Optimization of a Novel DEL Hit That Binds in the Cbl-b SH2 Domain and Blocks Substrate Binding.

We were attracted to the therapeutic potential of inhibiting Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING E3 ligase that plays a critical role in regulating the activation of T cells. However, given that only protein-protein interactions were involved, it was unclear whether inhibition by a small molecule would be a viable approach. After screening an ∼6 billion member DNA-encoded library (DEL) using activated Cbl-b, we identified compound 1 as a hit for which the cis-isomer (2) was confirmed by biochemical and surface plasmon resonance (SPR) assays. Our hit optimization effort was greatly accelerated when we obtained a cocrystal structure of 2 with Cbl-b, which demonstrated induced binding at the substrate binding site, namely, the Src homology-2 (SH2) domain. This was quite noteworthy given that there are few reports of small molecule inhibitors that bind to SH2 domains and block protein-protein interactions. Structure- and property-guided optimization led to compound 27, which demonstrated measurable cell activity, albeit only at high concentrations.

Nurse practitioner and physician assistant transition to practice: A scoping review of fellowships and onboarding programs.

BACKGROUND: Newly graduated nurse practitioners (NPs) and physician assistants (PAs) benefit from transition-to-practice (TTP) support to move successfully into practice. Transition-to-practice programs (i.e., onboarding programs and fellowships/residencies) hold promise for improving workforce outcomes. PURPOSE: The purpose of this scoping review was to describe the literature regarding NP/PA TTP programs. METHODOLOGY: Using the Joanna Briggs Institute methodology, a specific approach for systematically conducting reviews, publications from January 1990 to May 2022 were included for review if they addressed fellowships/residencies or onboarding programs for NPs or PAs. Final data extraction involved 216 articles. RESULTS: The pace of publication increased over time, with a noticeable increase since 2015. Articles were most commonly about fellowships/residencies, NPs, and programs set in United States nonrural, acute care settings, and academic health centers. CONCLUSIONS/IMPLICATIONS: There is a gap in our understanding of onboarding programs and programs focusing on PAs, as well as TTP support in rural and primary care settings. In addition, there are few articles that assess TTP program outcomes such as benefits and costs. This review describes the need for more published literature in these areas.

NP and PA transition to practice: A scoping review of fellowships and onboarding programs.

OBJECTIVES: Newly graduated NPs and physician associates/assistants (PAs) benefit from transition to practice (TTP) support to move successfully into practice. TTP programs (such as onboarding programs, fellowships, and residencies) hold promise for improving workforce outcomes. The purpose of this scoping review was to describe the literature regarding NP/PA TTP programs. METHODS: Using the Joanna Briggs Institute methodology, a specific approach for systematically conducting reviews, publications from January 1990 to May 2022 were included if they addressed fellowships, residencies, or onboarding programs for NPs or PAs. Final data extraction involved 216 articles. RESULTS: The pace of publication increased over time, with a noticeable increase since 2015. Articles were most commonly about fellowships or residencies, NPs, and programs set in nonrural, acute care US settings and in academic health centers. CONCLUSIONS: A gap exists in our understanding of onboarding programs and programs focusing on PAs, as well as TTP support in rural and primary care settings. In addition, few articles assess TTP program outcomes such as benefits and costs. This review describes the need for more published literature in these areas.

Impact of primary care usual provider type and provider interdependence on outcomes for patients with diabetes: a cohort study.

