Academic Medicine and Rural Health System Partnerships: Enhancing Education While Advancing Physician Workforce Priorities.

ABSTRACT: A worsening shortage of rural physicians paralleling increasing health disparities demands attention. Past and ongoing efforts to address this shortage have had positive effects and can inform new strategies to achieve even greater impact. Interventions have included the development of regional medical school campuses and rural-focused tracks to recruit medical students from rural areas, expansion of rural-based graduate medical education (GME) programs and tracks, and use of institutional and individual financial incentives for rural-based training and/or practice. National policy has also taken aim at this challenge with provisions aimed at expanding rural GME in the Medicare, Medicaid, and State Children's Health Insurance Program Balanced Budget Refinement Act of 1999 and the Consolidated Appropriations Act of 2021. Additionally, several states have funded growth in GME, and supportive pathways for Medicare reimbursement and for Veterans Administration funding have been implemented. The authors recommend a new strategy for bolstering the rural physician workforce, focused on using academic-rural partnerships to incorporate rural rotations as a routine part of GME. They explain how the current health care landscape supports this approach and outline additional steps toward implementation. Centralized data collection and analysis are noted as essential to guide future efforts.

Biochemical and metabolic characterization of a G6PC2 inhibitor.

Three glucose-6-phosphatase catalytic subunits, that hydrolyze glucose-6-phosphate (G6P) to glucose and inorganic phosphate, have been identified, designated G6PC1-3, but only G6PC1 and G6PC2 have been implicated in the regulation of fasting blood glucose (FBG). Elevated FBG has been associated with multiple adverse clinical outcomes, including increased risk for type 2 diabetes and various cancers. Therefore, G6PC1 and G6PC2 inhibitors that lower FBG may be of prophylactic value for the prevention of multiple conditions. The studies described here characterize a G6PC2 inhibitor, designated VU0945627, previously identified as Compound 3. We show that VU0945627 preferentially inhibits human G6PC2 versus human G6PC1 but activates human G6PC3. VU0945627 is a mixed G6PC2 inhibitor, increasing the Km but reducing the Vmax for G6P hydrolysis. PyRx virtual docking to an AlphaFold2-derived G6PC2 structural model suggests VU0945627 binds two sites in human G6PC2. Mutation of residues in these sites reduces the inhibitory effect of VU0945627. VU0945627 does not inhibit mouse G6PC2 despite its 84% sequence identity with human G6PC2. Mutagenesis studies suggest this lack of inhibition of mouse G6PC2 is due, in part, to a change in residue 318 from histidine in human G6PC2 to proline in mouse G6PC2. Surprisingly, VU0945627 still inhibited glucose cycling in the mouse islet-derived ßTC-3 cell line. Studies using intact mouse liver microsomes and PyRx docking suggest that this observation can be explained by an ability of VU0945627 to also inhibit the G6P transporter SLC37A4. These data will inform future computational modeling studies designed to identify G6PC isoform-specific inhibitors.

Ten-Year Outcomes: Community Health Center/Academic Medicine Partnership for Rural Family Medicine Training.

BACKGROUND AND OBJECTIVES: The widening gap between urban and rural health outcomes is exacerbated by physician shortages that disproportionately affect rural communities. Rural residencies are an effective mechanism to increase physician placement in rural and medically underserved areas yet are limited in number due to funding. Community health center/academic medicine partnerships (CHAMPs) can serve as a collaborative framework for expansion of academic primary care residencies outside of traditional funding models. This report describes 10-year outcomes of a rural training pathway developed as part of a CHAMP collaboration. METHODS: Using data from internal registries and public sources, our retrospective study examined demographic and postgraduation practice characteristics for rural pathway graduates. We identified the rates of postgraduation placement in rural (Federal Office of Rural Health Policy grant-eligible) and federally designated Medically Underserved Areas/Populations (MUA/Ps). We assessed current placement for graduates >3 years from program completion. RESULTS: Over a 10-year period, 25 trainees graduated from the two residency expansion sites. Immediately postgraduation, 84% (21) were in primary care Health Professional Shortage Areas (HPSAs), 80% (20) in MUA/Ps, and 60% (15) in rural locations. Sixteen graduates were >3 years from program completion, including 69% (11) in primary care HPSAs, 69% (11) in MUA/Ps, and 50% (5) in rural locations. CONCLUSIONS: This CHAMP collaboration supported development of a rural pathway that embedded family medicine residents in community health centers and effectively increased placement in rural and MUA/Ps. This report adds to national research on rural workforce development, highlighting the role of academic-community partnerships in expanding rural residency training outside of traditional funding models.

