Shifting the limits in wheat research and breeding using a fully annotated reference genome

Introduction: Wheat (Triticum aestivum L.) is the most widely cultivated crop on Earth, contributing about a fifth of the total calories consumed by humans. Consequently, wheat yields and production affect the global economy, and failed harvests can lead to social unrest. Breeders continuously strive to develop improved varieties by fine-tuning genetically complex yield and end-use quality parameters while maintaining stable yields and adapting the crop to regionally specific biotic and abiotic stresses. Rationale: Breeding efforts are limited by insufficient knowledge and understanding of wheat biology and the molecular basis of central agronomic traits. To meet the demands of human population growth, there is an urgent need for wheat research and breeding to accelerate genetic gain as well as to increase and protect wheat yield and quality traits. In other plant and animal species, access to a fully annotated and ordered genome sequence, including regulatory sequences and genome-diversity information, has promoted the development of systematic and more time-efficient approaches for the selection and understanding of important traits. Wheat has lagged behind, primarily owing to the challenges of assembling a genome that is more than five times as large as the human genome, polyploid, and complex, containing more than 85% repetitive DNA. To provide a foundation for improvement through molecular breeding, in 2005, the International Wheat Genome Sequencing Consortium set out to deliver a high-quality annotated reference genome sequence of bread wheat. Results: An annotated reference sequence representing the hexaploid bread wheat genome in the form of 21 chromosome-like sequence assemblies has now been delivered, giving access to 107,891 high-confidence genes, including their genomic context of regulatory sequences. This assembly enabled the discovery of tissue- and developmental stage–related gene coexpression networks using a transcriptome atlas representing all stages of wheat development. The dynamics of change in complex gene families involved in environmental adaptation and end-use quality were revealed at subgenome resolution and contextualized to known agronomic single-gene or quantitative trait loci. Aspects of the future value of the annotated assembly for molecular breeding and research were exemplarily illustrated by resolving the genetic basis of a quantitative trait locus conferring resistance to abiotic stress and insect damage as well as by serving as the basis for genome editing of the flowering-time trait. Conclusion: This annotated reference sequence of wheat is a resource that can now drive disruptive innovation in wheat improvement, as this community resource establishes the foundation for accelerating wheat research and application through improved understanding of wheat biology and genomics-assisted breeding. Importantly, the bioinformatics capacity developed for model-organism genomes will facilitate a better understanding of the wheat genome as a result of the high-quality chromosome-based genome assembly. By necessity, breeders work with the genome at the whole chromosome level, as each new cross involves the modification of genome-wide gene networks that control the expression of complex traits such as yield. With the annotated and ordered reference genome sequence in place, researchers and breeders can now easily access sequence-level information to precisely define the necessary changes in the genomes for breeding programs. This will be realized through the implementation of new DNA marker platforms and targeted breeding technologies, including genome editing

The association of smoking with venous thrombosis in women and its modification by exogenous hormones

Thesis (Master's)--University of Washington, 2012Background: The evidence for an association between smoking and venous thrombosis (VT) remains inconsistent. In particular, the nature of this association has not been reported among users of hormone therapy (HT). Methods: We studied 2125 women with validated VT and 5749 controls from a large healthcare system in Washington State. Smoking status (current, former, never) was assessed from medical records review and, for a subset, also by telephone interview. The agreement between the 2 measures was excellent (Kappa 0.84). Current hormone use was calculated from pharmacy databases. We used multivariate logistic regression to evaluate the association between smoking and VT, and its modification by the use of HT. Adjustment variables included BMI, race, diabetes and pregnancy. Results: Our sample comprised mostly postmenopausal white women, with a mean age of 65 years and a smoking prevalence of 10%. Current smokers were at higher risk of VT than non-smokers (OR 1.21, 95%CI 1.02-1.46). This risk did not differ between women not using and using HT: OR 1.2 (95%CI 1.0-1.5) and 1.2 (95%CI 0.8-1.9), respectively (p for interaction = 0.73). A subgroup analysis among women in their first year of use of HT suggested a higher risk for current smokers, compared to non-smokers, however without evidence of an interaction (OR 3.3, 95%CI 0.9-12.6, p for interaction = 0.13). In former smokers, an association between smoking and VT was only present during the first year after smoking cessation (OR 2.7, 95%CI 2.0-3.8), without suggestion of an increased risk thereafter. Conclusion: Among women in the US, smoking was a weak risk factor for VT and was not modified in women who had used HT for >1 year. Further studies are needed to elucidate the association of smoking with VT during the first year of treatment with HT

Approche diagnostique et prise en charge de la dissection aortique aiguë aux urgences : revue de la littérature

Une dissection aortique n'est suspectée que dans la moitié des cas aux urgences. Malgré son incidence faible, elle peut se cacher derrière toute douleur thoracique ou dorsale, ainsi que sous la forme d'une syncope. Aucun élément de la présentation clinique ou examen paraclinique de base n'est suffisant pour l'exclure. Par contre, une douleur brutale, sévère, migrante, déchirante, un déficit neurologique ou de pouls, ou un élargissement du médiastin sont des données spécifiques qui engagent la poursuite du processus diagnostic. Toute suspicion d'une dissection aortique doit être suivie d'un examen d'imagerie (CT spiralé, échocardiographie transoesophagienne ou IRM) selon son délai en raison d'une mortalité importante dans les 48 premières heures. Dans l'attente, le traitement doit viser une antalgie efficace et une baisse agressive de la tension artérielle par des bêta-bloquants. Le dosage des D-dimères n'est actuellement pas suffisamment validé pour avoir une place dans la stratégie diagnostique de tous les patients

