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1.
Nature ; 569(7756): 404-408, 2019 05.
Article in English | MEDLINE | ID: mdl-31092941

ABSTRACT

The identity of the dominant root-associated microbial symbionts in a forest determines the ability of trees to access limiting nutrients from atmospheric or soil pools1,2, sequester carbon3,4 and withstand the effects of climate change5,6. Characterizing the global distribution of these symbioses and identifying the factors that control this distribution are thus integral to understanding the present and future functioning of forest ecosystems. Here we generate a spatially explicit global map of the symbiotic status of forests, using a database of over 1.1 million forest inventory plots that collectively contain over 28,000 tree species. Our analyses indicate that climate variables-in particular, climatically controlled variation in the rate of decomposition-are the primary drivers of the global distribution of major symbioses. We estimate that ectomycorrhizal trees, which represent only 2% of all plant species7, constitute approximately 60% of tree stems on Earth. Ectomycorrhizal symbiosis dominates forests in which seasonally cold and dry climates inhibit decomposition, and is the predominant form of symbiosis at high latitudes and elevation. By contrast, arbuscular mycorrhizal trees dominate in aseasonal, warm tropical forests, and occur with ectomycorrhizal trees in temperate biomes in which seasonally warm-and-wet climates enhance decomposition. Continental transitions between forests dominated by ectomycorrhizal or arbuscular mycorrhizal trees occur relatively abruptly along climate-driven decomposition gradients; these transitions are probably caused by positive feedback effects between plants and microorganisms. Symbiotic nitrogen fixers-which are insensitive to climatic controls on decomposition (compared with mycorrhizal fungi)-are most abundant in arid biomes with alkaline soils and high maximum temperatures. The climatically driven global symbiosis gradient that we document provides a spatially explicit quantitative understanding of microbial symbioses at the global scale, and demonstrates the critical role of microbial mutualisms in shaping the distribution of plant species.


Subject(s)
Climate , Forests , Geographic Mapping , Mycorrhizae/physiology , Symbiosis , Trees/metabolism , Trees/microbiology , Nitrogen Fixation , Rain , Seasons
2.
Nature ; 571(7765): E8, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31249423

ABSTRACT

In this Letter, a middle initial and additional affiliation have been added for author G. J. Nabuurs; two statements have been added to the Supplementary Acknowledgements; and a citation to the French National Institute has been added to the Methods; see accompanying Author Correction for further details.

3.
Biom J ; 65(4): e2100386, 2023 04.
Article in English | MEDLINE | ID: mdl-36642810

ABSTRACT

Model-based geostatistical design involves the selection of locations to collect data to minimize an expected loss function over a set of all possible locations. The loss function is specified to reflect the aim of data collection, which, for geostatistical studies, could be to minimize the prediction uncertainty at unobserved locations. In this paper, we propose a new approach to design such studies via a loss function derived through considering the entropy about the model predictions and the parameters of the model. The approach includes a multivariate extension to generalized linear spatial models, and thus can be used to design experiments with more than one response. Unfortunately, evaluating our proposed loss function is computationally expensive so we provide an approximation such that our approach can be adopted to design realistically sized geostatistical studies. This is demonstrated through a simulated study and through designing an air quality monitoring program in Queensland, Australia. The results show that our designs remain highly efficient in achieving each experimental objective individually, providing an ideal compromise between the two objectives. Accordingly, we advocate that our approach could be adopted more generally in model-based geostatistical design.


Subject(s)
Air Pollution , Uncertainty , Bayes Theorem , Air Pollution/adverse effects , Linear Models
4.
Stat Pap (Berl) ; 64(4): 1275-1304, 2023.
Article in English | MEDLINE | ID: mdl-37650050

ABSTRACT

The paper covers the design and analysis of experiments to discriminate between two Gaussian process models with different covariance kernels, such as those widely used in computer experiments, kriging, sensor location and machine learning. Two frameworks are considered. First, we study sequential constructions, where successive design (observation) points are selected, either as additional points to an existing design or from the beginning of observation. The selection relies on the maximisation of the difference between the symmetric Kullback Leibler divergences for the two models, which depends on the observations, or on the mean squared error of both models, which does not. Then, we consider static criteria, such as the familiar log-likelihood ratios and the Fréchet distance between the covariance functions of the two models. Other distance-based criteria, simpler to compute than previous ones, are also introduced, for which, considering the framework of approximate design, a necessary condition for the optimality of a design measure is provided. The paper includes a study of the mathematical links between different criteria and numerical illustrations are provided.