Integrative analysis of pathogenic variants in glucose-6-phosphatase based on an AlphaFold2 model.

Mediating the terminal reaction of gluconeogenesis and glycogenolysis, the integral membrane protein glucose-6-phosphate catalytic subunit 1 (G6PC1) regulates hepatic glucose production by catalyzing hydrolysis of glucose-6-phosphate (G6P) within the lumen of the endoplasmic reticulum. Consistent with its vital contribution to glucose homeostasis, inactivating mutations in G6PC1 causes glycogen storage disease (GSD) type 1a characterized by hepatomegaly and severe hypoglycemia. Despite its physiological importance, the structural basis of G6P binding to G6PC1 and the molecular disruptions induced by missense mutations within the active site that give rise to GSD type 1a are unknown. In this study, we determine the atomic interactions governing G6P binding as well as explore the perturbations imposed by disease-linked missense variants by subjecting an AlphaFold2 G6PC1 structural model to molecular dynamics simulations and in silico predictions of thermodynamic stability validated with robust in vitro and in situ biochemical assays. We identify a collection of side chains, including conserved residues from the signature phosphatidic acid phosphatase motif, that contribute to a hydrogen bonding and van der Waals network stabilizing G6P in the active site. The introduction of GSD type 1a mutations modified the thermodynamic landscape, altered side chain packing and substrate-binding interactions, and induced trapping of catalytic intermediates. Our results, which corroborate the high quality of the AF2 model as a guide for experimental design and to interpret outcomes, not only confirm the active-site structural organization but also identify previously unobserved mechanistic contributions of catalytic and noncatalytic side chains.

Lessons Learned From State-Based Efforts to Leverage Medicaid Funds for Graduate Medical Education.

PURPOSE: Total Medicaid funds invested in graduate medical education (GME) increased from $3.78 billion in 2009 to $7.39 billion in 2022. States have flexibility in designing Medicaid GME payments to address population health needs. This study assessed states' impetus for using Medicaid funds for GME, structure of state Medicaid payments, composition and charge of advisory bodies that guide these investments, and degree of transparency and accountability to track whether Medicaid GME investments achieved desired workforce outcomes. METHOD: Structured interviews were conducted in 2015 to 2016 and 2020 to 2021 with subject matter experts representing 10 states. Interview transcripts were analyzed and coded in 6 thematic areas: impetus for using Medicaid funds, the structure of state Medicaid payments, the composition of advisory bodies, the degree of transparency of Medicaid investments, accountability of Medicaid investments, and challenges and changes. RESULTS: States used Medicaid GME funding to address maldistribution of physicians by geography, setting, and specialty, respond to population growth and undergraduate medical education expansion, offset potential loss of teaching health center program funds, and launch new programs and sustain existing ones. States leveraged Medicaid funding by modifying state plan amendments and redesigning funding formulas to meet specific health workforce needs. Many states had advisory bodies to educate legislators, reach consensus on workforce needs, recommend how to disburse funds, and navigate competing stakeholder interests. States identified a need for improved data and analytic systems to understand workforce needs and monitor the outcomes of GME investments. Determining which accountability measures to use and implementing metrics were challenges. CONCLUSIONS: States have much to learn from each other about strategies to best leverage Medicaid funds to develop and sustain residency programs to meet population health needs. Learning collaboratives should be developed to provide a forum for states to share best practices and strategies for overcoming challenges.

