An updated model of hydrocephalus in sheep to evaluate the performance of a device for ambulatory wireless monitoring of cerebral pressure through shunts.

BACKGROUND: Cerebrospinal fluid (CSF) diversion by shunts is the most common surgical treatment for hydrocephalus. Though effective, shunts are associated with risk of dysfunction leading to multiple surgical revisions, affecting patient quality-of-life and incurring high healthcare costs. There is a need for ambulatory monitoring systems for life-long assessment of shunt status. The present study aimed to develop a preclinical model assessing the feasibility of our wireless device for continuous monitoring of cerebral pressure in shunts. METHODS: We first adapted a previous hydrocephalus model in sheep, which used an intracisternal kaolin injection. Seven animals were used to establish the model, and 1 sheep with naturally dilated ventricles was used as control. Hydrocephalus was confirmed by clinical examination and brain imaging before inserting the ventriculoperitoneal shunts and the monitoring device allowing continuous measurement of the pressure through the shunt for a few days in 3 sheep. An external ventricular drain was used as gold standard. RESULTS: Our results showed that a reduction in kaolin dose associated to postoperative management was crucial to reduce morbidity and mortality rates in the model. Ventriculomegaly was confirmed by imaging 4 days after injection of 75mg kaolin into the cisterna magna. For the implanted sheep, recordings revealed high sensitivity of our sensor in detecting fluctuations in cerebral pressure compared to conventional measurements. CONCLUSIONS: This proof-of-concept study highlights the potential of this preclinical model for testing new shunt devices.

Use of a Multiplex PCR Assay To Assess the Presence of Treponema pallidum in Mucocutaneous Ulcerations in Patients with Suspected Syphilis.

We evaluated the utility of the commercial Allplex genital ulcer real-time PCR multiplex assay for detecting Treponema pallidum, herpes simplex virus 1 (HSV-1) and 2 (HSV-2), and Chlamydia trachomatis serovar L (lymphogranuloma venereum [LGV]) DNA in mucosal and genital ulcers in the context of suspected syphilis. In total, 374 documented genital and mucosal ulcers from patients with and without syphilis presenting at several sexually transmitted infection (STI) centers in France from October 2010 to December 2016 were analyzed at the National Reference Center (CNR) for Bacterial STIs at Cochin Hospital in Paris. T. pallidum subsp. pallidum detection results were compared with the final diagnosis based on a combination of clinical examination, serological results, and in-house nested PCR (nPCR). Detections of HSV and LGV were validated against reference methods. We found that 44.6% of the 374 samples tested were positive for T. pallidum subsp. pallidum, 21% for HSV, and 0.8% for LGV. No positive results were obtained for 30.7% of samples, and 4.8% presented coinfections. For T. pallidum subsp. pallidum detection, the overall sensitivity was 80% (95% confidence interval [CI], 76.1 to 84.1%), specificity was 98.8% (95% CI, 97.7 to 99.9%), positive predictive value was 98.8% (95% CI, 97.7 to 99.9%) and negative predictive value was 80.2% (95% CI, 76.2 to 84.2%), with a rate of concordance with the reference method of 92.5% (k = 0.85). This PCR multiplex assay is suitable for T. pallidum subsp. pallidum detection in routine use and facilitates the simultaneous rapid detection of a broad panel of pathogens relevant in a context of suspected syphilis lesions.

[Atypical hand, foot and mouth disease in adults: A note on 6 cases]. / Syndrome main-pied-bouche atypique de l'adulte : à propos de 6 observations.

INTRODUCTION: Hand, foot and mouth disease (HFMD) is form of viral dermatosis well known among the pediatric population, in whom it has a typical presentation. However, it is less common in adults, with a more heterogeneous presentation, potentially making diagnosis extremely challenging for the clinician. PATIENTS AND METHODS: This was a retrospective case series from 2013 to 2018 of HFMD in adults, with all cases being confirmed by cutaneous polymerase chain reaction (PCR). We studied the clinical, epidemiological and viral characteristics of each patient. RESULTS: This series of 6 cases comprised 4 men and 2 women, with a mean age of 42.5 years. Five patients presented extended purpuric lesions, four had bullous lesions, and three showed cutaneous signs without any mucosal lesions. Extended lesions on the trunk were found in four patients. One patient presented rosette-shaped pustular lesions on the limbs, one had eczema-like lesions on the scalp, and one presented extended purpuric lesions on the soles. DISCUSSION: These different cases of adult HFMD raise questions about differential diagnosis in relation to other acute cutaneous and mucous diseases. It is essential to be aware of these different types of presentation of the disease in order to determine the diagnosis and discuss preventive measures.

