Codesigning Online Continuing Medical Education on Social Health Integration and Social Risk-Informed Care for Primary Care Providers.

INTRODUCTION: Adapting clinical care decisions for patient-reported social risks is essential to social health integration and patient-centered care. Most research in this area focuses on awareness and assistance (social-needs-targeted care), such as screening and referral to food, financial, and other resources. Limited evidence for adjustment strategies (social risk-informed care) or adapting care for social risks made it difficult for Kaiser Permanente to implement new initiatives. This article describes a co-design process to build a novel, adjustment-focused continuing medical education course. METHODS: The authors co-developed the online continuing medical education course with patients and clinicians using user-centered design. Transcripts from co-design activities were coded and analyzed by thematic analysis to identify major themes, including perceptions of social risk-informed care and barriers to care adjustment. RESULTS: Practical hurdles for implementing social risk-informed care emerged, including clinicians' concerns about the ethics of adjustment as substandard care, particularly without robust assistance activities. However, patients expressed a desire for their care to be adapted to their social circumstances, to allow for more realistic care plans. DISCUSSION: Implementation barriers identified from the co-design were addressed through an interactive, case-study approach. Existing evidence on contextualized care and shared decision making informed a general framework for primary care providers to engage in awareness and adjustment activities, paired with 3 interactive case studies based on real-world, clinician-supplied scenarios. CONCLUSION: The authors recommend that multiple stakeholder perspectives be incorporated during the development of social health integration initiatives, particularly adjustment. Education complemented by active, nuanced, flexible implementation strategies may be necessary for the successful uptake of care-delivery-based social health integration activities.

Molecular Imaging of Monoamine Oxidase A Expression in Highly Aggressive Prostate Cancer: Synthesis and Preclinical Evaluation of Positron Emission Tomography Tracers.

The role of monoamine oxidase A (MAO-A) in the aggressiveness of prostate cancer (PCa) has been established in recent years. The molecular imaging of MAO-A expression could offer a noninvasive tool for the visualization and quantification of highly aggressive PCa. This study reports the synthesis and preclinical evaluation of 11C- and 18F-labeled MAO-A inhibitors as positron emission tomography (PET) tracers for proof-of-concept studies in animal models of PCa. Good manufacturing practice production and quality control of these radiotracers using an automated platform was achieved. PET imaging was performed in an LNCaP tumor model with high MAO-A expression. The tumor-to-muscle (T/M) uptake ratio of [11C]harmine (4.5 ± 0.5) was significantly higher than that for 2-[18F]fluoroethyl-harmol (2.3 ± 0.7) and [11C]clorgyline (2.0 ± 0.1). A comparable ex vivo biodistribution pattern in all radiotracers was observed. Furthermore, the tumor uptake of [11C]harmine showed a dramatic reduction (T/M = 1) in a PC3 tumor model with limited MAO-A expression, and radioactivity uptake in LNCaP tumors was blocked in the presence of nonradioactive harmine. Our findings suggest that [11C]harmine may serve as an attractive PET probe for the visualization of MAO-A expression in highly aggressive PCa. These radiotracers have the potential for clinical translation and may aid in the development of personalized therapeutic strategies for PCa patients.

Kaiser Permanente's Social Needs Network for Evaluation and Translation Empirical Research Agenda.

Introduction: Healthcare systems such as Kaiser Permanente are increasingly focusing on patients' social health. However, there is limited evidence to guide social health integration strategy. The purpose of this study was to identify social health research opportunities using a stakeholder-driven process. Methods: A modified Concept Mapping approach was implemented from June 2021 to February 2022. Stakeholders (n=746) received the prompt, "One thing I wish we knew more about to advance my work addressing social health..." An inductive content analysis approach was used to assign topics and synthesize and refine research-focused statements into research questions. Questions were then rated on impact and priority by researcher stakeholders (n=16). Mean impact and priority scores and an overall combined score were calculated. Question rankings were generated using the combined score. Results: Brainstorming produced 148 research-focused statements. A final list of 59 research questions was generated for rating. Question topics were (1) Data, Measures, and Metrics; (2) Intervention Approach and Impact; (3) Technology; (4) Role of Healthcare Systems; (5) Community-Based Organizations; (6) Equity; (7) Funding; and (8) Social Health Integration. On a scale from 1 (low) to 10 (high), the mean impact score was 6.12 (range=4.14-7.79), and the mean priority score was 5.61 (range=3.07-8.64). Twenty-four statements were rated as both high impact (>6.12) and high priority (>5.61). Conclusions: The broad range of topics with high impact and priority scores reveals how nascent the evidence base is, with fundamental research on the nature of social risk and health system involvement still needed.

CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline.

Emerging evidence suggests that immune receptors may participate in many aging-related processes such as energy metabolism, inflammation, and cognitive decline. CD300f, a TREM2-like lipid-sensing immune receptor, is an exceptional receptor as it integrates activating and inhibitory cell-signaling pathways that modulate inflammation, efferocytosis, and microglial metabolic fitness. We hypothesize that CD300f can regulate systemic aging-related processes and ultimately healthy lifespan. We closely followed several cohorts of two strains of CD300f-/- and WT mice of both sexes for 30 months and observed an important reduction in lifespan and healthspan in knockout mice. This was associated with systemic inflammaging, increased cognitive decline, reduced brain glucose uptake observed by 18FDG PET scans, enrichment in microglial aging/neurodegeneration phenotypes, proteostasis alterations, senescence, increased frailty, and sex-dependent systemic metabolic changes. Moreover, the absence of CD300f altered macrophage immunometabolic phenotype. Taken together, we provide strong evidence suggesting that myeloid cell CD300f immune receptor contributes to healthy aging.

Hypertension care during the COVID-19 pandemic in an integrated health care system.

Retention in hypertension care, medication adherence, and blood pressure (BP) may have been affected by the COVID-19 pandemic. In a retrospective cohort study of 64 766 individuals with treated hypertension from an integrated health care system, we compared hypertension care during the year pre-COVID-19 (March 2019-February 2020) and the first year of COVID-19 (March 2020-February 2021). Retention in hypertension care was defined as receiving clinical BP measurements during COVID-19. Medication adherence was measured using prescription refills. Clinical care was assessed by in-person and virtual visits and changes in systolic and diastolic BP. The cohort had a mean age of 67.8 (12.2) years, 51.2% were women, and 73.5% were White. In 60 757 individuals with BP measurements pre-COVID-19, 16618 (27.4%) had no BP measurements during COVID-19. Medication adherence declined from 86.0% to 80.8% (p < .001). In-person primary care visits decreased from 2.7 (2.7) to 1.4 (1.9) per year, while virtual contacts increased from 9.5 (12.2) to 11.2 (14.2) per year (both p < .001). Among individuals with BP measurements, mean (SD) systolic BP was 126.5 mm Hg (11.8) pre-COVID-19 and 127.3 mm Hg (12.6) during COVID-19 (p = .14). Mean diastolic BP was 73.5 mm Hg (8.5) pre-COVID-19 and 73.5 mm Hg (8.7) during COVID-19 (p = .77). Even in this integrated health care system, many individuals did not receive clinical BP monitoring during COVID-19. Most individuals who remained in care maintained pre-COVID BP. Targeted outreach may be necessary to restore care continuity and hypertension control at the population level.

[99m Tc]Tc-HYNIC-EcgDf21: A defensin short analogue with potential application in infection foci imaging.

Opportunistic infections are a problem of great relevance in public health and the precise detection and localization of infection in the early stages of the disease is of great importance for patient management as well as cost containment. Our proposal seeks to contribute to developing a new agent that meets the needs of diagnosis and follow-up of fungal and bacterial infections, focused on the design of a radiotracer with the potential for recognition of hidden infection foci. Defensins are plant antimicrobial peptides that not only show activity against plant pathogens but also against human ones. A short analogue of EcgDf1 defensin, EcgDf21d (NH2 -ERFTGGHCRGFRRRCFCTKHC-COOH), was labelled through the formation of a 99m Tc-HYNIC complex which was assessed for physicochemical and biological behaviour both in vitro and in vivo. The [99m Tc]Tc-HYNIC-EcgDf21 labelling procedure rendered a single product with remarkably high RCP and stability in the labelling milieu. The Log p value indicated that [99m Tc]Tc-HYNIC-EcgDf21 has a hydrophilic behaviour, confirmed by the biodistribution profiles. The optimal uptake value was obtained for Candida albicans infection model reaching a lesion/muscle ratio of 3, this correlates with in vitro binding studies, and the lesion can be definitely observed in the scintigraphic images.

