Apnea of prematurity induces short and long-term development-related transcriptional changes in the murine cerebellum.

Apnea of prematurity (AOP) affects more than 50% of preterm infants and leads to perinatal intermittent hypoxia (IH) which is a major cause of morbimortality worldwide. At birth, the human cerebellar cortex is still immature, making it vulnerable to perinatal events. Additionally, studies have shown a correlation between cerebellar functions and the deficits observed in children who have experienced AOP. Yet, the cerebellar alterations underpinning this link remain poorly understood. To gain insight into the involvement of the cerebellum in perinatal hypoxia-related consequences, we developed a mouse model of AOP. Our previous research has revealed that IH induces oxidative stress in the developing cerebellum, as evidenced by the over-expression of genes involved in reactive oxygen species production and the under-expression of genes encoding antioxidant enzymes. These changes suggest a failure of the defense system against oxidative stress and could be responsible for neuronal death in the cerebellum. Building upon these findings, we conducted a transcriptomic study of the genes involved in the processes that occur during cerebellar development. Using real-time PCR, we analyzed the expression of these genes at different developmental stages and in various cell types. This enabled us to pinpoint a timeframe of vulnerability at P8, which represents the age with the highest number of downregulated genes in the cerebellum. Furthermore, we discovered that our IH protocol affects several molecular pathways, including proliferation, migration, and differentiation. This indicates that IH can impact the development of different cell types, potentially contributing to the histological and behavioral deficits observed in this model. Overall, our data strongly suggest that the cerebellum is highly sensitive to IH, and provide valuable insights into the cellular and molecular mechanisms underlying AOP. In the long term, these findings may contribute to the identification of novel therapeutic targets for improving the clinical management of this prevalent pathology.

Outreach, Screening, and Randomization of APOE ε4 Carriers into an Alzheimer's Prevention Trial: A global Perspective from the API Generation Program.

BACKGROUND: Alzheimer's disease (AD) prevention trials require a large outreach and screening funnel to identify cognitively unimpaired adults who meet the study's inclusion criteria, such as certain clinical or demographic criteria, genetic risk factors, and/or biomarker evidence of the disease. OBJECTIVES: Describe tactics and strategies to identify and enroll cognitively unimpaired adults with one (heterozygotes [HT]) or two (homozygotes [HM]) copies of the APOE ε4 allele, a genetic risk factor for dementia due to AD, into the Alzheimer's Prevention Initiative (API) Generation Program, the largest and only prevention trials for late onset AD using this enrichment technique. DESIGN AND SETTING: The Generation Program was comprised of two global, randomized, double-blind, placebo-controlled, parallel group adaptive design with variable treatment duration clinical trials. Generation Study 1 randomized participants into one of two cohorts: Cohort 1 which evaluated CAD106 vs. placebo or Cohort 2 which evaluated umibecestat vs placebo. Generation Study 2 randomized participants into two doses of umibecestat vs. placebo. The Generation Program was terminated early in 2019, while enrollment was still occurring. PARTICIPANTS: Both Generation Study 1 and Generation Study 2 enrolled cognitively unimpaired APOE ε4 HMs aged 60-75; Generation Study 2 also enrolled APOE ε4 HTs ages 60-75 with elevated brain amyloid. METHODS AND MEASUREMENTS: Describe results of the centralized and localized outreach, recruitment, screening strategies and tactics as well as characteristics of sites successful at enrolling genetically eligible participants, with a particular focus on APOE ε4 HMs given the 2-3% prevalence of this genotype. RESULTS: At the time the trial program was terminated, 35,333 individuals had consented to the optional prescreening ICF1a/ICFA and provided a sample of DNA for APOE genotyping, 1,138 APOE ε4 HMs consented to screening for Generation Study 1 (ICF1b), and 1,626 APOE ε4 carriers were randomized into either Generation Study 1 or Generation Study 2. Genetic testing registries, partnerships with genetic testing/counseling companies, and the optional prescreening ICF1a/ICFA were the most successful strategies for identifying genetically eligible participants for screening. CONCLUSIONS: It is feasible to recruit, screen and randomize cognitively unimpaired APOE ε4 carriers, particularly APOE ε4 HMs for a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Factors that were key to this success included: working with sites to develop customizable outreach, recruitment, and screening programs specific to their site needs, providing forums for sites to exchange best practices, and developing partnerships between the sponsor team and trial sites.

