Showing papers by "Laval University published in 2017"
University of Tübingen1, World Health Organization2, University of Cape Town3, European Centre for Disease Prevention and Control4, Utrecht University5, Tel Aviv University6, Laval University7, Boston University8, Centers for Disease Control and Prevention9, European Medicines Agency10, Food and Drug Administration11, Biomedical Advanced Research and Development Authority12, University of Melbourne13, University of Otago14, George Washington University15
TL;DR: Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria, and include antibiotic-resistant bacteria responsible for community-acquired infections.
Abstract: Summary Background The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs. Methods We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria. Findings We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacterium's total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa , and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus . Of the bacteria typically responsible for community-acquired infections, clarithromycin-resistant Helicobacter pylori , and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae , and Salmonella typhi were included in the high-priority tier. Interpretation Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria. The global strategy should include antibiotic-resistant bacteria responsible for community-acquired infections such as Salmonella spp, Campylobacter spp, N gonorrhoeae , and H pylori . Funding World Health Organization.
3,184 citations
Harvard University1, Erasmus University Rotterdam2, University of Pennsylvania3, Laval University4, University of Ulsan5, University of California, San Francisco6, Yale University7, Radboud University Nijmegen8, University of Southern California9, Merck & Co.10, Memorial Sloan Kettering Cancer Center11
TL;DR: Pembrolizumab was associated with significantly longer overall survival and with a lower rate of treatment‐related adverse events than chemotherapy as second‐line therapy for platinum‐refractory advanced urothelial carcinoma.
Abstract: BackgroundPatients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options. MethodsIn this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1–expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more. ResultsThe median overall survival in the total population was 10.3 months (95% confidence interval [C...
2,362 citations
University of Cambridge1, Wellcome Trust Sanger Institute2, University of Melbourne3, Netherlands Cancer Institute4, University of Amsterdam5, University of Warwick6, Cancer Council Victoria7, University of Utah8, Columbia University9, Central Manchester University Hospitals NHS Foundation Trust10, Chapel Allerton Hospital11, Guy's and St Thomas' NHS Foundation Trust12, National Institute for Health Research13, University of Glasgow14, St George's, University of London15, Curie Institute16, Paris Descartes University17, Erasmus University Rotterdam18, Radboud University Nijmegen19, VU University Medical Center20, Cancer Prevention Institute of California21, Lunenfeld-Tanenbaum Research Institute22, University of Toronto23, Fox Chase Cancer Center24, Huntsman Cancer Institute25, Leipzig University26, German Cancer Research Center27, University of Cologne28, Hospital Clínico San Carlos29, Pomeranian Medical University30, Laval University31, University of New South Wales32, Peter MacCallum Cancer Centre33, St. Vincent's Health System34, Medical University of Vienna35, QIMR Berghofer Medical Research Institute36, Copenhagen University Hospital37, Karolinska Institutet38, Lund University39
TL;DR: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location, a large cohort study recruited in 1997-2011 provides estimates of cancer risk based on BRCA1 and BRCa2 mutation carrier status.
Abstract: Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures: BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). Conclusions and Relevance: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.
1,733 citations
01 Jan 2017
TL;DR: A new representation learning approach for domain adaptation, in which data at training and test time come from similar but different distributions, which can be achieved in almost any feed-forward model by augmenting it with few standard layers and a new gradient reversal layer.
Abstract: We introduce a new representation learning approach for domain adaptation, in which data at training and test time come from similar but different distributions. Our approach is directly inspired by the theory on domain adaptation suggesting that, for effective domain transfer to be achieved, predictions must be made based on features that cannot discriminate between the training (source) and test (target) domains.
