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Perfusion of porous scaffolds transports cells to the surface to yield cellular constructs for 3D models of disease and for tissue engineering applications. While ceramic scaffolds mimic the structure and composition of trabecular bone, their opacity and tortuous pores limit the penetration of light into the interior. Scaffolds that are both perfusable and amenable to fluorescence microscopy are therefore needed to visualize the spatiotemporal dynamics of cells in the bone microenvironment. In this study, a hybrid injection molding approach was designed to enable rapid prototyping of collector arrays with variable configurations that are amenable to longitudinal imaging of attached human mesenchymal stem cells (hMSCs) using fluorescence microscopy. Cylindrical collectors were arranged in an array that is permeable to perfusion in the xy -plane and to light in the z-direction for imaging from below. The effects of the collector radius, number, and spacing on the collection efficiency of perfused hMSCs was simulated using computational fluid dynamics (CFD) and measured experimentally using fluorescence microscopy. The effect of collector diameter on simulated and experimental cell collection efficiencies followed a trend similar to that predicted by interception theory corrected for intermolecular and hydrodynamic forces for the arrays with constant collector spacing. In contrast, arrays designed with constant collector number yielded collection efficiencies that poorly fit the trend with collector radius predicted by interception theory. CFD simulations of collection efficiency agreed with experimental measurements within a factor of two. These findings highlight the utility of CFD simulations and hybrid injection molding for rapid prototyping of collector arrays to optimize the longitudinal imaging of cells without the need for expensive and time-consuming tooling., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Scott Guelcher reports financial support was provided by Incyte Corporation. Michael Savona reports financial support was provided by Incyte Corporation. Sun Peck reports financial support was provided by 10.13039/100000738US Department of Veterans Affairs. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objectives: The objective of this study was to gain knowledge and ascertain challenges about periviability counseling among obstetricians to inform curricular development., Methods: Focus groups were utilized. A series of open-ended questions was posed to each group of obstetricians; responses were audio recorded and transcribed. Transcriptions were analyzed by two coders using thematic analysis., Results: Four focus groups were convened. Prominent themes included: (1) Obstetrician knowledge about neonatal outcomes is limited, (2) Periviability counseling is both time intensive and time-challenged, (3) Patient processing of information relies on the content, delivery and patient readiness, and (4) Obstetrician bias is toward advocating for maternal safety, which may run counter to parental instinct to "do everything." The last theme was specifically focused on the role of cesarean delivery., Conclusions: Curricula focused on improving obstetrician periviability counseling should focus on neonatal outcomes, the role of cesarean delivery, and utilization of shared decision-making., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Purpose: To gather and leverage the voices of students to drive creation of required, integrated palliative care curricula within undergraduate medical education in Massachusetts, which is lacking in a majority of U.S. medical schools., Method: The study was conducted by the Massachusetts Medical Schools' Collaborative, a working group committed to ensuring all medical students in Massachusetts receive foundational training in serious illness communication (SIC) and palliative care. Eight focus groups (2 per participating medical school) were conducted during January-May 2021 and included a total of 50 students from Boston University Chobanian & Avedisian School of Medicine, Harvard Medical School, Tufts University School of Medicine, and the UMass Chan Medical School. Data collected from focus groups were discussed and coded. Themes were identified using the immersion/crystallization qualitative data analysis approach., Results: Six key themes emerged. Students viewed SIC as essential to high-quality medical practice regardless of specialty, and believed training in SIC skills and palliative care should be required in medical school curricula. Students preferred to learn and practice these skills using frameworks, particularly in real-world situations. Students recognized the expertise of palliative care specialists and described them as a scarce, often misunderstood resource in health care. Students reported it was mostly "luck" if they were included in family meetings and observed good role models. Finally, students desired practice in debriefing after difficult and emotional situations., Conclusions: This study confirms long-standing themes on students' experiences with SIC and palliative care topics, including feeling inadequately prepared to care for seriously ill patients as future physicians. Our study collected students' perspectives as actionable data to develop recommendations for curricular change. Collaborative faculty also created recommendations based on the focus group data for immediate and ongoing SIC and palliative care curricular change in Massachusetts, which can apply to medical schools nationwide., (Copyright © 2024 the Association of American Medical Colleges.)

Objective: The objective of this study was to compare maternity leave satisfaction between physicians and nonphysicians. Currently, paid maternal leave is not guaranteed in the United States, resulting in palpable dissatisfaction among parents. Previous studies have shown associations between length of paid leave and career satisfaction and maternal happiness. Materials and Methods: A Qualtrics ® electronic survey was distributed to female professionals through email and social media from April 2019 to March 2020. Inclusion criterion was ≥1 child by birth or adoption, or active pregnancy. Continuous and categorical data were analyzed using two-sample t -test and chi-square, respectively. Results: Of 808 respondents, 77% were physicians. Mean age at birth/adoption of first child was higher in physicians versus nonphysicians (32.1 years vs. 29.7 years; p  < 0.001). Physicians took shorter maternity leave than nonphysicians (10.9 weeks vs. 12.0 weeks, p  = 0.017) with half of that time paid by employers (5.4 weeks vs. 5.9 weeks, p  = 0.2). Dissatisfaction was high among physicians (85.1%) and nonphysicians (92.4%) that correlates with maternity leave compensation dissatisfaction (49% vs. 71.3%, p  < 0.001). Thirty-four percent of physicians versus 41% of nonphysicians stated that their health was negatively impacted by maternity leave length. Physicians and nonphysicians reported similar incidences of depression, and breastfeeding, delivery, and other postpartum complications. When queried, 38.8% of physicians and 57% of nonphysicians said they would desire >16 weeks of paid maternity leave ( p  < 0.001). Conclusions: In conclusion, dissatisfaction among professional women on maternity leave duration and compensation is high in the United States. Given health implications for both mother and child, this should invite further discussion and changes.