Building composite indices in the age of big data - Application to honey bee exposure to infectious and parasitic agents.

Pollinator insects play a crucial role in maintaining biodiversity and agricultural production worldwide. Yet they are subject to various infectious and parasitic agents (IPAs). To better assess their exposure to IPAs, discriminative and quantitative molecular methods have been developed. These tools produce large datasets that need to be summarised so as to be interpreted. In this paper, we described the calculation of three types of composite indices (numerical, ordinal, nominal) to characterize the honey bee exposure to IPAs in 128 European sites. Our summarizing methods are based on component-based factorial analyses. The indices summarised the dataset of eight IPAs quantified at two sampling times, into synthetic values providing different yet complementary information. Because our dataset included two sampling times, we used Multiple Factor Analysis (MFA) to synthetize the information. More precisely, the numerical and ordinal indices were generated from the first component of MFA, whereas the nominal index used the first main components of MFA combined with a clustering analysis (Hierarchical Clustering on components). The numerical index was easy to calculate and to be used in further statistical analyses. However, it contained only about 20% of the original information. Containing the same amount of original information, the ordinal index was much easier to interpret. These two indices summarised information in a unidimensional manner. Instead, the nominal index summarised information in a multidimensional manner, which retained much more information (94%). In the practical example, the three indices showed an antagonistic relationship between N. ceranae and DWV-B. These indices represented a toolbox where scientists could pick one composite index according to the aim pursued. Indices could be used in further statistical analyses but could also be used by policy makers and public instances to characterize a given sanitary situation at a site level for instance.

A new boronate ester-based crosslinking strategy allows the design of nonswelling and long-term stable dynamic covalent hydrogels.

Dynamic hydrogels are viscoelastic materials that can be designed to be self-healing, malleable, and injectable, making them particularly interesting for a variety of biomedical applications. To design dynamic hydrogels, dynamic covalent crosslinking reactions are attracting increasing attention. However, dynamic covalent hydrogels tend to swell, and often lack stability. Boronate ester-based hydrogels, which result from the dynamic covalent reaction between a phenylboronic acid (PBA) derivative and a diol, are based on stable precursors, and can therefore address these limitations. Yet, boronate ester formation hardly occurs at physiological pH. To produce dynamic covalent hydrogels at physiological pH, we performed a molecular screening of PBA derivatives in association with a variety of diols, using hyaluronic acid as a polymer of interest. The combination of Wulff-type PBA (wPBA) and glucamine stood out as a unique couple to obtain the desired hydrogels. We showed that optimized wPBA/glucamine hydrogels are minimally- to non-swelling, stable long term (over months), tunable in terms of mechanical properties, and cytocompatible. We further characterized their viscoelastic and self-healing properties, highlighting their potential for biomedical applications.

Cerebellar syndrome associated with legionellosis: A case report and literature review.

INTRODUCTION: Legionnaire's disease is a community-acquired pneumonia caused by the Gram-negative bacterium Legionella pneumophila. This disease is often associated with neurological symptoms, the clinical presentation of which can be very varied. CASE REPORT: We report a 47-year-old female patient who developed Legionnaires' disease with cerebellar symptoms (ataxia, dysarthria and hypermetria). Laboratory tests revealed a biological inflammatory syndrome. The cerebrospinal fluid was sterile. Urinary antigen test and serology were positive for L. pneumophila. An interstitial syndrome of the right upper lobe was detected on chest computed tomography (CT) scan. Brain imaging (magnetic resonance imaging and CT angiography) showed no abnormalities. The outcome was favourable after treatment with spiramycin, levofloxacin and corticosteroids. DISCUSSION: Few cases only (n=110) of Legionnaires' disease with cerebellar symptoms have been reported in the literature. The pathogenic mechanism behind neurological dysfunction in patients with Legionnaires' disease is unknown. Neurological symptoms improve with antibiotic therapy and corticosteroids. Extra-pulmonary forms of Legionnaires' disease are frequent, with neurological symptoms being the most common symptoms. Cerebellar dysfunction may be underestimated and requires appropriate management with antibiotic therapy and corticosteroid therapy. Recommendations for the management of Legionnaire's disease with severe extra-pulmonary symptoms are needed.

