Identifying Authorship from Linguistic Text Patterns

Research that deals with linguistic text patterns is challenging because of the unstructured nature of text. This research presents a methodology to compare texts to identify whether two texts are written by the same or different authors. The methodology includes an algorithm to analyze the proximity of text, which is based upon Zipf’s Law [47][48]. The results have implications for text mining with applications to areas such as forensics, natural language processing, and information retrieval

State Responses to the Tax Cuts and Jobs Act: An Analysis from Indiana and Missouri

This Article, authored by lawyers from the Indiana Department of Revenue and Missouri Department of Revenue, is intended to address, and hopefully add clarity to, the complexities of state taxation under the Tax Cuts and Jobs Act of 2017 (“TCJA”). After a brief historical and general overview of the TCJA, this Article focuses on seven distinct topics within the TCJA from a state perspective. These topics are: (1) Business Assets Expensing; (2) the TCJA’s treatment of 529 Accounts; (3) the 30% Business Interest Limitation; (4) the Transition Tax (also referred to as “Deemed Repatriation”); (5) GILTI, or Global Intangible Low-Taxed Income; (6) the elimination of the Personal and Dependency Exemption Deductions; and (7) the Qualified Business Income Deduction. For each topic, this Article gives an overview of the associated TCJA provisions, addresses some responses of the states to these provisions, and provides opportunity for discussion of possible or actual responses by Indiana and/or Missouri

Major depressive disorder, suicidal thoughts and behaviours, and cannabis involvement in discordant twins:a retrospective cohort study

Background: Early and frequent cannabis use are associated with an increased likelihood of major depressive disorder (MDD) as well as suicidal thoughts and behaviours. We identify associations between aspects of cannabis use, MDD, and suicidal thoughts and behaviours and examine whether such associations persist after accounting for those predisposing factors, including genetic liability and early family environment, that are shared by identical twins who are discordant for cannabis exposure. Any residual association in such identical pairs might be indicative of individual-specific pathways that might be of a causal nature. Methods: We did a logistic regression analysis of cannabis use from retrospective data on same-sex male and female twin pairs drawn from 3 studies that had recruited twins from the Australian Twin Registry, 1992–93 (sample 1), 1996–2000 (sample 2), and 2005–09 (sample 3). We studied associations between early use and frequent use of cannabis and MDD, suicidal ideation (ever and persistent), and suicide plan and attempt in the full sample as well as in pairs of monozygotic and dizygotic twins that were discordant for each measure of cannabis involvement at a single timepoint. Significant monozygotic associations were further adjusted for covariates, such as early alcohol or nicotine use, early dysphoric or anhedonic mood, conduct disorder, and childhood sexual abuse. Interactions between each cannabis measure and sex, sample or study effects, and birth year category were also examined as covariates. Findings: In 13 986 twins (6181 monozygotic and 7805 dizygotic), cannabis use ranged from 1345 (30·4%) of 4432 people in sample 1 to 2275 (69·0%) of 3299 in sample 3. Mean age of first cannabis use ranged from 17·9 years (SD 3·3) in sample 3 to 21·1 years (5·2) in sample 1, and frequent use (≥100 times) was reported by 214 (15·9%) of 1345 users in sample 1 and 499 (21·9%) of 2275 in sample 3. The prevalence of suicidal ideation ranged from 1102 (24·9%) of 4432 people in sample 1 to 1644 (26·3%) of 6255 people in sample 2 and 865 (26·2%) of 3299 people in sample 3. Prevalence of MDD ranged from 901 (20·3%) people in sample 1 to 1773 (28·3%) in sample 2. The monozygotic twin who used cannabis frequently was more likely to report MDD (odds ratio 1·98, 95% CI 1·11–3·53) and suicidal ideation (2·47, 1·19–5·10) compared with their identical twin who had used cannabis less frequently, even after adjustment for covariates. For early cannabis use, the monozygotic point estimate was not significant but could be equated to the significant dizygotic estimate, suggesting a possible association with suicidal ideation. Interpretation: The increased likelihood of MDD and suicidal ideation in frequent cannabis users cannot be solely attributed to common predisposing factors

A large-scale genome-wide association study meta-analysis of cannabis use disorder

BACKGROUND: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. METHODS: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. FINDINGS: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10 INTERPRETATION: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. FUNDING: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences

Clofarabine ± Fludarabine with Once Daily i.v. Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and MDS

