Tryptophan-Kynurenine Pathway Activation and Cognition in Virally Suppressed Women With HIV.

BACKGROUND: Immune and cognitive dysfunction persists even in virally suppressed women with HIV (VS-WWH). Since inflammation and HIV proteins induce the enzyme indoleamine 2,3-dioxygenase (IDO), converting tryptophan (T) to kynurenine (K) while producing downstream neurotoxic metabolites, we investigated IDO activation (KT ratio) in relation to cognition in VS-WWH and demographically similar women without HIV (WWoH). METHODS: Ninety-nine VS-WWH on stable antiretroviral therapy and 102 WWoH (median age 52 vs 54 years; 73% vs 74% Black, respectively) from the New York and Chicago sites of the Women's Interagency HIV Study (WIHS) completed a neuropsychological test battery assessing motor function, processing speed, attention/working memory, verbal fluency, verbal learning and memory, and executive function and had plasma measured for tryptophan-kynurenine metabolites through liquid chromatography-tandem mass spectrometry and monocyte-derived [soluble cluster of differentiation-14 (sCD14), soluble cluster of differentiation-163 (sCD163), monocyte chemoattractant protein-1 (MCP-1)] plus general inflammatory markers [tumor necrosis factor alpha-2 receptor (TNF-R2), high-sensitivity C-reactive protein, high-sensitivity interleukin-6] through enzyme-linked immunosorbent assays between 2017 and 2020. RESULTS: VS-WWH had a higher KT ratio (P < 0.01) and higher sCD14 levels (P < 0.05) compared with WWoH. Higher sCD163 was associated with higher KT ratio (R = 0.29, P < 0.01) and worse fine motor function in VS-WWH; after adjusting for sCD163 and sCD14 in multivariable regressions, higher KT ratio remained significantly associated with impaired fine motor function in VS-WWH only (standardized ß = -0.29, P < 0.05). IDO activation was not associated with cognition in WWoH. CONCLUSIONS: IDO activation (K:T) was associated with worse fine motor control in VS-WWH independent of measured systemic inflammation. Further studies investigating biological mechanisms linking IDO activation to fine motor function among VS-WWH are warranted.

Tryptophan-kynurenine metabolic pathway and daytime dysfunction in women with HIV.

Sleep disturbances are prevalent in women with HIV (WWH). Tryptophan-kynurenine (T-K) pathway metabolites are associated with alterations in actigraphy derived sleep measures in WWH, although may not always correlate with functional impairment. We investigated the relationship between T-K pathway metabolites and self-reported daytime dysfunction in WWH and women without HIV (WWoH). 141 WWH on stable antiretroviral therapy and 140 demographically similar WWoH enrolled in the IDOze Study had targeted plasma T-K metabolites measured using liquid chromatography-tandem mass spectrometry. We utilized the daytime dysfunction component of the Pittsburgh Sleep Quality Index (PSQI) to assess functional impairment across HIV-serostatus. Lower levels of 5-hydroxytryptophan and serotonin were associated with greater daytime dysfunction in all women. In WWH, daytime dysfunction was associated with increased kynurenic acid (R = 0.26, p < 0.05), and kynurenic acid-tryptophan (KA-T) ratio (R = 0.28, p < 0.01). WWH with daytime dysfunction had a 0.7 log fold increase in kynurenic acid compared to WWH without daytime dysfunction. Kynurenic acid levels and the KA-T ratio were associated with daytime dysfunction in WWH but not in WWoH. Longitudinal studies are needed to establish a causal relationship and directionality between T-K metabolic changes and sleep impairment in WWH.

Brain N -acetyl-aspartyl-glutamate is associated with cognitive function in older virally suppressed people with HIV.

