Zimmer Biomet (France)

Estimates and variances of diversity and differentiation measures in subdivided populations are proposed that can be applied to haplotypes (ordered alleles such as DNA sequences, which may contain a record of their own histories). Hence, two measures of differentiation can be compared for a single data set: one (GST) that makes use only of the allelic frequencies and the other (NST) for which similarities between the haplotypes are taken into account in addition. Tests are proposed to compare NST and GST with zero and with each other. The difference between NST and GST can be caused by several factors, including sampling artefacts, unequal effect of mutation rates and phylogeographic structure. The method presented is applied to a published data set where a nuclear DNA sequence had been determined from individuals of a grasshopper distributed in 24 regions of Europe. Additional insights into the genetic subdivision of these populations are obtained by progressively combining related haplotypes and reanalyzing the data each time.

To determine whether gene expression patterns affect mutation rates and/or selection intensity in mammalian genes, we studied the relationships between substitution rates and tissue distribution of gene expression. For this purpose, we analyzed 2,400 human/rodent and 834 mouse/rat orthologous genes, and we measured (using expressed sequence tag data) their expression patterns in 19 tissues from three development states. We show that substitution rates at nonsynonymous sites are strongly negatively correlated with tissue distribution breadth: almost threefold lower in ubiquitous than in tissue-specific genes. Nonsynonymous substitution rates also vary considerably according to the tissues: the average rate is twofold lower in brain-, muscle-, retina- and neuron-specific genes than in lymphocyte-, lung-, and liver-specific genes. Interestingly, 5' and 3' untranslated regions (UTRs) show exactly the same trend. These results demonstrate that the expression pattern is an essential factor in determining the selective pressure on functional sites in both coding and noncoding regions. Conversely, silent substitution rates do not vary with expression pattern, even in ubiquitously expressed genes. This latter result thus suggests that synonymous codon usage is not constrained by selection in mammals. Furthermore, this result also indicates that there is no reduction of mutation rates in genes expressed in the germ line, contrary to what had been hypothesized based on the fact that transcribed DNA is more efficiently repaired than nontranscribed DNA.

Glioblastoma (GB) is the most frequent and aggressive primary tumor of the central nervous system. Prognosis remains poor despite ongoing progress. In cases where the gadolinium-enhanced portion of the GB is completely resected, 90% of recurrences occur at the margin of surgical resection in the macroscopically normal peritumoral brain zone (PBZ). Intratumoral heterogeneity in GB is currently a hot topic in neuro-oncology, and the GB PBZ may be involved in this phenomenon. Indeed, this region, which possesses specific properties, has been less studied than the core of the GB tumor. The high rate of local recurrence in the PBZ and the limited success of targeted therapies against GB demonstrate the need for a better understanding of the PBZ. We present here a review of the literature on the GB PBZ, focusing on its radiological, cellular, and molecular characteristics. We discuss how intraoperative analysis of the PBZ is important for the optimization of surgical resection and the development of targeted therapies against GB.

AIMS: To assess physicians' adherence to guideline-recommended medications for the treatment of chronic heart failure (CHF) with reduced ejection fraction. METHODS AND RESULTS: QUALIFY is an international prospective observational longitudinal survey of 7092 CHF outpatients recruited 1-15 months after hospitalization for heart failure from September 2013 to December 2014 in 547 centres in 36 countries. We constructed a five-class guideline adherence score for angiotensin converting enzyme inhibitors (ACEIs), beta-blockers, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, and ivabradine. The adherence score was good in 67%, moderate in 25%, and poor in 8% of patients. Adherence was lower in women than men but there were differences in age (65.7 ± 12.5 years women vs. 62.2 ± 12.4 years men, P < 0.001) and the proportion of women at ≥50% target dose of beta-blockers was lower in those >67 years (median) (11% vs. 16.2%, P = 0.005). Geographic variations were observed with lower adherence scores in Central/Eastern European countries. The proportion of patients at target dose and ≥50% of target dose was low (27.9% and 63.3% for ACEIs, 14.8% and 51.8% for beta-blockers, 6.9% and 39.5% for ARBs, and 6.9% and 39.5% for ivabradine, respectively). It was also lower in patients most recently hospitalized (<6 vs. ≥6 months) except for beta-blockers. CONCLUSION: This international survey shows that adherence to guideline-recommended medications is relatively satisfactory but the dosage of recommended CHF medications is usually suboptimal. Action plans aimed at improving adherence to guidelines are required.