5.
Adv Exp Med Biol ; 1354: 335-343, 2022.
Article in English | MEDLINE | ID: mdl-34807450

ABSTRACT

Much of biomedical oriented research is conducted with animal models. Over the years, rodents (primarily rats and mice) have emerged as the preferred species for basic biochemistry, cell biology, physiology and nutrition studies. In the past, dogs have been used for the evaluation of dietary protein quality and other aspects of animal nitrogen metabolism and physiology, cardiovascular and endocrine research. At an increasing rate, pigs have also been used as a model species in biomedical research. Pigs are readily available in various mature sizes and genotypic/phenotypic traits, and there are many anatomic, nutritional and physiologic similarities between human beings and pigs. Many notable reviews summarizing the role of pigs in biomedical studies have already been published and these are cited below. The present review focuses on characteristics that make pigs an excellent biomedical animal model in particular in obesity, diabetes and cardiovascular research. To procure an animal model for obesity, irrespective of species used, these animals must be fed a dense caloric diet (high fat) to achieve an experimental working model within a reasonable period. This review also focuses on a putative role of gastrointestinal microbiota in obesity as obese animals exhibit a shift in the distribution of gastrointestinal microbial phyla from lean animals. But to date such results have not pinpointed a treatable cause for obesity. Sometimes, the choice of sampling sites for microbial assessment in many reports can be questioned as the microbial content and phyla distribution in easily collected fecal samples may differ from those obtained directly from the small intestine and upper colon. While pigs are still utilized in many countries for medical surgery practice, this has been discontinued in US medical schools.


Subject(s)
Biomedical Research , Gastrointestinal Microbiome , Sus scrofa , Animals , Diet , Feces , Mice , Rats , Swine
6.
Biol Reprod ; 105(1): 76-86, 2021 07 02.
Article in English | MEDLINE | ID: mdl-33889948

ABSTRACT

Conditions of impaired energy and nutrient homeostasis, such as diabetes and obesity, are associated with infertility. Hyperglycemia increases endoplasmic reticulum stress as well as oxidative stress and reduces embryo development and quality. Oxidative stress also causes deoxyribonucleic acid damage, which impairs embryo quality and development. The natural bile acid tauroursodeoxycholic acid reduces endoplasmic reticulum stress and rescues developmentally incompetent late-cleaving embryos, as well as embryos subjected to nuclear stress, suggesting the endoplasmic reticulum stress response, or unfolded protein response, and the genome damage response are linked. Tauroursodeoxycholic acid acts via the Takeda-G-protein-receptor-5 to alleviate nuclear stress in embryos. To evaluate the role of tauroursodeoxycholic acid/Takeda-G-protein-receptor-5 signaling in embryo unfolded protein response, we used a model of glucose-induced endoplasmic reticulum stress. Embryo development was impaired by direct injection of tauroursodeoxycholic acid into parthenogenetically activated oocytes, whereas it was improved when tauroursodeoxycholic acid was added to the culture medium. Attenuation of the Takeda-G-protein-receptor-5 precluded the positive effect of tauroursodeoxycholic acid supplementation on development of parthenogenetically activated and fertilized embryos cultured under standard conditions and parthenogenetically activated embryos cultured with excess glucose. Moreover, attenuation of tauroursodeoxycholic acid/Takeda-G-protein-receptor-5 signaling induced endoplasmic reticulum stress, oxidative stress and cell survival genes, but decreased expression of pluripotency genes in parthenogenetically activated embryos cultured under excess glucose conditions. These data suggest that Takeda-G-protein-receptor-5 signaling pathways link the unfolded protein response and genome damage response. Furthermore, this study identifies Takeda-G-protein-receptor-5 signaling as a potential target for mitigating fertility issues caused by nutrient excess-associated blastomere stress and embryo death.