When breast cancer metastasizes to bone, treatment options are limited. Failure to treat bone metastases is thought to be due to therapy-resistant features of the bone marrow microenvironment. Using a murine model of bone metastatic mammary carcinoma, we demonstrate that systemic delivery of polymer nanoparticles loaded with cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) inhibited tumor growth and bone destruction after 7 days of treatment. Each dose of STING-activating nanoparticles trafficked to the bone marrow compartment and was retained within the tumor microenvironment for over 24 hours, enhancing antitumor immunity through proinflammatory cytokine production and early T-cell activation. While acquired resistance mechanisms, including increased levels of immunosuppressive cytokines and the infiltration of regulatory T cells, ultimately limited antitumor efficacy after 2 weeks of treatment, bone protective effects remained. Overall, these studies demonstrate that STING pathway activation, here enabled using a nanomedicine approach to enhance CDN delivery to bone metastatic sites, can reprogram the immune contexture of the bone marrow to an antitumor phenotype that inhibits bone colonization of metastatic breast cancer cells and protects from tumor-mediated bone destruction., Significance: Bone metastases are difficult to treat due to the inaccessibility of the bone marrow compartment and the immunosuppressive microenvironment that protects resident stem cells. Packaging a STING agonist into a nanoparticle that enables systemic administration and drug accumulation at tumor sites overcomes both barriers to stymie metastatic breast cancer growth., Competing Interests: N.E. Bennett reports grants from NIH during the conduct of the study. A.R. Merkel reports grants from Verteran's Administration and non-financial support from Vanderbilt University Medical Center during the conduct of the study; grants from NIH Clinical and Translational Science Award and National Center for Advancing Translational Sciences outside the submitted work. M.A. Fischer reports grants from Incyte Corporation during the conduct of the study. M.R. Savona reports grants from ALX Oncology, Astex, Incyte, Takeda, TG Therapeutics; personal fees from BMS, CTI, Forma, Geron, Novartis, Sierra Oncology, Taiho; personal fees and other from Ryvu and Karyopharm outside the submitted work. J.A. Rhoades reports grants from Veterans Administration during the conduct of the study. S.A. Guelcher reports grants from Incyte Corporation during the conduct of the study. J.T. Wilson reports a patent to 10,696,985 issued and a patent to PCT/US2019/058945 pending. No disclosures were reported by the other authors., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Treatment for myelodysplastic syndromes (MDS) remains insufficient due to clonal heterogeneity and lack of effective clinical therapies. Dysregulation of apoptosis is observed across MDS subtypes regardless of mutations and represents an attractive therapeutic opportunity. Venetoclax (VEN), a selective inhibitor of anti-apoptotic protein B-cell lymphoma- 2 (BCL2), has yielded impressive responses in older patients with acute myeloid leukemia (AML) and high risk MDS. BCL2 family anti-apoptotic proteins BCL-XL and induced myeloid cell leukemia 1 (MCL1) are implicated in leukemia survival, and upregulation of MCL1 is seen in VEN-resistant AML and MDS. We determined in vitro sensitivity of MDS patient samples to selective inhibitors of BCL2, BCL-XL and MCL1. While VEN response positively correlated with MDS with excess blasts, all MDS subtypes responded to MCL1 inhibition. Treatment with combined VEN + MCL1 inhibtion was synergistic in all MDS subtypes without significant injury to normal hematopoiesis and reduced MDS engraftment in MISTRG6 mice, supporting the pursuit of clinical trials with combined BCL2 + MCL1 inhibition in MDS.

Purpose: Hippocampus-avoidance whole brain radiotherapy with simultaneous integrated boost (HA-WBRT+SIB) is a complex treatment option for patients with multiple brain metastases, aiming to prevent neurocognitive decline and simultaneously increase tumor control. Achieving efficient hippocampal dose reduction in this context can be challenging. The aim of the current study is to present and analyze the efficacy of complete directional hippocampal blocking in reducing the hippocampal dose during HA-WBRT+SIB., Methods: A total of 30 patients with multiple metastases having undergone HA-WBRT+SIB were identified. The prescribed dose was 30 Gy in 12 fractions to the whole brain, with 98% of the hippocampus receiving ≤ 9 Gy and 2% ≤ 17 Gy and with SIB to metastases/resection cavities of 36-51 Gy in 12 fractions. Alternative treatment plans were calculated using complete directional hippocampal blocking and compared to conventional plans regarding target coverage, homogeneity, conformity, dose to hippocampi and organs at risk., Results: All alternative plans reached prescription doses. Hippocampal blocking enabled more successful sparing of the hippocampus, with a mean dose of 8.79 ± 0.99 Gy compared to 10.07 ± 0.96 Gy in 12 fractions with the conventional method (p < 0.0001). The mean dose to the whole brain (excluding metastases and hippocampal avoidance region) was 30.52 ± 0.80 Gy with conventional planning and 30.28 ± 0.11 Gy with hippocampal blocking (p = 0.11). Target coverage, conformity and homogeneity indices for whole brain and metastases, as well as doses to organs at risk were similar between planning methods (p > 0.003)., Conclusion: Complete directional hippocampal blocking is an efficient method for achieving improved hippocampal sparing during HA-WBRT+SIB., (© 2022. The Author(s).)

Background: All-trans retinoic acid (ATRA), a derivate of vitamin A, has been successfully used as a therapy to induce differentiation in M3 acute promyelocytic leukemia (APML), and has led to marked improvement in outcomes. Previously, attempts to use ATRA in non-APML in the clinic, however, have been underwhelming, likely due to persistent signaling through other oncogenic drivers. Dysregulated JAK/STAT signaling is known to drive several hematologic malignancies, and targeting JAK1 and JAK2 with the JAK1/JAK2 inhibitor ruxolitinib has led to improvement in survival in primary myelofibrosis and alleviation of vasomotor symptoms and splenomegaly in polycythemia vera and myelofibrosis., Objective: While dose-dependent anemia and thrombocytopenia limit the use of JAK2 inhibition, selectively targeting JAK1 has been explored as a means to suppress inflammation and STAT-associated pathologies related to neoplastogenesis. The objective of this study is to employ JAK1 inhibition (JAK1i) in the presence of ATRA as a potential therapy in non-M3 acute myeloid leukemia (AML)., Methods: Efficacy of JAK1i using INCB52793 was assessed by changes in cell cycle and apoptosis in treated AML cell lines. Transcriptomic and proteomic analysis evaluated effects of JAK1i. Synergy between JAK1i+ ATRA was assessed in cell lines in vitro while efficacy in vivo was assessed by tumor reduction in MV-4-11 cell line-derived xenografts., Results: Here we describe novel synergistic activity between JAK1i inhibition and ATRA in non-M3 leukemia. Transcriptomic and proteomic analysis confirmed structural and functional changes related to maturation while in vivo combinatory studies revealed significant decreases in leukemic expansion., Conclusions: JAK1i+ ATRA lead to decreases in cell cycle followed by myeloid differentiation and cell death in human leukemias. These findings highlight potential uses of ATRA-based differentiation therapy of non-M3 human leukemia., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Barriers to research participation by racial and ethnic minority group members are multi-factorial, stem from historical social injustices and occur at participant, research team, and research process levels. The informed consent procedure is a key component of the research process and represents an opportunity to address these barriers. This manuscript describes the development of the Strengthening Translational Research in Diverse Enrollment (STRIDE) intervention, which aims to improve research participation by individuals from underrepresented groups., Methods: We used a community-engaged approach to develop an integrated, culturally, and literacy-sensitive, multi-component intervention that addresses barriers to research participation during the informed consent process. This approach involved having Community Investigators participate in intervention development activities and using community engagement studios and other methods to get feedback from community members on intervention components., Results: The STRIDE intervention has three components: a simulation-based training program directed toward clinical study research assistants that emphasizes cultural competency and communication skills for assisting in the informed consent process, an electronic consent (eConsent) framework designed to improve health-related research material comprehension and relevance, and a "storytelling" intervention in which prior research participants from diverse backgrounds share their experiences delivered via video vignettes during the consent process., Conclusions: The community engaged development approach resulted in a multi-component intervention that addresses known barriers to research participation and can be integrated into the consent process of research studies. Results of an ongoing study will determine its effectiveness at increasing diversity among research participants., Competing Interests: The authors have no conflicts of interest to declare., (© The Association for Clinical and Translational Science 2021.)

