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Background: Medication disposal programs have been promoted as one solution to the opioid crisis, but uptake by community members has been minimal. Objectives: To clarify perceptions of medication disposal options among people who have been prescribed an opioid analgesic in North Carolina to inform interventions that can facilitate the disposal of unused opioids. Methods: In 2022, we conducted focus groups with participants who received an opioid medication in the past year to gain information to develop an intervention related to the disposal of unused opioid medication (12 focus group discussions (FGDs); total N  = 37; 30 identified as female, 6 as male, and 1 as another gender). Participants were shown a slide with the Food and Drug Administration's recommended disposal options and asked about their perceptions of each option. Themes were derived using an inductive, thematic, qualitative approach. Results: Seven themes about perceptions of medication disposal programs emerged from the data. Four of the themes reflect potential barriers to medication disposal: failed disposal attempts, lack of sufficient education on proper disposal, unclear meaning of specific disposal language, and concerns about existing disposal options. Three of the themes provide insight on potential facilitators of medication disposal: preference of low-cost disposal options, ease and accessibility among disposal methods, and preferred disposal methods. Conclusion: Patients should be provided clear and consistent guidance from prescribers and dispensing pharmacists on when and how to dispose of unused medications and opportunities to dispose of medications at no cost to the patient.

Background: Secure storage and disposal is a critical strategy to reduce prescription opioid misuse. We sought to develop effective messages to promote secure storage and disposal of unused opioid medications that can be used in interventions designed to reduce diversion of opioid medications for nonmedical use., Methods: We used a mixed-method design to develop and evaluate messages. First, we pretested 34 messages in focus group discussions (FGDs; n = 12 FGDs, n = 2-5 participants per FGD; 37 total participants). Then, we tested the 12 most salient messages in an online survey with a nationally representative Qualtrics ® panel (n = 1520 participants). A pretest-posttest design was conducted to assess change in beliefs about storage and disposal of opioid medication following message exposure., Results: All 12 messages favorably influenced participants' perceptions related to concerns and risks of retaining unused opioid medications and the importance of and self-efficacy in securely storing and disposing of unused opioid medications. Storage and disposal messages that included the sentence-"Your prescription can become someone else's addiction."-outperformed other messages in encouraging people to safely store or dispose of opioid medication., Conclusions: This study informs the development of a universal text message intervention using multimodal feedback from the target population that the intervention seeks to serve. The next step is to conduct a randomized controlled trial to assess efficacy of the intervention., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Multiplex molecular diagnostic panels have greatly enhanced detection of gastrointestinal pathogens. However, data on the impact of these tests on clinical and patient-centered outcomes are limited., Methods: We conducted a prospective, multicenter, stepped-wedge trial to determine the impact of multiplex molecular testing at 5 academic children's hospitals on children presenting to the emergency department with acute gastroenteritis. Caregivers were interviewed on enrollment and 7-10 days after enrollment to determine symptoms, risk factors, subsequent medical visits, and impact on family members. During the pre-intervention period, diagnostic testing was performed at the clinician's discretion . During the intervention period, multiplex molecular testing was performed on all children, with results available to clinicians. The primary outcome was return visits to a healthcare provider within 10 days of enrollment., Results: Potential pathogens were identified by clinician-ordered tests in 19 of 571 (3.3%) in the pre-intervention period compared with 434 of 586 (74%) in the intervention period; clinically relevant pathogens were detected in 2.1% and 15%, respectively. In the multivariate model, the intervention was associated with a 21% reduction in the odds of any return visit (odds ratio, 0.79; 95% confidence interval, .70-.90) after adjusting for potential confounders. Appropriate treatment was prescribed in 11.3% compared with 19.6% during the intervention period (P = .22)., Conclusions: Routine molecular multiplex testing for all children who presented to the ED with acute gastroenteritis detected more clinically relevant pathogens and led to a 21% decrease in return visits. Additional research is needed to define patients most likely to benefit from testing. Clinical Trials Registration. NCT02248285., Competing Interests: Potential conflicts of interest. J. D. B reports research support and consulting funding from bioMerieux. R. S. reports reseach funding from Biomerieux, Hologic, Qiagen, Abbott, Cepheid, and Luminex. J. M. B reports consulting fees from Gradientech. J. D. B. reports consulting fees from bioMerieux. K. M. H. and K. M. B. are employees of bioMerieux. A. M. L. reports consulting or research funding from Cepheid, Meridian Diagnostics, Diasorin, and Hologic. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Haematopoietically expressed homeobox transcription factor (Hhex) is a transcriptional repressor that is of fundamental importance across species, as evident by its evolutionary conservation spanning fish, amphibians, birds, mice and humans. Indeed, Hhex maintains its vital functions throughout the lifespan of the organism, beginning in the oocyte, through fundamental stages of embryogenesis in the foregut endoderm. The endodermal development driven by Hhex gives rise to endocrine organs such as the pancreas in a process which is likely linked to its role as a risk factor in diabetes and pancreatic disorders. Hhex is also required for the normal development of the bile duct and liver, the latter also importantly being the initial site of haematopoiesis. These haematopoietic origins are governed by Hhex, leading to its crucial later roles in definitive haematopoietic stem cell (HSC) self-renewal, lymphopoiesis and haematological malignancy. Hhex is also necessary for the developing forebrain and thyroid gland, with this reliance on Hhex evident in its role in endocrine disorders later in life including a potential role in Alzheimer's disease. Thus, the roles of Hhex in embryological development throughout evolution appear to be linked to its later roles in a variety of disease processes., Competing Interests: Author MM is an employee of the company iCamuno Biotherapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jackson, Nutt and McCormack.)

