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Journal ArticleDOI
TL;DR: Retrospective analysis of administrative health claims to determine the association between chronic opioid use and surgery among privately insured patients between January 1, 2001, and December 31, 2013 found male sex, age older than 50 years, and preoperative history of drug abuse, alcohol abuse, depression, benzodiazepine use, or antidepressant use were associated with chronic opioids use among surgical patients.
Abstract: Importance Chronic opioid use imposes a substantial burden in terms of morbidity and economic costs. Whether opioid-naive patients undergoing surgery are at increased risk for chronic opioid use is unknown, as are the potential risk factors for chronic opioid use following surgery. Objective To characterize the risk of chronic opioid use among opioid-naive patients following 1 of 11 surgical procedures compared with nonsurgical patients. Design, Setting, and Participants Retrospective analysis of administrative health claims to determine the association between chronic opioid use and surgery among privately insured patients between January 1, 2001, and December 31, 2013. The data concluded 11 surgical procedures (total knee arthroplasty [TKA], total hip arthroplasty, laparoscopic cholecystectomy, open cholecystectomy, laparoscopic appendectomy, open appendectomy, cesarean delivery, functional endoscopic sinus surgery [FESS], cataract surgery, transurethral prostate resection [TURP], and simple mastectomy). Multivariable logistic regression analysis was performed to control for possible confounders, including sex, age, preoperative history of depression, psychosis, drug or alcohol abuse, and preoperatice use of benzodiazepines, antipsychotics, and antidepressants. Exposures One of the 11 study surgical procedures. Main Outcomes and Measures Chronic opioid use, defined as having filled 10 or more prescriptions or more than 120 days’ supply of an opioid in the first year after surgery, excluding the first 90 postoperative days. For nonsurgical patients, chronic opioid use was defined as having filled 10 or more prescriptions or more than 120 days’ supply following a randomly assigned “surgery date.” Results The study included 641 941 opioid-naive surgical patients (169 666 men; mean [SD] age, 44.0 [12.8] years), and 18 011 137 opioid-naive nonsurgical patients (8 849 107 men; mean [SD] age, 42.4 [12.6] years). Among the surgical patients, the incidence of chronic opioid in the first preoperative year ranged from 0.119% for Cesarean delivery (95% CI, 0.104%-0.134%) to 1.41% for TKA (95% CI, 1.29%-1.53%) The baseline incidence of chronic opioid use among the nonsurgical patients was 0.136% (95% CI, 0.134%-0.137%). Except for cataract surgery, laparoscopic appendectomy, FESS, and TURP, all of the surgical procedures were associated with an increased risk of chronic opioid use, with odds ratios ranging from 1.28 (95% CI, 1.12-1.46) for cesarean delivery to 5.10 (95% CI, 4.67-5.58) for TKA. Male sex, age older than 50 years, and preoperative history of drug abuse, alcohol abuse, depression, benzodiazepine use, or antidepressant use were associated with chronic opioid use among surgical patients. Conclusions and Relevance In opioid-naive patients, many surgical procedures are associated with an increased risk of chronic opioid use in the postoperative period. A certain subset of patients (eg, men, elderly patients) may be particularly vulnerable.

824 citations


Posted Content
TL;DR: This article proposed two simple and effective classes of attentional mechanism: a global approach which always attends to all source words and a local one that only looks at a subset of source words at a time.
Abstract: An attentional mechanism has lately been used to improve neural machine translation (NMT) by selectively focusing on parts of the source sentence during translation. However, there has been little work exploring useful architectures for attention-based NMT. This paper examines two simple and effective classes of attentional mechanism: a global approach which always attends to all source words and a local one that only looks at a subset of source words at a time. We demonstrate the effectiveness of both approaches over the WMT translation tasks between English and German in both directions. With local attention, we achieve a significant gain of 5.0 BLEU points over non-attentional systems which already incorporate known techniques such as dropout. Our ensemble model using different attention architectures has established a new state-of-the-art result in the WMT'15 English to German translation task with 25.9 BLEU points, an improvement of 1.0 BLEU points over the existing best system backed by NMT and an n-gram reranker.

