PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals.

Ferroptosis is a form of programmed cell death that is pathogenic to several acute and chronic diseases and executed via oxygenation of polyunsaturated phosphatidylethanolamines (PE) by 15-lipoxygenases (15-LO) that normally use free polyunsaturated fatty acids as substrates. Mechanisms of the altered 15-LO substrate specificity are enigmatic. We sought a common ferroptosis regulator for 15LO. We discovered that PEBP1, a scaffold protein inhibitor of protein kinase cascades, complexes with two 15LO isoforms, 15LO1 and 15LO2, and changes their substrate competence to generate hydroperoxy-PE. Inadequate reduction of hydroperoxy-PE due to insufficiency or dysfunction of a selenoperoxidase, GPX4, leads to ferroptosis. We demonstrated the importance of PEBP1-dependent regulatory mechanisms of ferroptotic death in airway epithelial cells in asthma, kidney epithelial cells in renal failure, and cortical and hippocampal neurons in brain trauma. As master regulators of ferroptotic cell death with profound implications for human disease, PEBP1/15LO complexes represent a new target for drug discovery.

Neurobiology and systems biology of stress resilience.

Stress resilience is the phenomenon that some people maintain their mental health despite exposure to adversity or show only temporary impairments followed by quick recovery. Resilience research attempts to unravel the factors and mechanisms that make resilience possible and to harness its insights for the development of preventative interventions in individuals at risk for acquiring stress-related dysfunctions. Biological resilience research has been lagging behind the psychological and social sciences but has seen a massive surge in recent years. At the same time, progress in this field has been hampered by methodological challenges related to finding suitable operationalizations and study designs, replicating findings, and modeling resilience in animals. We embed a review of behavioral, neuroimaging, neurobiological, and systems biological findings in adults in a critical methods discussion. We find preliminary evidence that hippocampus-based pattern separation and prefrontal-based cognitive control functions protect against the development of pathological fears in the aftermath of singular, event-type stressors [as found in fear-related disorders, including simpler forms of posttraumatic stress disorder (PTSD)] by facilitating the perception of safety. Reward system-based pursuit and savoring of positive reinforcers appear to protect against the development of more generalized dysfunctions of the anxious-depressive spectrum resulting from more severe or longer-lasting stressors (as in depression, generalized or comorbid anxiety, or severe PTSD). Links between preserved functioning of these neural systems under stress and neuroplasticity, immunoregulation, gut microbiome composition, and integrity of the gut barrier and the blood-brain barrier are beginning to emerge. On this basis, avenues for biological interventions are pointed out.

An architecturally rational hemostat for rapid stopping of massive bleeding on anticoagulation therapy.

Hemostatic devices are critical for managing emergent severe bleeding. With the increased use of anticoagulant therapy, there is a need for next-generation hemostats. We rationalized that a hemostat with an architecture designed to increase contact with blood, and engineered from a material that activates a distinct and undrugged coagulation pathway can address the emerging need. Inspired by lung alveolar architecture, here, we describe the engineering of a next-generation single-phase chitosan hemostat with a tortuous spherical microporous design that enables rapid blood absorption and concentrated platelets and fibrin microthrombi in localized regions, a phenomenon less observed with other classical hemostats without structural optimization. The interaction between blood components and the porous hemostat was further amplified based on the charged surface of chitosan. Contrary to the dogma that chitosan does not directly affect physiological clotting mechanism, the hemostat induced coagulation via a direct activation of platelet Toll-like receptor 2. Our engineered porous hemostat effectively stopped the bleeding from murine liver wounds, swine liver and carotid artery injuries, and the human radial artery puncture site within a few minutes with significantly reduced blood loss, even under the anticoagulant treatment. The integration of engineering design principles with an understanding of the molecular mechanisms can lead to hemostats with improved functions to address emerging medical needs.

It matters what you see: Graphic media images of war and terror may amplify distress.