Missense mutations in PLCG2 can cause autoinflammation with phospholipase C gamma 2-associated antibody deficiency and immune dysregulation (APLAID). Here, we generated a mouse model carrying an APLAID mutation (p.Ser707Tyr) and found that inflammatory infiltrates in the skin and lungs were only partially ameliorated by removing inflammasome function via the deletion of caspase-1. Also, deleting interleukin-6 or tumor necrosis factor did not fully prevent APLAID mutant mice from autoinflammation. Overall, these findings are in accordance with the poor response individuals with APLAID have to treatments that block interleukin-1, JAK1/2 or tumor necrosis factor. Cytokine analysis revealed increased granulocyte colony-stimulating factor (G-CSF) levels as the most distinct feature in mice and individuals with APLAID. Remarkably, treatment with a G-CSF antibody completely reversed established disease in APLAID mice. Furthermore, excessive myelopoiesis was normalized and lymphocyte numbers rebounded. APLAID mice were also fully rescued by bone marrow transplantation from healthy donors, associated with reduced G-CSF production, predominantly from non-hematopoietic cells. In summary, we identify APLAID as a G-CSF-driven autoinflammatory disease, for which targeted therapy is feasible., (© 2023. The Author(s).)

Background: Unused prescription opioids from family and friends continue to be the primary access point to prescription opioids for nonmedical use among youth. Implementation of medicine disposal boxes at pharmacies is one approach to facilitate removal of unused prescription opioids from the home to prevent diversion., Objectives: We sought to examine the implementation rates of disposal boxes at pharmacies in North Carolina from 2016 to 2021 and place-based health disparities in availability., Methods: We identified pharmacies with a disposal box in 2016, 2018, and 2021 among licensed pharmacies in North Carolina in 2018 (N = 2587). We computed descriptive statistics to describe disposal box implementation rates over time and used geographic information systems to identify spatial trends. We used separate logistic regression models in 2018 and 2021 to assess the relationship between neighborhood characteristics and the likelihood of a pharmacy implementing a disposal box., Results: We found an increase in disposal boxes over time with 43 pharmacies (1.7%) in 2016, 144 (5.6%) in 2018, and 350 (13.5%) in 2021 implementing a disposal box. In 2018, independent pharmacies were more likely than chains to have a disposal box. In 2021, medical-affiliated and pharmacies defined as "other" were less likely than chains to have a disposal box. In both 2018 and 2021, pharmacies in census tracts with a higher percentage of the population below the federal poverty line were more likely to have a disposal box. In 2021, pharmacies in tracts with a higher percentage of the population unemployed were less likely to have a disposal box. In 2018, pharmacies located in counties with a greater number of opioid overdose deaths were more likely to have a disposal box., Conclusion: Our findings highlight the growth of disposal boxes in North Carolina over time and the potential for continued expansion to provide opportunities to prevent prescription opioid diversion., (Copyright © 2022 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Aims: To investigate the effects of a curriculum that teaches medical decision making and interpersonal communication in the context of prediabetes (preDM) and type 2 diabetes (T2DM)., Methods: This evaluation was an active-controlled trial of 56 patients, including patients who received their diagnosis from intervention-trained clinicians or a control group. Patients attended a research appointment for informed consent and collection of baseline measures. Over the following six months, both groups were mailed surveys and informational handouts monthly. Upon conclusion, we recorded the most recent A1c from the patient's record., Results: An analysis of covariance test revealed patients who received a T2DM diagnosis from an intervention-trained clinician reported higher reassurance from the diagnosing clinician and had a higher perception of threat. Although not statistically significant, patients with T2DM in the intervention group had a lower A1c at follow up and patients in the intervention group reported less poor eating and a higher degree of diet decision making., Conclusions: The curriculum itself does not influence glycemic control, but our results demonstrate the positive impact on patients of the curriculum to teach critical skills to clinicians delivering a diabetes diagnosis., (Published by Elsevier Ltd.)

Background: Effective self-management of type 2 diabetes requires receiving support, which can result from disclosing the diagnosis to a support network, including coworkers, family, and friends. As a primarily invisible disease, diabetes allows people to choose whether to disclose. This study qualitatively explores the factors that influence a person's decision to disclose diabetes to others., Methods: Research coordinators recruited 22 interview participants, ranging in age from 32 to 64 years, whose medical records included a diagnosis code for type 2 diabetes. Participants received care from one of two U.S. medical centers. Semi-structured interviews lasted approximately 1 hour and were audio-recorded and professionally transcribed. Verification strategies such as memo-keeping and maintaining methodological coherence/congruence were used throughout analysis to promote rigor., Results: In patients' descriptions of their decision-making processes regarding whether to disclose their diagnosis, six themes emerged. Three motivations prompted open disclosure: 1 ) to seek information, 2 ) to seek social support, and 3 ) to end the succession of diabetes, and the other three motivations prompted guarded disclosure: 4 ) to prepare for an emergency, 5 ) to maintain an image of health, and 6 ) to protect employment., Conclusion: Based on our findings, we recommend three communicative actions for clinicians as they talk to patients about a diabetes diagnosis. First, clinicians should talk about the benefits of disclosure. Second, they should directly address stereotypes in an effort to de-stigmatize diabetes. Finally, clinicians can teach the skills of disclosure. As disclosure efficacy increases, a person's likelihood to disclose also increases. Individuals can use communication as a tool to gain the knowledge and support they need for diabetes self-management and to interrupt the continuing multigenerational development of diabetes within their family., (© 2022 by the American Diabetes Association.)

Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon (IFN-αβ) and NF-κB signaling; however, the innate immune pathway driving this is currently unknown. Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress. PKR activation was observed in cellular models of decreased proteasome function and in multiple cell types from patients with proteasome-associated autoinflammatory disease (PRAAS). Furthermore, genetic deletion or small-molecule inhibition of PKR in vitro ameliorated inflammation driven by proteasome deficiency. In vivo, proteasome inhibitor-induced inflammatory gene transcription was blunted in PKR-deficient mice compared with littermate controls. PKR also acted as a rheostat for proteotoxic stress by triggering phosphorylation of eIF2α, which can prevent the translation of new proteins to restore homeostasis. Although traditionally known as a sensor of RNA, under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24). When misfolded IL-24 egress into the cytosol was blocked by inhibition of the endoplasmic reticulum-associated degradation pathway, PKR activation and subsequent inflammatory signaling were blunted. Cytokines such as IL-24 are normally secreted from cells; therefore, cytoplasmic accumulation of IL-24 represents an internal danger-associated molecular pattern. Thus, we have identified a mechanism by which proteotoxic stress is detected, causing inflammation observed in the disease PRAAS.

Background: Local health departments require assurance of competence of their workforce to prevent and mitigate outbreaks by supporting the implementation of evidence-based actions in clinical practice, medical procedures and infection control practices. Too often outdated policies or reduction in budgets prevent the appropriate training strategies or resources to recruit, retain or support this capability., Design and Methods: In this 2018 case study analysis, we coupled the Phillip's Return on Investment model with a standard financial proforma model to make a business case that investing in training, specifically the Certification in Infection Control (CIC), was worthwhile for cost reduction, improved knowledge, skills and abilities (KSA's) and improved employee retention., Results: Our model demonstrated that our initial investment (USD $1,840) was profitable based on the internal rate of return (IRR = 130%, Year. 5), payback period (0.71 years), Benefit Cost Ratio (BCR = 1.41) and Return of Investment (ROI = 41%), if an epidemiologist worked a minimum of 3 healthcare associated infection outbreaks per year. Data from 4 local epidemiologists demonstrated that the application of KSA's reduced investigation hours by 10%-25% for all types of outbreaks with payback periods of less than 6 months and positive ROIs for staff with retention greater than 1 year. Our model demonstrated that at the highest end of our investment costs (US $2940) with an investigation improve efficiency of 25%, the IRR was 85% after year 5 with a payback period of 1.13 years if the epidemiologist worked on 3 HAI outbreaks per year over the 5 years., Conclusions: Our results validate the profitability of investment into the CIC for local epidemiologists if they could be retained longer than the payback period. The model provides a method for managers to leverage training opportunities for employee retention while ensuring competencies in the workforce., (Copyright © 2021 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Many high-quality studies presented at conferences never reach the peer-reviewed literature, most likely because physician authors do not take the next step to fully write up the studies and submit them to a journal. We evaluated a curriculum designed to equip authors with the practical skills to submit research projects to peer-reviewed publication., Methods: We designed a mixed asynchronous-synchronous longitudinal curriculum, occurring across 4 months via a virtual platform. To evaluate the curriculum, we tracked process and production outcomes and conducted semistructured interviews with participants following participation., Results: Across two cohorts in 2019, nine participant authors completed the curriculum. Seven participants submitted their studies for publication; two were accepted. In interviews with eight participants, participant authors described the value of the program, expressing intention to participate again and to recommend it to colleagues., Conclusion: Through a coach-directed writing group, participant authors developed the skills and confidence needed to prepare and submit scientific manuscripts for peer review. Curriculum maintenance and enhancement is ongoing. We plan to scale up this innovation in support of other university departments and medical disciplines, developing an implementation guide to describe needed elements, including technological platforms, qualities of the coach, author recruitment, and group conduct., (© 2021 by the Society of Teachers of Family Medicine.)

