tbuckley/cabot-search huggingface dataset:
New Data on Opioid Use and Prescribing in the United States
Authors: Anne Schuchat, Debra Houry, Gery P. Guy
Journal: JAMA (2017)

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Associations of Prenatal Urinary Bisphenol A Concentrations with Child Behaviors and Cognitive Abilities
Authors: Joseph M. Braun, Gina Muckle, Tye Arbuckle, Maryse F. Bouchard, William D. Fraser, Emmanuel Ouellet, Jean R. Séguin, Youssef Oulhote, Glenys M. Webster, Bruce P. Lanphear
Journal: Environmental Health Perspectives (2017)

Background: Prenatal bisphenol A (BPA) exposure has been associated with adverse neurodevelopment in epidemiological studies. However, prior studies had limited statistical power to examine sex-specific effects, and few examined child cognition. Objectives: We estimated the association between prenatal BPA exposure and child neurobehavior at 3 y of age in a prospective cohort of 812 mothers and their children. Methods: We measured BPA concentration in urine samples collected at ∼12 wk gestation among women enrolled in a 10-city Canadian cohort study. At approximately 3 y of age, we assessed children's cognitive abilities with the Wechsler Primary and Preschool Scale of Intelligence™–III (WPPSI-III) and two scales of the Behavior Rating Inventory of Executive Function–Preschool (BRIEF-P). Parents reported children's behavior using the Behavior Assessment System for Children–2 (BASC-2) and the Social Responsiveness Scale™ – 2. (SRS-2). We estimated covariate-adjusted differences in neurobehavioral outcomes with a doubling in BPA concentration and sex-specific associations. Results: BPA was not associated with WPPSI-III scores; child sex did not modify these associations. The association between BPA and BRIEF-P scores was modified by child sex (BPA×sex p-values≤0.03). For example, a doubling of BPA concentration was associated with 1-point (95% CI: 0.3, 1.7) poorer working memory in boys and 0.5-point (95% CI: −1.1, 0.1) better scores in girls. BPA was not associated with most BASC-2 scales; however, it was associated with more internalizing and somatizing behaviors in boys, but not in girls (BPA×sex p-values≤0.08). A doubling of BPA concentration was associated with poorer SRS-2 scores [β=0.3 ( 95% CI: 0, 0.7)]; this association was not modified by sex. Conclusion: Prenatal urinary BPA concentration was associated with some aspects of child behavior in this cohort, and some associations were stronger among boys. https://doi.org/10.1289/EHP984
Comparison of Total Body Irradiation-Based with Intravenous Busulfan-Based Chemotherapy-Only Conditioning Regimens for Myeloablative Hematopoietic Cell Transplantation (HCT) in Adults with Acute Lymphoblastic Leukemia
Authors: Partow Kebriaei, Claudio Anasetti, Mei-Jie Zhang, Hai-Lin Wang, Ibrahim Aldoss, Marcos de Lima, H. Jean Khoury, Brenda M. Sandmaier, Mary M. Horowitz, Andrew Artz, Nelli Bejanyan, Stefan O. Ciurea, Hillard M. Lazarus, Robert Peter Gale, Mark Litzow, Christopher N. Bredeson, Matthew D. Seftel, Michael A Pulsipher, Jaap Jan Boelens, Joseph Alvarnas, Richard E. Champlin, Stephen J. Forman, Vinod Pullarkat, Daniel Weisdorf, David I. Marks
Journal: Blood (2016)
Successive governments have failed to tackle gaps in social mobility
Authors: Nigel Hawkes
Journal: BMJ (2017)

Britain remains a society with deep rooted divisions in health, wealth, and expectations, according to two reports, coincidentally published on the same day.12

The Social Mobility Commission, chaired by former health secretary Alan Milburn, reviews the stuttering progress made over the past 20 years in improving social mobility; while the Office for National Statistics identifies the social and lifestyle characteristics that differ between areas of high and low healthy life expectancies.

