Comparing Quality, Costs, and Outcomes of VA and Community Primary Care for Patients with Diabetes.

BACKGROUND: The Maintaining Internal Systems and Strengthening Integrated Outside Networks (MISSION) Act expanded access to independent community providers outside the Veterans Health Administration (VA). Little is known how quality, costs, and outcomes of primary care received in the community compare to that of the VA. OBJECTIVE: To compare quality, costs, and outcomes of community and VA-provided primary care for patients with diabetes over a 12-month episode. DESIGN: A cross-sectional study using VA administrative data and community care claims. Adjusted analyses were conducted using inverse probability weighted regression adjustment to balance patient characteristics. PARTICIPANTS: Veterans with diabetes receiving primary care in the VA or community. MAIN MEASURES: Quality measures included receipt of hemoglobin A1C tests, eye exams, microalbumin urine tests, and flu shots. Outcomes were measured by hospitalizations for an ambulatory care sensitive condition (ACSC). Costs were measured for VA and community outpatient care, inpatient care, and prescription drugs. KEY RESULTS: There were 652,648 VA patients and 3650 community care patients. VA patients were less likely to be White, had shorter mean drive time to VA primary care, and were less likely to be rural than community care patients. In adjusted analyses, community care patients had significantly lower probability of receiving a hemoglobin A1C test, eye exam, microalbumin urine test, and flu shot compared to the VA group. There was no difference in probability of an ACSC hospitalization. Community care patients had higher mean total costs ($1741 [95% CI, $431, $3052]), driven by higher inpatient and prescription drug costs but lower emergency care costs than VA patients. CONCLUSION: Patients receiving community primary care had worse diabetes quality and higher costs than patients receiving VA primary care. There was no difference in health outcomes. Care provided by an integrated delivery system may have advantages in quality and value.

Enhancing RNA-lipid nanoparticle delivery: Organ- and cell-specificity and barcoding strategies.

Recent advancements in RNA therapeutics highlight the critical need for precision gene delivery systems that target specific organs and cells. Lipid nanoparticles (LNPs) have emerged as key vectors in delivering mRNA and siRNA, offering protection against enzymatic degradation, enabling targeted delivery and cellular uptake, and facilitating RNA cargo release into the cytosol. This review discusses the development and optimization of organ- and cell-specific LNPs, focusing on their design, mechanisms of action, and therapeutic applications. We explore innovations such as DNA/RNA barcoding, which facilitates high-throughput screening and precise adjustments in formulations. We address major challenges, including improving endosomal escape, minimizing off-target effects, and enhancing delivery efficiencies. Notable clinical trials and recent FDA approvals illustrate the practical applications and future potential of LNP-based RNA therapies. Our findings suggest that while considerable progress has been made, continued research is essential to resolve existing limitations and bridge the gap between pre-clinical and clinical evaluation of the safety and efficacy of RNA therapeutics. This review highlights the dynamic progress in LNP research. It outlines a roadmap for future advancements in RNA-based precision medicine.

Longitudinal sex-specific impacts of high-fat diet on dopaminergic dysregulation and behavior from periadolescence to late adulthood.

OBJECTIVES: Obesity is recognized for its adverse impact on brain health and related behaviors; however, the specific longitudinal effects of a high-fat diet (HFD) from juvenile stages of development through late adulthood remain poorly understood, particularly sex-specific outcomes. This study aimed to determine how prolonged exposure to HFD, commencing during periadolescence, would differentially predispose male and female mice to an elevated risk of dopaminergic dysregulation and associated behavioral deficits. METHODS: One-month-old C57BL/6J male and female mice were subjected to either a control diet or an HFD for 5 and 9 months. Muscle strength, motor skills, sensorimotor integration, and anxiety-like behaviors were assessed at the end of the 5th and 8th months. Key dopaminergic molecules, including dopamine (DA), dopamine receptor D2 (DRD2), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2), were quantified at the end of the 5th or 9th months. RESULTS: Behaviorally, male mice exposed to HFD exhibited more pronounced alterations in sensorimotor integration, anxiety-like behavior, and muscle strength after the 5th month of dietary exposure. In contrast, female mice displayed most behavioral differences after the 8th month of HFD exposure. Physiologically, there were notable sex-specific variations in the dopaminergic pathway response to HFD. Male mice exposed to HFD exhibited elevated tissue levels of VMAT2 and DRD2, whereas female mice showed reduced levels of DRD2 and DAT compared to control groups. DISCUSSION: These findings indicate a general trend of altered time course susceptibility in male mice to chronic HFD consumption compared to their female counterparts, with male mice impacted earlier than females.

