Identification and Validation of Ifit1 as an Important Innate Immune Bottleneck

The innate immune system plays important roles in a number of disparate processes. Foremost, innate immunity is a first responder to invasion by pathogens and triggers early defensive responses and recruits the adaptive immune system. The innate immune system also responds to endogenous damage signals that arise from tissue injury. Recently it has been found that innate immunity plays an important role in neuroprotection against ischemic stroke through the activation of the primary innate immune receptors, Toll-like receptors (TLRs). Using several large-scale transcriptomic data sets from mouse and mouse macrophage studies we identified targets predicted to be important in controlling innate immune processes initiated by TLR activation. Targets were identified as genes with high betweenness centrality, so-called bottlenecks, in networks inferred from statistical associations between gene expression patterns. A small set of putative bottlenecks were identified in each of the data sets investigated including interferon-stimulated genes (Ifit1, Ifi47, Tgtp and Oasl2) as well as genes uncharacterized in immune responses (Axud1 and Ppp1r15a). We further validated one of these targets, Ifit1, in mouse macrophages by showing that silencing it suppresses induction of predicted downstream genes by lipopolysaccharide (LPS)-mediated TLR4 activation through an unknown direct or indirect mechanism. Our study demonstrates the utility of network analysis for identification of interesting targets related to innate immune function, and highlights that Ifit1 can exert a positive regulatory effect on downstream genes

LPS preconditioning redirects TLR signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury

<p>Abstract</p> <p>Background</p> <p>Toll-like receptor 4 (TLR4) is activated in response to cerebral ischemia leading to substantial brain damage. In contrast, mild activation of TLR4 by preconditioning with low dose exposure to lipopolysaccharide (LPS) prior to cerebral ischemia dramatically improves outcome by reprogramming the signaling response to injury. This suggests that TLR4 signaling can be altered to induce an endogenously neuroprotective phenotype. However, the TLR4 signaling events involved in this neuroprotective response are poorly understood. Here we define several molecular mediators of the primary signaling cascades induced by LPS preconditioning that give rise to the reprogrammed response to cerebral ischemia and confer the neuroprotective phenotype.</p> <p>Methods</p> <p>C57BL6 mice were preconditioned with low dose LPS prior to transient middle cerebral artery occlusion (MCAO). Cortical tissue and blood were collected following MCAO. Microarray and qtPCR were performed to analyze gene expression associated with TLR4 signaling. EMSA and DNA binding ELISA were used to evaluate NFκB and IRF3 activity. Protein expression was determined using Western blot or ELISA. MyD88-/- and TRIF-/- mice were utilized to evaluate signaling in LPS preconditioning-induced neuroprotection.</p> <p>Results</p> <p>Gene expression analyses revealed that LPS preconditioning resulted in a marked upregulation of anti-inflammatory/type I IFN-associated genes following ischemia while pro-inflammatory genes induced following ischemia were present but not differentially modulated by LPS. Interestingly, although expression of pro-inflammatory genes was observed, there was decreased activity of NFκB p65 and increased presence of NFκB inhibitors, including Ship1, Tollip, and p105, in LPS-preconditioned mice following stroke. In contrast, IRF3 activity was enhanced in LPS-preconditioned mice following stroke. TRIF and MyD88 deficient mice revealed that neuroprotection induced by LPS depends on TLR4 signaling via TRIF, which activates IRF3, but does not depend on MyD88 signaling.</p> <p>Conclusion</p> <p>Our results characterize several critical mediators of the TLR4 signaling events associated with neuroprotection. LPS preconditioning redirects TLR4 signaling in response to stroke through suppression of NFκB activity, enhanced IRF3 activity, and increased anti-inflammatory/type I IFN gene expression. Interestingly, this protective phenotype does not require the suppression of pro-inflammatory mediators. Furthermore, our results highlight a critical role for TRIF-IRF3 signaling as the governing mechanism in the neuroprotective response to stroke.</p

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\u27 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\u27s health and health care

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

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\u27 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\u27s health and health care

Direct and indirect pathways between childhood instability and adult homelessness in a low-income population

There is a homelessness crisis in the United States. Many investments have been made to reverse this crisis including building more affordable housing and providing rent subsidies, which create mechanisms to support people who are currently experiencing homelessness. However, less is known about how to invest upstream to prevent homelessness in the first place. In this paper, we explore the pathway to adult homelessness from childhood instability through potentially modifiable adolescent experiences including running away, school dropout, and abuse of drugs or alcohol. We used results from our life course survey of a Medicaid population (N = 2,348) in a large metropolitan area in Oregon to create a structural equation model that measured the relationships between these experiences and adult homelessness. The overall effect of childhood instability on adult homelessness was 0.475 (p \u3c 0.001). The direct effect of childhood instability on homelessness was 0.313 (p \u3c 0.001). Both running away from home and alcohol and drug abuse mediated the overall association between childhood instability and homelessness. Running away from home (0.108, p \u3c 0.001)) accounted for 22.7% of the overall association; alcohol and drug abuse (0.051, p = 0.053) accounted for 10.7%. In contrast, dropping out of school did not mediate the overall association between childhood instability and adult homelessness. These results strongly emphasize the importance of intervening upstream to reduce childhood instability to help prevent adult homelessness. Interventions that that support adolescents who run away from home and prevent or treat adolescent substance abuse may also reduce entry to adult homelessness

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\u27 preferred language, are needed to combat misperceptions and support ongoing, on-time mammography for NELP patients

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

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