OBJECTIVES: Cognitive impairment persists in virally suppressed people with HIV (VS-PWH) especially in higher order domains. One cortical circuit, linked to these domains, is regulated by N -acetyl-aspartyl glutamate (NAAG), the endogenous agonist of the metabotropic glutamate receptor 3. The enzyme glutamate carboxypeptidase II (GCPII) catabolizes NAAG and is upregulated in aging and disease. Inhibition of GCPII increases brain NAAG and improves learning and memory in rodent and primate models. DESIGN: As higher order cognitive impairment is present in VS-PWH, and NAAG has not been investigated in earlier magnetic resonance spectroscopy studies (MRS), we investigated if brain NAAG levels measured by MRS were associated with cognitive function. METHODS: We conducted a retrospective analysis of 7-Tesla MRS data from a previously published study on cognition in older VS-PWH. The original study did not separately quantify NAAG, therefore, work for this report focused on relationships between regional NAAG levels in frontal white matter (FWM), left hippocampus, left basal ganglia and domain-specific cognitive performance in 40 VS-PWH after adjusting for confounds. Participants were older than 50 years, negative for affective and neurologic disorders, and had no prior 3-month psychoactive-substance use. RESULTS: Higher NAAG levels in FWM were associated with better attention/working memory. Higher left basal ganglia NAAG related to better verbal fluency. There was a positive relationship between hippocampal NAAG and executive function which lost significance after correction for confounds. CONCLUSION: These data suggest brain NAAG serves as a biomarker of cognition in VS-PWH. Pharmacological modulation of brain NAAG warrants investigation as a therapeutic approach for cognitive deficits in VS-PWH.

Common antiretroviral combinations are associated with somatic depressive symptoms in women with HIV.

OBJECTIVE: While modern antiretroviral therapy (ART) is highly effective and safe, depressive symptoms have been associated with certain ART drugs. We examined the association between common ART regimens and depressive symptoms in women with HIV (WWH) with a focus on somatic vs. nonsomatic symptoms. DESIGN: Analysis of longitudinal data from the Women's Interagency HIV Study. METHODS: Participants were classified into three groups based on the frequency of positive depression screening (CES-D ≥16): chronic depression (≥50% of visits since study enrollment), infrequent depression (<50% of visits), and never depressed (no visits). Novel Bayesian machine learning methods building upon a subset-tree kernel approach were developed to estimate the combined effects of ART regimens on depressive symptoms in each group after covariate adjustment. RESULTS: The analysis included 1538 WWH who participated in 12 924 (mean = 8.4) visits. The mean age was 49.9 years, 72% were Black, and 14% Hispanic. In the chronic depression group, combinations including tenofovir alafenamide and cobicistat-boosted elvitegravir and/or darunavir were associated with greater somatic symptoms of depression, whereas those combinations containing tenofovir disoproxil fumarate and efavirenz or rilpivirine were associated with less somatic depressive symptoms. ART was not associated with somatic symptoms in the infrequent depression or never depressed groups. ART regimens were not associated with nonsomatic symptoms in any group. CONCLUSIONS: Specific ART combinations are associated with somatic depressive symptoms in WWH with chronic depression. Future studies should consider specific depressive symptoms domains as well as complete drug combinations when assessing the relationship between ART and depression.

Machine Learning Approaches to Understand Cognitive Phenotypes in People With HIV.

Cognitive disorders are prevalent in people with HIV (PWH) despite antiretroviral therapy. Given the heterogeneity of cognitive disorders in PWH in the current era and evidence that these disorders have different etiologies and risk factors, scientific rationale is growing for using data-driven models to identify biologically defined subtypes (biotypes) of these disorders. Here, we discuss the state of science using machine learning to understand cognitive phenotypes in PWH and their associated comorbidities, biological mechanisms, and risk factors. We also discuss methods, example applications, challenges, and what will be required from the field to successfully incorporate machine learning in research on cognitive disorders in PWH. These topics were discussed at the National Institute of Mental Health meeting on "Biotypes of CNS Complications in People Living with HIV" held in October 2021. These ongoing research initiatives seek to explain the heterogeneity of cognitive phenotypes in PWH and their associated biological mechanisms to facilitate clinical management and tailored interventions.

Trauma Across the Life Span and Multisystem Morbidity in Women With HIV.