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome characterized by monocytic proliferation in the presence of dysplastic bone marrow changes, inflammatory symptoms, and propensity for transformation to acute myeloid leukemia (AML), with a poor prognosis and limited treatment options. Unlike the α and β isoforms, the phosphatidylinositol-3-kinase (PI3K)-δ signaling protein is predominantly expressed by hematopoietic cells and therefore has garnered interest as a potential target for the treatment of lymphomas and leukemias. We revealed a pattern of increased PIK3CD:PIK3CA ratio in monocytic M5 AML patients and cell lines, and this ratio correlated with responsiveness to pharmacological PI3K-δ inhibition in vitro. Because CMML is a disease defined by monocytic clonal proliferation, we tested the PI3K-δ inhibitor umbralisib as a single agent and in combination with the JAK1/2 inhibitor ruxolitinib, in CMML. Our ex vivo experiments with primary CMML patient samples revealed synergistic inhibition of viability and clonogenicity with this combination. Phospho-specific flow cytometry revealed that dual inhibition had the unique ability to decrease STAT5, ERK, AKT, and S6 phosphorylation simultaneously, which offers a mechanistic hypothesis for the enhanced efficacy of the combination treatment. These preclinical data indicate promising activity by co-inhibition of PI3K-δ and JAK1/2 and support the use of ruxolitinib + umbralisib combination therapy in CMML under active clinical investigation., Competing Interests: Conflict of interest disclosure MRS receives research funding from Astex, Incyte, Millennium, and TG Therapeutics; serves on consultancy/advisory board/monitoring committees for AbbVie, Astex, BMS, Celgene, Geron, Karyopharm, Millennium, Ryvu, Sunesis, and TG Therapeutics; has equity in Karyopharm; and has patents and royalties with Boehringer-Ingelheim. The remaining authors have no competing financial interests., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients. Bromodomain and extraterminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with venetoclax to reduce AML without induction of hematopoietic toxicity., Experimental Design: INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines. In vivo efficacy was assessed by tumor reduction in MV-4-11 cell line-derived xenografts. Precision run-on and sequencing (PRO-seq) evaluated effects of INCB054329. Synergy between low-dose BETi and venetoclax was assessed in cell lines and patient samples in vitro and in vivo while efficacy and toxicity was assessed in patient-derived xenograft (PDX) models., Results: INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes, MYC and BCL2 , and genes involved in the cell cycle and metabolism. Combinations of BETi and venetoclax led to reduced cell viability in cell lines and patient samples. Low-dose combinations of INCB054329 and venetoclax in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity., Conclusions: Our findings suggest low dose combinations of venetoclax and BETi may be more efficacious for patients with AML than either monotherapy, potentially providing a longer, more tolerable dosing regimen., (©2020 American Association for Cancer Research.)

The COVID-19 pandemic has presented unprecedented challenges and opportunities for medical schools in the United States. In this Invited Commentary, the authors describe a unique collaboration between the University of Massachusetts Medical School (UMMS), the only public medical school in the state; the University of Massachusetts Memorial Medical Center (UMMMC); and the Commonwealth of Massachusetts. Through this partnership, UMMS was able to graduate fourth-year medical students 2 months early and deploy them to UMMMC to care for patients and alleviate workforce shortages during the COVID-19 surge, which peaked in Massachusetts in April 2020. The authors describe how they determined if students had fulfilled graduation requirements to graduate early, what commencement and the accompanying awards ceremony looked like this year as virtual events, the special emergency 90-day limited license these new graduates were given to practice at UMMMC during this time, and the impact these new physicians had in the hospital allowing residents and attendings to be redeployed to care for COVID-19 patients.

Objective: To discuss the study design and data analysis for three-phase interrupted time series (ITS) studies to evaluate the impact of health policy, systems, or environmental interventions. Simulation methods are used to conduct power and sample size calculation for these studies., Methods: We consider the design and analysis of three-phase ITS studies using a study funded by National Institutes of Health as an exemplar. The design and analysis of both one-arm and two-arm three-phase ITS studies are introduced., Results: A simulation-based approach, with ready-to-use computer programs, was developed to determine the power for two types of three-phase ITS studies. Simulations were conducted to estimate the power of segmented autoregressive (AR) error models when autocorrelation ranged from -0.9 to 0.9 with various effect sizes. The power increased as the sample size or the effect size increased. The power to detect the same effect sizes varied largely, depending on testing level change, trend changes, or both., Conclusion: This article provides a convenient tool for investigators to generate sample sizes to ensure sufficient statistical power when three-phase ITS study design is implemented., (© 2019 John Wiley & Sons, Ltd.)

Introduction: The updated common rule, for human subjects research, requires that consents "begin with a 'concise and focused' presentation of the key information that will most likely help someone make a decision about whether to participate in a study" (Menikoff, Kaneshiro, Pritchard. The New England Journal of Medicine . 2017; 376 (7): 613-615.). We utilized a community-engaged technology development approach to inform feature options within the REDCap software platform centered around collection and storage of electronic consent (eConsent) to address issues of transparency, clinical trial efficiency, and regulatory compliance for informed consent (Harris, et al. Journal of Biomedical Informatics 2009; 42 (2): 377-381.). eConsent may also improve recruitment and retention in clinical research studies by addressing: (1) barriers for accessing rural populations by facilitating remote consent and (2) cultural and literacy barriers by including optional explanatory material (e.g., defining terms by hovering over them with the cursor) or the choice of displaying different videos/images based on participant's race, ethnicity, or educational level (Phillippi, et al. Journal of Obstetric, Gynecologic, & Neonatal Nursing . 2018; 47 (4): 529-534.)., Methods: We developed and pilot tested our eConsent framework to provide a personalized consent experience whereby users are guided through a consent document that utilizes avatars, contextual glossary information supplements, and videos, to facilitate communication of information., Results: The eConsent framework includes a portfolio of eight features, reviewed by community stakeholders, and tested at two academic medical centers., Conclusions: Early adoption and utilization of this eConsent framework have demonstrated acceptability. Next steps will emphasize testing efficacy of features to improve participant engagement with the consent process., Competing Interests: The authors declare no conflicts of interest., (© The Association for Clinical and Translational Science 2020.)

The selective inhibitor of nuclear export (SINE) compounds selinexor (KPT-330) and eltanexor (KPT-8602) are from a novel class of small molecules that target exportin-1 (XPO1 [CRM1]), an essential nucleo-cytoplasmic transport protein responsible for the nuclear export of major tumor suppressor proteins and growth regulators such as p53, p21, and p27. XPO1 also affects the translation of messenger RNAs for critical oncogenes, including MYC, BCL2, MCL1, and BCL6, by blocking the export of the translation initiation factor eIF4E. Early trials with venetoclax (ABT-199), a potent, selective inhibitor of BCL2, have revealed responses across a variety of hematologic malignancies. However, many tumors are not responsive to venetoclax. We used models of acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) to determine in vitro and in vivo responses to treatment with venetoclax and SINE compounds combined. Cotreatment with venetoclax and SINE compounds demonstrated loss of viability in multiple cell lines. Further in vitro analyses showed that this enhanced cell death was the result of an increase in apoptosis that led to a loss of clonogenicity in methylcellulose assays, coinciding with activation of p53 and loss of MCL1. Treatment with SINE compounds and venetoclax combined led to a reduction in tumor growth in both AML and DLBCL xenografts. Immunohistochemical analysis of tissue sections revealed that the reduction in tumor cells was partly the result of an induction of apoptosis. The enhanced effects of this combination were validated in primary AML and DLBCL patient cells. Our studies reveal synergy with SINE compounds and venetoclax in aggressive hematologic malignancies and provide a rationale for pursuing this approach in a clinical trial., (© 2020 by The American Society of Hematology.)

In June 2018, the Warren Alpert Medical School of Brown University hosted a national, multidisciplinary, interprofessional symposium on opioid curricula in undergraduate medical education. This article presents the consensus of an interprofessional group who attended a session focused on elements of an opioid curriculum, including key areas of content, teaching modalities, and learner assessment. This report also includes further directions and next steps for undergraduate medical education collaboration on opioid curricula.