The approach implements this idea in the context of neural network architectures that are trained on labeled data from the source domain and unlabeled data from the target domain (no labeled target-domain data is necessary). As the training progresses, the approach promotes the emergence of features that are (i) discriminative for the main learning task on the source domain and (ii) indiscriminate with respect to the shift between the domains. We show that this adaptation behaviour can be achieved in almost any feed-forward model by augmenting it with few standard layers and a new gradient reversal layer. The resulting augmented architecture can be trained using standard backpropagation and stochastic gradient descent, and can thus be implemented with little effort using any of the deep learning packages.
We demonstrate the success of our approach for two distinct classification problems (document sentiment analysis and image classification), where state-of-the-art domain adaptation performance on standard benchmarks is achieved. We also validate the approach for descriptor learning task in the context of person re-identification application.
1,713 citations
TL;DR: The InTBIR Participants and Investigators have provided informed consent for the study to take place in Poland.
Abstract: Additional co-authors: Endre Czeiter, Marek Czosnyka, Ramon Diaz-Arrastia, Jens P Dreier, Ann-Christine Duhaime, Ari Ercole, Thomas A van Essen, Valery L Feigin, Guoyi Gao, Joseph Giacino, Laura E Gonzalez-Lara, Russell L Gruen, Deepak Gupta, Jed A Hartings, Sean Hill, Ji-yao Jiang, Naomi Ketharanathan, Erwin J O Kompanje, Linda Lanyon, Steven Laureys, Fiona Lecky, Harvey Levin, Hester F Lingsma, Marc Maegele, Marek Majdan, Geoffrey Manley, Jill Marsteller, Luciana Mascia, Charles McFadyen, Stefania Mondello, Virginia Newcombe, Aarno Palotie, Paul M Parizel, Wilco Peul, James Piercy, Suzanne Polinder, Louis Puybasset, Todd E Rasmussen, Rolf Rossaint, Peter Smielewski, Jeannette Soderberg, Simon J Stanworth, Murray B Stein, Nicole von Steinbuchel, William Stewart, Ewout W Steyerberg, Nino Stocchetti, Anneliese Synnot, Braden Te Ao, Olli Tenovuo, Alice Theadom, Dick Tibboel, Walter Videtta, Kevin K W Wang, W Huw Williams, Kristine Yaffe for the InTBIR Participants and Investigators
1,354 citations
TL;DR: The use of eDNA metabarcoding for surveying animal and plant richness, and the challenges in using eDNA approaches to estimate relative abundance are reviewed, which distill what is known about the ability of different eDNA sample types to approximate richness in space and across time.
Abstract: The genomic revolution has fundamentally changed how we survey biodiversity on earth. High-throughput sequencing ("HTS") platforms now enable the rapid sequencing of DNA from diverse kinds of environmental samples (termed "environmental DNA" or "eDNA"). Coupling HTS with our ability to associate sequences from eDNA with a taxonomic name is called "eDNA metabarcoding" and offers a powerful molecular tool capable of noninvasively surveying species richness from many ecosystems. Here, we review the use of eDNA metabarcoding for surveying animal and plant richness, and the challenges in using eDNA approaches to estimate relative abundance. We highlight eDNA applications in freshwater, marine and terrestrial environments, and in this broad context, we distill what is known about the ability of different eDNA sample types to approximate richness in space and across time. We provide guiding questions for study design and discuss the eDNA metabarcoding workflow with a focus on primers and library preparation methods. We additionally discuss important criteria for consideration of bioinformatic filtering of data sets, with recommendations for increasing transparency. Finally, looking to the future, we discuss emerging applications of eDNA metabarcoding in ecology, conservation, invasion biology, biomonitoring, and how eDNA metabarcoding can empower citizen science and biodiversity education.
1,038 citations
Kyriaki Michailidou1, Kyriaki Michailidou2, Sara Lindström3, Sara Lindström4 +393 more•Institutions (127)
TL;DR: A genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry finds that heritability of Breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2–5-fold enriched relative to the genome- wide average.
Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
1,014 citations
TL;DR: To facilitate network-based approaches to drug discovery, BioGRID now incorporates 27 501 chemical–protein interactions for human drug targets, as drawn from the DrugBank database.