The shoot apical meristem (SAM) is a small group of dividing cells that generate all of the aerial parts of the plant. With the goal of providing a framework for the analysis of Arabidopsis meristems at the cellular level, we performed a detailed morphometric study of actively growing inflorescence apices of the Landsberg erecta and Wassilewskija ecotypes. For this purpose, cell size, spatial distribution of mitotic cells, and the mitotic index were determined in a series of optical sections made with a confocal laser scanning microscope. The results allowed us to identify zones within the inflorescence SAM with different cell proliferation rates. In particular, we were able to define a central area that was four to six cells wide and had a low mitotic index. We used this technique to compare the meristem of the wild type with the enlarged meristems of two mutants, clavata3-1 (clv3-1) and mgoun2 (mgo2). One of the proposed functions of the CLV genes is to limit cell division rates in the center of the meristem. Our data allowed us to reject this hypothesis, because the mitotic index was reduced in the inflorescence meristem of the clv3-1 mutant. We also observed a large zone of slowly dividing cells in meristems of clv3-1 seedlings. This zone was not detectable in the wild type. These results suggest that the central area is increased in size in the mutant meristem, which is in line with the hypothesis that the CLV3 gene is necessary for the transition of cells from the central to the peripheral zone. Genetic and microscopic analyses suggest that mgo2 is impaired in the production of primordia, and we previously proposed that the increased size of the mgo2 meristem could be due to an accumulation of cells at the periphery. Our morphometric analysis showed that mgo2 meristems, in contrast to those of clv3-1, have an enlarged periphery with high cell proliferation rates. This confirms that clv3-1 and mgo2 lead to meristem overgrowth by affecting different aspects of meristem function.

Great apes are threatened with extinction, but precise information about the distribution and size of most populations is currently lacking. We conducted orangutan nest counts in the Malaysian state of Sabah (North Borneo), using a combination of ground and helicopter surveys, and provided a way to estimate the current distribution and size of the populations living throughout the entire state. We show that the number of nests detected during aerial surveys is directly related to the estimated true animal density and that a helicopter is an efficient tool to provide robust estimates of orangutan numbers. Our results reveal that with a total estimated population size of about 11,000 individuals, Sabah is one of the main strongholds for orangutans in North Borneo. More than 60% of orangutans living in the state occur outside protected areas, in production forests that have been through several rounds of logging extraction and are still exploited for timber. The role of exploited forests clearly merits further investigation for orangutan conservation in Sabah.

An analysis of the risk to the countries of the European Union from a possible introduction of Bursaphelenchus xylophilus and its vectors in the genus Monochamus is performed by assembling relevant biological, climatic and commercial information. The risks presented by different trade pathways are assessed and phytosanitary measures to reduce the risks are proposed. The conclusion of the PRA, based on EPPO PRA guideline no. 1, is that these pests present a serious risk to European coniferous forests.

ACNUC is a database structure and retrieval software for use with either the GenBank or EMBL nucleic acid sequence data collections. The nucleotide and textual data furnished by both collections are each restructured into a database that allows sequence retrieval on a multi-criterion basis. The main selection criteria are: species (or higher order taxon), keyword, reference, journal, author, and organelle; all logical combinations of these criteria can be used. Direct access to sequence regions that code for a specific product (protein, tRNA or rRNA) is provided. A versatile extraction procedure copies selected sequences, or fragments of them, from the database to user files suitable to be analysed by user-supplied application programs. A detailed help mechanism is provided to aid the user at any time during the retrieval session. All software has been written in FORTRAN 77 which guarantees a high degree of transportability to minicomputers or mainframes. reference, journal, author, and organelle; all logical combinations of these criteria can be used. Direct access to sequence regions that code for a specific product (protein, tRNA or rRNA) is provided. A versatile extraction procedure copies selected sequences, or fragments of them, from the database to user files suitable to be analysed by user-supplied application programs. A detailed help mechanism is provided to aid the user at any time during the retrieval session. All software has been written in FORTRAN 77 which guarantees a high degree of transportability to minicomputers or mainframes.