Implementing evidence-based practices to improve primary care for high-risk patients: study protocol for the VA high-RIsk VETerans (RIVET) type III effectiveness-implementation trial.

BACKGROUND: Patients with significant multimorbidity and other factors that make healthcare challenging to access and coordinate are at high risk for poor health outcomes. Although most (93%) of Veterans' Health Administration (VHA) patients at high risk for hospitalization or death ("high-risk Veterans") are primarily managed by primary care teams, few of these teams have implemented evidence-based practices (EBPs) known to improve outcomes for the high-risk patient population's complex healthcare issues. Effective implementation strategies could increase adoption of these EBPs in primary care; however, the most effective implementation strategies to increase evidence-based care for high-risk patients are unknown. The high-RIsk VETerans (RIVET) Quality Enhancement Research Initiative (QUERI) will compare two variants of Evidence-Based Quality Improvement (EBQI) strategies to implement two distinct EBPs for high-risk Veterans: individual coaching (EBQI-IC; tailored training with individual implementation sites to meet site-specific needs) versus learning collaborative (EBQI-LC; implementation sites trained in groups to encourage collaboration among sites). One EBP, Comprehensive Assessment and Care Planning (CACP), guides teams in addressing patients' cognitive, functional, and social needs through a comprehensive care plan. The other EBP, Medication Adherence Assessment (MAA), addresses common challenges to medication adherence using a patient-centered approach. METHODS: We will recruit and randomize 16 sites to either EBQI-IC or EBQI-LC to implement one of the EBPs, chosen by the site. Each site will have a site champion (front-line staff) who will participate in 18 months of EBQI facilitation. ANALYSIS: We will use a mixed-methods type 3 hybrid Effectiveness-Implementation trial to test EBQI-IC versus EBQI-LC versus usual care using a Concurrent Stepped Wedge design. We will use the Practical, Robust Implementation and Sustainability Model (PRISM) framework to compare and evaluate Reach, Effectiveness, Adoption, Implementation, and costs. We will then assess the maintenance/sustainment and spread of both EBPs in primary care after the 18-month implementation period. Our primary outcome will be Reach, measured by the percentage of eligible high-risk patients who received the EBP. DISCUSSION: Our study will identify which implementation strategy is most effective overall, and under various contexts, accounting for unique barriers, facilitators, EBP characteristics, and adaptations. Ultimately this study will identify ways for primary care clinics and teams to choose implementation strategies that can improve care and outcomes for patients with complex healthcare needs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05050643. Registered September 9th, 2021, https://clinicaltrials.gov/study/NCT05050643 PROTOCOL VERSION: This protocol is Version 1.0 which was created on 6/3/2020.

Impact of Referring High-Risk Patients to Intensive Outpatient Primary Care Services: A Propensity Score-Matched Analysis.

BACKGROUND: Many healthcare systems have implemented intensive outpatient primary care programs with the hopes of reducing healthcare costs. OBJECTIVE: The Veterans Health Administration (VHA) piloted primary care intensive management (PIM) for patients at high risk for hospitalization or death, or "high-risk." We evaluated whether a referral model would decrease high-risk patient costs. DESIGN: Retrospective cohort study using a quasi-experimental design comparing 456 high-risk patients referred to PIM from October 2017 to September 2018 to 415 high-risk patients matched on propensity score. PARTICIPANTS: Veterans in the top 10th percentile of risk for 90-day hospitalization or death and recent hospitalization or emergency department (ED) visit. INTERVENTION: PIM consisted of interdisciplinary teams that performed comprehensive assessments, intensive case management, and care coordination services. MAIN OUTCOMES AND MEASURES: Change in VHA and non-VHA outpatient utilization, inpatient admissions, and costs 12 months pre- and post-index date. KEY RESULTS: Of the 456 patients referred to PIM, 301 (66%) enrolled. High-risk patients referred to PIM had a marginal reduction in ED visits (- 0.7; [95% CI - 1.50 to 0.08]; p = 0.08) compared to propensity-matched high-risk patients; overall outpatient costs were similar. High-risk patients referred to PIM had similar number of medical/surgical hospitalizations (- 0.2; [95% CI, - 0.6 to 0.16]; p = 0.2), significant increases in length of stay (6.36; [CI, - 0.01 to 12.72]; p = 0.05), and higher inpatient costs ($22,628, [CI, $3587 to $41,669]; p = 0.02) than those not referred to PIM. CONCLUSIONS AND RELEVANCE: VHA intensive outpatient primary care was associated with higher costs. Referral to intensive case management programs targets the most complex patients and may lead to increased utilization and costs, particularly in an integrated healthcare setting with robust patient-centered medical homes. TRIAL REGISTRATION: PIM 2.0: Patient Aligned Care Team (PACT) Intensive Management (PIM) Project (PIM2). NCT04521816. https://clinicaltrials.gov/study/NCT04521816.