Abstract: The Biological General Repository for Interaction Datasets (BioGRID: https://thebiogrid.org) is an open access database dedicated to the annotation and archival of protein, genetic and chemical interactions for all major model organism species and humans. As of September 2016 (build 3.4.140), the BioGRID contains 1 072 173 genetic and protein interactions, and 38 559 post-translational modifications, as manually annotated from 48 114 publications. This dataset represents interaction records for 66 model organisms and represents a 30% increase compared to the previous 2015 BioGRID update. BioGRID curates the biomedical literature for major model organism species, including humans, with a recent emphasis on central biological processes and specific human diseases. To facilitate network-based approaches to drug discovery, BioGRID now incorporates 27 501 chemical-protein interactions for human drug targets, as drawn from the DrugBank database. A new dynamic interaction network viewer allows the easy navigation and filtering of all genetic and protein interaction data, as well as for bioactive compounds and their established targets. BioGRID data are directly downloadable without restriction in a variety of standardized formats and are freely distributed through partner model organism databases and meta-databases.
892 citations
TL;DR: High carbohydrate intake was associated with higher risk of total mortality, whereas total fat and individual types of fat were related to lower total mortality.
786 citations
University of Pittsburgh1, Riley Hospital for Children2, Washington University in St. Louis3, Baylor College of Medicine4, Texas Tech University5, Northwestern University6, University of British Columbia7, Medical College of Wisconsin8, Saint Barnabas Medical Center9, University of Pennsylvania10, University College London11, University of Alberta12, Duke University13, McMaster University14, Yeshiva University15, University of Michigan16, Laval University17, Kaiser Permanente18, Emory University19, University of Maryland, Baltimore20, Cornell University21, Nationwide Children's Hospital22, Children's Mercy Hospital23, Texas Tech University Health Sciences Center at El Paso24, University of Florida25, St Mary's Hospital26, University of Rochester27, University of Washington28, Stanford University29, University of California, San Diego30, Valley Hospital31, Royal Children's Hospital32, University of Melbourne33, Loma Linda University34, Great Ormond Street Hospital35, Boston Children's Hospital36, Austral University37, University of Colorado Denver38, Nemours Foundation39
TL;DR: A major new recommendation in the 2014 update of the 2007 American College of Critical Care Medicine “Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock” is consideration of institution—specific use of a recognition bundle containing a trigger tool for rapid identification of patients with septic shock.
Abstract: Objectives:The American College of Critical Care Medicine provided 2002 and 2007 guidelines for hemodynamic support of newborn and pediatric septic shock Provide the 2014 update of the 2007 American College of Critical Care Medicine “Clinical Guidelines for Hemodynamic Support of Neonates and Child
605 citations
University of Michigan1, Amgen2, University of Florence3, Laval University4, University of Lyon5, University of California, San Francisco6, University of Graz7, University of British Columbia8, University of Bern9, University of Liège10, Paris Descartes University11, Columbia University12, Leiden University Medical Center13
TL;DR: The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years, and serious adverse event rates were generally stable over time.
University of Toronto1, Tulane University2, Ohio State University3, Hannover Medical School4, University of Texas Southwestern Medical Center5, Washington University in St. Louis6, University of California, San Francisco7, Laval University8, Boston Children's Hospital9, University of Hamburg10, University of Pennsylvania11, Sheba Medical Center12, University of Padua13, University of Pittsburgh14, Oregon Health & Science University15, Medical College of Wisconsin16, University of New South Wales17, Medical University of South Carolina18, University of Manitoba19, Tel Aviv University20, Tel Aviv Sourasky Medical Center21, Saint George Hospital22, University of Wisconsin-Madison23
TL;DR: An extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations, uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load.
TL;DR: Chronic social defeat stress induces loss of protein claudin-5, leading to abnormalities in blood vessel morphology, increased blood brain barrier permeability, infiltration of immune signals and depression-like behaviors.
