Showing papers by "Wayne State University published in 2018"
TL;DR: The concepts of IoT, Industrial IoT, and Industry 4.0 are clarified and the challenges associated with the need of energy efficiency, real-time performance, coexistence, interoperability, and security and privacy are focused on.
Abstract: Internet of Things (IoT) is an emerging domain that promises ubiquitous connection to the Internet, turning common objects into connected devices. The IoT paradigm is changing the way people interact with things around them. It paves the way for creating pervasively connected infrastructures to support innovative services and promises better flexibility and efficiency. Such advantages are attractive not only for consumer applications, but also for the industrial domain. Over the last few years, we have been witnessing the IoT paradigm making its way into the industry marketplace with purposely designed solutions. In this paper, we clarify the concepts of IoT, Industrial IoT, and Industry 4.0. We highlight the opportunities brought in by this paradigm shift as well as the challenges for its realization. In particular, we focus on the challenges associated with the need of energy efficiency, real-time performance, coexistence, interoperability, and security and privacy. We also provide a systematic overview of the state-of-the-art research efforts and potential research directions to solve Industrial IoT challenges.
1,402 citations
Mayo Clinic1, Wayne State University2, University of Glasgow3, University of Oxford4, Harvard University5, Yokohama City University6, Mario Negri Institute for Pharmacological Research7, Duke University8, University of Tokyo9, Pierre-and-Marie-Curie University10, University Hospital Southampton NHS Foundation Trust11
TL;DR: Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population.
Abstract: Background Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. Methods We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. Results After 3263 events of disease recurrence or death had been reported in 12,834 patients, the n...
624 citations
Harvard University1, University of Cologne2, Memorial Sloan Kettering Cancer Center3, University of Texas MD Anderson Cancer Center4, University of Bologna5, University of California, Los Angeles6, University of Oxford7, Wayne State University8, Emory University9, University of Toronto10, University of British Columbia11, Charles University in Prague12, Bristol-Myers Squibb13
TL;DR: With extended follow-up, responses to nivolumab were frequent and durable and seems to be associated with a favorable safety profile and long-term benefits across a broad spectrum of patients with relapsed/refractory cHL.
Abstract: PurposeGenetic alterations causing overexpression of programmed death-1 ligands are near universal in classic Hodgkin lymphoma (cHL). Nivolumab, a programmed death-1 checkpoint inhibitor, demonstrated efficacy in relapsed/refractory cHL after autologous hematopoietic cell transplantation (auto-HCT) in initial analyses of one of three cohorts from the CheckMate 205 study of nivolumab for cHL. Here, we assess safety and efficacy after extended follow-up of all three cohorts.MethodsThis multicenter, single-arm, phase II study enrolled patients with relapsed/refractory cHL after auto-HCT treatment failure into cohorts by treatment history: brentuximab vedotin (BV)–naive (cohort A), BV received after auto-HCT (cohort B), and BV received before and/or after auto-HCT (cohort C). All patients received nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary end point was objective response rate per independent radiology review committee.ResultsOverall, 243 patients were treated...
477 citations
TL;DR: In this paper, the discriminating variables and the algorithms used for heavy-flavour jet identification during the first years of operation of the CMS experiment in proton-proton collisions at a centre-of-mass energy of 13 TeV, are presented.
Abstract: Many measurements and searches for physics beyond the standard model at the LHC rely on the efficient identification of heavy-flavour jets, i.e. jets originating from bottom or charm quarks. In this paper, the discriminating variables and the algorithms used for heavy-flavour jet identification during the first years of operation of the CMS experiment in proton-proton collisions at a centre-of-mass energy of 13 TeV, are presented. Heavy-flavour jet identification algorithms have been improved compared to those used previously at centre-of-mass energies of 7 and 8 TeV. For jets with transverse momenta in the range expected in simulated events, these new developments result in an efficiency of 68% for the correct identification of a b jet for a probability of 1% of misidentifying a light-flavour jet. The improvement in relative efficiency at this misidentification probability is about 15%, compared to previous CMS algorithms. In addition, for the first time algorithms have been developed to identify jets containing two b hadrons in Lorentz-boosted event topologies, as well as to tag c jets. The large data sample recorded in 2016 at a centre-of-mass energy of 13 TeV has also allowed the development of new methods to measure the efficiency and misidentification probability of heavy-flavour jet identification algorithms. The b jet identification efficiency is measured with a precision of a few per cent at moderate jet transverse momenta (between 30 and 300 GeV) and about 5% at the highest jet transverse momenta (between 500 and 1000 GeV).