Informing implementation and dissemination of a specialized primary care medical home for patients with serious mental illness: Clinician and administrator perspectives.

People with serious mental illness (SMI) have lower rates of use of preventative medical services and higher rates of mortality compared to the general population. Research shows that specialized primary care medical homes improve the health care of patients with SMI and are feasible to implement, safe, and more effective than usual care. However, specialized medical homes remain uncommon and model dissemination limited. As part of a controlled trial assessing an SMI-specialized medical home, we examined clinician and administrator perspectives regarding specialized versus mainstream primary care and identified ways to enhance the scale-up of a specialized primary care model for future dissemination. We conducted semistructured interviews with clinicians and administrators at three sites prior to the implementation of an SMI-specialized primary care medical home (n = 26) and at 1-year follow-up (n = 24); one site implemented the intervention, and two sites served as controls. Interviews captured service design features that affected the quality of care provided; contextual factors that supported or impeded medical home implementation; and knowledge, attitudes, and behaviors regarding the care of patients with SMI. Interviews were transcribed and coded. Clinicians and administrators described SMI-specialized primary care medical homes as advancing care coordination and outcomes for patients with SMI. Stakeholders identified elements of a specialized medical home that they viewed as superior to usual care, including having a holistic picture of patients' needs and greater care coordination. However, to enable scale-up, efforts are needed to increase staffing on care teams, develop robust clinician onboarding or training, and ensure close coordination with mental health care providers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Variation in benefit among patients with serious mental illness who receive integrated psychiatric and primary care.

PURPOSE: The population with serious mental illness has high risk for hospitalization or death due to unhealthy behaviors and inadequate medical care, though the level of risk varies substantially. Programs that integrate medical and psychiatric services improve outcomes but are challenging to implement and access is limited. It would be useful to know whether benefits are confined to patients with specific levels of risk. METHODS: In a population with serious mental illness and increased risk for hospitalization or death, a specialized medical home integrated services and improved treatment and outcomes. Treatment quality, chronic illness care, care experience, symptoms, and quality of life were assessed for a median of 385 days. Analyses examine whether improvements varied by baseline level of patient risk. RESULTS: Patients with greater risk were more likely to be older, more cognitively impaired, and have worse mental health. Integrated services increased appropriate screening for body mass index, lipids, and glucose, but increases did not differ significantly by level of risk. Integrated services also improved chronic illness care, care experience, mental health-related quality of life, and psychotic symptoms. There were also no significant differences by risk level. CONCLUSIONS: There were benefits from integration of primary care and psychiatric care at all levels of increased risk, including those with extremely high risk above the 95th percentile. When developing integrated care programs, patients should be considered at all levels of risk, not only those who are the healthiest.

Prescribing and Acceptance of Medications for Opioid Use Disorder in VA Primary Care: Veteran and Provider Perspectives.