Management of work-related common mental disorders in general practice: a cross-sectional study.

BACKGROUND: General practitioners (GPs) often manage individuals with work-related common mental disorders (CMD: depressive disorders, anxiety and alcohol abuse). However, little is known about the ways in which they proceed. The aim of this study is to analyze GPs' management and patterns of referral to other health professionals of patients with work-related CMD and associated factors. METHOD: We used data from a cross-sectional study of 2027 working patients of 121 GPs in the Nord - Pas-de-Calais region in France (April - August 2014). Statistical analyses focused on patients with work-related CMD detected by the GP and examined the ways in which GPs managed these patients' symptoms. Associations between patient, work, GP and contextual characteristics and GPs' management were explored using modified Poisson regression models with robust variance. RESULTS: Among the 533 patients with work-related CMD in the study, GPs provided psychosocial support to 88.0%, prescribed psychotropic treatment to 82.4% and put 50.7% on sick leave. Referral rates to mental health specialists and occupational physicians were respectively 39.8 and 26.1%. Several factors including patients' characteristics (occupational and sociodemographic), GPs' characteristics and environmental data were associated with the type of management used by the GP. CONCLUSION: Our study emphasizes the major and often lonesome role of the GP in the management of patients with work-related CMDs. Better knowledge of the way GPs manage those patients could help GPs in their practice, improve patients care and be a starting point to implement a more collaborative care approach.

[Impact of sonography simulation in the training of midwifery students]. / Impact de l'intégration de la simulation en échographie obstétricale dans le cursus des étudiants sages-femmes.

OBJECTIVE: During their studies, French midwives need to acquire basic ultrasound skills to measure the amniotic fluid index, fetal biometry and identify fetal lie and placental positions. They have a clinical ultrasound training during their curriculum to acquire these skills. Assess the contribution that a training on an obstetrical ultrasound simulator (OUS) could make to the competence of midwives and to evaluate the best time to integrate it into their curriculum. METHODS: Forty students in their 4th and final year in midwifery were randomized into 2 groups. Group A learned with the traditional academic course, with a clinical ultrasound training which was followed by an evaluation on an OUS (E1A). Group B was evaluated on a simulator before the clinical ultrasound training (E1B). After these initial assessments, both groups were provided with learning and training sessions on OUS, and re-evaluated in the same exercise (E2A and E2B). Group B then completed its clinical ultrasound training and was evaluated one month later on the simulator (E3B). The evaluation consisted of scoring the biometry images according to previously published quality criteria, and of assessing their competence based on a published objective and structured assessment score of ultrasound skills (OSAUS). RESULTS: Evaluation 1 found comparable OSAUS scores (2.375/5 vs. 2.24/5 P=0.52) between the two groups (E1A vs. E1B) but a significantly higher image quality score for Group A (P=0.02). In Evaluation 2, an improvement was noted for both groups with comparable OSAUS averages between the two groups (P=0.76). After the clinical training of Group B, their OSAUS score (E3B) was significantly better than that of Group A (E1A) after their clinical training (3.45/5 vs. 2.375/5 [P=0.00017]). The same was true for the quality of their images (12.67/16 vs. 9.95/16 [P=0.003]). CONCLUSION: Ultrasound simulation-based training, as an adjunct to ultrasound clinical training, significantly improves obstetrical ultrasound skills. The best time to train on simulators seems to be prior to clinical training on real patients.