454 citations
University of Cambridge1, Wayne State University2, University of Bristol3, Copenhagen University Hospital4, University of Copenhagen5, Innsbruck Medical University6, University of Glasgow7, Leiden University Medical Center8, Leiden University9, Utrecht University10, National Institute for Health Research11, University of Pennsylvania12, Wellcome Trust Sanger Institute13
TL;DR: The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe withCHD risk.
Abstract: Importance Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk. Objective To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design, Setting, and Participants A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. Exposures GeneticLPA score and plasma Lp(a) mass concentration. Main Outcomes and Measures Coronary heart disease. Results Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951;P = 3 × 10−37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893;P = 2 × 10−12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. Conclusions and Relevance The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).
403 citations
TL;DR: Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer samples, a novel subtype of prostate cancer typified by biallelic loss of CDK12 is identified that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations.
376 citations
Cold Spring Harbor Laboratory1, University of Arizona2, International Rice Research Institute3, University of Chicago4, University of Georgia5, Wayne State University6, Chinese Academy of Sciences7, Max Planck Society8, University of Hohenheim9, Rice University10, Sant'Anna School of Advanced Studies11, DuPont Pioneer12, National Taiwan University13, Academia Sinica14, Ghent University15, University of Perpignan16, Universidade Federal de Pelotas17, University of Maryland, College Park18, University of Zurich19, University of Queensland20, National Institute of Genetics21, United States Department of Agriculture22
TL;DR: This study resolves controversial areas of the Oryza phylogeny, showing a complex history of introgression among different chromosomes in the young ‘AA’ subclade containing the two domesticated species and announcing many new haplotypes of potential use for future crop protection.
Abstract: The genus Oryza is a model system for the study of molecular evolution over time scales ranging from a few thousand to 15 million years. Using 13 reference genomes spanning the Oryza species tree, we show that despite few large-scale chromosomal rearrangements rapid species diversification is mirrored by lineage-specific emergence and turnover of many novel elements, including transposons, and potential new coding and noncoding genes. Our study resolves controversial areas of the Oryza phylogeny, showing a complex history of introgression among different chromosomes in the young 'AA' subclade containing the two domesticated species. This study highlights the prevalence of functionally coupled disease resistance genes and identifies many new haplotypes of potential use for future crop protection. Finally, this study marks a milestone in modern rice research with the release of a complete long-read assembly of IR 8 'Miracle Rice', which relieved famine and drove the Green Revolution in Asia 50 years ago.
365 citations
University of Mississippi Medical Center1, Veterans Health Administration2, University of Louisville3, University at Buffalo4, The Heart Research Institute5, Albert Einstein College of Medicine6, University of Würzburg7, Virginia Tech8, University of Virginia9, University of Southern California10, Huntington Medical Research Institutes11, Louisiana State University12, Harvard University13, National Institutes of Health14, University of California, Los Angeles15, Wayne State University16, Sant'Anna School of Advanced Studies17, Temple University18, University of California, Davis19, Cedars-Sinai Medical Center20, University of Duisburg-Essen21
TL;DR: The goal of this review is to provide best practice information regarding myocardial ischemia-reperfusion and infarction models and to provide increasing awareness of the need for rigor and reproducibility in designing and performing scientific research to ensure validation of results.
Abstract: Myocardial infarction is a prevalent major cardiovascular event that arises from myocardial ischemia with or without reperfusion, and basic and translational research is needed to better understand...
357 citations
Cleveland Clinic1, Washington University in St. Louis2, University of Manitoba3, Mayo Clinic4, University of California, San Francisco5, University of Kansas6, University of Louisville7, St. Luke's University Health Network8, University of Virginia9, Wayne State University10, University of Southern California11, Kaiser Permanente12, National Multiple Sclerosis Society13, Heart Rhythm Society14, American Academy of Neurology15, University of Calgary16
TL;DR: The development of a guideline covering 23 medications and 143 randomized trials, as well as 30-plus recommendations and multiple development steps, is complex to the point of being overwhelming.