BACKGROUND: Medications to treat opioid use disorder (MOUD) such as buprenorphine/naloxone can effectively treat OUD and reduce opioid-related mortality, but they remain underutilized, especially in non-substance use disorder settings such as primary care (PC). OBJECTIVE: To uncover the factors that can facilitate successful prescribing of MOUD and uptake/acceptance of MOUD by patients in PC settings in the Veterans Health Administration. DESIGN: Semi-structured qualitative telephone interviews with 77 providers (e.g., primary care providers, hospitalists, nurses, addiction psychiatrists) and 22 Veteran patients with experience taking MOUD. Interviews were recorded, transcribed, and analyzed thematically using a combination a priori/inductive approach. KEY RESULTS: Providers and patients shared their general perceptions and experiences with MOUD, including high satisfaction with buprenorphine/naloxone with few side effects and caveats, although some patients reported drawbacks to methadone. Both providers and patients supported the idea of prescribing MOUD in PC settings to prioritize patient comfort and convenience. Providers described individual-level barriers (e.g., time, stigma, perceptions of difficulty level), structural-level barriers (e.g., pharmacy not having medications ready, space for inductions), and organizational-level barriers (e.g., inadequate staff support, lack of nursing protocols) to PC providers prescribing MOUD. Facilitators centered on education and knowledge enhancement, workflow and practice support, patient engagement and patient-provider communication, and leadership and organizational support. The most common barrier faced by patients to starting MOUD was apprehensions about pain, while facilitators focused on personal motivation, encouragement from others, education about MOUD, and optimally timed provider communication strategies. CONCLUSIONS: These findings can help improve provider-, clinic-, and system-level supports for MOUD prescribing across multiple settings, as well as foster communication strategies that can increase patient acceptance of MOUD. They also point to how interprofessional collaboration across service lines and leadership support can facilitate MOUD prescribing among non-addiction providers.

Meeting high-risk patient pain care needs through intensive primary care: a secondary analysis.

OBJECTIVE: Chronic pain disproportionately affects medically and psychosocially complex patients, many of whom are at high risk of hospitalisation. Pain prevalence among high-risk patients, however, is unknown, and pain is seldom a focus for improving high-risk patient outcomes. Our objective is to (1) evaluate pain frequency in a high-risk patient population and (2) identify intensive management (IM) programme features that patients and providers perceive as important for promoting patient-centred pain care within primary care (PC)-based IM. DESIGN: Secondary observational analysis of quantitative and qualitative evaluation data from a multisite randomised PC-based IM programme for high-risk patients. SETTING: Five integrated local Veterans Affairs (VA) healthcare systems within distinct VA administrative regions. PARTICIPANTS: Staff and high-risk PC patients in the VA. INTERVENTION: A multisite randomised PC-based IM programme for high-risk patients. OUTCOME MEASURES: (a) Pain prevalence based on VA electronic administrative data and (b) transcripts of interviews with IM staff and patients that mentioned pain. RESULTS: Most (70%, 2593/3723) high-risk patients had at least moderate pain. Over one-third (38%, 40/104) of the interviewees mentioned pain or pain care. There were 89 pain-related comments addressing IM impacts on pain care within the 40 interview transcripts. Patient-identified themes were that IM improved communication and responsiveness to pain. PC provider-identified themes were that IM improved workload and access to expertise. IM team member-identified themes were that IM improved pain care coordination, facilitated non-opioid pain management options and mitigated provider compassion fatigue. No negative IM impacts on pain care were mentioned. CONCLUSIONS: Pain is common among high-risk patients. Future IM evaluations should consider including a focus on pain and pain care, with attention to impacts on patients, PC providers and IM teams.

Patient experiences with a primary care medical home tailored for people with serious mental illness.

INTRODUCTION: People with serious mental illness (SMI) have low rates of primary care (PC) use and die years prematurely, mostly because of medical illnesses such as cardiovascular disease or cancer. To meet the needs of these individuals, a novel, specialized patient-centered medical home with care coordination ("SMI PACT") was developed and implemented in PC. This study qualitatively examined patients' experiences with this innovative care model. METHOD: After implementation of the medical home in 2018, one-on-one semistructured interviews were conducted with 28 patients (32% women, 43% Black, and 25% Hispanic). Interviews were professionally transcribed and coded prior to thematic analysis. RESULTS: Patients overwhelmingly described positive experiences with SMI PACT because of the qualities of interpersonal communication displayed by SMI PACT staff (e.g., nonjudgment, good listening, patience), structural features of the SMI PACT collaborative care model (e.g., frequent follow-up communication), and other unique aspects of the SMI PACT model tailored for SMI, such as easy-to-understand language. For these reasons, most patients expressed a desire to continue care in SMI PACT. Patients also self-reported improved engagement with their healthcare and self-management of diet, exercise, blood pressure, and diabetes control as a result of SMI PACT participation. DISCUSSION: Patients enrolled in a specialized PC medical home identified clinician characteristics and behaviors that informed an overwhelmingly positive impression of the program model. Their experiences can guide dissemination of specialized PC models and integrated services for people with SMI. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Caring for high-need patients.

