Quinupristin-dalfopristin combined with beta-lactams for treatment of experimental endocarditis due to Staphylococcus aureus constitutively resistant to macrolide-lincosamide-streptogramin B antibiotics.

Quinupristin-dalfopristin (Q-D) is an injectable streptogramin active against most gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). In experimental endocarditis, however, Q-D was less efficacious against MRSA isolates constitutively resistant to macrolide-lincosamide-streptogram B (C-MLS(B)) than against MLS(B)-susceptible isolates. To circumvent this problem, we used the checkerboard method to screen drug combinations that would increase the efficacy of Q-D against such bacteria. beta-Lactams consistently exhibited additive or synergistic activity with Q-D. Glycopeptides, quinolones, and aminoglycosides were indifferent. No drugs were antagonistic. The positive Q-D-beta-lactam interaction was independent of MLS(B) or beta-lactam resistance. Moreover, addition of Q-D at one-fourth the MIC to flucloxacillin-containing plates decreased the flucloxacillin MIC for MRSA from 500 to 1,000 mg/liter to 30 to 60 mg/liter. Yet, Q-D-beta-lactam combinations were not synergistic in bactericidal tests. Rats with aortic vegetations were infected with two C-MLS(B)-resistant MRSA isolates (isolates AW7 and P8) and were treated for 3 or 5 days with drug dosages simulating the following treatments in humans: (i) Q-D at 7 mg/kg two times a day (b.i.d.) (a relatively low dosage purposely used to help detect positive drug interactions), (ii) cefamandole at constant levels in serum of 30 mg/liter, (iii) cefepime at 2 g b.i.d., (iv) Q-D combined with either cefamandole or cefepime. Any of the drugs used alone resulted in treatment failure. In contrast, Q-D plus either cefamandole or cefepime significantly decreased valve infection compared to the levels of infection for both untreated controls and those that received monotherapy (P < 0.05). Importantly, Q-D prevented the growth of highly beta-lactam-resistant MRSA in vivo. The mechanism of this beneficial drug interaction is unknown. However, Q-D-beta-lactam combinations might be useful for the treatment of complicated infections caused by multiple organisms, including MRSA.

History of the rare cancer network and past research.

Approximately, twenty years ago, the Rare Cancer Network (RCN) was formed in Lausanne, Switzerland, to support the study of rare malignancies. The RCN has grown over the years and now includes 130 investigators from twenty-four nations on six continents. The network held its first international symposium in Nice, France, on March 21-22, 2014. The proceedings of that meeting are presented in two companion papers. This manuscript reviews the history of the growth of the RCN and contains the abstracts of fourteen oral presentations made at the meeting of prior RCN studies. From 1993 to 2014, 74 RCN studies have been initiated, of which 54 were completed, 10 are in progress or under analysis, and 9 were stopped due to poor accrual. Forty-four peer reviewed publications have been written on behalf of the RCN.

Novel therapeutic strategies targeting regulatory T cells and downstream TCR signaling in transplantation