Understanding the relationships between climate and carbon exchange by terrestrial ecosystems&#13;\nis critical to predict future levels of atmospheric carbon dioxide because of the potential&#13;\naccelerating effects of positive climate–carbon cycle feedbacks. However, directly observed&#13;\nrelationships between climate and terrestrial CO2 exchange with the atmosphere across biomes&#13;\nand continents are lacking. Here we present data describing the relationships between net&#13;\necosystem exchange of carbon (NEE) and climate factors as measured using the eddy&#13;\ncovariance method at 125 unique sites in various ecosystems over six continents with a total of&#13;\n559 site-years. We find that NEE observed at eddy covariance sites is (1) a strong function of&#13;\nmean annual temperature at mid- and high-latitudes, (2) a strong function of dryness at mid- and&#13;\nlow-latitudes, and (3) a function of both temperature and dryness around the mid-latitudinal belt&#13;\n(45◦N). The sensitivity of NEE to mean annual temperature breaks down at ∼16 ◦C (a threshold&#13;\nvalue of mean annual temperature), above which no further increase of CO2 uptake with&#13;\ntemperature was observed and dryness influence overrules temperature influence.

IMPORTANCE: The choice between chemotherapy and endocrine therapy as first-line treatment for hormone receptor-positive, ERBB2 (also known as HER2)-negative metastatic breast cancer is usually based on the presence of clinical features associated with a poor prognosis. In this setting, a high circulating tumor cell (CTC) count (≥5 CTCs/7.5 mL) is a strong adverse prognostic factor for overall survival and progression-free survival (PFS). OBJECTIVE: To compare the efficacy of a clinician-driven treatment choice vs a CTC-driven choice for first-line treatment. INTERVENTIONS: In the CTC arm, patients received chemotherapy or endocrine therapy according to the CTC count (chemotherapy if ≥5 CTCs/7.5 mL; endocrine therapy if <5 CTCs/7.5 mL), whereas in the control arm, the choice was left to the investigator. DESIGN, SETTING, AND PARTICIPANTS: In the STIC CTC randomized, open-label, noninferiority phase 3 trial, participants were randomized to a clinician-driven choice of first-line treatment or a CTC count-driven first-line treatment choice. Eligible participants were premenopausal and postmenopausal women 18 years or older diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer. Data were collected at 17 French cancer centers from February 1, 2012, to July 28, 2016, and analyzed June 2019 to October 2019. MAIN OUTCOME AND MEASURES: The primary end point was the investigator-assessed PFS in the per-protocol population, with a noninferiority margin of 1.25 for the 90% CI of the hazard ratio. RESULTS: Among the 755 women in the per-protocol population, the median (range) age was 63 (30-88) years [64 (30-88) years for the 377 patients allocated to the CTC arm and 63 (31-87) years for the 378 patients allocated to the standard arm]; 138 (37%) and 103 (27%) received chemotherapy, respectively. Median PFS was 15.5 months (95% CI, 12.7-17.3) in the CTC arm and 13.9 months (95% CI, 12.2-16.3) in the standard arm. The primary end point was met, with a hazard ratio of 0.94 (90% CI, 0.81-1.09). CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that the CTC count may be a reliable biomarker method for guiding the choice between chemotherapy and endocrine therapy as the first-line treatment in hormone receptor-positive, ERBB2-negative metastatic breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01710605.