OBJECTIVE: Sexual and physical abuse are highly prevalent among women living with HIV (WLWH) and are risk factors for the development of mental health and substance use disorders (MHDs, SUDs), and cognitive and medical comorbidities. We examined empirically derived patterns of trauma, MHD, and SUD, and associations with later cognitive and health outcomes. METHODS: A total of 1027 WLWH (average age = 48.6 years) in the Women's Interagency HIV Study completed the World Mental Health Composite International Diagnostic Interview from 2010 to 2013 to identify MHDs, SUDs, and age at onset of sexual and physical abuse. Then, cognitive impairment, cardiovascular/metabolic conditions, and HIV disease outcomes were assessed for up to 8.8 years. Latent class analysis identified patterns of co-occurring trauma, MHDs, and/or SUDs. Generalized estimating equations determined associations between these patterns and midlife cognitive and medical outcomes. RESULTS: Six distinct profiles emerged: no/negligible sexual/physical trauma, MHD, or SUD (39%); preadolescent/adolescent sexual trauma with anxiety and SUD (22%); SUD only (16%); MHD + SUD only (12%); early childhood sexual/physical trauma only (6%); and early childhood sexual/physical trauma with later MHD + SUD (4%). Profiles including early childhood trauma had the largest number of midlife conditions (i.e., cognitive, cardiovascular, HIV-related). Preadolescent/adolescent sexual trauma with anxiety and SUD predicted both global and domain-specific cognitive declines. Only SUD without trauma predicted lower CD4, whereas childhood trauma with MHD + SUD predicted increased CD8. CONCLUSIONS: WLWH have complex multisystem profiles of abuse, MHD, and/or SUD that predict midlife cognitive, metabolic/cardiovascular, and HIV outcomes. Understanding the interplay between these factors over time can identify risks and personalize preventative and treatment interventions.

Intricacies Affiliated With Post-COVID Vaccine Complications in Makkah Province, Saudi Arabia.

Introduction COVID-19 vaccine side effects have a fundamental role in public confidence in the vaccine and its uptake process. Thus far, evidence on vaccine safety has been exclusively obtained from manufacturer-sponsored studies; therefore, this study is designed to assess post-COVID-19 vaccine complications in Makkah province, Saudi Arabia. Method A cross-sectional study included 840 subjects conducted from August to November 2022 to collect data about COVID-19 vaccine side effects. A validated questionnaire was used with 21 multiple-choice items covering demographic data, COVID-19 vaccination type, side effects, and medication used to relieve side effects. The online Raosoft sample size calculator (Raosoft Inc., Seattle, Washington) was utilized for sample size calculation. The Statistical Package for the Social Sciences version 22.0 (IBM Inc., Armonk, New York) was utilized to carry out descriptive statistics. The Shapiro-Wilk test was used to evaluate normal data distribution. Significance of categorized data made by the Pearson's Chi-Squared test and of the vaccination side effects experienced in general wellbeing on a scale of 1-10 by the Kruskal-Wallis test. Result The survey found that most participants in the 18-26 age group were from Jeddah, women, and Saudis. Only 7.1% of participants had comorbidities alone, and 63.1% of participants had previously had COVID-19. The vaccine types used in this study were primarily Pfizer (83.3%), AstraZeneca (9.5%), Moderna (3.6%), and combination vaccines (3.6%). The majority of the participants received vaccination up to the third dose. No side effects were reported by 9.5% of participants, while mild and severe side effects were reported by 90.5% and 23.8% of participants, respectively. Mild side effects included injection site pain, redness, tenderness, or itching (34.5%), fatigue (22.6%), low-grade fever, chills, diarrhea, headache (17.9%), and myalgia (14.3%). Conclusion The majority of the side effects of COVID-19 vaccination were minor reactions (90.5%), but 23.8% were found to be serious side effects, most of which lasted one to three days. More independent studies are needed to investigate gender differences, COVID-19 vaccine efficacy, and the prevalence of side effects in other populations conducted by academic institutions. Additional independent research on vaccine safety is urgently needed to increase public confidence in vaccines and to better understand risk factors for vaccine side effects.

Tumor-derived extracellular vesicles modulate innate immune responses to affect tumor progression.

Immune cells are capable of influencing tumor progression in the tumor microenvironment (TME). Meanwhile, one mechanism by which tumor modulate immune cells function is through extracellular vesicles (EVs), which are cell-derived extracellular membrane vesicles. EVs can act as mediators of intercellular communication and can deliver nucleic acids, proteins, lipids, and other signaling molecules between cells. In recent years, studies have found that EVs play a crucial role in the communication between tumor cells and immune cells. Innate immunity is the first-line response of the immune system against tumor progression. Therefore, tumor cell-derived EVs (TDEVs) which modulate the functional change of innate immune cells serve important functions in the context of tumor progression. Emerging evidence has shown that TDEVs dually enhance or suppress innate immunity through various pathways. This review aims to summarize the influence of TDEVs on macrophages, dendritic cells, neutrophils, and natural killer cells. We also summarize their further effects on the progression of tumors, which may provide new ideas for developing novel tumor therapies targeting EVs.