Avec plus de 100000 transplantations d'organes solides (TOS) par année dans le monde, la transplantation d'organes reste actuellement l'un des meilleurs traitements disponibles pour de nombreuses maladies en phase terminale. Bien que les médicaments immunosuppresseurs couramment utilisés soient efficaces dans le contrôle de la réponse immune engendrant le rejet aigu d'une greffe, la survie du greffon à long terme ainsi que la présence d'effets secondaires indésirables restent un enjeu considérable en clinique. C'est pourquoi il est nécessaire de trouver de nouvelles approches thérapeutiques innovantes permettant de contrôler la réponse immunitaire et ainsi d'améliorer les résultats à long terme. L'utilisation des lymphocytes T régulateurs (Treg), suppresseurs naturels de la réponse inflammatoire, a fait l'objet de nombreuses études ces dix dernières années, et pourrait être considérée comme un moyen intéressant d'améliorer la tolérance immunologique de la greffe. Cependant, l'un des obstacles de l'utilisation des Treg comme agent thérapeutique est leur nombre insuffisant non seulement en conditions normales, mais en particulier lors d'une forte réponse immune avec expansion de cellules immunitaires alloréactives. En raison des limitations techniques connues pour l'induction des Treg ex-vivo ou in vitro, nous avons dédié la première partie du travail de thèse à la détermination de l'efficacité de l'induction des Treg in vivo grâce à l'utilisation d'un complexe protéique IL-2/JES6-1 (IL2c). Nous avons montré que l'expansion des Treg par IL2c permettait d'augmenter la survie du greffon sur un modèle murin de transplantation de peau avec mismatch entre le donneur et le receveur pour le complexe majeur d'histocompatibilité (CMH). De plus, nous avons vu qu'en combinant IL2c à une inhibition à court terme de la voie de co-stimulation CD40L-CD40 (anti-CD154/MRl, administré au moment de la transplantation) pour empêcher l'activation des lymphocytes T, il est possible d'induire une tolérance robuste à long terme. Finalement, nos résultats soulignent l'importance de cibler une voie de co-stimulation bien particulière. En effet, l'utilisation d'IL2c combinée au blocage de la co-stimulation CD28-B7.1/2 (CTLA-4 Ig) n'induit qu'une faible prolongation de la survie de la greffe et n'induit pas de tolérance. L'application chez l'humain des traitements induisant la tolérance dans des modèles expérimentaux murins ou de primates n'a malheureusement pas montré de résultats probants en recherche clinique ; une des principales raisons étant la présence de lymphocytes B et T mémoires provenant du systeme d immunité acquise. C est pourquoi nous avons testé si la combinaison d'IL2c et MR1 améliorait la survie de la greffe dans des souris pré¬sensibilisées. Nous avons trouvé qu'en présence de lymphocytes B et T mémoires alloréactifs, l'utilisation d'IL2c et MR1 permettait une amélioration de la survie de la greffe de peau des souris immunocompétentes mais comparé aux souris receveuses naïves, aucune tolérance n'a pu être induite. Toutefois, l'ajout d'un traitement anti-LFA-1 (permettant de bloquer la circulation des lymphocytes T activées) a permis d'améliorer de manière significative la survie de la greffe. Cependant, le rejet chronique, dû à la présence de lymphocytes B activés/mémoires et la production d'anticorps donneur-spécifiques, n'a pas pu être évité. Cibler l'activation des lymphocytes T est la stratégie immunothérapeutique prépondérente après une TOS. C'est pourquoi dans la deuxième partie de cette thèse nous nous sommes intéressés au système de signalisation d'un récepteur des lymphocytes T qui dépend de la paracaspase Malti en tant que nouvelle stratégie immunosuppressive pour le contrôle des lymphocytes T alloréactifs. Nous avons montré que bien que l'inhibition de la signalisation du lymphocyte T en aval de Malti induise une tolérance envers un greffon de peau avec incompatibilités antigéniques mineures, cela ne permet cependant qu'une régulation partielle de l'alloréponse contre des antigènes du CMH. Nous nous sommes aussi intéressés spécifiquement à l'activité protéolytique de Malti. L'inhibition constitutive de l'activité protéolytique de Malti chez les souris Malti-ki s'est révélée délétère pour l'induction de la tolérance car elle diminue la fonction des Treg et augmente l'alloréactivité des cellules Thl. Cependant, lors de l'utilisation d'un inhibiteur peptidique de l'activité protéase de Malti in vitro, il a été possible d'observer une atténuation de l'alloéactivité des lymphocytes T ainsi qu'un maintien de la population des Treg existants. Ces résultats nous laissent penser que des études plus poussées sur le rôle de la signalisation