824 citations


Posted Content
TL;DR: In this article, a black-box attack strategy consists in training a local model to substitute for the target DNN, using inputs synthetically generated by an adversary and labeled by the targeted DNN.
Abstract: Machine learning (ML) models, e.g., deep neural networks (DNNs), are vulnerable to adversarial examples: malicious inputs modified to yield erroneous model outputs, while appearing unmodified to human observers. Potential attacks include having malicious content like malware identified as legitimate or controlling vehicle behavior. Yet, all existing adversarial example attacks require knowledge of either the model internals or its training data. We introduce the first practical demonstration of an attacker controlling a remotely hosted DNN with no such knowledge. Indeed, the only capability of our black-box adversary is to observe labels given by the DNN to chosen inputs. Our attack strategy consists in training a local model to substitute for the target DNN, using inputs synthetically generated by an adversary and labeled by the target DNN. We use the local substitute to craft adversarial examples, and find that they are misclassified by the targeted DNN. To perform a real-world and properly-blinded evaluation, we attack a DNN hosted by MetaMind, an online deep learning API. We find that their DNN misclassifies 84.24% of the adversarial examples crafted with our substitute. We demonstrate the general applicability of our strategy to many ML techniques by conducting the same attack against models hosted by Amazon and Google, using logistic regression substitutes. They yield adversarial examples misclassified by Amazon and Google at rates of 96.19% and 88.94%. We also find that this black-box attack strategy is capable of evading defense strategies previously found to make adversarial example crafting harder.

824 citations


Journal ArticleDOI
TL;DR: The purpose of the dbNSFP is to provide a one‐stop resource for functional predictions and annotations for human nonsynonymous single‐nucleotide variants (nsSNVs) and splice‐site variants (ssSNVs), and to facilitate the steps of filtering and prioritizing SNVs from a large list of SNVs discovered in an exome‐sequencing study.
Abstract: The purpose of the dbNSFP is to provide a one-stop resource for functional predictions and annotations for human nonsynonymous single-nucleotide variants (nsSNVs) and splice-site variants (ssSNVs), and to facilitate the steps of filtering and prioritizing SNVs from a large list of SNVs discovered in an exome-sequencing study. A list of all potential nsSNVs and ssSNVs based on the human reference sequence were created and functional predictions and annotations were curated and compiled for each SNV. Here, we report a recent major update of the database to version 3.0. The SNV list has been rebuilt based on GENCODE 22 and currently the database includes 82,832,027 nsSNVs and ssSNVs. An attached database dbscSNV, which compiled all potential human SNVs within splicing consensus regions and their deleteriousness predictions, add another 15,030,459 potentially functional SNVs. Eleven prediction scores (MetaSVM, MetaLR, CADD, VEST3, PROVEAN, 4× fitCons, fathmm-MKL, and DANN) and allele frequencies from the UK10K cohorts and the Exome Aggregation Consortium (ExAC), among others, have been added. The original seven prediction scores in v2.0 (SIFT, 2× Polyphen2, LRT, MutationTaster, MutationAssessor, and FATHMM) as well as many SNV and gene functional annotations have been updated. dbNSFP v3.0 is freely available at http://sites.google.com/site/jpopgen/dbNSFP.

824 citations


Journal ArticleDOI
TL;DR: This cohort study examines medical records of 33 neonates born to women with COVID-19 to provide information on maternal-child transmission and infant outcomes.
Abstract: This cohort study examines medical records of 33 neonates born to women with COVID-19 to provide information on maternal-child transmission and infant outcomes.