Effect of a prospective audit with intervention and feedback on Clostridioides difficile infection management.

Background Clostridioides difficile infections are associated with morbidity and mortality in several countries. Their increasing incidence and frequent recurrence make them an urgent public health threat. The lack of adherence to international treatment guidelines for Clostridioides difficile infections is a proven mortality risk factor. Objective To evaluate long-term prescribers' adherence to recommendations on the management of Clostridioides difficile infections and its impact on clinical outcomes after an educational and Clostridioides difficile-prospective audit with intervention and feedback period. Setting All patients admitted to a 1500-bed university hospital with positive Clostridioides difficile tests identified were included. Methods Data were collected retrospectively over a baseline period (May-November 2014) and prospectively over a Clostridioides difficile-prospective audit with intervention and feedback period (November 2015-May 2016) and an observation period (November 2017-September 2018). All Clostridioides difficile cases were reviewed by a Clostridioides difficile-prospective audit with intervention and feedback team composed of pharmacists, an infectious diseases specialist and a microbiologist to obtain a complete overview of patient records in each area of expertise. Main outcome measures Percentage of conformity to the protocol, percentage of recovery at 10 days and percentage of relapse, as well as Clostridioides difficile incidence and percentage of Fidaxomicin use. Results A total of 183 patients were included over the three periods. A significant improvement in conformity to the local protocol was observed between the intervention period (23.9%) and the observation period (67.3%) (P < 10-3). Fidaxomicin prescriptions increased significantly (P = 0.006). Clinical outcomes improved significantly with an increase in the percentage of recovery at 10 days (P = 0.001) and a decrease in the percentage of relapse (P = 0.016). The Clostridioides difficile incidence rate improved significantly to 1.3 per 10,000 patient-days during the observation period. Conclusion This study shows the lasting effect of an educational and Clostridioides difficile-prospective audit with intervention and feedback period on prescribers' adherence to recommendations and a significant impact on clinical outcomes.

Assessing the relevance of carbapenem prescriptions by an antibiotic stewardship team.

OBJECTIVES: To assess the level and factors of compliance of carbapenem prescriptions with guidelines and to determine the impact of an antibiotic stewardship team in a university hospital. PATIENTS AND METHODS: Five-month prospective study in the intensive care, surgery, and medicine units to measure the compliance of carbapenem prescriptions with guidelines from French scientific societies; compliance was assessed by an infectious disease specialist warned by the pharmacy, and the prescribers' compliance with the infectious disease specialist's advice was then assessed. RESULTS: One hundred and four treatment initiations for 94 patients were included. Prescriptions were mostly empirical (64%), for pulmonary (35%), urinary tract (23%), and intra-abdominal (17%) infections. Prescriptions were mostly made in an intensive care unit (50%), by a junior physician (66%), with the use of imipenem (74%), and were followed by an objective reassessment (80%). Compliance with guidelines (82%) was significantly higher for empirical than documented prescriptions (91% vs 65%, P<0.001). Compliance was higher in intensive care units than medicine units (87% vs 61%, P=0.037). No change in the compliance rate was observed during the study. Compliance with the infectious disease specialist's advice (68%) improved, although not significantly (P=0.066). CONCLUSIONS: Because of a higher than expected compliance of carbapenem prescriptions with guidelines and a lower than expected inclusions in the study, we did not show any impact. The diffusion of guidelines and long-term control of carbapenem prescriptions seem to be possible and necessary in hospitals to limit their ecological impact.

Be careful about MICs to amoxicillin for patients with Streptococci-related infective endocarditis.