The majority of cases of T-cell acute lymphoblastic leukemia (T-ALL) contain chromosomal abnormalities that drive overexpression of oncogenic transcription factors. However, whether these initiating oncogenes are required for leukemia maintenance is poorly understood. To address this, we developed a tetracycline-regulated mouse model of T-ALL driven by the oncogenic transcription factor Lmo2. This revealed that whilst thymus-resident pre-Leukemic Stem Cells (pre-LSCs) required continuous Lmo2 expression, the majority of leukemias relapsed despite Lmo2 withdrawal. Relapse was associated with a mature phenotype and frequent mutation or loss of tumor suppressor genes including Ikzf1 (Ikaros), with targeted deletion Ikzf1 being sufficient to transform Lmo2-dependent leukemias to Lmo2-independence. Moreover, we found that the related transcription factor TAL1 was dispensable in several human T-ALL cell lines that contain SIL-TAL1 chromosomal deletions driving its overexpression, indicating that evolution to oncogene independence can also occur in human T-ALL. Together these results indicate an evolution of oncogene addiction in murine and human T-ALL and show that loss of Ikaros is a mechanism that can promote self-renewal of T-ALL lymphoblasts in the absence of an initiating oncogenic transcription factor., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Phosphatidylinositol-specific phospholipase Cγ2 (PLCγ2) is a critical signaling molecule activated downstream from a variety of cell surface receptors that contain an intracellular immunoreceptor tyrosine-based activation motif. These receptors recruit kinases such as Syk, BTK, and BLNK to phosphorylate and activate PLCγ2, which then generates 1D-myo-inositol 1,4,5-trisphosphate and diacylglycerol. These well-known second messengers are required for diverse membrane functionality including cellular proliferation, endocytosis, and calcium flux. As a result, PLCγ2 dysfunction is associated with a variety of diseases including cancer, neurodegeneration, and immune disorders. The diverse pathologies associated with PLCγ2 are exemplified by distinct genetic variants. Inherited mutations at this locus cause PLCγ2-associated antibody deficiency and immune dysregulation, in some cases with autoinflammation. Acquired mutations at this locus, which often arise as a result of BTK inhibition to treat chronic lymphocytic leukemia, result in constitutive downstream signaling and lymphocyte proliferation. Finally, a third group of PLCγ2 variants actually has a protective effect in a variety of neurodegenerative disorders, presumably by increased uptake and degradation of deleterious neurological aggregates. Therefore, manipulating PLCγ2 activity either up or down could have therapeutic benefit; however, we require a better understanding of the signaling pathways propagated by these variants before such clinical utility can be realized. Here, we review the signaling roles of PLCγ2 in hematopoietic cells to help understand the effect of mutations driving immune disorders and cancer and extrapolate from this to roles which may relate to protection against neurodegeneration., Competing Interests: Conflict of interest S. L. M. is a scientific advisor for IFM Therapeutics. J. T. J., E. M., and S. L. N. declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Remission of diabetes can be rewarding for patients and physicians, but there is limited study of how patients perceive the timeline of a disease along the continuum of glycaemic control., Objective: To explore how patients perceive the timeline of diabetes along the continuum of glycaemic control and their goals of care and to identify whether family physicians communicate the principles of regression and remission of diabetes., Design: Mixed methods approach of qualitative semi-structured interviews with purposive sampling followed by cross-sectional survey of physicians., Participants: Thirty-three patients living with prediabetes (preDM) or type 2 diabetes mellitus (T2DM) at medical centres in Georgia and Nevada; and 387 family physicians providing primary care within the same health system., Results: Patients described two timelines of diabetes: as a lifelong condition or as a condition that can be cured. Patients who perceived a lifelong condition described five treatment goals: reducing glucose-related laboratory values, losing weight, reducing medication, preventing treatment intensification and avoiding complications. For patients who perceived diabetes as a disease with an end, the goal of care was to achieve normoglycaemia. In response to patient vignettes that described potential cases of remission and regression, 38.2% of physician respondents would still communicate that a patient has preDM and 94.6% would tell the patient that he still had diabetes., Conclusions: Most physicians here exhibited reluctance to communicate remission or regression in patient care. Yet, patients describe two different potential timelines, including a subset who expect their diabetes can be 'cured'. Physicians should incorporate shared decision making to create a shared mental model of diabetes and its potential outcomes with patients., Patient or Public Contribution: In this mixed methods study, as patients participated in the qualitative phase of this study, we asked patients to tell us what additional questions we should ask in subsequent interviews. Data from this qualitative phase informed the design and interpretation of the quantitative phase with physician participants., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Health Expectations published by John Wiley & Sons Ltd.)

OBF1 is a specific coactivator of the POU family transcription factors OCT1 and OCT2. OBF1 and OCT2 are B cell-specific and indispensable for germinal center (GC) formation, but their mechanism of action is unclear. Here, we show by chromatin immunoprecipitation-sequencing that OBF1 extensively colocalizes with OCT1 and OCT2. We found that these factors also often colocalize with transcription factors of the ETS family. Furthermore, we showed that OBF1, OCT2, and OCT1 bind widely to the promoters or enhancers of genes involved in GC formation in mouse and human GC B cells. Short hairpin RNA knockdown experiments demonstrated that OCT1, OCT2, and OBF1 regulate each other and are essential for proliferation of GC-derived lymphoma cell lines. OBF1 downregulation disrupts the GC transcriptional program: genes involved in GC maintenance, such as BCL6, are downregulated, whereas genes related to exit from the GC program, such as IRF4, are upregulated. Ectopic expression of BCL6 does not restore the proliferation of GC-derived lymphoma cells depleted of OBF1 unless IRF4 is also depleted, indicating that OBF1 controls an essential regulatory node in GC differentiation., (© 2021 by The American Society of Hematology.)

Brevetoxins were confirmed in urine specimens from patients diagnosed with neurotoxic shellfish poisoning (NSP) after consumption of gastropods that were recreationally harvested from an area previously affected by a Karenia brevis bloom. Several species of gastropods (Triplofusus giganteus, Sinistrofulgur sinistrum, Cinctura hunteria, Strombus alatus, Fulguropsis spirata) and one clam (Macrocallista nimbosa) from the NSP implicated gastropod collection area (Jewfish Key, Sarasota Bay, Florida) were examined for brevetoxins using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and enzyme-linked immunosorbent assay (ELISA). All gastropods and the clam were contaminated with brevetoxins. Composite B-type toxin concentrations in gastropods ranged from 1.1 to 198 μg BTX-3 equiv./g by ELISA, levels likely capable of causing NSP in consumers. Several brevetoxin metabolites previously characterized in molluscan shellfish were identified in these gastropods. Brevetoxin analog profiles by ELISA were similar in the gastropod species examined. This work documents the occurrence of NSP through consumption of a type of seafood not typically monitored in Florida to protect human health, demonstrating the need to better assess and communicate the risk of NSP to gastropod harvesters in Karenia brevis endemic areas., (Published by Elsevier Ltd.)

