tbuckley/cabot-search huggingface dataset:
Effect of dose-dependent interaction between tamoxifen and antidepressants on patient adherence in breast cancer patients.
Authors: F. W. Frueh, J. Tinnirello, M. Khalid, N. J. Markward, M. Subar, R. E. Aubert, R. S. Epstein
Journal: Journal of Clinical Oncology (2010)

558 Background: Tamoxifen is a selective estrogen receptor modulator (SERM) that is commonly used to treat breast cancer. However, despite its established efficacy, recent studies indicate that 1) more than 50 percent of individuals will discontinue treatment prior to completing the recommended five-year therapeutic regimen and 2) the likelihood of discontinuation is moderated by the presence of polymorphisms in the gene encoding cytochrome P450 2D6 (CYP2D6), the enzyme responsible for metabolizing tamoxifen into its active form. Methods: We measured tamoxifen persistency rates in a cohort of breast cancer patients to test the hypothesis that tamoxifen adherence is modified by the dose administered and concomitant use of anti-depressant (SSRI) drugs known to interfere with CYP2D6 metabolism. Study subjects (N = 12,742) were identified in a large transactional claims database, cross-classified by tamoxifen dose (HIGH, NORMAL) and SSRI status (YES, NO), and followed for 360 days after initiation of therapy. Results: Cox regression was used to generate covariate-adjusted hazard ratios and 95% confidence intervals for each treatment combination [NORMAL/YES = 1.17 (1.10, 1.24); HIGH/YES = 2.38 (1.86, 3.049); HIGH/NO = 3.27 (2.86, 3.74)] relative to the reference group (NORMAL/NO). The results indicate that patients who receive a high dose of tamoxifen are more likely to discontinue therapy than patients who receive the standard regimen. Moreover, CYP2D6 inhibitor drugs (SSRI) significantly improve medication adherence when prescribed in concert with a high dose of tamoxifen. Both findings are consistent with the observation that CYP2D6 extensive (vs. poor) metabolizers are less likely to tolerate a high dose of tamoxifen and, thus, more likely to discontinue therapy before the drug's protective benefits are realized. Conclusions: The study highlights the need for education and research regarding tamoxifen dosing and careful consideration for when SSRI medications should be prescribed to enhance patient tolerance of tamoxifen-related side effects. The results may also support a role for CYP2D6 genotyping in the context of tamoxifen-based treatment of breast cancer. No significant financial relationships to disclose.
Chronic HBV Infection Alters Monocytes Subpopulations, Monocytic CD163 Expression and Plasma sCD163
Authors: A. Parfieniuk-Kowerda, A. Eljaszewicz, K. Grubczak, M. Świderska, M. Maciaszek, P. Miklasz, J. Jaroszewicz, R. Flisiak, M. Moniuszko
Journal: Journal of Hepatology (2016)
A heparin-controlled study of MK-383 in unstable angina
Authors: P Theroux, HD White, D David, Frans Van de Werf, CA Nienaber, B Charbonnier, L Erhardt, J Gill, WS Hilis, G Jennings, LB Tan, N Deschenes, Fitzpatrick, FL Sax
Journal: Circulation (1994)
Handling of Activation Status of Human Hepatic Stellate Cells by Low-Molecular-Weight FGF2 via the Induction of Cytoglobin
Authors: M. Sato-Matsubara, T. Matsubara, A. Daikoku, K. Ikeda, K. Rombouts, M. Pinzani, N. Kawada
Journal: Journal of Hepatology (2016)
PTU-125 The prevalence of vitamin b12 deficiency in patients with oesophagogastric cancer: Abstract PTU-125 Table 1
Authors: A Champion, O Hynes
Journal: Gut (2015)

