SBML qualitative models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools.

BACKGROUND: Qualitative frameworks, especially those based on the logical discrete formalism, are increasingly used to model regulatory and signalling networks. A major advantage of these frameworks is that they do not require precise quantitative data, and that they are well-suited for studies of large networks. While numerous groups have developed specific computational tools that provide original methods to analyse qualitative models, a standard format to exchange qualitative models has been missing. RESULTS: We present the Systems Biology Markup Language (SBML) Qualitative Models Package ("qual"), an extension of the SBML Level 3 standard designed for computer representation of qualitative models of biological networks. We demonstrate the interoperability of models via SBML qual through the analysis of a specific signalling network by three independent software tools. Furthermore, the collective effort to define the SBML qual format paved the way for the development of LogicalModel, an open-source model library, which will facilitate the adoption of the format as well as the collaborative development of algorithms to analyse qualitative models. CONCLUSIONS: SBML qual allows the exchange of qualitative models among a number of complementary software tools. SBML qual has the potential to promote collaborative work on the development of novel computational approaches, as well as on the specification and the analysis of comprehensive qualitative models of regulatory and signalling networks.

Appropriateness of respiratory care: development of evidence-based guidelines in an acute care hospital

Background: Respiratory care is universally recognised as useful, but its indications and practice vary markedly. In order to improve appropriateness of respiratory care in our hospital, we developed evidence-based local guidelines in a collaborative effort involving physiotherapists, physicians, and health services researchers. Methods: Recommendations were developed using the standardised RAND appropriateness method. A literature search was performed for the period between 1995 and 2008 based on terms associated with guidelines and with respiratory care. Publications were assessed according to the Oxford classification of quality of evidence. A working group prepared proposals for recommendations which were then independently rated by a multidisciplinary expert panel. All recommendations were then discussed in common and indications for procedures were rated confidentially a second time by the experts. Each indication for respiratory care was classified as appropriate, uncertain, or inappropriate, based on the panel median rating and the degree of intra-panel agreement. Results: Recommendations were formulated for the following procedures: non-invasive ventilation, continuous positive airway pressure, intermittent positive pressure breathing, intrapulmonary percussive ventilation, mechanical insufflation-exsufflation, incentive spirometry, positive expiratory pressure, nasotracheal suctioning, noninstrumental airway clearance techniques. Each recommendation referred to a particular medical condition, and was assigned to a hierarchical category based on the quality of evidence from literature supporting the recommendation and on the consensus of experts. Conclusion: Despite a marked heterogeneity of scientific evidence, the method used allowed us to develop commonly agreed local guidelines for respiratory care. In addition, this work fostered a closer relationship between physiotherapists and physicians in our institution.

Optimising translational oncology in clinical practice: Strategies to accelerate progress in drug development.

Despite intense efforts, the socioeconomic burden of cancer remains unacceptably high and treatment advances for many common cancers have been limited, suggesting a need for a new approach to drug development. One issue central to this lack of progress is the heterogeneity and genetic complexity of many tumours. This results in considerable variability in therapeutic response and requires knowledge of the molecular profile of the tumour to guide appropriate treatment selection for individual patients. While recent advances in the molecular characterisation of different cancer types have the potential to transform cancer treatment through precision medicine, such an approach presents a major economic challenge for drug development, since novel targeted agents may only be suitable for a small cohort of patients. Identifying the patients who would benefit from individual therapies and recruiting sufficient numbers of patients with particular cancer subtypes into clinical trials is challenging, and will require collaborative efforts from research groups and industry in order to accelerate progress. A number of molecular screening platforms have already been initiated across Europe, and it is hoped that these networks, along with future collaborations, will benefit not only patients but also society through cost reductions as a result of more efficient use of resources. This review discusses how current developments in translational oncology may be applied in clinical practice in the future, assesses current programmes for the molecular characterisation of cancer and describes possible collaborative approaches designed to maximise the benefits of translational science for patients with cancer.

Treatment strategies in primary vitreoretinal lymphoma: a 17-center European collaborative study.

