healthy patients paired with later regular updates as it seems to be the most effective way to inform patients about their end-of-life care options.

A comparison of the spatial dependence of body mass index among adults and children in a Swiss general population.

BACKGROUND: Body mass index (BMI) may cluster in space among adults and be spatially dependent. Whether BMI clusters among children and how age-specific BMI clusters are related remains unknown. We aimed to identify and compare the spatial dependence of BMI in adults and children in a Swiss general population, taking into account the area's income level. METHODS: Geo-referenced data from the Bus Santé study (adults, n=6663) and Geneva School Health Service (children, n=3601) were used. We implemented global (Moran's I) and local (local indicators of spatial association (LISA)) indices of spatial autocorrelation to investigate the spatial dependence of BMI in adults (35-74 years) and children (6-7 years). Weight and height were measured using standardized procedures. Five spatial autocorrelation classes (LISA clusters) were defined including the high-high BMI class (high BMI participant's BMI value correlated with high BMI-neighbors' mean BMI values). The spatial distributions of clusters were compared between adults and children with and without adjustment for area's income level. RESULTS: In both adults and children, BMI was clearly not distributed at random across the State of Geneva. Both adults' and children's BMIs were associated with the mean BMI of their neighborhood. We found that the clusters of higher BMI in adults and children are located in close, yet different, areas of the state. Significant clusters of high versus low BMIs were clearly identified in both adults and children. Area's income level was associated with children's BMI clusters. CONCLUSIONS: BMI clusters show a specific spatial dependence in adults and children from the general population. Using a fine-scale spatial analytic approach, we identified life course-specific clusters that could guide tailored interventions.

Specific vs general cognitive remediation for executive functioning in schizophrenia: A multicenter randomized trial.

BACKGROUND: This study assesses the benefits of an individualized therapy (RECOS program) compared with the more general cognitive remediation therapy (CRT). METHODS: 138 participants took part with 65 randomized to CRT and 73 to RECOS. In the RECOS group, participants were directed towards one of five training modules (verbal memory, visuo-spatial memory and attention, working memory, selective attention or reasoning) corresponding to their key cognitive concern whereas the CRT group received a standard program. The main outcome was the total score on BADS (Behavioural Assessment of Dysexecutive Syndrome) and the secondary outcomes were: cognition (executive functions; selective attention; visuospatial memory and attention; verbal memory; working memory) and clinical measures (symptoms; insight; neurocognitive complaints; self-esteem). All outcomes were assessed at baseline (T1), week 12 (posttherapy, T2), and follow-up (week 36, i.e., 6months posttherapy, T3). RESULTS: No difference was shown for the main outcome. A significant improvement was found for BADS' profile score for RECOS at T2 and T3, and for CRT at T3. Change in BADS in the RECOS and CRT arms were not significantly different between T1 and T2 (+0.86, p=0.108), or between T1 and T3 (+0.36, p=0.540). Significant improvements were found in several secondary outcomes including cognition (executive functions, selective attention, verbal memory, and visuospatial abilities) and clinician measures (symptoms and awareness to be hampered by cognitive deficits in everyday) in both treatment arms following treatment. Self-esteem improved only in RECOS arm at T3, and working memory improved only in CRT arm at T2 and T3, but there were no differences in changes between arms. CONCLUSIONS: RECOS (specific remediation) and CRT (general remediation) globally showed similar efficacy in the present trial.

The European Board of Physical and Rehabilitation Medicine : the past, the present and the future [Europejska Rada Medycyny Fizykalnej i Rehabilitacji: przeszłość, teraźniejszość i perspektywy]

Right from the beginning of the development of the medical specialty of Physical and Rehabilitation Medicine (PRM) the harmonization of the fields of competence and the specialist training across Europe was always an important issue. The initially informal European collaboration was formalized in 1963 under the umbrella of the European Federation of PRM. The European Academy of PRM and the UEMS section of PRM started to contribute in 1969 and 1974 respectively. In 1991 the European Board of Physical and Rehabilitation Medicine (EBPRM) was founded with the specific task of harmonizing education and training in PRM in Europe. The EBPRM has progressively defined curricula for the teaching of medical students and for the postgraduate education and training of PRM specialists. It also created a harmonized European certification system for medical PRM specialists, PRM trainers and PRM training sites. European teaching initiatives for PRM trainees (European PRM Schools) were promoted and learning material for PRM trainees and PRM specialists (e-learning, books and e-books, etc.) was created. For the future the Board will have to ensure that a minimal specific undergraduate curriculum on PRM based on a detailed European catalogue of learning objectives will be taught in all medical schools in Europe as a basis for the general medical practice. To stimulate the harmonization of national curricula, the existing postgraduate curriculum will be expanded by a syllabus of competencies related to PRM and a catalogue of learning objectives to be reached by all European PRM trainees. The integration of the certifying examination of the PRM Board into the national assessment procedures for PRM specialists will also have to be promoted.