<h3>Introduction</h3> Vitamin B12 deficiency is a recognised problem in patients after surgery for OG cancer owing to the implications of surgery on gastric acid and intrinsic factor (IF) production (which are needed for Vitamin B12 metabolism). However it is postulated that for some patients with OG cancer their deficiency predates surgery. This study investigates the prevalence of preoperative Vitamin B12 deficiency in patients with OG cancer. <h3>Method</h3> A retrospective observational study was undertaken of patients who had surgery for OG cancer between January–December 2014. Active Vitamin B12 levels considered ‘borderline deficiency’ are sent for Methylmalonic acid (MMA) analysis. MMA levels above the normal range for age indicate deficiency. Weight loss data was also collected. <h3>Results</h3> Active Vitamin B12 ±MMA levels were available for 89 patients. 16% of patients had a proven Vitamin B12 deficiency. 27% of patients with Gastric Adenocarcinoma (AC) had a deficiency. Table 1Demographics, prevalence of Vitamin B12 deficiency and weight loss in the study: <h3>Conclusion</h3> OG cancer most commonly affects people &gt;65 years of age. The prevalence of Vitamin B12 deficiency increases with age. This is attributed to a reduction in stomach acid and pepsin production. However the study population has a higher prevalence of Vitamin B12 deficiency than the general population (65–74 years age 1 in 6 vs 1 in 20).<sup>1</sup>Implications of deficiency include anaemia, which can have significant consequences for surgery, but also symptoms such as fatigue; depression; problems with memory and understanding; all of which can negatively impact on patients’ Quality of Life. Deficiency can be masked as symptoms which may be attributed to the cancer and/or its treatment. Older age, weight loss and poor nutrition can contribute to Vitamin B12 deficiency in these patients with OG cancer. However 1/5 of the deficient subgroup had stable/gained weight suggesting other possible causes of deficiency such as the use of antacid medication. The high prevalence of Vitamin B12 deficiency in patients with Gastric AC maybe related to the possible presence of gastritis, leading to malabsorption of Vitamin B12, and undiagnosed Pernicious Anaemia; both of which are risk factors for Gastric cancer. Assessment of Vitamin B12 preoperatively is therefore an important component of nutritional assessment in OG cancer. <h3>Disclosure of interest</h3> None Declared. <h3>Reference</h3> Clarke, <i>et al</i>. Vitamin B12 and folate deficiency in later life. Age Ageing 2004;33:34–41
Genotype-Phenotype Analysis across 130,422 Genetic Variants Identifies Rspo3 as the First Genome-Wide Significant Modifier Gene in Primary Sclerosing Cholangitis
Authors: R. Alberts, E.M. de Vries, G. Alexander, D. Alvaro, A. Bergquist, U. Beuers, E. Björnsson, K.M. Boberg, C.L. Bowlus, R.W. Chapman, O. Chazouilléres, A. Cheung, G. Dalekos, B. Eksteen, J.E. Eaton, D. Ellinghaus, M. Färkkilä, E.A. Festen, A. Floreani, T. Folseraas, E. Goode, D.N. Gotthardt, G.M. Hirschfield, B. van Hoek, S. Hohenester, K. Holm, J.R. Hov, F. Imhann, P. Invernizzi, X. Jiang, B.D. Juran, K.N. Lazaridis, V. Leppa, J.Z. Liu, J. Löfberg, M.P. Manns, H.-U. Marschall, M. Marzioni, A.L. Mason, E. Melum, T. Müller, P. Milkiewicz, A. Pares, V. Pelkonen, M. Pinzani, K. Rombouts, C. Rupp, S.M. Rushbrook, C. Rust, F. Sampaziotis, R.N. Sandford, C. Schramm, S. Schreiber, E. Schrumpf, M. Silverberg, B. Srivastava, M. Sterneck, A. Teufel, L. Tittmann, L. Vallier, A.V. Vila, B.A. de Vries, T.J. Weismüller, C. Wijmenga, K. Zachou, A. Franke, C.A. Anderson, T.H. Karlsen, C.Y. Ponsioen, K. Weersma
Journal: Journal of Hepatology (2016)
PD-0019 Benefit of Panitumumab (pmab) as Monotherapy in Patients with WT KRAS mCRC: A Number-Needed-To-Treat (NNT) Analysis
Authors: Eric Van Cutsem, Alan Rong, Yves Humblet, Salvatore Siena, Stephan Braun, Roger Sidhu, Marc Peeters
Journal: Annals of Oncology (2012)
Pharmacology and safety factors affecting use of flat (rather than weight-based) dosing of tesetaxel, an orally administered taxane
Authors: R. P. Warrell, M. Beeram, E. Spindler, K. Papadopoulos, A. Patnaik, A. W. Tolcher
Journal: Journal of Clinical Oncology (2009)