Abstract: Objective To develop recommendations for disease-modifying therapy (DMT) for multiple sclerosis (MS). Methods A multidisciplinary panel developed DMT recommendations, integrating findings from a systematic review; followed an Institute of Medicine–compliant process to ensure transparency and patient engagement; and developed modified Delphi consensus–based recommendations concerning starting, switching, and stopping DMTs pertinent to people with relapsing-remitting MS, secondary progressive MS, primary progressive MS, and clinically isolated syndromes of demyelination. Recommendations were supported by structured rationales, integrating evidence from one or more sources: systematic review, related evidence (evidence not from the systematic review), principles of care, and inference from evidence. Results Thirty recommendations were developed: 17 on starting DMTs, including recommendations on who should start them; 10 on switching DMTs if breakthrough disease develops; and 3 on stopping DMTs. Recommendations encompassed patient engagement strategies and individualization of treatment, including adherence monitoring and disease comorbidity assessment. The panel also discussed DMT risks, including counseling about progressive multifocal leukoencephalopathy risk in people with MS using natalizumab, fingolimod, rituximab, ocrelizumab, and dimethyl fumarate; and made suggestions for future research to evaluate relative merits of early treatment with higher potency DMTs vs standard stepped-care protocols, DMT comparative effectiveness, optimal switching strategies, long-term effects of DMT use, definitions of highly active MS, and effects of treatment on patient-specified priority outcomes. This guideline reflects the complexity of decision-making for starting, switching, or stopping MS DMTs. The field of MS treatment is rapidly changing; the Academy of Neurology development process includes planning for future updates.
325 citations
Albert M. Sirunyan1, Robin Erbacher2, C. A. Carrillo Montoya3, Wagner Carvalho4 +2355 more•Institutions (153)
TL;DR: In this paper, the performance of the modified system is studied using proton-proton collision data at center-of-mass energy √s=13 TeV, collected at the LHC in 2015 and 2016.
Abstract: The CMS muon detector system, muon reconstruction software, and high-level trigger underwent significant changes in 2013–2014 in preparation for running at higher LHC collision energy and instantaneous luminosity. The performance of the modified system is studied using proton-proton collision data at center-of-mass energy √s=13 TeV, collected at the LHC in 2015 and 2016. The measured performance parameters, including spatial resolution, efficiency, and timing, are found to meet all design specifications and are well reproduced by simulation. Despite the more challenging running conditions, the modified muon system is found to perform as well as, and in many aspects better than, previously. We dedicate this paper to the memory of Prof. Alberto Benvenuti, whose work was fundamental for the CMS muon detector.
303 citations
University of Rochester1, Technische Universität München2, Wayne State University3, Washington University in St. Louis4, University of Szeged5, Ludwig Maximilian University of Munich6, Edward Via College of Osteopathic Medicine7, University of Pécs8, University of California, San Diego9, University of Maryland, Baltimore10, United States Department of the Army11, University of Virginia12, University of North Carolina at Chapel Hill13, Charité14, University of Pittsburgh15, Virginia Commonwealth University16, Baylor College of Medicine17, University of Florida18, University of Pennsylvania19, Mount Sinai Health System20
TL;DR: Results show the high sensitivity and NPV of the UCH-L1 and GFAP test supports its potential clinical role for ruling out the need for a CT scan among patients with TBI presenting at emergency departments in whom a head CT is felt to be clinically indicated.
Abstract: Summary Background More than 50 million people worldwide sustain a traumatic brain injury (TBI) annually. Detection of intracranial injuries relies on head CT, which is overused and resource intensive. Blood-based brain biomarkers hold the potential to predict absence of intracranial injury and thus reduce unnecessary head CT scanning. We sought to validate a test combining ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), at predetermined cutoff values, to predict traumatic intracranial injuries on head CT scan acutely after TBI. Methods This prospective, multicentre observational trial included adults (≥18 years) presenting to participating emergency departments with suspected, non-penetrating TBI and a Glasgow Coma Scale score of 9–15. Patients were eligible if they had undergone head CT as part of standard emergency care and blood collection within 12 h of injury. UCH-L1 and GFAP were measured in serum and analysed using prespecified cutoff values of 327 pg/mL and 22 pg/mL, respectively. UCH-L1 and GFAP assay results were combined into a single test result that was compared with head CT results. The primary study outcomes were the sensitivity and the negative predictive value (NPV) of the test result for the detection of traumatic intracranial injury on head CT. Findings Between Dec 6, 2012, and March 20, 2014, 1977 patients were recruited, of whom 1959 had analysable data. 125 (6%) patients had CT-detected intracranial injuries and eight ( Interpretation These results show the high sensitivity and NPV of the UCH-L1 and GFAP test. This supports its potential clinical role for ruling out the need for a CT scan among patients with TBI presenting at emergency departments in whom a head CT is felt to be clinically indicated. Future studies to determine the value added by this biomarker test to head CT clinical decision rules could be warranted. Funding Banyan Biomarkers and US Army Medical Research and Materiel Command.