BACKGROUND: A variety of microorganisms can cause infective endocarditis (IE), with Staphylococci and Streptococci accounting for the majority of cases. Streptococci are a common cause of community-acquired IE but few studies have focused on this subgroup of endocarditis. METHODS: A retrospective multicentre study was conducted between 2012 and 2017 in 12 hospital centres in France. Data were extracted from the local diagnosis-related group database and matched with microbiological results. After identification, the records were retrospectively analysed. RESULTS: A total of 414 patients with streptococcal endocarditis were included. The patients were predominantly male (72.8%) and the median age was 73.2 years (interquartile range [IQR] 61.3-80.9). The majority of patients (70.6%) had native valve endocarditis. Embolic complications were seen in 38.8% of patients. Viridans group Streptococci (VGS) and bovis-equinus group Streptococci (BGS) accounted for 52.4% and 34.5% of isolated strains, respectively. Minimum inhibitory concentrations (MICs) of amoxicillin were <0.125, 0.125-2 and >2 mg/L for 59.6%, 27% and 1% of isolates, respectively. In-hospital mortality for patients with Streptococci-related IE was 17.8%. In multivariate analysis, the only factor associated with in-hospital mortality was MIC for amoxicillin between 0.25 and 2 mg/L (P = 0.04; OR = 2.23 [95% confidence interval (CI) 1.03-4.88]) whereas performance of cardiac surgery for IE was a protective factor (P = 0.001, OR = 0.23 [95% CI 0.1-0.56]). CONCLUSIONS: IE remains a serious and deadly disease despite recent advances in diagnosis and treatment. Adaptation of antibiotic doses to MICs for amoxicillin and surgery may improve patient outcome.

[Mindful neuropsychology: Mindfulness-based cognitive remediation]. / Mindful neuropsychology : repenser la réhabilitation neuropsychologique à travers la pleine conscience.

OBJECTIVES: Mindfulness based interventions (MBI) have recently gained much interest in western medicine. MBSR paradigm is based on teaching participants to pay complete attention to the present experience and act nonjudgmentally towards stressful events. During this mental practice the meditator focuses his or her attention on the sensations of the body. While the distractions (mental images, thoughts, emotional or somatic states) arise the participant is taught to acknowledge discursive thoughts and cultivate the state of awareness without immediate reaction. The effectiveness of these programs is well documented in the field of emotional response regulation in depression (relapse prevention), anxiety disorders, obsessive-compulsive disorder or eating disorders. Furthermore, converging lines of evidence support the hypothesis that mindfulness practice improves cognition, especially the ability to sustain attention and think in a more flexible manner. Nevertheless, formal rehabilitation programs targeting cognitive disturbances resulting from psychiatric (depression, disorder bipolar, schizophrenia) or neurologic conditions (brain injury, dementia) seldom rely on MBI principles. This review of literature aims at discussing possible links between MBI and clinical neuropsychology. METHODS: We conducted a review of literature using electronic databases up to December 2016, screening studies with variants of the keywords ("Mindfulness", "MBI", "MBSR", "Meditation") OR/AND ("Cognition", "Attention", "Executive function", "Memory", "Learning") RESULTS: In the first part, we describe key concepts of the neuropsychology of attention in the light of Posner's model of attention control. We also underline the potential scope of different therapeutic contexts where disturbances of attention may be clinically relevant. Second, we review the efficacy of MBI in the field of cognition (thinking disturbances, attention biases, memory and executive processes impairment or low metacognitive abilities), mood (emotional dysregulation, anxiety, depression, mood shifts) and somatic preoccupations (stress induced immune dysregulation, chronic pain, body representation, eating disorders, sleep quality, fatigue). In psychiatry, these three components closely coexist and interact which explains the complexity of patient assessment and care. Numerous studies show that meditation inspired interventions offer a promising solution in the prevention and rehabilitation of cognitive impairment. In the last part, we discuss the benefits and risks of integrating meditation practice into broader programs of cognitive remediation and therapeutic education in patients suffering from cognitive disorders. We propose a number of possible guidelines for developing mindfulness inspired cognitive remediation tools. Along with Jon Kabatt Zinn (Kabatt-Zinn & Maskens, 2012), we suggest that the construction of neuropsychological tools relies on seven attitudinal foundations of mindfulness practice. CONCLUSIONS: This paper highlights the importance of referring to holistic approaches such as MBI when dealing with patients with neuropsychological impairment, especially in the field of psychiatry. We advocate introducing mindfulness principles in order to help patients stabilize their attention and improve cognitive flexibility. We believe this transition in neuropsychological care may offer an interesting paradigm shift promoting a more efficient approach towards cognition and its links to emotion, body, and environment.

Dermatological emergencies: evolution from 2008 to 2014 and perspectives.