Association between changes in loneliness identified through screening and changes in depression or anxiety in older adults.

BACKGROUND: Changes in loneliness are associated with corresponding changes in depression, anxiety, and general health in population surveys, but few studies have assessed these associations through repeated screening in clinical settings. METHODS: Retrospective cohort study among individuals ≥age 65 in an integrated health care system who completed loneliness screening before two annual wellness visits, separated by a mean of 12.9 (SD 2.0) months, between 2013 and 2018. Their responses identified four subgroups: individuals who were persistently lonely; not lonely; experienced an increase (recently lonely); or decrease (previously lonely) in loneliness. Loneliness was assessed with a single item. Depression was assessed with the Patient Health Questionnaire-2. Anxiety was assessed with the Generalized Anxiety Disorder-2. Fair/poor general health was assessed by a single item. Linear mixed effects models assessed changes in outcomes after covariate adjustment. RESULTS: The cohort comprised 24,666 individuals (19.2% of older adults in the system). Mean age was 73.7 years (SD 6.4); 54.6% were female, and 11.6% were members of racial and ethnic minority groups. Of these individuals, 1936 (7.8%) were persistently lonely, 1687 (6.8%) were recently lonely, 1551 (6.3%) were previously lonely, and 19,492 (79.0%) were not lonely at either time point. After adjustment for sociodemographic, clinical and social variables, recent loneliness was associated with increases in depression (adjusted odds ratio [aOR] 1.76, 95% confidence interval [CI] 1.41-2.19) and anxiety (aOR 1.67, 95% CI 1.32-2.10). Previous loneliness was associated with decreases in depression (aOR, 0.46, 95% CI 0.36-0.58) and anxiety (aOR 0.69, 95% CI 0.54-0.90). Changes in loneliness were not associated with changes in general health. CONCLUSIONS: Changes in loneliness identified through screening were associated with corresponding changes in depression and anxiety. These findings support the potential value of identifying social risk factors in clinical settings among older adults.

Comparing the performance of two social risk screening tools in a vulnerable subpopulation.

BACKGROUND: Research shows the profound impact of social factors on health, lead many healths systems to incorporate social risk screening. To help healthcare systems select among various screening tools we compared two tools, the Your Current Life Situation (YCLS) and the Accountable Health Communities (AHC) Screening tools, on key psychometric properties. METHOD: Kaiser Permanente Southern California subsidized exchange members (n = 1008) were randomly invited to complete a survey containing either the YCLS or the AHC tool, as well as other measures related to care experience and health. Healthcare use was measured through the electronic health record. Agreement between the AHC and YCLS was assessed using adjusted kappas for six domains (food - worry, food - pay, insecure housing, housing quality, transportation, utilities). To assess predictive validity, items on the AHC and YCLS were compared to self-rated health and receipt of a flu shot. RESULTS: Responders (n = 450) and non-responders (n = 558) significantly differed on sex, language, and depression (P < 0.05) but not anxiety, race/ethnicity, or healthcare use. Agreement between the AHC and YCLS tools was substantial on all items (kappas > 0.60) except for housing quality (kappa 0.52). Four out of six screening questions on the AHC tool and four out of seven on the YCLS tool were associated with self-rated health (P < 0.03). No social needs were associated with flu shot receipt except utilities on the AHC tool (P = 0.028). CONCLUSION: In this sample, the AHC and YCLS tools are similar in their ability to screen for social risks. Differences observed likely stem from the timeframe and wording of the questions, which can be used to guide selection in healthcare systems.

Biological Assessment of a 18F-Labeled Sulforhodamine 101 in a Mouse Model of Alzheimer's Disease as a Potential Astrocytosis Marker.