Background: Palbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety of chemotherapy and letrozole-palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC. Patients and methods: NeoPAL (UCBG10/4, NCT02400567) is a randomised, parallel, non-comparative phase II study. Patients with ER-positive, HER2-negative, Prosigna®-defined luminal B, or luminal A and node-positive, stage II-III breast cancer, not candidate for breast-conserving surgery, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks, or to FEC100 (5FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)×3 21-day courses followed by docetaxel 100 mg/m2×3 21-day courses. Primary end point was residual cancer burden (RCB 0-I rate). Secondary end points included clinical response, proliferation-based markers, and safety. Results: Overall, 106 patients were randomised [median Prosigna® ROR Score 71 (22-93)]. RCB 0-I was observed in four and eight patients in LETPAL [7.7% (95% CI 0.4-14.9)] and chemotherapy [15.7% (95% CI 5.7-25.7)] arms, respectively. Pathological complete response rates were 3.8% and 5.9%. Clinical response (75%) and breast-conserving surgery rates (69%) were similar in both arms. Preoperative Endocrine Prognostic Index 0 scores (breast cancer-specific survival) were observed in 17.6% and 8.0% of patients in LETPAL and chemotherapy arms, respectively. Safety profile was as expected, with 2 versus 17 serious adverse events (including 11 grade 4 serious AEs in the chemotherapy arm). Conclusion: LETPAL combination was associated with poor pathological response but encouraging clinical and biomarker responses in Prosigna®-defined high-risk LBC. Contemporary chemotherapy regimen was associated with poor pathological and biomarker responses, with a much less favourable safety profile. LETPAL combination might represent an alternative to chemotherapy in early high-risk LBC. Clinical Trial Number: NCT02400567.

Abstract This paper presents the operational implementation of a 1D+4D‐Var assimilation system of rain‐affected satellite observations at the European Centre for Medium‐Range Weather Forecasts. The first part describes the methodology and performance analysis of the 1D‐Var retrieval scheme in clouds and precipitation that uses Special Sensor Microwave/Imager microwave radiance observations for the estimation of total‐column water vapour. The second part shows the global and long‐term impact of these observations on both model 4D‐Var analyses and medium‐range forecasts. The 1D‐Var scheme employs a complex observation operator that consists of linearized moist physics parametrization schemes and a multiple‐scattering radiative‐transfer model. The observation operator shows rather linear behaviour in most situations except in the presence of very intense precipitation suggesting a possible use even for a direct assimilation of radiances in 4D‐Var. A bias correction and observation‐error estimation method were implemented and indicate stable error behaviour. The 1D‐Var algorithm quality control shows the largest failure number in areas with mostly frozen precipitation where the Special Sensor Microwave/Imager channels have little sensitivity to changes in hydrometeor contents. From test analyses on a global scale, a small moisture increase was computed that was greatest in dry subtropical areas. Large‐scale and convective precipitation were increased similarly but showed a significantly different geographical distribution. The large‐scale precipitation scheme has a stronger sensitivity to moisture changes and therefore moisture increments mainly affect stratiform precipitation distributions. While the global mean moisture fields are only weakly affected by the assimilation of rain‐affected observations, the impact on local systems may be quite large. The forecast of synoptic system development through the 4D‐Var analysis can be significant. Copyright © 2006 Royal Meteorological Society

A morphometric study of the glomerular population in the olfactory bulb of the mouse has been carried out by using stereological methods. On the basis of the assumption that the glomerular population is a polydispersed system of spheres, glomerular profile distributions obtained from profile measurements were subjected to a mathematical unfolding procedure to obtain the actual glomerular size distribution. We used a distribution-free method to account for the combined effects of overprojection due to section thickness and truncation (two missing profile mechanisms). Results proved better than those obtained directly from profile measurements without stereological analysis. Several new findings were obtained. First, significant variations of the glomerulus sizes were found along the rostrocaudal axis. The glomeruli are larger in the middle region of the olfactory bulb, whereas their numerical density decreases in the same region. Moreover, the profile density is homogeneous along the rostrocaudal axis. In other words, the relative surface occupied by the periglomerular cells in the glomerular layer is invariant. As a consequence, it may be concluded that the variations in size and numerical density are inversely correlated. Thus, since the glomeruli are larger in the middle region, their number per unit volume is logically smaller in this same area. Finally, the computerization of all these data has led us to estimate the number of glomeruli (1,810 +/- 41) in the olfactory bulb of the mouse. In order to get a comparative idea of their advantages and disadvantages, other standard stereological methods were used in the present study to determine this number. Functional interpretations of the variations of the size and numerical density along the rostrocaudal axis of the olfactory bulb are discussed with respect to ontogenetic and morphofunctional data obtained elsewhere.

