The Lausanne Institutional Biobank: a new resource to catalyse research in personalised medicine and pharmaceutical sciences.

Breakthrough technologies which now enable the sequencing of individual genomes will irreversibly modify the way diseases are diagnosed, predicted, prevented and treated. For these technologies to reach their full potential requires, upstream, access to high-quality biomedical data and samples from large number of properly informed and consenting individuals and, downstream, the possibility to transform the emerging knowledge into a clinical utility. The Lausanne Institutional Biobank was designed as an integrated, highly versatile infrastructure to harness the power of these emerging technologies and catalyse the discovery and development of innovative therapeutics and biomarkers, and advance the field of personalised medicine. Described here are its rationale, design and governance, as well as parallel initiatives which have been launched locally to address the societal, ethical and technological issues associated with this new bio-resource. Since January 2013, inpatients admitted at Lausanne CHUV University Hospital have been systematically invited to provide a general consent for the use of their biomedical data and samples for research, to complete a standardised questionnaire, to donate a 10-ml sample of blood for future DNA extraction and to be re-contacted for future clinical trials. Over the first 18 months of operation, 14,459 patients were contacted, and 11,051 accepted to participate in the study. This initial 18-month experience illustrates that a systematic hospital-based biobank is feasible; it shows a strong engagement in research from the patient population in this University Hospital setting, and the need for a broad, integrated approach for the future of medicine to reach its full potential.

Development of pharmaceutical care services in nursing homes: practice and research in a Swiss canton.

OBJECTIVE: The aim of this study was to assess the implementation process and economic impact of a new pharmaceutical care service provided since 2002 by pharmacists in Swiss nursing homes. SETTING: The setting was 42 nursing homes located in the canton of Fribourg, Switzerland under the responsibility of 22 pharmacists. METHOD: We developed different facilitators, such as a monitoring system, a coaching program, and a research project, to help pharmacists change their practice and to improve implementation of this new service. We evaluated the implementation rate of the service delivered in nursing homes. We assessed the economic impact of the service since its start in 2002 using statistical evaluation (Chow test) with retrospective analysis of the annual drug costs per resident over an 8-year period (1998-2005). MAIN OUTCOME MEASURES: The description of the facilitators and their implications in implementation of the service; the economic impact of the service since its start in 2002. RESULTS: In 2005, after a 4-year implementation period supported by the introduction of facilitators of practice change, all 42 nursing homes (2,214 residents) had implemented the pharmaceutical care service. The annual drug costs per resident decreased by about 16.4% between 2002 and 2005; this change proved to be highly significant. The performance of the pharmacists continuously improved using a specific coaching program including an annual expert comparative report, working groups, interdisciplinary continuing education symposia, and individual feedback. This research project also determined priorities to develop practice guidelines to prevent drug-related problems in nursing homes, especially in relation to the use of psychotropic drugs. CONCLUSION: The pharmaceutical care service was fully and successfully implemented in Fribourg's nursing homes within a period of 4 years. These findings highlight the importance of facilitators designed to assist pharmacists in the implementation of practice changes. The economic impact was confirmed on a large scale, and priorities for clinical and pharmacoeconomic research were identified in order to continue to improve the quality of integrated care for the elderly.

E-Health and Society : An Empirical Study of Catalonia. Research report (synthesis document)

Aquest estudi va analitzar la interacció del canvi organitzatiu, els valors culturals i el canvi tecnològic en el sistema sanitari català. L'estudi se subdivideix en cinc parts diferents. La primera és una anàlisi de contingut de webs relacionats amb la salut a Catalunya. La segona és un estudi dels usos d'Internet en qüestions relacionades amb la salut entre la població en general, les associacions de pacients i els professionals de la salut, i es basa en un sondeig per Internet adaptat a cada un d'aquests grups. La tercera part és un estudi de treball de camp dels programes experimentals duts a terme pel Govern català en diverses àrees i hospitals locals per a integrar electrònicament la història clínica dels pacients. La quarta és un estudi de les implicacions organitzatives de la introducció de sistemes d'informació en la gestió d'hospitals i centres d'assistència primària a l'Institut Català de Salut, el principal proveïdor de salut pública a Catalunya, i es basa en un sondeig per Internet i entrevistes en profunditat. La cinquena part és un estudi de cas dels efectes organitzatius i socials de la introducció de les tecnologies de la informació i la comunicació en un dels principals hospitals de Catalunya, l'Hospital Clínic de Barcelona. L'estudi es va dur a terme entre el maig del 2005 i el juliol del 2007.