824 citations


Book ChapterDOI
08 Oct 2016
TL;DR: This work proposes to augment feedforward nets for object segmentation with a novel top-down refinement approach that is capable of efficiently generating high-fidelity object masks and is 50 % faster than the original DeepMask network.
Abstract: Object segmentation requires both object-level information and low-level pixel data. This presents a challenge for feedforward networks: lower layers in convolutional nets capture rich spatial information, while upper layers encode object-level knowledge but are invariant to factors such as pose and appearance. In this work we propose to augment feedforward nets for object segmentation with a novel top-down refinement approach. The resulting bottom-up/top-down architecture is capable of efficiently generating high-fidelity object masks. Similarly to skip connections, our approach leverages features at all layers of the net. Unlike skip connections, our approach does not attempt to output independent predictions at each layer. Instead, we first output a coarse ‘mask encoding’ in a feedforward pass, then refine this mask encoding in a top-down pass utilizing features at successively lower layers. The approach is simple, fast, and effective. Building on the recent DeepMask network for generating object proposals, we show accuracy improvements of 10–20% in average recall for various setups. Additionally, by optimizing the overall network architecture, our approach, which we call SharpMask, is 50 % faster than the original DeepMask network (under .8 s per image).

823 citations


Journal ArticleDOI
TL;DR: Psilocybin was associated with enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress, sustained benefits in existential distress and quality of life, as well as improved attitudes towards death.
Abstract: Background:Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a...

823 citations



Journal ArticleDOI
TL;DR: Almost 11 years of follow-up showed that the efficacy of Imatinib persisted over time and that long‐term administration of imatinib was not associated with unacceptable cumulative or late toxic effects.
Abstract: BackgroundImatinib, a selective BCR-ABL1 kinase inhibitor, improved the prognosis for patients with chronic myeloid leukemia (CML). We conducted efficacy and safety analyses on the basis of more than 10 years of follow-up in patients with CML who were treated with imatinib as initial therapy. MethodsIn this open-label, multicenter trial with crossover design, we randomly assigned patients with newly diagnosed CML in the chronic phase to receive either imatinib or interferon alfa plus cytarabine. Long-term analyses included overall survival, response to treatment, and serious adverse events. ResultsThe median follow-up was 10.9 years. Given the high rate of crossover among patients who had been randomly assigned to receive interferon alfa plus cytarabine (65.6%) and the short duration of therapy before crossover in these patients (median, 0.8 years), the current analyses focused on patients who had been randomly assigned to receive imatinib. Among the patients in the imatinib group, the estimated overall s...

823 citations


Journal ArticleDOI
TL;DR: This work converts the general SSP storylines into demographic scenarios for 195 countries, cross-classified by age, gender and level of education, and finds that future fertility and hence population growth will depend on female education.
Abstract: This paper applies the methods of multi-dimensional mathematical demography to project national populations based on alternative assumptions on future, fertility, mortality, migration and educational transitions that correspond to the five shared socioeconomic pathways (SSP) storylines. In doing so it goes a significant step beyond past population scenarios in the IPCC context which considered only total population size. By differentiating the human population not only by age and sex -- as is conventionally done in demographic projections -- but also by different levels of educational attainment the most fundamental aspects of human development and social change are being explicitly addressed through modeling the changing composition of populations by these three important individual characteristics. The scenarios have been defined in a collaborative effort of the international Integrated Assessment Modeling community with the medium scenario following that of a major new effort by the Wittgenstein Centre for Demography and Global Human Capital (IIASA, OEAW, WU) involving over 550 experts from around the world. As a result, in terms of total world population size the trajectories resulting from the five SSPs stay very close to each other until around 2030 and by the middle of the century already a visible differentiation appears with the range between the highest (SSP3) and the lowest (SSP1) trajectories spanning 1.5 billion. The range opens up much more with the SSP3 reaching 12.6 billion in 2100 and SSP1 falling to 6.9 billion which is lower than today's world population.