Subject(s)
Cholagogues and Choleretics/pharmacology , Endoplasmic Reticulum Stress/physiology , Oxidative Stress/physiology , Receptors, G-Protein-Coupled/genetics , Sus scrofa/embryology , Taurochenodeoxycholic Acid/pharmacology , Animals , Blastomeres/physiology , Embryo, Mammalian/drug effects , Embryo, Mammalian/metabolism , Embryonic Development/physiology , Glucose/adverse effects , Receptors, G-Protein-Coupled/metabolism , Unfolded Protein Response/physiology
7.
Adv Exp Med Biol ; 1285: 29-42, 2021.
Article in English | MEDLINE | ID: mdl-33770401

ABSTRACT

Proteins have been recognized for a long time as an important dietary nutritional component for all animals. Most amino acids were isolated and characterized in the late nineteenth and early twentieth century. Initially dietary proteins were ranked high to low quality by growth and N balance studies. By the 1950s interest had shifted to studying the roles of individual amino acids in amino acid requirements by feeding studies with non-ruminants as rodents, poultry and pigs. The direct protein feeding approaches followed by measurements of nutritional outcomes were not possible however in ruminants (cattle and sheep). The development of measuring free amino acids by ion exchange chromatography enabled plasma amino acid analysis. It was thought that plasma amino acid profiles were useful in nutritional studies on proteins and amino acids. With non-ruminants, nutritional interpretations of plasma amino acid studies were possible. Unfortunately with beef cattle, protein/amino acid nutritional adequacy or requirements could not be routinely determined with plasma amino acid studies. In dairy cows, however, much valuable understanding was gained from amino acid studies. Concurrently, others studied amino acid transport in ruminant small intestines, the role of peptides in ruminant N metabolism, amino acid catabolism (in the animal) with emphasis on branched-chain amino acid catabolism. In addition, workable methodologies for studying protein turnover in ruminants were developed. By the 1990s, nutritionists could still not determine amino acid requirements with empirical experimental studies in beef cattle. Instead, computer software (expert systems) based on the accumulated knowledge in animal and ruminal amino acids, energy metabolism and protein production were realized and revised frequently. With these tools, the amino acid requirements, daily energy needs, ruminal and total gastrointestinal tract digestion and performance of growing beef cattle could be predicted.


Subject(s)
Amino Acids , Animal Feed , Animal Feed/analysis , Animals , Cattle , Diet , Dietary Proteins , Digestion , Female , Sheep , Swine
8.
HNO ; 69(6): 517-528, 2021 Jun.
Article in German | MEDLINE | ID: mdl-33942126

ABSTRACT

Postoperative care is a crucial aspect for the success of paranasal sinus interventions. Basic procedures include saline nasal wash, which should be started on the first postoperative day, topical steroids, and antibiotics in cases of infection. Medical treatment involves aspiration of secretion in the inferior meatus during the first week. Removal of scabs in the surgical field should be carried out under endoscopic control beginning at the second week. Intervals are scheduled individually. Occlusion of the nose for the time of epithelium regeneration provides a moist space in the ethmoid, which improves wound healing.


Subject(s)
Paranasal Sinuses , Endoscopy , Humans , Paranasal Sinuses/surgery , Postoperative Care , Wound Healing
9.
Biom J ; 62(4): 1090-1104, 2020 07.
Article in English | MEDLINE | ID: mdl-31957085

ABSTRACT

Experimental design applications for discriminating between models have been hampered by the assumption to know beforehand which model is the true one, which is counter to the very aim of the experiment. Previous approaches to alleviate this requirement were either symmetrizations of asymmetric techniques, or Bayesian, minimax, and sequential approaches. Here we present a genuinely symmetric criterion based on a linearized distance between mean-value surfaces and the newly introduced tool of flexible nominal sets. We demonstrate the computational efficiency of the approach using the proposed criterion and provide a Monte-Carlo evaluation of its discrimination performance on the basis of the likelihood ratio. An application for a pair of competing models in enzyme kinetics is given.


Subject(s)
Biometry/methods , Models, Statistical , Bayes Theorem , Likelihood Functions , Monte Carlo Method
10.
J Pers ; 87(3): 566-578, 2019 06.
Article in English | MEDLINE | ID: mdl-29999525

ABSTRACT

OBJECTIVE: This study investigated the role of individual differences in neuroticism in conferring increased reactivity to the interpersonal antecedents for suicide proposed by the interpersonal theory of suicide. METHOD: Undergraduate students (N = 113) were screened and selected to form high (n = 58) and low (n = 55) neuroticism groups, and an experimental computer task was used to manipulate participants' experience of thwarted belongingness and perceived burdensomeness. Participants' self-reported desire to persist in the face of this induced interpersonal adversity was measured. RESULTS: Results indicate that high neuroticism confers increased reactivity to the experimental induction of the interpersonal antecedents of suicidal ideation: Thwarted belongingness and perceived burdensomeness. Furthermore, this vulnerability corresponds to a diminished desire to persist with the task in the face of interpersonal adversity. CONCLUSIONS: Neuroticism confers vulnerability for suicidal desire via an increased reactivity to the proximal, causal risk factors proposed by the interpersonal theory of suicide. This has implications for considering how personality risk factors such as neuroticism may interact with proximal interpersonal risk factors to increase suicidal ideation.