Core elements of the interpersonal care relationship between nurses and older patients without cognitive impairment during their stay at the hospital: A mixed-methods systematic review.

BACKGROUND: The fundamental importance of establishing an interpersonal care relationship for quality nursing care has been highlighted. However specific elements of the interpersonal care relationship of importance to older patients in the hospital have not been identified. OBJECTIVES: The aim of this review was to explore and synthesise research findings regarding the elements of the interpersonal care relationship concept from the perspectives of older patients. DESIGN: A systematic mixed-methods review. DATA SOURCES: An extensive search was conducted up until October 2018 for articles without any publication date time limit in PubMed, Web of Science, Cochrane Database of Systematic Reviews and CINAHL. REVIEW METHODS: Primary studies were included if they concerned patients aged 65 years or older and their perspectives on the elements of the interpersonal care relationship with nurses. Inclusion was limited to patients without cognitive impairment who were admitted to an acute hospital setting. The methodological quality of each study was assessed using the Critical Appraisal Skills Programme for qualitative studies, the Quality Assessment Tool for Quantitative Studies and the Mixed-Methods Appraisal Tool. Thematic analysis was used to structure the results of the included studies. RESULTS: Of the 7596 studies found, 24 were included in this review. Twenty articles had a qualitative, three a quantitative and one a mixed methods design. Older patients consider dignity and respect as core values that need to be met in the interpersonal care relationship. Five core elements of the interpersonal care relationship were identified to meet these core values: elements related to caring behaviour and attitude, person-centred care, patient participation, communication and situational aspects. These core elements were structured according to three categories, identified in the literature, that determine the quality of the interpersonal care relationship: nurse-, older-patient-related elements and situational aspects. CONCLUSIONS: The elements identified in this review can guide efforts to define the interpersonal care relationship between older patients and nurses. Nurses should be supported and motivated by education and practice to adapt their behaviour, attitudes and communication to meet older patients' expectations. Hospital management can also encourage nurses to communicate well. Investment in the current organisation of care is needed to improve nurses' work overload and presence. Further research is needed to clarify the underlying processes influencing the experience of the interpersonal care relationship from the perspectives of older patients, nurses, informal caregivers and hospital management.

Good farming practices in apiculture.

Modern European beekeeping is facing numerous challenges due to a variety of factors, mainly related to globalisation, agrochemical pollution and environmental changes. In addition to this, new pathogens threaten the health of European honey bees. In that context, correct colony management should encompass a wider vision, where productivity aspects are linked to a One Health approach in order to protect honey bees, humans and the environment. This paper describes a novel tool to be applied in beekeeping operations: good beekeeping practices (GBPs). The authors ranked a list of GBPs scored against their importance and validated by an international team, including researchers, national animal health authorities and international beekeepers' associations. These activities were carried out in the project 'BPRACTICES', approved within the transnational call of the European Research Area Network on Sustainable Animal Production (ERA-NET SusAn) in the Horizon 2020 Research and Innovation Programme of the European Union. This study, created through an international collaboration, aims to present an innovative and implementable approach, similar to applications already adopted in other livestock production systems.

L'apiculture moderne européenne est confrontée à de nombreuses difficultés dues à divers facteurs, pour la plupart liés à la mondialisation, à la pollution agrochimique et à la modification de l'environnement. À ces facteurs s'ajoute l'émergence de nouveaux agents pathogènes qui menacent la santé des abeilles mellifères d'Europe. Dans ce contexte, une gestion appropriée des colonies d'abeilles devrait reposer sur une vision plus large, dans laquelle les aspects relevant de la productivité sont examinés suivant une approche « Une seule santé ¼ afin de protéger les abeilles mellifères, les humains et l'environnement. Les auteurs décrivent un nouvel outil destiné à l'apiculture : les bonnes pratiques apicoles. Ils ont évalué et classé par ordre d'importance une liste de bonnes pratiques apicoles validées par une équipe internationale composée de chercheurs, d'autorités nationales de la santé animale et d'associations internationales d'apiculteurs. Ces activités ont été conduites dans le cadre du projet « BPRACTICES ¼, proposition retenue suite à l'appel à projets transnationaux du réseau ERA­NET SusAn (European Research Area Network on Sustainable Animal Production) au sein du Programme Horizon 2020 de l'Union européenne pour la recherche et l'innovation. Conçue sous forme de collaboration internationale, cette étude vise à proposer une approche innovante et pratique, similaire aux applications précédemment adoptées dans d'autres systèmes de production animale.