BACKGROUND: Our dermatological department includes a dermatological emergency unit (DEU) whose activity has grown in recent years. OBJECTIVES: An audit to characterize the activity of our DEU and its evolution in terms of medical demographics of the area. METHODS: We collected the following data from administrative services: number of patients consulting each year in the DEU and in the general emergency unit (GEU) of our hospital between 2008 and 2014; daily and seasonal activity of the DEU; occurrence of a second event in the department and proportion of patients from the DEU who were hospitalized and why. From the medical charts of a random sample of patients consulting in the first 15 days of January and August 2014, we studied the epidemiological profile, time to consultation and diagnoses. Data related to medical demographics (number of general practitioners and dermatologists) between 2007 and 2014 and projections were obtained. RESULTS: The activity in the DEU increased by 67% between 2008 and 2014 but remained stable in the GEU over the same period. The activity was higher on Mondays and in the summer (+30%). More than 15% of the patients were seen a second time in outpatient consultation; 1.2% were hospitalized. Infectious dermatosis was the main reason for consultation; seasonal-disease consultations were more frequent in the summer. Less than 40% of patients consulted in the first week after disease onset. Medical demographics continually decreased since 2007 in Paris and suburbs and will continue to decrease in the next years. CONCLUSION: The increasing activity of our DEU parallels the decrease in medical demographics in Paris. The proportion of patients hospitalized was low, in part due to specific healthcare networks implemented for some life-threatening dermatoses independent of the DEU. A better coordination between hospital and private practitioners for managing dermatologic emergencies, taking into account the decrease in medical demographics, is warranted.

In vitro antimicrobial susceptibility of Helcococcus kunzii and molecular analysis of macrolide and tetracycline resistance.

Thanks to the recent advent of matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) technology, Helcococcus kunzii is now easily identifiable and considered as an opportunistic pathogen. However, data about antimicrobial susceptibilities remain very limited. The aim of the study was, then, to assess its in vitro susceptibility to 18 antimicrobial agents and to investigate the genetic basis of macrolide and tetracycline resistance. Thirty-nine human clinical isolates of H. kunzii collected from 2008 to 2013 were studied, as well as the type strain ATCC 51366(T). Minimum inhibitory concentrations (MICs) of penicillin G, amoxicillin, cefotaxime, imipenem, gentamicin, erythromycin, clindamycin, quinupristin-dalfopristin, ciprofloxacin, levofloxacin, tetracycline, tigecycline, vancomycin, teicoplanin, linezolid, daptomycin, cotrimoxazole and rifampin were determined by the microdilution method. Screening for macrolide [erm(A) including erm(TR), erm(B), erm(C), erm(F), erm(T), erm(X), msr(A) and mef(A)] and tetracycline [tet(L), tet(M) and tet(O)] resistance genes was performed, as well as the detection of mutations in 23S rRNA. Except for one strain resistant to cefotaxime, all strains were categorised as susceptible to ß-lactams, glycopeptides, linezolid, daptomycin and tigecycline. Whereas ciprofloxacin and gentamicin exhibited limited activity, 95% of strains were categorised as susceptible to levofloxacin. Concerning erythromycin, a bimodal distribution was observed, with 29 'wild-type' strains (MICs from 0.25 to 2 mg/L) and 11 'resistant' strains (MICs ≥ 256 mg/L), including ten harbouring erm(TR). Two isolates exhibited acquired tetracycline resistance (MICs of 16 mg/L) by the production of tet(M). This large study on the in vitro antimicrobial susceptibility of H. kunzii suggests that ß-lactams (especially penicillins) should be preferred for the treatment.

Genomic organization, chromosomal assignment, and expression analysis of the mouse suppressor of fused gene (Sufu) coding a Gli protein partner.

Suppressor of fused (Sufu) is a negative regulator of the Hedgehog pathway both in Drosophila and vertebrates. Here, we report the genomic organization of the mouse Sufu gene (mSufu). This gene comprises 11 exons spanning more than 30 kb and encodes a protein with a putative PEST sequence. DNA-consensus sequences recognized by basic helix-loop-helix (bHLH) proteins, referred to as E-box motifs, are found in the 5' flanking region. Analysis by single-strand conformation polymorphism and radiation hybrid positioned the Sufu locus to the distal end of mouse Chr 19 between D19Mit102 and D19Mit9, near the Fgf8 and dactylin genes. Mouse Sufu is expressed in various tissues, particularly in the nervous system, ectoderm, and limbs, throughout the developing embryo. Sufu binds with all three Gli proteins, with different affinities. This report, in conjunction with recent studies, points out the importance of Sufu in mouse embryonic development.

