Human iPSC-derived glia models for the study of neuroinflammation.

Neuroinflammation is a complex biological process that plays a significant role in various brain disorders. Microglia and astrocytes are the key cell types involved in inflammatory responses in the central nervous system. Neuroinflammation results in increased levels of secreted inflammatory factors, such as cytokines, chemokines, and reactive oxygen species. To model neuroinflammation in vitro, various human induced pluripotent stem cell (iPSC)-based models have been utilized, including monocultures, transfer of conditioned media between cell types, co-culturing multiple cell types, neural organoids, and xenotransplantation of cells into the mouse brain. To induce neuroinflammatory responses in vitro, several stimuli have been established that can induce responses in either microglia, astrocytes, or both. Here, we describe and critically evaluate the different types of iPSC models that can be used to study neuroinflammation and highlight how neuroinflammation has been induced and measured in these cultures.

Complement receptor 1 is expressed on brain cells and in the human brain.

Genome wide association studies (GWAS) have highlighted the importance of the complement cascade in pathogenesis of Alzheimer's disease (AD). Complement receptor 1 (CR1; CD35) is among the top GWAS hits. The long variant of CR1 is associated with increased risk for AD; however, roles of CR1 in brain health and disease are poorly understood. A critical confounder is that brain expression of CR1 is controversial; failure to demonstrate brain expression has provoked the suggestion that peripherally expressed CR1 influences AD risk. We took a multi-pronged approach to establish whether CR1 is expressed in brain. Expression of CR1 at the protein and mRNA level was assessed in human microglial lines, induced pluripotent stem cell (iPSC)-derived microglia from two sources and brain tissue from AD and control donors. CR1 protein was detected in microglial lines and iPSC-derived microglia expressing different CR1 variants when immunostained with a validated panel of CR1-specific antibodies; cell extracts were positive for CR1 protein and mRNA. CR1 protein was detected in control and AD brains, co-localizing with astrocytes and microglia, and expression was significantly increased in AD compared to controls. CR1 mRNA expression was detected in all AD and control brain samples tested; expression was significantly increased in AD. The data unequivocally demonstrate that the CR1 transcript and protein are expressed in human microglia ex vivo and on microglia and astrocytes in situ in the human brain; the findings support the hypothesis that CR1 variants affect AD risk by directly impacting glial functions.

Conceptualizing and Measuring Abatement from the Opioid Epidemic: A Case Study from Pennsylvania.

Policy Points In 2021, four major pharmaceutical manufacturers and distributors reached a proposed settlement agreement with 46 state Attorneys General of $26 billion to address their liabilities in fueling the US opioid epidemic. It raises important questions about abatement conceptualization and measurement for allocating settlement funds among substate entities. We outline the political economy tensions undergirding the settlement and allocation, introduce an abatement conceptual framework, describe how an abatement formula was developed for Pennsylvania to allocate settlement funds, and summarize considerations for future settlement allocation efforts. Documenting the challenges and experiences of this task is essential to inform future efforts.

Assaying Microglia Functions In Vitro.

Microglia, the main immune modulators of the central nervous system, have key roles in both the developing and adult brain. These functions include shaping healthy neuronal networks, carrying out immune surveillance, mediating inflammatory responses, and disposing of unwanted material. A wide variety of pathological conditions present with microglia dysregulation, highlighting the importance of these cells in both normal brain function and disease. Studies into microglial function in the context of both health and disease thus have the potential to provide tremendous insight across a broad range of research areas. In vitro culture of microglia, using primary cells, cell lines, or induced pluripotent stem cell derived microglia, allows researchers to generate reproducible, robust, and quantifiable data regarding microglia function. A broad range of assays have been successfully developed and optimised for characterizing microglial morphology, mediation of inflammation, endocytosis, phagocytosis, chemotaxis and random motility, and mediation of immunometabolism. This review describes the main functions of microglia, compares existing protocols for measuring these functions in vitro, and highlights common pitfalls and future areas for development. We aim to provide a comprehensive methodological guide for researchers planning to characterise microglial functions within a range of contexts and in vitro models.

The Pennsylvania Rural Health Model: Hospitals' Early Experiences With Global Payment for Rural Communities.

