dataesr/scientific-paragraphs-categorization huggingface dataset:
21  Complementary to MR-Egger, we also employed a weighted median method to derive causal-effect estimates. This method provides consistent estimates even when up to 50% of the analysed genetic variants are invalid IVs. We also employed a multivariable MR approach  22  to adjust for potential horizontal pleiotropy acting in particular through body mass index (BMI), because rs10741657 has been associated with BMI (P ¼ 0. 01) and BMI has been associated with 25(OH)D concentrations  23  and breast-cancer risk. 24 Publicly available genetic data for BMI were retrieved from the GIANT consortium for 339 000 individuals (95% were of European descent). 25 urther, we performed a sensitivity analysis in which we excluded one SNP at a time and performed IVW on the remaining five SNPs to identify the potential influence of outlying variants on the estimates.
Michailidou et al. 2017 Michailidou et al. 2017 Milne et al. 2017 Schumacher et al. 2018 Schumacher et al. 2018 a Novel vitamin D GWAS-identified SNPs, beta coefficients were extracted from the pooled analysis (discovery dataset þ replication dataset). ER, oestrogen receptor. The beta coefficients for the association between SNPs and circulating vitamin D are based on per effect allele per unit change in log 25(OH)D. To enable better comparison with results from observational studies, we ran MR analyses after transforming these beta coefficients into the natural scale (nmol/L) using a formula suggested by Rodriguez-Barranco et al. BMC Med Res Methodol 2017;17:44.
Polycyclic aromatic hydrocarbon (PAH) exposure is widespread, and many PAHs are considered carcinogenic. e PAHcontaminated AWI Superfund site in Virginia provides a model for studying a complex PAH mixture and its extrapolation to cancer risk and PAH exposure in the general population. We examined cancer risk at the Superfund site due to sediment-derived PAHs and then evaluated PAH sources in the general population and potentially vulnerable subpopulations upon PAH mixture exposure. e PAH mixture was assessed for potential carcinogenicity using the US EPA's OncoLogic ™ ranking tool and the US EPA list of priority PAHs. Cancer risk due to PAH exposure was calculated for Superfund site users and compared to the US EPA assessment. Human intake and health endpoints of PAHs within the mixture were extracted from USEtox ® chemical fate database, while mean intake exposure was calculated for U.
S. adults for select PAHs using NHANES database urinary biomarkers. Eleven PAH compounds within the mixture were of carcinogenic concern, and seven PAHs conveyed significant excess cancer risk at the Superfund site and in the general population, wherein PAH-contaminated seafood ingestion was a main contributor. Other dietary sources of PAHs derived from PAH-contaminated soil or water could also play a role in total exposure. Vulnerable populations to PAH exposure and coinciding increased cancer risk may include, in addition to smokers, children and non-Hispanic blacks, which is a public health concern.
US EPA OncoLogic ™ Carcinogenic Concern Analysis. PAH chemical components of the PAH Superfund mixture were individually run through the OncoLogic ™ carcinogenic concern ranking tool  [16] , which is structure-based. PAH components that were present in the database and contained only a marginal or negligible carcinogenic concern ranking were not included in the results. OncoLogic ™ uses structure-activity relationship (SAR) analysis to predict potential carcinogenicity, based upon structural-and biological-based carcinogenicity of various chemical classes. It incorporates both chemicalspecific input as well as knowledge-based rules developed by cancer and system development experts based on scientific publications and cancer studies. Carcinogenicity of mixture components were also assessed using the US EPA list of sixteen priority PAHs  [17].
USEtox ® Chemical Fate and Human Health Analysis. Environmental fate and human intake data were pulled for 7 of the 36 PAHs present in the Superfund site PAH mixture from the USEtox ® chemical fate modeling results database. ese 7 PAHs are the same as the COCs identified in the Superfund site risk assessment. Intake from fresh water, sea water, natural soil, and agricultural soil was summed to reflect a mixture of all 7 PAHs and can be found in Supplementary Table  3. is intake was distributed by exposure route: inhalation, drinking water, produce, meat and dairy, and fish. Human health characterization data were also pulled in the form of excess cancer cases per kg emitted and daily adjusted life years for each of the seven Superfund site sediment PAH COCs and pooled to reflect excess cancer cases due to PAH mixture exposure, dependent on the environmental compartment into which the mixture is emitted.