New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: A pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials.

BACKGROUND: Prognostic models have been developed to predict survival of patients with newly diagnosed glioblastoma (GBM). To improve predictions, models should be updated with information at the recurrence. We performed a pooled analysis of European Organization for Research and Treatment of Cancer (EORTC) trials on recurrent glioblastoma to validate existing clinical prognostic factors, identify new markers, and derive new predictions for overall survival (OS) and progression free survival (PFS).¦METHODS: Data from 300 patients with recurrent GBM recruited in eight phase I or II trials conducted by the EORTC Brain Tumour Group were used to evaluate patient's age, sex, World Health Organisation (WHO) performance status (PS), presence of neurological deficits, disease history, use of steroids or anti-epileptics and disease characteristics to predict PFS and OS. Prognostic calculators were developed in patients initially treated by chemoradiation with temozolomide.¦RESULTS: Poor PS and more than one target lesion had a significant negative prognostic impact for both PFS and OS. Patients with large tumours measured by the maximum diameter of the largest lesion (⩾42mm) and treated with steroids at baseline had shorter OS. Tumours with predominant frontal location had better survival. Age and sex did not show independent prognostic values for PFS or OS.¦CONCLUSIONS: This analysis confirms performance status but not age as a major prognostic factor for PFS and OS in recurrent GBM. Patients with multiple and large lesions have an increased risk of death. With these data prognostic calculators with confidence intervals for both medians and fixed time probabilities of survival were derived.

Natalizumab versus Interferon B-1b to prevent CDMS in patients with CIS and poor prognostic factors: research protocol

About 85% of multiple sclerosis (MS) cases start as clinically isolated syndrome (CIS).When patients present with a CIS, clinicians face with many questions, most of themrelated with prognosis and treatment. Thereby, patients with CIS have been focus ofresearch. Several studies have demonstrated a relationship between positive IgM lipidspecific oligoclonal band pattern in CSF and higher lesion load on MRI brain scan, higher number of relapses and greater disability, even at the first stages of the disease. On the other hand, no studies have used this previous evidence to treat with more aggressive disease modifying therapy in initial stages of disease course to prevent the earlier axonal damage. The aim of this study is to assess the most effective approved treatment for MS and current therapy for CIS patients presenting high risk to develop CDMS and with biomarkers of poor prognosis. Among this group of patients any disease activity will eventually lead to disability. Therefore, the earlier the treatment is initiated, the more effective to prevent disability will be. It is considered that “time lost is brain lost” and since once damage is established, there is no therapy to be regained later on. In this phase III clinical trial, 172 patients will be randomized 1:1 to receive Interferon β-1b or natalizumab over 96 weeks. Time to develop clinical definitive multiple sclerosis (CDMS) will be included as primary endpoint. Other secondary endpoints will include clinical data, magnetic resonance imaging (MRI) measurements and quality of life tests

Natalizumab versus Interferon B-1b to prevent CDMS in patients with CIS and poor prognostic factors: research protocol

About 85% of multiple sclerosis (MS) cases start as clinically isolated syndrome (CIS).When patients present with a CIS, clinicians face with many questions, most of themrelated with prognosis and treatment. Thereby, patients with CIS have been focus ofresearch. Several studies have demonstrated a relationship between positive IgM lipidspecific oligoclonal band pattern in CSF and higher lesion load on MRI brain scan, higher number of relapses and greater disability, even at the first stages of the disease. On the other hand, no studies have used this previous evidence to treat with more aggressive disease modifying therapy in initial stages of disease course to prevent the earlier axonal damage. The aim of this study is to assess the most effective approved treatment for MS and current therapy for CIS patients presenting high risk to develop CDMS and with biomarkers of poor prognosis. Among this group of patients any disease activity will eventually lead to disability. Therefore, the earlier the treatment is initiated, the more effective to prevent disability will be. It is considered that “time lost is brain lost” and since once damage is established, there is no therapy to be regained later on. In this phase III clinical trial, 172 patients will be randomized 1:1 to receive Interferon β-1b or natalizumab over 96 weeks. Time to develop clinical definitive multiple sclerosis (CDMS) will be included as primary endpoint. Other secondary endpoints will include clinical data, magnetic resonance imaging (MRI) measurements and quality of life tests

The quest for surrogate markers of angiogenesis: a paradigm for translational research in tumor angiogenesis and anti-angiogenesis trials.