OBJECTIVE: We aimed to explore the construct of "high need" and identify common need domains among high-need patients, their care professionals, and healthcare organizations; and to describe the interventions that health care systems use to address these needs, including exploring the potential unintended consequences of interventions. METHODS: We conducted a modified Delphi panel informed by an environmental scan. Expert stakeholders included patients, interdisciplinary healthcare practitioners (physicians, social workers, peer navigators), implementation scientists, and policy makers. The environmental scan used a rapid literature review and semi-structured interviews with key informants who provide healthcare for high-need patients. We convened a day-long virtual panel meeting, preceded and followed by online surveys to establish consensus. RESULTS: The environmental scan identified 46 systematic reviews on high-need patients, 19 empirical studies documenting needs, 14 intervention taxonomies, and 9 studies providing construct validity for the concept "high need." Panelists explored the construct and terminology and established that individual patients' needs are unique, but areas of commonality exist across all high-need patients. Panelists agreed on 11 domains describing patient (e.g., social circumstances), 5 care professional (e.g., communication), and 8 organizational (e.g., staffing arrangements) needs. Panelists developed a taxonomy of interventions with 15 categories (e.g., care navigation, care coordination, identification and monitoring) directed at patients, care professionals, or the organization. The project identified potentially unintended consequences of interventions for high-need patients, including high costs incurred for patients, increased time and effort for care professionals, and identification of needs without resources to respond appropriately. CONCLUSIONS: Care for high-need patients requires a thoughtful approach; differentiating need domains provides multiple entry points for interventions directed at patients, care professionals, and organizations. Implementation efforts should consider outlined intended and unintended downstream effects on patients, care professionals, and organizations.

High fat diet reveals sex-specific fecal and liver metabolic alterations in C57BL/6J obese mice.

Obesity is a major health concern that poses significant risks for many other diseases, including diabetes, cardiovascular disease, and cancer. Prevalence of these diseases varies by biological sex. This study utilizes a mouse (C57BL/6J) model of obesity to analyze liver and fecal metabolic profiles at various time points of dietary exposure: 5, 9, and 12 months in control or high fat diet (HFD)-exposed mice. Our study discovered that the female HFD group has a more discernable perturbation and set of significant changes in metabolic profiles than the male HFD group. In the female mice, HFD fecal metabolites including pyruvate, aspartate, and glutamate were lower than control diet-exposed mice after both 9th and 12th month exposure time points, while lactate and alanine were significantly downregulated only at the 12th month. Perturbations of liver metabolic profiles were observed in both male and female HFD groups, compared to controls at the 12th month. Overall, the female HFD group showed higher lactate and glutathione levels compared to controls, while the male HFD group showed higher levels of glutamine and taurine compared to controls. These metabolite-based findings in both fecal and liver samples for a diet-induced effect of obesity may help guide future pioneering discoveries relating to the analysis and prevention of obesity in people, especially for females.

Types of Engagement Strategies to Engage High-Risk Patients in VA.

BACKGROUND: Many healthcare systems seek to improve care for complex high-risk patients, but engaging such patients to actively participate in their healthcare can be challenging. OBJECTIVE: To identify and describe types of patient engagement strategies reported as successfully deployed by providers/teams and experienced by patients in a Veterans Health Administration (VA) intensive primary care (IPC) pilot program. METHODS: We conducted semi-structured qualitative telephone interviews with 29 VA IPC staff (e.g., physicians, nurses, psychologists) and 51 patients who had at least four IPC team encounters. Interviews were recorded, transcribed, and analyzed thematically using a combination a priori/inductive approach. RESULTS: The engagement strategies successfully deployed by the IPC providers/teams could be considered either more "facilitative," i.e., facilitated by and dependent on staff actions, or more "self-sustaining," i.e., taught to patients, thus cultivating their ongoing patient self-care. Facilitative strategies revolved around enhancing patient access and coordination of care, trust-building, and addressing social determinants of health. Self-sustaining strategies were oriented around patient empowerment and education, caregiver and/or community support, and boundaries and responsibilities. When patients described their experiences with the "facilitative" strategies, many discussed positive proximal outcomes (e.g., increased access to healthcare providers). Self-sustaining strategies led to positive (self-reported) longer-term clinical outcomes, such as behavior change. CONCLUSION: We identified two categories of strategies for successfully engaging complex, high-risk patients: facilitative and self-sustaining. Intensive primary care program leaders may consider thoughtfully building "self-sustaining" engagement strategies into program development. Future research can confirm their effectiveness in improving health outcomes.