Christopher J L Murray1, Charlton S K H Callender1, Xie Rachel Kulikoff1, Vinay Srinivasan1 +1092 more•Institutions (424)
TL;DR: This work estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods and used the cohort-component method of population projection, with inputs of fertility, mortality, population, and migration data.
15 Jun 2018-Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine
TL;DR: The aim is to summarize recent diagnostic guidelines and both nonpharmacological and pharmacological strategies for the management of insomnia in the older population and conclude the most important aspect in evaluation of insomnia is detailed history taking and thorough physical examination.
Abstract: Background:Insomnia remains one of the most common sleep disorders encountered in the geriatric clinic population, frequently characterized by the subjective complaint of difficulty falling or main...
TL;DR: The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma.
Abstract: Summary Background Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Methods In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0–1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. Findings Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0–84·4) patients achieved an objective response (complete or partial response). Interpretation The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). Funding Pfizer Inc.
TL;DR: Estimates of annual global prevalence, estimated lifetime incidence and economic loss due to recurrent vulvovaginal candidiasis, and predicted the number of women at risk to 2030 are generated.
Abstract: Summary Recurrent vulvovaginal candidiasis is a debilitating, long-term condition that can severely affect the quality of life of affected women. No estimates of the global prevalence or lifetime incidence of this disease have been reported. For this systematic review, we searched PubMed, Embase, and Web of Science databases for population-based studies published between 1985 and 2016 that reported on the prevalence of recurrent vulvovaginal candidiasis, defined as four or more episodes of the infection every year. We identified 489 unique articles, of which eight were included, consisting of 17 365 patients from 11 countries. We generated estimates of annual global prevalence, estimated lifetime incidence and economic loss due to recurrent vulvovaginal candidiasis, and predicted the number of women at risk to 2030. Worldwide, recurrent vulvovaginal candidiasis affects about 138 million women annually (range 103–172 million), with a global annual prevalence of 3871 per 100 000 women; 372 million women are affected by recurrent vulvovaginal candidiasis over their lifetime. The 25–34 year age group has the highest prevalence (9%). By 2030, the population of women with recurrent vulvovaginal candidiasis each year is estimated to increase to almost 158 million, resulting in 20 240 664 extra cases with current trends using base case estimates in parallel with an estimated growth in females from 3·34 billion to 4·181 billion. In high-income countries, the economic burden from lost productivity could be up to US$14·39 billion annually. The high prevalence, substantial morbidity, and economic losses of recurrent vulvovaginal candidiasis require better solutions and improved quality of care for affected women.
TL;DR: Different strategies including crosslinking and non-crosslinking approaches designed to stabilize micelles are reviewed and perspectives on future research directions are offered.
Abstract: Micelles have been studied as drug delivery carriers for decades. Their use can potentially result in high drug accumulation at the target site through the enhanced permeability and retention effect. Nevertheless, the lack of stability of micelles in the physiological environment limits their efficacy as a drug carrier. In particular, micelles tend to disassociate and prematurely release the encapsulated drugs, lowering delivery efficacy and creating toxicity concerns. Many efforts to enhance the stability of micelles have focused mainly on decreasing the critical micelle forming concentration and improving blood circulation. Herein, we review different strategies including crosslinking and non-crosslinking approaches designed to stabilize micelles and offer perspectives on future research directions.
Cedars-Sinai Medical Center1, Mount Carmel Health2, Wayne State University3, Houston Methodist Hospital4, Providence Sacred Heart Medical Center and Children's Hospital5, UPMC Hamot6, St Vincent Hospital7, Vanderbilt University Medical Center8, Lankenau Medical Center9, Jewish Hospital10, East Jefferson General Hospital11, Memorial Hospital of South Bend12, University of Exeter13, Brigham and Women's Hospital14
TL;DR: Treatment with USCDT using a shorter delivery duration and lower-dose tPA was associated with improved right ventricular function and reduced clot burden compared with baseline, and improvement in refined modified Miller score was seen in all groups.