GOAL: In January 2019, the first cohort of rural hospitals began to operate under the Pennsylvania Rural Health Model for all-payer prospective global budget reimbursement as part of a demonstration funded by the Center for Medicare and Medicaid Innovation. Using information from primary source documents and interviews with key stakeholders, we sought to identify challenges and lessons learned throughout the design, development, and early implementation stages of the model. METHODS: We relied on two qualitative research approaches: (1) review of primary source documents such as peer-reviewed publications and news accounts related to the model and (2) semistructured interviews with key staff and stakeholders, including current and former members of the Pennsylvania Department of Health, first-year applicant hospitals, technical assistance providers, and members of state and federal organizations and agencies familiar with the Pennsylvania and Maryland payment reform efforts for rural health and rural hospitals (N = 20). PRINCIPAL FINDINGS: We identified four primary attributes that innovative projects such as the model need: (1) a champion at the state and hospital level, significant cooperation across state agencies and between federal and state agencies, and support from nongovernment stakeholders; (2) ongoing engagement and education of all stakeholders, particularly related to rural health disparities, the challenges faced by rural hospitals (especially resource limitations), and the differences between rural and urban health and health service delivery; (3) realistic time lines, noting that stakeholder relationships with hospital leadership develop over many months; and (4) multistakeholder collaboration, because participating hospitals must have ongoing engagement with community members (i.e., consumers of healthcare), nonacute community partners, and other rural hospitals to foster a "rural health movement." APPLICATIONS TO PRACTICE: A successful Pennsylvania model holds promise for other states seeking to address the needs of rural populations and the hospitals that are vital to those communities. The lessons in this article can assist others in making the transition from volume to value in rural healthcare.

How Much Superior Rectus Underaction is Considered Normal?

PURPOSE: It is considered normal to have a small amount of superior rectus weakness in laevo and dextro elevation; however, there is no documented definition for these normal parameters within a healthy young adult population using ocular movement testing and the synoptophore. The aim of this study was to collect normative data on the degree of superior rectus underaction in healthy young adults. METHOD: Twenty-nine healthy adults (3 males and 26 females, mean age 20.30 ± 1.70 years) were recruited. Superior recti underactions and inferior oblique overactions were recorded during routine ocular movement testing and mean and median values calculated. Subjective horizontal, vertical and torsional measurements were taken in degrees on the synoptophore in primary position, laevo elevation and dextro elevation. RESULTS: Most participants (79.31%) had some degree of observable superior rectus underaction in either eye or in both eyes on ocular movement testing (mean superior rectus underaction of -0.69 units in laevo elevation and -0.71 units in dextro elevation, range = -1.5 to -0.5 units; median -1 units, interquartile range (IQR) = -1 to -1 units). Most participants (62.07%) had some degree of superior rectus underaction in either eye or in both eyes on the synoptophore (mean left and right superior recti underactions of -0.48 degrees, range = -3 to -1 degrees; median 0 degrees, IQR = -1 to -1 degrees). CONCLUSION: The majority of young healthy adults in this study showed some degree of superior rectus underaction. On ocular movement testing, -0.70 units of underaction, and on the synoptophore, -0.48 degrees of underaction are the mean levels of weakness to be expected. Superior rectus underactions greater than -1 units for ocular movement testing and -1 degrees on the synoptophore in healthy young adults should be carefully evaluated, together with other important clinical signs.

The exercise in all chemotherapy trial.