Media exposure to graphic images of violence has proliferated in contemporary society, particularly with the advent of social media. Extensive exposure to media coverage immediately after the 9/11 attacks and the Boston Marathon bombings (BMB) was associated with more early traumatic stress symptoms; in fact, several hours of BMB-related daily media exposure was a stronger correlate of distress than being directly exposed to the bombings themselves. Researchers have replicated these findings across different traumatic events, extending this work to document that exposure to graphic images is independently and significantly associated with stress symptoms and poorer functioning. The media exposure-distress association also appears to be cyclical over time, with increased exposure predicting greater distress and greater distress predicting more media exposure following subsequent tragedies. The war in Israel and Gaza, which began on October 7, 2023, provides a current, real-time context to further explore these issues as journalists often share graphic images of death and destruction, making media-based graphic images once again ubiquitous and potentially challenging public well-being. For individuals sharing an identity with the victims or otherwise feeling emotionally connected to the Middle East, it may be difficult to avoid viewing these images. Through a review of research on the association between exposure to graphic images and public health, we discuss differing views on the societal implications of viewing such images and advocate for media literacy campaigns to educate the public to identify mis/disinformation and understand the risks of viewing and sharing graphic images with others.

Local Modulation of Antigen-Presenting Cell Development after Resolution of Pneumonia Induces Long-Term Susceptibility to Secondary Infections.

Lung infections cause prolonged immune alterations and elevated susceptibility to secondary pneumonia. We found that, after resolution of primary viral or bacterial pneumonia, dendritic cells (DC), and macrophages exhibited poor antigen-presentation capacity and secretion of immunogenic cytokines. Development of these "paralyzed" DCs and macrophages depended on the immunosuppressive microenvironment established upon resolution of primary infection, which involved regulatory T (Treg) cells and the cytokine TGF-ß. Paralyzed DCs secreted TGF-ß and induced local Treg cell accumulation. They also expressed lower amounts of IRF4, a transcription factor associated with increased antigen-presentation capacity, and higher amounts of Blimp1, a transcription factor associated with tolerogenic functions, than DCs present during primary infection. Blimp1 expression in DC of humans suffering sepsis or trauma correlated with severity and complicated outcomes. Our findings describe mechanisms underlying sepsis- and trauma-induced immunosuppression, reveal prognostic markers of susceptibility to secondary infections and identify potential targets for therapeutic intervention.

Amnesia after Repeated Head Impact Is Caused by Impaired Synaptic Plasticity in the Memory Engram.

Subconcussive head impacts are associated with the development of acute and chronic cognitive deficits. We recently reported that high-frequency head impact (HFHI) causes chronic cognitive deficits in mice through synaptic changes. To better understand the mechanisms underlying HFHI-induced memory decline, we used TRAP2/Ai32 transgenic mice to enable visualization and manipulation of memory engrams. We labeled the fear memory engram in male and female mice exposed to an aversive experience and subjected them to sham or HFHI. Upon subsequent exposure to natural memory recall cues, sham, but not HFHI, mice successfully retrieved fearful memories. In sham mice the hippocampal engram neurons exhibited synaptic plasticity, evident in amplified AMPA:NMDA ratio, enhanced AMPA-weighted tau, and increased dendritic spine volume compared with nonengram neurons. In contrast, although HFHI mice retained a comparable number of hippocampal engram neurons, these neurons did not undergo synaptic plasticity. This lack of plasticity coincided with impaired activation of the engram network, leading to retrograde amnesia in HFHI mice. We validated that the memory deficits induced by HFHI stem from synaptic plasticity impairments by artificially activating the engram using optogenetics and found that stimulated memory recall was identical in both sham and HFHI mice. Our work shows that chronic cognitive impairment after HFHI is a result of deficiencies in synaptic plasticity instead of a loss in neuronal infrastructure, and we can reinstate a forgotten memory in the amnestic brain by stimulating the memory engram. Targeting synaptic plasticity may have therapeutic potential for treating memory impairments caused by repeated head impacts.

Crepuscular rays - The bright side of complement after tissue injury.