2510 Background: As a class, taxanes have wide interpatient (pt) pharmacokinetic (PK) variability at their effective dose, which has been associated with adverse reactions, especially neutropenia. Tesetaxel is an oral taxane with Phase 2 activity in pretreated pts with colorectal, non-small cell lung, gastric, and breast cancers. Tesetaxel is not a substrate for P-glycoprotein; it is associated with lower neurotoxicity at equi-myelotoxic does, and it displays a long terminal half-life in plasma (∼180 hrs). We explored PK and clinical safety to determine the feasibility of using flat dosing in future studies. Methods: PK parameters were evaluated in 21 pts treated at the maximum tolerated dose (27 mg/m 2 ) either alone or in combination with capecitabine. We then compared actual dose (total mg) with the weight-based dose and correlated the incidence and severity of Grade 3–4 neutropenia with weight-based vs. flat dosing. Results: A total of 174 pts were treated with tesetaxel in Phase 2 trials at doses of 27 or 35 mg/m 2 once every 3 weeks. For pts prescribed with weight-based dosing (27 mg/m 2 ), mean C max in 3 separate cohorts was 24.6, 42.5, and 47.9 μg/L, with AUC 0-inf of 1363, 1592, and 1663 h*μg/L, respectively. In 103 pts prescribed a dose of 27 mg/m 2 , 17% and 16% of pts received doses of 40 mg or 60 mg, respectively, whereas 67% received 50 mg. Correlations between drug exposure AUC 0-inf and actual dose (mg and mg/m 2 ) across the entire range of administered doses showed r 2 values of 0.455 and 0.492, respectively. Similar correlations after a second repeat dose showed r 2 values of 0.731 and 0.653, respectively. The incidence of Grade 3–4 neutropenia at 27 mg/m 2 was 33%. Conclusions: PK and clinical safety suggest that weight-based dosing offers no substantial advantage compared with flat dosing. Future studies could incorporate a starting dose of 50 mg administered once every 3 weeks. Flat dosing should also be tested using different schedules, including weekly x 3 weeks and “metronomic dosing” (1–2 mg/d). [Table: see text]
Association Between Levels of High-Sensitivity C-Reactive Protein and General Psychological Distress Symptoms
Authors: Woojae Myung, Hong Choi, Chunsoo Lee, Jun Ro Lee, Bernard J. Carroll, Doh Kwan Kim
Journal: JAMA Psychiatry (2016)

2][3] A recent study reported that elevated levels of hs-CRP in the general population are associated with specific depressive symptoms of low energy, sleep disturbance, and appetite disturbance 3 ; however, common general psychological distress symptoms (GPDS) were not investigated.We tested the association between levels of hs-CRP and GPDS in the general population.Methods | We combined data on urban (n = 144 312) and rural (n = 6711) individuals from the Korean Genome and Epidemi-ology Study, conducted from January 1, 2004, to December 31, 2013, as well as those enrolled in the health check-up program at Samsung Medical Center (n = 63 014) from January 1, 2010, to December 31, 2014.A total of 214 037 ethnic Korean participants (mean [SD] age, 52.3 (9.7) years; male to female ratio, 4.0:6.0)were analyzed.Plasma levels of hs-CRP were measured using standard procedures (median, 0.61 mg/L; interquartile range, 0.37-1.25 mg/L) (to convert to nanomoles per liter, multiply by 9.524), and were log-transformed and standardized.General psychological distress symptoms were assessed using a validated 18-item scale (Table ). 4 We coded items as dichotomous variables with positive responses indicating clinically salient symptoms.
Differences in the C13orf25 miRNA Cluster in Non-Hodgkin Lymphoma and Normal B-Cell Subtypes.
Authors: Jan-Lukas Robertus, Miao Wang, Geert Harms, Tjasso Blokzijl, Rikst Nynke Schakel, Daphne de Jong, Rogier M. Reijmers, Steven T. Pals, Stefano Rosati, Ed Schuuring, Philip M. Kluin, Anke van den Berg
Journal: Blood (2007)
Clinicopathologic features of patients with breast cancer in a private oncology center in Brazil.
