Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort.

BACKGROUND: There are currently no validated clinical biomarkers of postacute sequelae of SARS-CoV-2 infection (PASC). OBJECTIVE: To investigate clinical laboratory markers of SARS-CoV-2 and PASC. DESIGN: Propensity score-weighted linear regression models were fitted to evaluate differences in mean laboratory measures by prior infection and PASC index (≥12 vs. 0). (ClinicalTrials.gov: NCT05172024). SETTING: 83 enrolling sites. PARTICIPANTS: RECOVER-Adult cohort participants with or without SARS-CoV-2 infection with a study visit and laboratory measures 6 months after the index date (or at enrollment if >6 months after the index date). Participants were excluded if the 6-month visit occurred within 30 days of reinfection. MEASUREMENTS: Participants completed questionnaires and standard clinical laboratory tests. RESULTS: Among 10 094 participants, 8746 had prior SARS-CoV-2 infection, 1348 were uninfected, 1880 had a PASC index of 12 or higher, and 3351 had a PASC index of zero. After propensity score adjustment, participants with prior infection had a lower mean platelet count (265.9 × 109 cells/L [95% CI, 264.5 to 267.4 × 109 cells/L]) than participants without known prior infection (275.2 × 109 cells/L [CI, 268.5 to 282.0 × 109 cells/L]), as well as higher mean hemoglobin A1c (HbA1c) level (5.58% [CI, 5.56% to 5.60%] vs. 5.46% [CI, 5.40% to 5.51%]) and urinary albumin-creatinine ratio (81.9 mg/g [CI, 67.5 to 96.2 mg/g] vs. 43.0 mg/g [CI, 25.4 to 60.6 mg/g]), although differences were of modest clinical significance. The difference in HbA1c levels was attenuated after participants with preexisting diabetes were excluded. Among participants with prior infection, no meaningful differences in mean laboratory values were found between those with a PASC index of 12 or higher and those with a PASC index of zero. LIMITATION: Whether differences in laboratory markers represent consequences of or risk factors for SARS-CoV-2 infection could not be determined. CONCLUSION: Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC. PRIMARY FUNDING SOURCE: National Institutes of Health.

Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later.

Stress is associated with numerous chronic diseases, beginning in fetal development with in utero exposures (prenatal stress) impacting offspring's risk for disorders later in life. In previous studies, we demonstrated adverse maternal in utero immune activity on sex differences in offspring neurodevelopment at age seven and adult risk for major depression and psychoses. Here, we hypothesized that in utero exposure to maternal proinflammatory cytokines has sex-dependent effects on specific brain circuitry regulating stress and immune function in the offspring that are retained across the lifespan. Using a unique prenatal cohort, we tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife. Functional MRI results showed that exposure to proinflammatory cytokines in utero was significantly associated with sex differences in brain activity and connectivity during response to negative stressful stimuli 45 y later. Lower maternal TNF-α levels were significantly associated with higher hypothalamic activity in both sexes and higher functional connectivity between hypothalamus and anterior cingulate only in men. Higher prenatal levels of IL-6 were significantly associated with higher hippocampal activity in women alone. When examined in relation to the anti-inflammatory effects of IL-10, the ratio TNF-α:IL-10 was associated with sex-dependent effects on hippocampal activity and functional connectivity with the hypothalamus. Collectively, results suggested that adverse levels of maternal in utero proinflammatory cytokines and the balance of pro- to anti-inflammatory cytokines impact brain development of offspring in a sexually dimorphic manner that persists across the lifespan.

Characterizing Long COVID in Children and Adolescents.

Importance: Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment. Objective: To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC. Design, Setting, and Participants: Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 89 prolonged symptoms across 9 symptom domains. Results: A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents. Conclusions and Relevance: This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

Immune Markers Are Associated With Asymptomatic Intracranial Large Artery Stenosis and Future Vascular Events in NOMAS.