Changes in Primary Care Quality Associated With Implementation of the Veterans Health Administration Preventive Health Inventory.

Importance: The COVID-19 pandemic caused significant disruptions in primary care delivery. The Veterans Health Administration (VHA) launched the Preventive Health Inventory (PHI) program-a multicomponent care management intervention, including a clinical dashboard and templated electronic health record note-to support primary care in delivering chronic disease care and preventive care that had been delayed by the pandemic. Objectives: To describe patient, clinician, and clinic correlates of PHI use in primary care clinics and to examine associations between PHI adoption and clinical quality measures. Design, Setting, and Participants: This quality improvement study used VHA administrative data from February 1, 2021, through February 28, 2022, from a national cohort of 216 VHA primary care clinics that have implemented the PHI. Participants comprised 829 527 veterans enrolled in primary care in clinics with the highest and lowest decile of PHI use as of February 2021. Exposure: Templated electronic health record note documenting use of the PHI. Main Outcomes and Measures: Diabetes and blood pressure clinical quality measures were the primary outcomes. Interrupted time series models were applied to estimate changes in diabetes and hypertension quality measures associated with PHI implementation. Low vs high PHI use was stratified at the facility level to measure whether systematic differences in uptake were associated with quality. Results: A total of 216 primary clinics caring for 829 527 unique veterans (mean [SD] age, 64.1 [16.9] years; 755 158 of 829 527 [91%] were men) formed the study cohort. Use of the PHI varied considerably across clinics. The clinics in the highest decile of PHI use completed a mean (SD) of 32 997.4 (14 019.3) notes in the electronic health record per 100 000 veterans compared with 56.5 (35.3) notes per 100 000 veterans at the clinics in the lowest decile of use (P < .001). Compared with the clinics with the lowest use of the PHI, clinics with the highest use had a larger mean (SD) clinic size (12 072 [7895] patients vs 5713 [5825] patients; P < .001), were more likely to be urban (91% vs 57%; P < .001), and served more non-Hispanic Black veterans (16% vs 5%; P < .001) and Hispanic veterans (14% vs 4%; P < .001). Staffing did not differ meaningfully between high- and low-use clinics (mean [SD] ratio of full-time equivalent staff to clinician, 3.4 [1.2] vs 3.4 [0.8], respectively; P < .001). After PHI implementation, compared with the clinics with the lowest use, those with the highest use had fewer veterans with a hemoglobin A1c greater than 9% or missing (mean [SD], 6577 [3216] per 100 000 veterans at low-use clinics; 9928 [4236] per 100 000 veterans at high-use clinics), more veterans with an annual hemoglobin A1c measurement (mean [SD], 13 181 [5625] per 100 000 veterans at high-use clinics; 8307 [3539] per 100 000 veterans at low-use clinics), and more veterans with adequate blood pressure control (mean [SD], 20 582 [12 201] per 100 000 veterans at high-use clinics; 12 276 [6850] per 100 000 veterans at low-use clinics). Conclusions and Relevance: This quality improvement study of the implementation of the VHA PHI suggests that higher use of a multicomponent care management intervention was associated with improved quality-of-care metrics. The study also found significant variation in PHI uptake, with higher uptake associated with clinics with more racial and ethnic diversity and larger, urban clinic sites.

Intensive care management for high-risk veterans in a patient-centered medical home - do some veterans benefit more than others?

BACKGROUND: Primary care intensive management programs utilize interdisciplinary care teams to comprehensively meet the complex care needs of patients at high risk for hospitalization. The mixed evidence on the effectiveness of these programs focuses on average treatment effects that may mask heterogeneous treatment effects (HTEs) among subgroups of patients. We test for HTEs by patients' demographic, economic, and social characteristics. METHODS: Retrospective analysis of a VA randomized quality improvement trial. 3995 primary care patients at high risk for hospitalization were randomized to primary care intensive management (n = 1761) or usual primary care (n = 1731). We estimated HTEs on ED and hospital utilization one year after randomization using model-based recursive partitioning and a pre-versus post-with control group framework. Splitting variables included administratively collected demographic characteristics, travel distance, copay exemption, risk score for future hospitalizations, history of hospital discharge against medical advice, homelessness, and multiple residence ZIP codes. RESULTS: There were no average or heterogeneous treatment effects of intensive management one year after enrollment. The recursive partitioning algorithm identified variation in effects by risk score, homelessness, and whether the patient had multiple residences in a year. Within each distinct subgroup, the effect of intensive management was not statistically significant. CONCLUSIONS: Primary care intensive management did not affect acute care use of high-risk patients on average or differentially for patients defined by various demographic, economic, and social characteristics. IMPLICATIONS: Reducing acute care use for high-risk patients is complex, and more work is required to identify patients positioned to benefit from intensive management programs.