Human Intake Exposure Analysis. Metabolite concentrations for four select PAHs were obtained from a National Health and Nutrition Examination Survey (NHANES) database report  [25]. Concentrations were stratified into groups by gender (male/female), race (non-Hispanic white, non-Hispanic black, and Mexican American), and smoking status (smoker, nonsmoker, and exposed to secondhand smoke in the home). ese concentrations were reported as the unadjusted geometric means of the entire population measured from 2003 to 2008. ese PAHs are naphthalene, fluorene, phenanthrene, and pyrene, all present in high concentrations in the complex Superfund-derived PAH mixture. Excretion fractions of these PAHs in urine were obtained from the literature  [26, 27] , as well as standardized daily adult urine output  [28]  and adult body weight  [21].
Results and Discussion 3. 1. Polycyclic Aromatic Hydrocarbons Are Present in Superfund Sediment and Are Cancer Relevant. In order to assess the cancer relevance of our Superfund site PAH mixture, the 36 known PAH chemical components in the mixture  [30]  were assessed for potential carcinogenicity. Most importantly, we report the cancer relevance of many of the PAH chemicals in the AWI Superfund site sediment mixture based on rankings by the US EPA and the OncoLogic ™ database tool. All 16 PAH chemicals on the US EPA list of priority PAHs  [17]  were present in the AWI sediment mixture. Furthermore, several PAHs within this PAH mixture also ranked at least low or low-moderate carcinogenic concern level by the US EPA OncoLogic ™ ranking tool of carcinogenic concern (Table  2 ). Additionally, there may be potential synergy between PAH compounds with different biological targets.
PAH Intake Exposure Varies by Environmental Compartment Source. e AWI Superfund site is currently closed for remediation, although adjacent sites are under evaluation for similar PAH contamination levels. In addition, the mixture described previously from Superfund site sediment represents a complex PAH mixture which could be present anywhere in varying amounts, more broadly applicable to the wider human population. We next analyzed the PAH mixture for potential increase in cancer incidence in this larger human population. To do this, we utilized the USEtox ® PAH chemical fate database, and the fate sche- matic from emission to human intake used for the database calculations is shown in Figure  3(a). e PAH mixture Figure  1 : Indirect PAH exposure drives sediment-based cancer risk at the Superfund site.
(a) Schematic calculation design of the original Superfund site cancer risk assessment due to sediment exposure, whereas our assessment does not take into account indirect oral exposure. Also includes the seven PAH contaminants of concern in sediment utilized for the cancer risk assessment, both AWI and our assessment. (b) Total cancer risk calculated in the original AWI risk assessment at the Superfund site due to sediment exposure, with the percentage of that cancer risk due to PAH or other contaminant exposure. Cancer risk due to Superfund site sediment exposure as calculated in the original AWI Superfund site risk assessment (c) and as calculated in our direct exposure assessment (d) in this experiment. e largest cancer risk and DALY came from emission into household indoor air (data not shown), but fresh water also increased cancer cases and DALY based on PAH mixture emissions, followed in magnitude by sea water, agricultural soil, and natural soil (Figure  2(c) ).
Certain Demographic Subpopulations Have Higher PAH Exposure. Perhaps one of the most important considerations when analyzing PAH exposure is to analyze human subpopulations most at risk for exposure, for the greatest translation and impact on public health interventions. We conducted reverse dosimetry modeling to estimate PAH intake exposure based on urinary biomarkers of four PAHs (naphthalene, fluorene, phenanthrene, and pyrene) available in the U. S. CDC NHANES database. Urinary PAH biomarkers have previously been used to estimate exposure, and although PAHs vary seasonally and potentially by the time of urine collection, they provide us with a method to rank subpopulations in terms of exposure rather than just providing exposure quantitations. Additionally, NHANES provides the best available data on PAH biomarkers across a wide range of U.
