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Danielle Schubbe,1 Renata W Yen,1 Marie-Anne Durand1– 3 1The Dartmouth Institute for Health Policy and Clinical Practice, Dartmouth College, Lebanon, NH, USA; 2UMR 1295, CERPOP, Université de Toulouse, INSERM, Université Toulouse II Paul Sabatier, Toulouse, France; 3Unisanté, Centre universitaire de médecine générale et santé publique, Lausanne, CH-1011, SwitzerlandCorrespondence: Danielle SchubbeThe Dartmouth Institute for Health Policy and Clinical Practice, 1 Medical Center Drive, Williamson Translational Research Building, Level 5, Lebanon, NH, 03756, USATel +1 214 477-7986Email danielleschubbe@gmail.comBackground: Breast cancer is the second leading cause of death in women across the world. Despite significant improvements in overall breast cancer survival, disparities still exist. Research shows that socioeconomic position (SEP) plays a strong role in disparities in breast cancer care. Lower SEP can be a predictor of poorer breast cancer health outcomes and treatment received. No recent review has focused on SEP and breast cancer surgery outcomes. We conducted a rapid review assessing how patient SEP affects breast cancer surgical outcomes.Methods: We developed and ran the search strategy in Ovid MEDLINE in January 2021. We assessed study eligibility using an adapted version of PICOS criteria. We included observational studies that assessed the relationship between SEP and breast cancer surgery treatment, including outcomes like surgery choice, survival, and wait time to surgery. We independently reviewed each article and independently extracted data using a pre-designed form. One reviewer narratively synthesized the data extracted from the included articles.Results: We found twelve articles that met inclusion criteria. Eight out of 12 articles showed a difference in breast cancer surgery outcomes based on at least one measure of SEP. Six out of eight articles that collected surgery choice data found that women with lower SEP had lower rates of breast conserving surgery. One out of three articles that collected survival data found that higher SEP had a positive effect on survival. Additionally, one article that collected wait time to surgery data found a significant correlation between lower SEP and longer delays to surgical treatment.Conclusion: In conclusion, our rapid review of SEP and breast cancer surgery outcomes found that there is a relationship between SEP and breast cancer surgery choice. This rapid review did not find enough evidence to see a relationship with overall survival and wait time to surgery.Keywords: breast cancer, socioeconomic position, disparity, review

Purpose: Ependymomas are the third most common brain tumors in children. Standard of care is surgery followed by adjuvant radiation therapy. Controversy in the literature still exists over optimal radiation therapy dose. We completed a systematic review and meta-analysis to determine the optimal dose for local control (LC), event-free survival (EFS), and overall survival (OS) in pediatric patients., Methods and Materials: We searched MEDLINE (PubMed), Cochrane Database of Systematic Reviews, and Web of Science through January 2024. We included cohort studies that compared adjuvant radiation therapy of ≤54 Gy with >54 Gy in pediatric patients (≤22 years) with nonmetastatic intracranial ependymomas. We assessed study quality using the Newcastle-Ottawa Quality Assessment Scale of Cohort Studies. We pooled studies using a random effects meta-analysis for hazard ratios (HR), 95% confidence intervals (CI), and assessed statistical heterogeneity via I 2 . When HRs were unavailable, we transformed risks using established methods. We narratively summarized qualitative outcomes., Results: Seven studies met our inclusion criteria, covering a combined 1321 patients. Studies included a range of doses from 45 to 66.6 Gy. Compared with >54 Gy, we found no difference in LC for those receiving ≤54 Gy (HR, 0.83; 95% CI, 0.56-1.24; I 2 , 49.1%), in EFS (HR, 1.02; 95% CI, 0.95-1.09; I 2 , 0.00%), and OS (HR, 0.99; 95% CI, 0.82-1.20; I 2 , 37.5%). Two studies reported on subtotal resection by radiation therapy dose, neither study reporting statistical differences in LC, EFS, or OS, although the number of patients was small (n ≤ 30). Five studies reported on late effects, with brainstem radionecrosis, radiation-induced vasculopathy, and secondary tumors being the most frequent. Overall study quality was high, although lower scores were consistently seen in comparability of cohorts. To our knowledge, no studies reported on molecular subgroups., Conclusions: We found no difference in LC, EFS, or OS for those treated with ≤54 Gy compared with >54 Gy. There were insufficient data to complete a subgroup meta-analysis on radiation therapy dosing based on extent of resection or molecular subgroups., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The increasing number of immigrants in the United States (U.S.) has resulted in more patients with limited English proficiency (LEP). LEP contributes to patient-provider language discordance, which may impact oncologic health outcomes., Objectives: To assess the effects of LEP compared to English proficiency (EP) for oncological outcomes in adult cancer patients in the United States., Search Methods: We searched MEDLINE (Ovid), the Cochrane Library (Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials), PsycINFO, CINAHL and Scopus from data inception to 26 January 2023. We also searched the reference lists and cited lists of included studies. Studies were limited to the United States and the English language., Selection Criteria: We included retrospective and cross-sectional studies that analyzed one or more clinical outcomes (survival, readmission, length of stay, complications and discharge disposition) in LEP and EP cancer patients. Studies were eligible if they assessed cancer patients in the United States who were 18 years and older., Data Collection and Analysis: Using a piloted, standardized data collection form, two non-blinded, independent reviewers extracted data in duplicate from studies meeting our inclusion criteria. Reviewers resolved discrepancies through discussion. We then performed a qualitative assessment of the findings., Main Results: We retrieved 2425 records from the database searches. We screened 1496 records by title and abstract and reviewed the full text of eight records. We retrieved 347 records from additional search methods and reviewed the full text of six records. We included 14 papers in total for analysis. The studies included 55,141 total patients and assessed outcomes in brain, oesophageal, head and neck, pancreatic and skin cancer. Our qualitative assessment demonstrated limited information on whether LEP impacted survival, complications and discharge disposition. We found no significant association between LEP and readmission or length of stay., Conclusions: Studies assessing the impact of LEP and EP on the health outcomes of cancer patients are sparse and inconsistent in the measurements of outcomes and data reporting. The inconclusiveness of our study indicates that further standardized research is needed to assess the impact of LEP on the outcomes of cancer patients in the United States., (© 2024 John Wiley & Sons Ltd.)

Background: It is unknown whether the identification of additional tumors in the breast using preoperative magnetic resonance imaging (pMRI) results in a lower risk of in-breast tumor recurrence (IBTR) after breast-conserving surgery (BCS)., Methods: A systematic review and meta-analysis of relevant studies were performed. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines., Results: From 768 citations, 20 studies met the inclusion criteria for the systematic review. The 20 studies consisted of 14 retrospective reviews, 3 matched cohorts, and 3 randomized controlled trials. Whereas 2 studies reported a statistically significant lower rate of IBTR with pMRI, 18 studies showed no difference, and no studies reported a higher rate. Of the 18 studies showing no significant difference, 12 demonstrated a trend toward a lower IBTR rate in the pMRI group. The criteria for meta-analysis were met by 16 studies. A meta-analysis of 11 studies that reported hazard ratios (HR) for IBTR showed a trend toward a lower rate of IBTR for patients who received preoperative MRI (hazard ratio (HR), 0.89; 95% confidence interval (CI), 0.74-1.05). A meta-analysis of five studies that reported event rates and had similar follow-up duration for both groups demonstrated a lower relative risk (RR) of IBTR (RR, 0.45; 95% CI 0.25-0.81)., Conclusions: Although some evidence supports the hypothesis that identification of additional tumors in the breast using pMRI results in lower rates of IBTR after BCS, the main meta-analysis in this study did not confirm this hypothesis., (© 2024. Society of Surgical Oncology.)

Purpose: Good communication and use of plain language in health care encounters improve outcomes, including emotional health, symptom resolution, and functional status. Yet there is limited research on how to measure and report spoken plain language, which is the use of familiar, clear language. The authors aimed to describe key, measurable elements of spoken plain language that can be assessed and reported back to clinicians for self-reflection., Method: The authors conducted secondary analysis of transcripts from recorded encounters between breast cancer surgeons and patients with early-stage breast cancer. Two coders used a hybrid qualitative analysis with a framework based on U.S. Federal Plain Language Guidelines. To develop major themes, they examined (1) alignment with the Guidelines and (2) code frequencies within and across transcripts. They also noted minor themes., Results: From 74 transcripts featuring 13 surgeons, the authors identified 2 major themes representing measurable elements of spoken plain language: (1) clinicians had a propensity to use both explained and unexplained medical terms, and (2) clinicians delivered information using either short turns (one unit of someone speaking) with 1 topic or long turns with multiple topics. There were 3 minor themes that were not indicative of whether or not clinicians used spoken plain language. First, clinicians regularly used absolute risk communication techniques. Second, question-asking techniques varied and included open-ended, close-ended, and comprehension checks. Third, some clinicians used imagery to describe complex topics., Conclusions: Clinicians' propensity to use medical terms with and without explanation and parse encounters into shorter or longer turns are measurable elements of spoken plain language. These findings will support further research on the development of a tool that can be used in medical education and other settings. This tool could provide direct and specific feedback to improve the plain language practices of clinicians in training and beyond., (Copyright © 2024 the Association of American Medical Colleges.)

