Showing papers by "University of Louisville published in 2016"

ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions.

Abstract: Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I (“Risk Of Bias In Non-randomised Studies - of Interventions”), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement

Abstract: Importance Colorectal cancer is the second leading cause of cancer death in the United States. In 2016, an estimated 134 000 persons will be diagnosed with the disease, and about 49 000 will die from it. Colorectal cancer is most frequently diagnosed among adults aged 65 to 74 years; the median age at death from colorectal cancer is 73 years. Objective To update the 2008 US Preventive Services Task Force (USPSTF) recommendation on screening for colorectal cancer. Evidence Review The USPSTF reviewed the evidence on the effectiveness of screening with colonoscopy, flexible sigmoidoscopy, computed tomography colonography, the guaiac-based fecal occult blood test, the fecal immunochemical test, the multitargeted stool DNA test, and the methylated SEPT9 DNA test in reducing the incidence of and mortality from colorectal cancer or all-cause mortality; the harms of these screening tests; and the test performance characteristics of these tests for detecting adenomatous polyps, advanced adenomas based on size, or both, as well as colorectal cancer. The USPSTF also commissioned a comparative modeling study to provide information on optimal starting and stopping ages and screening intervals across the different available screening methods. Findings The USPSTF concludes with high certainty that screening for colorectal cancer in average-risk, asymptomatic adults aged 50 to 75 years is of substantial net benefit. Multiple screening strategies are available to choose from, with different levels of evidence to support their effectiveness, as well as unique advantages and limitations, although there are no empirical data to demonstrate that any of the reviewed strategies provide a greater net benefit. Screening for colorectal cancer is a substantially underused preventive health strategy in the United States. Conclusions and Recommendations The USPSTF recommends screening for colorectal cancer starting at age 50 years and continuing until age 75 years (A recommendation). The decision to screen for colorectal cancer in adults aged 76 to 85 years should be an individual one, taking into account the patient’s overall health and prior screening history (C recommendation).

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial

Abstract: Summary Background Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. Methods In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAF V600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients. Findings Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1–25·7), 2-year overall survival was 63·8% (95% CI 53·3–72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1–66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43–1·26; p=0·26). Treatment-related grade 3–4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3–4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3–4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. Interpretation Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. Funding Bristol-Myers Squibb.

Nanostructured transition metal dichalcogenide electrocatalysts for CO2 reduction in ionic liquid.

Abstract: Conversion of carbon dioxide (CO2) into fuels is an attractive solution to many energy and environmental challenges. However, the chemical inertness of CO2 renders many electrochemical and photochemical conversion processes inefficient. We report a transition metal dichalcogenide nanoarchitecture for catalytic electrochemical CO2 conversion to carbon monoxide (CO) in an ionic liquid. We found that tungsten diselenide nanoflakes show a current density of 18.95 milliamperes per square centimeter, CO faradaic efficiency of 24%, and CO formation turnover frequency of 0.28 per second at a low overpotential of 54 millivolts. We also applied this catalyst in a light-harvesting artificial leaf platform that concurrently oxidized water in the absence of any external potential.

A lithium–oxygen battery based on lithium superoxide

Abstract: Lithium–oxygen batteries allow oxygen to be reduced at the battery’s cathode when a current is drawn; in present-day batteries, this results in formation of Li2O2, but it is now shown that another high energy density material, namely LiO2, with better electronic conduction can be used instead as the discharge product, if the electrode is decorated with iridium nanoparticles. Nonaqueous lithium–air batteries have a much superior theoretical gravimetric energy density compared to conventional lithium ion batteries, and thus have the potential for making long-range electric vehicles a reality. Batteries based on sodium and potassium superoxides have recently been reported, but thermodynamically unstable lithium superoxide (LiO2), with its potential high energy density, has proved more problematic. This paper demonstrates that crystalline LiO2 can be stabilized in a Li–O2 battery by using a suitable cathode material — reduced graphene oxide decorated with iridium nanoparticles. A battery based on this new lithium–oxygen chemistry was demonstrated through 40 cycles before failure, achieving high efficiency and good capacity. Batteries based on sodium superoxide and on potassium superoxide have recently been reported1,2,3. However, there have been no reports of a battery based on lithium superoxide (LiO2), despite much research4,5,6,7,8 into the lithium–oxygen (Li–O2) battery because of its potential high energy density. Several studies9,10,11,12,13,14,15,16 of Li–O2 batteries have found evidence of LiO2 being formed as one component of the discharge product along with lithium peroxide (Li2O2). In addition, theoretical calculations have indicated that some forms of LiO2 may have a long lifetime17. These studies also suggest that it might be possible to form LiO2 alone for use in a battery. However, solid LiO2 has been difficult to synthesize in pure form18 because it is thermodynamically unstable with respect to disproportionation, giving Li2O2 (refs 19, 20). Here we show that crystalline LiO2 can be stabilized in a Li–O2 battery by using a suitable graphene-based cathode. Various characterization techniques reveal no evidence for the presence of Li2O2. A novel templating growth mechanism involving the use of iridium nanoparticles on the cathode surface may be responsible for the growth of crystalline LiO2. Our results demonstrate that the LiO2 formed in the Li–O2 battery is stable enough for the battery to be repeatedly charged and discharged with a very low charge potential (about 3.2 volts). We anticipate that this discovery will lead to methods of synthesizing and stabilizing LiO2, which could open the way to high-energy-density batteries based on LiO2 as well as to other possible uses of this compound, such as oxygen storage.

Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1.

Abstract: Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. However, the omental stromal cell-derived molecular determinants that modulate ovarian cancer growth have not been characterized. Here, using next-generation sequencing technology, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and tissue lysates isolated from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) than in those from ovarian cancer cells. Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where it suppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target, APAF1. These data suggest that the malignant phenotype of metastatic ovarian cancer cells can be altered by miR21 delivered by exosomes derived from neighbouring stromal cells in the omental tumour microenvironment, and that inhibiting the transfer of stromal-derived miR21 is an alternative modality in the treatment of metastatic and recurrent ovarian cancer.

The libRadtran software package for radiative transfer calculations (version 2.0.1)

Abstract: . libRadtran is a widely used software package for radiative transfer calculations. It allows one to compute (polarized) radiances, irradiance, and actinic fluxes in the solar and thermal spectral regions. libRadtran has been used for various applications, including remote sensing of clouds, aerosols and trace gases in the Earth's atmosphere, climate studies, e.g., for the calculation of radiative forcing due to different atmospheric components, for UV forecasting, the calculation of photolysis frequencies, and for remote sensing of other planets in our solar system. The package has been described in Mayer and Kylling (2005). Since then several new features have been included, for example polarization, Raman scattering, a new molecular gas absorption parameterization, and several new parameterizations of cloud and aerosol optical properties. Furthermore, a graphical user interface is now available, which greatly simplifies the usage of the model, especially for new users. This paper gives an overview of libRadtran version 2.0.1 with a focus on new features. Applications including these new features are provided as examples of use. A complete description of libRadtran and all its input options is given in the user manual included in the libRadtran software package, which is freely available at http://www.libradtran.org .

Exposure to Fine Particulate Air Pollution Is Associated With Endothelial Injury and Systemic Inflammation.

Abstract: Rationale:Epidemiological evidence indicates that exposures to fine particulate matter air pollution (PM2.5) contribute to global burden of disease, primarily as a result of increased risk of cardi...

Inherent bacterial DNA contamination of extraction and sequencing reagents may affect interpretation of microbiota in low bacterial biomass samples

Abstract: The advent and use of highly sensitive molecular biology techniques to explore the microbiota and microbiome in environmental and tissue samples have detected the presence of contaminating microbial DNA within reagents. These microbial DNA contaminants may distort taxonomic distributions and relative frequencies in microbial datasets, as well as contribute to erroneous interpretations and identifications. We herein report on the occurrence of bacterial DNA contamination within commonly used DNA extraction kits and PCR reagents and the effect of these contaminates on data interpretation. When compared to previous reports, we identified an additional 88 bacterial genera as potential contaminants of molecular biology grade reagents, bringing the total number of known contaminating microbes to 181 genera. Many of the contaminants detected are considered normal inhabitants of the human gastrointestinal tract and the environment and are often indistinguishable from those genuinely present in the sample. Laboratories working on bacterial populations need to define contaminants present in all extraction kits and reagents used in the processing of DNA. Any unusual and/or unexpected findings need to be viewed as possible contamination as opposed to unique findings.

Preoperative Modified FOLFIRINOX Treatment Followed by Capecitabine-Based Chemoradiation for Borderline Resectable Pancreatic Cancer: Alliance for Clinical Trials in Oncology Trial A021101.

Abstract: Importance Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported. Objective To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting. Design, Setting, and Participants A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014. Interventions Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2of irinotecan hydrochloride, 400 mg/m2of leucovorin calcium, and then 2400 mg/m2of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2orally twice daily) prior to pancreatectomy. Main Outcomes and Measures Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate. Results The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration. Conclusions and Relevance The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial’s completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients. Trial Registration clinicaltrials.gov Identifier:NCT01821612

Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer's Disease: Understanding the Therapeutics Strategies.