Introduction: Leadership is an area of education and training that is critical to the development of medical providers as health care professionals, yet few medical school curricula offer formal training in this area., Methods: We designed and implemented a course to develop and enhance the leadership and teamwork skills of first-year medical students to better prepare them for medical practice. Following a systematic literature review to identify leadership core competencies, the Leadership in Medicine Optional Enrichment Elective (OEE) was developed in accordance with the University of Massachusetts Medical School's course guidelines. The elective included six interactive sessions to advance skills in the areas of recognizing and utilizing effective leadership styles, communication within the health care team, giving and receiving feedback, delegating responsibilities, and direction setting. We designed a robust, evidence-based, scholarly evaluation plan for the OEE that was integral to ongoing quality improvement of the course., Results: Outcomes were assessed in alignment with the Kirkpatrick method of standardized evaluation. A total of 26 participants completed the course. At completion, participants demonstrated learning and advancement of skills in all five leadership domains. Furthermore, participants found meaning in the course and planned to utilize their skills in future medical practice., Discussion: The development, implementation, and evaluation of this program can serve as a model for future course development, and the program can be adapted and implemented by other institutions in an effort to address the learning gap regarding leadership education., Competing Interests: None to report., (Copyright © 2019 Richard et al.)

Objective: The purpose of this study was to present the design, model, and data analysis of an interrupted time series (ITS) model applied to evaluate the impact of health policy, systems, or environmental interventions using count outcomes. Simulation methods were used to conduct power and sample size calculations for these studies., Methods: We proposed the models and analyses of ITS designs for count outcomes using the Strengthening Translational Research in Diverse Enrollment (STRIDE) study as an example. The models we used were observation-driven models, which bundle a lagged term on the conditional mean of the outcome for a time series of count outcomes., Results: A simulation-based approach with ready-to-use computer programs was developed to calculate the sample size and power of two types of ITS models, Poisson and negative binomial, for count outcomes. Simulations were conducted to estimate the power of segmented autoregressive (AR) error models when autocorrelation ranged from -0.9 to 0.9, with various effect sizes. The power to detect the same magnitude of parameters varied largely, depending on the testing level change, the trend change, or both. The relationships between power and sample size and the values of the parameters were different between the two models., Conclusion: This article provides a convenient tool to allow investigators to generate sample sizes that will ensure sufficient statistical power when the ITS study design of count outcomes is implemented., Competing Interests: None., (© 2019 The Authors.)

Inhibitors of the bromodomain and extraterminal domain family (BETi) offer a new approach to treat hematological malignancies, with leukemias containing mixed lineage leukemia rearrangements being especially sensitive due to a reliance on the regulation of transcription elongation. We explored the mechanism of action of BETi in cells expressing the t(8;21), and show that these compounds reduced the size of acute myeloid leukemia cells, triggered a rapid but reversible G 0 /G 1 arrest, and with time, cause cell death. Meta-analysis of PRO-seq data identified ribosomal genes, which are regulated by MYC, were downregulated within 3 hours of addition of the BETi. This reduction of MYC regulated metabolic genes coincided with the loss of mitochondrial respiration and large reductions in the glycolytic rate. In addition, gene expression analysis showed that transcription of BCL2 was rapidly affected by BETi but this did not cause dramatic increases in cell death. Cell cycle arrest, lowered metabolic activity, and reduced BCL2 levels suggested that a second compound was needed to push these cells over the apoptotic threshold. Indeed, low doses of the BCL2 inhibitor, venetoclax, in combination with the BETi was a potent combination in t(8;21) containing cells. Thus, BET inhibitors that affect MYC and BCL2 expression should be considered for combination therapy with venetoclax., (© 2018 Wiley Periodicals, Inc.)

Suppression of apoptosis by expression of antiapoptotic BCL2 family members is a hallmark of acute myeloblastic leukemia (AML). Induced myeloid leukemia cell differentiation protein (MCL1), an antiapoptotic BCL2 family member, is commonly upregulated in AML cells and is often a primary mode of resistance to treatment with the BCL2 inhibitor venetoclax. Here, we describe VU661013, a novel, potent, selective MCL1 inhibitor that destabilizes BIM/MCL1 association, leads to apoptosis in AML, and is active in venetoclax-resistant cells and patient-derived xenografts. In addition, VU661013 was safely combined with venetoclax for synergy in murine models of AML. Importantly, BH3 profiling of patient samples and drug-sensitivity testing ex vivo accurately predicted cellular responses to selective inhibitors of MCL1 or BCL2 and showed benefit of the combination. Taken together, these data suggest a strategy of rationally using BCL2 and MCL1 inhibitors in sequence or in combination in AML clinical trials. SIGNIFICANCE: Targeting antiapoptotic proteins in AML is a key therapeutic strategy, and MCL1 is a critical antiapoptotic oncoprotein. Armed with novel MCL1 inhibitors and the potent BCL2 inhibitor venetoclax, it may be possible to selectively induce apoptosis by combining or thoughtfully sequencing these inhibitors based on a rational evaluation of AML. See related commentary by Leber et al., p. 1511 . This article is highlighted in the In This Issue feature, p. 1494 ., (©2018 American Association for Cancer Research.)

Abdominal pelvic organ prolapse repair is efficacious for uterovaginal and apical prolapse. We describe the safety and efficacy of robotic prolapse repair in a large teaching institution., Methods: Consecutive robotic-assisted prolapse repairs at a single institution between 2006 and 2014 were retrospectively reviewed for patient characteristics, operative information, and outcomes., Results: A total of 196 women (mean age, 61 ± 9 years) underwent robotic prolapse repair (189 sacrocolpopexy, 6 sacrohysteropexy, 1 enterocele repair). Concomitant procedures included hysterectomy (88), midurethral sling (84), and/or Burch colposuspension (7). Mean odds ratio time was 242 ± 69.9 minutes, and median length of stay was 1 day. Intraoperative complications were as follows: cystotomy (4), vaginotomy (4), conversion to open (2), bowel injury/aborted (1), adhesions/aborted (1), and ureteral injury (1). Women with complications had greater blood loss than those without complications (P = 0.0015). Immediate (<30 days) postoperative complications were rare: port-site hernia (2), discitis (1), ileus (1), and ulnar neuropraxia (3). At median follow-up of 9 months (range, 0-85 months), 14 women had recurrent grade 3 prolapse, and 4 had grade 2 apical prolapse. Nine of 14 women had additional prolapse repair at a mean of 9.5 ± 6.3 months. Vaginal mesh exposure was detected in 12 (6.3%) of 192 women. There were 6 procedures for mesh exposure and 2 procedures for exposed sutures. One mesh erosion into the bladder required open excision., Conclusions: In this large series of robotic prolapse repair, complications are infrequent. Short-term apical outcomes are excellent. Few women required additional compartment repairs within 1 year with 6% rate of mesh exposure.

As the global burden of neurologic disease increases, educating future neurologists about the principles of global health through global health curricula is of utmost importance. However, few neurology residency training programs have developed and implemented comprehensive global health curricula. This report outlines the design, implementation, and evaluation of the University of Massachusetts Medical School neurology residency global health curriculum. Using accepted curriculum development methods and incorporating an innovative use of technology, we created a global health curriculum focused on neurology to engage trainees. The implementation of curricula and organization of elective opportunities also incorporates learning objectives and an evaluation process. The University of Massachusetts Medical School neurology global health curriculum can be used as a framework for other residency programs developing global health programs. Global health education increases young neurologists' awareness of the growing burden of neurologic disease and, subsequently, may motivate them to address the need for neurologic expertise around the world., (© 2018 American Academy of Neurology.)