Background: Adherence is often a barrier to curative treatment of Mycobacterium tuberculosis (TB). There have been numerous interventions focused on increasing TB treatment adherence in Southeast Asia, but it is unclear if they are effective. This systematic review and meta-analysis aimed to compile and evaluate the literature on interventions designed to increase TB treatment adherence in Southeast Asia., Methods: We searched Cochrane Library Reviews (CDSR) and Cochrane Library Trials (CENTRAL), Medline, CINAHL, Scopus, and Web of Science from 2000 to 2022 with no language restrictions. We included studies of any design conducted in Southeast Asia that implemented interventions to increase treatment completion in people diagnosed with TB and assessed completion as an outcome. We did not require a control group. Four investigators used a standardized data collection form to collate results. The heterogeneity across studies was explored by I 2 statistics. We assessed bias using the Newcastle-Ottawa Scale and Cochrane ROB 2.0. We used a random effects meta-analysis to calculate a pooled risk ratio with 95% confidence intervals., Results: From 1881 abstracts, we included 14 articles. There were 7198 subjects with 3163 (44%) receiving a TB treatment adherence intervention across eight countries. Interventions included directly observed therapy, text-message reminders, food incentives, and more. The risk ratio, derived from the meta-analysis of eight included studies with a control group and 6618 participants overall, was 1.04 (95% CI 1.01,1.08; I 2  = 29%), favoring the interventions over controls with little concern for heterogeneity or risk of bias. When narratively assessed, the other six studies all reported increased adherence in the intervention group., Discussion: The results suggested there is a small, statistically significant benefit of using interventions to promote TB treatment completion. Future research could look at additional strategies and combinations of strategies to promote adherence., (Copyright © 2023 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Background: Shared decision making (SDM) in breast cancer care improves outcomes, but it is not routinely implemented. Results from the What Matters Most trial demonstrated that early-stage breast cancer surgery conversation aids, when used by surgeons after brief training, improved SDM and patient-reported outcomes. Trial surgeons and patients both encouraged using the conversation aids in routine care. We will develop and evaluate an online learning collaborative, called the SHared decision making Adoption Implementation Resource (SHAIR) Collaborative, to promote early-stage breast cancer surgery SDM by implementing the conversation aids into routine preoperative care. Learning collaboratives are known to be effective for quality improvement in clinical care, but no breast cancer learning collaborative currently exists. Our specific aims are to (1) provide the SHAIR Collaborative resources to clinical sites to use with eligible patients, (2) examine the relationship between the use of the SHAIR Collaborative resources and patient reach, and (3) promote the emergence of a sustained learning collaborative in this clinical field, building on a partnership with the American Society of Breast Surgeons (ASBrS)., Methods: We will conduct a two-phased implementation project: phase 1 pilot at five sites and phase 2 scale up at up to an additional 32 clinical sites across North America. The SHAIR Collaborative online platform will offer free access to conversation aids, training videos, electronic health record and patient portal integration guidance, a feedback dashboard, webinars, support center, and forum. We will use RE-AIM for data collection and evaluation. Our primary outcome is patient reach. Secondary data will include (1) patient-reported data from an optional, anonymous online survey, (2) number of active sites and interviews with site champions, (3) Normalization MeAsure Development questionnaire data from phase 1 sites, adaptations data utilizing the Framework for Reporting Adaptations and Modifications-Extended/-Implementation Strategies, and tracking implementation facilitating factors, and (4) progress on sustainability strategy and plans with ASBrS., Discussion: The SHAIR Collaborative will reach early-stage breast cancer patients across North America, evaluate patient-reported outcomes, engage up to 37 active sites, and potentially inform engagement factors affecting implementation success and may be sustained by ASBrS., (© 2023. The Author(s).)

There is a long-standing stigma associated with the use of epinephrine in digital nerve blocks (DNBs) over the concern of digital necrosis. We conducted a systematic review to assess the duration of anesthesia, onset of anesthesia, and complications of lidocaine with epinephrine compared with plain lidocaine for DNBs in adults. We searched Medline via Ovid, Cochrane Library, and ClinicalTrials.gov on January 28, 2020. We included randomized controlled trials that examined lidocaine with epinephrine 1:80,000 to 1:1,000,000 (1-12.5 µg/mL) and plain lidocaine for DNBs of fingers or toes in adults. We completed a blinded review of all unique articles, followed by full-text reviews, data extraction, and quality assessment of all eligible trials. Risk of bias was assessed to inform qualitative data analysis. We identified seven studies with a combined 363 adults and 442 DNBs that met the inclusion criteria. All five studies that reported duration of anesthesia established longer duration in the epinephrine-supplemented lidocaine group, with significant increases in three. Two of the three studies that reported the onset of anesthesia demonstrated significant differences. The two studies that reported complications did not have a single case of digital necrosis. In adults, the use of lidocaine with epinephrine 1:80,000 to 1:1,000,000 (1-12.5 µg/mL) for DNB yields a longer duration of anesthetic effect and seems to be as safe as plain lidocaine in healthy adults. Several studies had some concern for bias, and additional studies are warranted.

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Background: Clinical and real-world effectiveness data for the COVID-19 vaccines have shown that they are the best defense in preventing severe illness and death throughout the pandemic. However, in the US, some groups remain more hesitant than others about receiving COVID-19 vaccines. One important group is long-term care workers (LTCWs), especially because they risk infecting the vulnerable and clinically complex populations they serve. There is a lack of research about how best to increase vaccine confidence, especially in frontline LTCWs and healthcare staff. Our aims are to: (1) compare the impact of two interventions delivered online to enhanced usual practice on LTCW COVID-19 vaccine confidence and other pre-specified secondary outcomes, (2) determine if LTCWs' characteristics and other factors mediate and moderate the interventions' effect on study outcomes, and (3) explore the implementation characteristics, contexts, and processes needed to sustain a wider use of the interventions., Methods: We will conduct a three-arm randomized controlled effectiveness-implementation hybrid (type 2) trial, with randomization at the participant level. Arm 1 is a dialogue-based webinar intervention facilitated by a LTCW and a medical expert and guided by an evidence-based COVID-19 vaccine decision tool. Arm 2 is a curated social media web application intervention featuring interactive, dynamic content about COVID-19 and relevant vaccines. Arm 3 is enhanced usual practice, which directs participants to online public health information about COVID-19 vaccines. Participants will be recruited via online posts and advertisements, email invitations, and in-person visits to care settings. Trial data will be collected at four time points using online surveys. The primary outcome is COVID-19 vaccine confidence. Secondary outcomes include vaccine uptake, vaccine and booster intent for those unvaccinated, likelihood of recommending vaccination (both initial series and booster), feeling informed about the vaccines, identification of vaccine information and misinformation, and trust in COVID-19 vaccine information provided by different people and organizations. Exploration of intervention implementation will involve interviews with study participants and other stakeholders, an in-depth process evaluation, and testing during a subsequent sustainability phase., Discussion: Study findings will contribute new knowledge about how to increase COVID-19 vaccine confidence and effective informational modalities for LTCWs., Trial Registration: NCT05168800 at ClinicalTrials.gov, registered December 23, 2021., (© 2023. The Author(s).)