Identification of structural motifs critical for human G6PC2 function informed by sequence analysis and an AlphaFold2-predicted model.

G6PC2 encodes a glucose-6-phosphatase (G6Pase) catalytic subunit, primarily expressed in pancreatic islet ß cells, which modulates the sensitivity of insulin secretion to glucose and thereby regulates fasting blood glucose (FBG). Mutational analyses were conducted to validate an AlphaFold2 (AF2)-predicted structure of human G6PC2 in conjunction with a novel method to solubilize and purify human G6PC2 from a heterologous expression system. These analyses show that residues forming a predicted intramolecular disulfide bond are essential for G6PC2 expression and that residues forming part of a type 2 phosphatidic acid phosphatase (PAP2) motif are critical for enzyme activity. Additional mutagenesis shows that residues forming a predicted substrate cavity modulate enzyme activity and substrate specificity and residues forming a putative cholesterol recognition amino acid consensus (CRAC) motif influence protein expression or enzyme activity. This CRAC motif begins at residue 219, the site of a common G6PC2 non-synonymous single-nucleotide polymorphism (SNP), rs492594 (Val219Leu), though the functional impact of this SNP is disputed. In microsomal membrane preparations, the L219 variant has greater activity than the V219 variant, but this difference disappears when G6PC2 is purified in detergent micelles. We hypothesize that this was due to a differential association of the two variants with cholesterol. This concept was supported by the observation that the addition of cholesteryl hemi-succinate to the purified enzymes decreased the Vmax of the V219 and L219 variants ∼8-fold and ∼3 fold, respectively. We anticipate that these observations should support the rational development of G6PC2 inhibitors designed to lower FBG.

Pharmacists Colocated With Primary Care Physicians: Understanding Delivery of Interprofessional Primary Care.

BACKGROUND: While evidence supports interprofessional primary care models that include pharmacists, the extent to which pharmacists are working in primary care and the factors associated with colocation is unknown. OBJECTIVES: This study aimed to analyze the physical colocation of pharmacists with primary care providers (PCPs) and examine predictors associated with colocation. RESEARCH DESIGN: This is a retrospective cross-sectional study of pharmacists and PCPs with individual National Provider Identifiers in the National Plan and Provider Enumeration System's database. Pharmacist and PCP practice addresses of the health care professionals were geocoded, and distances less than 0.1 miles were considered physically colocated. SUBJECTS: In all, 502,373 physicians and 221,534 pharmacists were included. RESULTS: When excluding hospital-based pharmacists, 1 in 10 (11%) pharmacists were colocated with a PCP. Pharmacists in urban settings were more likely to be colocated than those in rural areas (OR=1.32, CI: 1.26-1.38). Counties with the highest proportion of licensed pharmacists per 100,000 people in the county had higher colocation (OR=1.38, CI: 1.32-1.45). Colocation was significantly higher in states with an expanded scope of practice (OR 1.37, CI: 1.32-1.42) and those that have expanded Medicaid (OR 1.07, CI: 1.03-1.11). Colocated pharmacists more commonly worked in larger physician practices. CONCLUSION: Although including pharmacists on primary care teams improves clinical outcomes, reduces health care costs, and enhances patient and provider experience, colocation appears to be unevenly dispersed across the United States, with lower rates in rural areas. As the integration of pharmacists in primary care continues to expand, knowing the prevalence and facilitators of growth will be helpful to policymakers, researchers, and clinical administrators.

Characteristics of Hospitals by Graduate Medical Education Expense Category: Implications for Rural Residency Program Expansion.