MTG16 is a member of the myeloid translocation gene (MTG) family of transcriptional corepressors. While MTGs were originally identified in chromosomal translocations in acute myeloid leukemia, recent studies have uncovered a role in intestinal biology. For example, Mtg16-/- mice have increased intestinal proliferation and are more sensitive to intestinal injury in colitis models. MTG16 is also underexpressed in patients with moderate/severe ulcerative colitis. Based on these findings, we postulated that MTG16 might protect against colitis-associated carcinogenesis. MTG16 was downregulated at the protein and RNA levels in patients with inflammatory bowel disease and in those with colitis-associated carcinoma. Mtg16-/- mice subjected to inflammatory carcinogenesis modeling exhibited worse colitis and increased tumor multiplicity and size. Loss of MTG16 also increased severity of dysplasia, apoptosis, proliferation, DNA damage, and WNT signaling. Moreover, transplantation of WT marrow into Mtg16-/- mice failed to rescue the Mtg16-/- protumorigenic phenotypes, indicating an epithelium-specific role for MTG16. While MTG dysfunction is widely appreciated in hematopoietic malignancies, the role of this gene family in epithelial homeostasis, and in colon cancer, was unrealized. This report identifies MTG16 as an important modulator of colitis and tumor development in inflammatory carcinogenesis.

Marine alginates are well established in wound management. Compared with different modern wound dressings, marine alginates cannot prove superior effects on wound healing. Alginates from bacteria have never been studied for medical applications so far, although the microbial polymer raises expectations for improved binding of wound factors because of its unique O-acetylation. Due to its possible positive effects on wound healing, alginates from bacteria might be a superior future medical product for clinical use. To prove the binding capacity of microbial alginates to pathophysiological factors in chronic wounds, we processed microbial alginate fibres, produced from fermentation of the soil bacterium Azotobacter vinelandii ATCC 9046, into needle web dressings and compared them with commercial dressings made of marine alginate. Four dressings were assessed: Marine alginate dressings containing either ionic silver or zinc/manganese/calcium, and microbial alginate dressings with and without nanosilver. All dressings were tested in an in vitro approach for influence on chronic wound parameters such as elastase, matrix metalloproteases-2, tumour necrosis factor-α, interleukin-8, and free radical formation. Despite the alginate origin or addition of antimicrobials, all dressings were able to reduce the concentration of the proinflammatory cytokines TNF-α and IL-8. However, microbial alginate was found to bind considerable larger amounts of elastase and matrix metalloproteases-2 in contrast to the marine alginate dressings. The incorporation of zinc, silver or nanosilver into alginate fibres did not improve their binding capacity for proteases or cytokines. The addition of nanosilver slightly enhanced the antioxidant capacity of microbial alginate dressings, whereas the marine alginate dressing containing zinc/manganese/calcium was unable to inhibit the formation of free radicals. The enhanced binding affinity by microbial alginate of Azotobacter vinelandii to pathophysiological factors may be interesting to support optimal conditions for wound healing.

Background: In recent years there has been a surge in the number of global health programs operated by academic institutions. However, most of the existing programs describe partnerships that are primarily faculty-driven and supported by extramural funding., Program Description: Research and Advocacy for Health in India (RAHI, or "pathfinder" in Hindi) and Support and Action Towards Health-Equity in India (SATHI, or "partnership" in Hindi) are 2 interconnected, collaborative efforts between the University of Massachusetts Medical School (UMMS) and Charutar Arogya Mandal (CAM), a medical college and a tertiary care center in rural western India. The RAHI-SATHI program is the culmination of a series of student/trainee-led research and capacity strengthening initiatives that received institutional support in the form of faculty mentorship and seed funding. RAHI-SATHI's trainee-led twinning approach overcomes traditional barriers faced by global health programs. Trainees help mitigate geographical barriers by acting as a bridge between members from different institutions, garner cultural insight through their ability to immerse themselves in a community, and overcome expertise limitations through pre-planned structured mentorship from faculty of both institutions. Trainees play a central role in cultivating trust among the team members and, in the process, they acquire personal leadership skills that may benefit them in their future careers., Conclusion: This paradigm of trainee-led twinning partnership promotes sustainability in an uncertain funding climate and provides a roadmap for conducting foundational work that is essential for the development of a broad, university-wide global health program., (© Soni et al.)

Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3' to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death., Competing Interests: The authors have declared that no conflict of interest exists., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Newborn screening has dramatically reduced rates of untreated congenital hypothyroidism (CH). However, in low-income nations where newborn screening programs do not exist, untreated CH remains a significant health and societal challenge. The goal of this report is to alert health care providers about the potential of undiagnosed CH in unscreened immigrant children. We report 3 siblings of Somali descent with CH who started treatment with levothyroxine at age 0.5 years, 7.7 years, and 14.8 years and were followed for 8 years. This case series demonstrates a spectrum of severity, response to treatment, and neurocognitive and growth outcomes depending on the age at treatment initiation. Patient 1, now 22 years old, went undiagnosed for 14.8 years. On diagnosis, his height was -7.5 SDs with a very delayed bone age of -13.5 SDs. His longstanding CH was associated with empty sella syndrome, static encephalopathy, and severe musculoskeletal deformities. Even after treatment, his height (-5.2 SDs) and cognitive deficits remained the most severe of the 3 siblings. Patient 2, diagnosed at 7.7 years, had moderate CH manifestations and thus a relatively intermediate outcome after treatment. Patient 3, who had the earliest diagnosis at 0.5 years, displayed the best response, but continues to have residual global developmental delay. In conclusion, untreated CH remains an important diagnostic consideration among immigrant children., (Copyright © 2016 by the American Academy of Pediatrics.)

The discovery of JAK2 (V617F) a decade ago led to optimism for a rapidly developing treatment revolution in Ph(-) myeloproliferative neoplasms. Unlike BCR-ABL, however, JAK2 was found to have a more heterogeneous role in carcinogenesis. Therefore, for years, development of new therapies was slow, despite standard treatment options that did not address the overwhelming symptom burden in patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, post-polycythemia vera MF, and myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) syndromes. JAK-STAT inhibitors have changed this, drastically ameliorating symptoms and ultimately beginning to show evidence of impact on survival. Now, the genetic foundations of myelofibrosis and MDS/MPN are rapidly being elucidated and contributing to targeted therapy development. This has been empowered through updated response criteria for MDS/MPN and refined prognostic scoring systems in these diseases. The aim of this article is to summarize concisely the current and rationally designed investigational therapeutics directed at JAK-STAT, hedgehog, PI3K-Akt, bone marrow fibrosis, telomerase, and rogue epigenetic signaling. The revolution in immunotherapy and novel treatments aimed at previously untargeted signaling pathways provides hope for considerable advancement in therapy options for those with chronic myeloid disease.

Marine alginate fibre dressings are well established in wound management. Alginate fibres can absorb plenty of wound exudate due to their gel forming abilities and ion exchange. Alginates from bacteria have never been studied for medical applications so far, although the microbial polymer raises expectations for improved gelling capacity due to its unique O-acetylation. To prove the gelling capacity of bacterial alginate, we extracted the co-polymer from fermentation of the soil bacterium Azotobacter vinelandii ATCC 9046, cultivated on crude glycerol as an alternative carbon source. Bacterial alginate was isolated in high purity and extruded by a wet spinning method. Fibre structure and properties were characterised by infrared spectroscopy, NMR, GPC, scanning electron microscopy and tensile testing. The fibres could be processed into biocompatible needle web dressings, which showed more than twice the gel formation in saline compared to commercial dressings made of marine alginates. Gelled dressings of bacterial alginate formed stable hydrogels of sufficient shape and strength for wound healing applications. This work suggests that the increased gel formation of bacterial alginate from A. vinelandii may be optimal for the preparation of novel wound dressings.