Objective: To conduct a scoping review of literature on the duration of patients' opening statements in clinical encounters, with or without an interruption., Methods: We conducted a scoping review to identify articles based on pre-specified inclusion and exclusion criteria. One reviewer extracted study details and outcomes related to the length of patients' opening statements. A second reviewer verified this data., Results: We included 14 studies from 1185 citations reviewed. Encounters were in primary care clinics, specialty clinics, and hospitals. Across six studies, the mean time to interruption was 18.2 s. The mean length of uninterrupted opening statements was 45.9 s across nine studies., Conclusion: Clinicians interrupting their patients' opening statements, compared to not interrupting, takes away time from the patient to fully present their concerns. Research has not focused on the nature of clinician interruptions. For instance, an interruption encouraging expansion or more detail facilitates understanding. Therefore, the impact these interruptions have on the clinical encounter remains unknown., Practice Implications: Interrupting the average patient does not save time, so clinicians may benefit from allowing their patients to complete their opening statements., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Shared decision making can help patients feel supported and empowered when deciding between healthcare options. Decision regret can be a meaningful measure of the quality of that encounter. However, in a patient-engaged research study examining shared decision making for breast cancer surgery, decision regret was a difficult construct to assess, and asking questions about decision regret caused the patient to experience that emotion upon reflection. In this article, we consider the complexity of decision regret, and discuss the difficulty of measuring that emotion through existing instruments. We call for clarity in definitions of decision regret and offer suggestions for developing a set of questions that can capture regret in a more meaningful way., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Racial disparities are a major issue in health care but the overall extent of the issue in spinal surgery outcomes is unclear. We conducted a systematic review/meta-analysis of disparities in outcomes among patients belonging to different racial groups who had undergone surgery for degenerative spine disease., Methods: We searched Ovid MEDLINE, Scopus, Cochrane Review Database, and ClinicalTrials.gov from inception to January 20, 2021 for relevant articles assessing outcomes after spine surgery stratified by race. We included studies that compared outcomes after spine surgery for degenerative disease among different racial groups., Results: We found 30 studies that met our inclusion criteria (28 articles and 2 published abstracts). We included data from 20 cohort studies in our meta-analysis (3,501,830 patients), which were assessed to have a high risk of observation/selection bias. Black patients had a 55% higher risk of dying after spine surgery compared with white patients (relative risk [RR], 1.55, 95% confidence interval [CI], 1.28-1.87; I 2  = 70%). Similarly, black patients had a longer length of stay (mean difference, 0.93 days; 95% CI, 0.75-1.10; I 2  = 73%), and higher risk of nonhome discharge (RR, 1.63; 95% CI, 1.47-1.81; I 2  = 89%), and 30-day readmission (RR, 1.45; 95% CI, 1.03-2.04; I 2  = 96%). No significant difference was noted in the pooled analyses for complication or reoperation rates., Conclusions: Black patients have a significantly higher risk of unfavorable outcomes after spine surgery compared with white patients. Further work in understanding the reasons for these disparities will help develop strategies to narrow the gap among the racial groups., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Shared decision-making is recommended for decisions with multiple reasonable options, yet clinicians often subtly or explicitly guide choices. Using purposive sampling, we performed a secondary analysis of 142 audio-recorded encounters between 13 surgeons and women eligible for breast-conserving surgery with radiation or mastectomy. We trained 9 surgeons in shared decision-making and provided them one of two conversation aids; 4 surgeons practiced as usual. Based on a published taxonomy of treatment recommendations (pronouncements, suggestions, proposals, offers, assertions), we examined how surgeons framed choices with patients. Many surgeons made assertions providing information and advice (usual care 71% vs. intervention 66%; p = 0.54). Some made strong pronouncements (usual care 51% vs. intervention 36%; p = .09). Few made proposals and offers, leaving the door open for deliberation (proposals usual care 21% vs. intervention 26%; p = 0.51; offers usual care 40% vs. intervention 40%; p = 0.98). Surgeons were significantly more likely to describe options as comparable when using a conversation aid, mentioning this in all intervention group encounters (usual care 64% vs. intervention 100%; p<0.001). Conversation aids can facilitate offers of comparable options, but other conversational actions can inhibit aspects of shared decision-making., Competing Interests: Marie-Anne Durand and Glyn Elwyn have developed the Option Grid patient decision aids, which are licensed to EBSCO Health. They receive consulting income from EBSCO Health and may receive royalties.

Background: The effectiveness of patient decision aids (PtDAs) and other shared decision-making (SDM) interventions for socially disadvantaged populations has not been well studied., Purpose: To assess whether PtDAs and other SDM interventions improve outcomes or decrease health inequalities among socially disadvantaged populations and determine the critical features of successful interventions., Data Sources: MEDLINE, CINAHL, Cochrane, PsycINFO, and Web of Science from inception to October 2019. Cochrane systematic reviews on PtDAs., Study Selection: Randomized controlled trials of PtDAs and SDM interventions that included socially disadvantaged populations., Data Extraction: Independent double data extraction using a standardized form and the Template for Intervention Description and Replication checklist., Data Synthesis: Twenty-five PtDA and 13 other SDM intervention trials met our inclusion criteria. Compared with usual care, PtDAs improved knowledge (mean difference = 13.91, 95% confidence interval [CI] 9.01, 18.82 [I 2 = 96%]) and patient-clinician communication (relative risk = 1.62, 95% CI 1.42, 1.84 [I 2 = 0%]). PtDAs reduced decisional conflict (mean difference = -9.59; 95% CI -18.94, -0.24 [I 2 = 84%]) and the proportion undecided (relative risk = 0.39; 95% CI 0.28, 0.53 [I 2 = 75%]). PtDAs did not affect anxiety (standardized mean difference = 0.02, 95% CI -0.22, 0.26 [I 2 = 70%]). Only 1 trial looked at clinical outcomes (hemoglobin A1C). Five of the 12 PtDA studies that compared outcomes by disadvantaged standing found that outcomes improved more for socially disadvantaged participants. No evidence indicated which intervention characteristics were most effective. Results were similar for SDM intervention trials., Limitations: Sixteen PtDA studies had an overall unclear risk of bias. Heterogeneity was high for most outcomes. Most studies only had short-term follow-up., Conclusions: PtDAs led to better outcomes among socially disadvantaged populations but did not reduce health inequalities. We could not determine which intervention features were most effective.[Box: see text].

Background: Many randomized controlled trials fail to reach their target sample size. When coupled with the omission and underrepresentation of disadvantaged groups in randomized controlled trials, many trials fail to obtain data that accurately represents the true diversity of their target population. Policies and practices have been implemented to increase representation of disadvantaged groups in many randomized controlled trials, with some trials specifically targeting such groups. To our knowledge, no systematic review has quantified the enrollment metrics and effectiveness of inclusion and retention strategies in randomized controlled trials focused on disadvantaged populations specifically., Methods: We will conduct a systematic search across EMBASE, MEDLINE, Web of Science, and CINAHL as well as grey literature, conference proceedings, research monographs, and Google Scholar from inception onwards. We will include randomized controlled trials where at least 50% of enrolled participants are considered to be disadvantaged, as per the RCT authors' definition and in line with our inclusion criteria. Two independent researchers per article will conduct preliminary title and abstract screening, subsequent full text review, and data extraction for the selected trials, with a third reviewer available to resolve conflicts. We will assess the quality of all included studies using specific criteria regarding data reporting, external validity, and internal validity. We will combine all selected studies and conduct a narrative synthesis to assess enrollment metrics. If there is sufficient homogeneity and sufficient trials comparing recruitment strategies within disadvantaged populations, we will conduct a random effects meta-analysis to evaluate the effectiveness of strategies designed to maximize the inclusion of disadvantaged populations in randomized controlled trials., Discussion: The findings of this systematic review will establish baseline recruitment and enrollment metrics of trials targeting disadvantaged populations to elucidate the scope of the challenge of recruiting such populations. We hope that our findings will promote future research on the distinct barriers that may prevent disadvantaged populations from participating in health intervention research, will encourage more trials exploring effective, tailored recruitment strategies, and will establish a foundation to track future progress in the recruitment of disadvantaged populations., Trial Registrations: PROSPERO ID: CRD42020152814., (© 2021. The Author(s).)