Acknowledgments is research was supported in part by developmental funds from the  Duke Cancer Institute  ( P3917733  and  P30CA014236  to GRD) and  Department of Surgery Bolognesi Award  (to GRD). LMGS was supported by the training grant  NIEHS   T32-ES021432  and as part of the projects in  NIH  Award  P20CA202924  (to GRD).
with the increased cancer risk seen at the Superfund site due to USEtox ® chemical fate database intake factors revealed that PAH exposure in the general human population can occur contaminated sediment exposure. PAH mixture intake can also occur through drinking water and produce (Figure 2(b)). via multiple routes, and human exposure to PAHs varies us, lifestyle and diet factors can substantially impact an depending on where the PAH is emitted. For this study, we individual's exposure to these PAH chemicals. focused on soil and water matrices, closely applicable to our USEtox Superfund sediment-derived PAH mixture. For example, if the PAH mixture is emitted into continental fresh water, conti- nental sea water, or continental natural soil, the mixture is ® also allows analysis of midpoint and end- point human health effects due to chemical emission and exposure.
Acknowledgements. We are grateful to the anonymous referee for his/her careful reading of the manuscript. The authors acknowledge funding support from  French Research National Agency  ( CHAOS  project  ANR-12-BS05-0009  http://www. chaos-project. fr), Centre National de l'Enseignement Superieur (CNES)  and  Programme National des Hautes Energies (PNHE) in France. SC is supported by the  SERB National Postdoctoral  Fellowship (File No. PDF/2017/000841 ).
These data were enlightening, motivational, and realistic for a diverse group of trainees. Another well-appreciated aspect of the workshop was the use of quotes describing perceived barriers and successes of diverse trainees in pursuing academia and the personal journeys of the facilitators. Lastly, the participants enjoyed the proof of benefits of having diverse academic medicine faculty. It was important for our workshop to have both small-group and large-group discussions as these were validating for many students. There were several opportunities for improvement of the workshop. Some students felt that our presenters placed an emphasis on URM individuals and not enough on gender or sexual orientation. We also acknowledge that our presentation has a significant number of slides describing workforce demographics by race and ethnicity while there are fewer slides describing gender or sexual orientation.
Speakers are therefore encouraged to spend time describing ways of overcoming obstacles they have encountered in their personal journey. The workshop has been updated in response to several of the well-received comments by participants. The introduction has been updated to reflect more recent data. We are providing examples of data from our sources and as our projects become published. We suggest that facilitators download the most recent data, such as the annual report to date, to present more current data. For example, as referenced in slide 9 of the PPT, census data sources and the Association of American Medical Colleges' Faculty Roster can be used to update data on the racial/ethnic demographics of both the U. S. population and medical school faculty. We chose to report on data from 2012 because that was the most recent year for which we were able to secure data across subgroups (e.
In other words, IM creates completely new dimensions for data transmission. Since the initial skepticism of both academia and industry on the potential and applicability of IM technologies has now gone away, we strongly believe that IM is not another simple digital modulation alternative, but rather can be a game-changing communication paradigm whose time has come! There has been a tremendous interest in IM schemes over the past few years. Therefore, we decided to organize this IEEE ACCESS Special Section, which has been the first in the literature in this frontier, at the end of 2016. The aim of this IEEE ACCESS Special Section has been to provide a forum for the latest research and advances in the field of emerging IM techniques. With this purpose, we have accepted 23 highquality articles from leading research groups worldwide during the period of June 2017-January 2018.
Another problem that may have compromised the utility of tau measures was the use of different scanners and non-standardized white matter regions of interest. EXPEDITION3 also provided interesting data relevant to the use of amyloid positivity as an inclusion criterion for a clinical trial. For inclusion, participants had to have a positive amyloid scan as determined by a visual read. When PET scans for these participants were quantified using the typical metric of whole brain cortical-to-cerebellar standardized uptake value ratio (SUVR), the mean was 1. 51, whereas mild patients in EXPEDITION and EXPEDITION2 had mean SUVRs of only 1. 31, suggesting that clinically mild patients in EXPEDITION3 may have had more advanced pathology than those in EXPEDITION and EXPEDITION2. This observation suggests that small differences in amyloid load at baseline may have a significant impact on a trial, and that more precise methods for establishing inclusion criteria may be needed.