Abstract: Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood–brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of the endothelial cell tight junction protein claudin-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression. Chronic social defeat stress induces loss of protein claudin-5, leading to abnormalities in blood vessel morphology, increased blood brain barrier permeability, infiltration of immune signals and depression-like behaviors.
TL;DR: The meaning of “resistance” related to leishmaniasis and its molecular epidemiology are discussed, particularly for Leishmania donovani that causes visceral leish maniasis, and how resistance can affect drug combination therapies are discussed.
Abstract: Reevaluation of treatment guidelines for Old and New World leishmaniasis is urgently needed on a global basis because treatment failure is an increasing problem. Drug resistance is a fundamental determinant of treatment failure, although other factors also contribute to this phenomenon, including the global HIV/AIDS epidemic with its accompanying impact on the immune system. Pentavalent antimonials have been used successfully worldwide for the treatment of leishmaniasis since the first half of the 20th century, but the last 10 to 20 years have witnessed an increase in clinical resistance, e.g., in North Bihar in India. In this review, we discuss the meaning of “resistance” related to leishmaniasis and discuss its molecular epidemiology, particularly for Leishmania donovani that causes visceral leishmaniasis. We also discuss how resistance can affect drug combination therapies. Molecular mechanisms known to contribute to resistance to antimonials, amphotericin B, and miltefosine are also outlined.
The Dartmouth Institute for Health Policy and Clinical Practice1, Radboud University Nijmegen2, Johns Hopkins University3, Palo Alto Medical Foundation4, University of Wolverhampton5, Akershus University Hospital6, Maine Medical Center7, University of Hamburg8, Cardiff University9, Tokyo University of Technology10, University of Sydney11, Laval University12, Maastricht University Medical Centre13
TL;DR: The revised three-talk model of shared decision making depicts conversational steps, initiated by providing support when introducing options, followed by strategies to compare and discuss trade-offs, before deliberation based on informed preferences.
Abstract: OBJECTIVES
To revise an existing three-talk model for learning how
to achieve shared decision making, and to consult
with relevant stakeholders to update and obtain wider
engagement.
DESIGN
Multistage consultation process.
SETTING
Key informant group, communities of interest, and
survey of clinical specialties.
PARTICIPANTS
19 key informants, 153 member responses from
multiple communities of interest, and 316 responses
to an online survey from medically qualified clinicians
from six specialties.
RESULTS
After extended consultation over three iterations, we
revised the three-talk model by making changes to
one talk category, adding the need to elicit patient
goals, providing a clear set of tasks for each talk
category, and adding suggested scripts to illustrate
each step. A new three-talk model of shared decision
making is proposed, based on “team talk,” “option
talk,” and “decision talk,” to depict a process of
collaboration and deliberation. Team talk places
emphasis on the need to provide support to patients
when they are made aware of choices, and to elicit
their goals as a means of guiding decision making
processes. Option talk refers to the task of comparing
alternatives, using risk communication principles.
Decision talk refers to the task of arriving at decisions
that reflect the informed preferences of patients,
guided by the experience and expertise of health
professionals.
CONCLUSIONS
The revised three-talk model of shared decision
making depicts conversational steps, initiated by
providing support when introducing options, followed
by strategies to compare and discuss trade-offs,
before deliberation based on informed preferences.
University of Alberta1, Montreal Heart Institute2, University Health Network3, McGill University4, McMaster University5, University of Waterloo6, University of Calgary7, Université de Sherbrooke8, University of Western Ontario9, St. Michael's Hospital10, Halifax11, Royal Jubilee Hospital12, University of British Columbia13, St. Boniface General Hospital14, Sunnybrook Health Sciences Centre15, University of Saskatchewan16, Durham University17, Laval University18, University of Colorado Boulder19, Université de Montréal20, St. John's University21
TL;DR: The 2017 HF guidelines provide updated guidance on the diagnosis and management that should aid in day-to-day decisions for caring for patients with HF, with attention to strategies and treatments to prevent HF, to the organization of HF care, comorbidity management, as well as practical issues around the timing of referral and follow-up care.