T-cell activation state differentially contributes to neuropsychiatric complications in women with HIV.

Neuropsychiatric complications are common among women with HIV (WWH). The pathophysiological mechanisms underlying these complications are not fully known but likely driven in part by immune modulation. We examined associations between T-cell activation states which are required to mount an effective immune response (activation, co-stimulation/normal function, exhaustion, senescence) and neuropsychiatric complications in WWH. 369 WWH (78% HIV RNA undetectable/<20cp/mL) enrolled in the Women's Interagency HIV Study completed neuropsychological testing and measures of depression (Center for Epidemiological Studies Depression Scale-CES-D), self-reported stress levels (Perceived Stress Scale-10), and post-traumatic stress (PTSD Checklist-Civilian Scale). Multiparametric flow cytometry evaluated T-cell activation state. Partial least squares regressions were used to examine T-cell phenotypes and neuropsychiatric outcome associations after confounder adjustment. In the total sample and among virally suppressed (VS)-WWH, CD4+ T-cell exhaustion was associated with poorer learning and attention/working memory (P's < 0.05). In the total sample, CD4+ T-cell activation was associated with better attention/working memory and CD8+ T-cell co-stimulation and senescence was associated with poorer executive function (P's < 0.05). For mental health outcomes, in the total sample, CD4+ T-cell activation was associated with more perceived stress and CD4+ T-cell exhaustion was associated with less depressive symptoms (P's < 0.05). Among VS-WWH, CD4+ senescence was associated with less perceive stress and CD8+ T-cell co-stimulation and senescence was associated with higher depression (P's < 0.05). Together, results suggest the contribution of peripheral CD4+ and CD8+ T-cell activation status to neuropsychiatric complications in WWH.

Patterns and Predictors of Cognitive Function Among Virally Suppressed Women With HIV.

Cognitive impairment remains frequent and heterogeneous in presentation and severity among virally suppressed (VS) women with HIV (WWH). We identified cognitive profiles among 929 VS-WWH and 717 HIV-uninfected women from 11 Women's Interagency HIV Study sites at their first neuropsychological (NP) test battery completion comprised of: Hopkins Verbal Learning Test-Revised, Trail Making, Symbol Digit Modalities, Grooved Pegboard, Stroop, Letter/Animal Fluency, and Letter-Number Sequencing. Using 17 NP performance metrics (T-scores), we used Kohonen self-organizing maps to identify patterns of high-dimensional data by mapping participants to similar nodes based on T-scores and clustering those nodes. Among VS-WWH, nine clusters were identified (entropy = 0.990) with four having average T-scores ≥45 for all metrics and thus combined into an "unimpaired" profile (n = 311). Impaired profiles consisted of weaknesses in: (1) sequencing (Profile-1; n = 129), (2) speed (Profile-2; n = 144), (3) learning + recognition (Profile-3; n = 137), (4) learning + memory (Profile-4; n = 86), and (5) learning + processing speed + attention + executive function (Profile-5; n = 122). Sociodemographic, behavioral, and clinical variables differentiated profile membership using Random Forest models. The top 10 variables distinguishing the combined impaired vs. unimpaired profiles were: clinic site, age, education, race, illicit substance use, current and nadir CD4 count, duration of effective antiretrovirals, and protease inhibitor use. Additional variables differentiating each impaired from unimpaired profile included: depression, stress-symptoms, income (Profile-1); depression, employment (Profile 2); depression, integrase inhibitor (INSTI) use (Profile-3); employment, INSTI use, income, atazanavir use, non-ART medications with anticholinergic properties (Profile-4); and marijuana use (Profile-5). Findings highlight consideration of NP profile heterogeneity and potential modifiable factors contributing to impaired profiles.

Astrocytes deliver CK1 to neurons via extracellular vesicles in response to inflammation promoting the translation and amyloidogenic processing of APP.