Increase of hippocampal atrophy in the treated group have also to be carefully studied The investigators concluded that amyloid production does not drive the ongoing disease process once patients have progressed to mild-moderate AD dementia. These results suggest that BACE inhibition is unlikely to be effective in patients who already have dementia. Indeed, animal data suggest that there is a critical window for BACE inhibition to rescue cognitive decline despite reductions in amyloid  (14). While more biomarker data are needed to better characterize the critical window, the results of the EPOCH trial suggest that BACE inhibition should be tested at an earlier stage of disease. A prodromal trial of verubecestat is fully enrolled. While the results of EPOCH suggest that the probability of success in this trial may be lower than originally believed, the rationale for looking at BACE inhibition at the prodromal stage of illness was that the disease might present a more tractable target for intervention when a lower burden of disease is present, and this remains an important hypothesis to test.
The objective of this analysis was to evaluate the change over time in age at first symptoms, age at diagnosis, and delay in diagnosis using data from the Icatibant Outcome Survey (IOS). Patients with a diagnosis of C1-INH-HAE who were born before the year 1990 and who were diagnosed before they reached 25 years of age were included in the analysis. Both age at diagnosis and delay in diagnosis of C1-INH-HAE appear to decline with later decade of birth, despite wide variation across the countries assessed, suggesting that improved disease awareness causes increased rates of earlier diagnosis over time. Our findings demonstrate that some patients are still experiencing long delays to diagnosis, indicating an ongoing need for improved disease awareness.
Although awareness of C1-INH-HAE has improved over recent decades, it is not clear if this has translated into earlier diagnosis. Here, we evaluated the change in age at first symptoms, age at diagnosis, and delay in diagnosis by decade of birth in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey (IOS). IOS is an ongoing, international, multicenter, prospective, observational study (NCT01034969) designed to monitor the safety and effectiveness of icatibant, a bradykinin B 2 receptor antagonist  [9]. As of January 2017, 11 countries (Austria, Brazil, Czech Republic, Denmark, France, Germany, Greece, Israel, Italy, Spain, and the United Kingdom) were involved in the registry. Participation is voluntary, at the discretion of the physician and the patient, and patients are managed under the direction of their physician in accordance with routine clinical practice.
Age at symptom onset remained unchanged irrespective of decade of birth (Fig. 2a-c ). Patients with a family history of C1-INH-HAE (n = 180; 72. 0%) had a median delay in diagnosis of 2. 0 years compared with 5. 6 years for those with no or unknown family history (p = 0. 0092). Our findings demonstrate improvements in C1-INH-HAE diagnosis over time, with patients now more frequently being diagnosed at a younger age, and with shorter delays between symptom onset and diagnosis. However, patients diagnosed prior to symptom onset were excluded from this analysis, precluding the evaluation of diagnosis rates for those with a family history of HAE. Though data from registries such as IOS provide a valuable source of real-world information, the voluntary nature of participation presents a number of limitations, including missing or incomplete data and potential selection bias.
Acknowledgements Under the direction of the authors,  Lindsay Napier, Ph. D. , and  Sally Hassan, Ph. D. , employees of Excel Medical Affairs, provided writing assistance for this publication. Editorial assistance in formatting, proofreading, copy editing, and fact checking also was provided by  Excel Medical Affairs. Shire HGT  provided funding to Excel Medical Affairs for support in writing and editing this manuscript. The interpretation of the data was made by the authors independently.
EGFR protein expression EGFR protein expression level has been assessed as a predictive biomarker for response to treatment with EGFR-directed mAbs in patients with NSCLC, including SqCLC. FLEX clinical trial. The phase III FLEX clinical trial (NCT00148798) assessed the efficacy of cetuximab, an EGFRdirected mAb for the treatment of patients with advanced NSCLC, including those with SqCLC histology  [23]. This trial compared cetuximab plus cisplatin-vinorelbine chemotherapy versus cisplatin-vinorelbine chemotherapy alone for the treatment of chemotherapy-naı ¨ve patients with advanced NSCLC that express EGFR in !1 positively immunostained tumor cell. Median OS was significantly increased by 1 month in patients treated with cetuximab plus chemotherapy compared with those who received chemotherapy alone [hazard ratio (HR)¼0.