BACKGROUND: Interprofessional primary care (PC) teams are key to the provision of high-quality care. PC providers often 'share' patients (eg, a patient may see multiple providers in the same clinic), resulting in between-visit interdependence between providers. However, concern remains that PC provider interdependence will reduce quality of care, causing some organisations to hesitate in creating multiple provider teams. If PC provider teams are formalised, the PC usual provider of care (UPC) type (physician, nurse practitioner (NP) or physician assistant/associate (PA)) should be determined for patients with varying levels of medical complexity. OBJECTIVE: To evaluate the impact of PC provider interdependence, UPC type and patient complexity on diabetes-specific outcomes for adult patients with diabetes. DESIGN: Cohort study using electronic health record data from 26 PC practices in central North Carolina, USA. PARTICIPANTS: Adult patients with diabetes (N=10 498) who received PC in 2016 and 2017. OUTCOME: Testing for diabetes control, testing for lipid levels, mean glycated haemoglobin (HbA1c) values and mean low-density lipoprotein (LDL) values in 2017. RESULTS: Receipt of guideline recommended testing was high (72% for HbA1c and 66% for LDL testing), HbA1c values were 7.5% and LDL values were 88.5 mg/dL. When controlling for a range of patient and panel level variables, increases in PC provider interdependence were not significantly associated with diabetes-specific outcomes. Similarly, there were no significant differences in the diabetes outcomes for patients with NP/PA UPCs when compared with physicians. The number and type of a patient's chronic conditions did impact the receipt of testing, but not average values for HbA1c and LDL. CONCLUSIONS: A range of UPC types on PC multiple provider teams can deliver guideline-recommended diabetes care. However, the number and type of a patient's chronic conditions alone impacted the receipt of testing, but not average values for HbA1c and LDL.

Physician assistant and nurse practitioner onboarding in primary care: The participant perspective.

BACKGROUND: Many new graduate primary care physician assistants (PAs) and nurse practitioners (NPs) can experience stress and difficulty as they transition to practice. Feelings of anxiety and role ambiguity are common and can lead to costly turnover, impact care continuity, and place patients at risk for poor clinical outcomes. Onboarding, the process of helping new hires adjust to social and performance aspects of their new job and has the potential to ease transition to practice for PAs and NPs. Recent research has linked PA/NP onboarding programs to increased engagement, decreased turnover, and higher clinical productivity. PURPOSE: To describe new graduate PA and NP perspectives of onboarding programs they completed in their first primary care position. METHODOLOGY: Thirteen semistructured interviews were conducted with new graduate PAs and NPs who participated in onboarding programs. Interviews were transcribed and then analyzed using an inductive coding methodology. RESULTS: Analyses revealed nine thematic concepts that are described within two frameworks. Structural components include improving competence, training on the electronic health record, promoting mentorship, orienting to organizational dynamics, tailoring ramp-up of patient scheduling, clarifying expectations, and providing clear organizational support. Psychosocial factors include creating comfort and building self-confidence. CONCLUSION: Understanding participants' experiences with onboarding programs is essential for ensuring successful transition to practice for new graduate PAs and NPs. IMPLICATIONS: These findings are beneficial to the health care workforce. Administrators can incorporate these findings into existing and future programs, and new graduate PAs and NPs can negotiate for the inclusion of these components in their first position.

PA and NP onboarding in primary care: The participant perspective.

OBJECTIVE: To describe new graduate physician associate/assistant (PA) and NP perspectives of onboarding programs in their first primary care position. METHODS: Thirteen semistructured interviews were conducted with new graduate PAs and NPs who participated in onboarding programs. Interviews were transcribed and then analyzed using an inductive coding methodology. RESULTS: Analyses revealed nine thematic concepts that are described in two frameworks. Structural components are improving competence, training on the electronic health record (EHR), promoting mentorship, orienting to organizational dynamics, tailoring ramp-up of patient scheduling, clarifying expectations, and providing clear organizational support. Psychosocial factors are creating comfort and building self-confidence. DISCUSSION: The results describe and delineate important components for onboarding that administrators can incorporate into existing and future programs. CONCLUSION: Understanding participants' experiences with onboarding programs is essential for ensuring successful transition to practice for new graduate PAs and NPs.

When is caring sharing? Primary care provider interdependence and continuity of care.

ABSTRACT: Efforts to improve access to high-quality, efficient primary care have highlighted the need for team-based care. Most primary care teams are designed to maintain continuity of care between patients and primary care providers (PCPs), because continuity of care can improve some patient outcomes. However, PCPs are interdependent because they care for, or share, patients. PCP interdependence, and its association with continuity of care, is not well described. This study describes a measure of PCP interdependence. We also evaluate the association between patient and panel characteristics, including PCP interdependence. Our results found that the extent of interdependence between PCPs in the same clinic varies widely. A range of patient and panel characteristics affect continuity of care, including patient complexity and PCP interdependence. These results suggest that continuity of care for complex patients is sensitive to panel characteristics, including PCP interdependence and panel size. This information can be used by primary care organizations for evidence-based team design.