BACKGROUND: Inflammation contributes to atherosclerosis but is incompletely characterized in intracranial large artery stenosis (ICAS). We hypothesized that immune markers would be associated with ICAS and modify the risk ICAS confers on future vascular events. METHODS: This study included a subsample of stroke-free participants in the prospective NOMAS (Northern Manhattan Study), who had blood samples analyzed with a 60-plex immunoassay (collected from 1993 to 2001) and ICAS assessment with time-of-flight magnetic resonance angiography (obtained from 2003 to 2008). We dichotomized ICAS as either ≥50% stenosis or not (including no ICAS). We ascertained post-magnetic resonance imaging vascular events. We used least absolute shrinkage and selection operator procedures to select immune markers independently associated with ICAS. Then, we grouped selected immune markers into a derived composite Z score. Using proportional odds regression, we quantified the association of the composite immune marker Z score, ICAS, and risk of vascular events. RESULTS: Among 1211 participants (mean age, 71±9 years; 59% women; 65% Hispanic participants), 8% had ≥50% ICAS. Using least absolute shrinkage and selection operator regression, we identified CXCL9 (C-X-C motif chemokine ligand 9), HGF (hepatocyte growth factor), resistin, SCF (stem cell factor), and VEGF-A(vascular endothelial growth factor A) to have the strongest positive relationships with ≥50% ICAS in fully adjusted models. Selected markers were used to derive a composite immune marker Z score. Over an average follow-up of 12 years, we found that each unit increase in immune marker Z scores was associated with an 8% (95% CI, 1.05-1.11), 11% (95% CI, 1.06-1.16), and 5% (95% CI, 1.01-1.09) increased hazard of death, vascular death, and any vascular event, respectively, in adjusted models. We did not find a significant interaction between immune marker Z scores and ICAS in their relationship with any longitudinal outcome. CONCLUSIONS: Among a diverse stroke-free population, selected serum immune markers were associated with ICAS and future vascular events. Further study is needed to better understand their role in the pathogenesis of ICAS and as a potential therapeutic target in stroke prevention.

Proteomics and cytokine analyses distinguish myalgic encephalomyelitis/chronic fatigue syndrome cases from controls.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, heterogenous disease characterized by unexplained persistent fatigue and other features including cognitive impairment, myalgias, post-exertional malaise, and immune system dysfunction. Cytokines are present in plasma and encapsulated in extracellular vesicles (EVs), but there have been only a few reports of EV characteristics and cargo in ME/CFS. Several small studies have previously described plasma proteins or protein pathways that are associated with ME/CFS. METHODS: We prepared extracellular vesicles (EVs) from frozen plasma samples from a cohort of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) cases and controls with prior published plasma cytokine and plasma proteomics data. The cytokine content of the plasma-derived extracellular vesicles was determined by a multiplex assay and differences between patients and controls were assessed. We then performed multi-omic statistical analyses that considered not only this new data, but extensive clinical data describing the health of the subjects. RESULTS: ME/CFS cases exhibited greater size and concentration of EVs in plasma. Assays of cytokine content in EVs revealed IL2 was significantly higher in cases. We observed numerous correlations among EV cytokines, among plasma cytokines, and among plasma proteins from mass spectrometry proteomics. Significant correlations between clinical data and protein levels suggest roles of particular proteins and pathways in the disease. For example, higher levels of the pro-inflammatory cytokines Granulocyte-Monocyte Colony-Stimulating Factor (CSF2) and Tumor Necrosis Factor (TNFα) were correlated with greater physical and fatigue symptoms in ME/CFS cases. Higher serine protease SERPINA5, which is involved in hemostasis, was correlated with higher SF-36 general health scores in ME/CFS. Machine learning classifiers were able to identify a list of 20 proteins that could discriminate between cases and controls, with XGBoost providing the best classification with 86.1% accuracy and a cross-validated AUROC value of 0.947. Random Forest distinguished cases from controls with 79.1% accuracy and an AUROC value of 0.891 using only 7 proteins. CONCLUSIONS: These findings add to the substantial number of objective differences in biomolecules that have been identified in individuals with ME/CFS. The observed correlations of proteins important in immune responses and hemostasis with clinical data further implicates a disturbance of these functions in ME/CFS.

A multicenter virome analysis of blood, feces, and saliva in myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is estimated to affect 0.4%-2.5% of the global population. Most cases are unexplained; however, some patients describe an antecedent viral infection or response to antiviral medications. We report here a multicenter study for the presence of viral nucleic acid in blood, feces, and saliva of patients with ME/CFS using polymerase chain reaction and high-throughput sequencing. We found no consistent group-specific differences other than a lower prevalence of anelloviruses in cases compared to healthy controls. Our findings suggest that future investigations into viral infections in ME/CFS should focus on adaptive immune responses rather than surveillance for viral gene products.

Maternal mid-gestational and child cord blood immune signatures are strongly associated with offspring risk of ASD.