High-Risk Patient Experiences Associated With an Intensive Primary Care Management Program in the Veterans Health Administration.

Intensive management programs may improve health care experiences among high-risk and complex patients. We assessed patient experience among (1) prior enrollees (n = 59) of an intensive management program (2014-2018); (2) nonenrollees (n = 356) at program sites; and (3) nonprogram site patients (n = 728), using a patient survey based on the Consumer Assessment of Healthcare Providers and Systems in 2019. Outcomes included patient ratings of patient-centered care; overall health care experience; and satisfaction with their usual outpatient care provider. In multivariate models, enrollees were more satisfied with their current provider versus nonenrollees within program sites (adjusted odds ratio 2.36; 95% confidence interval 1.15-4.85).

Lipid membrane mimetics and oligomerization tune functional properties of proteorhodopsin.

The functional properties of proteorhodopsin (PR) have been found to be strongly modulated by oligomeric distributions and lipid membrane mimetics. This study aims to distinguish and explain their effects by investigating how oligomer formation impacts PR's function of proton transport in lipid-based membrane mimetic environments. We find that PR forms stable hexamers and pentamers in both E. coli membranes and synthetic liposomes. Compared with the monomers, the photocycle kinetics of PR oligomers is ∼2 and ∼4.5 times slower for transitions between the K and M and the M and N photointermediates, respectively, indicating that oligomerization significantly slows PR's rate of proton transport in liposomes. In contrast, the apparent pKa of the key proton acceptor residue D97 (pKaD97) of liposome-embedded PR persists at 6.2-6.6, regardless of cross-protomer modulation of D97, suggesting that the liposome environment helps maintain PR's functional activity at neutral pH. By comparison, when extracted directly from E. coli membranes into styrene-maleic acid lipid particles, the pKaD97 of monomer-enriched E50Q PR drastically increases to 8.9, implying that there is a very low active PR population at neutral pH to engage in PR's photocycle. These findings demonstrate that oligomerization impacts PR's photocycle kinetics, while lipid-based membrane mimetics strongly affect PR's active population via different mechanisms.

Crisaborole efficacy in murine models of skin inflammation and Staphylococcus aureus infection.

Phosphodiesterase 4 (PDE4) is highly expressed in keratinocytes and immune cells and promotes pro-inflammatory responses upon activation. The activity of PDE4 has been attributed to various inflammatory conditions, leading to the development and approval of PDE4 inhibitors as host-directed therapeutics in humans. For example, the topical PDE4 inhibitor, crisaborole, is approved for the treatment of mild-to-moderate atopic dermatitis and has shown efficacy in patients with psoriasis. However, the role of crisaborole in regulating the immunopathogenesis of inflammatory skin diseases and infection is not entirely known. Therefore, we evaluated the effects of crisaborole in multiple mouse models, including psoriasis-like dermatitis, AD-like skin inflammation with and without filaggrin mutations, and Staphylococcus aureus skin infection. We discovered that crisaborole dampens myeloid cells and itch in the skin during psoriasis-like dermatitis. Furthermore, crisaborole was effective in reducing skin inflammation in the context of filaggrin deficiency. Importantly, crisaborole reduced S. aureus skin colonization during AD-like skin inflammation. However, crisaborole was not efficacious in treating S. aureus skin infections, even as adjunctive therapy to antibiotics. Taken together, we found that crisaborole reduced itch during psoriasis-like dermatitis and decreased S. aureus skin colonization upon AD-like skin inflammation, which act as additional mechanisms by which crisaborole dampens the immunopathogenesis in mouse models of inflammatory skin diseases. Further examination is warranted to translate these preclinical findings to human disease.