Modulation of Hedgehog target gene expression by the Fused serine-threonine kinase in wing imaginal discs.

The Fused (Fu) serine-threonine kinase and the Suppressor of fused (Su(fu)) product are part of the Hedgehog (Hh) signaling pathway both in embryos and in imaginal discs. In wing imaginal discs, the Hh signal induces Cubitus interruptus (Ci) accumulation and activates patched (ptc) and decapentaplegic (dpp) expression along the anterior/posterior (A/P) boundary. In this paper, we have examined the role of the Fu and Su(fu) proteins in the regulation of Hh target gene expression in wing imaginal discs, by using different classes of fu alleles and an amorphic Su(fu) mutation. We show that, at the A/P boundary, Fu kinase activity is involved in the maintenance of high ptc expression and in the induction of late anterior engrailed (en) expression. These combined effects can account for the modulation of Ci accumulation and for the precise localization of the Dpp morphogen stripe. In contrast, in more anterior cells which do not receive Hh signal, we show that Fu plays a role independent of its kinase function in the regulation of Ci accumulation. In these cells, Fu may be involved in the stabilization of a large protein complex which is probably responsible for the regulation of Ci cleavage and/or targeting to nucleus. We propose that the Fused function is necessary for the activation of full-length Ci and counteracts the negative Su(fu) effect on the pathway, leading to en, ptc and dpp expression.

Suppressor of fused links fused and Cubitus interruptus on the hedgehog signalling pathway.

The Hedgehog (Hh) family of signalling proteins [1] mediate inductive interactions either directly or by controlling the transcription of other secreted proteins through the action of Gli transcription factors, such as Cubitus interruptus (Ci) [2]. In Drosophila, the transcription of Hh targets requires the activation of the protein kinase Fused (Fu) and the inactivation of both Suppressor of fused (Su(fu)) and Costal-2 (Cos-2) [3]. Fu is required for Hh signalling in the embryo and in the wing imaginal disc and acts also as an antitumorigen in ovaries [4]. All fu- phenotypes are suppressed by the loss of function of Su(fu) [5]. Fu, Cos-2 and Ci are co-associated in vivo in large complexes that are bound to microtubules in a Hh-dependent manner [6,7]. Here we investigate the role of Su(fu) in the intracellular part of the Hh signalling pathway. Using the yeast two-hybrid method and an in vitro binding assay, we show that Su(fu), Ci and Fu can interact directly to form a trimolecular complex, with Su(fu) binding to both its partners simultaneously. Su(fu) and Ci also co-immunoprecipitate from embryo extracts. We propose that, in the absence of Hh signalling, Su(fu) inhibits Ci by binding to it and that, upon reception of the Hh signal, Fu is activated and counteracts Su(fu), leading to the activation of Ci.

Functional domains of fused, a serine-threonine kinase required for signaling in Drosophila.

fused (fu) is a segment-polarity gene encoding a putative serine-threonine kinase. In a wild-type context, all fu mutations display the same set of phenotypes. Nevertheless, mutations of the Suppressor of fused [Su(fu)] gene define three classes of alleles (fuO, fuI, fuII). Here, we report the molecular analysis of known fu mutations and the generation of new alleles by in vitro mutagenesis. We show that the Fused (Fu) protein functions in vivo as a kinase. The N-terminal kinase and the extreme C-terminal domains are necessary for Fu+ activity while a central region appears to be dispensable. We observe a striking correlation between the molecular lesions of fu mutations and phenotype displayed in their interaction with Su(fu). Indeed, fuI alleles which are suppressed by Su(fu) mutations are defined by inframe alterations of the N-terminal catalytic domain whereas the C-terminal domain is missing or altered in all fuII alleles. An unregulated FuII protein, which can be limited to the 80 N-terminal amino acids of the kinase domain, would be responsible for the neomorphic costal-2 phenotype displayed by the fuII-Su(fu) interaction. We propose that the Fu C-terminal domain can differentially regulate the Fu catalytic domain according to cell position in the parasegment.