Two versions of England emerge: the wealthy, healthy, and economically prosperous south where pockets of deprivation and poor life prospects are the exception, and the less successful north where they are the rule. “A new geographical divide has opened up, a new income divide has opened up, and a new generational divide has opened up,” said …
Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Ibiayi Dagogo-Jack, Eric Bernicker, Tianhong Li, Victoria Wang, Jeffrey S. Ross, Lauren Young, Philip J. Stephens, Jon Chung, Alice Tsang Shaw, Siraj Mahamed Ali, Vincent A. Miller, Alexa Betzig Schrock, David R. Spigel, Sai-Hong Ignatius Ou
Journal: Journal of Clinical Oncology (2017)

9025 Background: Tissue biopsy is the gold standard for detection of genomic alterations (GA) and selection of matched targeted therapies in NSCLC, but ctDNA assay provides a possible complementary approach for some pts. Methods: Hybrid-capture based genomic profiling of 62 genes using a ctDNA assay (FoundationACT™) was performed on blood samples from 1,019 consecutive NSCLC pts. The fraction of ctDNA in the blood was estimated using the maximum somatic allele frequency (MSAF) for each sample. Results: Pt characteristics: Median age 69 years (range 8-94); 54% were female. Histologies included adenocarcinoma (n = 720), NSCLC not otherwise specified (NSCLC NOS; n = 179), squamous cell (n = 57), LC NOS (n = 51), large cell (n = 6), and sarcomatoid (n = 6). ≥1 reportable GA was detected in 71% of all cases and in 83% of cases with evidence of ctDNA in the blood (MSAF &gt; 0). For 22 pts with paired blood and tissue samples collected within 30 days and MSAF &gt; 0, 33/64 (52%) GA detected in tissue were also detected in ctDNA. In 55 pts for whom tissue was insufficient for analysis, ≥1 GA was detected in ctDNA in 43 (78%) cases. For 856 cases with MSAF &gt; 0, an average of 1.8 GA/sample were reported. GA were most frequently detected in TP53 (57%), EGFR (23%) and KRAS (17%). Comparative analysis with the tissue-based FoundationCORE™ database (n = 19,264) showed similar frequencies of GA per gene, although KRAS mutation was more frequent in tissue than ctDNA (27% vs 17%, P &lt; 0.0001), and EGFR T790M was more frequent in ctDNA than tissue (7% vs 2%, P &lt; 0.0001), likely reflecting use of liquid versus tissue biopsy after relapse on targeted therapy .Kinase fusions ( ALK, ROS1, RET, FGFR3, PDGFRA) were identified in 5% (39/856) of cases. Diverse and novel mechanisms of acquired resistance (AR) were detected in ctDNA including MET Y1230C and EGFR amplification post-crizotinib, FGFR3-TACC3 fusion post-EGFR inhibitor, and multiple EGFRAR mutations post-osimertinib. Conclusions: In this series, use of a rigorously validated capture-based assay revealed evidence of ctDNA in the blood in 84% of cases. Our results provide clinical support for use of this assay as a complementary technology to tissue-based genomic testing in a subset of pts with NSCLC.
Insights into innate immune signalling in controlling cardiac remodelling
Authors: Yaxing Zhang, Zan Huang, Hongliang Li
Journal: Cardiovascular Research (2017)

Canonical innate immune signalling involves complex cascades: multiple germline-encoded pattern recognition receptors rapidly recognize pathogen-associated or damage-associated molecular patterns to induce the production of cytokines, which bind to their corresponding receptors to orchestrate subsequent host defense phases. Inflammation is a healthy response to pathogenic signals, which are typically rapid and specific, and they terminate once the threat has passed. However, excessive activation or suppression of innate immune or inflammatory responses can lead to considerable human suffering, such as cardiac remodelling. Interestingly, recent studies have revealed that innate immune molecules in the parenchymal cells of the heart influence cardiac homeostasis not only by directly regulating innate immune responses but also through reprogrammed signalling pathways, which are independent of conventional innate immune signalling. Elucidating 'innate immune signalling reprogramming' events will help us better understand the functions of innate immune molecules and, moreover, the pathogenesis of cardiac diseases.
Ulcerative Colitis in a Provincial Hospital- A Very Different Perspective
Authors: A Saleem, P Murchan, AM Eustace-Ryan, C O'Leary, P O'Regan
Journal: Endoscopy (2006)

