Capturing the emotional and social experiences of COVID-19 through journal entries: A qualitative study of COVID-19 experiences over six weeks following infection.

COVID-19's wide-ranging effects on patients' physical health are well-documented, but comparatively less research has explored the impact on patients' emotional and social experiences. We examined how patients across a multi-state health system experience the emotional and social aspects of COVID-19 during the first six weeks of recovery from infection. We leveraged the larger My COVID Diary project to capture open-ended journal data from an app-based platform available to patients who test positive for COVID-19 within the health system. Our sample was limited to participants with multiple journal entries during the first six weeks after infection, with one entry in the top 5% of all participants for word count to ensure sufficient journal content was available for analysis. We randomly selected 100 eligible participants and coded and analyzed all of their journal entries in weeks 1-6 after infection, utilizing a thematic analysis approach. Despite journal entry prompts' orientation towards physical symptoms, the majority of participants discussed emotional experiences (such as anxiety, depression, and gratitude) and social factors (such as work and family) when describing their COVID-19-related experiences. Physical, emotional, and social experiences related to COVID-19 infection and recovery were often interconnected and overlapping. These findings demonstrate that a holistic understanding of the patient experience that extends beyond physical symptoms is necessary to fully support patient care and recovery.

Participation in genetic screening: testing different outreach methods across a diverse hospital system based patient population.

Introduction: Genomics has the potential to transform medicine by identifying genetic risk factors that predispose people to certain illnesses. Use of genetic screening is rapidly expanding and shifting towards screening all patients regardless of known risk factors, but research is limited on the success of broad population-level outreach for genetic testing and the effectiveness of different outreach methods across diverse populations. In this study, we tested the effectiveness of Digital Only (emailing and texting) and Brochure Plus Digital (mailed brochure, emailing, and texting) outreach to encourage a diverse patient population to participate in a large hospital system's whole genome sequencing program. Methods: Disproportionate stratified sampling was used to create a study population more demographically diverse than the eligible population and response rates were analyzed overall and by demographics to understand the effectiveness of different outreach strategies. Results: 7.5% of all eligible patients enrolled in the program. While approximately 70% of patients invited to complete genetic testing identified in their EHR as being Hispanic, Black or African America, Asian, or another non-White race, these patients generally enrolled at lower rates than the overall population. Other underrepresented groups had higher enrollment rates including people with Medicaid coverage (8.7%) and those residing in rural areas (10.6%). We found no significant difference in enrollment rates between our Digital-Only and our Brochure Plus Digital outreach approaches in the overall population, but enrollment rates were significantly higher for Asian patients and patients who resided in rural areas in the Brochure Plus Digital group. Across both outreach approaches, links provided in emails were most commonly used for enrollment. Discussion: Our study reveals expected enrollment rates for proactive outreach by a hospital system for genetic testing in a diverse population. As more hospital systems are adopting population-scale genetic testing, these findings can inform future outreach efforts to recruit patients for genetic testing including those patients traditionally underrepresented in genomics.

Assessing the impact of recovery housing on healthcare utilization in Portland, Oregon.

Introduction: Central City Concern (CCC) operates several recovery housing sites in the Portland, Oregon metropolitan region, including the Blackburn Center (Blackburn) and the Richard L. Harris Building (Harris). This retrospective, observational study was designed to assess recovery housing's impact on inpatient detoxification readmission rates and healthcare utilization patterns. Methods: Our study population consisted of individuals discharged from CCC's Hooper Detox Stabilization Center from June 2019 to September 2020. A total of 75 clients housed at Blackburn, 63 clients housed at Harris, and 57 clients discharged as unhoused were included in the study sample. Using logistic regression for each of the two recovery housing groups relative to the unhoused group, we examined differences in readmissions to inpatient detoxification after their qualifying discharge. We then used Difference-In-Difference model to compare the per member per year (PMPY) use of different domains of health care before and after their qualifying discharge. Results: Compared to clients discharged as unhoused, Blackburn and Harris residents had lower risk of readmissions to inpatient detoxification treatment at 90- and 180-days post-discharge. Additionally, while the mean number of PMPY emergency department visits increased for clients discharged as unhoused in the post period, the average number of emergency department visits decreased for clients who obtained recovery housing at Blackburn (DiD=-3.65 PMPY, p-value=0.02) and at Harris (DiD=-3.87 PMPY, p-value=0.01). Conclusion: Findings highlight the impact and importance of recovery housing for individuals managing a substance use disorder and the value of healthcare system and public sector investment housing like Blackburn and Harris.