A classical view of blood cell development is that multipotent hematopoietic stem and progenitor cells (HSPCs) become lineage-restricted at defined stages. Lin - c-Kit + Sca-1 + Flt3 + cells, termed lymphoid-primed multipotent progenitors (LMPPs), have lost megakaryocyte and erythroid potential but are heterogeneous in their fate. Here, through single-cell RNA sequencing, we identify the expression of Dach1 and associated genes in this fraction as being coexpressed with myeloid/stem genes but inversely correlated with lymphoid genes. Through generation of Dach1-GFP reporter mice, we identify a transcriptionally and functionally unique Dach1-GFP - subpopulation within LMPPs with lymphoid potential with low to negligible classic myeloid potential. We term these 'lymphoid-primed progenitors' (LPPs). These findings define an early definitive branch point of lymphoid development in hematopoiesis and a means for prospective isolation of LPPs.

Hhex encodes a homeobox transcriptional regulator important for embryonic development and hematopoiesis. Hhex is highly expressed in NK cells, and its germline deletion results in significant defects in lymphoid development, including NK cells. To determine if Hhex is intrinsically required throughout NK cell development or for NK cell function, we generate mice that specifically lack Hhex in NK cells. NK cell frequency is dramatically reduced, while NK cell differentiation, IL-15 responsiveness, and function at the cellular level remain largely normal in the absence of Hhex. Increased IL-15 availability fails to fully reverse NK lymphopenia following conditional Hhex deletion, suggesting that Hhex regulates developmental pathways extrinsic to those dependent on IL-15. Gene expression and functional genetic approaches reveal that Hhex regulates NK cell survival by directly binding Bcl2l11 (Bim) and repressing expression of this key apoptotic mediator. These data implicate Hhex as a transcriptional regulator of NK cell homeostasis and immunity., Competing Interests: Declaration of Interests N.D.H. and J.R. are cofounders and shareholders in oNKo-Innate. The other authors declared no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Most interventions to date regarding breaking bad news focus on late-stage disease or disclosing a cancer diagnosis. Little attention has been given to delivery of chronic metabolic disease diagnoses such as prediabetes/type 2 diabetes., Methods: Informed by the American Diabetes Association standards of care and formative research conducted by our research team, we developed this curriculum through the six-step approach to curriculum development. The curriculum consists of a 2- or 3-hour intervention that teaches medical decision-making, interpersonal communication, and clinical documentation in the context of prediabetes and type 2 diabetes followed by role-play and clinical practice., Results: Across three cohorts, 53 clinicians completed the curriculum. Across the three iterations, learners rated the curricular intervention as worthwhile and delivered at an appropriate level. In a community hospital setting, learners scored significantly higher on a knowledge check than did a control group of six clinicians ( p < .001). Learners in the community hospital also indicated high response efficacy and self-efficacy. At the academic medical center, simulated patients indicated high measures on the Diabetes Health Threat Communication Questionnaire., Discussion: The moment of diagnosis presents a key opportunity to affect patients' perceptions of the disease. This curriculum guides clinicians in making the most of diagnosis delivery. Pairing of qualitative, patient-centered research alongside the iterative curriculum design process allows the curriculum to be adaptable and scalable to multiple settings and learner types., (© 2020 Ledford et al.)

Background and Objectives: Research shows that limited time, lack of funding, difficulty identifying mentors, and lack of technical support limit resident and faculty ability to fully participate in scholarly activity. Most research to date focuses on medical student and resident attitudes toward research. This study aimed to understand the underlying attitudes of family medicine residency (FMR) leaders toward scholarship., Methods: Two focus groups of family medicine residency leaders were conducted in March 2018. The sample (N=19) was recruited through the membership directory of the Family Physicians Inquiry Network., Results: Leaders shared positive attitudes toward scholarship; however, motivation to engage residents and residency faculty in scholarship diverged. Motivations for promoting scholarly activity among participants were either extrinsic (through ACGME, program graduation, or promotion requirements) or intrinsic (through personal interest and natural drive)., Conclusions: Emerging themes illustrate differences in how FMR program leaders perceive the role of scholarship in residency programs. As programs aim to increase research and scholarship, more attention must be paid to the motivating messages communicated by the program's leadership.

The transcription factor Hhex (hematopoietically expressed homeobox gene) is critical for development of multiple lymphoid lineages beyond the common lymphoid progenitor. In addition, Hhex regulates hematopoietic stem cell (HSC) self-renewal, emergency hematopoiesis, and acute myeloid leukemia initiation and maintenance. Hhex mediates its effects on HSCs and acute myeloid leukemia stem cells via repression of the Cdkn2a tumor suppressor locus. However, we report here that loss of Cdkn2a does not rescue the failure of lymphoid development caused by loss of Hhex. As loss of Hhex causes apoptosis of lymphoid progenitors associated with impaired Bcl2 expression and defective Stat5b signaling, we tested the effects of rescuing these pathways using transgenic mice. Expression of the anti-apoptotic factor Bcl2, but not activated Stat5, rescued the development of T-, B-, and NK-cell lineages in the absence of Hhex. These results indicate that Bcl2 expression, but not Stat5b signaling or loss of Cdkn2a, can overcome the lymphoid deficiencies caused by the absence of Hhex, suggesting that the primary role of this transcription factor is to promote survival of lymphoid progenitors during early lymphoid development., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aims: To identify communication cycles patients use to make sense of a diabetes diagnosis and barriers patients encounter in their sensemaking process., Methods: Researchers conducted interviews with 33 participants with type 2 diabetes mellitus or prediabetes at medical centers in Georgia and Nevada. A thematic analysis using the constant comparative method identified communication cycles., Results: Patients reported engaging three communication cycles to make sense of the diagnosis: (1) interacting with healthcare clinicians; (2) seeking information online; and (3) taking a nutrition/diabetes management class. Patients reported system-level barriers that impact sensemaking: (1) lack of consistent or routine care; and (2) lack of access to resources., Conclusion: Results here reinforce the theoretical proposition that receiving a diagnosis is an equivocal process that requires patients to make sense of new information through communication cycles. Patients in this sample repeatedly described communication cycles to interpret this new information rather than relying on assembly rules. Clinicians can promote patient understanding of diabetes and self-management by taking time to explain the diagnosis, maintaining consistent care, providing guidance to online sources, and ensuring patients have access to diabetes education., (Published by Elsevier B.V.)