Inhibition of tumor angiogenesis suppresses tumor growth and metastatic spreading in many experimental models, suggesting that anti-angiogenic drugs may be used to treat human cancer. During the past decade more than eighty molecules that showed anti-angiogenic activity in preclinical studies were tested in clinical cancer trials, but most of them failed to demonstrate any measurable anti-tumor activity and none have been approved for clinical use. Recent results stemming from trials with anti-VEGF antibodies, used alone or in combination with chemotherapy, suggest that systemic anti-angiogenic therapy may indeed have a measurable impact on cancer progression and patient survival. From the clinical studies it became nevertheless clear that the classical endpoints used in anti-cancer trials do not bring sufficient discriminative power to monitor the effects of anti-angiogenic drugs. It is therefore necessary to identify and validate molecular, cellular and functional surrogate markers of angiogenesis to monitor activity and efficacy of anti-angiogenic drugs in patients. Availability of such markers will be instrumental to re-evaluate the role of tumor angiogenesis in human cancer, to identify new molecular targets and drugs, and to improve planning, monitoring and interpretation of future studies. Future anti-angiogenesis trials integrating biological endpoints and surrogate markers or angiogenesis will require close collaboration between clinical investigators and laboratory-based researchers.

Unexpected genomic variability in clinical and environmental strains of the pathogenic yeast Candida parapsilosis

Invasive candidiasis is the most commonly reported invasive fungal infection worldwide. Although Candida albicans remains the main cause, the incidence of emerging Candida species, such as C. parapsilosis is increasing. It has been postulated that C. parapsilosis clinical isolates result from a recent global expansion of a virulent clone. However, the availability of a single genome for this species has so far prevented testing this hypothesis at genomic scales. We present here the sequence of three additional strains from clinical and environmental samples. Our analyses reveal unexpected patterns of genomic variation, shared among distant strains, that argue against the clonal expansion hypothesis. All strains carry independent expansions involving an arsenite transporter homolog, pointing to the existence of directional selection in the environment, and independent origins of the two clinical isolates. Furthermore, we report the first evidence for the existence of recombination in this species. Altogether, our results shed new light onto the dynamics of genome evolution in C. parapsilosis.

Methadone maintenance treatment in the Swiss Canton of Vaud: demographic and clinical data on 1,782 ambulatory patients.

Using data from the Public Health Service, we studied the demographic and clinical characteristics of 1,782 patients enrolled in methadone maintenance treatment (MMT) during 2001 in the Swiss Canton of Vaud, comparing our findings with the results of a previous study from 1976 to 1986. In 2001, most patients (76.9%) were treated in general practice. Mortality is low in this MMT population (1%/year). While patient age and sex profiles were similar to those found in the earlier study, we did observe a substantial increase in the number of patients and the number of practitioners treating MMT patients, probably reflecting the low-threshold governmental policies and the creation of specialized centers. In conclusion, easier access to MMT enhances the number of patients, but new concerns about the quality of management emerge: benzodiazepine as a concomitant prescription; low rates of screening for hepatitis B, C and HIV, and social and psychiatric preoccupations.

The French adaptation of the Health of the Nation Outcome Scale for Children and Adolescents Self-Rated Form (F-HoNOSCA-SR): Validation and clinical routine use.