Aims: Reports on Ulcerative Colitis (UC) from tertiary referral / teaching hospitals have an inherent bias towards problem cases. This report details UC in a secondary referral hospital and presents a more complete picture by comparing with a tertiary centre.
A review of the quality of statistical methods employed for analyzing quality of life data in cancer RCTs.
Authors: Andrew Bottomley, Corneel Coens, Jammbe Musoro, Francesca Martinelli, Efstathios Zikos, Irina Ghislain, Jean-Francois Hamel
Journal: Journal of Clinical Oncology (2016)

10058 Background: Over the last decades Quality of Life (QoL) endpoints have become an important outcome of the randomized controlled trials (RCTs). QoL methodology in RCTs has improved following international consensus recommendations. However, no international recommendations exist for analyzing QoL data from RCTs. Lack of such guidelines implies that a high variability of statistical methods is used, possibly leading to lack of consistency. The aim of our study was to identify and characterize the quality of the statistical methods commonly used for analyzing QoL data in cancer RCTs. Methods: We analyzed a total of 31 published RCTs, involving some 10,000 patients identified in a previous systematic review studying the QoL methods reported in RCTs since 1991. We focused on the ability of the methods to deal with the three major problems commonly encountered when analyzing QoL data: their multidimensional and longitudinal structure and the commonly high rate of missing data. Results: Data was systematically extracted from the 31 RCTs. All studies reported QoL being assessed repeatedly over time for a period ranging from 2 to 36 months. Missing data were common, with compliance rates ranging from 45% to 90%. From the 31 studies considered, 12 different statistical methods were identified. 27 studies analyzed each of the questionnaire sub-dimensions without type I error adjustment. 11 studies analyzed QoL by repeating scores comparison at each assessment time, but again did not adjust for type I error. Only 7 studies used methods suitable for repeated measurements: repeated measurement ANOVA, Generalized Estimating Equations (GEE), or Mixed Models (MM). As imputation procedures were never used for dealing with missing data, mm was the only method suitable when data were not missing completely at random but missing due to patients’ observable characteristics. Conclusions: Our results show a lack of consistency in statistical methods for analyzing QOL data from RCTs. Problems related to multiple comparisons were rarely considered leading to a high risk of false positive results. It is therefore critical that international recommendations for improving such statistical practices are developed.
First things first: Prevention, screening or care?
Authors: François Eisinger, Jerome Viguier, Alexis B. Cortot, Chantal Touboul, Jean-Yves Blay, Laurent Greillier, Christine Lhomel, Xavier B. Pivot, Sebastien Couraud, Jean F. Morere
Journal: Journal of Clinical Oncology (2016)

1550 Background: The main tools used in cancer control are prevention, early diagnosis and treatment. In the context of investment rationalization, different population subgroups are likely to have different priorities for resource allocation. We looked at the priorities of lay persons and physicians regarding this issue. Methods: The 4th French nationwide observational survey, EDIFICE 4, was conducted from June 12-July 10, 2014 by phone interviews of a representative sample of 1602 individuals (age 40-75 years). A mirror survey was also conducted by phone on a sample of 301 physicians (201 general practitioners [GPs] and 100 oncologists); both surveys used the quota method. Interviewees were asked to give their opinion on resource allocation for cancer prevention, screening and care. Answers were analyzed according to standard sociodemographic features. Results: Lay persons favor prevention (45%), and allocate similar priorities to care (29%) and diagnosis (26%). Age had a significant impact on prioritization of prevention. Compared to persons in the 40-49-year age range, older persons (70-75 years) were more likely to prioritize the funding of prevention (63% vs 35%, P < 0.01, Odd ratio: 3.13 [2.18–4.51]), at the expense of diagnosis (15% vs 32%, P < 0.01). Income category had a moderate impact on preferred allocation of resources (Chi2 = 18.55, P < 0.01). Prevention was a priority for 48% of respondents from the high income category ( > USD3300/month) vs. 41% of lower income category respondents ( < USD1100/month, NS). No statistically significant differences were observed between genders. Physicians (pooled GPs and oncologists) were even more likely than lay persons to give priority to prevention (64% vs 45%, P < 0.01) at the expense of diagnosis (7% vs 26%, P < 0.01). Lastly, there is one striking difference between GPs and oncologists, with 38% of the latter giving priority to care vs 24% of the former (P = 0.02). Conclusions: The present results show a strong demand from both physicians and laypersons for allocation of resources to cancer prevention. Lay persons’ preferences should be taken into account by healthcare policy makers even if responses in our survey are “naïve”, and based neither on education nor prior information about the efficacy or the anticipated impact.
Palliative care awareness among health care professionals in Nigeria.
Authors: Yinka Akinyemiju, Tracey L. O'Connor, Omolola Salako, Mutiu Jimoh, Chukwumere E. Nwogu
Journal: Journal of Clinical Oncology (2015)