La apicultura europea hace frente a numerosos problemas resultantes de diversos factores, relacionados principalmente con la mundialización, la contaminación agroquímica y los cambios ambientales, a todo lo cual se suman nuevos patógenos que amenazan la salud de las abejas melíferas europeas. En este contexto, una correcta gestión de las colonias debe traer aparejada una visión más global, en la que las cuestiones de productividad se consideren en clave de «Una sola salud¼ con objeto de proteger tanto a las abejas melíferas como a las personas y el medio ambiente. En este artículo se describe una novedosa herramienta aplicable a la actividad apícola: las buenas prácticas de apicultura. Los autores jerarquizaron una serie de buenas prácticas de apicultura seleccionadas, validadas y puntuadas según su importancia por un equipo internacional que incluía a investigadores, autoridades nacionales de sanidad animal y asociaciones internacionales de apicultores. Este trabajo formaba parte del proyecto «BPRACTICES¼, aprobado con ocasión de la convocatoria internacional abierta por la Red del espacio europeo de investigación en sanidad animal sostenible (ERA­NET SusAn), inscrita a su vez en Horizonte 2020, el programa de investigación e innovación de la Unión Europea. El estudio aquí descrito, fruto de la colaboración internacional, tiene por objeto presentar un planteamiento novedoso y viable, parecido a las aplicaciones ya implantadas en otros sistemas de producción animal.

Work intensity in men and work-related emotional demands in women are associated with increased suicidality among persons attending primary care.

BACKGROUND: A large proportion of persons died by suicide are employed at the time of death and work-related factors partly contribute to suicide risk. Our aim was to examine the association between multiple aspects of work organization and suicidal ideation in a study conducted in primary care. METHODS: Data came from a study of 2027 working patients attending a GP representative of patients in the Nord Pas-de-Calais region in France (April-August 2014). Suicidality was assessed using the MINI (Mini International Neuropsychiatric Interview). Six emergent worked-related factors were explored (work intensity, emotional demands, autonomy, social relationships at work, conflict of values, insecurity of work). Several covariates were considered: patient's and GP's characteristics, and area-level data (material and social deprivation, psychiatrist and GPs' density, suicide attempts and suicide rates). RESULTS: 8.0% of participants reported suicidal ideation in the preceding month (7.5% of men and 8.6% of women, p = .03). In multivariate analyses adjusted for covariates, suicidality was significantly associated with work intensity (OR = 1.65; 95%CI [1.18-2.31]) in men and with work-related emotional demands (OR = 1.35; 95%CI [1.01-1.80]) in women. Area-level data were not associated. LIMITATIONS: Our cross-sectional study cannot assess the direction of the relationships under study. CONCLUSION: Our results emphasise a central role for GPs in suicide prevention among workers and highlight the importance of work-related factors with regard to suicidality in primary care.

Prevalence of work-related common psychiatric disorders in primary care: The French Héraclès study.