Acute injuries trigger an intense activation of the body's defense mechanisms aiming to limit damage and initiate healing. Among the crucial components of the intravascular immune system, the complement system plays a significant role in traumatic injuries, albeit often negatively. It has been suggested that excessive activation of the complement system, transitioning from a localized and timed response to a systemic one, can lead to a loss of its host-protective characteristics. Complement activation products have been associated with the severity of injuries, which sometimes serve as predictors for the onset of organ dysfunctions. Animal studies utilizing complement-targeting agents have provided the basis for considering complement in the management of traumatic injuries in humans. However, numerous studies suggest that the spatial and temporal aspects of complement inhibition are crucial for its efficacy. Understanding the underlying mechanism of the injury is essential to determine where, when, and whether complement inhibition is warranted. Despite the detrimental effects of uncontrolled complement activation, its regulated activation may contribute to essential aspects of healing, such as waste removal and regeneration. This review focuses on the beneficial roles of complement activation in trauma, which are often overlooked or given less consideration but are of immense importance.

Resilience and Disaster: Flexible Adaptation in the Face of Uncertain Threat.

Disasters cause sweeping damage, hardship, and loss of life. In this article, we first consider the dominant psychological approach to disasters and its narrow focus on psychopathology (e.g., posttraumatic stress disorder). We then review research on a broader approach that has identified heterogeneous, highly replicable trajectories of outcome, the most common being stable mental health or resilience. We review trajectory research for different types of disasters, including the COVID-19 pandemic. Next, we consider correlates of the resilience trajectory and note their paradoxically limited ability to predict future resilient outcomes. Research using machine learning algorithms improved prediction but has not yet illuminated the mechanism behind resilient adaptation. To that end, we propose a more direct psychological explanation for resilience based on research on the motivational and mechanistic components of regulatory flexibility. Finally, we consider how future research might leverage new computational approaches to better capture regulatory flexibility in real time.

Individuals with adverse childhood experiences explore less and underweight reward feedback.

Adverse childhood experiences (ACEs) are extreme stressors that lead to negative psychosocial outcomes in adulthood. Nonhuman animals explore less after exposure to early stress. Therefore, in this preregistered study, we hypothesized that reduced exploration following ACEs would also be evident in human adults. Further, we predicted that adults with ACEs, in a foraging task, would adopt a decision-making policy that relies on the most-recent reward feedback, a rational strategy for unstable environments. We analyzed data from 145 adult participants, 47 with four or more ACEs and 98 with fewer than four ACEs. In the foraging task, participants evaluated the trade-off between exploiting a known patch with diminishing rewards and exploring a novel one with a fresh distribution of rewards. Using computational modeling, we quantified the degree to which participants' decisions weighted recent feedback. As predicted, participants with ACEs explored less. However, contrary to our hypothesis, they underweighted recent feedback. These unexpected findings indicate that early adversity may dampen reward sensitivity. Our results may help to identify cognitive mechanisms that link childhood trauma to the onset of psychopathology.

Transcriptomic responses of peripheral blood leukocytes to cardiac surgery after acute inflammation, and three months recovery.

Traumatic perioperative conditions may trigger early systemic responses, activate leukocytes and reprogram the immune system. We hypothesize that leukocyte activation may not revert to pre-surgical states, and that protracted activation may emerge with increased risks of comorbidities. We tested this concept by examining the transcriptomes of monocytes and T cells in a representative observational cohort of patients (n = 13) admitted for elective cardiac surgery. Transcriptomes in T cells and monocytes were compared from before surgery (t0), and monocytes were analyzed longitudinally after acute (t24hr), and convalescent (t3m) time points. Monocytes and T cells expressed distinct transcriptomes, reflected by statistically significant differential expression of 558 T cell related genes. Monocytes expressed genes related to protein degradation and presented atypical activation of surface markers and cytoplasmic functions over time. Additionally, monocytes exhibited limited transcriptomic heterogeneity prior to surgery, and long-term patterns of gene expression associated with atherosclerosis showed three temporally distinct signatures. These data establish that post-cardiac surgery transcriptomes of monocytes differ even at three months compared to baselines, which may reflect latent ('smoldering') inflammation and persistent progression of tissue degenerative processes that should inform clinical care.

Amino-terminal proteolytic fragment of the axon growth inhibitor Nogo-A (Rtn4A) is upregulated by injury and promotes axon regeneration.