Integrating patient-reported physical, mental, and social impacts to classify long COVID experiences.

Long COVID was originally identified through patient-reported experiences of prolonged symptoms. Many studies have begun to describe long COVID; however, this work typically focuses on medical records, instead of patient experiences, and lacks a comprehensive view of physical, mental, and social impacts. As part of our larger My COVID Diary (MCD) study, we captured patient experiences using a prospective and longitudinal patient-reported outcomes survey (PROMIS-10) and free-text narrative submissions. From this study population, we selected individuals who were still engaged in the MCD study and reporting poor health (PROMIS-10 scores < 3) at 6 months (n = 634). We used their PROMIS-10 and narrative data to describe and classify their long COVID experiences. Using Latent Class Analysis of the PROMIS-10 data, we identified four classifications of long COVID experiences: a few lingering issues (n = 107), significant physical symptoms (n = 113), ongoing mental and cognitive struggles (n = 235), and numerous compounding challenges (n = 179); each classification included a mix of physical, mental, and social health struggles with varying levels of impairment. The classifications were reinforced and further explained by patient narratives. These results provide a new understanding of the varying ways that long COVID presents to help identify and care for patients.

Mammogram perceptions, communication, and gaps in care among individuals with non-English language preference in Oregon and Washington states.

This study examined perceptions of and communication about mammography as drivers of gaps in screening among individuals with non-English language preference (NELP). A survey was fielded in fall 2021 in five languages (Cantonese, English, Russian, Spanish, or Vietnamese) to individuals identified using electronic medical records in Oregon and Washington. The analytic sample consisted of 420 respondents with a median age of 61; approximately 45% of respondents identified as Asian, 37% as Hispanic, Latino, or Spanish origin, and 18% as some other race, ethnicity, or origin. Logistic regression models examined associations between screening and perception and communication items. Individuals who believed mammograms are unnecessary when healthy (aRR = 0.72 [0.57, 0.91]) or absent symptoms (aRR = 0.85 [0.72, 1.00]) were less likely to report a mammogram within the past two years (i.e., be current). Having a provider recommend (aRR = 1.27 [1.09, 1.47]) and discuss mammography (aRR = 1.18 [1.05, 1.32]) were associated with a higher likelihood of being current. Few respondents received written or verbal information in their preferred language (35% and 28.3%, respectively). Financial and logistical support, including language services were most frequently identified as types of support needed to obtain a mammogram. Overall, misperceptions about mammography may act as a barrier but communication may act as a facilitator for individuals with NELP. Provider-patient communication could be an effective way to encourage mammography. Culturally-responsive health promotion materials and provider communication, available in patients' preferred language, are needed to combat misperceptions and support ongoing, on-time mammography for NELP patients.

Evaluation of an Integrated Intervention to Address Clinical Care and Social Needs Among Patients with Type 2 Diabetes.

BACKGROUND: The Providence Diabetes Collective Impact Initiative (DCII) was designed to address the clinical challenges of type 2 diabetes and the social determinants of health (SDoH) challenges that exacerbate disease impact. OBJECTIVE: We assessed the impact of the DCII, a multifaceted intervention approach to diabetes treatment that employed both clinical and SDoH strategies, on access to medical and social services. DESIGN: The evaluation employed a cohort design and used an adjusted difference-in-difference model to compare treatment and control groups. PARTICIPANTS: Our study population consisted of 1220 people (740 treatment, 480 control), aged 18-65 years old with a pre-existing type 2 diabetes diagnosis who visited one of the seven Providence clinics (three treatment and four control) in the tri-county area of Portland, Oregon, between August 2019 and November 2020. INTERVENTIONS: The DCII threaded together clinical approaches such as outreach, standardized protocols, and diabetes self-management education and SDoH strategies including social needs screening, referral to a community resource desk, and social needs support (e.g., transportation) to create a comprehensive, multi-sector intervention. MAIN MEASURES: Outcome measures included SDoH screens, diabetes education participation, HbA1c, blood pressure, and virtual and in-person primary care utilization, as well as inpatient and emergency department hospitalization. KEY RESULTS: Compared to patients at the control clinics, patients at DCII clinics saw an increase in diabetes education (15.5%, p<0.001), were modestly more likely to receive SDoH screening (4.4%, p<0.087), and had an increase in the average number of virtual primary care visits of 0.35 per member, per year (p<0.001). No differences in HbA1c, blood pressure, or hospitalization were observed. CONCLUSIONS: DCII participation was associated with improvements in diabetes education use, SDoH screening, and some measures of care utilization.