General practitioners (GP), on the frontline for individuals with mental health problems, often deal with work-related common psychiatric disorders. We aimed to determine the prevalence of work-related common psychiatric disorders in general practice and associated patients' and GPs' characteristics. HERACLES, a cross-sectional study among 2019 working patients of 121 GPs in the Nord - Pas-de-Calais region in France. Common psychiatric disorders were assessed using the MINI International Neuropsychiatric Interview, patient-perceived psychological distress and GP-diagnosed psychiatric disorders. The work-relatedness of common psychiatric disorders was ascertained by the GP and/or the patient. Prevalence rates adjusted on age were calculated by sex and associated characteristics were ascertained using multilevel Poisson regression models. The prevalence of work-related common psychiatric disorders ascertained using the MINI was estimated at 25.6% [23.7-27.5], 24.5% [22.6-26.4] for self-reported psychological distress and 25.8% [23.9-27.7] for GP-diagnosed psychiatric disorders. Age, history of psychiatric disorders, consultation for psychological purpose and GP's characteristics were associated with MINI-identified psychiatric disorders. The prevalence of work-related common psychiatric disorders among working adults seen in general practice is high but further studies are needed to support this results.

The Alzheimer's Prevention Initiative Generation Program: Evaluating CNP520 Efficacy in the Prevention of Alzheimer's Disease.

Alzheimer's disease pathology begins decades before the onset of clinical symptoms. This provides an opportunity for interventional clinical trials to potentially delay or prevent the onset of cognitive impairment or dementia. CNP520 (a beta-site-amyloid precursor protein-cleaving enzyme inhibitor) is in clinical development for the treatment of preclinical Alzheimer's disease under the Alzheimer's Prevention Initiative Generation Program. The Alzheimer's Prevention Initiative is a public-private partnership intended to accelerate the evaluation of Alzheimer's disease prevention therapies. The Generation Program comprises two pivotal phase II/III studies with similar designs to assess the efficacy and safety of investigational treatments in a cognitively unimpaired population at increased risk for developing Alzheimer's disease based on age and apolipoprotein E (APOE) genotype (i.e., presence of the APOE ε4 allele). The program has been designed to maximize benefit to Alzheimer's disease research. Generation Study 1 (NCT02565511) and Generation Study 2 (NCT03131453) are currently enrolling; their key features are presented here.

Fundus autofluorescence in retinal artery occlusion: A more precise diagnosis.

IMPORTANCE: Retinal artery occlusion (RAO) is a medical emergency associated with a high risk of cerebral vascular accident and other cardiovascular events. Among patients with non-arteritic RAO, a retinal embolus is observed in approximately 40% of cases. Fundus examination and retinography are not reliable to predict the nature of the emboli. OBSERVATIONS: We report three consecutive cases of central and branch RAO that were investigated with fundus autofluorescence, fluorescein angiography and color retinal photographs. All patients underwent complete neurological and cardiovascular workups, with brain imaging, cardiac Doppler ultrasound, carotid Dopplers and Holter ECG's, to determine the underlying mechanism of retinal embolism. In the three cases, aged 77.7±4 years (2 women and 1 man), fundus autofluorescence demonstrated hyperautofluorescent emboli. In two cases, it allowed visualization of emboli that were not detected with fundus examination or retinography. The cardiovascular work-up demonstrated atheromatous carotid or aortic plaques in all patients. In one case, it permitted the diagnosis of RAO. Two of the three cases were considered to be of atherosclerotic origin and one of undefined origin. CONCLUSION AND RELEVANCE: Fundus autofluorescence may help to detect and characterize retinal emboli. Since lipofuscin, which is present in large quantity in atherosclerotic plaques, is the main fluorophore detected with fundus autofluorescence, this non-invasive and simple examination may give information about the underlying mechanism of retinal embolism, and thus impact the etiologic assessment of RAO. Additional studies are necessary to confirm this potential role of autofluorescence.

Regional and local environmental conditions do not shape the response to warming of a marine habitat-forming species.