Chronic inflammation is thought to contribute to the early pathogenesis of Alzheimer's disease (AD). However, the precise mechanism by which inflammatory cytokines promote the formation and deposition of Aß remains unclear. Available data suggest that applications of inflammatory cytokines onto isolated neurons do not promote the formation of Aß, suggesting an indirect mechanism of action. Based on evidence astrocyte derived extracellular vesicles (astrocyte derived EVs) regulate neuronal functions, and data that inflammatory cytokines can modify the molecular cargo of astrocyte derived EVs, we sought to determine if IL-1ß promotes the formation of Aß indirectly through actions of astrocyte derived EVs on neurons. The production of Aß was increased when neurons were exposed to astrocyte derived EVs shed in response to IL-1ß (astrocyte derived EV-IL-1ß). The mechanism for this effect involved an enrichment of Casein kinase 1 (CK1) in astrocyte derived EV-IL-1ß. This astrocyte derived CK1 was delivered to neurons where it formed a complex with neuronal APC and GSK3 to inhibit the ß-catenin degradation. Stabilized ß-catenin translocated to the nucleus and bound to Hnrnpc gene at promoter regions. An increased cellular concentration of hnRNP C promoted the translation of APP by outcompeting the translational repressor fragile X mental retardation protein (FMRP) bound to APP mRNA. An increased amount of APP protein became co-localized with BACE1 in enlarged membrane microdomains concurrent with increased production of Aß. These findings identify a mechanism whereby inflammation promotes the formation of Aß through the actions of astrocyte derived EV-IL-1ß on neurons.

Stimulus-dependent modifications in astrocyte-derived extracellular vesicle cargo regulate neuronal excitability.

Extracellular vesicles have now emerged as key players in cell-to-cell communication. This is particularly important in the central nervous system, where glia-neuron cross-talk helps maintain normal neuronal function. Astrocyte-derived extracellular vesicles (ADEVs) secreted constitutively promote neurite outgrowth and neuronal survival. However, extracellular stimuli can alter the cargo and downstream functions of ADEVs. For example, ADEVs secreted in response to inflammation contain cargo microRNAs and proteins that reduce neurite outgrowth, neuronal firing, and promote neuronal apoptosis. We performed a comprehensive quantitative proteomic analysis to enumerate the proteomic cargo of ADEVs secreted in response to multiple stimuli. Rat primary astrocytes were stimulated with a trophic stimulus (adenosine triphosphate, ATP), an inflammatory stimulus (IL-1ß) or an anti-inflammatory stimulus (IL10) and extracellular vesicles secreted within a 2 hr time frame were collected using sequential ultracentrifugation method. ADEVs secreted constitutively without exposure to any stimulus were used a control. A tandem mass tag-based proteomic platform was used to identify and quantify proteins in the ADEVs. Ingenuity pathway analysis was performed to predict the downstream signaling events regulated by ADEVs. We found that in response to ATP or IL10, ADEVs contain a set of proteins that are involved in increasing neurite outgrowth, dendritic branching, regulation of synaptic transmission, and promoting neuronal survival. In contrast, ADEVs secreted in response to IL-1ß contain proteins that regulate peripheral immune response and immune cell trafficking to the central nervous system.

MEAnalyzer - a Spike Train Analysis Tool for Multi Electrode Arrays.

Despite a multitude of commercially available multi-electrode array (MEA) systems that are each capable of rapid data acquisition from cultured neurons or slice cultures, there is a general lack of available analysis tools. These analysis gaps restrict the efficient extraction of meaningful physiological features from data sets, and limit interpretation of how experimental manipulations modify neural network activity. Here, we present the development of a user-friendly, publicly-available software called MEAnalyzer. This software contains several spike train analysis methods including relevant statistical calculations, periodicity analysis, functional connectivity analysis, and advanced data visualizations in a user-friendly graphical user interface that requires no coding from the user. Widespread availability of this user friendly and mathematically advanced program will stimulate and enhance the use of MEA technologies.

Monocarboxylate transporter 1 in Schwann cells contributes to maintenance of sensory nerve myelination during aging.