Abstract: Synapses are formed by interneuronal connections that permit a neuronal cell to pass an electrical or chemical signal to another cell. This passage usually gets damaged or lost in most of the neurodegenerative diseases. It is widely believed that the synaptic dysfunction and synapse loss contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although pathological hallmarks of AD are senile plaques, neurofibrillary tangles, and neuronal degeneration which are associated with increased oxidative stress, synaptic loss is an early event in the pathogenesis of AD. The involvement of major kinases such as mitogen-activated protein kinase (MAPK), extracellular receptor kinase (ERK), calmodulin-dependent protein kinase (CaMKII), glycogen synthase-3β (GSK-3β), cAMP response element-binding protein (CREB), and calcineurin is dynamically associated with oxidative stress-mediated abnormal hyperphosphorylation of tau and suggests that alteration of these kinases could exclusively be involved in the pathogenesis of AD. N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation and beta amyloid (Aβ) toxicity alter the synapse function, which is also associated with protein phosphatase (PP) inhibition and tau hyperphosphorylation (two main events of AD). However, the involvement of oxidative stress in synapse dysfunction is poorly understood. Oxidative stress and free radical generation in the brain along with excitotoxicity leads to neuronal cell death. It is inferred from several studies that excitotoxicity, free radical generation, and altered synaptic function encouraged by oxidative stress are associated with AD pathology. NMDARs maintain neuronal excitability, Ca(2+) influx, and memory formation through mechanisms of synaptic plasticity. Recently, we have reported the mechanism of the synapse redox stress associated with NMDARs altered expression. We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.

Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans.

Abstract: Misfolded alpha-synuclein (AS) and other neurodegenerative disorder proteins display prion-like transmission of protein aggregation. Factors responsible for the initiation of AS aggregation are unknown. To evaluate the role of amyloid proteins made by the microbiota we exposed aged rats and transgenic C. elegans to E. coli producing the extracellular bacterial amyloid protein curli. Rats exposed to curli-producing bacteria displayed increased neuronal AS deposition in both gut and brain and enhanced microgliosis and astrogliosis compared to rats exposed to either mutant bacteria unable to synthesize curli, or to vehicle alone. Animals exposed to curli producing bacteria also had more expression of TLR2, IL-6 and TNF in the brain than the other two groups. There were no differences among the rat groups in survival, body weight, inflammation in the mouth, retina, kidneys or gut epithelia, and circulating cytokine levels. AS-expressing C. elegans fed on curli-producing bacteria also had enhanced AS aggregation. These results suggest that bacterial amyloid functions as a trigger to initiate AS aggregation through cross-seeding and also primes responses of the innate immune system.

Cardio-Oncology: An Update on Cardiotoxicity of Cancer-Related Treatment.

Abstract: Through the success of basic and disease-specific research, cancer survivors are one of the largest growing subsets of individuals accessing the healthcare system. Interestingly, cardiovascular disease is the second leading cause of morbidity and mortality in cancer survivors after recurrent malignancy. This recognition has helped stimulate a collaboration between oncology and cardiology practitioners and researchers, and the portmanteau cardio-oncology (also known as onco-cardiology) can now be found in many medical centers. This collaboration promises new insights into how cancer therapies impact cardiovascular homeostasis and long-term effects on cancer survivors. In this review, we will discuss the most recent views on the cardiotoxicity related to various classes of chemotherapy agents and radiation. We will also discuss broadly the current strategies for treating and preventing cardiovascular effects of cancer therapy.

Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis

Abstract: Mixed lineage kinase domain-like pseudokinase (MLKL) mediates necroptosis by translocating to the plasma membrane and inducing its rupture. The activation of MLKL occurs in a multimolecular complex (the 'necrosome'), which is comprised of MLKL, receptor-interacting serine/threonine kinase (RIPK)-3 (RIPK3) and, in some cases, RIPK1. Within this complex, RIPK3 phosphorylates the activation loop of MLKL, promoting conformational changes and allowing the formation of MLKL oligomers, which migrate to the plasma membrane. Previous studies suggested that RIPK3 could phosphorylate the murine MLKL activation loop at Ser345, Ser347 and Thr349. Moreover, substitution of the Ser345 for an aspartic acid creates a constitutively active MLKL, independent of RIPK3 function. Here we examine the role of each of these residues and found that the phosphorylation of Ser345 is critical for RIPK3-mediated necroptosis, Ser347 has a minor accessory role and Thr349 seems to be irrelevant. We generated a specific monoclonal antibody to detect phospho-Ser345 in murine cells. Using this antibody, a series of MLKL mutants and a novel RIPK3 inhibitor, we demonstrate that the phosphorylation of Ser345 is not required for the interaction between RIPK3 and MLKL in the necrosome, but is essential for MLKL translocation, accumulation in the plasma membrane, and consequent necroptosis.