Abstract A multiple‐scattering radiative transfer model for microwave radiance data assimilation in global numerical weather‐prediction models is presented. The model is part of the RTTOV software package and includes forward, tangent‐linear, adjoint and Jacobian models. The model is based on the Eddington approximation to radiative transfer which produces mean errors of less than 0.5 K at the targeted microwave frequencies between 10 and 200 GHz. The simplified treatment of subgrid‐scale cloud cover may produce biased model calculations that show a maximum at 0.5 cloud cover and may reach several degrees K. These errors may be corrected with a simple bias correction. Linearity tests indicate that, given a screening procedure that excludes situations in which the model responds nonlinearly to input perturbations, channels near 50.3, 19.35, 22.235 and 183.31 GHz may be used in global radiance data assimilation. Copyright © 2006 Royal Meteorological Society.

Interpreting two factor interaction is often difficult, but may sometimes be eased by making use of eovariates associated to each factor. Some linear and non-linear models are considered to this end. In the orthogonal case, the model structure is given by tensor products of vector subspaces. Such a structure naturally applies to main effects. The estimators and their variances'and covariances are given (asymptotic variances in the non-linear case). The choice of a submodel is discussed in the linear case. Finally some remarks are made to generalize these models to models with more than two factors

Confocal endomicroscopes aim at providing to the clinician microscopic imaging of a living tissue. The currently available microendoscopic devices use the principle of confocal fluorescent microscopy, in which the objective is replaced by an optical fiber and a miniaturized scanhead at the distal end of the endoscope or by a retractable bundle of optical fibers. Such systems have recently been applied to the explorations of several organs, including the gastrointestinal tract, and more recently to the proximal and distal airways in vivo. Respiratory fluorescence microendoscopes use 488 nm or 660 nm excitation laser light and thin flexible miniprobes that are introduced into the working channel of the bronchoscope. The devices have a lateral resolution of 3 microm, a field of view of 600 microm, and produce real-time imaging at 9 frames per second. For in vivo imaging, the miniprobe is applied onto the bronchial wall surface or advanced into a distal bronchiole down to the acinus. In nonsmokers, the 488-nm excitation device images the autofluorescence of the elastin that is contained in the basement membrane of the proximal airways and that participates to the axial backbone of the peripheral interstitial respiratory system. In smokers, a specific tobacco tar-induced fluorescence allows in vivo macrophage and alveolar wall imaging. Using 660 nm excitation and topical methylene blue, the technique enables cellular imaging of both bronchial epithelial layer and peripheral lung nodules. This article reviews the capabilities and possible limitations of confocal microendoscopy for in vivo proximal and distal lung explorations.

Abstract Both soil water retention curve and unsaturated hydraulic conductivity data are often necessary for solving soil unsaturated flow problems. This study investigated two versions of a simple laboratory method for determining soil hydraulic properties of homogeneous and rigid soil samples. Three evaporation experiments (soil columns of 106‐mm diam. and 60‐mm height) were made with a silt loam soil packed at different bulk densities (0.96, 1.31, and 1.54 Mg m −3 ). Bulk density and water content profiles were determined by gamma attenuation ( 137 Cs and 241 Am), while pressure head profiles were recorded using microtensiometers, and average column water contents were computed using sample weight measurements. Evaporation experiments were also simulated by solving Richards' equation with a Galerkin finite‐element method. Three methods for the estimation of the hydraulic properties were used: the reference method, which requires the pressure head and water content profiles at several times, and the original and modified Wind methods, which require the average column water content at several times instead of the water content profile. Experimental results showed that the hydraulic properties obtained with the modified Wind method agreed well with those obtained with the reference method. Simulated data were used to compare the original and modified Wind methods, and to determine the effect of added noise on the determination of soil hydraulic properties. Using the numerical experiments, it was shown that the modified Wind method provided results slightly better than those of the original Wind method when the number of tensiometers was greater than three. When measurement errors were taken into account, estimation of the water retention curves using the modified Wind method was not very sensitive to experimental errors, but small uncertainties in tensiometric data influenced greatly the hydraulic conductivities determined in wet conditions.