823 citations


Journal ArticleDOI
TL;DR: This Delphi exercise highlights reasons for disagreements about terminology for language disorders and proposes standard definitions and nomenclature.
Abstract: BACKGROUND: Lack of agreement about criteria and terminology for children's language problems affects access to services as well as hindering research and practice. We report the second phase of a study using an online Delphi method to address these issues. In the first phase, we focused on criteria for language disorder. Here we consider terminology. METHODS: The Delphi method is an iterative process in which an initial set of statements is rated by a panel of experts, who then have the opportunity to view anonymised ratings from other panel members. On this basis they can either revise their views or make a case for their position. The statements are then revised based on panel feedback, and again rated by and commented on by the panel. In this study, feedback from a second round was used to prepare a final set of statements in narrative form. The panel included 57 individuals representing a range of professions and nationalities. RESULTS: We achieved at least 78% agreement for 19 of 21 statements within two rounds of ratings. These were collapsed into 12 statements for the final consensus reported here. The term ‘Language Disorder’ is recommended to refer to a profile of difficulties that causes functional impairment in everyday life and is associated with poor prognosis. The term, ‘Developmental Language Disorder’ (DLD) was endorsed for use when the language disorder was not associated with a known biomedical aetiology. It was also agreed that (a) presence of risk factors (neurobiological or environmental) does not preclude a diagnosis of DLD, (b) DLD can co-occur with other neurodevelopmental disorders (e.g. ADHD) and (c) DLD does not require a mismatch between verbal and nonverbal ability. CONCLUSIONS: This Delphi exercise highlights reasons for disagreements about terminology for language disorders and proposes standard definitions and nomenclature.

Posted Content
TL;DR: A new pre-trainable generic representation for visual-linguistic tasks, called Visual-Linguistic BERT (VL-BERT), which adopts the simple yet powerful Transformer model as the backbone, and extends it to take both visual and linguistic embedded features as input.
Abstract: We introduce a new pre-trainable generic representation for visual-linguistic tasks, called Visual-Linguistic BERT (VL-BERT for short). VL-BERT adopts the simple yet powerful Transformer model as the backbone, and extends it to take both visual and linguistic embedded features as input. In it, each element of the input is either of a word from the input sentence, or a region-of-interest (RoI) from the input image. It is designed to fit for most of the visual-linguistic downstream tasks. To better exploit the generic representation, we pre-train VL-BERT on the massive-scale Conceptual Captions dataset, together with text-only corpus. Extensive empirical analysis demonstrates that the pre-training procedure can better align the visual-linguistic clues and benefit the downstream tasks, such as visual commonsense reasoning, visual question answering and referring expression comprehension. It is worth noting that VL-BERT achieved the first place of single model on the leaderboard of the VCR benchmark. Code is released at \url{this https URL}.

Journal ArticleDOI
TL;DR: The Disk Substructures at High Angular Resolution Project (DSHARP) as mentioned in this paper was the first large-scale project to find and characterize substructures in the spatial distributions of solid particles for a sample of 20 nearby protoplanetary disks, using very high resolution (similar to 0'' 035 or 5 au, FWHM) observations of their 240 GHz (1.25 mm) continuum emission.
Abstract: We introduce the Disk Substructures at High Angular Resolution Project (DSHARP), one of the initial Large Programs conducted with the Atacama Large Millimeter/submillimeter Array (ALMA). The primary goal of DSHARP is to find and characterize substructures in the spatial distributions of solid particles for a sample of 20 nearby protoplanetary disks, using very high resolution (similar to 0.'' 035, or 5 au, FWHM) observations of their 240 GHz (1.25 mm) continuum emission. These data provide a first homogeneous look at the small-scale features in disks that are directly relevant to the planet formation process, quantifying their prevalence, morphologies, spatial scales, spacings, symmetry, and amplitudes, for targets with a variety of disk and stellar host properties. We find that these substructures are ubiquitous in this sample of large, bright disks. They are most frequently manifested as concentric, narrow emission rings and depleted gaps, although large-scale spiral patterns and small arc-shaped azimuthal asymmetries are also present in some cases. These substructures are found at a wide range of disk radii (from a few astronomical units to more than 100 au), are usually compact (less than or similar to 10 au), and show a wide range of amplitudes (brightness contrasts). Here we discuss the motivation for the project, describe the survey design and the sample properties, detail the observations and data calibration, highlight some basic results, and provide a general overview of the key conclusions that are presented in more detail in a series of accompanying articles. The DSHARP data-including visibilities, images, calibration scripts, and more-are released for community use at https://almascience.org/alma-data/lp/DSHARP.