Background: Conversation aids can facilitate shared decision-making and improve patient-centered outcomes. However, few examples exist of sustained use of conversation aids in routine care due to numerous barriers at clinical and organizational levels. We explored factors that will promote the sustained use of two early-stage breast cancer conversation aids. We examined differences in opinions between the two conversation aids and across socioeconomic strata., Methods: We nested this study within a randomized controlled trial that demonstrated the effectiveness of two early-stage breast cancer surgery conversation aids, one text-based and one picture-based. These conversation aids facilitated more shared decision-making and improved the decision process, among other outcomes, across four health systems with socioeconomically diverse patient populations. We conducted semi-structured interviews with a purposive sample of patient participants across conversation aid assignment and socioeconomic status (SES) and collected observations and field notes. We interviewed trial surgeons and other stakeholders. Two independent coders conducted framework analysis using the NOrmalization MeAsure Development through Normalization Process Theory. We also conducted an inductive analysis. We conducted additional sub-analyses based on conversation aid assignment and patient SES., Results: We conducted 73 semi-structured interviews with 43 patients, 16 surgeons, and 14 stakeholders like nurses, cancer center directors, and electronic health record (EHR) experts. Patients and surgeons felt the conversation aids should be used in breast cancer care in the future and were open to various methods of giving and receiving the conversation aid (EHR, email, patient portal, before consultation). Patients of higher SES were more likely to note the conversation aids influenced their treatment discussion, while patients of lower SES noted more influence on their decision-making. Intervention surgeons reported using the conversation aids did not lengthen their typical consultation time. Most intervention surgeons felt using the conversation aids enhanced their usual care after using it a few times, and most patients felt it appeared part of their normal routine., Conclusions: Key factors that will guide the future sustained implementation of the conversation aids include adapting to existing clinical workflows, flexibility of use, patient characteristics, and communication preferences., Trial Registration: ClinicalTrials.gov Identifier: NCT03136367 , registered on May 2, 2017.

Background: Women of lower socioeconomic status (SES) with early-stage breast cancer are more likely to report poorer physician-patient communication, lower satisfaction with surgery, lower involvement in decision making, and higher decision regret compared to women of higher SES. The objective of this study was to understand how to support women across socioeconomic strata in making breast cancer surgery choices., Methods: We conducted a 3-arm (Option Grid, Picture Option Grid, and usual care), multisite, randomized controlled superiority trial with surgeon-level randomization. The Option Grid (text only) and Picture Option Grid (pictures plus text) conversation aids were evidence-based summaries of available breast cancer surgery options on paper. Decision quality (primary outcome), treatment choice, treatment intention, shared decision making (SDM), anxiety, quality of life, decision regret, and coordination of care were measured from T0 (pre-consultation) to T5 (1-year after surgery., Results: Sixteen surgeons saw 571 of 622 consented patients. Patients in the Picture Option Grid arm (n = 248) had higher knowledge (immediately after the visit [T2] and 1 week after surgery or within 2 weeks of the first postoperative visit [T3]), an improved decision process (T2 and T3), lower decision regret (T3), and more SDM (observed and self-reported) compared to usual care (n = 257). Patients in the Option Grid arm (n = 66) had higher decision process scores (T2 and T3), better coordination of care (12 weeks after surgery or within 2 weeks of the second postoperative visit [T4]), and more observed SDM (during the surgical visit [T1]) compared to usual care arm. Subgroup analyses suggested that the Picture Option Grid had more impact among women of lower SES and health literacy. Neither intervention affected concordance, treatment choice, or anxiety., Conclusions: Paper-based conversation aids improved key outcomes over usual care. The Picture Option Grid had more impact among disadvantaged patients., Lay Summary: The objective of this study was to understand how to help women with lower incomes or less formal education to make breast cancer surgery choices. Compared with usual care, a conversation aid with pictures and text led to higher knowledge. It improved the decision process and shared decision making (SDM) and lowered decision regret. A text-only conversation aid led to an improved decision process, more coordinated care, and higher SDM compared to usual care. The conversation aid with pictures was more helpful for women with lower income or less formal education. Conversation aids with pictures and text helped women make better breast cancer surgery choices., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: We examined self-reported financial toxicity and out-of-pocket expenses among adult women with breast cancer., Methods: Patients spoke English, Spanish, or Mandarin Chinese, were aged 18+ years, had stage I-IIIA breast cancer, and were eligible for breast-conserving and mastectomy surgery. Participants completed surveys about out-of-pocket costs and financial toxicity at 1 week, 12 weeks, and 1 year postsurgery., Results: Three hundred ninety-five of 448 eligible patients (88.2%) from the parent trial completed surveys. Excluding those reporting zero costs, crude mean ± SD out-of-pocket costs were $1,512 ± $2,074 at 1 week, $2,609 ± $6,369 at 12 weeks, and $3,308 ± $5,000 at 1 year postsurgery. Controlling for surgery, cancer stage, and demographics with surgeon and clinic as random effects, higher out-of-pocket costs were associated with higher financial toxicity 1 week and 12 weeks postsurgery (p < .001). Lower socioeconomic status (SES) was associated with lower out-of-pocket costs at each time point (p = .002-.013). One week postsurgery, participants with lower SES reported financial toxicity scores 1.02 points higher than participants with higher SES (95% confidence interval [CI], 0.08-1.95). Black and non-White/non-Black participants reported financial toxicity scores 1.91 (95% CI, 0.46-3.37) and 2.55 (95% CI, 1.11-3.99) points higher than White participants. Older (65+ years) participants reported financial toxicity scores 2.58 points lower than younger (<65 years) participants (95% CI, -3.41, -1.74). Younger participants reported significantly higher financial toxicity at each time point., Discussion: Younger age, non-White race, and lower SES were associated with higher financial toxicity regardless of costs. Out-of-pocket costs increased over time and were positively associated with financial toxicity. Future work should reduce the impact of cancer care costs among vulnerable groups., Implications for Practice: This study was one of the first to examine out-of-pocket costs and financial toxicity up to 1 year after breast cancer surgery. Younger age, Black race, race other than Black or White, and lower socioeconomic status were associated with higher financial toxicity. Findings highlight the importance of addressing patients' financial toxicity in several ways, particularly for groups vulnerable to its effects., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Objectives: Graphic display formats are often used to enhance health information. Yet limited attention has been paid to graph literacy in people of lower education and lower socioeconomic status (SES). This study aimed to: 1) examine the relationship between graph literacy, numeracy, health literacy and sociodemographic characteristics in a Medicaid-eligible population 2) determine the impact of graph literacy on comprehension and preference for different visual formats., Methods: We conducted a cross-sectional online survey among people in the US on Medicaid, and of presumed lower education and SES., Results: The mean graph literacy score among 436 participants was 1.47 (SD 1.05, range: 0 to 4). Only graph literacy was significantly associated with overall comprehension (p < .001). Mean comprehension scores were highest for the table format (1.91), closely followed by bar graph (1.85) and icon array (1.80). Information comprehension was aligned with preference scores., Conclusions: Graph literacy in a Medicaid-eligible population was lower than previous estimates in the US. Tables were better understood, with icon arrays yielding the lowest score. Preferences aligned with comprehension., Practice Implications: It may be necessary to reconsider the use of graphic display formats when designing information for people with lower educational levels. Further research is needed., Competing Interests: M-A D receives consulting income from EBSCO Health and may receive royalties in the future. She is also a consultant for ACCESS Community Health Network. GE has edited and published books that provide royalties on sales by the publishers: the books include Shared Decision Making (Oxford University Press) and Groups (Radcliffe Press). He has provided consultancy on patient support tools for organizations, the most recent being Emmi Solutions, National Quality Forum, and Washington State Health Department. He is the director of &think LLC, which owns the registered trademark for Option Grids patient decision aids. He currently provides consultancy to Access Community Health Network, and EBSCO Health Option GridsTM patient decision aids. He owns copyright in measures of shared decision making and care integration: collaboRATE, integRATE, consideRATE, and Observer OPTION-5 and Observer OPTION-12. These measures are freely available for use. No other competing interests declared. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: To determine if two encounter conversation aids for early-stage breast cancer surgery increased observed and patient-reported shared decision making (SDM) compared with usual care and if observed and patient-reported SDM were associated., Methods: Surgeons in a cluster randomized trial at four cancer centers were randomized to use an Option Grid, Picture Option Grid, or usual care. We used bivariate statistics, linear regression, and multilevel models to evaluate the influence of trial arm, patient socioeconomic status and health literacy on observed SDM (via OPTION-5) and patient-reported SDM (via collaboRATE)., Results: From 311 recordings, OPTION-5 scores were 73/100 for Option Grid (n = 40), 56.3/100 for Picture Option Grid (n = 144), and 41.0/100 for usual care (n = 127; p < 0.0001). Top collaboRATE scores were 81.6 % for Option Grid, 80.0 % for Picture Option Grid, and 56.4 % for usual care (p < 0.001). Top collaboRATE scores correlated with an 8.60 point (95 %CI 0.66, 13.7) higher OPTION-5 score (p = 0.008) with no correlation in the multilevel analysis. Patients of lower socioeconomic status had lower OPTION-5 scores before accounting for clustering., Conclusions: Both conversation aids led to meaningfully higher observed and patient-reported SDM. Observed and patient-reported SDM were not strongly correlated., Practice Implications: Healthcare providers could implement these conversation aids in real-world settings., Competing Interests: Declaration of Competing Interest GE has edited and published books that provide royalties on sales by the publishers: the books include Shared Decision Making (Oxford University Press) and Groups (Radcliffe Press). He owns copyright in measures of shared decision making and care integration, namely collaboRATE, integRATE (measure of care integration, consideRATE (patient experience of care in serious illness), coopeRATE (measure of goal setting), toleRATE (clinician attitude to shared decision making, Observer OPTION-5 and Observer OPTION-12 (observer measures of shared decision making). He has in the past provided consultancy for organizations, including: 1) Emmi Solutions LLC who developed patient decision support tools; 2) National Quality Forum on the certification of decision support tools; 3) Washington State Health Department on the certification of decision support tools; 4) SciMentum LLC, Amsterdam (workshops for shared decision making). He is the Founder and Director of &think LLC which owns the registered trademark for Option Grids™ patient decision aids; Founder and Director of SHARPNETWORK LLC, a provider of training for shared decision making. He provides advice in the domain of shared decision making and patient decision aids to: 1) Access Community Health Network, Chicago (Adviser to Federally Qualified Medical Centers); 2) EBSCO Health for Option Grids ™ patient decision aids (Consultant); 3) Bind On Demand Health Insurance (Consultant), 4) PatientWisdom Inc (Adviser); 5) abridge AI Inc (Chief Clinical Research Scientist). M-A D helped develop the Option Grid patient decision aids, which are licensed to EBSCO Health. She receives consulting income from EBSCO Health, and may receive royalties in the future. M-A D is a consultant for ACCESS Community Health Network. CHS holds copyright in The consideRATE Suite of tools. No other competing interests declared., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Assess the effect of pictorial health information on patients' and consumers' health behaviors and outcomes, evaluate these effects in lower health literacy populations, and examine the attributes of the interventions., Methods: We included randomized controlled trials (RCTs) that assessed the effect of pictorial health information on patient and consumer health behaviors and outcomes. We conducted a meta-analysis of RCTs that assessed knowledge/understanding, recall, or adherence, and a subgroup analysis of those outcomes on lower health literacy populations. We narratively reviewed characteristics of pictorial health interventions that significantly improved outcomes for lower health literacy populations., Results: From 4160 records, we included 54 RCTs (42 in meta-analysis). Pictorial health information moderately improved knowledge/understanding and recall overall, but largely increased knowledge/understanding for lower health literacy populations (n = 13), all with substantial heterogeneity. Icons with few words may be most helpful in conveying health information., Conclusion: Our results support including pictures in health communication to improve patient knowledge. Our results should be interpreted with caution considering the significant heterogeneity of the meta-analysis outcomes., Practice Implications: Future research should assess which types and characteristics of pictures that best convey health information and are most useful and the implementation and sustainability in healthcare contexts., Systematic Review Registration: PROSPERO CRD42018084743., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background. Patients frequently worry about care costs, but clinicians seldom address the topic. Cost information is not typically included in patient decision aids (DAs). We examined whether including cost information in an encounter DA, with clinician training, influenced cost conversations. Method. As part of a larger trial, 14 surgeons from 4 cancer centers were randomized to 1 of 3 interventions: (1) Picture Option Grid DA that included a prompt to discuss relative treatment costs, hereafter called "cost prompt group"; (2) a text-only Option Grid DA that did not include cost information; (3) usual care. Groups 2 and 3 hereafter are referred to as "non-cost prompt groups." Adult (18+) female patients, with stages I-IIIA breast cancer, eligible for both breast-conserving surgery and mastectomy were included. We gave surgeons feedback about adherence to the study protocol at 3, 6, and 12-months. We adapted a checklist to code the content of the audio-recorded clinical encounters. Results. 424/622 (68%) patients consented; 311 (73%) were eligible and successfully recorded (143 in the cost prompt group, 168 in the non-cost prompt groups). Costs were discussed in 132/311 (42.4%) encounters, and occurred more often in the cost prompt versus non-cost prompt groups (66.7% versus 33.3%; p<.001). Surgeons initiated the cost discussion in 86.4% of encounters in the cost prompt group vs. 34.1% in the non-cost prompt groups (p<0.001). In the non-cost prompt groups, insurance or employment questions led patients to ask about costs. Cost discussions lasted about 34 seconds when present and had sparse comparative details. Conclusions. Encounter DAs containing cost information trigger cost discussions. Additional support should help clinicians improve the quality of cost discussions and address financial distress.