IMPORTANCE: The best treatment option for primary vitreoretinal lymphoma (PVRL) without signs of central nervous system lymphoma (CNSL) involvement determined on magnetic resonance imaging or in cerebrospinal fluid is unknown. OBJECTIVE: To evaluate the outcomes of treatment regimens used for PVRL in the prevention of subsequent CNSL. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted at 17 referral ophthalmologic centers in Europe. We reviewed clinical, laboratory, and imaging data on 78 patients with PVRL who did not have CNSL on presentation between January 1, 1991, and December 31, 2012, with a focus on the incidence of CNS manifestations during the follow-up period. INTERVENTIONS: The term extensive treatment was used for various combinations of systemic and intrathecal chemotherapy, whole-brain radiotherapy, and peripheral blood stem cell transplantation. Therapy to prevent CNSL included ocular radiotherapy and/or ocular chemotherapy (group A, 31 patients), extensive systemic treatment (group B, 21 patients), and a combination of ocular and extensive treatment (group C, 23 patients); 3 patients did not receive treatment. A total of 40 patients received systemic chemotherapy. MAIN OUTCOMES AND MEASURES: Development of CNSL following the diagnosis of PVRL relative to the use or nonuse of systemic chemotherapy and other treatment regimens. RESULTS: Overall, CNSL developed in 28 of 78 patients (36%) at a median follow-up of 49 months. Specifically, CNSL developed in 10 of 31 (32%) in group A, 9 of 21 (43%) in group B, and 9 of 23 (39%) in group C. The 5-year cumulative survival rate was lower in patients with CNSL (35% [95% CI, 50% to 86%]) than in patients without CNSL (68% [95% CI, 19% to 51%]; P = .003) and was similar among all treatment groups (P = .10). Adverse systemic effects occurred in 9 of 40 (23%) patients receiving systemic chemotherapy; the most common of these effects was acute renal failure. CONCLUSIONS AND RELEVANCE: In the present series of patients with isolated PVRL, the use of systemic chemotherapy was not proven to prevent CNSL and was associated with more severe adverse effects compared with local treatment.

Early change in maladaptive defense style and development of the therapeutic alliance

Résumé Cette étude examine les changements précoces dans le Style Défensif Maladaptatif (SDM), le développement de l'alliance thérapeutique et la relation entre le SDM et l'alliance au cours d'une psychothérapie psychodynamique ultra-brève. Soixante-huit patients ambulatoires du centre de consultation psychiatrique et psychothérapique ont bénéficié d'une intervention psychodynamique en quatre séances. Les mesures des défenses et de l'alliance étaient effectuées à la première et à la dernière séance. Les patients qui ont débuté l'intervention avec une alliance faible et qui l'ont terminée avec une alliance haute (groupe de patients avec une alliance de croissance linéaire) ont diminué leur utilisation de défenses maladaptatives de manière significative au cours de la thérapie, alors que ce n'a pas été le cas pour les patients des groupes à alliances haute-stable et basse-stable. Les résultats ont montré qu'à la fin de l'intervention, le SDM et l'alliance étaient corrélés pour tous les patients. Cette corrélation intéressait plus particulièrement le groupe avec une alliance de croissance linéaire. Ces résultats suggèrent, que le développement de l'alliance thérapeutique reflètent le travail de collaboration entre le patient et son thérapeute alors qu'ils essayent de mieux comprendre les causes de la crise du patient. Cette compréhension peut aider à réduire les défenses initialement activées pour permettre au patient de se défendre de l'anxiété et d'un sentiment de détresse. Abstract This study examined the early change in Maladaptive Defense Style (MDS), the development of the Therapeutic Alliance, and the relationship between MDS and alliance, in a short psychodynamic intervention. Sixty-eight outpatients from a psychiatric clinic completed a four-session psychodynamic intervention. Defense and alliance measures were collected at the intake and the final session. Patients who began the intervention with a poor alliance but ended with a good alliance (linear growth therapeutic alliance group) significantly decreased their use of maladaptive defenses over the course of therapy, while patients in the high and low alliance groups did not. Results showed that at the end of the intervention, MDS and alliance were related across all patients. This relation concerned particularly the linear growth therapeutic alliance profile. These results suggest that the developing therapeutic alliance might reflect the collaborative work between the patient and the therapist as they try to understand the causes of the crisis. This understanding might help reduce maladaptive defenses that were initially activated to ward off anxiety and distress.

Evaluation of the compliance with recommended procedures in newborns exposed to HBsAg-positive mothers: a multicenter collaborative study.