Critical thinking is essential to a health professional's competence to assess, diagnose, and care for patients. Defined as the ability to apply higher-order cognitive skills (conceptualization, analysis, evaluation) and the disposition to be deliberate about thinking (being open-minded or intellectually honest) that lead to action that is logical and appropriate, critical thinking represents a "meta-competency" that transcends other knowledge, skills, abilities, and behaviors required in health care professions. Despite its importance, the developmental stages of critical thinking have not been delineated for nurses and physicians. As part of a task force of educators who considered different developmental stage theories, the authors have iteratively refined and proposed milestones in critical thinking. The attributes associated with unreflective, beginning, practicing, advanced, accomplished, and challenged critical thinkers are conceived as independent of an individual's level of training. Depending on circumstances and environmental factors, even the most experienced clinician may demonstrate attributes associated with a challenged thinker. The authors use the illustrative case of a patient with abdominal pain to demonstrate how critical thinking may manifest in learners at different stages of development, analyzing how the learner at each stage applies information obtained in the patient interaction to arrive at a differential diagnosis and plan for evaluation. The authors share important considerations and provide this work as a foundation for the development of effective approaches to teaching and promoting critical thinking and to establishing expectations for learners in this essential meta-competency.

Penile strangulation is an infrequent clinical condition that has widely been reported. It usually results following placement of a constriction device to enhance sexual stimulation. Early treatment is essential to avoid potential complications, including ischemic necrosis and autoamputation. We describe the use of a Large Orthopedic Pin Cutter to remove a metal penile constriction device in the Emergency Department (ED). This case report describes the relatively safe technique of using an instrument available in many hospitals that can be added to the physician's arsenal in the removal of metal constriction devices.

Objective: To determine whether the rates of nontraumatic dental condition (NTDC)-related emergency department (ED) visits are higher during the typical working hours of dental offices and lower during night hours, as well as the associated factors., Methods: We analyzed data from the National Hospital Ambulatory Medical Care Survey for 1997 through 2007 using multivariate binary and polytomous logistic regression adjusted for survey design to determine the effect of predictors on specified outcome variables., Results: Overall, 4,726 observations representing 16.4 million NTDC-related ED visits were identified. Significant differences in rates of NTDC-related ED visits were observed with 40%-50% higher rates during nonworking hours and 20% higher rates on weekends than the overall average rate of 170 visits per hour. Compared with 19-33 year olds, subjects < 18 years old had significantly higher relative rates of NTDC-related ED visits during nonworking hours [relative rate ratio (RRR) = 1.6 to 1.8], whereas those aged 73 and older had lower relative rates during nonworking hours (RRR = 0.4; overall P = 0.0005). Compared with those having private insurance, Medicaid and self-pay patients had significantly lower relative rates of NTDC visits during nonworking and night hours (RRR = 0.6 to 0.7, overall P < 0.0003). Patients with a dental reason for visit were overrepresented during the night hours (RRR = 1.3; overall P = 0.04)., Conclusion: NTDC-related visits to ED occurred at a higher rate during nonworking hours and on weekends and were significantly associated with age, patient-stated reason for visit and payer type.

Histone deacetylase 3 (HDAC3) contributes to the regulation of gene expression, chromatin structure, and genomic stability. Because HDAC3 associates with oncoproteins that drive leukemia and lymphoma, we engineered a conditional deletion allele in mice to explore the physiological roles of Hdac3 in hematopoiesis. We used the Vav-Cre transgenic allele to trigger recombination, which yielded a dramatic loss of lymphoid cells, hypocellular bone marrow, and mild anemia. Phenotypic and functional analysis suggested that Hdac3 was required for the formation of the earliest lymphoid progenitor cells in the marrow, but that the marrow contained 3-5 times more multipotent progenitor cells. Hdac3(-/-) stem cells were severely compromised in competitive bone marrow transplantation. In vitro, Hdac3(-/-) stem and progenitor cells failed to proliferate, and most cells remained undifferentiated. Moreover, one-third of the Hdac3(-/-) stem and progenitor cells were in S phase 2 hours after BrdU labeling in vivo, suggesting that these cells were impaired in transit through the S phase. DNA fiber-labeling experiments indicated that Hdac3 was required for efficient DNA replication in hematopoietic stem and progenitor cells. Thus, Hdac3 is required for the passage of hematopoietic stem/progenitor cells through the S phase, for stem cell functions, and for lymphopoiesis.

Objectives: To evaluate clinical, demographic, and surgical factors that may be associated with mesh exposure after vaginal repair of pelvic organ prolapse (POP)., Methods: Records of women who underwent POP repair with Elevate or Prolift were retrospectively reviewed. Body mass index (BMI), prolapse grade, smoking history, diabetes, steroid and estrogen use, parity, compartment repaired, concurrent hysterectomy, operative time, postoperative pain, change in hemoglobin (ΔHgb) and other characteristics were evaluated for associations with mesh exposure.Categorical variables were examined using Pearson χ test where appropriate, or the Fisher exact test was used. The continuous variables were examined using Wilcoxon rank tests. A multivariable logistic regression analysis was completed to examine predictors of mesh exposure. All analyses used SAS for Windows version 9.2 (Cary, NC)., Results: Three hundred thirty-five women underwent repair from 2006 to 2011. Vaginal mesh exposure was identified in 27 (8.1%) of the 335 women. Patients with exposure had longer median follow-up than the group with no exposure (357 vs 145 days; P = 0.0003). The median time to exposure was 96 days (15-1129 days). Mesh exposure was associated with lower BMI (25.2 ± 2.5 vs 27.4 ± 5.1; P = 0.020) and greater ΔHgb (-3.7 ± 1.7 mg/dL vs -2.5 ±1.3; P = 0.0011). Change in hemoglobin decreased over time (P = 0.0005). Exposure rates also decreased over time (17% in 2005 to 12% in 2006, then 5%-8% in 2006-2011) but were not statistically significant (P = 0.49)., Conclusions: In this study, vaginal mesh exposure was only associated with ΔHgb and lower BMI.

Introduction and Hypothesis: We compared the operative and immediate postoperative experience of the trocar-based Prolift and non-trocar-based Elevate techniques used to repair vaginal prolapse., Methods: A retrospective review of Prolift and Elevate repairs was performed. Baseline characteristics and operative and postoperative variables evaluated included compartment(s) repaired, adjacent organ injury, operative time (OT), change in hemoglobin (ΔH), pain score, narcotic use, length of stay (LOS), and short-term complications. Categorical variables were assessed as counts and percent frequency. Data were compared using chi-squared analysis and paired t test., Results: Prolift (n = 143) and Elevate (n = 77) patients were similar in age (p = 0.19). Concurrent hysterectomy was done in 22 (15.4 %) and 24 (31.2 %), respectively, and concurrent midurethral sling placed in 100 (70 %) and 50 (65 %), respectively. LOS (median, 25th,75th) after anterior/apical compartment repairs was shorter with Elevate, whether with (1.0; 1.0,1.5 vs. 2.0 days;1.0, 2.0; p = 0.003) or without (2.0; 1.0, 2.0 vs. 2.0 days; 2.0, 3.0; p = 0.024) hysterectomy, but no differences in OT, ΔH, pain score, or narcotic use occurred. Posterior compartment mean pain scores were lower with Prolift (3.6 ± 2.2 vs. 1.7 ± 1.5, p = 0.035), and three-compartment-repair pain scores were lower with Elevate (0.6 ± 1.3 vs 2.5 ± 1.9; p = 0.013). Three bladder injuries occurred with Prolift but none with Elevate., Conclusions: Operative and postoperative experiences were similar between groups; however, Elevate anterior/apical repairs had shorter LOS, which might reflect more aggressive discharge planning. There were no bowel or major vascular injuries, and the Prolift trocar bladder injuries did not alter the surgical procedure.