Introduction. We aimed to conduct a multinational cross-sectional online survey of medical students' attitudes toward, knowledge of, and experience with shared decision making (SDM). Methods. We conducted the survey from September 2016 until May 2017 using the following: 1) a convenience sample of students from four medical schools each in Canada, the United States, and the Netherlands ( n = 12), and 2) all medical schools in the United Kingdom through the British Medical School Council ( n = 32). We also distributed the survey through social media. Results. A total of 765 students read the information sheet and 619 completed the survey. Average age was 24, 69% were female. Mean SDM knowledge score was 83.6% (range = 18.8% to 100%; 95% confidence interval [CI] = 82.8% to 84.5%). US students had the highest knowledge scores (86.2%, 95% CI = 84.8% to 87.6%). The mean risk communication score was 57.4% (range = 0% to 100%; 95% CI = 57.4% to 60.1%). Knowledge did not vary with age, race, gender, school, or school year. Attitudes were positive, except 46% believed SDM could only be done with higher educated patients, and 80.9% disagreed that physician payment should be linked to SDM performance (increased with years in training, P < 0.05). Attitudes did not vary due to any tested variable. Students indicated they were more likely than experienced clinicians to practice SDM (72.1% v. 48.8%). A total of 74.7% reported prior SDM training and 82.8% were interested in learning more about SDM. Discussion. SDM knowledge is high among medical students in all four countries. Risk communication is less well understood. Attitudes indicate that further research is needed to understand how medical schools deliver and integrate SDM training into existing curricula., (© The Author(s) 2019.)

UHRF1 facilitates the establishment and maintenance of DNA methylation patterns in mammalian cells. The establishment domains are defined, including E3 ligase function, but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1 histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintain cancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disrupting either chromatin reader activity reverses DNA hypermethylation, reactivates epigenetically silenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover, an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progression and reduced patient survival. Defining critical UHRF1 domain functions and its relationship with CRC prognosis suggests directions for, and value of, targeting this protein to develop therapeutic DNA demethylating agents., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We addressed the precursor role of aging-like spontaneous promoter DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show that promoter hypermethylation spontaneously arises in cells mimicking the human aging-like phenotype. The silenced genes activate the Wnt pathway, causing a stem-like state and differentiation defects. These changes render aged organoids profoundly more sensitive than young ones to transformation by Braf V600E , producing the typical human proximal BRAF V600E -driven colon adenocarcinomas characterized by extensive, abnormal gene-promoter CpG-island methylation, or the methylator phenotype (CIMP). Conversely, CRISPR-mediated simultaneous inactivation of a panel of the silenced genes markedly sensitizes to Braf V600E -induced transformation. Our studies tightly link aging-like epigenetic abnormalities to intestinal cell fate changes and predisposition to oncogene-driven colon tumorigenesis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction. Breast cancer is the second most common malignancy in women. The Decision Quality Instrument (DQI) measures the extent to which patients are informed and involved in breast surgery decisions and receive treatment that aligns with their preferences. There are limited data on the performance of the DQI in women of lower socioeconomic status (SES). Our aims were to 1) examine (and if necessary adapt) the readability, usability, and acceptability of the DQI and 2) explore whether it captures factors important to breast cancer surgery decisions among women of lower SES (relevance). Methods. We conducted semistructured cognitive interviews with women of lower SES (based on insurance status, income, and education) who had completed early-stage breast cancer treatments at three cancer centers. We used a two-step thematic analysis with dual independent coding. The study team (including Patient Partners and a Community Advisory Board) reviewed and refined suggested changes. The revised DQI was presented in two focus groups of breast cancer survivors. Results. We conducted 39 interviews. Participants found most parts of the DQI to be helpful and easy to understand. We made the following suggested changes: 1) added a glossary of key terms, 2) added two answer choices and an open text question in the goals and concerns subscale, 3) reworded the treatment intention question, and 4) revised the knowledge subscale instructions since several women disliked the wording and were unsure of what was expected. Discussion. The readability, usability, acceptability, and relevance of a measure that was primarily developed and validated in women of higher SES required adaptation for optimal use by women of lower SES. Further research will test these adaptations in lower SES populations., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: GE and M-AD have developed the Option Grid patient decision aids, which are licensed to EBSCO Health. They receive consulting income from EBSCO Health and may receive royalties in the future. M-AD is a consultant for ACCESS Community Health Network. KS receives salary support as a member of the scientific advisory board for Healthwise, a not-for-profit foundation that develops and distributes patient education and decision support materials. MCP received a speaker fee from Merck & Co. and as a research contract from Merck, both unrelated to this study or manuscript. The other authors have no conflicts of interest to disclose.