The current study aimed to explore the validity of an adaptation into French of the self-rated form of the Health of the Nation Outcome Scales for Children and Adolescents (F-HoNOSCA-SR) and to test its usefulness in a clinical routine use. One hundred and twenty nine patients, admitted into two inpatient units, were asked to participate in the study. One hundred and seven patients filled out the F-HoNOSCA-SR (for a subsample (N=17): at two occasions, one week apart) and the strengths and difficulties questionnaire (SDQ). In addition, the clinician rated the clinician-rated form of the HoNOSCA (HoNOSCA-CR, N=82). The reliability (assessed with split-half coefficient, item response theory (IRT) models and intraclass correlations (ICC) between the two occasions) revealed that the F-HoNSOCA-SR provides reliable measures. The concurrent validity assessed by correlating the F-HoNOSCA-SR and the SDQ revealed a good convergent validity of the instrument. The relationship analyses between the F-HoNOSCA-SR and the HoNOSCA-CR revealed weak but significant correlations. The comparison between the F-HoNOSCA-SR and the HoNOSCA-CR with paired sample t-tests revealed a higher score for the self-rated version. The F-HoNSOCA-SR was reported to provide reliable measures. In addition, it allows us to measure complementary information when used together with the HoNOSCA-CR.

Official Positions for FRAX® clinical regarding prior fractures from Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX®.

The 2010 Position Development Conference addressed four questions related to the impact of previous fractures on 10-year fracture risk as calculated by FRAX(®). To address these questions, PubMed was searched on the keywords "fracture, epidemiology, osteoporosis." Titles of retrieved articles were reviewed for an indication that risk for future fracture was discussed. Abstracts of these articles were reviewed for an indication that one or more of the questions listed above was discussed. For those that did, the articles were reviewed in greater detail to extract the findings and to find additional past work and citing works that also bore on the questions. The official positions and the supporting literature review are presented here. FRAX(®) underestimates fracture probability in persons with a history of multiple fractures (good, A, W). FRAX(®) may underestimate fracture probability in individuals with prevalent severe vertebral fractures (good, A, W). While there is evidence that hip, vertebral, and humeral fractures appear to confer greater risk of subsequent fracture than fractures at other sites, quantification of this incremental risk in FRAX(®) is not possible (fair, B, W). FRAX(®) may underestimate fracture probability in individuals with a parental history of non-hip fragility fracture (fair, B, W). Limitations of the methodology include performance by a single reviewer, preliminary review of the literature being confined to titles, and secondary review being limited to abstracts. Limitations of the evidence base include publication bias, overrepresentation of persons of European descent in the published studies, and technical differences in the methods used to identify prevalent and incident fractures. Emerging topics for future research include fracture epidemiology in non-European populations and men, the impact of fractures in family members other than parents, and the genetic contribution to fracture risk.

Traitement pharmacologique de la schizophrénie : évaluation comparative de la qualité des recommandations de pratique clinique = Comparative evaluation of clinical practice guidelines for the treatment of schizophrenia

De nombreuses recommandations de pratique clinique (RPC) ont été publiées, en réponse au développement du concept de la médecine fondée sur les preuves et comme solution à la difficulté de synthétiser et trier l'abondante littérature médicale. Pour faire un choix parmi le foisonnement de nouvelles RPC, il est primordial d'évaluer leur qualité. Récemment, le premier instrument d'évaluation standardisée de la qualité des RPC, appelé " AGREE " pour appraisal of guidelines for research and evaluation, a été validé. Nous avons comparé - avec l'aide de la grille " AGREE " - les six principales RPC publiées depuis une dizaine d'années sur le traitement de la schizophrénie : (1) les Recommandations de l'Agence nationale pour le développement de l'évaluation médicale (ANDEM) ; (2) The American Psychiatric Association (APA) practice guideline for the treatment of patients with schizophrenia ; (3) The quick reference guide of APA practice guideline for the treatment of patients with schizophrenia [APA - guide rapide de référence] ; (4) The schizophrenia patient outcomes research team (PORT) treatment recommandations ; (5) The Texas medication algorithm project " T-MAP " ; (6) The expert consensus guideline for the treatment of schizophrenia. Les résultats de notre étude ont ensuite été comparés avec ceux d'une étude similaire publiée en 2005 par Gæbel et al. portant sur 24 RPC abordant le traitement de la schizophrénie, réalisée également avec l'aide de la grille " AGREE " et deux évaluateurs [Br J Psychiatry 187 (2005) 248-255]. De manière générale, les scores des deux études ne sont pas trop éloignés et les deux évaluations globales des RPC convergent : chacune des six RPC est perfectible et présente différemment des points faibles et des points forts. La rigueur d'élaboration des six RPC est dans l'ensemble très moyenne, la prise en compte de l'opinion des utilisateurs potentiels est lacunaire et un effort sur la présentation des recommandations faciliterait leur utilisation clinique. L'applicabilité des recommandations est également peu considérée par les auteurs. Globalement, deux RPC se distinguent et peuvent être fortement recommandées selon les critères de la grille " AGREE " : " l'APA - guide rapide de référence " et le " T-MAP ".