Schwann cell (SC)-specific monocarboxylate transporter 1 (MCT1) knockout mice were generated by mating MCT1 f/f mice with myelin protein zero (P0)-Cre mice. P0-Cre+/- , MCT1 f/f mice have no detectable early developmental defects, but develop hypomyelination and reduced conduction velocity in sensory, but not motor, peripheral nerves during maturation and aging. Furthermore, reduced mechanical sensitivity is evident in aged P0-Cre+/- , MCT1 f/f mice. MCT1 deletion in SCs impairs both their glycolytic and mitochondrial functions, leading to altered lipid metabolism of triacylglycerides, diacylglycerides, and sphingomyelin, decreased expression of myelin-associated glycoprotein, and increased expression of c-Jun and p75-neurotrophin receptor, suggesting a regression of SCs to a less mature developmental state. Taken together, our results define the contribution of SC MCT1 to both SC metabolism and peripheral nerve maturation and aging.

Cognitive Trajectory Phenotypes in Human Immunodeficiency Virus-Infected Patients.

OBJECTIVE: The presentation of cognitive impairments in HIV-infected individuals has transformed since the introduction of antiretroviral therapies. Although the overall prevalence of cognitive impairments has not changed considerably, frank dementia is now infrequent, and milder forms of cognitive impairments predominate. Mechanistic insights to the underlying causes of these residual cognitive impairments have been elusive, in part due to the heterogenous etiology of cognitive dysfunction in this population. Here, we sought to categorize longitudinal change in HIV-infected patients based on the performance in specific cognitive domains. DESIGN: This study consisted of 193 participants from the CHARTER cohort with detailed demographic, clinical, and neuropsychological testing data obtained from 2 study visits interspersed by ∼6 months. Cognitive testing assessed executive function, learning and delayed recall, working memory, verbal fluency, speed of information processing, and motor skills. Change scores were calculated for each domain between the 2 study visits. Dimension reduction and clustering was accomplished by principal component analysis of change scores and k-means clustering to identify cognitive domains that group together and groups of subjects with similar patterns of change. RESULTS: We identified 4 distinct cognitive change phenotypes that included declines in: (1) verbal fluency, (2) executive function (3) learning and recall, and (4) motor function, with approximately equal numbers of participants in each phenotype. CONCLUSIONS: Each of the 4 cognitive change phenotypes identify deficits that imply perturbations in specific neural networks. Future studies will need to validate if cognitive change phenotypes are associated with alterations in associated neural pathways.

Non-puerperal uterine inversion associated with adenosarcoma of the uterus: A case report.

INTRODUCTION: Uterine inversion is an uncommon condition characterized by the invagination of the fundus of the uterus through the vagina and is extremely rare in non-pregnancy settings. Non-puerperal uterine inversion is usually precipitated by tumours exerting traction force on the fundus of the uterus, turning the uterus partially or completely inside out. It is most frequently associated with benign tumours such as submucosal leiomyomas; however, malignant tumours are a rare association. CASE PRESENTATION: A 67-year-old woman, G18P18, presented to the emergency department with a bleeding mass that had acutely prolapsed out of the vagina. She had a two-year history of postmenopausal bleeding but had not sought medical advice. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy. Pathological evaluation revealed an adenosarcoma of the uterine fundus, measuring 6 cm in its largest diameter, which invaded the myometrium only superficially. The patient recovered well from the operation with no complications and was referred to an oncologist for further treatment. A computerized tomography scan with intravenous contrast showed no evidence of metastasis. CONCLUSION: Uterine sarcoma is a malignant tumour of the uterus that typically presents with vaginal bleeding, and rarely as prolapsed uterine inversion. Uterine inversion rarely occurs outside the puerperal setting; however, when it does occur, the possibility of an underlying malignancy should not be neglected.

Transection of the appendix and omentum following a seat belt injury; case report and literature review.

INTRODUCTION: Appendiceal injuries following a blunt abdominal trauma are rare. Upon literature review, several cases have been reported to develop appendicitis following blunt abdominal trauma, but total transection of the appendix is extremely rare. CASE PRESENTATION: Our case involves a 24-year-old male restrained driver who was involved in a motor vehicle accident. He had bruising corresponding to the pattern of the seatbelt, the 'seatbelt sign', on admission. On his second day of admission, he was found to have a rigid abdomen. On exploratory laparotomy, the patient had a completely transected appendix with a 10 × 10 cm piece of transected omentum lying in the pelvic cavity. DISCUSSION: Literature suggests that seat belts may play a role in the mechanism of injury leading to transection. CONCLUSION: Since the introduction of seatbelt in the 1970s, fatalities from road traffic accidents have fallen by up to 60%. However, the seat belt itself is associated with a unique injury profile, including intestinal tears, perforations, and transections, collectively termed "the seatbelt syndrome". Seat belt syndrome injuries may sometimes have a delayed presentation, thus repeated abdominal examination is recommended even if the patient is initially stable. Appendiceal transection is rare but may occur. A thorough inspection of the abdominal soft tissue to look for accompanying injuries is important if case an exploratory laparotomy is warranted.