BACKGROUND: Multiple international organizations have called for exercise to become standard practice in the setting of oncology care. The feasibility of integrating exercise within systemic chemotherapy has not been investigated. METHODS: Patients slated to receive infusion therapy between April 2017 and October 2018 were screened for possible inclusion. The study goal was to establish the acceptability and feasibility of embedding an exercise professional into the chemotherapy infusion suite as a method of making exercise a standard part of cancer care. The exercise prescriptions provided to patients were individualized according to results of brief baseline functional testing. RESULTS: In all, 544 patients were screened, and their respective treating oncologists deemed 83% of them to be medically eligible to participate. After further eligibility screening, 226 patients were approached. Nearly 71% of these patients (n = 160) accepted the invitation to participate in the Exercise in All Chemotherapy trial. Feasibility was established because 71%, 55%, 69%, and 63% of the aerobic, resistance, balance, and flexibility exercises prescribed to patients were completed. Qualitative data also supported the acceptability and feasibility of the intervention from the perspective of patients and clinicians. The per-patient cost of the intervention was $190.68 to $382.40. CONCLUSIONS: Embedding an exercise professional into the chemotherapy infusion suite is an acceptable and feasible approach to making exercise standard practice. Moreover, the cost of the intervention is lower than the cost of other common community programs. Future studies should test whether colocating an exercise professional with infusion therapy could reach more patients in comparison with not colocating. LAY SUMMARY: Few studies have tested the implementation of exercise for patients with cancer by embedding an exercise professional directly into the chemotherapy infusion suite. The Exercise in All Chemotherapy trial shows that this approach is both acceptable and feasible from the perspective of clinicians and patients.

Are health systems redesigning how health care is delivered?

OBJECTIVE: To explore why and how health systems are engaging in care delivery redesign (CDR)-defined as the variety of tools and organizational change processes health systems use to pursue the Triple Aim. STUDY SETTING: A purposive sample of 24 health systems across 4 states as part of the Agency for Healthcare Research and Quality's Comparative Health System Performance Initiative. STUDY DESIGN: An exploratory qualitative study design to gain an "on the ground" understanding of health systems' motivations for, and approaches to, CDR, with the goals of identifying key dimensions of CDR, and gauging the depth of change that is possible based on the particular approaches to redesign care being adopted by the health systems. DATA COLLECTION: Semi-structured telephone interviews with health system executives and physician organization leaders from 24 health systems (n = 162). PRINCIPAL FINDINGS: We identify and define 13 CDR activities and find that the health systems' efforts are varied in terms of both the combination of activities they are engaging in and the depth of innovation within each activity. Health system executives who report strong internal motivation for their CDR efforts describe more confidence in their approach to CDR than those who report strong external motivation. Health system leaders face uncertainty when implementing CDR due to a limited evidence base and because of the slower than expected pace of payment change. CONCLUSIONS: The ability to validly and reliably measure CDR activities-particularly across varying organizational contexts and markets-is currently limited but is key to better understanding CDR's impact on intended outcomes, which is important for guiding both health system decision making and policy making.

Understanding how health systems facilitate primary care redesign.

OBJECTIVE: To understand how health systems are facilitating primary care redesign (PCR), examine the PCR initiatives taking place within systems, and identify barriers to this work. STUDY SETTING: A purposive sample of 24 health systems in 4 states. STUDY DESIGN: Data were systematically reviewed to identify how system leaders define and implement initiatives to redesign primary care delivery and identify challenges. Researchers applied codes which were based on the theoretical PCR literature and created new codes to capture emerging themes. Investigators analyzed coded data then produced and applied a thematic analysis to examine how health systems facilitate PCR. DATA COLLECTION: Semi-structured telephone interviews with 162 system executives and physician organization leaders from 24 systems. PRINCIPAL FINDINGS: Leaders at all 24 health systems described initiatives to redesign the delivery of primary care, but many were in the early stages. Respondents described the use of centralized health system resources to facilitate PCR initiatives, such as regionalized care coordinators, and integrated electronic health records. Team-based care, population management, and care coordination were the most commonly described initiatives to transform primary care delivery. Respondents most often cited improving efficiency and enhancing clinician job satisfaction, as motivating factors for team-based care. Changes in payment and risk assumption as well as community needs were commonly cited motivators for population health management and care coordination. Return on investment and the slower than anticipated rate in moving from fee-for-service to value-based payment were noted by multiple respondents as challenges health systems face in redesigning primary care. CONCLUSIONS: Given their expanding role in health care and the potential to leverage resources, health systems are promising entities to promote the advancement of PCR. Systems demonstrate interest and engagement in this work but face significant challenges in getting to scale until payment models are in alignment with these efforts.

Level of agreement on health information technology adoption and use in survey data: a mixed-methods analysis of ambulatory clinics in 1 US state.