Abstract: Objectives The aim of this study was to determine the lowest optimal tissue plasminogen activator (tPA) dose and delivery duration using ultrasound-facilitated catheter-directed thrombolysis (USCDT) for the treatment of acute intermediate-risk (submassive) pulmonary embolism. Background Previous trials of USCDT used tPA over 12 to 24 h at doses of 20 to 24 mg for acute pulmonary embolism. Methods Hemodynamically stable adults with acute intermediate-risk pulmonary embolism documented by computed tomographic angiography were randomized into this prospective multicenter, parallel-group trial. Patients received treatment with 1 of 4 USCDT regimens. The tPA dose ranged from 4 to 12 mg per lung and infusion duration from 2 to 6 h. The primary efficacy endpoint was reduction in right ventricular–to–left ventricular diameter ratio by computed tomographic angiography. A major secondary endpoint was embolic burden by refined modified Miller score, measured on computed tomographic angiography 48 h after initiation of USCDT. Results One hundred one patients were randomized, and improvements in right ventricular–to–left ventricular diameter ratio were as follows: arm 1 (4 mg/lung/2 h), 0.40 (24%; p = 0.0001); arm 2 (4 mg/lung/4 h), 0.35 (22.6%; p = 0.0001); arm 3 (6 mg/lung/6 h), 0.42 (26.3%; p = 0.0001); and arm 4 (12 mg/lung/6 h), 0.48 (25.5%; p = 0.0001). Improvement in refined modified Miller score was also seen in all groups. Four patients experienced major bleeding (4%). Of 2 intracranial hemorrhage events, 1 was attributed to tPA delivered by USCDT. Conclusions Treatment with USCDT using a shorter delivery duration and lower-dose tPA was associated with improved right ventricular function and reduced clot burden compared with baseline. The major bleeding rate was low, but 1 intracranial hemorrhage event due to tPA delivered by USCDT did occur.
TL;DR: In this article, a measurement of the H→ττ signal strength is performed using events recorded in proton-proton collisions by the CMS experiment at the LHC in 2016 at a center-of-mass energy of 13TeV.
Reiner Schlitzer1, Robert F. Anderson2, Elena Masferrer Dodas3, Maeve C. Lohan4 +310 more•Institutions (98)
TL;DR: The GEOTRACES Intermediate Data Product 2017 (IDP2017) as discussed by the authors is the second publicly available data product of the international GEOTrACES programme, and contains data measured and quality controlled before the end of 2016.
VU University Amsterdam1, Harvard University2, University of Cologne3, Memorial Sloan Kettering Cancer Center4, University of Texas MD Anderson Cancer Center5, Humanitas University6, University of Bologna7, University of California, Los Angeles8, University of Oxford9, Wayne State University10, Emory University11, University Health Network12, Charles University in Prague13, Mayo Clinic14, Bristol-Myers Squibb15, Brigham and Women's Hospital16
TL;DR: Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade.
Abstract: Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p241/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial Methods HRS cells from archival tumor biopsies were evaluated for 9p241 alterations by fluorescence in situ hybridization and for expression of PD ligand 1 (PD-L1) and the antigen presentation pathway components-β2-microglobulin, MHC class I, and MHC class II-by immunohistochemistry These parameters were correlated with clinical responses and progression-free survival (PFS) after PD-1 blockade Results Patients with higher-level 9p241 copy gain and increased PD-L1 expression on HRS cells had superior PFS HRS cell expression of β2-microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy In contrast, HRS cell expression of MHC class II was predictive for complete remission In patients with a > 12-month interval between myeloablative autologous stem-cell transplantation and nivolumab therapy, HRS cell expression of MHC class II was associated with prolonged PFS Conclusion Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade In cHL, clinical responses to nivolumab were not dependent on HRS cell expression of MHC class I
TL;DR: The current understanding of the complex role that mitochondrial quality control plays in the progression of acute vs chronic diseases is summarized and the possibility that targeted manipulation of mitochondria quality control mechanisms may be exploited for the rationale design of novel therapeutic interventions is speculated.
Abstract: Mitochondria are key regulators of cell fate during disease. They control cell survival via the production of ATP that fuels cellular processes and, conversely, cell death via the induction of apoptosis through release of pro-apoptotic factors such as cytochrome C. Therefore, it is essential to have stringent quality control mechanisms to ensure a healthy mitochondrial network. Quality control mechanisms are largely regulated by mitochondrial dynamics and mitophagy. The processes of mitochondrial fission (division) and fusion allow for damaged mitochondria to be segregated and facilitate the equilibration of mitochondrial components such as DNA, proteins, and metabolites. The process of mitophagy are responsible for the degradation and recycling of damaged mitochondria. These mitochondrial quality control mechanisms have been well studied in chronic and acute pathologies such as Parkinson’s disease, Alzheimer’s disease, stroke, and acute myocardial infarction, but less is known about how these two processes interact and contribute to specific pathophysiologic states. To date, evidence for the role of mitochondrial quality control in acute and chronic disease is divergent and suggests that mitochondrial quality control processes can serve both survival and death functions depending on the disease state. This review aims to provide a synopsis of the molecular mechanisms involved in mitochondrial quality control, to summarize our current understanding of the complex role that mitochondrial quality control plays in the progression of acute vs chronic diseases and, finally, to speculate on the possibility that targeted manipulation of mitochondrial quality control mechanisms may be exploited for the rationale design of novel therapeutic interventions.