Atomic Source of Single Photons in the Telecom Band.

Single atoms and atomlike defects in solids are ideal quantum light sources and memories for quantum networks. However, most atomic transitions are in the ultraviolet-visible portion of the electromagnetic spectrum, where propagation losses in optical fibers are prohibitively large. Here, we observe for the first time the emission of single photons from a single Er^{3+} ion in a solid-state host, whose optical transition at 1.5 µm is in the telecom band, allowing for low-loss propagation in optical fiber. This is enabled by integrating Er^{3+} ions with silicon nanophotonic structures, which results in an enhancement of the photon emission rate by a factor of more than 650. Dozens of distinct ions can be addressed in a single device, and the splitting of the lines in a magnetic field confirms that the optical transitions are coupled to the electronic spin of the Er^{3+} ions. These results are a significant step towards long-distance quantum networks and deterministic quantum logic for photons based on a scalable silicon nanophotonics architecture.

TNFα and IL-1ß modify the miRNA cargo of astrocyte shed extracellular vesicles to regulate neurotrophic signaling in neurons.

Astrocytes are known to be critical regulators of neuronal function. However, relatively few mediators of astrocyte to neuron communication have been identified. Recent advancements in the biology of extracellular vesicles have begun to implicate astrocyte derived extracellular vesicles (ADEV) as mediators of astrocyte to neuron communication, suggesting that alterations in the release and/or composition of ADEVs could influence gliotransmission. TNFα and IL-1ß are key mediators of glial activation and neuronal damage, but the effects of these cytokines on the release or molecular composition of ADEVs is unknown. We found that ADEVs released in response to IL-1ß (ADEV-IL-1ß) and TNFα (ADEV-TNFα) were enriched with miRNAs that target proteins involved in neurotrophin signaling. We confirmed that miR-125a-5p and miR-16-5p (both enriched in ADEV-IL-1ß and ADEV-TNFα) targeted NTKR3 and its downstream effector Bcl2. Downregulation of these targets in neurons was associated with reductions in dendritic growth, dendritic complexity, reduced spike rates, and burst activity. Molecular interference of miR-125a-5p and miR-16-5p prevented ADEV-IL-1ß from reducing dendritic complexity, spike, and burst rates. These findings suggest that astrocytes respond to inflammatory challenge by modifying the miRNA cargo of ADEVs to diminish the activity of target neurons by regulating the translational expression of proteins controlling programs essential for synaptic stability and neuronal excitability.

Polyethylene Glycol Coatings on Plastic Substrates for Chemically Defined Stem Cell Culture.

Human mesenchymal stem cells (hMSCs) are a widely available and clinically relevant cell type with a host of applications in regenerative medicine. Current clinical expansion methods can lead to selective changes in hMSC phenotype potentially resulting from relatively undefined cell culture surfaces. Chemically defined synthetic surfaces can aid in understanding the influence of cell-material interactions on stem cell behavior. Here, a thin copolymer coating for hMSC culture on plastic substrates is developed. The random copolymer is synthesized by living free radical polymerization and characterized in solution before application to the substrate, ensuring a homogeneous coating and limiting the sample-to-sample variations. The ability to coat multiple substrate types and cover large surface areas is reported. Arg-Gly-Asp-containing peptides are incorporated into the coating under aqueous conditions via their lysine or cysteine side chains, resulting in amide and thioester linkages, respectively. Stability studies show amide linkages to be stable and thioester linkages to be labile under standard serum-containing culture conditions. In addition, chemically defined passaging of hMSCs using only ethylenediaminetetraacetic acid on polystyrene dishes is shown. After passage, the hMSCs can be seeded back onto the same plate, indicating potential reusability of the coating.