Screening for Cancer in Patients with Acute Venous Thromboembolic Disease

Active cancer causes approximately 25% of all acute events of venous thromboembolism (VTE). While most of the cancer diagnoses are known or clinically apparent at the time of VTE, care providers and patients may be worried about the 3 to 8% risk of occult cancer occurring in the year after VTE. Several studies have compared limited to extensive cancer screening after acute VTE, especially with the addition of abdominal computed tomography (CT) or whole-body PET-CT, with the hope to shorten the time to cancer diagnosis and lead to less advanced cancer stages. These studies have not shown improved clinical outcomes with an extensive screening, and have led to current recommendations of limited screening for cancer in patients with acute VTE, including unprovoked cases. Several risk assessment models have been developed to identify patients at greatest risk of occult cancer, however, with low discriminative performances and no current clinical usefulness. Some clinical situations may empirically deserve a more thorough cancer screening, such as unprovoked upper extremity deep vein thrombosis (DVT), bilateral leg DVT, descending leg DVT, or recurrent VTE during anticoagulation

Hospital thromboprophylaxis: one size should not fit all

Venous thromboembolism, comprised of deep vein thrombosis and pulmonary embolism, is commonly found during or shortly after hospital stays. To prevent such events, processes of thromboprophylaxis have emerged for all types of inpatients through the use of low-dose anticoagulants (heparins or low-molecular-weight heparins). In this thesis, the evidence behind thromboprophylaxis in medical and obstetrical inpatients is reviewed, including my own research in these fields. While there are many differences between these populations, our approach remains very simplistic, with one similar treatment for all high-risk patients and no treatment for low-risk patients. Reflections on how to bring more granularity to medical thromboprophylaxis and stronger evidence to obstetrical thromboprophylaxis are discussed

Underuse of medical thromboprophylaxis in mobile elderly inpatients: The SWITCO65+ cohort

Background Hospital‐associated venous thromboembolism (HA‐VTE) can be prevented by pharmacologic thromboprophylaxis. Thrombotic risk assessment models (RAMs) are essential tools to improve inadequately prescribed thromboprophylaxis. Among cases of HA‐VTE, our study objectives are to explore the classifications of available thrombosis RAMs, the adequacy of thromboprophylaxis and risk factors for inadequate thromboprophylaxis. Methods We identified cases of HA‐VTE occurring during medical hospitalizations within a multicenter Swiss venous thromboembolism (VTE) cohort (2009‐2013). We calculated the proportion of VTE cases deemed at high risk with 4 VTE RAMs (Geneva, Simplified Geneva, Padua, and Improve) and the adequacy of administered pharmacologic thromboprophylaxis, and explored risk factors for underprescription of thromboprophylaxis in high‐risk inpatients. Results Among 66 medical inpatients with HA‐VTE, 60.6% had pulmonary embolism. The sensitivities of the Geneva, Simplified Geneva, Padua, and Improve RAMs were 86.4%, 80.3%, 72.7%, and 57.6%, respectively. The proportion of inadequate thromboprophylaxis was high, as 62.5%‐71.1% of high‐risk inpatients had not received it. Among the high‐risk group according to the Simplified Geneva RAM, absence of immobilization was the only variable significantly associated with an inadequate use of thromboprophylaxis (odds ratio, 3.59; 95% confidence interval, 1.08‐11.88). Conclusions We found a dramatically high proportion of inadequate medical thromboprophylaxis among inpatients who suffered from HA‐VTE. This reinforces the need for global and local quality‐improvement efforts to promote adequate use of thromboprophylaxis in elderly inpatients. Mobility may favor the underuse of thromboprophylaxis, and clinicians should stay alert to other thrombotic risk factors in mobile inpatients

Evaluation du risque hémorragique en cas de maladie thromboembolique veineuse: état des lieux en 2012

About 2 to 2,5% of patients with venous thromboembolism suffer from a major bleed in the first 90 days of treatment with anticoagulation. Many predictors of hemorrhages have been identified, and include the stability of INRs, a bleeding history, cancer, chronic kidney disease and an advanced age. This knowledge may help care-providers to identify high-risk situations and to determine the best duration of treatment for their patients. Bleeding prediction rules for prevalent users of warfarin have not been validated for patients in venous thromboembolism, and their usefulness remains to be determined

Evaluation du risque hémorragique en cas de maladie thromboembolique veineuse: état des lieux en 2012

About 2 to 2,5% of patients with venous thromboembolism suffer from a major bleed in the first 90 days of treatment with anticoagulation. Many predictors of hemorrhages have been identified, and include the stability of INRs, a bleeding history, cancer, chronic kidney disease and an advanced age. This knowledge may help care-providers to identify high-risk situations and to determine the best duration of treatment for their patients. Bleeding prediction rules for prevalent users of warfarin have not been validated for patients in venous thromboembolism, and their usefulness remains to be determined