Albert M. Sirunyan1, Robin Erbacher2, C. A. Carrillo Montoya3, Wagner Carvalho4 +2283 more•Institutions (140)
TL;DR: These are the first direct limits for N mass above 500 GeV and the first limits obtained at a hadron collider for N masses below 40 Ge V.
Abstract: A search for a heavy neutral lepton N of Majorana nature decaying into a W boson and a charged lepton is performed using the CMS detector at the LHC. The targeted signature consists of three prompt charged leptons in any flavor combination of electrons and muons. The data were collected in proton-proton collisions at a center-of-mass energy of 13 TeV, with an integrated luminosity of 35.9 fb^(−1). The search is performed in the N mass range between 1 GeV and 1.2 TeV. The data are found to be consistent with the expected standard model background. Upper limits are set on the values of |V_(eN)|^2and |V_(μN)|^2, where V_(lN) is the matrix element describing the mixing of N with the standard model neutrino of flavor l. These are the first direct limits for N masses above 500 GeV and the first limits obtained at a hadron collider for N masses below 40 GeV.
TL;DR: The power of scRNA-seq to deconstruct adipogenic niches is demonstrated and novel functional interactions among resident stromal cell subpopulations are suggested to suggest novel functional interaction among resident immune cells.
TL;DR: A GAN model using a single T1-weighted MR image as the input that generates robust, high quality synCTs in seconds is developed and validated and offers strong potential for supporting near real-time MR-only treatment planning in the brain.
Abstract: PURPOSE While MR-only treatment planning using synthetic CTs (synCTs) offers potential for streamlining clinical workflow, a need exists for an efficient and automated synCT generation in the brain to facilitate near real-time MR-only planning. This work describes a novel method for generating brain synCTs based on generative adversarial networks (GANs), a deep learning model that trains two competing networks simultaneously, and compares it to a deep convolutional neural network (CNN). METHODS Post-Gadolinium T1-Weighted and CT-SIM images from fifteen brain cancer patients were retrospectively analyzed. The GAN model was developed to generate synCTs using T1-weighted MRI images as the input using a residual network (ResNet) as the generator. The discriminator is a CNN with five convolutional layers that classified the input image as real or synthetic. Fivefold cross-validation was performed to validate our model. GAN performance was compared to CNN based on mean absolute error (MAE), structural similarity index (SSIM), and peak signal-to-noise ratio (PSNR) metrics between the synCT and CT images. RESULTS GAN training took ~11 h with a new case testing time of 5.7 ± 0.6 s. For GAN, MAEs between synCT and CT-SIM were 89.3 ± 10.3 Hounsfield units (HU) and 41.9 ± 8.6 HU across the entire FOV and tissues, respectively. However, MAE in the bone and air was, on average, ~240-255 HU. By comparison, the CNN model had an average full FOV MAE of 102.4 ± 11.1 HU. For GAN, the mean PSNR was 26.6 ± 1.2 and SSIM was 0.83 ± 0.03. GAN synCTs preserved details better than CNN, and regions of abnormal anatomy were well represented on GAN synCTs. CONCLUSIONS We developed and validated a GAN model using a single T1-weighted MR image as the input that generates robust, high quality synCTs in seconds. Our method offers strong potential for supporting near real-time MR-only treatment planning in the brain.
University of Kiel1, Southern Illinois University Carbondale2, University of Florida3, Max Planck Society4, Novosibirsk State University5, Otto-von-Guericke University Magdeburg6, Hebrew University of Jerusalem7, New York University8, University of Turin9, Duke University10, Vanderbilt University11, Cedars-Sinai Medical Center12, University of Texas MD Anderson Cancer Center13, Wayne State University14, Russian Academy of Sciences15
TL;DR: Considerable progress has been made in the past decade in the area of pH2 -based hyperpolarization techniques for biomedical applications, covering the areas of spin physics, catalysis, instrumentation, preparation of the contrast agents, and applications.