e20548 Background: There has been a marked increase in the global incidence of cancer and HIV. In low to middle income countries like Nigeria, 70% of patients present late. With limited resources for treatment, palliative care is critical in improving the quality of life of these patients. In Nigeria, the awareness of palliative care is low. This study aims to assess the awareness of palliative care among some health care professionals in Lagos, Nigeria. Methods: A cross sectional questionnaire was distributed to 100 participants at a breast cancer workshop at a university teaching hospital in the major urban center in Nigeria. It sought information about the socio-demographic profile of the respondents as well as their palliative care knowledge, acceptance and challenges in their practices. Information obtained was entered and analyzed using SPSS version 16. Results: 71% of the questionnaires were completed. 52% of participants were male. The median age of participants was 40 years. 46% were general practitioners, 7% were nurses, and 47% were ancillary staff. 23% of the respondents work in teaching hospitals while the rest work in private hospitals.98% had heard of palliative care. 46% of the respondents manage patients with either cancer or HIV, out of which 72% had learnt some aspects of palliative care on the job without any formal training. 90% of the respondents desire training in palliative care. The most common challenges faced with establishing palliative care units were poor awareness, the lack of trained professionals and poor funding. Conclusions: Even though most physicians in Lagos are aware of what palliative care is, few offer it to patients or even refer patients for it. Most health care professionals are keen to be trained in palliative care and would welcome institutional programs. We recommend the introduction of palliative care principles in the Nigerian medical school curriculum as well as in most residency programs. However, the training of physicians currently in practice is crucial and can be accomplished through various seminars and workshops as part of continuing medical education programs. With such knowledge, physicians would be able to offer basic palliative care or refer patients to appropriate providers.
Dollars and Deadlines: Rule Reforms in Short Time Frames
Authors: Toby Schonfeld, Melinda Gormley, Daniel K. Nelson
Journal: The American Journal of Bioethics (2017)

In “At Last! Aye, and there’s the Rub,” (2017), Capron describes challenges related to the timing for development, adoption, and revision of the Common Rule. Capron argues that the difficulty of making changes over the ten years required before agencies adopted the original Common Rule created an “all or nothing” atmosphere. That is, because of the effort required, agencies were loath to make incremental changes and instead “take up every possible revision at once” with the process that culminated in the recently revised Rule. Here we briefly describe the efforts of one agency -- the U.S. Environmental Protection Agency (EPA) -- that made interim changes to its human subjects protections within a 180 day time frame, and the opportunities and challenges that such an ambitious goal created.
Trastuzumab (T) and pertuzumab (P)-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) in tyrosine kinase inhibitor (TKI)-treated breast cancer (BC) cell lines.
Authors: Denis Collins, Norma O'Donovan, Thamir Mahgoub, Kathy Gately, Clare Hughes, Anthony Davies, Kenneth O'Byrne, John Crown
Journal: Journal of Clinical Oncology (2014)