Background: The Institute of Medicine has called for physician education as a key step in medical error prevention. In our 2002 national survey, pediatric resident education about medical error prevention was sporadic. We sought to describe the amount and type of pediatric resident training about medical errors and to assess the change in training since 2002., Methods: We surveyed a national sample of 50 pediatric chief residents randomly selected from the 198 Accreditation Council for Graduate Medical Education-accredited residency programs from August to November 2010. The 31-item telephone survey was developed from the 2002 survey, with the addition of 10 items about electronic learning and resident quality improvement projects. The survey included 4 domains: current patient safety curriculum, chief resident knowledge, learning from medical errors, and demographics., Results: We phoned 55 chief residents and contacted 51. Fifty participated (90% participation rate). Ninety-four percent of chief residents stated that their program had a formalized curriculum to discuss medical errors, compared to only 50% (P < .001) in 2002. Ninety-six percent understood that the response to a medical error should be systemic change. The primary method for educating residents about medical error reported was informal teaching. Ninety-two percent reported never or rarely discussing medical error in an outpatient setting. Seventy-four percent of chief residents reported that they never or rarely learn from an error made by an attending physician, and 50% never or rarely learned from an error made by a fellow resident., Conclusions: Although resident education about medical errors has improved since 2002, opportunities to model learning from mistakes are frequently missed., (Copyright © 2013 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

The t(8;21) and t(16;21) that are associated with acute myeloid leukaemia disrupt two closely related genes termed Myeloid Translocation Genes 8 (MTG8) and 16 (MTG16), respectively. Many of the transcription factors that recruit Mtg16 regulate haematopoietic stem and progenitor cell functions and are required to maintain stem cell self-renewal potential. Accordingly, we found that Mtg16-null bone marrow (BM) failed in BM transplant assays. Moreover, when removed from the animal, Mtg16-deficient stem cells continued to show defects in stem cell self-renewal assays, suggesting a requirement for Mtg16 in this process. Gene expression analysis indicated that Mtg16 was required to suppress the expression of several key cell-cycle regulators including E2F2, and chromatin immunoprecipitation assays detected Mtg16 near an E2A binding site within the first intron of E2F2. BrdU incorporation assays indicated that in the absence of Mtg16 more long-term stem cells were in the S phase, even after competitive BM transplantation where normal stem and progenitor cells are present, suggesting that Mtg16 plays a role in the maintenance of stem cell quiescence.

Purpose: Growing data support interprofessional teams as an important part of medical education. This study describes attitudes, barriers, and practices regarding interprofessional education (IPE) in internal medicine (IM) clerkships in the United States and Canada., Method: In 2009, a section on IPE was included on the Clerkship Directors in Internal Medicine annual survey. This section contained 23 multiple-choice questions exploring both core and subinternship experiences. Data were analyzed using descriptive statistics and Rasch analysis., Results: Sixty-nine of 107 institutional members responded to the survey (64% response rate). Approximately 68% of responding clerkship directors believed that IPE is important to the practice of IM. However, only 57% believed that it should become a part of the undergraduate clinical curriculum. The three most significant barriers to IPE in the IM clerkship were scheduling alignment, time in the existing curriculum, and resources in time and money. Although more than half of respondents felt IPE should be included in the clinical curriculum, 81% indicated that there was no formal curriculum on IPE in their core IM clerkship, and 84% indicated that there was no formal curriculum during IM subinternship rotations at their institution., Conclusions: There is limited penetration of IPE into one of the foundational clinical training episodes for medical students in Liaison Committee for Medical Education-accredited schools. This may be related to misperceptions of the relative value of these experiences and limitations of curricular time. Learning in and from successful models of interprofessional teams in clinical practice may help overcome these barriers.

Mtg16/Eto2 is a transcriptional corepressor that is disrupted by t(16;21) in acute myeloid leukemia. Using mice lacking Mtg16, we found that Mtg16 is a critical regulator of T-cell development. Deletion of Mtg16 led to reduced thymocyte development in vivo, and after competitive bone marrow transplantation, there was a nearly complete failure of Mtg16(-/-) cells to contribute to thymocyte development. This defect was recapitulated in vitro as Mtg16(-/-) Lineage(-)/Sca1(+)/c-Kit(+) (LSK) cells of the bone marrow or DN1 cells of the thymus failed to produce CD4(+)/CD8(+) cells in response to a Notch signal. Complementation of these defects by reexpressing Mtg16 showed that 3 highly conserved domains were somewhat dispensable for T-cell development but required the capacity of Mtg16 to suppress E2A-dependent transcriptional activation and to bind to the Notch intracellular domain. Thus, Mtg16 integrates the activities of signaling pathways and nuclear factors in the establishment of T-cell fate specification.

Myeloid Translocation Gene, Related-1 (MTGR1) CBFA2T2 is a member of the Myeloid Translocation Gene (MTG) family of transcriptional corepressors. The remaining two family members, MTG8 (RUNX1T1) and MTG16 (CBFA2T3) are identified as targets of chromosomal translocations in acute myeloid leukemia (AML). Mtgr1(-/-) mice have defects in intestinal lineage allocation and wound healing. Moreover, these mice show signs of impaired intestinal stem cell function. Based on these phenotypes, we hypothesized that MTGR1 may influence tumorigenesis arising in an inflammatory background. We report that Mtgr1(-/-) mice were protected from tumorigenesis when injected with azoxymethane (AOM) and then subjected to repeated cycles of dextran sodium sulfate (DSS). Tumor cell proliferation was comparable, but Mtgr1(-/-) tumors had significantly higher apoptosis rates. These phenotypes were dependent on epithelial injury, the resultant inflammation, or a combination of both as there was no difference in aberrant crypt foci (ACF) or tumor burden when animals were treated with AOM as the sole agent. Gene expression analysis indicated that Mtgr1(-/-) tumors had significant upregulation of inflammatory networks, and immunohistochemistry (IHC) for immune cell subsets revealed a marked multilineage increase in infiltrates, consisting predominately of CD3(+) and natural killer T (NKT) cells as well as macrophages. Transplantation of wild type (WT) bone marrow into Mtgr1(-/-) mice, and the reciprocal transplant, did not alter the phenotype, ruling out an MTGR1 hematopoietic cell-autonomous mechanism. Our findings indicate that MTGR1 is required for efficient inflammatory carcinogenesis in this model, and implicate its dysfunction in colitis-associated carcinoma. This represents the first report functionally linking MTGR1 to intestinal tumorigenesis., (©2011 AACR.)