Objective: Shared decision making (SDM) training is shown to be effective and is increasingly embedded in continuing medical education. There is little evidence, however, about undergraduate medical education for SDM. The aim of this scoping review was to identify existing SDM training embedded in the undergraduate medical curriculum and analyze their impact., Methods: The authors systematically searched the extant literature for peer reviewed articles, hand searched key journals and reference lists of key articles, and contacted relevant stakeholders as part of a key informant analysis., Results: Included in the qualitative synthesis were 12 studies evaluating 11 SDM courses in medical education across six countries. Most courses integrated SDM training in clinical clerkship and varied in length from one to seven hours. The majority of studies assessed course impact on students' skills in SDM. Most studies suggested that students' skills and confidence in SDM significantly increased post-training, but three studies reported no significant improvement in SDM. Ten courses continue to be taught routinely., Conclusion: Overall, studies suggested a positive impact on medical students' skills, confidence, and attitudes regarding SDM. Embedding SDM training in undergraduate medical education may be a practical and effective solution for current barriers to the widespread adoption of SDM., Competing Interests: Glyn Elwyn and Marie-Anne Durand have developed the Option Grid patient decision aids, which are licensed to EBSCO Health. They receive consulting income from EBSCO Health, and may receive royalties in the future. Glyn Elwyn and Marie-Anne Durand are consultants for ACCESS Community Health Network. No other competing interests are declared. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: In this study, we aim to compare shared decision-making (SDM) knowledge and attitudes between US-based physician assistants (PAs), nurse practitioners (NPs) and physicians across surgical and family medicine specialties., Setting: We administered a cross-sectional, web-based survey between 20 September 2017 and 1 November 2017., Participants: 272 US-based NPs, PA and physicians completed the survey. 250 physicians were sent a generic email invitation to participate, of whom 100 completed the survey. 3300 NPs and PAs were invited, among whom 172 completed the survey. Individuals who met the following exclusion criteria were excluded from participation: (1) lack of English proficiency; (2) area of practice other than family medicine or surgery; (3) licensure other than physician, PA or NP; (4) practicing in a country other than the US., Results: We found few substantial differences in SDM knowledge and attitudes across clinician types, revealing positive attitudes across the sample paired with low to moderate knowledge. Family medicine professionals (PAs) were most knowledgeable on several items. Very few respondents (3%; 95% CI 1.5% to 6.2%) favoured a paternalistic approach to decision-making., Conclusions: Recent policy-level promotion of SDM may have influenced positive clinician attitudes towards SDM. Positive attitudes despite limited knowledge warrant SDM training across occupations and specialties, while encouraging all clinicians to promote SDM. Given positive attitudes and similar knowledge across clinician types, we recommend that SDM is not confined to the patient-physician dyad but instead advocated among other health professionals., Competing Interests: Competing interests: M-AD was involved in developing the Option Grid patient decision aids, which are licensed to EBSCO Health. She receives consulting income from EBSCO Health and may receive royalties in the future. M-AD is also a consultant for ACCESS Community Health Network and delivers shared decision making training to ACCESS clinicians. GE has edited and published books that provide royalties on sales by the publishers: the books include Shared Decision Making (Oxford University Press) and Groups (Radcliffe Press). He has in the past provided consultancy for (1) Emmi Solutions LLC who develop patient decision support tools; (2) National Quality Forum on the certification of decision support tools; (3) Washington State Health Department on the certification of decision support tools; (4) SciMentum LLC, Amsterdam (workshops for shared decision making). GE is Director of &think LLC which owns the registered trademark for Option GridsTM patient decision aids. He provides consultancy in the domain of shared decision making and patient decision aids to: (1) Access Community Health Network, Chicago (Federally Qualified Medical Centers) and to (2) EBSCO Health Option GridsTM patient decision aids. GE initiated the Option Grid Collaborative, tools that are hosted on a website managed by Dartmouth College, on http://optiongrid.org/). Existing Option Grids hosted at this website are freely available until such time as the tools have expired. He owns copyright in measures of shared decision making and care integration, namely CollaboRATE, IntegRATE and Observer OPTION. These measures are freely available for use., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Most health information is verbal or written, yet words alone may not be the most effective way to communicate health information. Lower health literacy is prevalent in the US and is linked to limited understanding of one's medical condition and treatment. Pictures increase comprehension, recall, adherence and attention in health settings. This is called pictorial superiority. No systematic review has examined the impact of pictorial health information among patients and consumers, including those with lower health literacy., Methods and Analysis: This systematic review and meta-analysis will assess the characteristics and effectiveness of pictorial health information on patient and consumer health behaviours and outcomes, as well as differentially among individuals of lower literacy/lower health literacy. We will conduct a systematic search across selected databases, as well as grey literature, from inception until June 2018. We will include randomised controlled trials in all languages with all types of participants that assess the effect of pictorial health information on patients' and consumers' health behaviours and outcomes. Two independent reviewers will conduct the primary screening of articles and data extraction for the selected articles with a third individual available to resolve conflicts. We will assess the quality of all included studies using the Cochrane risk of bias tool. We will combine all selected studies and do a test of heterogeneity. If there is sufficient homogeneity, we will pool studies into a meta-analysis. Independent of the heterogeneity of included studies, we will also conduct a narrative synthesis., Ethics and Dissemination: No ethics approval is required. The results will be published in a peer-reviewed journal and presented at relevant conferences., Prospero Registration Number: CRD42018084743., Competing Interests: Competing interests: M-AD has developed the Option Grid patient decision aids, which are licensed to EBSCO Health. She receives consulting income from EBSCO Health and may receive royalties in the future. M-AD is a consultant for ACCESS Community Health Network., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Breast cancer is the most commonly diagnosed malignancy in women. Mastectomy and breast-conserving surgery (BCS) have equivalent survival for early stage breast cancer. However, each surgery has different benefits and harms that women may value differently. Women of lower socioeconomic status (SES) diagnosed with early stage breast cancer are more likely to experience poorer doctor-patient communication, lower satisfaction with surgery and decision-making, and higher decision regret compared to women of higher SES. They often play a more passive role in decision-making and are less likely to undergo BCS. Our aim is to understand how best to support women of lower SES in making decisions about early stage breast cancer treatments and to reduce disparities in decision quality across socioeconomic strata., Methods: We will conduct a three-arm, multi-site randomized controlled superiority trial with stratification by SES and clinician-level randomization. At four large cancer centers in the United States, 1100 patients (half higher SES and half lower SES) will be randomized to: (1) Option Grid, (2) Picture Option Grid, or (3) usual care. Interviews, field-notes, and observations will be used to explore strategies that promote the interventions' sustained use and dissemination. Community-Based Participatory Research will be used throughout. We will include women aged at least 18 years of age with a confirmed diagnosis of early stage breast cancer (I to IIIA) from both higher and lower SES, provided they speak English, Spanish, or Mandarin Chinese. Our primary outcome measure is the 16-item validated Decision Quality Instrument. We will use a regression framework, mediation analyses, and multiple informants analysis. Heterogeneity of treatment effects analyses for SES, age, ethnicity, race, literacy, language, and study site will be performed., Discussion: Currently, women of lower SES are more likely to make treatment decisions based on incomplete or uninformed preferences, potentially leading to poorer decision quality, quality of life, and decision regret. This study hopes to identify solutions that effectively improve patient-centered care across socioeconomic strata and reduce disparities in decision and care quality., Trial Registration: NCT03136367 at ClinicalTrials.gov Protocol version: Manuscript based on study protocol version 2.2, 7 November 2017.

Overall shared DNA methylation patterns between senescence (Sen) and cancers have led to the model that tumor-promoting epigenetic patterns arise through senescence. We show that transformation-associated methylation changes arise stochastically and independently of programmatic changes during senescence. Promoter hypermethylation events in transformation involve primarily pro-survival and developmental genes, similarly modified in primary tumors. Senescence-associated hypermethylation mainly involves metabolic regulators and appears early in proliferating "near-senescent" cells, which can be immortalized but are refractory to transformation. Importantly, a subset of transformation-associated hypermethylated developmental genes exhibits highest methylation gains at all age-associated cancer risk states across tissue types. These epigenetic changes favoring cell self-renewal and survival, arising during tissue aging, are fundamentally important for stratifying cancer risk and concepts for cancer prevention., (Copyright © 2018 Elsevier Inc. All rights reserved.)