Epidemiological studies and work in animal models indicate that immune activation may be a risk factor for autism spectrum disorders (ASDs). We measured levels of 60 cytokines and growth factors in 869 maternal mid-gestational (MMG) and 807 child cord blood (CB) plasma samples from 457 ASD (385 boys, 72 girls) and 497 control children (418 boys, 79 girls) from the Norwegian Autism Birth Cohort. We analyzed associations first using sex-stratified unadjusted and adjusted logistic regression models, and then employed machine learning strategies (LASSO + interactions, Random Forests, XGBoost classifiers) with cross-validation and randomly sampled test set evaluation to assess the utility of immune signatures as ASD biomarkers. We found prominent case-control differences in both boys and girls with alterations in a wide range of analytes in MMG and CB plasma including but not limited to IL1RA, TNFα, Serpin E1, VCAM1, VEGFD, EGF, CSF1, and CSF2. MMG findings were most striking, with particularly strong effect sizes in girls. Models did not change appreciably upon adjustment for maternal conditions, medication use, or emotional distress ratings. Findings were corroborated using machine learning approaches, with area under the receiver operating characteristic curve values in the test sets ranging from 0.771 to 0.965. Our results are consistent with gestational immunopathology in ASD, may provide insights into sex-specific differences, and have the potential to lead to biomarkers for early diagnosis.

Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease characterized by unexplained physical fatigue, cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. People with ME/CFS often report a prodrome consistent with infections. Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of plasma from 106 ME/CFS cases and 91 frequency-matched healthy controls. Subjects in the ME/CFS group had significantly decreased levels of plasmalogens and phospholipid ethers (p < 0.001), phosphatidylcholines (p < 0.001) and sphingomyelins (p < 0.001), and elevated levels of dicarboxylic acids (p = 0.013). Using machine learning algorithms, we were able to differentiate ME/CFS or subgroups of ME/CFS from controls with area under the receiver operating characteristic curve (AUC) values up to 0.873. Our findings provide the first metabolomic evidence of peroxisomal dysfunction, and are consistent with dysregulation of lipid remodeling and the tricarboxylic acid cycle. These findings, if validated in other cohorts, could provide new insights into the pathogenesis of ME/CFS and highlight the potential use of the plasma metabolome as a source of biomarkers for the disease.

Immune markers are associated with cognitive performance in a multiethnic cohort: The Northern Manhattan Study.

OBJECTIVE: To determine whether immune protein panels add significant information to correlates of cognition. BACKGROUND: Immune mechanisms in vascular cognitive aging are incompletely characterized. DESIGN/METHODS: A subsample of the prospective Northern Manhattan Study underwent detailed neuropsychological testing. Cognitive scores were converted into Z-scores and categorized into four domains (memory, language, processing speed, and executive function) based on factor analysis. Blood samples were analyzed using a 60-plex immunoassay. We used least absolute shrinkage and selection operator (LASSO) procedures to select markers and their interactions independently associated with cognitive scores. Linear regression models assessed cross-sectional associations of known correlates of cognition with cognitive scores, and assessed model fit before and after addition of LASSO-selected immune markers. RESULTS: Among 1179 participants (mean age 70 ± 8.9 years, 60% women, 68% Hispanic), inclusion of LASSO-selected immune markers improved model fit above age, education, and other risk factors (p for likelihood ratio test < 0.005 for all domains). C-C Motif Chemokine Ligand 11 (CCL 11, eotaxin), C-X-C Motif Chemokine Ligand 9 (CXCL9), hepatocyte growth factor (HGF), and serpin E1 (plasminogen activator inhibitor-1) were associated with each of the domains and with overall cognitive function. Immune marker effects were comparable to conventional risk factors: for executive function, each standard deviation (SD) increase in CCL11 was associated with an effect equivalent to aging three years; for memory, HGF had twice the effect of aging. CONCLUSIONS: Immune markers associate with cognitive function in a multi-ethnic cohort. Further work is needed to validate these findings and determine optimal treatment targets.

Age of walking and intellectual ability in autism spectrum disorder and other neurodevelopmental disorders: a population-based study.