Introduction: Understanding patients' perspectives about their diabetes and what causes those perspectives to shift is critical to building a treatment strategy with the patient and facilitating patient self-management behavior. Key "turning points" can provide crucial opportunities to enact a change in perspective. The goal of this study is to identify "turning points" that have significance to diabetes-related health., Methods: Research coordinators interviewed 33 patients aged 25 to 65 diagnosed with type 2 diabetes mellitus or prediabetes at medical centers in Augusta, Georgia, and Las Vegas, Nevada. Retrospective interview technique and turning point analysis was employed to plot health or diabetes management changes from diagnosis up to the present day. The constant comparative method was used to conduct a thematic analysis. Axial coding identified properties characterizing each turning point., Results: Patients reported 5 interrelated turning points occurring at various times after diagnosis: 1) gaining knowledge, either through patients own research and/or a health care class; 2) making lifestyle changes, including exercising and healthier eating; 3) encountering a life-changing event/transition, including events that derailed healthy behavior, motivated health behavior, and removed barriers to enacting healthy behavior; 4) receiving social support, either through holding patients accountable or encouraging them to enact healthy behavior; and 5) interacting with clinicians, such as medication changes or behavior changes critical to disease management., Discussion: These turning points provide specific moments throughout diabetes care in which family physicians can effectively partner with patients. By prompting, facilitating, or attending to these turning points, family physicians can partner with patients throughout diabetes care., Competing Interests: Conflicts of interest: None., (© Copyright 2020 by the American Board of Family Medicine.)

Introduction: Recent evidence reveals that diabetes and prediabetes (preDM) can be reversed to normal glucose regulation (NGR) through significant weight loss, but how physicians clinically identify the principles of partial and complete remission of diabetes is largely unknown., Methods: As part of the cross-sectional omnibus survey conducted in March 2019 at a professional annual meeting in the United States, physician participants answered case scenario questions about the diagnosis and documentation of patients with preDM and type 2 diabetes (T2DM)., Results: Of the registered conference attendees, 387 (72.7%) responded. When presented with the initial case of preDM, 201 physicians (70.8%) selected R73.03 Prediabetes. In a follow-up encounter with improved lab results, 118 physicians (58.7%) indicated that they would not chart any diabetes-related code and 62 (30.8%) would chart preDM again. When presented with the case of T2DM, 256 physicians (90.1%) indicated E11.0-E11.9 Type 2 Diabetes. In the follow-up encounter, only 38 (14.8%) coded a diagnosis reflecting remission from T2DM to prediabetes and 211 (82.4%) charted T2DM., Conclusion: Physicians may be reluctant to document diabetes regression as there is little evidence for long-term outcomes and "downgrading" the diagnosis in the medical record may cause screenings to be missed. Documenting this regression in the medical record should communicate the accurate point on the continuum of glucose intolerance with both the patient and the care team.

Objective: This qualitative study sought to identify and describe patients' variant perceptions of disease severity after receiving a type 2 diabetes (T2DM) or prediabetes (preDM) diagnosis. Design: Researchers interviewed 29 patients from two US medical centers to ascertain perceptions of severity. We used the constant comparative method from a grounded theory approach to identify themes from patients' perspectives that inform their disease severity. This approach was used to help translate research to practice and ultimately identify intervention strategies informed by authentic experiences of preDM and T2DM patients. Results: Perceptions of disease severity fell into two groups: high and low severity. Patients diagnosed with T2DM and preDM emerged in both groups and were comparative in terms of sample size, gender, and ethnic diversity. Several factors contributed to patients' beliefs, including what they were told about the disease, observations from experiences within their own social network, and information from formal diabetes classes and their own research. The two perspectives diverged when patients described how their belief was informed by three thematic properties or personal factors: (i) fears ; (ii) clinician communication ; and (iii) social comparisons . Conclusions: Beliefs about severity are influenced by patients' fears, interactions with clinicians, and experiences within their social networks. These findings show that when interacting with patients with T2DM or preDM, clinicians should elicit patient perceptions of disease severity so they may then tailor the discussion to address these perceptions and help patients grasp the severity of these conditions.

T cell acute lymphoblastic leukaemia (T-ALL) cases include subfamilies that overexpress the TAL1/LMO, TLX1/3 and HOXA transcription factor oncogenes. While it has been shown that TAL1/LMO transcription factors induce self-renewal of thymocytes, whether this is true for other transcription factor oncogenes is unknown. To address this, we have studied NUP98-HOXD13-transgenic (NHD13-Tg) mice, which overexpress HOXA transcription factors throughout haematopoiesis and develop both myelodysplastic syndrome (MDS) progressing to acute myeloid leukaemia (AML) as well as T-ALL. We find that thymocytes from preleukaemic NHD13-Tg mice can serially transplant, demonstrating that they have self-renewal capacity. Transcriptome analysis shows that NHD13-Tg thymocytes exhibit a stem cell-like transcriptional programme closely resembling that induced by Lmo2, including Lmo2 itself and its critical cofactor Lyl1. To determine whether Lmo2/Lyl1 are required for NHD13-induced thymocyte self-renewal, NHD13-Tg mice were crossed with Lyl1 knockout mice. This showed that Lyl1 is essential for expression of the stem cell-like gene expression programme in thymocytes and self-renewal. Surprisingly however, NHD13 transgenic mice lacking Lyl1 showed accelerated T-ALL and absence of transformation to AML, associated with a loss of multipotent progenitors in the bone marrow. Thus multiple T cell oncogenes induce thymocyte self-renewal via Lmo2/Lyl1; however, NHD13 can also promote T-ALL via an alternative pathway.