Assessment of the 10-year probability of osteoporotic hip fracture combining clinical risk factors and heel bone ultrasound: the EPISEM prospective cohort of 12,958 elderly women.

This study aimed to develop a hip screening tool that combines relevant clinical risk factors (CRFs) and quantitative ultrasound (QUS) at the heel to determine the 10-yr probability of hip fractures in elderly women. The EPISEM database, comprised of approximately 13,000 women 70 yr of age, was derived from two population-based white European cohorts in France and Switzerland. All women had baseline data on CRFs and a baseline measurement of the stiffness index (SI) derived from QUS at the heel. Women were followed prospectively to identify incident fractures. Multivariate analysis was performed to determine the CRFs that contributed significantly to hip fracture risk, and these were used to generate a CRF score. Gradients of risk (GR; RR/SD change) and areas under receiver operating characteristic curves (AUC) were calculated for the CRF score, SI, and a score combining both. The 10-yr probability of hip fracture was computed for the combined model. Three hundred seven hip fractures were observed over a mean follow-up of 3.2 yr. In addition to SI, significant CRFs for hip fracture were body mass index (BMI), history of fracture, an impaired chair test, history of a recent fall, current cigarette smoking, and diabetes mellitus. The average GR for hip fracture was 2.10 per SD with the combined SI + CRF score compared with a GR of 1.77 with SI alone and of 1.52 with the CRF score alone. Thus, the use of CRFs enhanced the predictive value of SI alone. For example, in a woman 80 yr of age, the presence of two to four CRFs increased the probability of hip fracture from 16.9% to 26.6% and from 52.6% to 70.5% for SI Z-scores of +2 and -3, respectively. The combined use of CRFs and QUS SI is a promising tool to assess hip fracture probability in elderly women, especially when access to DXA is limited.

Official positions of the International Society for Clinical Densitometry (ISCD) on DXA evaluation in children and adolescents.

Dual-energy X-ray absorptiometry (DXA) is the most widely used technical instrument for evaluating bone mineral content (BMC) and density (BMD) in patients of all ages. However, its use in pediatric patients, during growth and development, poses a much more complex problem in terms of both the technical aspects and the interpretation of the results. For the adults population, there is a well-defined term of reference: the peak value of BMD attained by young healthy subjects at the end of skeletal growth. During childhood and adolescence, the comparison can be made only with healthy subjects of the same age, sex and ethnicity, but the situation is compounded by the wide individual variation in the process of skeletal growth (pubertal development, hormone action, body size and bone size). The International Society for Clinical Densitometry (ISCD) organized a Pediatric Position Development Conference to discuss the specific problems of bone densitometry in growing subjects (9-19 years of age) and to provide essential recommendations for its clinical use.

Transplantation tolerance: Clinical potential of regulatory T cells.

The major challenge in transplantation medicine remains long-term allograft acceptance, with preserved allograft function under minimal chronic immunosuppression. To safely achieve the goal of sustained donor-specific T and B cell non-responsiveness, research efforts are now focusing on therapies based on cell subsets with regulatory properties. In particular the transfusion of human regulatory T cells (Treg) is currently being evaluated in phase I/II clinical trials for the treatment of graft versus host disease following hematopoietic stem cell transplantation, and is also under consideration for solid organ transplantation. The purpose of this review is to recapitulate current knowledge on naturally occurring as well as induced human Treg, with emphasis on their specific phenotype, suppressive function and how these cells can be manipulated in vitro and/or in vivo for therapeutic purposes in transplantation medicine. We highlight the potential but also possible limitations of Treg-based strategies to promote long-term allograft survival. It is evident that the bench-to-beside translation of these protocols still requires further understanding of Treg biology. Nevertheless, current data already suggest that Treg therapy alone will not be sufficient and needs to be combined with other immunomodulatory approaches in order to induce allograft tolerance.