An oncogenic role for CHD4, a NuRD component, is defined for initiating and supporting tumor suppressor gene (TSG) silencing in human colorectal cancer. CHD4 recruits repressive chromatin proteins to sites of DNA damage repair, including DNA methyltransferases where it imposes de novo DNA methylation. At TSGs, CHD4 retention helps maintain DNA hypermethylation-associated transcriptional silencing. CHD4 is recruited by the excision repair protein OGG1 for oxidative damage to interact with the damage-induced base 8-hydroxydeoxyguanosine (8-OHdG), while ZMYND8 recruits it to double-strand breaks. CHD4 knockdown activates silenced TSGs, revealing their role for blunting colorectal cancer cell proliferation, invasion, and metastases. High CHD4 and 8-OHdG levels plus low expression of TSGs strongly correlates with early disease recurrence and decreased overall survival., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In vitro human tissue engineered human blood vessels (TEBV) that exhibit vasoactivity can be used to test human toxicity of pharmaceutical drug candidates prior to pre-clinical animal studies. TEBVs with 400-800 μM diameters were made by embedding human neonatal dermal fibroblasts or human bone marrow-derived mesenchymal stem cells in dense collagen gel. TEBVs were mechanically strong enough to allow endothelialization and perfusion at physiological shear stresses within 3 hours after fabrication. After 1 week of perfusion, TEBVs exhibited endothelial release of nitric oxide, phenylephrine-induced vasoconstriction, and acetylcholine-induced vasodilation, all of which were maintained up to 5 weeks in culture. Vasodilation was blocked with the addition of the nitric oxide synthase inhibitor L-N(G)-Nitroarginine methyl ester (L-NAME). TEBVs elicited reversible activation to acute inflammatory stimulation by TNF-α which had a transient effect upon acetylcholine-induced relaxation, and exhibited dose-dependent vasodilation in response to caffeine and theophylline. Treatment of TEBVs with 1 μM lovastatin for three days prior to addition of Tumor necrosis factor - α (TNF-α) blocked the injury response and maintained vasodilation. These results indicate the potential to develop a rapidly-producible, endothelialized TEBV for microphysiological systems capable of producing physiological responses to both pharmaceutical and immunological stimuli.

Epigenetic therapy is emerging as a potential therapy for solid tumors. To investigate its mechanism of action, we performed integrative expression and methylation analysis of 63 cancer cell lines (breast, colorectal, and ovarian) after treatment with the DNA methyltransferase inhibitor 5-azacitidine (AZA). Gene Set Enrichment Analysis demonstrated significant enrichment for immunomodulatory pathways in all three cancers (14.4-31.3%) including interferon signaling, antigen processing and presentation, and cytokines/chemokines. Strong upregulation of cancer testis antigens was also observed. An AZA IMmune gene set (AIMs) derived from the union of these immunomodulatory pathway genes classified primary tumors from all three types, into "high" and "low" AIM gene expression subsets in tumor expression data from both TCGA and GEO. Samples from selected patient biopsies showed upregulation of AIM genes after treatment with epigenetic therapy. These results point to a broad immune stimulatory role for DNA demethylating drugs in multiple cancers.

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade.

Reversal of promoter DNA hypermethylation and associated gene silencing is an attractive cancer therapy approach. The DNA methylation inhibitors decitabine and azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not explain the prolonged time to response observed in patients. We show that transient exposure of cultured and primary leukemic and epithelial tumor cells to clinically relevant nanomolar doses, without causing immediate cytotoxicity, produce an antitumor "memory" response, including inhibition of subpopulations of cancer stem-like cells. These effects are accompanied by sustained decreases in genomewide promoter DNA methylation, gene reexpression, and antitumor changes in key cellular regulatory pathways. Low-dose decitabine and azacitidine may have broad applicability for cancer management., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The tumor suppressor gene hypermethylated in cancer 1 (HIC1), which encodes a transcriptional repressor, is epigenetically inactivated in various human cancers. In this study, we show that HIC1 is a direct transcriptional repressor of the gene encoding ephrin-A1, a cell surface ligand implicated in the pathogenesis of epithelial cancers. We also show that mouse embryos lacking both Hic1 alleles manifest developmental defects spatially associated with the misexpression of ephrin-A1, and that overexpression of ephrin-A1 is a feature of tumors arising in Hic1 heterozygous mice in which the remaining wild-type allele is epigenetically silenced. In breast cancer, we find that ephrin-A1 expression is common in vivo, but that in cell culture, expression of the EphA receptors is predominant. Restoration of HIC1 function in breast cancer cells leads to a reduction in tumor growth in vivo, an effect that can be partially rescued by co-overexpression of ephrin-A1. Interestingly, overexpression of ephrin-A1 in vitro triggers downregulation of EphA2 and EphA4 levels, resulting in an expression pattern similar to that seen in vivo. We conclude that Hic1 spatially restricts ephrin-A1 expression in development, and that upregulated expression of ephrin-A1 resulting from epigenetic silencing of HIC1 in cancer cells may be an important mechanism in epithelial malignancy.

A major obstacle toward understanding how patterns of abnormal mammalian cytosine DNA methylation are established is the difficulty in quantitating the de novo methylation activities of DNA methyltransferases (DNMT) thought to catalyze these reactions. Here, we describe a novel method, using native human CpG island substrates from genes that frequently become hypermethylated in cancer, which generates robust activity for measuring de novo CpG methylation. We then survey colon cancer cells with genetically engineered deficiencies in different DNMTs and find that the major activity against these substrates in extracts of these cells is DNMT1, with minor contribution from DNMT 3b and none from DNMT3a, the only known bona fide de novo methyltransferases. The activity of DNMT1 against unmethylated CpG rich DNA was further tested by introducing CpG island substrates and DNMT1 into Drosophila melanogaster cells. The exogenous DNMT1 methylates the integrated mammalian CpG islands but not the Drosophila DNA. Additionally, in human cancer cells lacking DNMT1 and DNMT3b and having nearly absent genomic methylation, gene-specific de novo methylation can be initiated by reintroduction of DNMT1. Our studies provide a new assay for de novo activity of DNMTs and data suggesting a potential role for DNMT1 in the initiation of promoter CpG island hypermethylation in human cancer cells.

The role of DNA methyltransferase 1, DNMT1, in human cancer cells has recently been contested. In this setting, DNMT1's function as the sole maintenance methyltransferase was based on the assumption that its biological activity is identical to the mouse homologue. However, the application of recent technological advances, including gene targeting and siRNA mediated ablation studies, has cast doubt on this presumed role. Here, we attempt to shed light on these new data within the context of previous experiments.

The role of the primary mammalian DNA methyltransferase, DNMT1, in maintaining CpG island methylation in human colon cancer cells has recently been questioned. This controversy has arisen from discrepancies between genetic knockout and RNA interference-mediated knockdown studies. Here, we re-examined the RNA interference-based approach and found that hypermethylation of single-copy genes is maintained in cells transiently and stably depleted of DNMT1.

The gene hypermethylated in cancer-1 (HIC1) encodes a zinc-finger transcription factor that belongs to a group of proteins known as the POZ family. HIC1 is hypermethylated and transcriptionally silent in several types of human cancer. Homozygous disruption of Hic1 impairs development and results in embryonic and perinatal lethality in mice. Here we show that mice disrupted in the germ line for only one allele of Hic1 develop many different spontaneous malignant tumors, including a predominance of epithelial cancers in males and lymphomas and sarcomas in females. The complete loss of Hic1 function in the heterozygous mice seems to involve dense methylation of the promoter of the remaining wild-type allele. We conclude that HIC1 is a candidate tumor-suppressor gene for which loss of function in both mouse and human cancers is associated only with epigenetic modifications.

Inactivation of tumour suppressor genes is central to the development of all common forms of human cancer. This inactivation often results from epigenetic silencing associated with hypermethylation rather than intragenic mutations. In human cells, the mechanisms underlying locus-specific or global methylation patterns remain unclear. The prototypic DNA methyltransferase, Dnmt1, accounts for most methylation in mouse cells, but human cancer cells lacking DNMT1 retain significant genomic methylation and associated gene silencing. We disrupted the human DNMT3b gene in a colorectal cancer cell line. This deletion reduced global DNA methylation by less than 3%. Surprisingly, however, genetic disruption of both DNMT1 and DNMT3b nearly eliminated methyltransferase activity, and reduced genomic DNA methylation by greater than 95%. These marked changes resulted in demethylation of repeated sequences, loss of insulin-like growth factor II (IGF2) imprinting, abrogation of silencing of the tumour suppressor gene p16INK4a, and growth suppression. Here we demonstrate that two enzymes cooperatively maintain DNA methylation and gene silencing in human cancer cells, and provide compelling evidence that such methylation is essential for optimal neoplastic proliferation.