Subject(s)
Neuroticism , Suicidal Ideation , Adolescent , Adult , Female , Humans , Male , Middle Aged , Risk Factors , Students , Surveys and Questionnaires , Universities , Young Adult
11.
J Acoust Soc Am ; 145(4): 2435, 2019 04.
Article in English | MEDLINE | ID: mdl-31046370

ABSTRACT

The objective of the current paper was to characterize indoor wind turbine sound pressure levels (SPLs) to assess the audibility of wind turbine noise indoors, accounting for window opening, frequency spectra, and presbycusis. Loudspeaker generated noise was used to determine the outdoor to indoor SPL differences at 11 representative dwellings using ISO 140-5:1998. The procedure was extended to 16 Hz. With windows closed, indoor broadband A- and C-weighted SPLs were lower by 25.9 and 15.3 dB, respectively, for wind turbine noise spectra. With windows opened, the corresponding results were 13.8 and 9.9 dB, respectively. Standard deviations for these results were 3 dB so that indoor and outdoor SPL would tend to be highly correlated. For 35 dBA outdoor SPL, the indoor SPL was potentially audible at frequencies as low as 31.5 Hz. Specifically, at 35 dBA, 80% to 100% of adults below the age of 60 years, would potentially be able to hear wind turbine noise indoors with windows partially open. This would drop to 10% to 30% with closed windows. Uncertainties around these estimates are discussed.

12.
Child Psychiatry Hum Dev ; 50(1): 83-94, 2019 02.
Article in English | MEDLINE | ID: mdl-29956016

ABSTRACT

For parents of children with a mental health disorder, self-stigma can negatively impact their self-esteem and empowerment. Although measures of self-stigma exist, these have not been created in consultation with parents of children with a mental health disorder. Thus, the aim of this study was to construct a new scale based on parents' experiences and developed in partnership with parents through participatory action research (PAR). Draft items that reflect parents' self-stigmas were drawn from qualitative research. A PAR group further developed these items for conceptual and experiential representativeness, and wording suitability and interpretability. With data from 424 parents of children with a mental health disorder, factor analyses indicated three factors: self-blame, self-shame, and bad-parent self-beliefs. These factors were negatively correlated with self-esteem and empowerment. Internal consistencies were acceptable. In sum, parent self-stigma is best operationalised as including self-blame, self-shame, and bad-parent self-beliefs. A valid, PAR-informed measure is provided to promote consistent, authentic, and sensitive measurement of these components.


Subject(s)
Disabled Children/psychology , Mental Disorders/psychology , Parents/psychology , Self Concept , Shame , Adult , Child , Factor Analysis, Statistical , Female , Humans , Male , Power, Psychological , Professional-Family Relations , Qualitative Research , Reproducibility of Results , Social Stigma
13.
Mol Reprod Dev ; 85(12): 909-920, 2018 12.
Article in English | MEDLINE | ID: mdl-30298966

ABSTRACT

Oocytes collected from prepubertal animals are known to be less developmentally competent than those from adult animals. There is evidence suggesting that acquisition of developmental competence in bovine oocytes may be linked to the expression profile of genes in the granulosa cells (GCs). Cumulus-oocyte complexes (COC) and GCs were collected from 12 Holstein heifers between 2 and 6 months of age (nine follicle-stimulating hormone [FSH] treated and three untreated) and eight FSH-treated cows. The COCs from prepubertal animals were matured, fertilized, and cultured in vitro to assess development to the blastocyst stage. The relative messenger RNA (mRNA) abundance of FSHR, StAR, CYP19A1, HSD3B1, CX43, FOXO1, and XIAP in GCs were quantified by real-time quantitative polymerase chain reaction. Results from this study revealed that GCs of prepubertal animals respond to FSH treatment by increasing mRNA levels of genes promoting estradiol synthesis and follicular growth ( FSHR and CYP19A1), and preventing cell apoptosis ( XIAP), and by decreasing mRNA levels of genes promoting progesterone production ( StAR and HSD3B1). This study also revealed that the relative mRNA abundance of FOXO1 in GCs is associated with oocyte competence to support embryo development to the blastocyst stage in prepubertal Holstein heifers.