Transition-to-practice programs for newly graduated advanced practice registered nurses and physician assistants: a scoping review protocol.

OBJECTIVE: The objective of this scoping review is to map the evidence on transition-to-practice programs for newly graduated advanced practice registered nurses and physician assistants, and describe how they differ. Additional objectives include summarizing what outcomes are evaluated and what gaps remain within the literature. By consolidating this information, health care administrators may more easily reference transition-to-practice methods to enhance their own programs for advanced practice registered nurses and physician assistants.z. INTRODUCTION: Transition to practice involves 2 program types: onboarding and postgraduate training. However, no existing reviews describe the state of the literature regarding these program types, and how they compare with regard to location, setting, and outcomes. Because transition-to-practice programs may improve workforce outcomes, understanding how these programs differ, and what gaps exist, is needed to help these programs grow. INCLUSION CRITERIA: This review will include articles describing transition to practice for advanced practice registered nurses and/or physician assistants, including onboarding and fellowship/residency programs. Articles will be included regardless of geographic location if they take place within a professional, clinical setting. METHODS: The scoping review will follow the JBI approach. Databases to be searched include MEDLINE (PubMed), CINAHL, Cochrane Central Register of Controlled Trials, Embase, ProQuest Dissertations and Theses, Scopus, and Web of Science. All included manuscripts will be screened by two reviewers and relevant data will be extracted. These data will summarize what transition to practice programs are used, how they differ, and what gaps exist.

Loss of the intracellular enzyme QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity.

Tumor-associated macrophages are composed of distinct populations arising from monocytes or tissue macrophages, with a poorly understood link to disease pathogenesis. Here, we demonstrate that mouse monocyte migration was supported by glutaminyl-peptide cyclotransferase-like (QPCTL), an intracellular enzyme that mediates N-terminal modification of several substrates, including the monocyte chemoattractants CCL2 and CCL7, protecting them from proteolytic inactivation. Knockout of Qpctl disrupted monocyte homeostasis, attenuated tumor growth and reshaped myeloid cell infiltration, with loss of monocyte-derived populations with immunosuppressive and pro-angiogenic profiles. Antibody targeting of the receptor CSF1R, which more broadly eliminates tumor-associated macrophages, reversed tumor growth inhibition in Qpctl-/- mice and prevented lymphocyte infiltration. Modulation of QPCTL synergized with anti-PD-L1 to expand CD8+ T cells and limit tumor growth. QPCTL inhibition constitutes an effective approach for myeloid cell-targeted cancer immunotherapy.

Oncostatin M expression induced by bacterial triggers drives airway inflammatory and mucus secretion in severe asthma.

Exacerbations of symptoms represent an unmet need for people with asthma. Bacterial dysbiosis and opportunistic bacterial infections have been observed in, and may contribute to, more severe asthma. However, the molecular mechanisms driving these exacerbations remain unclear. We show here that bacterial lipopolysaccharide (LPS) induces oncostatin M (OSM) and that airway biopsies from patients with severe asthma present with an OSM-driven transcriptional profile. This profile correlates with activation of inflammatory and mucus-producing pathways. Using primary human lung tissue or human epithelial and mesenchymal cells, we demonstrate that OSM is necessary and sufficient to drive pathophysiological features observed in severe asthma after exposure to LPS or Klebsiella pneumoniae. These findings were further supported through blockade of OSM with an OSM-specific antibody. Single-cell RNA sequencing from human lung biopsies identified macrophages as a source of OSM. Additional studies using Osm-deficient murine macrophages demonstrated that macrophage-derived OSM translates LPS signals into asthma-associated pathologies. Together, these data provide rationale for inhibiting OSM to prevent bacterial-associated progression and exacerbation of severe asthma.

Teaming up in primary care: Membership boundaries, interdependence, and coordination.