After adult mammalian central nervous system injury, axon regeneration is extremely limited or absent, resulting in persistent neurological deficits. Axon regeneration failure is due in part to the presence of inhibitory proteins, including NogoA (Rtn4A), from which two inhibitory domains have been defined. When these inhibitory domains are deleted, but an amino-terminal domain is still expressed in a gene trap line, mice show axon regeneration and enhanced recovery from injury. In contrast, when there is no amino-terminal Nogo-A fragment in the setting of inhibitory domain deletion, then axon regeneration and recovery are indistinguishable from WT. These data indicated that an amino-terminal Nogo-A fragment derived from the gene trap might promote axon regeneration, but this had not been tested directly and production of this fragment without gene targeting was unclear. Here, we describe posttranslation production of an amino-terminal fragment of Nogo-A from the intact gene product. This fragment is created by proteolysis near amino acid G214-N215 and levels are enhanced by axotomy. Furthermore, this fragment promotes axon regeneration in vitro and acts cell autonomously in neurons, in contrast to the inhibitory extracellular action of other Nogo-A domains.Proteins interacting with the amino-terminal Nogo-A fragment by immunoprecipitation include HSPA8 (HSC70, HSP7C). Suppression of HSPA8 expression by shRNA decreases axon regeneration from cerebral cortical neurons and overexpression increases axon regeneration. Moreover, the amino-terminal Nogo-A fragment increases HSPA8 chaperone activity. These data provide an explanation for varied results in different gene-targeted Nogo-A mice, as well as revealing an axon regeneration promoting domain of Nogo-A.

Head Injury and Risk of Incident Ischemic Stroke in Community-Dwelling Adults.

BACKGROUND: While stroke is a recognized short-term sequela of traumatic brain injury, evidence about long-term ischemic stroke risk after traumatic brain injury remains limited. METHODS: The Atherosclerosis Risk in Communities Study is an ongoing prospective cohort comprised of US community-dwelling adults enrolled in 1987 to 1989 followed through 2019. Head injury was defined using self-report and hospital-based diagnostic codes and was analyzed as a time-varying exposure. Incident ischemic stroke events were physician-adjudicated. We used Cox regression adjusted for sociodemographic and cardiovascular risk factors to estimate the hazard of ischemic stroke as a function of head injury. Secondary analyses explored the number and severity of head injuries; the mechanism and severity of incident ischemic stroke; and heterogeneity within subgroups defined by race, sex, and age. RESULTS: Our analysis included 12 813 participants with no prior head injury or stroke. The median follow-up age was 27.1 years (25th-75th percentile=21.1-30.5). Participants were of median age 54 years (25th-75th percentile=49-59) at baseline; 57.7% were female and 27.8% were Black. There were 2158 (16.8%) participants with at least 1 head injury and 1141 (8.9%) participants with an incident ischemic stroke during follow-up. For those with head injuries, the median age to ischemic stroke was 7.5 years (25th-75th percentile=2.2-14.0). In adjusted models, head injury was associated with an increased hazard of incident ischemic stroke (hazard ratio [HR], 1.34 [95% CI, 1.12-1.60]). We observed evidence of dose-response for the number of head injuries (1: HR, 1.16 [95% CI, 0.97-1.40]; ≥2: HR, 1.94 [95% CI, 1.39-2.71]) but not for injury severity. We observed evidence of stronger associations between head injury and more severe stroke (National Institutes of Health Stroke Scale score ≤5: HR, 1.31 [95% CI, 1.04-1.64]; National Institutes of Health Stroke Scale score 6-10: HR, 1.64 [95% CI, 1.06-2.52]; National Institutes of Health Stroke Scale score ≥11: HR, 1.80 [95% CI, 1.18-2.76]). Results were similar across stroke mechanism and within strata of race, sex, and age. CONCLUSIONS: In this community-based cohort, head injury was associated with subsequent ischemic stroke. These results suggest the importance of public health interventions aimed at preventing head injuries and primary stroke prevention among individuals with prior traumatic brain injuries.

It takes more than rainbows: Supporting sexual and gender minority patients with trauma-informed cancer care.