Patient-Reported Outcomes for Fully Vaccinated COVID-19 Patients Over 6 Weeks: The Experiences of Clinical Breakthrough Cases.

BACKGROUND: While coronavirus disease 2019 (COVID-19) vaccines have high rates of efficacy, fully vaccinated individuals can become infected with COVID-19. Among this population, symptoms tend to be less severe and shorter lasting. Less is known about how vaccinated individuals who contract COVID-19 experience the disease through patient-reported outcomes (PROs) and how this changes over time. OBJECTIVE: The aim of this study was to describe the physical, mental, and social health PROs for fully vaccinated individuals who contracted COVID-19 over a 6-week period. DESIGN: Prospective design using the Patient-Reported Outcomes Measurement Information System short-form (PROMIS-10) collected through a mobile application-based platform. PARTICIPANT: 1114 fully vaccinated patients who tested positive for COVID-19 at a large US health system and engaged with the study on or after 1 March 2021 and reported onset of illness prior to 1 November 2021. MAIN MEASURES: Global physical and mental health PROMIS-10 T-scores for the 6-week period, component PROMIS-10 questions for the 6-week period, and component PROMIS-10 questions restricted to a subset of participants for the first month to measure individual recovery were analyzed. KEY RESULTS: Mean global physical and mental health T-scores increased over time and remained within one standard deviation of the population mean. At baseline, at least 40% of participants reported good health for all component questions except Fatigue (25%), and the proportion reporting good health increased over time for all questions, with the largest improvements in Fatigue (25.5 to 67.5%), Pain (59.1 to 82.8%), and Emotional Problems (42.3 to 62.5%). Over the first month, the greatest positive changes in individual recovery were observed for Fatigue (65.0%), Pain (53.0%), and Emotional Problems (41.1%); at least 30% of respondents reported no change in at least one category, and the greatest decreases were for Usual Social Activities (23.9%), Social Satisfaction (23.2%), and Mental Health (21.8%). CONCLUSIONS: This study provides an important step towards better understanding the impact of 'breakthrough' COVID-19 infections on clinically engaged, fully vaccinated patients' physical and mental health to improve support for their treatment and recovery.

Patient experience and healthcare utilization for a COVID-19 telemedicine home monitoring program offered in English and Spanish.

BACKGROUND: Telemedicine is a vital component of the healthcare system's response to COVID-19. In March of 2020, Providence health system rapidly implemented a telemedicine home monitoring program (HMP) for COVID-19 patients that included use of at-home pulse oximeters and thermometers and text-based surveys to monitor symptoms. By June 2020, Providence updated the HMP to be offered in Spanish. This program was implemented before COVID-19 testing was readily available and therefore was offered to all patients suspected of having COVID-19. This study examines engagement, experience, and utilization patterns for English and Spanish-speaking patients engaged in the COVID-19 HMP. METHODS: A retrospective review of program data was used to understand HMP patient engagement (responsiveness to three daily text to monitor symptoms), satisfaction with the program (likelihood to recommend the program) as well as comfort using home monitoring devices and comfort recovering from home. To understand impact on care for COVID-19 confirmed cases, we used electronic health records to measure patterns in healthcare use for COVID-19 positive HMP participants and non-HMP propensity weighted controls. All patients enrolled in the COVID-19 HMP from March-October 2020 were included in the study. Patients tested for COVID-19 during the time window and not enrolled in HMP were included in the propensity-weighted comparison group. Descriptive and regression analyses were performed overall and stratified by English and Spanish speakers. RESULTS: Of the 4,358 HMP participants, 75.5% identified as English speakers and 18.2% identified as Spanish speakers. There was high level of responsiveness to three daily text-based surveys monitoring symptoms engagement (>80%) and a high level of comfort using the home monitoring devices (thermometers and pulse oximeters) for English- and Spanish-speaking participants (97.3% and 99.6%, respectively). The majority of English (95.7%) and Spanish-speaking (100%) patients felt safe monitoring their condition from home and had high satisfaction with the HMP (76.5% and 83.6%, respectively). English and Spanish-speaking COVID-19 positive HMP participants had more outpatient and emergency departments (ED) encounters than non-participants 7 and 30 days after their positive test. CONCLUSION: This widely implemented HMP provided participants with a sense of safety and satisfaction and its use was associated with more outpatient care and ED encounters. These outcomes were comparable across English and Spanish-speakers, highlighting the importance and potential impact of language-concordant telemedicine.