médiée par Malti seraient à envisager dans le domaine de la transplantation. En résumé, les résultats obtenus durant cette thèse nous ont permis d'élucider certains mécanismes immunologiques propres à de nouvelles stratégies thérapeutiques potentielles dont le but est d'induire une tolérance lors de TOS. De plus, ces résultats nous ont permis de souligner l'importance d'utiliser des modèles davantage physiologiques contenant, notamment en tenant compte des lymphocytes B et T mémoires alloréactifs. -- Organ transplantation remains the best available treatment for many forms of end-stage organ diseases, with over 100,000 solid organ transplantations (SOT) occurring worldwide eveiy year. Although the available immunosuppressive (IS) drugs are efficient in controlling acute immune activation and graft rejection, the off-target side effects as well as long-term graft and patient survival remain a challenge in the clinic. Hence, innovative therapeutic approaches are needed to improve long-term outcome across immunological barriers. Based on extensive experimental data obtained over the last decade, it is tempting to consider immunotherapy using Treg; the natural suppressors of overt inflammatory responses, in promoting transplantation tolerance. The first hurdle for the therapeutic use of Treg is their insufficient numbers in non- manipulated individuals, in particular when facing strong immune activation and expanding alloreactive effector cells. Because of the limitations associated with current protocols aiming at ex-vivo expansion or in vitro induction of Treg, the aim of the first part of this thesis was to determine the efficacy of direct in vivo expansion of Treg using the IL-2/JES6- 1 immune complex (IL2c). We found that whilst IL2c mediated Treg expansion alone allowed the prolonged graft survival of fìlli MHC-mismatched skin grafts, its combination with short-term CD40L-CD40 co-stimulation blockade (anti-CD 154/MR1) to inhibit T cell activation administered at the time of transplantation was able to achieve long-term robust tolerance. This study also highlighted the importance of combining Treg based therapies with the appropriate co-stimulation blockade as a combination of IL2c and CD28-B7.1/2 co- stimulation blockade (CTLA-4 Ig) only resulted in slight prolongation of graft survival but not tolerance. The translation of tolerance induction therapies modelled in rodents into non-human primates or into clinical trials has seldom been successful. One main reason being the presence of pre-existing memory T- and B-cells due to acquired immunity in humans versus laboratory animals. Hence, we tested whether IL2c+MRl could promote graft survival in pre-sensitized mice. We found that in the presence of alloreactive memory T- and B-cells, IL2c+MRl combination therapy could prolong MHC-mismatched skin graft survival in immunocompetent mice but tolerance was lost compared to the naïve recipients. The addition of anti-LF A-1 treatment, which prevents the trafficking of memory T cells worked synergistically to significantly further enhance graft survival. However, late rejection mediated by activated/memory B cells and persistent donor-specific alloantibodies still occurred. Immunotherapeutic strategies targeting the activation of T cells are the cornerstone in the current immunosuppressive management after SOT. Therefore, in the next part of this thesis we investigated the paracaspase Malti-dependent T-cell receptor signalling as a novel immunosuppressive strategy to control alloreactive T cells in transplantation. We observed that although the inhibition of Malti downstream T signalling lead to tolerance of a minor H- mismatch skin grafts, it was however not sufficient to regulate alloresponses against MHC mismatches and only prolonged graft survival. Furthermore, we investigated the potential of more selectively targeting the protease activity of Malti. Constitutive inhibition of Malti protease activity in Malti-ki mice was detrimental to tolerance induction as it diminished Treg function and increased Thl alloreactivity. However, when using a small peptide inhibitor of Malti proteolytic activity in vitro, we observed an attenuation of alloreactive T cells and sparing of the pre-existing Treg pool. This indicates that further investigation of the role of Malti signalling in the field of transplantation is required. Collectively, the findings of this thesis provide immunological mechanisms underlying novel therapeutic strategies for the promotion of tolerance in SOT. Moreover, we highlight the importance of testing tolerance induction therapies in more physiological models with pre-existing alloreactive memory T and B cells.