Yeast RNA polymerases are being extensively studied at the gene level. The entire gene encoding the largest subunit of RNA polymerase A, A190, was isolated and characterized in detail. Southern hybridization and gene disruption experiments showed that the RPA190 gene is unique in the haploid yeast genome and essential for cell viability. Nuclease S1 mapping was used to identify mRNA 5' and 3' termini. RPA190 encodes a polypeptide chain of 186,270 daltons in a large uninterrupted reading frame. A dot matrix comparison of the deduced amino acid sequence of subunit A190 with Escherichia coli beta' and cognate subunits B220 and C160 from yeast RNA polymerases B and C showed a conserved pattern of homology regions (I-VI). A potential DNA-binding site (zinc-binding motif) is conserved in the N-terminal region I. Remarkably, the A190 subunit does not harbor the heptapeptide repeated sequence present in the B220 subunit. The sequence of the A190 subunit diverges from B220 and C160 by the presence of two hydrophilic domains inserted between homology regions I and II, and V and VI. From their codon usage and third base pyrimidine bias, RNA polymerase genes RPA190, RPB220, RPC160, and RPC40 fall among yeast genes expressed at an average level. The RPA190 5'-flanking region contains features present in other polymerase genes that might function in regulation.

We tested the efficacy and tolerability of one-year treatment with memantine (10 mg bid) in behavioral variant frontotemporal dementia (bvFTD). BvFTD patients aged 45 to 75 years, with a Mini-Mental Status Examination (MMSE) score ≥19, were enrolled in a national, randomized, double-blind, placebo-controlled (DBPC), Phase II trial. The primary endpoint was the CIBIC-Plus (Clinician's Interview-Based Impression of Change Plus Caregiver Input). The secondary endpoints included: Neuropsychiatric Inventory (NPI), Frontal Behavioral Inventory (FBI), Mattis Dementia Rating Scale (MDRS), MMSE, Disability Assessment for Dementia (DAD), and the Zarit Burden Inventory (ZBI). Forty-nine patients were analyzed. At baseline, mean age was 65.6 years and mean MMSE was 25.0 (range: 19-30). On the CIBIC-Plus, 52 weeks after baseline, there were no significant differences between the memantine group (n = 23) and the placebo group (n = 26); p = 0.4458; however, 10 patients had worsened in the memantine group versus 17 in the placebo group. For the secondary endpoints there were no differences in the evolution of score between the memantine group and the placebo group (MMSE, p = 0.63); (MDRS, p = 0.95); (NPI, p = 0.25); (ZBI, p = 0.43); (DAD, p = 0.10) except for the FBI score, which was lower in the memantine group (p = 0.0417). Memantine was well-tolerated. This is the first DBPC trial in a large group of bvFTD patients involving neuroprotective treatment. A multinational study with a larger number of patients is now needed in order to verify the results of our study. The trial is registered with ClinicalTrials.gov; number NCT 00200538.

We studied the reproductive strategy of a population of fat dormice (Myoxus glis) breeding in nest boxes in a beech forest on the southern Alps, Italy. In eight years of data collection (1991–1998), we observed births only in 1991, 1992, and 1995. We did not observe young during the autumn dispersal in the remaining five years. Reproduction was not correlated with high rainfall, low temperature in summer, or with population density. Reproduction was only observed in years of beech mast seeding. Body condition of adults when they emerged from hibernation did not differ between years with and without reproduction, suggesting that the adults may avoid breeding when the young have a low probability of surviving their first winter. A capture–recapture analysis on individually marked adult fat dormice identified a very high yearly survival rate (0.86–0.92), close to that of large herbivorous mammals and much higher than that typical of other rodent species with similar body size. No influence of sex on survival or recapture probability was detected. The long life span expectancy of an adult dormouse (averaging nine years) is the prerequisite for the infrequent breeding strategy adopted by this rodent species to cope with an unpredictable food source. A high survival rate despite the small body size may have been possible because of the long hibernation time (>6 months). Long life span and intermittent breeding make the life history of fat dormice unique among rodents.