BACKGROUND/PURPOSE: The American Society of Clinical Oncology has called for an increased priority to improve cancer care for sexual and gender minority (SGM) populations because of heightened risk of receiving disparate treatment and having suboptimal experiences, including perceived discrimination. We demonstrate how integrating trauma-informed care (TIC) principles across the cancer continuum is a key strategy to improving care delivery and outcomes among SGM populations. METHOD: This empirically informed perspective expands on the concepts generated through the American Society of Clinical Oncology position statement and uses the Substance Abuse and Mental Health Services Association's "Four Rs" Toward Trauma Informed Care: Realize, Recognize, Response, and Resist Traumatization. RESULTS: Recommendations for each component of TIC include: (1) Realize: Implement SGM cultural humility training, including modules on SGM-specific trauma, discrimination, harassment, and violence; (2) Recognize: Routinely screen for emotional distress using methods to ensure privacy, and/or normalize mental health screenings to cancer patients; (3) Respond: Create and widely disseminate policies and patients' rights that prohibit discrimination and ensure access to gender-neutral clinical environments; and (4) Resist Traumatization: Establish and respond to quality metrics (e.g., standardized patients, patient satisfaction surveys) that are informed by a community advisory board with the purpose of ensuring and maintaining quality care. CONCLUSIONS AND IMPLICATIONS: Integrating TIC principles into cancer care for SGM populations is crucial to address disparities in treatment and clinical outcomes. Our recommendations offer practical approaches for oncology teams to implement TIC care and ensure equitable and inclusive cancer care for patients and their families.

Trauma and sporadic desmoid tumor development: An approach toward real incidence and aspects of causality.

OBJECTIVES: The development of desmoid tumors (DT) is associated with trauma, which is an aspect with medicolegal relevance. The objective of this study was to analyze the proportion and type of trauma (surgical, blunt/fracture, implants), its lag time, and mutations of the CTNNB1 gene in patients with sporadic DT. METHODS: We analyzed a prospectively kept database of 381 females and 171 males, median age at disease onset 37.7 years (females) and 39.3 years (males) with a histologically confirmed DT. Patients with germline mutation of the APC gene were excluded. Details of the history particularly of traumatic injuries to the site of DT were provided by 501 patients. RESULTS: In 164 patients (32.7%), a trauma anteceding DT could be verified with a median lag time of 22.9 months (SD, 7.7 months; range, 9-44 months). A prior surgical procedure was relevant in 98 patients, a blunt trauma in 35 patients, a punctuated trauma (injections, trocar) in 18 patients, and site of an implant in 10 patients. In 220 patients, no trauma was reported (43.9%), and 58 females (11.6%) had a postpregnancy DT in the rectus abdominis muscle. In 42 patients (8.4%), data were inconclusive. The distribution of mutations in the CTNNB1 gene (codon 41 vs. 45) was similar in patients with and without a history of trauma before DT development. CONCLUSIONS: A significant subgroup of patients suffers from a trauma-associated DT, predominantly at a prior surgical site including implants to breast or groin, accounting for 77.9% of the cases, whereas blunt trauma was responsible in 22.1%. We found no data to support that trauma-associated DT have different molecular features in the CTNNB1 gene.

A novel animal model for understanding secondary traumatic stress and visceral pain in male rats.

Empathetic relationships and the social transference of behaviours have been shown to occur in humans, and more recently through the development of rodent models, where both fear and pain phenotypes develop in observer animals. Clinically, observing traumatic events can induce 'trauma and stressor-related disorders' as defined in the DSM 5. These disorders are often comorbid with pain and gastrointestinal disturbances; however, our understanding of how gastrointestinal - or visceral - pain can be vicariously transmitted is lacking. Visceral pain originates from the internal organs, and despite its widespread prevalence, remains poorly understood. We established an observation paradigm to assess the impact of witnessing visceral pain. We utilised colorectal distension (CRD) to induce visceral pain behaviours in a stimulus rodent while the observer rodent observed. Twenty four hours post-observation, the observer rodent's visceral sensitivity was assessed using CRD. The observer rodents were found to have significant hyperalgesia as determined by lower visceral pain threshold and higher number of total pain behaviours compared with controls. The behaviours of the observer animals during the observation were found to be correlated with the behaviours of the stimulus animal employed. We found that observer animals had hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis, highlighted by reduced corticosterone at 90 minutes post-CRD. Using c-Fos immunohistochemistry we showed that observer animals also had increased activation of the anterior cingulate cortex, and decreased activation of the paraventricular nucleus, compared with controls. These results suggest that witnessing another animal in pain produces a behavioural phenotype and impacts the brain-gut axis.