Is the Effect of Procedural Justice on Police Legitimacy Invariant? Testing the Generality of Procedural Justice and Competing Antecedents of Legitimacy

Abstract: This study tests the generality of Tyler’s process-based model of policing by examining whether the effect of procedural justice and competing variables (i.e., distributive justice and police effectiveness) on police legitimacy evaluations operate in the same manner across individual and situational differences. Data from a random sample of mail survey respondents are used to test the “invariance thesis” (N = 1681). Multiplicative interaction effects between the key antecedents of legitimacy (measured separately for obligation to obey and trust in the police) and various demographic categories, prior experiences, and perceived neighborhood conditions are estimated in a series of multivariate regression equations. The effect of procedural justice on police legitimacy is largely invariant. However, regression and marginal results show that procedural justice has a larger effect on trust in law enforcement among people with prior victimization experience compared to their counterparts. Additionally, the distributive justice effect on trust in the police is more pronounced for people who have greater fear of crime and perceive higher levels of disorder in their neighborhood. The results suggest that Tyler’s process-based model is a “general” theory of individual police legitimacy evaluations. The police can enhance their legitimacy by ensuring procedural fairness during citizen interactions. The role of procedural justice also appears to be particularly important when the police interact with crime victims.

Observation of Long-Range Elliptic Azimuthal Anisotropies in s =13 and 2.76 TeV pp Collisions with the ATLAS Detector

Abstract: ATLAS has measured two-particle correlations as a function of relative azimuthal-angle, $\Delta \phi$, and pseudorapidity, $\Delta \eta$, in $\sqrt{s}$=13 and 2.76 TeV $pp$ collisions at the LHC using charged particles measured in the pseudorapidity interval $|\eta|$<2.5. The correlation functions evaluated in different intervals of measured charged-particle multiplicity show a multiplicity-dependent enhancement at $\Delta \phi \sim 0$ that extends over a wide range of $\Delta\eta$, which has been referred to as the "ridge". Per-trigger-particle yields, $Y(\Delta \phi)$, are measured over 2<$|\Delta\eta|$<5. For both collision energies, the $Y(\Delta \phi)$ distribution in all multiplicity intervals is found to be consistent with a linear combination of the per-trigger-particle yields measured in collisions with less than 20 reconstructed tracks, and a constant combinatoric contribution modulated by $\cos{(2\Delta \phi)}$. The fitted Fourier coefficient, $v_{2,2}$, exhibits factorization, suggesting that the ridge results from per-event $\cos{(2\phi)}$ modulation of the single-particle distribution with Fourier coefficients $v_2$. The $v_2$ values are presented as a function of multiplicity and transverse momentum. They are found to be approximately constant as a function of multiplicity and to have a $p_{\mathrm{T}}$ dependence similar to that measured in $p$+Pb and Pb+Pb collisions. The $v_2$ values in the 13 and 2.76 TeV data are consistent within uncertainties. These results suggest that the ridge in $pp$ collisions arises from the same or similar underlying physics as observed in $p$+Pb collisions, and that the dynamics responsible for the ridge has no strong $\sqrt{s}$ dependence.

Automating Biomedical Data Science Through Tree-Based Pipeline Optimization

Abstract: Over the past decade, data science and machine learning has grown from a mysterious art form to a staple tool across a variety of fields in academia, business, and government. In this paper, we introduce the concept of tree-based pipeline optimization for automating one of the most tedious parts of machine learning—pipeline design. We implement a Tree-based Pipeline Optimization Tool (TPOT) and demonstrate its effectiveness on a series of simulated and real-world genetic data sets. In particular, we show that TPOT can build machine learning pipelines that achieve competitive classification accuracy and discover novel pipeline operators—such as synthetic feature constructors—that significantly improve classification accuracy on these data sets. We also highlight the current challenges to pipeline optimization, such as the tendency to produce pipelines that overfit the data, and suggest future research paths to overcome these challenges. As such, this work represents an early step toward fully automating machine learning pipeline design.