Local Housing Choice Voucher Distribution Policies Impact Healthcare Utilization: a Randomized Natural Experiment.

While associations between obtaining affordable housing and improved health care are well documented, insufficient funding often forces housing authorities to prioritize limited housing vouchers to specific populations. We assessed the impact of obtaining housing on health care utilization at two urban housing authorities with different distribution policies: Housing Authority A prioritized seniors and people with disabilities, while Housing Authority B prioritized medically complex individuals and families with school-aged children. Both housing authorities used random selection to distribute vouchers, allowing us to conduct a randomized natural experiment of cases and waitlisted controls. No significant demographic differences were present between those receiving vouchers and waitlisted controls. Housing Authority A vouchers were associated with increased outpatient visits (OR = 1.19; P = 0.051). Housing Authority B vouchers decreased the likelihood of emergency department visits (OR = 0.61; P = 0.042). This study provides evidence that, while obtaining housing can result in better health care outcomes overall, local prioritization policies can influence that impact.

Health and Health Care Use Strongly Associated with Cumulative Burden of Social Determinants of Health.

Understanding health outcomes and patterns of health care utilization associated with patients' cumulative social determinant of health (SDOH) risk is essential to supporting better health care. This study compared mental and physical health outcomes and health care utilization by increasing number of social needs among a clinical adult population. Surveys were sent to 6000 patients with recent visits to 7 primary care clinics in Portland, Oregon in 2018. The final study sample included respondents who matched to medical claims data, N = 1748. The authors used a modified logistic regression model to estimate risk ratios for the relationship between cumulative SDOH factors and self-reported chronic conditions, and a 2-part model to estimate the effects of cumulative SDOH risk on health care utilization. Increased SDOH need was associated with increasing likelihood of worse self-reported health outcomes, especially mental health. Compared with those with no SDOH need, having 1-2 SDOH need(s) (adjusted risk ratio [aRR] 1.25; 95% confidence interval [CI]: 1.06-1.46) and 3 or more SDOH needs (aRR 1.45; 95% CI: 1.22-1.73) had a greater risk of reporting any behavioral health condition. However, the number of SDOH had a graded but inverse impact on use of mental health care services where fewer visits were observed among those using care. Having SDOH was associated with increased likelihood of having an emergency department visit and increased number of primary care visits. This study demonstrates the compounding impact of SDOH on health and health care use. This highlights the importance of collecting SDOH, including the total number of SDOH needs, when considering a patient's health and health care.

Major disparities in COVID-19 test positivity for patients with non-English preferred language even after accounting for race and social factors in the United States in 2020.