Neurodegenerative diseases have mainly been associated with neuronal death. Recent investigations have shown that astroglia may modulate neuroinflammation in the early and late stages of the disease. [11C]Deuterodeprenyl ([11C]DED) is a tracer that has been used for reactive astrocyte detection in Alzheimer's disease, Creutzfeldt-Jakob disease and amyotrophic lateral sclerosis, among others, with some limitations. To develop a new radiotracer for detecting astrocytosis and overcoming associated difficulties, we recently reported the synthesis of a sulfonamide derivative of Sulforhodamine 101 (SR101), labeled with 18F, namely SR101 N-(3-[18F]Fluoropropyl) sulfonamide ([18F]2B-SRF101). The red fluorescent dye SR101 has been used as a specific marker of astroglia in the neocortex of rodents using in vivo models. In the present work we performed a biological characterisation of the new tracer including biodistribution and micro-PET/computed tomography (CT) images. PET/CT studies with [11C]DED were also done to compare with [18F]2B-SRF101 in order to assess its potential as an astrocyte marker. Biodistribution studies with [18F]2B-SRF101 were carried out in C57BL6J black and transgenic (3xTg) mice. A hepatointestinal metabolization as well as the pharmacokinetic profile were determined, showing appropriate characteristics to become a PET diagnostic agent. Dynamic PET/CT studies were carried out with [18F]2B-SRF101 and [11C]DED to evaluate the distribution of both tracers in the brain. A significant difference in [18F]2B-SRF101 uptake was especially observed in the cortex and hippocampus, and it was higher in 3xTg mice than it was in the control group. These results suggested that [18F]2B-SRF101 is a promising candidate for more extensive evaluation as an astrocyte tracer. The difference observed for [18F]2B-SRF101 was not found in the case of [11C]DED. The comparative studies between [18F]2B-SRF101 and [11C]DED suggest that both tracers have different roles as astrocytosis markers in this animal model, and could provide different and complementary information at the same time. In this way, by means of a multitracer approach, useful information could be obtained for the staging of the disease.

The longitudinal relationship between food insecurity in older adults with diabetes and emergency department visits, hospitalizations, hemoglobin A1c, and medication adherence.

AIMS: To examine the relationship between food insecurity and emergency department (ED) visits, hospitalizations, A1c, and diabetes medication adherence over one year of follow-up among individuals >65 years with diabetes mellitus. METHODS: We conducted a longitudinal cohort study of adults >65 years with diabetes who did (n = 742) or did not (n = 2226) report food insecurity at baseline. We used conditional logistic regression for the ED visits or hospitalization outcomes, and mixed effects models for A1c and non-insulin diabetes medication adherence. RESULTS: In bivariate analyses, individuals with food insecurity were more likely to have an ED visit (OR = 1.40, 95% CI 1.15-1.72) or hospitalization (OR = 1.41, 95% CI 1.11-1.78) in the year after the food security assessment. In addition, A1c was higher (7.5% vs. 7.2%, p < 0.001). There was no difference in medication adherence. These differences persisted with adjustment for basic demographic and clinical characteristics, but were attenuated with further adjustment for socioeconomic status. CONCLUSIONS: Differences in diabetes outcomes by food insecurity status were attenuated by adjustment for socioeconomic status. Adverse outcomes in individuals with diabetes and food insecurity may be driven by effects of food insecurity per se or be mediated by a constellation of basic resource needs or lower socioeconomic status.

Food Insecurity in Older Adults in an Integrated Health Care System.

OBJECTIVES: To estimate food insecurity prevalence and develop a statistical prediction model for food insecurity. DESIGN: Retrospective cohort study. SETTING: Kaiser Permanente Colorado. PARTICIPANTS: Adult members who completed a pre-Medicare Annual Wellness Visit survey. MEASUREMENTS: Food insecurity was assessed using a single screening question. Sociodemographic and clinical characteristics from electronic health records and self-reported characteristics from the survey were used to develop the prediction model. RESULTS: Of 130,208 older adult members between January 2012 and December 2015, 50,097 (38.5%) completed food insecurity screening, 2,859 of whom (5.7% of respondents) reported food insecurity. The prevalence of food insecurity was 10.0% or greater among individuals who were black or Hispanic, had less than high school education, had Medicaid insurance, were extremely obese, had poor health status or quality of life, had depression or anxiety, had impairments in specific activities of daily living, had other nutritional risk factors, or were socially isolated (all p<.001). A multivariable model based on these and other characteristics showed moderate discrimination (c-statistic = 0.74) between individuals with food insecurity and those without and 14.3% of individuals in the highest quintile of risk reported food insecurity. CONCLUSION: Food insecurity is prevalent even in older adults with private-sector healthcare coverage. Specific individual characteristics, and a model based on those characteristics, can identify older adults at higher risk of food insecurity. System-level interventions will be necessary to connect older adults with community-based food resources.

Stakeholders' views on data sharing in multicenter studies.