OBJECTIVE: Adoption of health information technology (HIT) is often assessed in surveys of organizations. The validity of data from such surveys for ambulatory clinics has not been evaluated. We compared level of agreement between 1 ambulatory statewide survey and 2 other data sources: a second survey and interviews with survey respondents. MATERIALS AND METHODS: We used 2016 data from 2 surveys of ambulatory providers in Minnesota-the Healthcare Information and Management Systems Society (HIMSS) survey and the Minnesota HIT Ambulatory Clinic Survey-and primary data collected through qualitative interviews with survey respondents. We conducted a concurrent triangulation mixed-methods assessment of the Minnesota HIT survey by assessing level of agreement between it and HIMSS, and a thematic analysis of interview data to assess the respondent's understanding of what was being asked and their approach to responding. RESULTS: We find high agreement between the 2 surveys on questions related to common HIT functionalities-such as computerized provider order entry, medication-based decision support, and e-prescribing-which were widely adopted by respondents' organizations. Qualitative data suggest respondents found wording of items about these functionalities clear but encountered multiple challenges including interpreting items for less commonly adopted functionalities, estimating degree of HIT usage, and indicating relevant barriers. Respondents identified multiple errors in responses and likely reported greater within-group homogeneity than actually existed. CONCLUSIONS: Survey items related to the presence or absence of widely adopted HIT functionalities may be more valid than items about less common functionalities, degree of usage, and barriers.

The Aligning Forces for Quality initiative: background and evolution from 2005 to 2015.

OBJECTIVE: The Robert Wood Johnson Foundation's (RWJF's) Aligning Forces for Quality (AF4Q) program was the largest privately funded, community-based quality improvement initiative to date, providing funds and technical assistance (TA) to 16 multi-stakeholder alliances located throughout the United States. This article describes the AF4Q initiative's underlying theory of change, its evolution over time, and the key activities undertaken by alliances. STUDY DESIGN: Descriptive overview of a multi-site, community-based quality improvement initiative. METHODS: We summarized information from program documents, program meetings, observation of alliance activities, and interviews with RWJF staff, TA providers, and AF4Q alliance stakeholders. RESULTS: The AF4Q program was a dynamic initiative, expanding and evolving over time. The underlying theory of change was based on the notion that an aligned, multi-stakeholder approach is superior to independent siloed efforts by stakeholders. Participating alliances developed or strengthened programming to varying degrees in 5 main programmatic areas: (1) measurement and public reporting of healthcare quality, patient experience, cost, and efficiency for ambulatory physician practices and hospitals; (2) efforts to engage consumers in health, healthcare, and alliance governance (consumer engagement); (3) adoption and spread of effective strategies to improve care delivery; (4) advancing healthcare equity; and (5) integration of alliance activities with payment reform initiatives. CONCLUSION: The AF4Q initiative was an ambitious program affecting multiple leverage points in the healthcare system. AF4Q alliances were provided a similar set of expectations, and given financial support and access to substantial TA. There was considerable variation in how alliances addressed the AF4Q programmatic areas, given differences in their composition, market structure, and history.

Reporting provider performance: what can be learned from the experience of multi-stakeholder community coalitions?

OBJECTIVES: This analysis assessed the evolution of public reporting of provider performance in Aligning Forces for Quality (AF4Q) alliances, contrasted alliances that stopped reporting with those that plan to continue, and drew insights from alliance public reporting efforts for the national transparency movement. METHODS: Combined with document review, qualitative research methods were used to analyze interview data collected, over a nearly 10-year period, from the 16 participating alliances. RESULTS: AF4Q alliances made their greatest contributions to provider transparency in reporting ambulatory quality and patient experience measures. However, reporting ambulatory cost/efficiency/utilization measures was more challenging for alliances. Alliances contributed the least with respect to measures of inpatient performance. Six alliances ceased reporting at the end of the AF4Q program because of their inability to develop stable funding sources and overcome stakeholder skepticism about the value of public reporting. Insights provided by alliance leaders included the need to: focus on provider, rather than consumer, responses to public reports as the most likely avenue for improving quality; address the challenge of funding the reporting infrastructure from the beginning; explore collaborations with other entities to increase public reporting efficiency; and develop a strategy for responding to efforts at the national level to increase the availability of information on provider performance. CONCLUSION: The AF4Q initiative demonstrated that a wide variety of voluntary stakeholder coalitions could develop public reports with financial and technical support. However, the contents of these reports varied considerably, reflecting differences in local environments and alliance strategies. The challenges faced by alliances to maintain their reporting efforts were substantial, and not all alliances chose to report. Nevertheless, there are potential roles for alliances going forward in contributing to the national transparency movement.