TL;DR: Light is shed on the essential role of the surface and other physicochemical properties of a library of nanoparticles on their in vivo pharmacokinetics and how physicochemical characteristics influence blood circulation and early distribution.
Abstract: In vitro incubation of nanomaterials with plasma offer insights on biological interactions, but cannot fully explain the in vivo fate of nanomaterials Here, we use a library of polymer nanoparticles to show how physicochemical characteristics influence blood circulation and early distribution For particles with different diameters, surface hydrophilicity appears to mediate early clearance Densities above a critical value of approximately 20 poly(ethylene glycol) chains (MW 5 kDa) per 100 nm2 prolong circulation times, irrespective of size In knockout mice, clearance mechanisms are identified for nanoparticles with low and high steric protection Studies in animals deficient in the C3 protein showed that complement activation could not explain differences in the clearance of nanoparticles In nanoparticles with low poly(ethylene glycol) coverage, adsorption of apolipoproteins can prolong circulation times In parallel, the low-density-lipoprotein receptor plays a predominant role in the clearance of nanoparticles, irrespective of poly(ethylene glycol) density These results further our understanding of nanopharmacology Understanding the interaction between nanoparticles and biomolecules is crucial for improving current drug-delivery systems Here, the authors shed light on the essential role of the surface and other physicochemical properties of a library of nanoparticles on their in vivo pharmacokinetics
TL;DR: It is suggested that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates and numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberration outperformed well-described prognostic biomarkers.
Abstract: Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.
TL;DR: Preeclampsia and fetal growth restriction using aspirin in early pregnancy is associated with a dose‐response effect, with higher dosages of aspirin being associated with greater reduction of the 3 outcomes.
TL;DR: Higher total fruit, vegetable, and legume intake was inversely associated with major cardiovascular disease, myocardial infarction, cardiovascular mortality, non-cardiovascular mortality, and total mortality in the models adjusted for age, sex, and centre (random effect).
International Agency for Research on Cancer1, Lunenfeld-Tanenbaum Research Institute2, Dartmouth College3, Harvard University4, National Institutes of Health5, University of Cambridge6, Gentofte Hospital7, Copenhagen University Hospital8, University of Copenhagen9, University of Texas MD Anderson Cancer Center10, University of Hawaii11, University of Göttingen12, Vanderbilt University Medical Center13, Case Western Reserve University14, University of Oviedo15, Technion – Israel Institute of Technology16, University of Sheffield17, University of Liverpool18, Radboud University Nijmegen19, Washington State University Spokane20, National Institute of Occupational Health21, BC Cancer Agency22, Nanjing Medical University23, New Generation University College24, University of Pittsburgh25, University of Milan26, Princess Margaret Cancer Centre27, University of Southern California28, Sejong University29, Lund University30, Imperial College London31, Aarhus University32, Prevention Institute33, Fred Hutchinson Cancer Research Center34, Ludwig Maximilian University of Munich35, Technische Universität München36, University Hospital Heidelberg37, Umeå University38, University of Kentucky39, Charles University in Prague40, University of Ostrava41, University of Belgrade42, Nofer Institute of Occupational Medicine43, University of Bergen44, National University of Singapore45, Institute of Cancer Research46, American Cancer Society47, Merck & Co.48, University of British Columbia49, University Medical Center Groningen50, University of Leicester51, National Institute for Health Research52, Amgen53, Research Triangle Park54, Washington University in St. Louis55, Baylor College of Medicine56, Anschutz Medical Campus57, University of Washington58, University of Toronto59, Centre for Addiction and Mental Health60, QIMR Berghofer Medical Research Institute61, Laval University62
TL;DR: 18 susceptibility loci achieving genome-wide significance are identified, including 10 new loci linked with lung cancer overall and six loci associated with lung adenocarcinoma, highlighting the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer.