Authors: A. Boukai, N. Teich, F. M. Vieira, J. G. Musacchio, R. C. Helal, A. O. Victorino, I. Á. Small, M. Zukin, A. N. Assiz, D. D. Corrêa
Journal: Journal of Clinical Oncology (2010)

e12063 Background: Breast cancer is the most common female cancer in Brazil. According to the Brazilian National Cancer Institute, 49,240 new cases are estimated for the year 2010. Studies have shown that there are marked differences between patients treated by the private and public health system, especially on overall survival, diagnosis and staging. The objective of the present report is to determine the epidemiological characteristics and risk factors related to breast cancer observed in a private clinic in Rio de Janeiro, Brazil. Methods: We reviewed data from 550 patients with breast cancer treated in a Brazilian private oncology institution between 1999 and 2009. Results: In our series, clinical stage I, II, III and IV were 45%, 34%, 17% and 3%, respectively. Median age was 54 years, 61% were hormonal receptor positive, and 25% were HER2-positive with overexpression. After a median follow-up of 44 months, progression-free survival was 97%, 89% and 75% for stages I, II and III, respectively. The overall survival for these groups was 99%, 96%, 85%, and 40% for stage IV. Conclusions: Our findings were in agreement with actual worldwide literature and these patients had a similar prognosis to those treated in developed countries. No significant financial relationships to disclose.
Adherence to oral anticancer drugs (OAD) in patients (pts) with metastatic renal cancer (mRCC): First results of the prospective observational multicenter IPSOC study (Investigating Patient Satisfaction with Oral Anti-cancer Treatment).
Authors: Pascal Wolter, Tine Hendrickx, Vincent Renard, Jeroen Mebis, Philip R. Debruyne, Wim Wynendaele, Denis C. C. Schallier, Joanna Vermeij, Aldrik Nielander, Jean-Pascal H. Machiels, Sylvie Rottey, Stephanie Delande, Jean-Charles Goeminne, Patrick Schoffski, Sandra De Coster, Valerie Lacour, Veerle Foulon
Journal: Journal of Clinical Oncology (2012)

4622 Background: Patient adherence to oral therapy is a critical issue in cancer treatment. The aim of this study is to investigate the prevalence and severity of non-adherence to OAD in mRCC and to identify factors predictive of non-adherence. Methods: Prospective observational multicenter trial performed at 11 Belgian academic and non-academic centers. All pts with mRCC starting OADs (sunitinib, pazopanib, everolimus or sorafenib) are eligible for the study. Pts are contacted by phone at baseline and at 1, 3, 6 and 12 months. At each contact, pts are asked to complete questionnaires investigating 1) medication adherence (MMAS), 2) patient satisfaction with treatment (CTSQ) and with treatment education (PS-CaTE), 3) the extent of information desire (EID), 4) quality of life (FACT-G and FKSI) and 5) the role of the pharmacist (SWiP). Adherence is measured using an electronic medication event monitoring system (MEMS, Aardex). Results: Between 02/2011 and 11/2011, 49 pts (m: 33, f: 16) with a median age of 63 years (range 25 - 87) have participated in the IPSOC study. Twenty-nine pts (64%) were treated with an OAD in first-line, 15 pts (33%) in second-line. With a median follow-up of 131 days (range 2 - 313) 45 pts (92%) claimed to be fully adherent to their treatment (based on MMAS and CTSQ data). Four patients indicated to have missed at least one dose, of whom two indicated they occasionally forgot their medication and two others interrupted treatment because of side effects. Based on MEMS data, mean adherence, defined as the percentage of days with at least the prescribed number of dosage taken, was 98.91%. Conclusions: The IPSOC study, the first to examine adherence to OAD among mRCC pts, shows that mRCC pts are almost fully adherent to treatment recommendations. This seems to be in contrast to adherence data for other, long-lasting, anti-cancer treatments. Further investigations will focus on the question whether extensive counseling and participation in side-effect programs contribute to the high percentage of adherence in this study.