Advancing Payment Reform at the Community Level.

BACKGROUND: Multistakeholder alliances-groups of payers, purchasers, providers, and consumers that voluntarily work together to address local health goals-have increasingly been used to improve health care quality within their communities. Under the Robert Wood Johnson Foundation's Aligning Forces for Quality (AF4Q) initiative, 16 multistakeholder alliances were charged with advancing payment reform as part of a larger effort to achieve dramatic and sustainable quality improvement. METHODS: Drawing upon key informant interviews with alliance leaders and document reviews conducted from 2010 to 2014, we describe the payment reform projects undertaken by the AF4Q alliances and the roles that the alliances played to advance them. RESULTS: The most common types of projects pursued by alliances were those that introduced supplemental payments to fee-for-service reimbursement and built upon alliances' ongoing quality improvement initiatives. Alliances advanced payment reform through 4 roles: (1) educating and advocating, (2) designing payment reform projects, (3) recruiting participants, and (4) supporting the operation of projects. However, less than half of alliances' payment reform projects were operational by 2014. CONCLUSIONS: Quality improvement-focused multistakeholder alliances may play meaningful roles to advance payment reform, but they are not a panacea for overcoming well-documented barriers to reform.

Producing public reports of physician quality at the community level: the Aligning Forces for Quality initiative experience.

OBJECTIVES: To describe the approaches used by the Aligning Forces for Quality (AF4Q) alliances in producing community-based reports of physician quality and to assess the contribution of these reports to existing physician performance information. STUDY DESIGN: The study included semi-structured interviews with alliance stakeholders and tracking of the number and content of physician performance reports in 14 AF4Q initiative communities and 7 comparison communities. METHODS: The study used qualitative analysis of interview data and systematic tracking of the number and content of physician performance reports over time. RESULTS: Report production occurred in several stages including initiation, measure selection/specification, measure construction, and dissemination. The measure selection/specification process was often the first major act undertaken by alliances under the AF4Q initiative grant. Alliances utilized nationally endorsed performance measures and made a strategic decision to gain buy-in with physicians. Alliances have experienced greater difficulty in producing buy-in for patient experience measures. The primary decision point for measure construction was the use of administrative claims data or physician-provided medical records data. Overall, AF4Q alliances have contributed to an increase in physician performance information in their communities. CONCLUSIONS: Our findings suggest that the AF4Q initiative has accelerated the development and content of physician performance measures in AF4Q communities.

Using websites to engage consumers in managing their health and healthcare.

OBJECTIVE: This study provides insight into the potential of local community health information websites to cultivate and support consumer engagement through website positioning and content choices. STUDY DESIGN: This descriptive study compared health-related websites maintained by 16 multi-stakeholder community alliances charged with improving consumer engagement and public reporting of provider performance data. METHODS: We systematically assessed website messaging, content, and the presence of explicit connections among information and tools related to consumer engagement behaviors for 32 websites maintained by alliances as of November 2011. These findings were triangulated with information about alliances' public reporting activities from key informant interviews (2007-2011) with stakeholders in 14 alliances. RESULTS: A total of 25 of the 32 alliance websites contained information for consumers, and 14 of those included information related to at least 3 of 4 consumer engagement behaviors: shopping for high-quality providers or treatments, self-advocacy in healthcare encounters, self-management of illness, and partaking in general healthy behaviors. Positioning strategies and tactics to attract consumers varied widely across alliances. Some targeted specific conditions or behaviors; others took a broader community approach. Two alliances had strong alignment between website messaging and consumer engagement content, 7 had moderate alignment, and 7 had limited alignment. CONCLUSIONS: Although alliances have been experimenting with a wide array of website approaches, their promise as a tool to improve consumer engagement is still uncertain. Further research that addresses the comparative value of different website approaches is needed.