Abstract: Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
TL;DR: A rapid and systematic review of the evidence for causality found sufficient evidence to say that Zika virus is a cause of congenital abnormalities and is a trigger of GBS.
Abstract: Background: The Zika virus (ZIKV) caused a large outbreak in the Americas leading to the declaration of a Public Health Emergency of International Concern in February 2016. A causal relation between infection and adverse congenital outcomes such as microcephaly was declared by the World Health Organization (WHO) informed by a systematic review structured according to a framework of ten dimensions of causality, based on the work of Bradford Hill. Subsequently, the evidence has continued to accumulate, which we incorporate in regular updates of the original work, rendering it a living systematic review. Methods: We present an update of our living systematic review on the causal relation between ZIKV infection and adverse congenital outcomes and between ZIKV and GBS for four dimensions of causality: strength of association, dose-response, specificity, and consistency. We assess the evidence published between January 18, 2017 and July 1, 2019. Results: We found that the strength of association between ZIKV infection and adverse outcomes from case-control studies differs according to whether exposure to ZIKV is assessed in the mother (OR 3.8, 95% CI: 1.7-8.7, I 2=19.8%) or the foetus/infant (OR 37.4, 95% CI: 11.0-127.1, I 2=0%). In cohort studies, the risk of congenital abnormalities was 3.5 times higher after ZIKV infection (95% CI: 0.9-13.5, I 2=0%). The strength of association between ZIKV infection and GBS was higher in studies that enrolled controls from hospital (OR: 55.8, 95% CI: 17.2-181.7, I 2=0%) than in studies that enrolled controls at random from the same community or household (OR: 2.0, 95% CI: 0.8-5.4, I 2=74.6%). In case-control studies, selection of controls from hospitals could have biased results. Conclusions: The conclusions that ZIKV infection causes adverse congenital outcomes and GBS are reinforced with the evidence published between January 18, 2017 and July 1, 2019.
TL;DR: It is concluded that CBTI, either its components or the full package, is effective in the treatment of insomnia.
ETH Zurich1, University of Ulm2, Vrije Universiteit Brussel3, Royal Museum for Central Africa4, University of Coimbra5, University of Helsinki6, University of Victoria7, University of Innsbruck8, University of Milan9, Czech University of Life Sciences Prague10, Spanish National Research Council11, Swiss Federal Institute for Forest, Snow and Landscape Research12, Institut national de la recherche agronomique13, Laval University14, University of Ljubljana15, United States Geological Survey16, Ben-Gurion University of the Negev17, Center for International Forestry Research18, Dresden University of Technology19, Technical University of Berlin20, University of Arkansas21, University of Kansas22, Max Planck Society23, National Museum of Natural History24, Desert Botanical Garden25, Humboldt State University26, Sukachev Institute of Forest27, National University of Comahue28, National Scientific and Technical Research Council29, Agricultural Research Organization, Volcani Center30, Wageningen University and Research Centre31, Naturalis32, Pablo de Olavide University33, Autonomous University of Barcelona34, University of Lisbon35, Mediterranean University36, Technical University of Madrid37, University of Western Sydney38, University of Debrecen39, Natural Resources Canada40, American Hotel & Lodging Educational Institute41, Open University of Cyprus42, University of Cyprus43, University of Patras44, University of Colorado Boulder45, Northern Arizona University46, University of Novi Sad47, European Forest Institute48, Estonian University of Life Sciences49, University of Alberta50, University of Minnesota51, University of Forestry, Sofia52
TL;DR: The results imply that growth-based mortality algorithms may be a powerful tool for predicting gymnosperm mortality induced by chronic stress, but not necessarily so for angiosperms and in case of intense drought or bark-beetle outbreaks.