Interpretable principal component analysis for multilevel multivariate functional data.

Many studies collect functional data from multiple subjects that have both multilevel and multivariate structures. An example of such data comes from popular neuroscience experiments where participants' brain activity is recorded using modalities such as electroencephalography and summarized as power within multiple time-varying frequency bands within multiple electrodes, or brain regions. Summarizing the joint variation across multiple frequency bands for both whole-brain variability between subjects, as well as location-variation within subjects, can help to explain neural reactions to stimuli. This article introduces a novel approach to conducting interpretable principal components analysis on multilevel multivariate functional data that decomposes total variation into subject-level and replicate-within-subject-level (i.e., electrode-level) variation and provides interpretable components that can be both sparse among variates (e.g., frequency bands) and have localized support over time within each frequency band. Smoothness is achieved through a roughness penalty, while sparsity and localization of components are achieved by solving an innovative rank-one based convex optimization problem with block Frobenius and matrix $L_1$-norm-based penalties. The method is used to analyze data from a study to better understand reactions to emotional information in individuals with histories of trauma and the symptom of dissociation, revealing new neurophysiological insights into how subject- and electrode-level brain activity are associated with these phenomena. Supplementary materials for this article are available online.

Trauma diagnostic-related target proteins and their detection techniques.

Trauma is a significant health issue that not only leads to immediate death in many cases but also causes severe complications, such as sepsis, thrombosis, haemorrhage, acute respiratory distress syndrome and traumatic brain injury, among trauma patients. Target protein identification technology is a vital technique in the field of biomedical research, enabling the study of biomolecular interactions, drug discovery and disease treatment. It plays a crucial role in identifying key protein targets associated with specific diseases or biological processes, facilitating further research, drug design and the development of treatment strategies. The application of target protein technology in biomarker detection enables the timely identification of newly emerging infections and complications in trauma patients, facilitating expeditious medical interventions and leading to reduced post-trauma mortality rates and improved patient prognoses. This review provides an overview of the current applications of target protein identification technology in trauma-related complications and provides a brief overview of the current target protein identification technology, with the aim of reducing post-trauma mortality, improving diagnostic efficiency and prognostic outcomes for patients.

Fronto-limbic white matter microstructural changes in psychiatrically healthy adults with childhood trauma.

Childhood trauma (CT) may influence brain white matter microstructure; however, few studies have examined the differential impact of distinct CT types on white matter microstructure in psychiatrically healthy adults living in a developing country. In adults without significant medical or psychiatric disorders, we investigated the association(s) between CT, including abuse and neglect, and fractional anisotropy (FA) of limbic tracts previously shown to be associated with CT. Participants underwent diffusion tensor imaging and completed the Childhood Trauma Questionnaire. Multivariate analysis of variance models were used to test the effects of total overall CT, as well as CT subtypes, on FA in six fronto-limbic tracts, adjusting for age, sex, and educational level. The final sample included 69 adults (age 47 ± 17 years; 70% female). Overall, CT had a significant main effect on FA for tracts of interest (p < .001). Greater CT severity was associated with lower FA for the bilateral and left stria terminalis (uncorrected) as well as the bilateral, left, and right anterior limb of the internal capsule (ALIC; corrected). Exposure to total non-violent/deprivational trauma specifically was associated with lower FA of the bilateral, left, and right ALIC, suggesting that distinct types of CT are associated with differential white matter changes in apparently healthy adults. The ALIC predominantly carries fibers connecting the thalamus with prefrontal cortical regions. Microstructural alterations in the ALIC may be associated with functional brain changes, which may be adaptive or increase the risk of accelerated age-related cognitive decline, maladaptive behaviors, and subsyndromal psychiatric symptoms.