PURPOSE: To describe how the characteristics of the hospitals and communities they serve vary across the 4 hospital graduate medical education (GME) expense categories (according to Section 131 of the Consolidated Appropriations Act of 2021) and identify the rurally located never claimer hospitals that are most similar to teaching hospitals, signaling that they might be good candidates for new rural GME programs. METHOD: Hospital categories and characteristics were gathered from the March 2022 Medicare Cost Reports; 2022 County Health Rankings & Roadmaps data were used for community characteristics. Each acute hospital was classified into 1 of the following 4 mutually exclusive hospital categories: category A, category B, established teaching hospital (ETH), and never claimer. Multinomial logistic regressions were conducted to estimate the adjusted associations of hospital characteristics with hospital categories and to identify the never claimer hospitals in rural locations that have characteristics similar to teaching hospitals (category A, category B, and ETHs). RESULTS: Out of 3,590 hospitals, 2,075 (57.8%) were never claimer hospitals. After adjusting for multiple characteristics, rural hospitals had a similar probability of being in each hospital category as that of urban hospitals. Never claimer hospitals served an older population and were located in communities with more uninsured adults and children and less availability of primary care physicians, dentists, and mental health professionals. CONCLUSIONS: This study demonstrated that most hospitals in every category, but especially teaching hospitals (i.e., category A hospitals, category B hospitals, and ETHs), were concentrated in urban areas. Larger hospitals (measured by net patient revenue) were more likely to report GME expenses (i.e., be a category A hospital, a category B hospital, or an ETH). The study suggests that there are roughly 145 rural never claimer hospitals that might be strong candidates for initiating new residency programs.

G6PC1 and G6PC2 influence G6P flux but not HSD11B1 activity.

In the endoplasmic reticulum (ER) lumen, glucose-6-phosphatase catalytic subunit 1 and 2 (G6PC1; G6PC2) hydrolyze glucose-6-phosphate (G6P) to glucose and inorganic phosphate whereas hexose-6-phosphate dehydrogenase (H6PD) hydrolyzes G6P to 6-phosphogluconate (6PG) in a reaction that generates NADPH. 11ß-hydroxysteroid dehydrogenase type 1 (HSD11B1) utilizes this NADPH to convert inactive cortisone to cortisol. HSD11B1 inhibitors improve insulin sensitivity whereas G6PC inhibitors are predicted to lower fasting blood glucose (FBG). This study investigated whether G6PC1 and G6PC2 influence G6P flux through H6PD and vice versa. Using a novel transcriptional assay that utilizes separate fusion genes to quantitate glucocorticoid and glucose signaling, we show that overexpression of H6PD and HSD11B1 in the islet-derived 832/13 cell line activated glucocorticoid-stimulated fusion gene expression. Overexpression of HSD11B1 blunted glucose-stimulated fusion gene expression independently of altered G6P flux. While overexpression of G6PC1 and G6PC2 blunted glucose-stimulated fusion gene expression, it had minimal effect on glucocorticoid-stimulated fusion gene expression. In the liver-derived HepG2 cell line, overexpression of H6PD and HSD11B1 activated glucocorticoid-stimulated fusion gene expression but overexpression of G6PC1 and G6PC2 had no effect. In rodents, HSD11B1 converts 11-dehydrocorticosterone (11-DHC) to corticosterone. Studies in wild-type and G6pc2 knockout mice treated with 11-DHC for 5 weeks reveal metabolic changes unaffected by the absence of G6PC2. These data suggest that HSD11B1 activity is not significantly affected by the presence or absence of G6PC1 or G6PC2. As such, G6PC1 and G6PC2 inhibitors are predicted to have beneficial effects by reducing FBG without causing a deleterious increase in glucocorticoid signaling.

An Enhancer Within Abcb11 Regulates G6pc2 in C57BL/6 Mouse Pancreatic Islets.