Subject(s)
Apoptosis/drug effects , Follicle Stimulating Hormone/pharmacology , Granulosa Cells/metabolism , Oocytes/metabolism , Sexual Maturation/drug effects , Signal Transduction/drug effects , Animals , Cattle , Female , Granulosa Cells/cytology , Oocytes/cytology
14.
Eur J Clin Microbiol Infect Dis ; 37(5): 959-967, 2018 May.
Article in English | MEDLINE | ID: mdl-29478197

ABSTRACT

High-throughput sequencing (HTS) has successfully identified novel resistance genes in enterococci and determined clonal relatedness in outbreak analysis. We report the use of HTS to investigate two concurrent outbreaks of glycopeptide-resistant Enterococcus faecium (GRE) with an uncharacterised resistance mechanism to quinupristin-dalfopristin (QD). Seven QD-resistant and five QD-susceptible GRE isolates from a two-centre outbreak were studied. HTS was performed to identify genes or predicted proteins that were associated with the QD-resistant phenotype. MLST and SNP typing on HTS data was used to determine clonal relatedness. Comparative genomic analysis confirmed this GRE outbreak involved two distinct clones (ST80 and ST192). HTS confirmed the absence of known QD resistance genes, suggesting a novel mechanism was conferring resistance. Genomic analysis identified two significant genetic determinants with explanatory power for the high level of QD resistance in the ST80 QD-resistant clone: an additional 56aa leader sequence at the N-terminus of the lsaE gene and a transposon containing seven genes encoding proteins with possible drug or drug-target modification activities. However, HTS was unable to conclusively determine the QD resistance mechanism and did not reveal any genetic basis for QD resistance in the ST192 clone. This study highlights the usefulness of HTS in deciphering the degree of relatedness in two concurrent GRE outbreaks. Although HTS was able to reveal some genetic candidates for uncharacterised QD resistance, this study demonstrates the limitations of HTS as a tool for identifying putative determinants of resistance to QD.


Subject(s)
Anti-Bacterial Agents/pharmacology , Disease Outbreaks , Drug Resistance, Bacterial , Enterococcus faecium/drug effects , Glycopeptides/pharmacology , Gram-Positive Bacterial Infections/epidemiology , Gram-Positive Bacterial Infections/microbiology , Virginiamycin/pharmacology , Enterococcus faecium/classification , Enterococcus faecium/genetics , Genes, Bacterial , High-Throughput Nucleotide Sequencing , Humans , Microbial Sensitivity Tests , Multilocus Sequence Typing , Phylogeny , Polymorphism, Single Nucleotide
15.
Mol Reprod Dev ; 84(1): 19-29, 2017 01.
Article in English | MEDLINE | ID: mdl-27879032

ABSTRACT

Epigenetics is a fundamental regulator underlying many biological functions, such as development and cell differentiation. Epigenetic modifications affect key chromatin regulation, including transcription and DNA repair, which are critical for normal embryo development. In this study, we profiled the expression of epigenetic modifiers and patterns of epigenetic changes in porcine embryos around the period of embryonic genome activation (EGA). We observed that Brahma-related gene 1 (BRG1) and Lysine demethylase 1A (KDM1A), which can alter the methylation status of lysine 4 in histone 3 (H3K4), localize to the nucleus at Day 3-4 of development. We then compared the abundance of epigenetic modifiers between early- and late-cleaving embryos, which were classified based on the time to the first cell cleavage, to investigate if their nuclear localization contributes to developmental competence. The mRNA abundance of BRG1, KDM1A, as well as other lysine demethylases (KDM1B, KDM5A, KDM5B, and KDM5C), were significantly higher in late- compared to early-cleaving embryos near the EGA period, although these difference disappeared at the blastocyst stage. The abundance of H3K4 mono- (H3K4me) and di-methylation (H3K4me2) during the EGA period was reduced in late-cleaving and less developmentally competent embryos. By contrast, BRG1, KDM1A, and H3K4me2 abundance was greater in embryos with more than eight cells at Day 3-4 of development compared to those with fewer than four cells. These findings suggest that altered epigenetic modifications of H3K4 around the EGA period may affect the developmental capacity of porcine embryos to reach the blastocyst stage. Mol. Reprod. Dev. 84: 19-29, 2017. © 2016 Wiley Periodicals, Inc.