AIM: To understand stakeholders' views on data sharing in multicenter comparative effectiveness research studies and the value of privacy-protecting methods. MATERIALS & METHODS: Semistructured interviews with five US stakeholder groups. RESULTS: We completed 11 interviews, involving patients (n = 15), researchers (n = 10), Institutional Review Board and regulatory staff (n = 3), multicenter research governance experts (n = 2) and healthcare system leaders (n = 4). Perceptions of the benefits and value of research were the strongest influences toward data sharing; cost and security risks were primary influences against sharing. Privacy-protecting methods that share summary-level data were acknowledged as being appealing, but there were concerns about increased cost and potential loss of research validity. CONCLUSION: Stakeholders were open to data sharing in multicenter studies that offer value and minimize security risks.

A novel non-Hodgkin lymphoma murine model closer to the standard clinical scenario.

BACKGROUND: Non-Hodgkin lymphomas (NHL) are the most frequent hemato-oncological malignancies. Despite recent major advances in treatment, a substantial proportion of patients relapses highlighting the need for new therapeutic modalities. Promissory results obtained in pre-clinical studies are usually not translated when moving into clinical trials. Pre-clinical studies are mainly conducted in animals with high tumor burden; instead patients undergo chemotherapy as first line of treatment and most likely are under remission when immunotherapies are applied. Thus, an animal model that more closely resembles patients' conditions would be a valuable tool. METHODS: BALB/c mice were injected subcutaneously with A20 lymphoma cells and after tumor development different doses of chemotherapy were assessed to find optimal conditions for minimal residual disease (MRD) establishment. Tumor growth and survival, as well as drugs side effects, were all evaluated. Complete lymphoma remission was monitored in vivo using positron emission tomography (PET), and the results were correlated with histology. Immunological status was assessed by splenocytes proliferation assays in NHL-complete remission mice and by analyzing tumor cell infiltrates and chemokines/cytokines gene expression in the tumor microenvironment of animals with residual lymphoma. RESULTS: Two cycles of CHOP chemotherapy at days 25 and 35 post-tumor implantation induced complete remission for around 20 days. PET showed to be a suitable follow-up technique for MRD condition with 85.7 and 75% of sensibility and specificity respectively. Proliferative responses upon mitogen stimulation were similar in animals that received chemotherapy and wild type mice. Tumors from animals with residual lymphoma showed higher numbers of CD4+ and CD8+ and similar numbers of NK, neutrophils and Tregs infiltrating cells as compared with non-treated animals. Gene expression of several cytokines as well as an array of chemokines associated with migration of activated T cells to tumor sites was upregulated in the tumor microenvironment of animals that received chemotherapy treatment. CONCLUSIONS: We established a NHL-B pre-clinical model using standard chemotherapy to achieve MRD in immunocompetent animals. The MRD condition is maintained for approximately 20 days providing a therapeutic window of time where new immunotherapies can be tested in conditions closer to the clinics.

Building a Governance Strategy for CER: The Patient Outcomes Research to Advance Learning (PORTAL) Network Experience.

INTRODUCTION: The Patient Outcomes Research to Advance Learning (PORTAL) Network was established with funding from the Patient-Centered Outcomes Research Institute (PCORI) in 2014. The PORTAL team adapted governance structures and processes from past research network collaborations. We will review and outline the structures and processes of the PORTAL governance approach and describe how proactively focusing on priority areas helped us to facilitate an ambitious research agenda. BACKGROUND: For years a variety of funders have supported large-scale infrastructure grants to promote the use of clinical datasets to answer important comparative effectiveness research (CER) questions. These awards have provided the impetus for health care systems to join forces in creating clinical data research networks. Often, these scientific networks do not develop governance processes proactively or systematically, and address issues only as problems arise. Even if network leaders and collaborators foresee the need to develop governance approaches, they may underestimate the time and effort required to develop sound processes. The resulting delays can impede research progress. INNOVATION: Because the PORTAL sites had built trust and a foundation of collaboration by participating with one another in past research networks, essential elements of effective governance such as guiding principles, decision making processes, project governance, data governance, and stakeholders in governance were familiar to PORTAL investigators. This trust and familiarity enabled the network to rapidly prioritize areas that required sound governance approaches: responding to new research opportunities, creating a culture of trust and collaboration, conducting individual studies, within the broader network, assigning responsibility and credit to scientific investigators, sharing data while protecting privacy/security, and allocating resources. The PORTAL Governance Document, complete with a Toolkit of Appendices is included for reference and for adaptation by other networks. CREDIBILITY: As a result of identifying project-based governance priorities (IRB approval, subcontracting, selection of new research including lead PI and participating sites, and authorship) and data governance priorities (reciprocal data use agreement, analytic plan procedures, and other tools for data governance), PORTAL established most of its governance structure by Month 6 of the 18 month project. This allowed science to progress and collaborators to experience first-hand how the structures and procedures functioned in the remaining 12 months of the project, leaving ample time to refine them and to develop new structures or processes as necessary. DISCUSSION: The use of procedures and processes with which participating investigators and their home institutions were already familiar allowed project and regulatory requirements to be established quickly to protect patients, their data, and the health care systems that act as stewards for both. As the project progressed, PORTAL was able to test and adjust the structures it put place, and to make substantive revisions by Month 17. As a result, priority processes have been predictable, transparent and effective. CONCLUSION/NEXT STEPS: Strong governance practices are a stewardship responsibility of research networks to justify the trust of patients, health plan members, health care delivery organizations, and other stakeholders. Well-planned governance can reduce the time necessary to initiate the scientific activities of a network, a particular concern when the time frame to complete research is short. Effective network and data governance structures protect patient and institutional data as well as the interests of investigators and their institutions, and assures that the network has built an environment to meet the goals of the research.