Abstract: Tree mortality is a key factor influencing forest functions and dynamics, but our understanding of the mechanisms
leading to mortality and the associated changes in tree growth rates are still limited. We compiled a new pan-conti-
nental tree-ring width database from sites where both dead and living trees were sampled (2970 dead and 4224 living
trees from 190 sites, including 36 species), and compared early and recent growth rates between trees that died and
those that survived a given mortality event. We observed a decrease in radial growth before death in ca. 84% of the
mortality events. The extent and duration of these reductions were highly variable (1–100 years in 96% of events) due
to the complex interactions among study species and the source(s) of mortality. Strong and long-lasting declines were
found for gymnosperms, shade- and drought-tolerant species, and trees that died from competition. Angiosperms
and trees that died due to biotic attacks (especially bark-beetles) typically showed relatively small and short-term
growth reductions. Our analysis did not highlight any universal trade-off between early growth and tree longevity
within a species, although this result may also reflect high variability in sampling design among sites. The intersite
and interspecific variability in growth patterns before mortality provides valuable information on the nature of the
mortality process, which is consistent with our understanding of the physiological mechanisms leading to mortality.
Abrupt changes in growth immediately before death can be associated with generalized hydraulic failure and/or
bark-beetle attack, while long-term decrease in growth may be associated with a gradual decline in hydraulic performance coupled with depletion in carbon reserves. Our results imply that growth-based mortality algorithms may be
a powerful tool for predicting gymnosperm mortality induced by chronic stress, but not necessarily so for angiosperms and in case of intense drought or bark-beetle outbreaks.
TL;DR: In this paper, the authors quantified the duration and magnitude of neonicotinoid exposure in Canada's corn-growing regions and used these data to design realistic experiments to investigate the effect of such insecticides on honey bees.
Abstract: Experiments linking neonicotinoids and declining bee health have been criticized for not simulating realistic exposure. Here we quantified the duration and magnitude of neonicotinoid exposure in Canada’s corn-growing regions and used these data to design realistic experiments to investigate the effect of such insecticides on honey bees. Colonies near corn were naturally exposed to neonicotinoids for up to 4 months—the majority of the honey bee’s active season. Realistic experiments showed that neonicotinoids increased worker mortality and were associated with declines in social immunity and increased queenlessness over time. We also discovered that the acute toxicity of neonicotinoids to honey bees doubles in the presence of a commonly encountered fungicide. Our work demonstrates that field-realistic exposure to neonicotinoids can reduce honey bee health in corn-growing regions.
TL;DR: Aspirin reduces the risk of preterm preeclampsia, but not term preeclampedia, and only when it is initiated at ≤16 weeks of gestation and at a daily dose of ≥100 mg.
TL;DR: Among adults with physician-diagnosed asthma, a current diagnosis of asthma could not be established in 33.1% who were not using daily asthma medications or had medications weaned, and reassessing the asthma diagnosis may be warranted.
Abstract: Importance Although asthma is a chronic disease, the expected rate of spontaneous remissions of adult asthma and the stability of diagnosis are unknown. Objective To determine whether a diagnosis of current asthma could be ruled out and asthma medications safely stopped in randomly selected adults with physician-diagnosed asthma. Design, Setting, and Participants A prospective, multicenter cohort study was conducted in 10 Canadian cities from January 2012 to February 2016. Random digit dialing was used to recruit adult participants who reported a history of physician-diagnosed asthma established within the past 5 years. Participants using long-term oral steroids and participants unable to be tested using spirometry were excluded. Information from the diagnosing physician was obtained to determine how the diagnosis of asthma was originally made in the community. Of 1026 potential participants who fulfilled eligibility criteria during telephone screening, 701 (68.3%) agreed to enter into the study. All participants were assessed with home peak flow and symptom monitoring, spirometry, and serial bronchial challenge tests, and those participants using daily asthma medications had their medications gradually tapered off over 4 study visits. Participants in whom a diagnosis of current asthma was ultimately ruled out were followed up clinically