Abstract: Magnetic resonance (MR) is one of the most versatile and useful physical effects used for human imaging, chemical analysis, and the elucidation of molecular structures. However, its full potential is rarely used, because only a small fraction of the nuclear spin ensemble is polarized, that is, aligned with the applied static magnetic field. Hyperpolarization methods seek other means to increase the polarization and thus the MR signal. A unique source of pure spin order is the entangled singlet spin state of dihydrogen, parahydrogen (pH2 ), which is inherently stable and long-lived. When brought into contact with another molecule, this "spin order on demand" allows the MR signal to be enhanced by several orders of magnitude. Considerable progress has been made in the past decade in the area of pH2 -based hyperpolarization techniques for biomedical applications. It is the goal of this Review to provide a selective overview of these developments, covering the areas of spin physics, catalysis, instrumentation, preparation of the contrast agents, and applications.
Alfred I. duPont Hospital for Children1, University of Pennsylvania2, Wayne State University3, New York University4, University of Utah5, Children's Memorial Hospital6, Florida International University7, Boston Children's Hospital8, University of Southern California9, Harvard University10, Emory University11, University of Crete12, Istituto Giannina Gaslini13, University of Sheffield14
TL;DR: This consensus document reduces confusion by recommending to judges and jurors the tools necessary to distinguish genuine evidence-based opinions of the relevant medical community from legal arguments or etiological speculations that are unwarranted by the clinical findings, medical evidence and evidence- based literature.
Abstract: Abusive head trauma (AHT) is the leading cause of fatal head injuries in children younger than 2 years. A multidisciplinary team bases this diagnosis on history, physical examination, imaging and laboratory findings. Because the etiology of the injury is multifactorial (shaking, shaking and impact, impact, etc.) the current best and inclusive term is AHT. There is no controversy concerning the medical validity of the existence of AHT, with multiple components including subdural hematoma, intracranial and spinal changes, complex retinal hemorrhages, and rib and other fractures that are inconsistent with the provided mechanism of trauma. The workup must exclude medical diseases that can mimic AHT. However, the courtroom has become a forum for speculative theories that cannot be reconciled with generally accepted medical literature. There is no reliable medical evidence that the following processes are causative in the constellation of injuries of AHT: cerebral sinovenous thrombosis, hypoxic-ischemic injury, lumbar puncture or dysphagic choking/vomiting. There is no substantiation, at a time remote from birth, that an asymptomatic birth-related subdural hemorrhage can result in rebleeding and sudden collapse. Further, a diagnosis of AHT is a medical conclusion, not a legal determination of the intent of the perpetrator or a diagnosis of murder. We hope that this consensus document reduces confusion by recommending to judges and jurors the tools necessary to distinguish genuine evidence-based opinions of the relevant medical community from legal arguments or etiological speculations that are unwarranted by the clinical findings, medical evidence and evidence-based literature.
TL;DR: A new multiobjective optimization problem with tunable weighting coefficients is first formulated for dc microgrids and a new distributed control scheme, which only requires local communications among neighbors, is proposed to solve the optimization problem.
Abstract: One of the fundamental and challenging issues in microgrids is to guarantee fairness of load sharing while realizing voltage regulation of distributed generations. In order to address this issue, a new multiobjective optimization problem with tunable weighting coefficients is first formulated for dc microgrids. Second, a new distributed control scheme, which only requires local communications among neighbors, is proposed to solve the optimization problem. It is theoretically proved that the distributed control scheme can exponentially achieve the global optimal outputs of voltages and currents at distributed generations. Compared with a centralized control scheme, the proposed distributed control scheme provides remarkable advantages in improving reliability and scalability of microgrids. Third, the distributed control scheme is extended to accommodate a constant communication delay. The effects of the communication delay on the stability of microgrids are explicitly characterized. Finally, the performance of the proposed control schemes is evaluated by a modified six-bus microgrid with dc-powered trolleybus systems in terms of their convergence, robustness to load variations, plug-and-play functionality, tradeoff ability, and effects of communication delays.
TL;DR: Improvements in sleepiness, quality of life, and respiratory outcomes are observed with 5 years of UAS, a nonanatomic surgical treatment with long-term benefit for individuals with moderate to severe OSA who have failed nasal continuous positive airway pressure.