Although a combination of i.v. busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for acute myelogenous leukemia/myelodysplastic syndromes (AML/MDS), recurrent leukemia posttransplantation remains a problem. To enhance the conditioning regimen’s antileukemic effect, we decided to supplant Flu with clofarabine (Clo), and assayed the interactions of these nucleoside analogs alone and in combination with Bu in Bu-resistant human cell lines in vitro. We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu. We then designed a 4-arm clinical trial in patients with myeloid leukemia undergoing allogeneic stem cell transplantation (allo-SCT). Patients were adaptively randomized as follows: Arm I–Clo:Flu 10:30 mg/m2, Arm II—20:20 mg/m2, Arm III—30:10 mg/m2, and Arm IV–single-agent Clo at 40 mg/m2. The nucleoside analog(s) were/was infused over 1 hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily area under the curve (AUC) of 6000 μMol-min ± 10%. Fifty-one patients have been enrolled with a minimum follow-up exceeding 100 days. There were 32 males and 19 females, with a median age of 45 years (range: 6-59). Nine patients had chronic myeloid leukemia (CML) (BC: 2, second AP: 3, and tyrosine-kinase inhibitor refractory first chronic phase [CP]: 4). Forty-two patients had AML: 14 were induction failures, 8 in first chemotherapy-refractory relapse, 7 in untreated relapse, 3 in second or subsequent relapse, 4 were in second complete remission (CR), and 3 in second CR without platelet recovery (CRp), 2 were in high-risk CR1. Finally, 1 patient was in first CRp. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methorexate (MTX), and those who had an unrelated or 1 antigen-mismatched donor received low-dose rabbit-ATG (Thymoglobulin™). All patients engrafted. Forty-one patients had active leukemia at the time of transplant, and 35 achieved CR (85%). Twenty of the 42 AML patients and 5 of 9 CML patients are alive with a projected median overall survival (OS) of 23 months. Marrow and blood (T cell) chimerism studies at day +100 revealed that both in the lower-dose Clo groups (groups 1+2) and the higher-dose Clo groups (groups 3+4), the patients had a median of 100% donor (T cell)-derived DNA. There has been no secondary graft failure. In the first 100 days, 1 patient died of pneumonia, and 1 of liver GVHD. We conclude that (1) Clo ± Flu with i.v. Bu as pretransplant conditioning is safe in high-risk myeloid leukemia patients; (2) clofarabine is sufficiently immunosuppressive to support allo-SCT in myeloid leukemia; and (3) the median OS of 23 months in this high-risk patient population is encouraging. Additional studies to evaluate the antileukemic efficacy of Clo ± Flu with i.v. Bu as pretransplant conditioning therapy are warranted

A Mechanistic Framework for Integrating Chemical Structure and High-Throughput Screening Results to Improve Toxicity Predictions

Adverse Outcome Pathways (AOPs) establish a connection between a molecular initiating event (MIE) and an adverse outcome. Detailed understanding of the MIE provides the ideal data for determining chemical properties required to elicit the MIE. This study utilized high-throughput screening data from the ToxCast program, coupled with chemical structural information, to generate chemical clusters using three similarity methods pertaining to nine MIEs within an AOP network for hepatic steatosis. Three case studies demonstrate the utility of the mechanistic information held by the MIE for integrating biological and chemical data. Evaluation of the chemical clusters activating the glucocorticoid receptor identified activity differences in chemicals within a cluster. Comparison of the estrogen receptor results with previous work showed that bioactivity data and structural alerts can be combined to improve predictions in a customizable way where bioactivity data are limited. The aryl hydrocarbon receptor (AHR) highlighted that while structural data can be used to offset limited data for new screening efforts, not all ToxCast targets have sufficient data to define robust chemical clusters. In this context, an alternative to additional receptor assays is proposed where assays for proximal key events downstream of AHR activation could be used to enhance confidence in active calls. These case studies illustrate how the AOP framework can support an iterative process whereby in vitro toxicity testing and chemical structure can be combined to improve toxicity predictions. In vitro assays can inform the development of structural alerts linking chemical structure to toxicity. Consequently, structurally related chemical groups can facilitate identification of assays that would be informative for a specific MIE. Together, these activities form a virtuous cycle where the mechanistic basis for the in vitro results and the breadth of the structural alerts continually improve over time to better predict activity of chemicals for which limited toxicity data exist

Molecular Fingerprint-Derived Similarity Measures for Toxicological Read-Across: Recommendations for Optimal Use

Computational approaches are increasingly used to predict toxicity, in part due to pressures to find alternatives to animal testing. Read-across is the “new paradigm” which aims to predict toxicity by identifying similar, data rich, source compounds. This assumes that similar molecules tend to exhibit similar activities, i.e. molecular similarity is integral to read-across. Various molecular fingerprints and similarity measures may be used to calculate molecular similarity. This study investigated the value and concordance of the Tanimoto similarity values calculated using six widely used fingerprints within six toxicological datasets. There was considerable variability in the similarity values calculated from the various molecular fingerprints for diverse compounds, although they were reasonably concordant for homologous series acting via a common mechanism. The results suggest generic fingerprint-derived similarities are likely to be optimally predictive for local datasets, i.e. following sub-categorisation. Thus, for read-across, generic fingerprint-derived similarities are likely to be most predictive after chemicals are placed into categories (or groups), then similarity is calculated within those categories, rather than for a whole chemically diverse dataset

The Global Task Force for Chronic Pain in People with HIV (PWH):Developing a research agenda in an emerging field

Chronic pain is a common comorbidity in people with HIV (PWH), with prevalence estimates of 25-85%. Research in this area is growing, but significant gaps remain. A Global Task Force of HIV experts was organized to brainstorm a scientific agenda and identify measurement domains critical to advancing research in this field. Experts were identified through literature searches and snowball sampling. Two online questionnaires were developed by Task Force members. Questionnaire 1 asked participants to identify knowledge gaps in the field of HIV and chronic pain and identify measurement domains in studies of chronic pain in PWH. Responses were ranked in order of importance in Questionnaire 2, which was followed by a group discussion. 29 experts completed Questionnaire 1, 25 completed Questionnaire 2, and 21 participated in the group. Many important clinical and research priorities emerged, including the need to examine etiologies of chronic pain in PWH. Pain-related measurement domains were discussed, with a primary focus on domains that could be assessed in a standardized manner across various cohorts that include PWH in different countries. We collaboratively identified clinical and research priorities, as well as gaps in standardization of measurement domains, that can be used to move the field forward