Sustained-release steroids for the treatment of diabetic macular edema.

Glucocorticoids have been used for decades in the treatment of ocular disorders via topical, periocular, and more recently intravitreal routes. However, their exact mechanisms of action on ocular tissues remain imperfectly understood. Fortunately, two recently approved intravitreal sustained-release drug delivery systems have opened new perspectives for these very potent drugs. To date, among other retinal conditions, their label includes diabetic macular edema, for which a long-lasting therapeutic effect has been demonstrated both morphologically and functionally in several randomized clinical trials. The rate of ocular complications of intravitreal sustained-release steroids, mainly cataract formation and intraocular pressure elevation, is higher than with anti-vascular endothelial growth factor agents. Yet, a better understanding of the mechanisms underlying these adverse effects and the search for the minimal efficient dose should help optimize their therapeutic window.

The use of beta-blockers is associated with the occurrence of acute kidney injury in severe alcoholic hepatitis.

BACKGROUND & AIMS: The beneficial effect of nonselective beta-blockers (NSBB) has recently been questioned in patients with end-stage cirrhosis. We analysed the impact of NSBB on outcomes in severe alcoholic hepatitis (AH). METHODS: This study was based on a prospective database of patients with severe, biopsy-proven AH. Patients admitted from July, 2006 to July, 2014 were retrospectively studied. Patients were divided into two groups (with and without NSBB) and assessed for the occurrence of Acute Kidney Injury (AKI) and transplant-free mortality during a 168-day follow-up period. RESULTS: One hundred thirty-nine patients were included, the mean Maddrey score was 71 ± 34 and 86 patients (61.9%) developed AKI. Forty-eight patients (34.5%) received NSBB. The overall 168-day transplant-free mortality was 50.5% (95%CI, 41.3-60.0%). The overall 168-day cumulative incidence of AKI was 61.9% (95%CI, 53.2-69.4%). When compared, patients with NSBB had a lower heart rate (65 ± 13 vs 92 ± 12, P < 0.0001) and a lower mean arterial pressure (MAP, 78 ± 3 vs 87 ± 5, P < 0.0001). Patients with NSBB had comparable MELD scores, Maddrey scores, and medical histories. The 168-day transplant-free mortality was 56.8% (95%CI, 41.3-69.7%) in patients with NSBB and 46.7% (95%CI, 35.0-57.6%) without NSBB (P = 0.25). The 168-day cumulative incidence of AKI was 89.6% (95%CI, 74.9-95.9%) with NSBB compared to 50.4% (95%CI: 39.0-60.7) for no NSBB (P = 0.0001). The independent factors predicting AKI were a higher MELD score and the presence of NSBB. CONCLUSIONS: The use of NSBB in patients with severe AH is independently associated with a higher cumulative incidence of AKI.

Therapeutic drug monitoring of targeted anticancer therapy.

New oral targeted anticancer therapies are revolutionizing cancer treatment by transforming previously deadly malignancies into chronically manageable conditions. Nevertheless, drug resistance, persistence of cancer stem cells, and adverse drug effects still limit their ability to stabilize or cure malignant diseases in the long term. Response to targeted anticancer therapy is influenced by tumor genetics and by variability in drug concentrations. However, despite a significant inter-patient pharmacokinetic variability, targeted anticancer drugs are essentially licensed at fixed doses. Their therapeutic use could however be optimized by individualization of their dosage, based on blood concentration measurements via the therapeutic drug monitoring (TDM). TDM can increase the probability of therapeutic responses to targeted anticancer therapies, and would help minimize the risk of major adverse reactions.

Managing the Sick Child in the Era of Declining Malaria Transmission: Development of ALMANACH, an Electronic Algorithm for Appropriate Use of Antimicrobials.

OBJECTIVE: To review the available knowledge on epidemiology and diagnoses of acute infections in children aged 2 to 59 months in primary care setting and develop an electronic algorithm for the Integrated Management of Childhood Illness to reach optimal clinical outcome and rational use of medicines. METHODS: A structured literature review in Medline, Embase and the Cochrane Database of Systematic Review (CDRS) looked for available estimations of diseases prevalence in outpatients aged 2-59 months, and for available evidence on i) accuracy of clinical predictors, and ii) performance of point-of-care tests for targeted diseases. A new algorithm for the management of childhood illness (ALMANACH) was designed based on evidence retrieved and results of a study on etiologies of fever in Tanzanian children outpatients. FINDINGS: The major changes in ALMANACH compared to IMCI (2008 version) are the following: i) assessment of 10 danger signs, ii) classification of non-severe children into febrile and non-febrile illness, the latter receiving no antibiotics, iii) classification of pneumonia based on a respiratory rate threshold of 50 assessed twice for febrile children 12-59 months; iv) malaria rapid diagnostic test performed for all febrile children. In the absence of identified source of fever at the end of the assessment, v) urine dipstick performed for febrile children <2 years to consider urinary tract infection, vi) classification of 'possible typhoid' for febrile children >2 years with abdominal tenderness; and lastly vii) classification of 'likely viral infection' in case of negative results. CONCLUSION: This smartphone-run algorithm based on new evidence and two point-of-care tests should improve the quality of care of <5 year children and lead to more rational use of antimicrobials.

Cardiologie [Cardiology update in 2014].