Hypermethylation is associated with the silencing of tumour susceptibility genes in several forms of cancer; however, the mechanisms responsible for this aberrant methylation are poorly understood. The prototypic DNA methyltransferase, DNMT1, has been widely assumed to be responsible for most of the methylation of the human genome, including the abnormal methylation found in cancers. To test this hypothesis, we disrupted the DNMT1 gene through homologous recombination in human colorectal carcinoma cells. Here we show that cells lacking DNMT1 exhibited markedly decreased cellular DNA methyltransferase activity, but there was only a 20% decrease in overall genomic methylation. Although juxtacentromeric satellites became significantly demethylated, most of the loci that we analysed, including the tumour suppressor gene p16INK4a, remained fully methylated and silenced. These results indicate that DNMT1 has an unsuspected degree of regional specificity in human cells and that methylating activities other than DNMT1 can maintain the methylation of most of the genome.

DNA (cytosine-5)-methyltransferases (EC 2.1.1.37) maintain patterns of methylated cytosine residues in the mammalian genome; faithful maintenance of methylation patterns is required for normal development of mice, and aberrant methylation patterns are associated with certain human tumors and developmental abnormalities. The organization of coding sequences at the 5'-end of the murine and human DNA methyltransferase genes was investigated, and the DNA methyltransferase open reading frame was found to be longer than previously suspected. Expression of the complete open reading frame by in vitro transcription-translation and by transfection of expression constructs into COS7 cells resulted in the production of an active DNA methyltransferase of the same apparent mass as the endogenous protein, while translation from the second in-frame ATG codon produced a slightly smaller but fully active protein. Characterization of mRNA 5' sequences and the intron-exon structure of the 5' region of the murine and human genes indicated that a previously described promoter element (Rouleau, J., Tanigawa, G., and Szyf, M. (1992) J. Biol. Chem. 267, 7368-7377) actually lies in an intron that is more than 5 kilobases downstream of the transcription start sites.

Recent studies showing a correlation between the levels of DNA (cytosine-5-)-methyltransferase (DNA MTase) enzyme activity and tumorigenicity have implicated this enzyme in the carcinogenic process. Moreover, hypermethylation of CpG island-containing promoters is associated with the inactivation of genes important to tumor initiation and progression. One proposed role for DNA MTase in tumorigenesis is therefore a direct role in the de novo methylation of these otherwise unmethylated CpG islands. In this study, we sought to determine whether increased levels of DNA MTase could directly affect CpG island methylation. A full-length cDNA for human DNA MTase driven by the cytomegalovirus promoter was constitutively expressed in human fibroblasts. Individual clones derived from cells transfected with DNA MTase (HMT) expressed 1- to 50-fold the level of DNA MTase protein and enzyme activity of the parental cell line or clones transfected with the control vector alone (Neo). To determine the effects of DNA MTase overexpression on CpG island methylation, we examined 12 endogenous CpG island loci in the HMT clones. HMT clones expressing > or = 9-fold the parental levels of DNA MTase activity were significantly hypermethylated relative to at least 11 Neo clones at five CpG island loci. In the HMT clones, methylation reached nearly 100% at susceptible CpG island loci with time in culture. In contrast, there was little change in the methylation status in the Neo clones over the same time frame. Taken together, the data indicate that overexpression of DNA MTase can drive the de novo methylation of susceptible CpG island loci, thus providing support for the idea that DNA MTase can contribute to tumor progression through CpG island methylation-mediated gene inactivation.

In neoplastic cells, levels of DNA methyltransferase activity are often increased, and evidence is accruing to suggest an important role for this event in tumorigenesis. To evaluate this possibility further, and to investigate the contribution of increasing de novo, as opposed to maintenance, DNA methylation in mammalian cells, we expressed the bacterial HhaI methyltransferase in cultured murine fibroblasts. This enzyme is a pure de novo DNA methyltransferase that methylates the internal C in the sequence GCGC. We find that both constitutive and induced expression of the wild-type HhaI results, primarily, in lethality to the cells. However, surviving cell clones that express low levels of M. HhaI demonstrate increased tumorigenicity as assessed by soft agar cloning efficiency (8.6% for sense HhaI-transduced PA 317 cells versus 0.4% for antisense controls; 1.7% for sense HhaI-transfected NIH 3T3 cells versus 0% for a mutant HhaI control) and tumorigenicity in nude mouse heterotransplants (75% for sense HhaI-transduced PA 317 cells versus 18.5% for antisense controls). DNA isolated from the clonogenic sense HhaI clones, versus clones expressing the mutant HhaI gene, has no increase in overall CpG methylation but an average of 27% (range, 16.7-38.9) increase in methylcytosine content at GCGC sites. These findings suggest that eukaryotic cells tolerate a narrow window of increase de novo DNA methylating capacity, above which cell death occurs and within cell transformation results. Our results further emphasize the potential role of increased DNA methyltransferase activity in the evolution of cancer.

We have cloned a series of overlapping cDNA clones encoding a 5194 bp transcript for human DNA methyltransferase (DNA MTase). This sequence potentially codes for a protein of 1495 amino acids with a predicted molecular weight of 169 kDa. The human DNA MTase cDNA has eighty percent homology at the nucleotide level, and the predicted protein has seventy-four percent identity at the amino acid level, to the DNA MTase cDNA cloned from mouse cells. Like the murine DNA MTase, the amino terminal two-thirds of the human protein contains a cysteine-rich region suggestive of a metal-binding domain. The carboxy terminal one-third of the protein shows considerable similarity to prokaryotic (cytosine-5)-methyltransferases. The arrangement of multiple motifs conserved in the prokaryotic genes is preserved in the human DNA MTase, including the relative position of a proline-cysteine dipeptide thought to be an essential catalytic site in all (cytosine-5)-methyltransferases. A single 5.2 kb transcript was detected in all human tissues tested, with the highest levels of expression observed in RNA from placenta, brain, heart and lung. DNA MTase cDNA clones were used to screen a chromosome 19 genomic cosmid library. The DNA MTase-positive cosmids which are estimated to span a genomic distance of 93 kb have been localized to 19p13.2-p13.3 by fluorescence in situ hybridization. Isolation of the cDNA for human DNA MTase will allow further study of the regulation of DNA MTase expression, and of the role of this enzyme in establishing DNA methylation patterns in both normal and neoplastic cells.

An imbalance of DNA methylation, involving widespread hypomethylation, regional hypermethylation and increased cellular capacity for methylation, is characteristic of human neoplasia. This imbalance begins in preneoplastic cells and becomes more extensive throughout subsequent stages of tumor progression. In normal cells, a primary function of DNA methylation may be to modulate compartmentalization of DNA to ensure that regional areas of transcriptionally active chromatin replicate earlier than the bulk transcriptionally inactive chromatin. We argue here that the altered methylation patterns observed during tumor progression, especially regional hypermethylation, may mark--or even help to establish--abnormalities of chromatin organization. In turn, these changes in chromatin structure may, through direct transcriptional inactivation of genes, predisposition to mutations, and allelic deletions, mediate the progressive losses of gene expression associated with tumor development.

DNA methylation abnormalities occur consistently in human neoplasia including widespread hypomethylation and more recently recognized local increases in DNA methylation that hold potential for gene inactivation events. To study this imbalance further, we have cloned and localized to chromosome 19 a portion of the human DNA methyltransferase gene that codes for the enzyme catalyzing DNA methylation. Expression of this gene is low in normal human cells, significantly increased (30- to 50-fold by PCR analysis) in virally transformed cells, and strikingly elevated in human cancer cells (several hundredfold). In comparison to colon mucosa from patients without neoplasia, median levels of DNA methyltransferase transcripts are 15-fold increased in histologically normal mucosa from patients with cancers or the benign polyps that can precede cancers, 60-fold increased in the premalignant polyps, and greater than 200-fold increased in the cancers. Thus, increases in DNA methyltransferase gene expression precede development of colonic neoplasia and continue during progression of colonic neoplasms. These increases may play a role in the genetic instability of cancer and mark early events in cell transformation.