Background: Physician burnout is an ongoing problem that affects both physician wellbeing and patient care. Burnout is characterized by emotional exhaustion and depersonalization. Studies have explored ways to prevent and alleviate burnout. Receiving training in acupuncture may reduce physician burnout., Objective: The purpose of this study is to determine if acupuncture training is associated with less patient depersonalization and less emotional exhaustion among physicians., Methods: These self-reported data were collected from a cross-sectional survey of family physicians at the Uniformed Services Academy of Family Physicians 2017 conference. Physicians answered questions regarding their level of acupuncture training as well as questions about burnout (depersonalization and emotional exhaustion)., Results: The overall response rate was 66% (325/492). Of these, 233 cases provided complete datasets. In a model controlling for years' practice and clinical pace, acupuncture training was significantly associated with decreased depersonalization, F (1, 194) = 5.82, P < .05., Conclusion: Study data show an association between decreased physician depersonalization and acupuncture training, suggesting acupuncture training may be a helpful strategy to reduce family physicians' depersonalization of patients., Competing Interests: Conflict of interest: none declared., (© Copyright 2019 by the American Board of Family Medicine.)

Objective: To demonstrate how the chronic care model can be applied in prenatal care., Methods: This study was conducted through analysis of data generated in the women's health and family medicine departments of one community hospital and two medical centers across three states (Georgia, Nevada, and Virginia). 159 low-risk obstetric patients were monitored throughout their pregnancy for patient activation and biometric measures including: blood pressure at each appointment, baby's gestational age at birth, and mode of delivery. Patient activation was assessed with the validated, licensed patient activation measure., Results: Patient activation was strongly associated with the Prenatal Interpersonal Processes of Care metric (F (2, 155) = 3.41, p < .05). Also, increased age, decreased Prenatal Interpersonal Processes of Care, fewer pregnancies, and increased diastolic blood pressure were associated with an increased likelihood of cesarean delivery and the model correctly predicted 81% of cases., Conclusion: Women who identified as feeling more activated reported more positive pregnancy experiences, and women who reported more positive pregnancy experiences were more likely to experience a vaginal delivery., Practice Implications: Activated patients, more positive prenatal experience, and improved delivery outcomes can be achieved through applying the chronic care model., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The hematopoietically expressed homeobox (Hhex) transcription factor is overexpressed in human myeloid leukemias. Conditional knockout models of murine acute myeloid leukemia indicate that Hhex maintains leukemia stem cell self-renewal by enabling Polycomb-mediated epigenetic repression of the Cdkn2a tumor suppressor locus, encoding p16 Ink4a and p19 Arf However, whether Hhex overexpression also affects hematopoietic differentiation is unknown. To study this, we retrovirally overexpressed Hhex in hematopoietic progenitors. This enabled serial replating of myeloid progenitors, leading to the rapid establishment of interleukin-3 (IL-3)-dependent promyelocytic cell lines. Use of a Hhex-ERT2 fusion protein demonstrated that continuous nuclear Hhex is required for transformation, and structure function analysis demonstrated a requirement of the DNA-binding and N-terminal-repressive domains of Hhex for promyelocytic transformation. This included the N-terminal promyelocytic leukemia protein (Pml) interaction domain, although deletion of Pml failed to prevent Hhex -induced promyelocyte transformation, implying other critical partners. Furthermore, deletion of p16 Ink4a or p19 Arf did not promote promyelocyte transformation, indicating that repression of distinct Hhex target genes is required for this process. Indeed, transcriptome analysis showed that Hhex overexpression resulted in repression of several myeloid developmental genes. To test the potential for Hhex overexpression to contribute to leukemic transformation, Hhex -transformed promyelocyte lines were rendered growth factor-independent using a constitutively active IL-3 receptor common β subunit (βcV449E). The resultant cell lines resulted in a rapid promyelocytic leukemia in vivo. Thus, Hhex overexpression can contribute to myeloid leukemia via multiple mechanisms including differentiation blockade and enabling epigenetic repression of the Cdkn2a locus., (© 2018 by The American Society of Hematology.)

Introduction: Assisting polypharmacy patients with complex health regimens is a part of health provider responsibilities. The concepts of adherence and concordance contrast the traditional emphasis on patient compliance. However, health provider students may not be able to empathize with polypharmacy patients. The purpose of this study was to measure the effect of a medication simulation on medical, nursing, and pharmacy students' beliefs about adherence and concordance., Methods: A prospective, quasi-experimental, pretest, and posttest design was used with institutional review board approval. The participants (N = 62) took four simulated medications (varied dosing schedules) for 1 week. Attitudes toward adherence and concordance were assessed before and after the intervention., Results: Subjects averaged 24.6 years (SD = 4.32), 72.6% female, and 79% white. Most were medical students (n = 33, 53%), followed by nursing (n = 21, 34%) and pharmacy students (n = 8, 13%). There were significant changes [t(61) = 3.92, P < 0.001] in beliefs about adherence from time 1 (mean = 25.13, SD = 5.77) to time 2 (mean = 22.05, SD = 6.06), and about concordance (mean = 41.85, SD = 5.58 time 1) to (mean = 44.29, SD = 6.32 time 2) [t(61) = 3.31, P < 0.05], for the entire group. Most students (84%) predicted that they would be able to take four medications correctly for 1 week. Fifty-eight students (94%) found that adherence was 'much harder' or 'a little harder' than anticipated. Most (89%) felt that the simulation will impact their patient care., Conclusions: Participation in a medication simulation exercise affected health provider students' attitudes toward adherence and concordant behaviors. These experiences may influence future patient interactions.