Journal ArticleDOI
TL;DR: Future studies on the epidemiology of peri-implant diseases should consider applying consistent case definitions and assessing random patient samples of adequate size and function time, according to the meta-regression analysis.
Abstract: Background To develop preventive strategies addressing peri-implant diseases, a thorough understanding of the epidemiology is required Aim The aim was to systematically assess the scientific literature in order to evaluate the prevalence, extent and severity of peri-implant diseases Material & Methods Data were extracted from identified studies Meta-analyses for prevalence of peri-implant mucositis and peri-implantitis were performed The effect of function time and disease definition on the prevalence of peri-implantitis was evaluated by meta-regression analyses Data on extent and severity of peri-implant diseases were estimated if not directly reported Results Fifteen articles describing 11 studies were included Case definitions for mucositis and peri-implantitis varied The prevalence of peri-implant mucositis and peri-implantitis ranged from 19 to 65% and from 1 to 47%, respectively Meta-analyses estimated weighted mean prevalences of peri-implant mucositis and peri-implantitis of 43% (CI: 32–54%) and 22% (CI: 14–30%), respectively The meta-regression showed a positive relationship between prevalence of peri-implantitis and function time and a negative relationship between prevalence of peri-implantitis and threshold for bone loss Extent and severity of peri-implant diseases were rarely reported Conclusion Future studies on the epidemiology of peri-implant diseases should consider (i) applying consistent case definitions and (ii) assessing random patient samples of adequate size and function time

Journal ArticleDOI
TL;DR: Investigating the immunogenicity of human epidermal growth factor receptor 2 -positive and triple-negative breast cancers and immunologically relevant genes in the neoadjuvant GeparSixto trial found immunologic factors were highly significant predictors of therapy response in the trial, particularly in patients treated with Cb.
Abstract: Purpose Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) –positive and triple-negative (TN) breast cancers (BCs), we evaluated tumor-infiltrating lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial. Patients and Methods GeparSixto investigated the effect of adding carboplatin (Cb) to an anthracycline-plus-taxane combination (PM) on pathologic complete response (pCR). A total of 580 tumors were evaluated before random assignment for stromal TILs and lymphocyte-predominant BC (LPBC). mRNA expression of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) as well as immunosuppressive factors (IDO1, PD-1, PD-L1, CTLA4, FOXP3) was measured in 481 tumors. Results Increased levels of stromal TILs predicted pCR in univariable (P < .001) and multivariable analyses (P < .001). pCR rate was 59.9% in LPBC and 33.8% for non-LPBC (P < .001). pC...

Proceedings ArticleDOI
07 Jun 2015
TL;DR: Extensive evaluations on several benchmark image datasets show that the proposed simultaneous feature learning and hash coding pipeline brings substantial improvements over other state-of-the-art supervised or unsupervised hashing methods.
Abstract: Similarity-preserving hashing is a widely-used method for nearest neighbour search in large-scale image retrieval tasks. For most existing hashing methods, an image is first encoded as a vector of hand-engineering visual features, followed by another separate projection or quantization step that generates binary codes. However, such visual feature vectors may not be optimally compatible with the coding process, thus producing sub-optimal hashing codes. In this paper, we propose a deep architecture for supervised hashing, in which images are mapped into binary codes via carefully designed deep neural networks. The pipeline of the proposed deep architecture consists of three building blocks: 1) a sub-network with a stack of convolution layers to produce the effective intermediate image features; 2) a divide-and-encode module to divide the intermediate image features into multiple branches, each encoded into one hash bit; and 3) a triplet ranking loss designed to characterize that one image is more similar to the second image than to the third one. Extensive evaluations on several benchmark image datasets show that the proposed simultaneous feature learning and hash coding pipeline brings substantial improvements over other state-of-the-art supervised or unsupervised hashing methods.