99). Similarly, median OS was significantly increased by >2 months in patients with SqCLC in the EGFR-high group treated with cetuximab plus cisplatin-vinorelbine chemotherapy compared with cisplatin-vinorelbine chemotherapy alone (HR ¼ 0. 62; 95% CI 0. 43-0. 88) (Figure  1A ). Contrary to the findings from the retrospective FLEX analysis, however, a phase III study of patients with NSCLC treated with docetaxel or pemetrexed with or without cetuximab did not show an interaction between H-score (200 cut-off) and OS (P ¼ 0. 35) or progression-free survival (PFS) (P ¼ 0. 71), although other cut-offs were not evaluated and the evaluators differed from those who developed the classification  [27]. BMS099 clinical trial. In the phase III BMS099 clinical trial (NCT00112294), an accompanying trial to the FLEX trial that did not include restrictions on EGFR expression or histological subtypes, the addition of cetuximab to taxane-carboplatin chemotherapy significantly improved the overall response rate (ORR) compared with chemotherapy alone in patients with advanced NSCLC (25.
7% versus 17. 2%, respectively; P ¼ 0. 007)  [28]. Median OS was also improved, although this did not reach statistical significance [9. 69 months with cetuximab versus 8. 38 months in the taxanecarboplatin arm (HR ¼ 0. 89; 95% CI 0. 75-1. 05; P < 0. 1685)]. Improvement in PFS with the addition of cetuximab was only shown in a post hoc analysis of the SqCLC patient population (HR ¼ 0. 70; 95% CI 0. 47-1. 05). The contrasts in clinical benefit between the FLEX and BMS099 clinical trials supported the need for a biomarker for the selection of patients with NSCLC who would benefit from therapy with EGFR-directed mAbs. SQUIRE clinical trial. The phase III SQUIRE trial (NCT00981058) compared necitumumab plus gemcitabine and cisplatin chemotherapy versus chemotherapy alone in chemotherapy-naı ¨ve patients with advanced SqCLC  [25].
Biomarkers analyzed included KRAS and EGFR mutations, EGFR protein expression, and EGFR gene copy number. Mutations in KRAS and EGFR were found in 17% (35 of 202) and 10% (17 of 166) of patients, respectively. EGFR protein expression was detected in 89% of patients (131 of 148), and FISHþ (FISHþ defined as !40% cells with !4 EGFR copies and gene amplification in !10% of analyzed cells) was detected in 52% of patients (54 of 104). However, there was no significant association between response to treatment and EGFR expression, mutation, or copy number. Similar results for KRAS and EGFR mutations and EGFR gene copy numbers were reported in a retrospective analysis of the FLEX trial  [35]. SWOG 0819 clinical trial. The phase III SWOG 0819 trial (NCT00946712) compared cetuximab with carboplatin-paclitaxel chemotherapy versus carboplatin-paclitaxel chemotherapy alone in chemotherapy-naı ¨ve patients with advanced NSCLC  [36].
SQUIRE clinical trial (NCT00981058). In a pre-specified exploratory analysis of the phase III SQUIRE clinical trial that used FISH to assess EGFR gene expression, treatment with necitumumab plus cisplatin-gemcitabine versus cisplatin-gemcitabine alone was favored in patients in the EGFR FISHþ group (median OS 12. 6 versus 9. 2 months, respectively; HR ¼ 0. 70; 95% CI 0. 52-0. 96), but was not favored in those in the EGFR FISHgroup (11. 1 versus 10. 7 months, respectively; HR ¼ 1. 02; 95% CI 0. 80-1. 29) [30]. Taken together, results from subgroup analyses of phase III clinical trials support the use of EGFR expression and EGFR FISHþ as predictive biomarkers to aid in the selection of patients with advanced NSCLC, including SqCLC, who would derive the most benefit from clinical therapy with EGFR-directed mAbs cetuximab and necitumumab.
Based on these findings, guidelines now recommend that patients with advanced metastatic disease be tested for PD-L1 expression once diagnosed  [3]. However, routine implementation of PD-L1 testing in the clinical setting has been adversely affected by the different companion/complementary PD-L1 IHC assays that have been specifically developed for each of the approved anti-PD-1/anti-PD-L1 immunotherapies  [47]. A phase Ib study (NCT02451930) has recently completed assessing the efficacy and safety of pembrolizumab and NSCLC, non-small-cell lung cancer; PD-L1, programmed death ligand-1; SqCLC, squamous non-small-cell lung cancer.