BACKGROUND: Delayed walking is common in intellectual disability (ID) but may be less common when ID occurs with autism spectrum disorder (ASD). Previous studies examining this were limited by reliance on clinical samples and exclusion of children with severe motor deficits. OBJECTIVE: To examine in a population-based sample if age of walking is differentially related to intellectual ability in children with ASD versus other neurodevelopmental disorders (NDD). METHODS: Participants were from the nested Autism Birth Cohort Study of the Norwegian Mother, Father and Child Cohort Study (MoBa). Cox proportional hazards regression assessed if diagnosis (ASD n = 212 vs. NDD n = 354), continuous nonverbal IQ, and their interaction, were associated with continuous age of walking. RESULTS: The relationship between nonverbal IQ and age of walking was stronger for NDD than for ASD (Group × nonverbal IQ interaction, χ2  = 13.93, p = .0002). This interaction was characterized by a 21% decrease in the likelihood of walking onset at any given time during the observation period per 10-point decrease in nonverbal IQ (hazard ratio = 0.79, 95% CI: 0.78-0.85) in the NDD group compared to 8% (hazard ratio = 0.92, 95% CI: 0.86-0.98) in the ASD group. CONCLUSIONS: The finding that age of walking is less strongly related to low intellectual ability in children with ASD than in children without other NDDs supports the hypothesis that ID in ASD may result from heterogeneous developmental pathways. Late walking may be a useful stratification variable in etiological research focused on ASD and other NDDs.

Invited Commentary: The Disillusionment of Developmental Origins of Health and Disease (DOHaD) Epidemiology.

The developmental origins of health and disease (DOHaD) model promises a greater understanding of early development but has left unresolved the balance of risks and benefits to offspring of medication use during pregnancy. Masarwa et al. (Am J Epidemiol. 2018;187(8):1817-1827) conducted a meta-analysis of the association between in utero acetaminophen exposure and risks of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). A challenge of meta-analyzing results from observational studies is that summary measures of risk do not correspond to well-defined interventions when the individual studies adjusted for different covariate sets, which was the case here. This challenge limits the usefulness of observational meta-analyses for inferences about etiology and treatment planning. With that limitation understood, Masarwa et al. reported a 20%-30% higher risk of ADHD and ASD following prenatal acetaminophen exposure. Surprisingly, most of the original studies did not report diagnoses of ADHD or ASD. As a result, their summary estimates of risk are not informative about children's likelihood of ADHD and ASD diagnoses. The long-term promise of DOHaD remains hopeful, but more effort is needed in the short-term to critically evaluate observational studies suggesting risks associated with medications used to treat conditions during pregnancy that might have adverse consequences for a developing fetus.

Maternal Immune activity during pregnancy and socioeconomic disparities in children's self-regulation.

Maternal immune activity during pregnancy has been associated with risk for psychiatric disorders in offspring, but less is known about its implications for children's emotional and behavioral development. This study examined whether concentrations of five cytokines assayed from prenatal serum were associated with socioeconomic status (SES) and racial disparities in their offspring's self-regulation abilities. Participants included 1628 women in the Collaborative Perinatal Project (CPP). Seven behavioral items conceptually related to self-regulation were rated by CPP psychologists when children were 4 years old. Concentrations of interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF)-α, and IL-10 were assessed. Covariates included child sex and mother's age, psychiatric disorders, and medical conditions during pregnancy. There were significant SES differences in child self-regulation, with higher SES children scoring higher on self-regulation (ß = 0.18, 95% CI [0.11, 0.25]), but no racial differences. The concentration of IL-8 in maternal serum was associated with higher child self-regulation, ß = 0.09, 95% CI [0.02, 0.16]. In mediation analyses, variation in maternal IL-8 contributed to the association between family SES and child self-regulation (ß = 0.02, 95% CI [0.003, 0.030]), explaining about one-tenth of the SES disparities. This study suggests pregnancy as an early sensitive period and maternal immune activity as an important context for child development.

Socioeconomic disadvantage, gestational immune activity, and neurodevelopment in early childhood.