Journal ArticleDOI
TL;DR: It is suggested that most people who become infected with SARS-CoV-2 will not remain asymptomatic throughout the course of the infection, and combination prevention measures will continue to be needed.
Abstract: BACKGROUND There is disagreement about the level of asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We conducted a living systematic review and meta-analysis to address three questions: (1) Amongst people who become infected with SARS-CoV-2, what proportion does not experience symptoms at all during their infection? (2) Amongst people with SARS-CoV-2 infection who are asymptomatic when diagnosed, what proportion will develop symptoms later? (3) What proportion of SARS-CoV-2 transmission is accounted for by people who are either asymptomatic throughout infection or presymptomatic? METHODS AND FINDINGS We searched PubMed, Embase, bioRxiv, and medRxiv using a database of SARS-CoV-2 literature that is updated daily, on 25 March 2020, 20 April 2020, and 10 June 2020. Studies of people with SARS-CoV-2 diagnosed by reverse transcriptase PCR (RT-PCR) that documented follow-up and symptom status at the beginning and end of follow-up or modelling studies were included. One reviewer extracted data and a second verified the extraction, with disagreement resolved by discussion or a third reviewer. Risk of bias in empirical studies was assessed with an adapted checklist for case series, and the relevance and credibility of modelling studies were assessed using a published checklist. We included a total of 94 studies. The overall estimate of the proportion of people who become infected with SARS-CoV-2 and remain asymptomatic throughout infection was 20% (95% confidence interval [CI] 17-25) with a prediction interval of 3%-67% in 79 studies that addressed this review question. There was some evidence that biases in the selection of participants influence the estimate. In seven studies of defined populations screened for SARS-CoV-2 and then followed, 31% (95% CI 26%-37%, prediction interval 24%-38%) remained asymptomatic. The proportion of people that is presymptomatic could not be summarised, owing to heterogeneity. The secondary attack rate was lower in contacts of people with asymptomatic infection than those with symptomatic infection (relative risk 0.35, 95% CI 0.10-1.27). Modelling studies fit to data found a higher proportion of all SARS-CoV-2 infections resulting from transmission from presymptomatic individuals than from asymptomatic individuals. Limitations of the review include that most included studies were not designed to estimate the proportion of asymptomatic SARS-CoV-2 infections and were at risk of selection biases; we did not consider the possible impact of false negative RT-PCR results, which would underestimate the proportion of asymptomatic infections; and the database does not include all sources. CONCLUSIONS The findings of this living systematic review suggest that most people who become infected with SARS-CoV-2 will not remain asymptomatic throughout the course of the infection. The contribution of presymptomatic and asymptomatic infections to overall SARS-CoV-2 transmission means that combination prevention measures, with enhanced hand hygiene, masks, testing tracing, and isolation strategies and social distancing, will continue to be needed.

Journal ArticleDOI
TL;DR: The efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed is assessed.
Abstract: Summary Background Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed. Methods The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01771458. Findings Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8–11·6) in the experimental group and 11·3 months (8·1–11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7–3·8) in the experimental group versus 2·0 months (1·8–2·1) in the control group (hazard ratio 0·88, 95% CI 0·65–1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3–4 adverse events (p=0·30). Interpretation The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy. Funding Institut Curie.

Journal ArticleDOI
TL;DR: The Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients, and makes recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD.
Abstract: Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of >90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD.

Journal ArticleDOI
TL;DR: Interestingly, CsPbBr3 is found to be highly defect-tolerant in terms of its electronic structure, which can maintain its good electronic quality despite the presence of defects.
Abstract: The formation energies and charge-transition levels of intrinsic point defects in lead halide perovskite CsPbBr3 are studied from first-principles calculations. It is shown that the formation energy of dominant defect under Br-rich growth condition is much lower than that under moderate or Br-poor conditions. Thus avoiding the Br-rich condition can help to reduce the defect concentration. Interestingly, CsPbBr3 is found to be highly defect-tolerant in terms of its electronic structure. Most of the intrinsic defects induce shallow transition levels. Only a few defects with high formation energies can create deep transition levels. Therefore, CsPbBr3 can maintain its good electronic quality despite the presence of defects. Such defect tolerance feature can be attributed to the lacking of bonding–antibonding interaction between the conduction bands and valence bands.

Journal ArticleDOI
TL;DR: Marlieke de Kraker and colleagues reflect on the need for better global estimates for the burden of antimicrobial resistance and suggest that more needs to be done to estimate this burden.
Abstract: Marlieke de Kraker and colleagues reflect on the need for better global estimates for the burden of antimicrobial resistance.