BACKGROUND: The COVID-19 pandemic has further exposed inequities in our society, demonstrated by disproportionate COVID-19 infection rate and mortality in communities of color and low-income communities. One key area of inequity that has yet to be explored is disparities based on preferred language. METHODS: We conducted a retrospective cohort study of 164,368 adults tested for COVID-19 in a large healthcare system across Washington, Oregon, and California from March - July 2020. Using electronic health records, we constructed multi-level models that estimated the odds of testing positive for COVID-19 by preferred language, adjusting for age, race/ethnicity, and social factors. We further investigated interaction between preferred language and both race/ethnicity and state. Analysis was performed from October-December 2020. RESULTS: Those whose preferred language was not English had higher odds of having a COVID-19 positive test (OR 3.07, p < 0.001); this association remained significant after adjusting for age, race/ethnicity, and social factors. We found significant interaction between language and race/ethnicity and language and state, but the odds of COVID-19 test positivity remained greater for those whose preferred language was not English compared to those whose preferred language was English within each race/ethnicity and state. CONCLUSIONS: People whose preferred language is not English are at greater risk of testing positive for COVID-19 regardless of age, race/ethnicity, geography, or social factors - demonstrating a significant inequity. Research demonstrates that our public health and healthcare systems are centered on English speakers, creating structural and systemic barriers to health. Addressing these barriers are long overdue and urgent for COVID-19 prevention.

Effect of a Health System-Sponsored Mobile App on Perinatal Health Behaviors: Retrospective Cohort Study.

BACKGROUND: Pregnancy mobile apps are becoming increasingly popular, with parents-to-be seeking information related to their pregnancy and their baby through mobile technology. This increase raises the need for prenatal apps with evidence-based content that is personalized and reliable. Previous studies have looked at whether prenatal apps impact health and behavior outcomes among pregnant and postpartum individuals; however, research has been limited. OBJECTIVE: The primary objective of this study is to assess whether the use of a health system-sponsored mobile app-Circle by Providence-aimed at providing personalized and reliable health information on pregnancy, postpartum recovery, and infant care is associated with improved health outcomes and increased healthy behaviors and knowledge among users. METHODS: This observational study compared app users and app nonusers using a self-reported survey and electronic medical records. The study took place over 18 months and was conducted at Providence St. Joseph Health in Portland, Oregon. The sample included patients who received prenatal care at one of seven Providence clinics and had a live birth at a Providence hospital. Recruitment occurred on a rolling basis and only those who completed the survey were included. Survey respondents were separated into app users and app nonusers, and survey responses and clinical outcomes were compared across groups using univariate and adjusted multivariate logistic regression. RESULTS: A total of 567 participants were enrolled in the study-167 in the app user group and 400 in the nonuser group. We found statistically significant differences between the two groups for certain behavior outcomes: subjects who used the app had 75% greater odds of breastfeeding beyond 6 months postpartum (P=.012), were less likely to miss prenatal appointments (P=.046), and were 50% more likely to exercise 3 or more times a week during pregnancy (P=.04). There were no differences in nutritional measures, including whether they took prenatal vitamins, ate 5 fruits or vegetables a day, or drank caffeine. We found no differences in many of the infant care outcomes; however, there was an increase in awareness of "purple crying." Finally, there were no significant differences in measured clinical health outcomes, including cesarean births, length of hospital stays (in minutes), low birth weight infants, preterm births, small-for-gestational-age births, large-for-gestational-age births, and neonatal intensive care unit stays. CONCLUSIONS: The use of the Circle app, which provides access to personalized and evidence-based health information, was associated with an increase in certain healthy behaviors and health knowledge, although there was no impact on clinical health outcomes. More research is needed to determine the impact of mobile prenatal apps on healthy pregnancies, clinical health outcomes, and infant care.

Understanding the Socioeconomic and Health Challenges of the Medicaid Expansion Population in Oregon.

Following the Patient Protection and Affordable Care Act, Medicaid eligibility in the United States expanded to include low-income adults. One key challenge for organizations and providers serving the Medicaid population was predicting if and how this change would alter the composition of enrollees. This study characterized demographics, socioeconomic challenges, and health of the expansion and non-expansion Medicaid populations in a metropolitan area in Oregon using a survey and Medicaid claims. Results showed that the expansion population has more men and non-English speakers than the non-expansion population. They also have greater education and employment, but face similar socioeconomic challenges including struggling to meet basic needs and housing instability. This study also found comparable self-reported physical and mental health, but lower prevalence of physical or mental health diagnoses and several ambulatory care reactive conditions including hypertension, obesity, and type 2 diabetes. The authors concluded that expansion and non-expansion populations differ in sex, language, education, employment, and health, but they face similar socioeconomic challenges. This information is useful for organizations coordinating and providing care to Medicaid members so they can understand the needs of the population and set appropriate population health management strategies.