OBJECTIVE: Increased demand for quality primary care and value-based payment has prompted interest in implementing primary care teams. Evidence-based recommendations for implementing teams will be critical to successful PA participation. This study sought to describe how primary care providers (PCPs) define team membership boundaries and coordinate tasks. METHODS: This mixed-methods study included 28 PCPs from a primary care network. We analyzed survey data using descriptive statistics and interview data using content analysis. RESULTS: Ninety-six percent of PCPs reported team membership. Team models fell into one of five categories. The predominant coordination mechanism differed by whether coordination was required in a visit or between visits. CONCLUSIONS: Team-based primary care is a strategy for improving access to quality primary care. Most PCPs define team membership based on within-visit task interdependencies. Our findings suggest that team-based interventions can focus on clarifying team membership, increasing interaction between clinicians, and enhancing the electronic health record to facilitate between-visit coordination.

A framework for microbiome science in public health.

Human microbiome science has advanced rapidly and reached a scale at which basic biology, clinical translation and population health are increasingly integrated. It is thus now possible for public health researchers, practitioners and policymakers to take specific action leveraging current and future microbiome-based opportunities and best practices. Here we provide an outline of considerations for research, education, interpretation and scientific communication concerning the human microbiome and public health. This includes guidelines for population-scale microbiome study design; necessary physical platforms and analysis methods; integration into public health areas such as epidemiology, nutrition, chronic disease, and global and environmental health; entrepreneurship and technology transfer; and educational curricula. Particularly in the near future, there are both opportunities for the incorporation of microbiome-based technologies into public health practice, and a growing need for policymaking and regulation around related areas such as prebiotic and probiotic supplements, novel live-cell therapies and fecal microbiota transplants.

Overview of the Microbiome Among Nurses study (Micro-N) as an example of prospective characterization of the microbiome within cohort studies.

A lack of prospective studies has been a major barrier for assessing the role of the microbiome in human health and disease on a population-wide scale. To address this significant knowledge gap, we have launched a large-scale collection targeting fecal and oral microbiome specimens from 20,000 women within the Nurses' Health Study II cohort (the Microbiome Among Nurses study, or Micro-N). Leveraging the rich epidemiologic data that have been repeatedly collected from this cohort since 1989; the established biorepository of archived blood, urine, buccal cell, and tumor tissue specimens; the available genetic and biomarker data; the cohort's ongoing follow-up; and the BIOM-Mass microbiome research platform, Micro-N furnishes unparalleled resources for future prospective studies to interrogate the interplay between host, environmental factors, and the microbiome in human health. These prospectively collected materials will provide much-needed evidence to infer causality in microbiome-associated outcomes, paving the way toward development of microbiota-targeted modulators, preventives, diagnostics and therapeutics. Here, we describe a generalizable, scalable and cost-effective platform used for stool and oral microbiome specimen and metadata collection in the Micro-N study as an example of how prospective studies of the microbiome may be carried out.

Emerging practices in onboarding programs for PAs: Strategies for onboarding.

OBJECTIVE: This is the final article in a series that examines the role of onboarding programs for new physician assistants (PAs) and NPs. On-the-job learning is highly relevant for this workforce. Here we examine the strategies organizations use to impart information and skills in onboarding programs. METHODS: In 2018, we interviewed 13 administrators of onboarding programs. Interviews were transcribed and analyzed for themes by a team of researchers, with feedback from interviewees. RESULTS: Seven strategies were identified and are described in this article: Clinical mentoring, personal and professional mentoring, meeting with/shadowing other professionals, checking in by administrators, delivering didactic content, tailoring content or ramp-up, and assessing/ensuring competency. CONCLUSIONS: This article describes commonly used strategies in onboarding programs for PAs and NPs and can provide guidance to those designing their own onboarding programs. The programs we examined relied heavily on mentoring and other strategies appropriate for adult learners. Future work should evaluate the effectiveness of onboarding programs.

State Scope of Practice Laws: An Analysis of Physician Assistant Programs and Graduates.