Proceedings ArticleDOI
27 Jun 2016
TL;DR: This paper proposes a matching network which is able to produce very accurate results in less than a second of GPU computation, and exploits a product layer which simply computes the inner product between the two representations of a siamese architecture.
Abstract: In the past year, convolutional neural networks have been shown to perform extremely well for stereo estimation. However, current architectures rely on siamese networks which exploit concatenation followed by further processing layers, requiring a minute of GPU computation per image pair. In contrast, in this paper we propose a matching network which is able to produce very accurate results in less than a second of GPU computation. Towards this goal, we exploit a product layer which simply computes the inner product between the two representations of a siamese architecture. We train our network by treating the problem as multi-class classification, where the classes are all possible disparities. This allows us to get calibrated scores, which result in much better matching performance when compared to existing approaches.

Journal ArticleDOI
TL;DR: The adduct approach proposed in this Account is a very promising methodology to achieve high quality perovskite films with high photovoltaic performance and single crystal growth on the conductive substrate is expected to be possible if the authors kinetically control the elimination of Lewis base in the adduct.
Abstract: ConspectusSince the first report on the long-term durable 9.7% solid-state perovskite solar cell employing methylammonium lead iodide (CH3NH3PbI3), mesoporous TiO2, and 2,2′,7,7′-tetrakis[N,N-di(4-methoxyphenyl)amino]-9,9′-spirobifluorene (spiro-MeOTAD) in 2012, following the seed technologies on perovskite-sensitized liquid junction solar cells in 2009 and 2011, a surge of interest has been focused on perovskite solar cells due to superb photovoltaic performance and extremely facile fabrication processes. The power conversion efficiency (PCE) of perovskite solar cells reached 21% in a very short period of time. Such an unprecedentedly high photovoltaic performance is due to the intrinsic optoelectronic property of organolead iodide perovskite material. Moreover, a high dielectric constant, sub-millimeter scale carrier diffusion length, an underlying ferroelectric property, and ion migration behavior can make organolead halide perovskites suitable for multifunctionality. Thus, besides solar cell applicati...

Journal ArticleDOI
TL;DR: A unique type of pH/H2 O2 dual-responsive intelligent nanoscale delivery system based on albumin-coated MnO2 is presented, which is capable of modulating the tumor microenvironment by relieving hypoxia.
Abstract: A unique type of pH/H2 O2 dual-responsive intelligent nanoscale delivery system based on albumin-coated MnO2 is presented, which is capable of modulating the tumor microenvironment (TME) by relieving hypoxia. Additionally, TME-responsive size changes enable effective intratumor diffusion. A highly effective combined photodynamic and chemotherapy is realized with these nanoparticles in a mouse tumor model.

Journal ArticleDOI
TL;DR: These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018, and are based on the differences reached in therapeutic efficacy of real vs. sham rT MS protocols.

Posted Content
TL;DR: A simple and modular Split-Attention block that enables attention across feature-map groups ResNet-style is presented that preserves the overall ResNet structure to be used in downstream tasks straightforwardly without introducing additional computational costs.
Abstract: It is well known that featuremap attention and multi-path representation are important for visual recognition. In this paper, we present a modularized architecture, which applies the channel-wise attention on different network branches to leverage their success in capturing cross-feature interactions and learning diverse representations. Our design results in a simple and unified computation block, which can be parameterized using only a few variables. Our model, named ResNeSt, outperforms EfficientNet in accuracy and latency trade-off on image classification. In addition, ResNeSt has achieved superior transfer learning results on several public benchmarks serving as the backbone, and has been adopted by the winning entries of COCO-LVIS challenge. The source code for complete system and pretrained models are publicly available.