G6PC2 is predominantly expressed in pancreatic islet ß-cells where it encodes a glucose-6-phosphatase catalytic subunit that modulates the sensitivity of insulin secretion to glucose by opposing the action of glucokinase, thereby regulating fasting blood glucose (FBG). Prior studies have shown that the G6pc2 promoter alone is unable to confer sustained islet-specific gene expression in mice, suggesting the existence of distal enhancers that regulate G6pc2 expression. Using information from both mice and humans and knowledge that single nucleotide polymorphisms (SNPs) both within and near G6PC2 are associated with variations in FBG in humans, we identified several putative enhancers 3' of G6pc2. One region, herein referred to as enhancer I, resides in the 25th intron of Abcb11 and binds multiple islet-enriched transcription factors. CRISPR-mediated deletion of enhancer I in C57BL/6 mice had selective effects on the expression of genes near the G6pc2 locus. In isolated islets, G6pc2 and Spc25 expression were reduced ∼50%, and Gm13613 expression was abolished, whereas Cers6 and nostrin expression were unaffected. This partial reduction in G6pc2 expression enhanced islet insulin secretion at basal glucose concentrations but did not affect FBG or glucose tolerance in vivo, consistent with the absence of a phenotype in G6pc2 heterozygous C57BL/6 mice.

The Distribution of Additional Residency Slots to Rural and Underserved Areas.

This study analyzes data from the Centers for Medicare & Medicaid Services to identify whether new residency training slots went to rural and underserved areas with the greatest need.

Postgraduate education to expand access to dental care: A roadmap to community dental program development.

Evidence indicates an increasing shortage of dentists in communities across the United States with potentially significant implications for oral health, as well as overall health and well-being. One strategy to increase access to dental care in rural and underserved communities is community-based postgraduate dental training. However, developing new dental programs requires navigating complex accreditation, financial and community governance, among other, barriers. The Roadmap for Teaching Health Center Dental Program Development presents a framework that guides institutions through the successive steps of developing new postgraduate training programs from identification of need to ultimate maintenance and sustainability. The tool assists programs in anticipating and understanding requirements, reducing time, expense, and uncertainty. While the framework was developed for community-based programs, the steps are applicable to postgraduate programs sponsored by academic institutions as well.

Molecular mechanisms of catalytic inhibition for active site mutations in glucose-6-phosphatase catalytic subunit 1 linked to glycogen storage disease.

Mediating the terminal reaction of gluconeogenesis and glycogenolysis, the integral membrane protein G6PC1 regulates hepatic glucose production by catalyzing hydrolysis of glucose-6-phosphate (G6P) within the lumen of the endoplasmic reticulum. Consistent with its vital contribution to glucose homeostasis, inactivating mutations in G6PC1 cause glycogen storage disease (GSD) type 1a characterized by hepatomegaly and severe hypoglycemia. Despite its physiological importance, the structural basis of G6P binding to G6PC1 and the molecular disruptions induced by missense mutations within the active site that give rise to GSD type 1a are unknown. Exploiting a computational model of G6PC1 derived from the groundbreaking structure prediction algorithm AlphaFold2 (AF2), we combine molecular dynamics (MD) simulations and computational predictions of thermodynamic stability with a robust in vitro screening platform to define the atomic interactions governing G6P binding as well as explore the energetic perturbations imposed by disease-linked variants. We identify a collection of side chains, including conserved residues from the signature phosphatidic acid phosphatase motif, that contribute to a hydrogen bonding and van der Waals network stabilizing G6P in the active site. Introduction of GSD type 1a mutations into the G6PC1 sequence elicits changes in G6P binding energy, thermostability and structural properties, suggesting multiple pathways of catalytic impairment. Our results, which corroborate the high quality of the AF2 model as a guide for experimental design and to interpret outcomes, not only confirm active site structural organization but also suggest novel mechanistic contributions of catalytic and non-catalytic side chains.

Bolstering the rural physician workforce in underserved communities: Are Rural Residency Planning and Development Programs finding the sweet spot?