Examining the Prevalence of Adverse Childhood Experiences and Associated Cardiovascular Disease Risk Factors Among Low-Income Uninsured Adults.

BACKGROUND: Adverse childhood experiences (ACEs) are linked to poor adult health outcomes, including cardiovascular disease. However, little is known about its prevalence, specifically in low-income populations. The objective of this study was to estimate the extent of ACEs in a low-income, nonclinical, uninsured adult population and assess the relationship between ACEs and cardiovascular disease risk factors. METHODS AND RESULTS: This study leverages the OHIE's (Oregon Health Insurance Experiment) study population, uninsured adults who were randomly selected to apply for Medicaid, and data collected through in-person health screenings. We objectively measured obesity, cholesterol, blood pressure, and blood sugar. Smoking, physical activity, and history of chronic disease were self-reported. Independent variables were the 10-item ACEs questions covering neglect, abuse, and household dysfunction. The sample consisted of 12 229 low-income, nonelderly uninsured adults who participated in the OHIE health screenings from 2009 to 2010. A total of 5929 (48%) returned a follow-up survey reporting ACEs in 2012. ACEs were more prevalent in low-income adults compared with previous estimates in a general clinical population, with notably high rates of emotional abuse, emotional neglect, and household dysfunction. ACEs were statistically associated with higher rates of obesity, smoking, and physical inactivity, but not high cholesterol or diabetes mellitus. We detected a strong relationship between ACEs and a self-reported history of a hypertension diagnosis but no statistically significant differences in being hypertensive. CONCLUSIONS: This study design allowed us to assess the prevalence of ACEs among uninsured low-income adults and the association between ACEs and clinical indicators of cardiovascular disease risk that are difficult to ordinarily observe. Low-income adults have high rates of ACEs than previous prevalence estimates and ACEs were associated with higher rates of multiple cardiovascular disease risk factors. As states continue to expand Medicaid to the previously uninsured, providers may want to consider incorporating trauma-based approaches to care delivery.

Identifying underlying constructs of childhood adversity in a low-income population.

BACKGROUND: Extensive research has documented the association between adverse childhood experiences (ACEs) and poor outcomes later in life, as well as the high prevalence of ACEs in the American population. Studies consistently find that over half of American adults have experienced at least one ACE. Despite this, research on the long-term impacts of ACEs is challenging due to the complex nature of adversity. OBJECTIVE: Our study aimed to define underlying constructs of adversity, and explore how they changed throughout childhood, in a low-income population. PARTICIPANTS AND SETTING: We fielded a survey to Medicaid-enrolled adults in the Portland, OR metropolitan area. METHODS: Our survey captured different experiences in childhood, including relationships and support, educational challenges, housing and employment stability, neighborhood environment, discrimination, abuse, neglect, and household dysfunction; questions were asked for 6-12 and 13-18 years of age. We then used factor analysis to identify underlying constructs of adversity in the two age ranges. RESULTS: We identified two factors - Inadequate Emotional Support and Instability - in each age range. Inadequate Emotional Support remained consistent in both time periods while the Instability factor changed, expanding from household-centric experiences in childhood to a wider variety of experiences in adolescence. Additionally, a number of variables did not load on either factor in either age range. CONCLUSIONS: These results underscore the importance of expanding how we think about instability specifically, and childhood adversity in general.

Formerly Homeless People Had Lower Overall Health Care Expenditures After Moving Into Supportive Housing.

The provision of supportive housing is often recognized as important public policy, but it also plays a role in health care reform. Health care costs for the homeless reflect both their medical complexity and psychosocial risk factors. Supportive housing attempts to moderate both by providing stable places to live along with on-site integrated health services. In this pilot study we used a mixture of survey and administrative claims data to evaluate outcomes for formerly homeless people who were living in a supportive housing facility in Oregon between 2010 and 2014. Results from the claims analysis showed significantly lower overall health care expenditures for the people after they moved into supportive housing. Expenditure changes were driven primarily by reductions in emergency and inpatient care. Survey data suggest that the savings were not at the expense of quality: Respondents reported improved access to care, stronger primary care connections, and better subjective health outcomes. Together, these results indicate a potential association between supportive housing and reduced health care costs that warrants deeper consideration as part of ongoing health care reforms.