The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin - Sca + Kit + cells showed that Hhex deletion leads to derepression of polycomb repressive complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16 Ink 4 a and p19 Arf . Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress. Stem Cells 2017;35:1948-1957., (© 2017 AlphaMed Press.)

Unlike clustered HOX genes, the role of nonclustered homeobox gene family members in hematopoiesis and leukemogenesis has not been extensively studied. Here we found that the hematopoietically expressed homeobox gene Hhex is overexpressed in acute myeloid leukemia (AML) and is essential for the initiation and propagation of MLL-ENL-induced AML but dispensable for normal myelopoiesis, indicating a specific requirement for Hhex for leukemic growth. Loss of Hhex leads to expression of the Cdkn2a-encoded tumor suppressors p16(INK4a) and p19(ARF), which are required for growth arrest and myeloid differentiation following Hhex deletion. Mechanistically, we show that Hhex binds to the Cdkn2a locus and directly interacts with the Polycomb-repressive complex 2 (PRC2) to enable H3K27me3-mediated epigenetic repression. Thus, Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal., (© 2016 Shields et al.; Published by Cold Spring Harbor Laboratory Press.)

Interprofessional collaboration has become a critical component of accreditation standards in dentistry and medicine. This article reports on implementation in an academic setting of a prenatal oral health program (pOHP) that addresses coordinated care, accreditation standards, and new clinical practice guidelines. The pOHP is an educational intervention for third-year medical students, residents, and faculty members to deliver preventive oral health information and referral to a dental home for pregnant women. At the same time, senior dental students and faculty members are introduced to prenatal oral health principles and delivery of comprehensive oral health care to pregnant women. A systems-based approach was used to guide the pOHP implementation during the 2012-13 academic year. Participants were 96 third-year medical students (50% of the total in an obstetrics and gynecology clerkship) and all 81 fourth-year dental students. During that academic year, 126 dental referrals were made to the School of Dentistry, and 55 women presented for care, resulting in 50% (n=40) of dental students participating in the clinical experience and delivery of simple to complex oral health procedures. The prenatal period is a frequently missed opportunity to address oral health care. The pOHP is an interprofessional collaboration model designed to educate dental and medical providers and provide a system of referral for comprehensive clinical care of pregnant patients, including educating women about their oral health and that of their children. Such programs can help meet interprofessional accreditation standards and encourage implementation of practice guidelines.

The hematopoietically expressed homeobox gene, Hhex, is a transcription factor that is important for development of definitive hematopoietic stem cells (HSCs) and B cells, and that causes T-cell leukemia when overexpressed. Here, we have used an Hhex inducible knockout mouse model to study the role of Hhex in adult hematopoiesis. We found that loss of Hhex was tolerated in HSCs and myeloid lineages, but resulted in a progressive loss of B lymphocytes in the circulation. This was accompanied by a complete loss of B-cell progenitors in the bone marrow and of transitional B-cell subsets in the spleen. In addition, transplantation and in vitro culture experiments demonstrated an almost complete failure of Hhex-null HSCs to contribute to lymphoid lineages beyond the common lymphoid precursor stage, including T cells, B cells, NK cells, and dendritic cells. Gene expression analysis of Hhex-deleted progenitors demonstrated deregulated expression of a number of cell cycle regulators. Overexpression of one of these, cyclin D1, could rescue the B-cell developmental potential of Hhex-null lymphoid precursors. Thus, Hhex is a key regulator of early lymphoid development, functioning, at least in part, via regulation of the cell cycle., (© 2015 by The American Society of Hematology.)

Lmo2 is an oncogenic transcription factor that is frequently overexpressed in T-cell acute lymphoblastic leukemia (T-ALL), including early T-cell precursor ALL (ETP-ALL) cases with poor prognosis. Lmo2 must be recruited to DNA by binding to the hematopoietic basic helix-loop-helix factors Scl/Tal1 or Lyl1. However, it is unknown which of these factors can mediate the leukemic activity of Lmo2. To address this, we have generated Lmo2-transgenic mice lacking either Scl or Lyl1 in the thymus. We show that although Scl is dispensable for Lmo2-driven leukemia, Lyl1 is critical for all oncogenic functions of Lmo2, including upregulation of a stem cell-like gene signature, aberrant self-renewal of thymocytes, and subsequent generation of T-cell leukemia. Lyl1 expression is restricted to preleukemic and leukemic stem cell populations in this model, providing a molecular explanation for the stage-specific expression of the Lmo2-induced gene expression program. Moreover, LMO2 and LYL1 are coexpressed in ETP-ALL patient samples, and LYL1 is required for growth of ETP-ALL cell lines. Thus, the LMO2-LYL1 interaction is a promising therapeutic target for inhibiting self-renewing cancer stem cells in T-ALL, including poor-prognosis ETP-ALL cases.