PURPOSE: The purpose of this study was to understand the association between physician assistant (PA) state scope of practice (SOP) laws and (1) PA program growth and (2) PA graduate demographics. METHODS: Scope of practice laws were categorized as ideal, average, and restrictive. Descriptive statistics by year and SOP categories were determined for the number of states, population density, PA programs, and PA graduate number, gender, race, and mean age. The Mann-Whitney U test was used to analyze demographic data by SOP categories. Adjusted risk ratios were generated for the number of PA programs and SOP categories. RESULTS: The number of PA programs is not associated with ideal SOP states. As of 2017, only 10 states have restrictive SOP laws. A minority of PA students now graduate from states with restrictive SOP laws. CONCLUSION: There is heterogeneity in PA SOP laws throughout the United States but only a minority of PA graduates now come from restrictive SOP states. This study provides foundational information prior to the implementation of optimal team practice.

Emerging practices in onboarding programs for PAs: Program content.

OBJECTIVE: Healthcare organizations are interested in creating onboarding programs to assist new PA and NP employees as they transition to practice settings. There is a need for information on what the ideal content and topic areas are for clinics to include in their onboarding programs. METHODS: In 2018, we interviewed 13 administrators of onboarding programs. Interviews were transcribed and analyzed for themes by a team of researchers, with feedback from interviewees. RESULTS: Eight content areas were identified and described in this paper: culture and values; goals and strategies; task proficiency; rules and policies; structure; working relationships; wellness; and navigation and politics. CONCLUSIONS: These common content areas may provide a starting point for organizations designing onboarding programs for their unique organizations.

PA job availability in primary care during 2014 and 2016.

OBJECTIVES: The objective of this project was to evaluate demand for PAs by examination of job postings. We compared proportions of PAs in primary care with proportions of job postings in primary care in 2014 and 2016 and described job postings for PAs by specialty in 2014 and 2016. METHODS: Internet job postings for PAs supplied by Burning Glass Technologies were evaluated for practice specialty. Job postings were compared with existing filled positions by specialty as reported by the National Commission for the Certification of Physician Assistants. RESULTS: In both years, more than 25% of PAs in practice were in primary care and fewer than 20% of job openings were in primary care. More than half of postings were in medical and surgical subspecialties. CONCLUSIONS: Our findings provide insights into which specialties have emerging high demand for PAs. The demand for PAs appears to remain much stronger for specialty jobs than for primary care jobs.

Utilization and Costs by Primary Care Provider Type: Are There Differences Among Diabetic Patients of Physicians, Nurse Practitioners, and Physician Assistants?

OBJECTIVE: The objective of this study was to compare health care utilization and costs among diabetes patients with physician, nurse practitioner (NP), or physician assistant (PA) primary care providers (PCPs). RESEARCH DESIGN AND METHODS: Cohort study using Veterans Affairs (VA) electronic health record data to examine the relationship between PCP type and utilization and costs over 1 year in 368,481 adult, diabetes patients. Relationship between PCP type and utilization and costs in 2013 was examined with extensive adjustment for patient and facility characteristics. Emergency department and outpatient analyses used negative binomial models; hospitalizations used logistic regression. Costs were analyzed using generalized linear models. RESULTS: PCPs were physicians, NPs, and PAs for 74.9% (n=276,009), 18.2% (n=67,120), and 6.9% (n=25,352) of patients respectively. Patients of NPs and PAs have lower odds of inpatient admission [odds ratio for NP vs. physician 0.90, 95% confidence interval (CI)=0.87-0.93; PA vs. physician 0.92, 95% CI=0.87-0.97], and lower emergency department use (0.67 visits on average for physicians, 95% CI=0.65-0.68; 0.60 for NPs, 95% CI=0.58-0.63; 0.59 for PAs, 95% CI=0.56-0.63). This translates into NPs and PAs having ~$500-$700 less health care costs per patient per year (P<0.0001). CONCLUSIONS: Expanded use of NPs and PAs in the PCP role for some patients may be associated with notable cost savings. In our cohort, substituting care patterns and creating similar clinical situations in which they practice, NPs and PAs may have reduced costs of care by up to 150-190 million dollars in 2013.