Abstract: Objective To present 5-year outcomes from a prospective cohort of patients with obstructive sleep apnea (OSA) who were treated with upper airway stimulation (UAS) via a unilateral hypoglossal nerve implant. Study Design A multicenter prospective cohort study. Setting Industry-supported multicenter academic and clinical trial. Methods From a cohort of 126 patients, 97 completed protocol, and 71 consented to a voluntary polysomnogram. Those having continuous positive airway pressure failure with moderate to severe OSA, body mass index 50% reduction) was 75% (n = 71). When a last observation carried forward analysis was applied, the responder rate was 63% at 5 years. Serious device-related events all related to lead/device adjustments were reported in 6% of patients. Conclusions Improvements in sleepiness, quality of life, and respiratory outcomes are observed with 5 years of UAS. Serious adverse events are uncommon. UAS is a nonanatomic surgical treatment with long-term benefit for individuals with moderate to severe OSA who have failed nasal continuous positive airway pressure.
Cleveland Clinic1, American Society of Clinical Oncology2, CHI Health3, University of Texas MD Anderson Cancer Center4, University of Utah5, Pancreatic Cancer Action Network6, Memorial Sloan Kettering Cancer Center7, Wayne State University8, Mayo Clinic9, Cornell University10, University of Michigan11, Duke University12, United States Department of Veterans Affairs13, Johns Hopkins University14
TL;DR: Testing select patients for mismatch repair deficiency or microsatellite instability is recommended, and pembrolizumab is recommended for patients with mismatch Repair deficiency or high micros satellite instability tumors.
Abstract: PurposeIn 2016, ASCO published a guideline to assist in clinical decision making in metastatic pancreatic cancer for initial assessment after diagnosis, first- and second-line treatment options, palliative and supportive care, and follow-up. The purpose of this update is to incorporate new evidence related to second-line therapy for patients who have experienced disease progression or intolerable toxicity during first-line therapy.MethodsASCO convened an Expert Panel to conduct a systematic review of the literature on second-line therapy published between June 2015 and January 2018. Recommendations on other topics covered in the 2016 Metastatic Pancreatic Cancer Guideline were endorsed by the Expert Panel.ResultsTwo new studies were found that met the inclusion criteria.RecommendationsFor second-line therapy, gemcitabine plus nanoparticle albumin-bound paclitaxel should be offered to patients with first-line treatment with FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin), an Eastern Coop...
University of Wisconsin-Madison1, University of Vermont2, Lund University3, University of Cincinnati4, University of Kiel5, North Dakota State University6, Ghent University7, Agricultural Research Service8, Moscow State University9, Prince of Songkla University10, Wayne State University11, University of Valencia12, Baylor College of Medicine13, National Institute of Science Education and Research14, University of Padua15, Polish Academy of Sciences16, Institut national de la recherche agronomique17, King Abdulaziz University18, Aix-Marseille University19, University of Kentucky20, Texas A&M University21, German Cancer Research Center22, Nanjing Agricultural University23, Skolkovo Institute of Science and Technology24, Illinois Institute of Technology25, University of Wisconsin–Oshkosh26, Lawrence Berkeley National Laboratory27, University of Cologne28, University of Warwick29, Max Planck Society30, University of Illinois at Urbana–Champaign31, Michigan State University32, Indiana University33, Cincinnati Children's Hospital Medical Center34, Ohio State University35
TL;DR: Surprisingly, the suite of genes involved in insecticide resistance is similar to other beetles, and duplications in the RNAi pathway might explain why Leptinotarsa decemlineata has high sensitivity to dsRNA.
Abstract: The Colorado potato beetle is one of the most challenging agricultural pests to manage. It has shown a spectacular ability to adapt to a variety of solanaceaeous plants and variable climates during its global invasion, and, notably, to rapidly evolve insecticide resistance. To examine evidence of rapid evolutionary change, and to understand the genetic basis of herbivory and insecticide resistance, we tested for structural and functional genomic changes relative to other arthropod species using genome sequencing, transcriptomics, and community annotation. Two factors that might facilitate rapid evolutionary change include transposable elements, which comprise at least 17% of the genome and are rapidly evolving compared to other Coleoptera, and high levels of nucleotide diversity in rapidly growing pest populations. Adaptations to plant feeding are evident in gene expansions and differential expression of digestive enzymes in gut tissues, as well as expansions of gustatory receptors for bitter tasting. Surprisingly, the suite of genes involved in insecticide resistance is similar to other beetles. Finally, duplications in the RNAi pathway might explain why Leptinotarsa decemlineata has high sensitivity to dsRNA. The L. decemlineata genome provides opportunities to investigate a broad range of phenotypes and to develop sustainable methods to control this widely successful pest.