Context: academic medical centres may adopt new learning technologies with little data on their effectiveness or on how they compare with traditional methodologies. We conducted a comparative study of student reflective writings produced using either an electronic (blog) format or a traditional written (essay) format to assess differences in content, depth of reflection and student preference., Methods: students in internal medicine clerkships at two US medical schools during the 2008-2009 academic year were quasi-randomly assigned to one of two study arms according to which they were asked to either write a traditional reflective essay and subsequently join in faculty-moderated, small-group discussion (n = 45), or post two writings to a faculty-moderated group blog and provide at least one comment on a peer's posts (n = 50). Examples from a pilot block were used to refine coding methods and determine inter-rater reliability. Writings were coded for theme and level of reflection by two blinded authors; these coding processes reached inter-rater reliabilities of 91% and 80%, respectively. Anonymous pre- and post-clerkship surveys assessed student perceptions and preferences., Results: student writing addressed seven main themes: (i) being humanistic; (ii) professional behaviour; (iii) understanding caregiving relationships; (iv) being a student; (v) clinical learning; (vi) dealing with death and dying, and (vii) the health care system, quality, safety and public health. The distribution of themes was similar across institutions and study arms. The level of reflection did not differ between study arms. Post-clerkship surveys showed that student preferences for blogging or essay writing were predicted by experience, with the majority favouring the method they had used., Conclusions: our study suggests there is no significant difference in themes addressed or levels of reflection achieved when students complete a similar assignment via online blogging or traditional essay writing. Given this, faculty staff should feel comfortable in utilising the blog format for reflective exercises. Faculty members could consider the option of using either format to address different learning styles of students.

Purpose: To describe current patient safety curricula at U.S. and Canadian medical schools and identify factors associated with adoption of these programs., Method: A survey was mailed to institutional members of the Clerkship Directors in Internal Medicine at U.S. and Canadian academic medical schools in 2006. Respondents self-reported implementation of patient safety curricula and associated methods of instruction at the institution level., Results: The survey had a 76% response rate (83/110). Only 25% of institutional members reported that their schools had explicit patient safety curricula. All respondents that reported having curricula use lectures and small-group instruction, and these were more likely to occur in preclinical settings. Topics and methods of instruction included reporting adverse incidents and analysis of medical errors; improvement of physician order writing to prevent medication errors; core measures; national patient safety goals; and standardization of medical care through the use of clinical guidelines and order set templates. Although only 25% of respondents reported having explicit curricula, 72% agreed that patient safety instruction should occur during medical school., Conclusions: Despite calls from regulatory, medical, and educational organizations to increase patient safety training of medical students, internal medicine clerkship directors report that few schools in the United States and Canada have implemented specific patient safety curricula. Most existing patient safety curricula use lecture and small-group discussion as preferred methods of instruction.

Context: Research suggests that pharmaceutical marketing influences prescribing and may cause cognitive dissonance for prescribers. This work has primarily been with physicians and physician-trainees. Questions remain regarding why prescribers continue to meet with pharmaceutical representatives (PRs)., Objective: To describe the reasons that prescribers from various health professions continue to interact with PRs despite growing evidence of the influence of these interactions., Design, Setting, and Participants: Multi-disciplinary focus groups with 61 participants held in practice settings and at society meetings., Results: Most prescribers participating in our focus groups believe that overall PR interactions are beneficial to patient care and practice health. They either trust the information from PRs or feel that they are equipped to evaluate it independently. Despite acknowledgement of study findings to the contrary, prescribers state that they are able to effectively manage PR interactions such that their own prescribing is not adversely impacted. Prescribers describe few specific strategies or policies for these interactions, and report that policies are not consistently implemented with all members of a clinic or institution. Some prescribers perceive an inherent contradiction between academic centers and national societies receiving money from pharmaceutical companies, and then recommending restriction at the level of the individual prescriber. Prescribers with different training backgrounds present a few novel reasons for these meetings., Conclusions: Despite evidence that PR detailing influences prescribing, providers from several health professions continue to believe that PR interactions improve patient care, and that they can adequately evaluate and filter information presented to them by PRs. Focus group comments suggest that cultural change is necessary to break the norms that exist in many settings. Applying policies consistently, considering non-physician members of the healthcare team, working with trainees, restructuring the current primary care model and offering convenient, individualized, non-biased educational options may aid success.

Objective: To report how patient viewpoints on caring inform curriculum development for teaching sessions on delivering bad news, making the transition to palliative care, and communicating about a medical error., Methods: We conducted focus groups that used patients recruited from the surrounding community to view videotapes of physicians delivering bad news, talking with a patient about palliative care, and communicating about a medical error. We used focus group results, combined with evidence from the medical literature to inform curriculum content for workshops conducted with Internal Medicine and Family Medicine residents at the University of Massachusetts Medical School., Results: Patient perspectives on caring gathered through focus groups differed in significant ways from the existing medical literature on caring when providers are communicating in the challenging situations that were depicted. Our data pointed out that individual reactions were unique and sometimes contradictory in that one person saw behavior as caring that others thought was uncaring. Participants often used qualifiers in their comments like "appropriate" amounts of information, "measured" empathy, chooses words carefully to reflect the relative nature of caring. "Arranges to meet healthcare needs," an issue that extends beyond the encounter, was seen as a new component of caring not previously described. Applying these concepts to curriculum required that we not only focus on the behavioral skills involved in these tasks, but also the processes of assessing patient's informational and emotional needs, and then taking steps to meet them, while adjusting behavior in real time to meet patients needs for caring. Workshops delivered were highly evaluated by residents., Conclusion: Patient perspectives on caring when providers deliver bad news, discuss transitions to palliative care, and communicate about a medical error reinforce that patient expectations for caring are highly contextualized and physician behavior needs to be individualized. We taught residents not only behavioral skills, but also the process skills of anticipating patient reactions, recognizing patient clues, planning and choosing effective strategies on the fly, and assessing one's own performance characteristic of communication expertise., Practice Implications: Teaching caring attitudes with challenging communication tasks requires that learners appreciate and value not only caring behaviors but also learn the process by which they must adjust and titrate their actions to meet patient needs.

Objective: Caring is closely associated with reduced malpractice litigation, adherence to treatment and even symptom relief. Caring also is included in pay for performance formulas as well as widely utilized for quality improvement purposes. Our objective in this prospective qualitative study was to define caring behaviors associated with three challenging encounters: discussing the transition from curative to palliative care, delivering bad news (cancer), and discussing a medical error (misplaced test result). The purpose was to lay the groundwork for the creation of a 'patient-centered' caring attitude checklist that could help the healthcare provider understand and ultimately enhance the patient's experience of care., Methods: Groups of randomly selected lay people, henceforth referred to as patients: (1) engaged in 'think aloud' exercises to help create a 15-item caring behavior checklist; (2) used the checklist to rate videotapes of simulated challenging encounters conducted by twenty primary care physicians (total of 600 ratings sets); and (3) participated in 12 separate 1.5 h focus groups discussing the caring (and non-caring) behaviors exhibited in videotapes of the highest and lowest rated encounters., Results: Thirteen behaviors emerged as focal for describing a doctor's caring attitude but with disagreement as to whether specific examples of these behaviors were 'caring' or 'uncaring.' For example, although the concept of empathic inquiry was considered important by most patients, the physician question, "Is there someone you can call or talk with" (about a cancer diagnosis) was interpreted by one patient as 'very caring' while another was 'impressed with how uncaring' the statement appeared., Conclusion: At the conceptual level there is a set of behaviors that represent caring, however, the manifestation of these behaviors is 'in the eye of the beholder.' The most important element of caring may not be the set of behaviors but a set of underlying abilities that include taking the patient's perspective and reflecting on the patient's responses., Practice Implications: Medical education must focus on the underlying abilities of caring.