with repeated bronchial challenge tests over 1 year. Exposure Physician-diagnosed asthma established within the past 5 years. Main Outcomes and Measures The primary outcome was the proportion of participants in whom a diagnosis of current asthma was ruled out, defined as participants who exhibited no evidence of acute worsening of asthma symptoms, reversible airflow obstruction, or bronchial hyperresponsiveness after having all asthma medications tapered off and after a study pulmonologist established an alternative diagnosis. Secondary outcomes included the proportion with asthma ruled out after 12 months and the proportion who underwent an appropriate initial diagnostic workup for asthma in the community. Results Of 701 participants (mean [SD] age, 51 [16] years; 467 women [67%]), 613 completed the study and could be conclusively evaluated for a diagnosis of current asthma. Current asthma was ruled out in 203 of 613 study participants (33.1%; 95% CI, 29.4%-36.8%). Twelve participants (2.0%) were found to have serious cardiorespiratory conditions that had been previously misdiagnosed as asthma in the community. After an additional 12 months of follow-up, 181 participants (29.5%; 95% CI, 25.9%-33.1%) continued to exhibit no clinical or laboratory evidence of asthma. Participants in whom current asthma was ruled out, compared with those in whom it was confirmed, were less likely to have undergone testing for airflow limitation in the community at the time of initial diagnosis (43.8% vs 55.6%, respectively; absolute difference, 11.8%; 95% CI, 2.1%-21.5%). Conclusions and Relevance Among adults with physician-diagnosed asthma, a current diagnosis of asthma could not be established in 33.1% who were not using daily asthma medications or had medications weaned. In patients such as these, reassessing the asthma diagnosis may be warranted.
Catherine M. Phelan, Karoline Kuchenbaecker1, Karoline Kuchenbaecker2, Jonathan Tyrer2 +440 more•Institutions (156)
TL;DR: Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Abstract: To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Harvard University1, University of Groningen2, Laval University3, University of Leicester4, University of Nottingham5, National Institutes of Health6, University of North Carolina at Chapel Hill7, St George's, University of London8, Johns Hopkins University9, Anschutz Medical Campus10, University of Colorado Denver11, University of Washington12, Group Health Cooperative13, Utrecht University14, GlaxoSmithKline15, University of Nebraska Medical Center16, AstraZeneca17, University of Manchester18, University of British Columbia19, Boston University20, Kangwon National University21, University of Ulsan22, Erasmus University Rotterdam23, Lovelace Respiratory Research Institute24, University of Virginia25, Columbia University26, University of Bergen27, Ghent University28, Wake Forest University29, University of California, San Francisco30, University College London31, Seoul National University32, University of Edinburgh33, Glenfield Hospital34
TL;DR: In the combined meta-analysis, 22 loci associated at genome-wide significance are identified, including 13 new associations with COPD, including 12 associated with lung function in general population samples, while 4 are new.
Abstract: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.
TL;DR: An end-to-end deep neural network is trained that directly regresses a limited field-of-view photo to HDR illumination, without strong assumptions on scene geometry, material properties, or lighting, which allows to automatically recover high-quality HDR illumination estimates that significantly outperform previous state- of-the-art methods.
Abstract: We propose an automatic method to infer high dynamic range illumination from a single, limited field-of-view, low dynamic range photograph of an indoor scene. In contrast to previous work that relies on specialized image capture, user input, and/or simple scene models, we train an end-to-end deep neural network that directly regresses a limited field-of-view photo to HDR illumination, without strong assumptions on scene geometry, material properties, or lighting. We show that this can be accomplished in a three step process: 1) we train a robust lighting classifier to automatically annotate the location of light sources in a large dataset of LDR environment maps, 2) we use these annotations to train a deep neural network that predicts the location of lights in a scene from a single limited field-of-view photo, and 3) we fine-tune this network using a small dataset of HDR environment maps to predict light intensities. This allows us to automatically recover high-quality HDR illumination estimates that significantly outperform previous state-of-the-art methods. Consequently, using our illumination estimates for applications like 3D object insertion, produces photo-realistic results that we validate via a perceptual user study.