The differential response of marine populations to climate change remains poorly understood. Here, we combine common garden thermotolerance experiments in aquaria and population genetics to disentangle the factors driving the population response to thermal stress in a temperate habitat-forming species: the octocoral Paramuricea clavata. Using eight populations separated from tens of meters to hundreds of kilometers, which were differentially impacted by recent mortality events, we identify 25 °C as a critical thermal threshold. After one week of exposure at this temperature, seven of the eight populations were affected by tissue necrosis and after 30 days of exposure at this temperature, the mean % of affected colonies increased gradually from 3 to 97%. We then demonstrate the weak relation between the observed differential phenotypic responses and the local temperature regimes experienced by each population. A significant correlation was observed between these responses and the extent of genetic drift impacting each population. Local adaptation may thus be hindered by genetic drift, which seems to be the main driver of the differential response. Accordingly, conservation measures should promote connectivity and control density erosion in order to limit the impact of genetic drift on marine populations facing climate change.

Designs of drug-combination phase I trials in oncology: a systematic review of the literature.

BACKGROUND: Combining several anticancer agents can increase the overall antitumor action, but at the same time, it can also increase the overall observed toxicity. Adaptive dose-escalation designs for drug combinations have recently emerged as an attractive alternative to algorithm-based designs, and they seem more effective in combination recommendations. These methods are not used in practice currently. Our aim is to describe international scientific practices in the setting of phase I drug combinations in oncology. MATERIAL AND METHODS: A bibliometric study on phase I dose-finding combination trials was conducted using the Medline(®) PubMed database between 1 January, 2011, and 31 December 2013. Sorting by abstract, we selected all papers involving a minimum of two agents and then retained only those in which at least two agents were dose-escalated. RESULTS: Among the 847 references retrieved, 162 papers reported drug-combination phase I trials in which at least two agents were dose-escalated. In 88% of trials, a traditional or modified 3 + 3 dose-escalation design was used. All except one trial used a design developed for single-agent evaluation. Our study suggests that drug-combination phase I trials in oncology are very safe, as revealed by the calculated median dose-limiting toxicity rate of 6% at the recommended dose, which is far below the target rate in these trials (33%). We also examined requirements of phase I clinical trials in oncology with drug combinations and the potential advantages of novel approaches in early phases. CONCLUSION: Efforts to promote novel and innovative approaches among statisticians and clinicians appear valuable. Adaptive designs have an important role to play in early phase development.

Competing designs for drug combination in phase I dose-finding clinical trials.

The aim of phase I combination dose-finding studies in oncology is to estimate one or several maximum tolerated doses (MTDs) from a set of available dose levels of two or more agents. Combining several agents can indeed increase the overall anti-tumor action but at the same time also increase the toxicity. It is, however, unreasonable to assume the same dose-toxicity relationship for the combination as for the simple addition of each single agent because of a potential antagonist or synergistic effect. Therefore, using single-agent dose-finding methods for combination therapies is not appropriate. In recent years, several authors have proposed novel dose-finding designs for combination studies, which use either algorithm-based or model-based methods. The aim of our work was to compare, via a simulation study, six dose-finding methods for combinations proposed in recent years. We chose eight scenarios that differ in terms of the number and location of the true MTD(s) in the combination space. We then compared the performance of each design in terms of correct combination selection, patient allocation, and mean number of observed toxicities during the trials. Our results showed that the model-based methods performed better than the algorithm-based ones. However, none of the compared model-based designs gave consistently better results than the others.

Cephalometric assessment of craniofacial dysmorphologies in relation with Msx2 mutations in mouse.