La maladie de Wilson: un caméléon clinique auquel il faut penser [A primer on Wilson disease for the general practitioner].

Wilson disease (WD) is an inherited disorder of hepatic copper excretion leading to toxic accumulation of copper in the liver as well as the brain, cornea, and other organs. The defect is due to mutations of the copper-transporting ATPase ATP7B. Clinical manifestations are highly variable and comprise acute liver failure, chronic hepatitis and cirrhosis as well as neurological or psychiatric symptoms. The Kayser-Fleischer corneal ring is pathognomonic but absent in about 50% of patients with hepatic manifestations alone. A high index of suspicion in clinically compatible situations is key, with a combination of laboratory tests allowing the diagnosis of WD. Treatment is based on the use of chelating agents, D-penicillamine or trientine. Liver transplantation should be considered for patients with acute liver failure or advanced cirrhosis.

"INTERMED": a method to assess health service needs. I. Development and reliability.

The purpose of this paper is to describe the development and to test the reliability of a new method called INTERMED, for health service needs assessment. The INTERMED integrates the biopsychosocial aspects of disease and the relationship between patient and health care system in a comprehensive scheme and reflects an operationalized conceptual approach to case mix or case complexity. The method is developed to enhance interdisciplinary communication between (para-) medical specialists and to provide a method to describe case complexity for clinical, scientific, and educational purposes. First, a feasibility study (N = 21 patients) was conducted which included double scoring and discussion of the results. This led to a version of the instrument on which two interrater reliability studies were performed. In study 1, the INTERMED was double scored for 14 patients admitted to an internal ward by a psychiatrist and an internist on the basis of a joint interview conducted by both. In study 2, on the basis of medical charts, two clinicians separately double scored the INTERMED in 16 patients referred to the outpatient psychiatric consultation service. Averaged over both studies, in 94.2% of all ratings there was no important difference between the raters (more than 1 point difference). As a research interview, it takes about 20 minutes; as part of the whole process of history taking it takes about 15 minutes. In both studies, improvements were suggested by the results. Analyses of study 1 revealed that on most items there was considerable agreement; some items were improved. Also, the reference point for the prognoses was changed so that it reflected both short- and long-term prognoses. Analyses of study 2 showed that in this setting, less agreement between the raters was obtained due to the fact that the raters were less experienced and the scoring procedure was more susceptible to differences. Some improvements--mainly of the anchor points--were specified which may further enhance interrater reliability. The INTERMED proves to be a reliable method for classifying patients' care needs, especially when used by experienced raters scoring by patient interview. It can be a useful tool in assessing patients' care needs, as well as the level of needed adjustment between general and mental health service delivery. The INTERMED is easily applicable in the clinical setting at low time-costs.

Appropriateness of colonoscopy in Europe (EPAGE II): presentation of methodology, general results, and analysis of complications.

BACKGROUND AND STUDY AIMS: Appropriate use of colonoscopy is a key component of quality management in gastrointestinal endoscopy. In an update of a 1998 publication, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy (EPAGE II) defined appropriateness criteria for various colonoscopy indications. This introductory paper therefore deals with methodology, general appropriateness, and a review of colonoscopy complications. METHODS:The RAND/UCLA Appropriateness Method was used to evaluate the appropriateness of various diagnostic colonoscopy indications, with 14 multidisciplinary experts using a scale from 1 (extremely inappropriate) to 9 (extremely appropriate). Evidence reported in a comprehensive updated literature review was used for these decisions. Consolidation of the ratings into three appropriateness categories (appropriate, uncertain, inappropriate) was based on the median and the heterogeneity of the votes. The experts then met to discuss areas of disagreement in the light of existing evidence, followed by a second rating round, with a subsequent third voting round on necessity criteria, using much more stringent criteria (i. e. colonoscopy is deemed mandatory). RESULTS: Overall, 463 indications were rated, with 55 %, 16 % and 29 % of them being judged appropriate, uncertain and inappropriate, respectively. Perforation and hemorrhage rates, as reported in 39 studies, were in general < 0.1 % and < 0.3 %, respectively CONCLUSIONS: The updated EPAGE II criteria constitute an aid to clinical decision-making but should in no way replace individual judgment. Detailed panel results are freely available on the internet (www.epage.ch) and will thus constitute a reference source of information for clinicians.