Children raised in economically disadvantaged households face increased risks of poor health in adulthood, suggesting that inequalities in health have early origins. From the child's perspective, exposure to economic hardship may begin as early as conception, potentially via maternal neuroendocrine-immune responses to prenatal stressors, which adversely impact neurodevelopment. Here we investigate whether socioeconomic disadvantage is associated with gestational immune activity and whether such activity is associated with abnormalities among offspring during infancy. We analyzed concentrations of five immune markers (IL-1ß, IL-6, IL-8, IL-10, and TNF-α) in maternal serum from 1,494 participants in the New England Family Study in relation to the level of maternal socioeconomic disadvantage and their involvement in offspring neurologic abnormalities at 4 mo and 1 y of age. Median concentrations of IL-8 were lower in the most disadvantaged pregnancies [-1.53 log(pg/mL); 95% CI: -1.81, -1.25]. Offspring of these pregnancies had significantly higher risk of neurologic abnormalities at 4 mo [odds ratio (OR) = 4.61; CI = 2.84, 7.48] and 1 y (OR = 2.05; CI = 1.08, 3.90). This higher risk was accounted for in part by fetal exposure to lower maternal IL-8, which also predicted higher risks of neurologic abnormalities at 4 mo (OR = 7.67; CI = 4.05, 14.49) and 1 y (OR = 2.92; CI = 1.46, 5.87). Findings support the role of maternal immune activity in fetal neurodevelopment, exacerbated in part by socioeconomic disadvantage. This finding reveals a potential pathophysiologic pathway involved in the intergenerational transmission of socioeconomic inequalities in health.

Birth seasonality and risk of autism spectrum disorder.

Season of birth has been hypothesized to be a risk factor for autism spectrum disorder (ASD). However, the evidence has been mixed and limited due to methodological challenges. We examine ASD birth trends for 5,464,628 births across 5 countries. ASD birth prevalence data were obtained from the International Collaboration for Autism Registry Epidemiology database, including children born in Denmark, Finland, Norway, Sweden, and Western Australia. Empirical mode decomposition and cosinor modeling were used to assess seasonality. We show seasonal variation in ASD births for the countries of Finland and Sweden. There was a modest increase in risk for children born in the fall and a modest decrease in risk for children born in the spring. Solar radiation levels around conception and the postnatal period were inversely correlated with seasonal trends in ASD risk. In the first multinational study of birth seasonality of ASD, there was evidence supporting the presence of seasonal trends in Finland and Sweden. The observations that risk was highest for fall births (i.e., conceived in the winter) and lowest for spring births (i.e., conceived in the summer), and sunlight levels during critical neurodevelopmental periods explained much of the seasonal trends, are consistent with the hypothesis that a seasonally fluctuating risk factor may influence risk of ASD.

Apgar score and risk of autism.

Low Apgar score has been associated with higher risk for several neurological and psychiatric disorders, including cerebral palsy and intellectual disability. Studies of the association between Apgar score and autism spectrum disorder (ASD) have been inconsistent. We aimed to investigate (1) the association between low Apgar score at 5 min and risk for ASD, and (2) the modifying effects of gestational age and sex on this association in the largest multinational database of ASD. We included prospective data from 5.5 million individuals and over 33,000 cases of ASD from Norway, Sweden, Denmark and Western Australia who were born between 1984 and 2007. We calculated crude and adjusted risk ratios (RR) with 95% confidence intervals (95% CIs) for the associations between low Apgar score and ASD. All analyses for ASD were repeated for autistic disorder (AD). We used interaction terms and stratified analysis to investigate the effects of sex, gestational age, and birth weight on the association. In fully adjusted models, low Apgar scores (1-3) (RR, 1.42; 95% CI, 1.16-1.74), and intermediate Apgar scores (4-6) (RR, 1.50; 95% CI, 1.36-1.65) were associated with a higher RR of ASD than optimal Apgar score (7-10). The point estimates for low (RR, 1.88; 95% CI, 1.41-2.51) and intermediate Apgar score (RR, 1.54; 95% CI, 1.32-1.81) were larger for AD than for ASD. This study suggests that low Apgar score is associated with higher risk of ASD, and in particular AD. We did not observe any major modifying effects of gestational age and sex, although there seems to be substantial confounding by gestational age and birth weight on the observed association.

Central Nervous System Infection with Borna Disease Virus Causes Kynurenine Pathway Dysregulation and Neurotoxic Quinolinic Acid Production.