Development and Validation of a Risk Score System Inclusive of Antiviral Therapy for Predicting Liver Cirrhosis Risk in Diverse Patients with Chronic Hepatitis B Infection
Authors: M. Jin, H.-I. Yang, A.K. Le, M.-H. Lee, J. Hoang, N.H. Nguyen, D. Lin, H. Trinh, J. Li, J. Zhang, C.-J. Chen, M. Nguyen
Journal: Journal of Hepatology (2016)
Dichotomy of All-Trans Retinoic Acid Inducing Signals for Adult T-Cell Leukemia.
Authors: Yasuhiro Maeda, Terufumi Yamaguchi, Yasuki Hijikata, Yasuyoshi Morita, Chikara Hirase, Syunsuke Takai, Jun-ichi Miyatake, Mitsuhiro Matsuda, Akihisa Kanamaru
Journal: Blood (2005)
Crosstalk between Nucleotide Synthesis Pathways with Cellular Immunity in Constraining Hepatitis E Virus Replication
Authors: Y. Wang, W. Wang, L. Xu, X. Zhou, K. Felczak, L. Van Der Laan, K. Pankiewicz, D. Sprengers, H. Metselaar, M. Peppelenbosch, Q. Pan
Journal: Journal of Hepatology (2016)
Myosin light chains 9 and 12 are functional ligands for CD69 that regulate airway inflammation
Authors: Koji Hayashizaki, Motoko Y. Kimura, Koji Tokoyoda, Hiroyuki Hosokawa, Kenta Shinoda, Kiyoshi Hirahara, Tomomi Ichikawa, Atsushi Onodera, Asami Hanazawa, Chiaki Iwamura, Jungo Kakuta, Kenzo Muramoto, Shinichiro Motohashi, Damon J. Tumes, Tomohisa Iinuma, Heizaburo Yamamoto, Yuzuru Ikehara, Yoshitaka Okamoto, Toshinori Nakayama
Journal: Science Immunology (2016)

Recent decades have witnessed a rapid worldwide increase in chronic inflammatory disorders such as asthma. CD4+ T helper 2 cells play critical roles in the pathogenesis of allergic airway inflammation, and CD69 expression on activated CD4 T cells is required to induce allergic inflammation in tissues. However, how CD69 mechanistically controls allergic inflammation remains poorly defined. In lymphoid tissues, CD69 regulates cellular retention through inhibition of S1P1 expression and requires no specific ligands to function. In contrast, we show herein that myosin light chain (Myl) 9 and Myl12 are new functional ligands for CD69. Blockade of CD69-Myl9/12 interaction ameliorates allergic airway inflammation in ovalbumin-induced and house dust mite-induced mouse models of asthma. Within the inflamed mouse airways, we found that the expression of Myl9/12 was increased and that platelet-derived Myl9/12 localized to the luminal surface of blood vessels and formed intravascular net-like structures. Analysis of nasal polyps of eosinophilic chronic rhinosinusitis patients revealed that Myl9/12 expression was increased in inflammatory lesions and was distributed within net-like structures in the intravascular space. In addition, we detected Myl9/12 in perivascular spaces where many CD69+ cells were positioned within Myl9/12 structures. Thus, CD69-Myl9/12 interaction is a key event in the recruitment of activated CD69+ T cells to inflamed tissues and could be a therapeutic target for intractable airway inflammatory diseases.
Feasibiliy of Recruiting People who Inject Drugs into a Nurse-Led Model of Care Trial: The Tap Study
Authors: S. von Bibra, J.S. Doyle, P. Higgs, P. Dietze, P. Desmond, M. Stoove, E. McBryde, L. Burke, J. Lupi, M. Bryant, A.J. Thompson, M.E. Hellard
Journal: Journal of Hepatology (2016)
Platelet Adrenergic Receptor Dysfunction Is Associated with Both Aggregation and Adhesion Defects: Application of the Cone and Plate(let) Analyzer for Diagnosis and Monitoring of the Response to DDAVP Therapy.