Journal ArticleDOI
TL;DR: In the first worldwide synthesis of in situ and satellite-derived lake data, this paper found that lake summer surface water temperatures rose rapidly (global mean = 0.34°C decade−1) between 1985 and 2009.
Abstract: In this first worldwide synthesis of in situ and satellite-derived lake data, we find that lake summer surface water temperatures rose rapidly (global mean = 0.34°C decade−1) between 1985 and 2009. Our analyses show that surface water warming rates are dependent on combinations of climate and local characteristics, rather than just lake location, leading to the counterintuitive result that regional consistency in lake warming is the exception, rather than the rule. The most rapidly warming lakes are widely geographically distributed, and their warming is associated with interactions among different climatic factors—from seasonally ice-covered lakes in areas where temperature and solar radiation are increasing while cloud cover is diminishing (0.72°C decade−1) to ice-free lakes experiencing increases in air temperature and solar radiation (0.53°C decade−1). The pervasive and rapid warming observed here signals the urgent need to incorporate climate impacts into vulnerability assessments and adaptation efforts for lakes.

Journal ArticleDOI
22 Jan 2016-Science
TL;DR: In this paper, the authors developed and tested a direct gene-editing approach to induce exon deletion and recover dystrophin expression in the mdx mouse model of Duchenne muscular dystrophy.
Abstract: Frame-disrupting mutations in the DMD gene, encoding dystrophin, compromise myofiber integrity and drive muscle deterioration in Duchenne muscular dystrophy (DMD). Removing one or more exons from the mutated transcript can produce an in-frame mRNA and a truncated, but still functional, protein. In this study, we developed and tested a direct gene-editing approach to induce exon deletion and recover dystrophin expression in the mdx mouse model of DMD. Delivery by adeno-associated virus (AAV) of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 endonucleases coupled with paired guide RNAs flanking the mutated Dmd exon23 resulted in excision of intervening DNA and restored the Dmd reading frame in myofibers, cardiomyocytes, and muscle stem cells after local or systemic delivery. AAV-Dmd CRISPR treatment partially recovered muscle functional deficiencies and generated a pool of endogenously corrected myogenic precursors in mdx mouse muscle.

Proceedings ArticleDOI
18 Jun 2018
TL;DR: This work introduces new sparse convolutional operations that are designed to process spatially-sparse data more efficiently, and uses them to develop Spatially-Sparse Convolutional networks, which outperform all prior state-of-the-art models on two tasks involving semantic segmentation of 3D point clouds.
Abstract: Convolutional networks are the de-facto standard for analyzing spatio-temporal data such as images, videos, and 3D shapes. Whilst some of this data is naturally dense (e.g., photos), many other data sources are inherently sparse. Examples include 3D point clouds that were obtained using a LiDAR scanner or RGB-D camera. Standard "dense" implementations of convolutional networks are very inefficient when applied on such sparse data. We introduce new sparse convolutional operations that are designed to process spatially-sparse data more efficiently, and use them to develop spatially-sparse convolutional networks. We demonstrate the strong performance of the resulting models, called submanifold sparse convolutional networks (SS-CNs), on two tasks involving semantic segmentation of 3D point clouds. In particular, our models outperform all prior state-of-the-art on the test set of a recent semantic segmentation competition.

Journal ArticleDOI
TL;DR: Tarascon and Assat as mentioned in this paper discuss the underlying science that triggers a reversible and stable anionic redox activity and highlight its practical limitations and outline possible approaches for improving such materials and designing new ones.
Abstract: Our increasing dependence on lithium-ion batteries for energy storage calls for continual improvements in the performance of their positive electrodes, which have so far relied solely on cationic redox of transition-metal ions for driving the electrochemical reactions. Great hopes have recently been placed on the emergence of anionic redox—a transformational approach for designing positive electrodes as it leads to a near-doubling of capacity. But questions have been raised about the fundamental origins of anionic redox and whether its full potential can be realized in applications. In this Review, we discuss the underlying science that triggers a reversible and stable anionic redox activity. Furthermore, we highlight its practical limitations and outline possible approaches for improving such materials and designing new ones. We also summarize their chances for market implementation in the face of the competing nickel-based layered cathodes that are prevalent today. The discovery of anionic redox chemistry in Li-rich cathode materials provides much hope for enhancing battery performance. Tarascon and Assat analyse the underlying science behind anionic redox and discuss its practical limitations as well as the routes to overcome the application barriers.