CpG preconditioning regulates miRNA expression that modulates genomic reprogramming associated with neuroprotection against ischemic injury.

Cytosine-phosphate-guanine (CpG) preconditioning reprograms the genomic response to stroke to protect the brain against ischemic injury. The mechanisms underlying genomic reprogramming are incompletely understood. MicroRNAs (miRNAs) regulate gene expression; however, their role in modulating gene responses produced by CpG preconditioning is unknown. We evaluated brain miRNA expression in response to CpG preconditioning before and after stroke using microarray. Importantly, we have data from previous gene microarrays under the same conditions, which allowed integration of miRNA and gene expression data to specifically identify regulated miRNA gene targets. CpG preconditioning did not significantly alter miRNA expression before stroke, indicating that miRNA regulation is not critical for the initiation of preconditioning-induced neuroprotection. However, after stroke, differentially regulated miRNAs between CpG- and saline-treated animals associated with the upregulation of several neuroprotective genes, implicating these miRNAs in genomic reprogramming that increases neuroprotection. Statistical analysis revealed that the miRNA targets were enriched in the gene population regulated in the setting of stroke, implying that miRNAs likely orchestrate this gene expression. These data suggest that miRNAs regulate endogenous responses to stroke and that manipulation of these miRNAs may have the potential to acutely activate novel neuroprotective processes that reduce damage.

Modeling dynamic regulatory processes in stroke.

The ability to examine the behavior of biological systems in silico has the potential to greatly accelerate the pace of discovery in diseases, such as stroke, where in vivo analysis is time intensive and costly. In this paper we describe an approach for in silico examination of responses of the blood transcriptome to neuroprotective agents and subsequent stroke through the development of dynamic models of the regulatory processes observed in the experimental gene expression data. First, we identified functional gene clusters from these data. Next, we derived ordinary differential equations (ODEs) from the data relating these functional clusters to each other in terms of their regulatory influence on one another. Dynamic models were developed by coupling these ODEs into a model that simulates the expression of regulated functional clusters. By changing the magnitude of gene expression in the initial input state it was possible to assess the behavior of the networks through time under varying conditions since the dynamic model only requires an initial starting state, and does not require measurement of regulatory influences at each time point in order to make accurate predictions. We discuss the implications of our models on neuroprotection in stroke, explore the limitations of the approach, and report that an optimized dynamic model can provide accurate predictions of overall system behavior under several different neuroprotective paradigms.

Poly-ICLC preconditioning protects the blood-brain barrier against ischemic injury in vitro through type I interferon signaling.

Preconditioning with a low dose of harmful stimulus prior to injury induces tolerance to a subsequent ischemic challenge resulting in neuroprotection against stroke. Experimental models of preconditioning primarily focus on neurons as the cellular target of cerebral protection, while less attention has been paid to the cerebrovascular compartment, whose role in the pathogenesis of ischemic brain injury is crucial. We have shown that preconditioning with polyinosinic polycytidylic acid (poly-ICLC) protects against cerebral ischemic damage. To delineate the mechanism of poly-ICLC protection, we investigated whether poly-ICLC preconditioning preserves the function of the blood-brain barrier (BBB) in response to ischemic injury. Using an in vitro BBB model, we found that poly-ICLC treatment prior to exposure to oxygen-glucose deprivation maintained the paracellular and transcellular transport across the endothelium and attenuated the drop in transendothelial electric resistance. We found that poly-ICLC treatment induced interferon (IFN) ß mRNA expression in astrocytes and microglia and that type I IFN signaling in brain microvascular endothelial cells was required for protection. Importantly, this implicates a potential mechanism underlying neuroprotection in our in vivo experimental stroke model, where type I IFN signaling is required for poly-ICLC-induced neuroprotection against ischemic injury. In conclusion, we are the first to show that preconditioning with poly-ICLC attenuates ischemia-induced BBB dysfunction. This mechanism is likely an important feature of poly-ICLC-mediated neuroprotection and highlights the therapeutic potential of targeting BBB signaling pathways to protect the brain against stroke.