Authors: David Varon, Jacob Luboshits, Gili Kenet, Boris Shenkman, Naphtali Savion, Aharon Lubetsky
Journal: Blood (2004)
Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine
Authors: James Nagarajah, Mina Le, Jeffrey A. Knauf, Giuseppe Ferrandino, Cristina Montero-Conde, Nagavarakishore Pillarsetty, Alexander Bolaender, Christopher Irwin, Gnana Prakasam Krishnamoorthy, Mahesh Saqcena, Steven M. Larson, Alan L. Ho, Venkatraman Seshan, Nobuya Ishii, Nancy Carrasco, Neal Rosen, Wolfgang A. Weber, James A. Fagin
Journal: Journal of Clinical Investigation (2016)

Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer. Although the MEK inhibitor selumetinib transiently inhibited ERK signaling, which subsequently rebounded, the MEK inhibitor CKI suppressed ERK signaling in a sustained manner by preventing RAF reactivation. A small increase in ERK inhibition markedly increased the expression of thyroid differentiation genes, increased iodide accumulation in cancer cells, and thereby improved responses to RAI therapy. Only a short exposure to the drug was necessary to obtain a maximal response to RAI. These data suggest that potent inhibition of ERK signaling is required to adequately induce iodide uptake and indicate that this is a promising strategy for the treatment of BRAF-mutant thyroid cancer.
Polatuzumab Vedotin Combined with Obinutuzumab, Cyclophosphamide, Doxorubicin, and Prednisone (G-CHP) for Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Preliminary Results of a Phase Ib/II Dose-Escalation Study
Authors: Andres Forero-Torres, Kathryn S. Kolibaba, Thierry Lamy, Surai Jones, Calvin Lee, Jeff Sharman
Journal: Blood (2016)
Delta-Like Homolog 1 (DLK1), Profibrogenic Protein Overexpressed in CCL4 Rat Liver Fibrosis
Authors: S. Carvajal, V. Reichenbach, D. Oró, S. Marfà, G. Fernández-Varo, S. Lamas, W. Jiménez
Journal: Journal of Hepatology (2016)
Add-On Peginterferon Alfa-2a Significantly Reduces HBsAg Levels in HBeAg-Negative, Genotype D Chronic Hepatitis B Patients Fully Suppressed on Nucleot(s)ide Analogues Treatment: Final Results of the Hermes Study
Authors: P. Lampertico, M.R. Brunetto, A. Craxi, G.B. Gaeta, M. Rizzetto, A. Rozzi, M. Colombo
Journal: Journal of Hepatology (2016)
How accurate is clinician reporting of chemotherapy side effects? A prospective study comparing clinician with patient-reported symptoms.
Authors: S. Ghosh, M. Van Hemelrijck, C. D. Holdridge, J. F. Gibson, P. J. Ross, J. Mansi, R. Lal, P. A. Ellis, P. G. Harper, S. Chowdhury
Journal: Journal of Clinical Oncology (2010)

9079 Background: There is increasing evidence that patient reporting is superior to that of clinicians when identifying treatment-related toxicities. This prospective study compares clinician and patient toxicity reporting of common chemotherapy toxicities. Methods: Patients were given a questionnaire to record the severity of chemotherapy-related toxicities. This questionnaire had been adapted from The Common Terminology Criteria for Adverse Events (CTCAE), which is used in our institute as a standard for grading toxicities. Medical records were analyzed to obtain the most recent toxicity grading reported by clinicians. The correlation between the toxicity scores by patients and doctors were examined using Cohen's weighted kappa. Results: 102 patients were recruited. The mean age was 58.5 years (range 21 to 89 years), with 43% being male. The percentage of patients treated for each malignancy was as follows: breast (35%), upper GI (19%), lung (19%), urological (19%), and gynecologic (9%). The majority of patients received chemotherapy on a 3 weekly cycle (81%). 46% of patients received platinum containing regimens and 21% taxanes. Compared to patient reporting, clinicians undergraded all toxicities. This was statistically significant for all toxicities. The toxicity reported with the greatest accuracy was diarrhea (Cohen's Kappa 0.56, p <0.001). The largest variations in reporting were observed for infection (Cohen's Kappa 0.20, p 0.001), performance status (Cohen's Kappa 0.21, p 0.010) and cystitis (Coheny's Kappa 0.21, p 0.021). Conclusions: The results of this study demonstrate that significant differences exist in toxicity reporting with clinicians undergrading all toxicities when compared to patient reporting. The study suggests that patient reporting of toxicities should be incorporated into standard practice. No significant financial relationships to disclose.