Regulation of vascular endothelial integrity by mesenchymal stem cell extracellular vesicles after hemorrhagic shock and trauma.

BACKGROUND: Patients with hemorrhagic shock and trauma (HS/T) are vulnerable to the endotheliopathy of trauma (EOT), characterized by vascular barrier dysfunction, inflammation, and coagulopathy. Cellular therapies such as mesenchymal stem cells (MSCs) and MSC extracellular vesicles (EVs) have been proposed as potential therapies targeting the EOT. In this study we investigated the effects of MSCs and MSC EVs on endothelial and epithelial barrier integrity in vitro and in vivo in a mouse model of HS/T. This study addresses the systemic effects of HS/T on multiorgan EOT. METHODS: In vitro, pulmonary endothelial cell (PEC) and Caco-2 intestinal epithelial cell monolayers were treated with control media, MSC conditioned media (CM), or MSC EVs in varying doses and subjected to a thrombin or hydrogen peroxide (H2O2) challenge, respectively. Monolayer permeability was evaluated with a cell impedance assay, and intercellular junction integrity was evaluated with immunofluorescent staining. In vivo, a mouse model of HS/T was used to evaluate the effects of lactated Ringer's (LR), MSCs, and MSC EVs on endothelial and epithelial intercellular junctions in the lung and small intestine as well as on plasma inflammatory biomarkers. RESULTS: MSC EVs and MSC CM attenuated permeability and preserved intercellular junctions of the PEC monolayer in vitro, whereas only MSC CM was protective of the Caco-2 epithelial monolayer. In vivo, both MSC EVs and MSCs mitigated the loss of endothelial adherens junctions in the lung and small intestine, though only MSCs had a protective effect on epithelial tight junctions in the lung. Several plasma biomarkers including MMP8 and VEGF were elevated in LR- and EV-treated but not MSC-treated mice. CONCLUSIONS: In conclusion, MSC EVs could be a potential cell-free therapy targeting endotheliopathy after HS/T via preservation of the vascular endothelial barrier in multiple organs early after injury. Further research is needed to better understand the immunomodulatory effects of these products following HS/T and to move toward translating these therapies into clinical studies.

Clinical HIV outcome trajectories associated with a history of child protective service out-of-home care: Longitudinal cohort findings with women living with HIV in Canada.

OBJECTIVES: Knowledge gaps exist regarding the effects of experiencing child protective services (CPS) out-of-home care (e.g. foster homes) among women with HIV. We examined whether CPS out-of-home care was associated with HIV clinical outcome trajectories among women with HIV in a longitudinal cohort study in Ontario, British Columbia, and Quebec, Canada. METHODS: At three timepoints across 5 years (2013-2018), we examined self-reported current antiretroviral therapy (ART) use and viral load (VL) detectability (>50 copies/mL). We used latent class growth analysis (LCGA) to identify trajectories of ART use and VL outcomes across study waves. LCGA identifies subgroups (classes) with similar trajectories within the sample. We assessed whether HIV outcome trajectories could be predicted by CPS history. We then conducted a mediation analysis to test whether a mental health latent construct mediated the association between CPS history and detectable VL. RESULTS: Nearly one-fifth (n = 272; 19%) of participants (n = 1422; mean age 42.8 years) reported CPS out-of-home care. Most participants (89%) were in classes that consistently used ART and had an undetectable VL. Individuals with CPS out-of-home care histories were twice as likely to have a consistently detectable VL (ß = 0.72, p = 0.02); there were no differences in ART use trajectories. In mediation analyses, we found an indirect path from CPS history to a consistently detectable VL via baseline mental health status (ß = 0.02, 95% confidence interval 0.005-0.04, p = 0.02), with a significant odds ratio (1.12, z = 2.43, p = 0.02). CONCLUSION: Among women with HIV in Canada, experiencing childhood CPS out-of-home care was associated with a reduced likelihood of achieving viral suppression, via poorer mental health.