643 Background: Monoclonal antibody (mAb) therapy and TKI combinations are under investigation for the treatment of HER2-positive (HER2 gene amplification/IHC 3+/2+) BC. A further ~50% of BCs can be described as HER2-low (IHC 1+/2+/non-amplified). The HER2-targeted TKI lapatinib (LAP) can modulate HER2 levels and potentiate T-mediated ADCC in pre-clinical models. This study compares the effects of three HER2-targeted TKIs, LAP, neratinib (NER) and afatinib (AFAT) on HER2 levels in HER2-positive SKBR3 and HER2-low MCF-7 cells and examines the associated effects on T and P-induced ADCC in vitro. Methods: MCF-7 and SKBR3 were treated with LAP, NER or AFAT (0.2, 1 and 2µM, 48 hr). Membrane HER2 protein levels were determined by high content analysis (HCA) using an extracellular domain (ECD)-targeted antibody. A flow cytometry-based ADCC assay utilized TKI pre-treated SKBR3 and MCF-7 (2µM TKI, 48 hr) and healthy volunteer CD56+ NK cells or PBMCs. Results: LAP treatment increased HER2 in SKBR3 and MCF-7. Following LAP treatment, T and P-induced ADCC was increased in MCF-7 and reduced in SKBR3 using PBMCs.Using NK cells, T-induced ADCC was reduced in both LAP-treated cell lines.NER decreased HER2 expression in both cell lines but reduced T-related ADCC in MCF-7 only. AFAT reduced HER2 levels in SKBR3 cells only, but did not significantly reduce ADCC response in SKBR3 cells. (Table, *p< 0.05 relative to DMSO control). Conclusions: ADCC optimal TKI/mAb combinations may differ between HER2-positive and HER2-low models, and PBMC sub-populations other than NK cells may be required as mediators. Further pre-clinical assessment is required to elucidate the mechanisms of ADCC modulation by TKIs. SKBR3 MCF-7 Membrane HER2 (fold change) PBMC (5:1, PBMC:TC) % ADCC CD56+ (1:1, NK:TC) % ADCC Membrane HER2 (fold change) PBMC (5:1, PBMC:TC) % ADCC CD56+ (1:1, NK:TC) % ADCC TKI (2µM) ECD T P T P ECD T P T P LAP 1.4±0.2* 11±5* 10±6* 3±8* 9±4 1.6±0.2* 22±4* 9±1* 9±3* 8±2 NER 0.4±0.1* 24±4 21±7 28±4 29±9 0.5±0.1* 7±1* 0.8±1 10±1* 7±4 AFAT 0.5±0.1* 18±3 16±4 15±8 17±7 1.1±0.7 8±3 3±3 5±1* 3±1* DMSO 1.01±0.1 22±3 22±5 20±6 19±8 1.04±0.2 10±1 4±3 19±5 15±4
Abnormal Increase in a Distinct Subset of Nestin-Expressing Cells in the Bone Marrow of Myelodysplastic Syndromes
Authors: Luan Cao-Sy, Naoshi Obara, Tatsuhiro Sakamoto, Takayasu Kato, Hidekazu Nishikii, Mamiko Sakata-Yanagimoto, Shigeru Chiba
Journal: Blood (2016)
Strength of functional signature correlates with effect size in autism
Authors: Sara Ballouz, Jesse Gillis
Journal: Genome Medicine (2017)

Disagreements over genetic signatures associated with disease have been particularly prominent in the field of psychiatric genetics, creating a sharp divide between disease burdens attributed to common and rare variation, with study designs independently targeting each. Meta-analysis within each of these study designs is routine, whether using raw data or summary statistics, but combining results across study designs is atypical. However, tests of functional convergence are used across all study designs, where candidate gene sets are assessed for overlaps with previously known properties. This suggests one possible avenue for combining not study data, but the functional conclusions that they reach. In this work, we test for functional convergence in autism spectrum disorder (ASD) across different study types, and specifically whether the degree to which a gene is implicated in autism is correlated with the degree to which it drives functional convergence. Because different study designs are distinguishable by their differences in effect size, this also provides a unified means of incorporating the impact of study design into the analysis of convergence. We detected remarkably significant positive trends in aggregate (p < 2.2e-16) with 14 individually significant properties (false discovery rate <0.01), many in areas researchers have targeted based on different reasoning, such as the fragile X mental retardation protein (FMRP) interactor enrichment (false discovery rate 0.003). We are also able to detect novel technical effects and we see that network enrichment from protein–protein interaction data is heavily confounded with study design, arising readily in control data. We see a convergent functional signal for a subset of known and novel functions in ASD from all sources of genetic variation. Meta-analytic approaches explicitly accounting for different study designs can be adapted to other diseases to discover novel functional associations and increase statistical power.