BACKGROUND: Maternal-infant transmission of hepatitis B virus (HBV) during birth carries a high risk for chronic HBV infection in infants with frequent subsequent development of chronic disease. This can be efficiently prevented by early immunization of exposed newborns. The purpose of this study was to determine the compliance with official recommendations for prevention of perinatal HBV transmission in hepatitis B surface antigen (HBsAg) exposed infants. METHODS: Records of pregnant women at 4 sites in Switzerland, admitted for delivery in 2005 and 2006, were screened for maternal HBsAg testing. In HBsAg-exposed infants, recommended procedures (postnatal active and passive immunization, completion of immunization series, and serological success control) were checked. RESULTS: Of 27,131 women tested for HBsAg, 194 (0.73%) were positive with 196 exposed neonates. Of these neonates, 143 (73%) were enrolled and 141 (99%) received simultaneous active and passive HBV immunization within 24 hours of birth. After discharge, the HBV immunization series was completed in 83%. Only 38% of children were tested for anti-HBs afterwards and protective antibody values (>100 U/L) were documented in 27% of the study cohort. No chronically infected child was identified. Analysis of hospital discharge letters revealed significant quality problems. CONCLUSIONS: Intensified efforts are needed to improve the currently suboptimal medical care in HBsAg-exposed infants. We propose standardized discharge letters, as well as reminders to primary care physicians with precise instructions on the need to complete the immunization series in HBsAg-exposed infants and to evaluate success by determination of anti-HBs antibodies after the last dose.

Development of a cross-European virtual sample repository and HIV resistance database

BACKGROUND: Several European HIV observational data bases have, over the last decade, accumulated a substantial number of resistance test results and developed large sample repositories, There is a need to link these efforts together, We here describe the development of such a novel tool that allows to bind these data bases together in a distributed fashion for which the control and data remains with the cohorts rather than classic data mergers.METHODS: As proof-of-concept we entered two basic queries into the tool: available resistance tests and available samples. We asked for patients still alive after 1998-01-01, and between 180 and 195 cm of height, and how many samples or resistance tests there would be available for these patients, The queries were uploaded with the tool to a central web server from which each participating cohort downloaded the queries with the tool and ran them against their database, The numbers gathered were then submitted back to the server and we could accumulate the number of available samples and resistance tests.RESULTS: We obtained the following results from the cohorts on available samples/resistance test: EuResist: not availableI11,194; EuroSIDA: 20,71611,992; ICONA: 3,751/500; Rega: 302/302; SHCS: 53,78311,485, In total, 78,552 samples and 15,473 resistance tests were available amongst these five cohorts. Once these data items have been identified, it is trivial to generate lists of relevant samples that would be usefuI for ultra deep sequencing in addition to the already available resistance tests, Saon the tool will include small analysis packages that allow each cohort to pull a report on their cohort profile and also survey emerging resistance trends in their own cohort,CONCLUSIONS: We plan on providing this tool to all cohorts within the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN) and will provide the tool free of charge to others for any non-commercial use, The potential of this tool is to ease collaborations, that is, in projects requiring data to speed up identification of novel resistance mutations by increasing the number of observations across multiple cohorts instead of awaiting single cohorts or studies to reach the critical number needed to address such issues.

The new final Clinical Skills examination in human medicine in Switzerland: Essential steps of exam development, implementation and evaluation, and central insights from the perspective of the national Working Group.

OBJECTIVE: Since 2011, the new national final examination in human medicine has been implemented in Switzerland, with a structured clinical-practical part in the OSCE format. From the perspective of the national Working Group, the current article describes the essential steps in the development, implementation and evaluation of the Federal Licensing Examination Clinical Skills (FLE CS) as well as the applied quality assurance measures. Finally, central insights gained from the last years are presented. METHODS: Based on the principles of action research, the FLE CS is in a constant state of further development. On the foundation of systematically documented experiences from previous years, in the Working Group, unresolved questions are discussed and resulting solution approaches are substantiated (planning), implemented in the examination (implementation) and subsequently evaluated (reflection). The presented results are the product of this iterative procedure. RESULTS: The FLE CS is created by experts from all faculties and subject areas in a multistage process. The examination is administered in German and French on a decentralised basis and consists of twelve interdisciplinary stations per candidate. As important quality assurance measures, the national Review Board (content validation) and the meetings of the standardised patient trainers (standardisation) have proven worthwhile. The statistical analyses show good measurement reliability and support the construct validity of the examination. Among the central insights of the past years, it has been established that the consistent implementation of the principles of action research contributes to the successful further development of the examination. CONCLUSION: The centrally coordinated, collaborative-iterative process, incorporating experts from all faculties, makes a fundamental contribution to the quality of the FLE CS. The processes and insights presented here can be useful for others planning a similar undertaking.