An Innovative Approach to Informing Research: Gathering Perspectives on Diabetes Care Challenges From an Online Patient Community.

BACKGROUND: Funding agencies and researchers increasingly recognize the importance of patient stakeholder engagement in research. Despite calls for greater patient engagement, few studies have engaged a broad-based online community of patient stakeholders in the early stages of the research development process. OBJECTIVE: The objective of our study was to inform a research priority-setting agenda by using a Web-based survey to gather perceptions of important and difficult aspects of diabetes care from patient members of a social networking site-based community. METHODS: Invitations to participate in a Web-based survey were sent by email to members of the PatientsLikeMe online diabetes community. The survey asked both quantitative and qualitative questions addressing individuals' level of difficulty with diabetes care, provider communication, medication management, diet and exercise, and relationships with others. Qualitative responses were analyzed using content analysis. RESULTS: Of 6219 PatientsLikeMe members with diabetes who were sent survey invitations, 1044 (16.79%) opened the invitation and 320 (5.15% of 6219; 30.65% of 1044) completed the survey within 23 days. Of the 320 respondents, 33 (10.3%) reported having Type 1 diabetes; 107 (33.4%), Type 2 diabetes and taking insulin; and 180 (56.3%), Type 2 diabetes and taking oral agents or controlling their diabetes with lifestyle modifications. Compared to 2005-2010 National Health and Nutrition Examination Survey data for individuals with diabetes, our respondents were younger (mean age 55.8 years, SD 9.9 vs 59.4 years, SE 0.5); less likely to be male (111/320, 34.6% vs 48.4%); and less likely to be a racial or ethnic minority (40/312, 12.8% vs 37.5%). Of 29 potential challenges in diabetes care, 19 were categorized as difficult by 20% or more of respondents. Both quantitative and qualitative results indicated that top patient challenges were lifestyle concerns (diet, physical activity, weight, and stress) and interpersonal concerns (trying not to be a burden to others, getting support from family/friends). In our quantitative analysis, similar concerns were expressed across patient subgroups. CONCLUSIONS: Lifestyle and interpersonal factors were particularly challenging for our online sample of adults with Type 1 or Type 2 diabetes. Our study demonstrates the innovative use of social networking sites and online communities to gather rapid, meaningful, and relevant patient perspectives that can be used to inform the development of research agendas.

Methods for engaging stakeholders in comparative effectiveness research: a patient-centered approach to improving diabetes care.

Engaging stakeholders in the research process has the potential to improve quality of care and the patient care experience. Online patient community surveys can elicit important topic areas for comparative effectiveness research. Stakeholder meetings with substantial patient representation, as well as representation from health care delivery systems and research funding agencies, are a valuable tool for selecting and refining pilot research and quality improvement projects. Giving patient stakeholders a deciding vote in selecting pilot research topics helps ensure their 'voice' is heard. Researchers and health care leaders should continue to develop best-practices and strategies for increasing patient involvement in comparative effectiveness and delivery science research.

Accelerating regulatory progress in multi-institutional research.