Subject(s)
Blastocyst/metabolism , DNA Helicases/biosynthesis , Gene Expression Regulation, Developmental/physiology , Gene Expression Regulation, Enzymologic/physiology , Histone Demethylases/biosynthesis , Histones/metabolism , Animals , Blastocyst/cytology , Female , Methylation , Swine
16.
Mol Reprod Dev ; 84(6): 486-494, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28337827

ABSTRACT

Prostaglandin F2α (PGF) induces the precipitous loss of steroidogenic capabilities and cellular death in the corpus luteum of many species, yet the molecular mechanisms underlying this event are not completely understood. Signal transducer and activator of transcription 3 (STAT3) was activated in granulosa cells during follicle atresia, whereas AKT is immediately down-regulated in the corpus luteum after PGF treatment in cattle; however, their involvement in both functional and morphological luteolysis in monovular species still need to be determined. Blood samples and corpus lutea were collected from cows before (0) and 2, 12, 24, and 48 hr after PGF treatment on Day 10 of the estrous cycle (4-5 cows per time point). Serum progesterone concentrations decreased by threefold (p < 0.05) within 2 hr, confirming functional luteolysis. The mRNA abundance of the pro-apoptotic gene BAX increased 12-48 hr post-PGF treatment (p < 0.05), while morphological luteolysis was observed 24 and 48 hr after PGF treatment, based on the loss of plasma membrane integrity, reduction of cytoplasmic volume, and pyknotic nuclei. Phosphorylated STAT3 increased, peaking at 12 hr, and remained elevated until 48 hr after PGF treatment. SOCS3 transcript abundance also increased (p < 0.05) starting at 2 hr post-PGF treatment. In contrast, AKT phosphorylation decreased by 12 hr after treatment. Thus, activation of STAT3 and inactivation of AKT signaling are involved in structural regression of the corpus luteum.


Subject(s)
Corpus Luteum/metabolism , Dinoprost/pharmacology , Luteolysis/metabolism , Proto-Oncogene Proteins c-akt/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Animals , Cattle , Female
17.
Qual Health Res ; 27(11): 1628-1639, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28799479

ABSTRACT

Parents of children with mental health disorders are often faced with the dilemma of disclosing or concealing their child's disorder. These decisions have important implications for both child and parent. Our aim is to describe mothers' experiences with the disclosure dilemma; specifically, we describe what is disclosed (or concealed), how, and why, as well as the consequences of these decisions. Data from interviews with 11 mothers of children (aged 5-13 years) with mental health disorders, and a participatory action research group (four mothers) were thematically analyzed. Mothers selectively disclosed (and concealed) to protect and advocate for their child. Their decisions were often influenced by, or were a reactance to, others' opinions, with mothers not only avoiding, but also defending against stigma, and exercising their right to privacy. Despite anticipating negative feedback, mothers more often experienced empathy and support following disclosure. Recommendations are made for developing mothers' confidence in disclosing.


Subject(s)
Decision Making , Disclosure , Mothers/psychology , Neurodevelopmental Disorders , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Interviews as Topic , Middle Aged , Qualitative Research , Social Stigma
18.
Stat Methods Appt ; 26(3): 403-418, 2017.
Article in English | MEDLINE | ID: mdl-29755310

ABSTRACT

Optimum experimental design theory has recently been extended for parameter estimation in copula models. The use of these models allows one to gain in flexibility by considering the model parameter set split into marginal and dependence parameters. However, this separation also leads to the natural issue of estimating only a subset of all model parameters. In this work, we treat this problem with the application of the [Formula: see text]-optimality to copula models. First, we provide an extension of the corresponding equivalence theory. Then, we analyze a wide range of flexible copula models to highlight the usefulness of [Formula: see text]-optimality in many possible scenarios. Finally, we discuss how the usage of the introduced design criterion also relates to the more general issue of copula selection and optimal design for model discrimination.