Central nervous system infection of neonatal and adult rats with Borna disease virus (BDV) results in neuronal destruction and behavioral abnormalities with differential immune-mediated involvement. Neuroactive metabolites generated from the kynurenine pathway of tryptophan degradation have been implicated in several human neurodegenerative disorders. Here, we report that brain expression of key enzymes in the kynurenine pathway are significantly, but differentially, altered in neonatal and adult rats with BDV infection. Gene expression analysis of rat brains following neonatal infection showed increased expression of kynurenine amino transferase II (KATII) and kynurenine-3-monooxygenase (KMO) enzymes. Additionally, indoleamine 2,3-dioxygenase (IDO) expression was only modestly increased in a brain region- and time-dependent manner in neonatally infected rats; however, its expression was highly increased in adult infected rats. The most dramatic impact on gene expression was seen for KMO, whose activity promotes the production of neurotoxic quinolinic acid. KMO expression was persistently elevated in brain regions of both newborn and adult BDV-infected rats, with increases reaching up to 86-fold. KMO protein levels were increased in neonatally infected rats and colocalized with neurons, the primary target cells of BDV infection. Furthermore, quinolinic acid was elevated in neonatally infected rat brains. We further demonstrate increased expression of KATII and KMO, but not IDO, in vitro in BDV-infected C6 astroglioma cells. Our results suggest that BDV directly impacts the kynurenine pathway, an effect that may be exacerbated by inflammatory responses in immunocompetent hosts. Thus, experimental models of BDV infection may provide new tools for discriminating virus-mediated from immune-mediated impacts on the kynurenine pathway and their relative contribution to neurodegeneration.IMPORTANCE BDV causes persistent, noncytopathic infection in vitro yet still elicits widespread neurodegeneration of infected neurons in both immunoincompetent and immunocompetent hosts. Here, we show that BDV infection induces expression of key enzymes of the kynurenine pathway in brains of newborn and adult infected rats and cultured astroglioma cells, shunting tryptophan degradation toward the production of neurotoxic quinolinic acid. Thus, our findings newly implicate this metabolic pathway in BDV-induced neurodegeneration. Given the importance of the kynurenine pathway in a wide range of human infections and neurodegenerative and neuropsychiatric disorders, animal models of BDV infection may serve as important tools for contrasting direct viral and indirect antiviral immune-mediated impacts on kynurenine pathway dysregulation and the ensuing neurodevelopmental and neuropathological consequences.

Commentary: Objective aids for the assessment of ADHD - further clarification of what FDA approval for marketing means and why NEBA might help clinicians. A response to Arns et al. (2016).

Neuropsychiatric EEG-Based ADHD Assessment Aid (NEBA) is an EEG-based device designed to aid in the diagnostic process for ADHD by identifying individuals less likely to have ADHD by virtue of a lower theta/beta ratio. In using NEBA as an example, the Arns et al. commentary misstates the purpose of NEBA, which is to widen the differential rather than to make the diagnosis. Arns et al. caution about missing an ADHD diagnosis, but fail to mention the impact of overdiagnosis. If we are to advance our knowledge of the etiology and pathophysiology of ADHD, as well as develop tailored treatments and ultimately improve outcomes for ADHD, then biomarkers and objective assessment aids such as NEBA are needed to improve and refine diagnostic accuracy beyond symptom description and clinical history.

Genital inflammation and the risk of HIV acquisition in women.

BACKGROUND: Women in Africa, especially young women, have very high human immunodeficiency virus (HIV) incidence rates that cannot be fully explained by behavioral risks. We investigated whether genital inflammation influenced HIV acquisition in this group. METHODS: Twelve selected cytokines, including 9 inflammatory cytokines and chemokines (interleukin [IL]-1α, IL-1ß, IL-6, tumor necrosis factor-α, IL-8, interferon-γ inducible protein-10 [IP-10], monocyte chemoattractant protein-1, macrophage inflammatory protein [MIP]-1α, MIP-1ß), hematopoietic IL-7, and granulocyte macrophage colony-stimulating factor, and regulatory IL-10 were measured prior to HIV infection in cervicovaginal lavages from 58 HIV seroconverters and 58 matched uninfected controls and in plasma from a subset of 107 of these women from the Centre for the AIDS Programme of Research in South Africa 004 tenofovir gel trial. RESULTS: HIV seroconversion was associated with raised genital inflammatory cytokines (including chemokines MIP-1α, MIP-1ß, and IP-10). The risk of HIV acquisition was significantly higher in women with evidence of genital inflammation, defined by at least 5 of 9 inflammatory cytokines being raised (odds ratio, 3.2; 95% confidence interval, 1.3-7.9; P = .014). Genital cytokine concentrations were persistently raised (for about 1 year before infection), with no readily identifiable cause despite extensive investigation of several potential factors, including sexually transmitted infections and systemic cytokines. CONCLUSIONS: Elevated genital concentrations of HIV target cell-recruiting chemokines and a genital inflammatory profile contributes to the high risk of HIV acquisition in these African women.