PURPOSE: Multi-institutional collaborations are necessary in order to create large and robust data sets that are needed to answer important comparative effectiveness research (CER) questions. Before scientific work can begin, a complex maze of administrative and regulatory requirements must be efficiently navigated to avoid project delays. INNOVATION: Staff from research, regulatory, and administrative teams involved in three HMO Research Network (HMORN) multi-institutional collaborations developed and employed novel approaches: to secure and maintain Institutional Review Board (IRB) approvals; to enable data sharing, and to expedite subawards for two data-only minimal risk studies. These novel approaches accelerated required processes and approvals while maintaining regulatory, human subjects, and institutional protections. CREDIBILITY: Outcomes from the processes described here are compared with processes outlined in the research and regulatory literature and with processes that have been used in previous multisite research collaborations. CONCLUSION AND DISCUSSION: Research, regulatory, and administrative staff are essential contributors to the success of multi-institutional collaborations. Their flexibility, creativity, and effective communication skills can lead to the development of efficient approaches to achieving the necessary oversight for these complex projects. Elements of these specific strategies can be adapted and used by other research networks. Other efforts in these areas should be evaluated and shared. The processes that help develop a "learning research system" play an important and complementary role in sustaining multi-institutional research collaborations.

Sustaining Research Networks: the Twenty-Year Experience of the HMO Research Network.

PURPOSE: As multi-institutional research networks assume a central role in clinical research, they must address the challenge of sustainability. Despite its importance, the concept of network sustainability has received little attention in the literature, and the sustainability strategies of durable scientific networks have not been described. INNOVATION: The Health Maintenance Organization Research Network (HMORN) is a consortium of 18 research departments in integrated health care delivery systems with over 15 million members in the United States and Israel. The HMORN has coordinated federally funded scientific networks and studies since 1994. This case study describes the HMORN approach to sustainability, proposes an operational definition of network sustainability, and identifies 10 essential elements that can enhance sustainability. CREDIBILITY: The sustainability framework proposed here is drawn from prior publications on organizational issues by HMORN investigators and from the experience of recent HMORN leaders and senior staff. CONCLUSION AND DISCUSSION: Network sustainability can be defined as (1) the development and enhancement of shared research assets to facilitate a sequence of research studies in a specific content area or multiple areas, and (2) a community of researchers and other stakeholders who reuse and develop those assets. Essential elements needed to develop the shared assets of a network include: network governance; trustworthy data and processes for sharing data; shared knowledge about research tools; administrative efficiency; physical infrastructure; and infrastructure funding. The community of researchers within a network is enhanced by: a clearly defined mission, vision and values; protection of human subjects; a culture of collaboration; and strong relationships with host organizations. While the importance of these elements varies based on the membership and goals of a network, this framework for sustainability can enhance strategic planning within the network and can guide relationships with external stakeholders.

Design and development of (99m)tc-'4+1'-labeled dextran-mannose derivatives as potential radiopharmaceuticals for sentinel lymph node detection.

The synthesis, labeling, and biological evaluation of a dextran derivative (DCM-30-iso) as potential radiopharmaceutical for sentinel lymph node imaging is presented. DCM-30-iso bears mannose as active moiety and isocyanide as ligand for technetium through the formation of a '4+1' Tc(III) mixed-ligand complex. A second derivative without mannose (DC-25-iso) was also prepared and evaluated as control. DCM-30-iso and DC-25-iso were synthesized from dextran in four steps (>50% overall yield) and characterized by spectroscopic methods. Labeling with (99m)Tc was achieved by reaction with 2,2',2''-nitrilotris(ethanethiol) and (99m)Tc-EDTA. Radiochemical purity was above 90% and was stable for at least 4 hours postlabeling at 37°C. The identity of the (99m)Tc complex was established through comparative HPLC studies using the well-characterized analogous Re-DC-25-iso complex. Biodistribution and imaging experiments of (99m)Tc-DCM-30-iso showed high uptake in the popliteal lymph node, which could be blocked with preinjection of mannose, and very low uptake in other nodes and organs. The nonmannosylated (99m)Tc-DC-25-iso derivative showed negligible uptake in all lymph nodes. The novel dextran-mannose derivative DCM-30-iso can be successfully labeled with (99m)Tc to give a well-characterized '4+1' complex with favorable biological properties as sentinel lymph node imaging agent.