19.
J Antimicrob Chemother ; 71(4): 871-81, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26682961

ABSTRACT

OBJECTIVES: Tigecycline represents one of the last-line therapeutics to combat multidrug-resistant bacterial pathogens, including VRE and MRSA. The German National Reference Centre for Staphylococci and Enterococci has received 73 tigecycline-resistant Enterococcus faecium and Enterococcus faecalis isolates in recent years. The precise mechanism of how enterococci become resistant to tigecycline remains undetermined. This study documents an analysis of the role of efflux pumps in tigecycline resistance in clinical isolates of Enterococcus spp. METHODS: Various tigecycline MICs were found for the different isolates analysed. Tigecycline-resistant strains were analysed with respect to genome and transcriptome differences by means of WGS and RT-qPCR. Genes of interest were cloned and expressed in Listeria monocytogenes for verification of their functionality. RESULTS: Detailed comparative whole-genome analyses of three isogenic strains, showing different levels of tigecycline resistance, revealed the major facilitator superfamily (MFS) efflux pump TetL and the ribosomal protection protein TetM as possible drug resistance proteins. Subsequent RT-qPCR confirmed up-regulation of the respective genes. A correlation of gene copy number and level of MIC was inferred from further qPCR analyses. Expression of both tet(L) and tet(M) in L. monocytogenes unequivocally demonstrated the potential to increase tigecycline MICs upon acquisition of either locus. CONCLUSIONS: Our results indicate that increased expression of two tetracycline resistance determinants, a tet(L)-encoded MFS pump and a tet(M)-encoded ribosomal protection protein, is capable of conferring tigecycline resistance in enterococcal clinical isolates.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/genetics , Drug Resistance, Microbial/genetics , Enterococcus faecium/drug effects , Gram-Negative Bacterial Infections/drug therapy , Minocycline/analogs & derivatives , Plasmids/genetics , Base Sequence , Enterococcus faecium/genetics , Gene Dosage , Gram-Negative Bacterial Infections/microbiology , Microbial Sensitivity Tests , Minocycline/pharmacology , Polymerase Chain Reaction , Tetracycline Resistance/genetics , Tigecycline , Up-Regulation/genetics
20.
Catheter Cardiovasc Interv ; 87(6): 1092-100, 2016 May.
Article in English | MEDLINE | ID: mdl-26268482

ABSTRACT

OBJECTIVE: To demonstrate the safety and efficacy of a new sirolimus eluting stent with bioresorbable polymer, Ultimaster, (BP-SES) compared with everolimus-eluting, permanent polymer, Xience stent (PP-EES) in bifurcation lesions with respect to the freedom from Target Lesion Failure at 1-year. METHODS: Within 1,119 patients enrolled in the CENTURY II randomized controlled multicenter trial, 194 patients were treated for bifurcation lesions and randomized to either BP-SES (n = 95) or PP-EES (n = 99). The primary endpoint was freedom from target lesion failure (TLF) composite endpoint [cardiac death, MI not clearly attributable to a non-target vessel, and clinically driven target lesion revascularization (TLR)] at 1-year. RESULTS: Baseline patient demographic, angiographic, and stenting characteristics were similar in both study arms. A single stent technique with provisional or "cross over" stenting were the most widely used in both arms (93.2% BP-SES vs. 92.4% PP-EES). Freedom from TLF at 1-year was 94.7% for BP-SES and 91.9% for PP-EES (P for noninferiority 0.031). The rate of clinically driven target lesion revascularization (TLR) at 1-year was 3.2% for BP-SES and 3.0% for PP-EES (P = 0.95). There were no significant differences detected in any of the individual clinical endpoints or other secondary clinical endpoints between the study arms at 1-year follow up. CONCLUSIONS: The new bioresorbable polymer sirolimus-eluting stent showed safety and efficacy profiles similar to durable polymer everolimus-eluting in the treatment of patients with bifurcation lesions at 1-year follow up. © 2015 Wiley Periodicals, Inc.


Subject(s)
Absorbable Implants , Coronary Vessels/diagnostic imaging , Drug-Eluting Stents , Everolimus/pharmacology , Percutaneous Coronary Intervention/methods , Polymers , Sirolimus/pharmacology , Aged , Coronary Angiography , Coronary Artery Disease , Coronary Vessels/surgery , Female , Follow-Up Studies , Humans , Immunosuppressive Agents/pharmacology , Male , Middle Aged , Prospective Studies , Prosthesis Design , Single-Blind Method , Time Factors
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