PURPOSE: The purpose of this study is to describe the characteristics of Rural Residency Planning and Development (RRPD) Programs, compare the characteristics of counties with and without RRPD programs, and identify rural places where future RRPD programs could be developed. METHODS: The study sample comprised 67 rural sites training residents in 40 counties in 24 US states. Descriptive statistics were used to describe RRPD programs and logistic regression to predict the probability of a county being an RRPD site as a function of population, primary care physicians (PCP) per 10,000 population, and the social vulnerability index (SVI) compared to a control sample of nonmetro counties without RRPD sites. FINDINGS: Most RRPD grantees (78%) were family medicine programs affiliated with medical schools (97%). RRPD counties were more populous (P<.01), had a higher population density (P<.05), and a higher percent of the non-White or Hispanic population (P = .05) compared to non-RRPD counties. Both higher population (P<.001) and PCP ratio (P = .046) were strong predictors, while SVI (P = .07) was a weak predictor of being an RRPD county. CONCLUSIONS: RRPD sites appear to represent a "sweet spot" of rural counties that have the population and physician supply to support a training program but also are relatively more socially vulnerable with high-need populations. Additional counties fitting this "sweet spot" could be targeted for funding to address health disparities and health workforce maldistribution.

Responding to One Rural Community's Primary Care Needs: Investing in Workforce and Broad Community Stakeholder Engagement.

Lack of access to high-quality primary care has been shown to contribute to urban-rural health disparities. We describe a model in which an academic health system made targeted primary care investments to address rural health disparities while building the health workforce to ensure sustainability.

Improving the Health of Rural Communities Through Academic-Community Partnerships and Interprofessional Health Care and Training Models.

Health disparities between rural and urban areas are widening at a time when urban health care systems are increasingly buying rural hospitals to gain market share. New payment models, shifting from fee-for-service to value-based care, are gaining traction, creating incentives for health care systems to manage the social risk factors that increase health care utilization and costs. Health system consolidation and value-based care are increasingly linking the success of urban health care systems to rural communities. Yet, despite the natural ecosystem rural communities provide for interprofessional learning and collaborative practice, many academic health centers (AHCs) have not invested in building team-based models of practice in rural areas. With responsibility for training the future health workforce and major investments in research infrastructure and educational capacity, AHCs are uniquely positioned to develop interprofessional practice and training opportunities in rural areas and evaluate the cost savings and quality outcomes associated with team-based care models. To accomplish this work, AHCs will need to develop academic-community partnerships that include networks of providers and practices, non-AHC educational organizations, and community-based agencies. In this commentary, the authors highlight 3 examples of academic-community partnerships that developed and implemented interprofessional practice and education models and were designed around specific patient populations with measurable outcomes: North Carolina's Asheville Project, the Boise Interprofessional Academic Patient Aligned Care model, and the Interprofessional Care Access Network framework. These innovative models demonstrate the importance of academic-community partnerships to build teams that address social needs, improve health outcomes, and lower costs. They also highlight the need for more rigorous reporting on the components of the academic-community partnerships involved, the different types of health workers deployed, and the design of the interprofessional training and practice models implemented.

New Opportunities for Expanding Rural Graduate Medical Education to Improve Rural Health Outcomes: Implications of the Consolidated Appropriations Act of 2021.

Evidence shows that those living in rural communities experience consistently worse health outcomes than their urban and suburban counterparts. One proven strategy to address this disparity is to increase the physician supply in rural areas through graduate medical education (GME) training. However, rural hospitals have faced challenges developing training programs in these underserved areas, largely due to inadequate federal funding for rural GME. The Consolidated Appropriations Act of 2021 (CAA) contains multiple provisions that seek to address disparities in Medicare funding for rural GME, including funding for an increase in rural GME positions or "slots" (Section 126), expansion of rural training opportunities (Section 127), and relief for hospitals that have very low resident payments and/or caps (Section 131). In this Invited Commentary, the authors describe historical factors that have impeded the growth of training programs in rural areas, summarize the implications of each CAA provision for rural GME, and provide guidance for institutions seeking to avail themselves of the opportunities presented by the CAA. These policy changes create new opportunities for rural hospitals and partnering urban medical centers to bolster rural GME training, and consequently the physician workforce in underserved communities.