Important clinical trials and therapeutic advances in the field of cardiology have been presented in 2014. New evidences on the management of acute myocardial infarction and the duration of dual antiplatelet therapy after coronary stent implantation have been published. A new class of therapeutic agents seems to offer promising perspectives for patients with heart failure and reduced ejection fraction. The new generation of subcutaneous or MRI-compatible implantable defibrillators is a major technological breakthrough. Finally, the European Society of Cardiology published new recommendations for the management of patients with cardiovascular diseases. This selective review of the literature summarizes the most important studies in the field of interventional cardiology, rhythmology, heart failure and cardiac imaging.

The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.

UNLABELLED: Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7-7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4-5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46-103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1-2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir. TRIAL REGISTRATION: clinicaltrials.gov NTC02092116.

Analytical Strategies for Doping Control Purposes: Needs, Challenges, and Perspectives.

The fight against doping in sports has been governed since 1999 by the World Anti-Doping Agency (WADA), an independent institution behind the implementation of the World Anti-Doping Code (Code). The intent of the Code is to protect clean athletes through the harmonization of anti-doping programs at the international level with special attention to detection, deterrence and prevention of doping.1 A new version of the Code came into force on January 1st 2015, introducing, among other improvements, longer periods of sanctioning for athletes (up to four years) and measures to strengthen the role of anti-doping investigations and intelligence. To ensure optimal harmonization, five International Standards covering different technical aspects of the Code are also currently in force: the List of Prohibited Substances and Methods (List), Testing and Investigations, Laboratories, Therapeutic Use Exemptions (TUE) and Protection of Privacy and Personal Information. Adherence to these standards is mandatory for all anti-doping stakeholders to be compliant with the Code. Among these documents, the eighth version of International Standard for Laboratories (ISL), which also came into effect on January 1st 2015, includes regulations for WADA and ISO/IEC 17025 accreditations and their application for urine and blood sample analysis by anti-doping laboratories.2 Specific requirements are also described in several Technical Documents or Guidelines in which various topics are highlighted such as the identification criteria for gas chromatography (GC) and liquid chromatography (LC) coupled to mass spectrometry (MS) techniques (IDCR), measurements and reporting of endogenous androgenic anabolic agents (EAAS) and analytical requirements for the Athlete Biological Passport (ABP).

Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial.

IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.

Patterns of care in recurrent glioblastoma in Switzerland: a multicentre national approach based on diagnostic nodes.

Despite moderate improvements in outcome of glioblastoma after first-line treatment with chemoradiation recent clinical trials failed to improve the prognosis of recurrent glioblastoma. In the absence of a standard of care we aimed to investigate institutional treatment strategies to identify similarities and differences in the pattern of care for recurrent glioblastoma. We investigated re-treatment criteria and therapeutic pathways for recurrent glioblastoma of eight neuro-oncology centres in Switzerland having an established multidisciplinary tumour-board conference. Decision algorithms, differences and consensus were analysed using the objective consensus methodology. A total of 16 different treatment recommendations were identified based on combinations of eight different decision criteria. The set of criteria implemented as well as the set of treatments offered was different in each centre. For specific situations, up to 6 different treatment recommendations were provided by the eight centres. The only wide-range consensus identified was to offer best supportive care to unfit patients. A majority recommendation was identified for non-operable large early recurrence with unmethylated MGMT promoter status in the fit patients: here bevacizumab was offered. In fit patients with late recurrent non-operable MGMT promoter methylated glioblastoma temozolomide was recommended by most. No other majority recommendations were present. In the absence of strong evidence we identified few consensus recommendations in the treatment of recurrent glioblastoma. This contrasts the limited availability of single drugs and treatment modalities. Clinical situations of greatest heterogeneity may be suitable to be addressed in clinical trials and second opinion referrals are likely to yield diverging recommendations.

L'année 2014 mise en perspective par les internistes hospitaliers [What is new in 2014 for the specialist in hospital internal medicine? The point of view of university hospital chief residents].

The year 2014 was rich in significant advances in all areas of internal medicine. Many of them have an impact on our daily practice and on the way we manage one problem or another. From the use of the ultrasound for the diagnosis of pneumonia to the choice of the site of venous access and the type of line, and the increasing complexity of choosing an oral anticoagulant agent, this selection offers to the readers a brief overview of the major advances. The chief residents in the Service of internal medicine of the Lausanne University hospital are pleased to share their readings.