COVID-19 and practice transformation: Building an office-based opioid treatment program in a family medicine residency practice.

INTRODUCTION: This brief report describes how a family medicine residency practice (FMRP) leveraged a resident-led quality improvement project and a grant-funded Addiction Integrated Care Team (AICT) to initiate an office-based opioid treatment (OBOT) program to provide medications for opioid use disorder during the COVID-19 pandemic. METHOD: In 2020, the practice experienced four disruptors that shifted motivation for practice development: (a) The COVID-19 pandemic demanded rapid change in primary care processes/staffing, including pivoting to telehealth/remote practice. (b) The practice's transition to a federally qualified community health center model meant a shift in organizational priorities that required offering OBOT services. (c) External grant resources became available through the AICT program to support practice core for OBOT, and 10 implementation strategies were utilized. (d) A resident champion implemented an OBOT quality improvement project. RESULTS: These efforts resulted in the practice offering the OBOT program and 18 patients receiving OBOT from January 2020 to February 2021, with 10 of 18 patients engaged for 12 months or longer. Further, the cumulative adoption and reach from January 2020 through September 2022 was 15 faculty and 14 residents becoming prescribers and 101 patients served within the OBOT program, respectively. DISCUSSION: FMRPs striving for significant practice transformation, such as implementing an OBOT program during a pandemic, may benefit from synergistic guidance and resources including established theory, strategies from the implementation science literature, and resident-led quality improvement efforts. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Designing and Evaluating a Prediabetes Shared Decision Aid.

BACKGROUND: Prediabetes is increasing in prevalence and is associated with risk of developing diabetes, heart disease, stroke, and retinopathy. Clinicians have limited tools to facilitate prediabetes discussions within primary care visits. PURPOSE: 1) Develop a Patient and Stakeholder Advisory Committee (PASAC) to design, evaluate, and revise a prediabetes shared decision aid, and 2) evaluate the feasibility and experience of implementing the tool within primary care practice. METHODS: A prediabetes decision aid (double-sided infographic with decision questions) was created by a PASAC that included patients, primary care clinicians, diabetes educators, endocrinologists, and pharmacists. Five clinicians within 3 primary care practices tested the prediabetes tool with 50 adult patients with prediabetes. Patients completed 2 surveys immediately after the office visit and 6 weeks later. Clinicians and PASAC members completed a postintervention survey. RESULTS: The prediabetes shared decision aid was created through a deliberative process over 3 PASAC meetings. Ninety-six percent of patients felt the tool prepared them to decide on a diabetes prevention plan, and 100% of clinicians would use the tool again and felt the tool did not extend visit length. DISCUSSION: It was feasible to cocreate a prediabetes shared decision aid within a PASAC and implement the tool within a primary care setting. Patients and clinicians reported a prediabetes discussion, which may mitigate rates of progression to diabetes and associated complications. Future research should evaluate which of the intervention components most effectively promotes discussion of prediabetes within a primary care setting.

Self-association motifs in the enteroaggregative Escherichia coli heat-resistant agglutinin 1.

The heat-resistant agglutinin 1 (Hra1) is an integral outer membrane protein found in strains of Escherichia coli that are exceptional colonizers. Hra1 from enteroaggregative E. coli strain 042 is sufficient to confer adherence to human epithelial cells and to cause bacterial autoaggregation. Hra1 is closely related to the Tia invasin, which also confers adherence, but not autoaggregation. Here, we have demonstrated that Hra1 mediates autoaggregation by self-association and we hypothesize that at least some surface-exposed amino acid sequences that are present in Hra1, but absent in Tia, represent autoaggregation motifs. We inserted FLAG tags along the length of Hra1 and used immune-dot blots to verify that four in silico-predicted outer loops were indeed surface exposed. In Hra1 we swapped nine candidate motifs in three of these loops, ranging from one to ten amino acids in length, to the corresponding sequences in Tia. Three of the motifs were required for Hra1-mediated autoaggregation. The database was searched for other surface proteins containing these motifs; the GGXWRDDXK motif was also present in a surface-exposed region of Rck, a Salmonella enterica serotype Typhimurium complement resistance protein. Cloning and site-specific mutagenesis demonstrated that Rck can confer weak, GGXWRDDXK-dependent autoaggregation by self-association. Hra1 and Rck appear to form heterologous associations and GGXWRDDXK is required on both molecules for Hra1-Rck association. However, a GGYWRDDLKE peptide was not sufficient to interfere with Hra1-mediated autoaggregation. In the present study, three autoaggregation motifs in an integral outer membrane protein have been identified and it was demonstrated that at least one of them works in the context of a different cell surface.

Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia.

Notch is needed for T-cell development and is a common oncogenic driver in T-cell acute lymphoblastic leukemia. The protooncogene c-Myc (Myc) is a critical target of Notch in normal and malignant pre-T cells, but how Notch regulates Myc is unknown. Here, we identify a distal enhancer located >1 Mb 3' of human and murine Myc that binds Notch transcription complexes and physically interacts with the Myc proximal promoter. The Notch1 binding element in this region activates reporter genes in a Notch-dependent, cell-context-specific fashion that requires a conserved Notch complex binding site. Acute changes in Notch activation produce rapid changes in H3K27 acetylation across the entire enhancer (a region spanning >600 kb) that correlate with Myc expression. This broad Notch-influenced region comprises an enhancer region containing multiple domains, recognizable as discrete H3K27 acetylation peaks. Leukemia cells selected for resistance to Notch inhibitors express Myc despite epigenetic silencing of enhancer domains near the Notch transcription complex binding sites. Notch-independent expression of Myc in resistant cells is highly sensitive to inhibitors of bromodomain containing 4 (Brd4), a change in drug sensitivity that is accompanied by preferential association of the Myc promoter with more 3' enhancer domains that are strongly dependent on Brd4 for function. These findings indicate that altered long-range enhancer activity can mediate resistance to targeted therapies and provide a mechanistic rationale for combined targeting of Notch and Brd4 in leukemia.

Expression of Notch signaling components in cutaneous foreign body and sarcoidal granulomas and fusing macrophages.

The evolutionarily conserved Notch signaling pathway affects tissue-specific cell differentiation, proliferation, and apoptosis. In the immune system, Notch has been implicated in the development and function of both adoptive and innate immune cells. Notch signaling is initiated by Notch receptor binding to cognate ligands, which results in the enzymatic cleavage and intranuclear translocation of the intracellular domain of Notch receptor (ICN). Recent murine models of chronic inflammation highlighted a critical role for a Notch ligand, Delta-like ligand (Dll)-4, in granuloma formation. In this study, we aimed to assess Notch-1 receptor activation and Dll4 expression in human cutaneous granulomas and in cultured human macrophages and multinucleated giant cells. ICN1 and Dll4 expression was evaluated by immunohistochemistry of cutaneous foreign body (n = 15) and sarcoidal (n = 19) granulomas. The results showed consistent intranuclear staining for ICN1 in foreign body but not in sarcoidal granulomas and strong cytoplasmic staining for Dll4 in mononuclear histiocytes and multinucleate giant cells in both types of granulomas. Additionally, immunofluorescence confocal microscopy showed ICN1 and Dll4 expression by cultured human macrophages undergoing fusion in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4. These findings indicate a potential role for the Notch-1-Dll4 signaling pathway in foreign body-induced granulomatous reactions and possibly distinct Notch pathway utilization in sarcoidal granulomas.

The heat-resistant agglutinin family includes a novel adhesin from enteroaggregative Escherichia coli strain 60A.

Heat-resistant agglutinin 1 (Hra1) is an accessory colonization factor of enteroaggregative Escherichia coli (EAEC) strain 042. Tia, a close homolog of Hra1, is an invasin and adhesin that has been described in enterotoxigenic E. coli. We devised a PCR-restriction fragment length polymorphism screen for the associated genes and found that they occur among 55 (36.7%) of the enteroaggregative E. coli isolates screened, as well as lower proportions of enterotoxigenic, enteropathogenic, enterohemorrhagic, and commensal E. coli isolates. Overall, 25%, 8%, and 3% of 150 EAEC strains harbored hra1 alone, tia alone, or both genes, respectively. One EAEC isolate, 60A, produced an amplicon with a unique restriction profile, distinct from those of hra1 and tia. We cloned and sequenced the full-length agglutinin gene from strain 60A and have designated it hra2. The hra2 gene was not detected in any of 257 diarrheagenic E. coli isolates in our collection but is present in the genome of Salmonella enterica serovar Heidelberg strain SL476. The cloned hra2 gene from strain 60A, which encodes a predicted amino acid sequence that is 64% identical to that of Hra1 and 68% identical to that of Tia, was sufficient to confer adherence on E. coli K-12. We constructed an hra2 deletion mutant of EAEC strain 60A. The mutant was deficient in adherence but not autoaggregation or invasion, pointing to a functional distinction from the autoagglutinin Hra1 and the Tia invasin. Hra1, Tia, and the novel accessory adhesin Hra2 are members of a family of integral outer membrane proteins that confer different colonization-associated phenotypes.