OBJECTIVES: To determine the role of Msx2 in craniofacial morphology and growth, we used a mouse model and performed a quantitative morphological characterization of the Msx2 (-/-) and the Msx2 (+/-) phenotype using a 2D cephalometric analysis applied on micrographs. MATERIALS AND METHODS: Forty-four three-and-a-half-month-old female CD1 mice were divided into the following three groups: Msx2 (+/+) (n = 16), Msx2 (+/-) (n = 16), and Msx2 (-/-) (n = 12). Profile radiographs were scanned. Modified cephalometric analysis was performed to compare the three groups. RESULTS: Compared with the wild-type mice, the Msx2 (-/-) mutant mice presented an overall craniofacial size decrease and modifications of the shape of the different parts of the craniofacial skeleton, namely the neurocranium, the viscerocranium, the mandible, and the teeth. In particular, dysmorphologies were seen in the cochlear apparatus and the teeth (taurodontism, reduced incisor curvature). Finally contrary to previous published results, we were able to record a specific phenotype of the Msx2 (+/-) mice with this methodology. This Msx2 (+/-) mouse phenotype was not intermediate between the Msx2 (-/-) and the wild-type animals. CONCLUSION: Msx2 plays an important role in craniofacial morphogenesis and growth because almost all craniofacial structures were affected in the Msx2(-/-) mice including both intramembranous and endochondral bones, the cochlear apparatus, and the teeth. In addition, Msx2 haploinsufficiency involves a specific phenotype with subtle craniofacial structures modifications compared with human mutations.

Recent molecular biology methods for foulbrood and nosemosis diagnosis.

Honey-bee colony losses are an increasing problem in Western countries. There are many different causes, including infections due to various pathogens. Molecular biology techniques have been developed to reliably detect and identify honey-bee pathogens. The most sensitive, specific and reliable is the quantitative real-time polymerase chain reaction (qPCR) methodology. This review of the literature describes various studies where qPCR was used to detect, identify and quantify four major honey-bee pathogens: the bacteria Paenibacillus larvae and Melissococcus plutonius (the causative agents of American foulbrood and European foulbrood, respectively) and the microsporidia Nosema apis and N. ceranae (the causative agents of nosemosis). The application of qPCR to honey-bee pathogens is very recent, and techniques are expected to improve rapidly, leading to potential new prospects for diagnosis and control. Thus, qPCR techniques could shortly become a powerful tool for investigating pathogenic infections and increasing our understanding of colony losses.

[Dermohypodermitis and gut translocation Escherichia coli septicemia in a newborn infant]. / Dermo-hypodermite et septicémie àEscherichia Coli par translocation digestive chez un nouveau-né : à propos d'un cas.

The burden of neonatal bacterial infections continues. They remain a significant cause of death and morbidity, despite recommendations for prevention. The epidemiology of these infections has changed. Currently the two most causative pathogens for early-onset neonatal sepsis and for late-onset sepsis in term infants are Group B streptococci (GBS) and Escherichia coli. E. coli's role is increasingly important since the widespread use of intrapartum antibiotic prophylaxis. In late-onset infections, one of the suggested pathophysiological mechanisms is microbial translocation in the gut secondary to digestive colonization, particularly when E. coli is isolated in blood cultures. This can occur either before or after birth. Bacterial sepsis can be associated with various non-specific peripheral manifestations involving skin and soft tissues. We report the case of a full-term, 26-day-old newborn admitted to the hospital for fever. She presented with dermohypodermitis of the left trunk and was diagnosed with E. coli septicemia. She was discharged in good condition after appropriate intravenous antibiotic therapy.

Head-neck and mediastinal emphysema caused by playing a wind instrument.

INTRODUCTION: Etiology of head-and-neck emphysema is mainly infectious (cellulitis) or traumatic (rupture of the aerodigestive tract mucosa, usually in the larynx and trachea). CASE REPORT: We report a case of head-and-neck and mediastinal emphysema due to oral hyperpressure inducing parotid acini rupture. The aim is to highlight the importance of precise interview of patient and family so as to identify this mechanism. DISCUSSION: Pneumoparotid is a rare cause of swelling induced by insufflation into Stensen's duct. This reflux is caused by intra-oral hyperpressure, and can cause extensive subcutaneous emphysema induced by capsule rupture. The disorder is common in players of wind instruments and glass-blowers. Positive diagnosis is based on focused interview, looking for trigger factors, and on imaging assessment. Evolution is reported to be spontaneously favorable with simple antibiotherapy. Patient education is the best means of limiting recurrence. CONCLUSION: In case of cervical emphysema, it is important to determine the mechanism of onset and explore for pneumoparotid on CT, so as to adapt treatment and prevent possible recurrence.