Childhood adversity is associated with reduced BOLD response in inhibitory control regions amongst preadolescents from the ABCD study.

Adolescence is characterized by dynamic neurodevelopment, which poses opportunities for risk and resilience. Adverse childhood experiences (ACEs) confer additional risk to the developing brain, where ACEs have been associated with alterations in functional magnetic resonance imaging (fMRI) BOLD signaling in brain regions underlying inhibitory control. Socioenvironmental factors like the family environment may amplify or buffer against the neurodevelopmental risks associated with ACEs. Using baseline to Year 2 follow-up data from the Adolescent Brain Cognitive Development (ABCD) Study, the current study examined how ACEs relate to fMRI BOLD signaling during successful inhibition on the Stop Signal Task in regions associated with inhibitory control and examined whether family conflict levels moderated that relationship. Results showed that greater ACEs were associated with reduced BOLD response in the right opercular region of the inferior frontal gyrus and bilaterally in the pre-supplementary motor area, which are key regions underlying inhibitory control. Further, greater BOLD response was correlated with less impulsivity behaviorally, suggesting reduced activation may not be behaviorally adaptive at this age. No significant two or three-way interactions with family conflict levels or time were found. Findings highlight the continued utility of examining the relationship between ACEs and neurodevelopmental outcomes and the importance of intervention/prevention of ACES.

Cannabis use and neurocognitive performance at 13-14 Years-Old: Optimizing assessment with hair toxicology in the Adolescent brain cognitive development (ABCD) study.

OBJECTIVE: Cannabis is widely used, including in early adolescence, with prevalence rates varying by measurement method (e.g., toxicology vs. self-report). Critical neurocognitive development occurs throughout adolescence. Given conflicting prior brain-behavior results in cannabis research, improved measurement of cannabis use in younger adolescents is needed. METHODS: Data from the Adolescent Brain Cognitive Development (ABCD) Study Year 4 follow-up (participant age: 13-14 years-old) included hair samples assessed by LC-MS/MS and GC-MS/MS, quantifying THCCOOH (THC metabolite), THC, and cannabidiol concentrations, and the NIH Toolbox Cognitive Battery. Youth whose hair was positive for cannabinoids or reported past-year cannabis use were included in a Cannabis Use (CU) group (n = 123) and matched with non-using Controls on sociodemographics (n = 123). Standard and nested ANCOVAs assessed group status predicting cognitive performance, controlling for family relationships. Follow-up correlations assessed cannabinoid hair concentration, self-reported cannabis use, and neurocognition. RESULTS: CU scored lower on Picture Memory (p = .03) than Controls. Within the CU group, THCCOOH negatively correlated with Picture Vocabulary (r = -0.20, p = .03) and Flanker Inhibitory Control and Attention (r = -0.19, p = .04), and past-year cannabis use was negatively associated with List Sorting Working Memory (r = -0.33, p = .0002) and Picture Sequence Memory (r = -0.19, p = .04) performances. CONCLUSIONS: Youth who had used cannabis showed lower scores on an episodic memory task, and more cannabis use was linked to poorer performances on verbal, inhibitory, working memory, and episodic memory tasks. Combining hair toxicology with self-report revealed more brain-behavior relationships than self-report data alone. These youth will be followed to determine long-term substance use and neurocognition trajectories.

Concordance between substance use self-report and hair analysis in community-based adolescents.

Background: Accurate drug use identification through subjective self-report and toxicological biosample (hair) analysis are necessary to determine substance use sequelae in youth. Yet consistency between self-reported substance use and robust, toxicological analysis in a large sample of youth is understudied.Objectives: We aim to assess concordance between self-reported substance use and hair toxicological analysis in community-based adolescents.Methods: Hair results by LC-MS/MS and GC-MS/MS and self-reported past-year substance use from an Adolescent Brain Cognitive Development (ABCD) Study subsample (N = 1,390; ages 9-13; 48% female) were compared. The participants were selected for hair selection through two methods: high scores on a substance risk algorithm selected 93%; 7% were low-risk, randomly selected participants. Kappa coefficients the examined concordance between self-report and hair results.Results: 10% of youth self-reported any past-year substance use (e.g. alcohol, cannabis, nicotine, and opiates), while a mostly non-overlapping 10% had hair results indicating recent substance use (cannabis, alcohol, non-prescription amphetamines, cocaine, nicotine, opiates, and fentanyl). In randomly selected low-risk cases, 7% were confirmed positive in hair. Combining methods, 19% of the sample self-reported substance use and/or had a positive hair sample. Kappa coefficient of concordance between self-report and hair results was low (kappa = 0.07; p = .007).Conclusions: Hair toxicology identified substance use in high-risk and low-risk ABCD cohort subsamples. Given low concordance between hair results and self-report, reliance on either method alone would incorrectly categorize 9% as non-users. Multiple methods for characterizing substance use history in youth improves accuracy. Larger representative samples are needed to assess the prevalence of substance use in youth.

Stand-Biased Desks Impact on Cognition in Elementary Students Using a Within-Classroom Crossover Design.

Background: There is emerging literature that standing desk interventions may help to improve cognitive performance in school-aged children. The current study examines how desks that promote standing affect cognition over the course of a school year in third, fourth, and sixth graders. Methods: Nighty-nine students between the ages of 8 and 12 (M = 10.23; 58% Male) were assigned to either stand-biased desks or traditional sitting desks. A within-classroom design was used with students switching desks after 9 weeks. Cognitive assessments and teacher behavioral ratings were administered at baseline and readministered before students switched desks and at the conclusion of the study. Results: There were no significant effects on cognition or behavioral ratings from standing-biased desk intervention. Grade significantly moderated the relationship between stand-biased desks and cognition in that third graders showed increased cognitive control (p = 0.02, f2 = 0.06). Further, sex moderated the relationship in that females at stand-biased desks showed increased cognitive control (p = 0.03, f2 = 0.04). Conclusions: These results suggest that stand-biased desks impact cognition depending on grade and sex, indicating a complex relationship that should be teased out further in future research. Stand-biased desks showed moderate improvements in cognition and no deleterious effects, suggesting that they may be a helpful classroom intervention for children in elementary school.

Examining Inhibitory Affective Processing Within the Rostral Anterior Cingulate Cortex Among Abstinent Cannabis-Using Adolescents and Young Adults.

Cannabis use has been associated with deficits in self-regulation, including inhibitory control. Cannabis users have previously exhibited both structural and functional deficits in the rostral anterior cingulate cortex (rACC), a region involved in self-regulation of emotional response and inhibitory control. The present study aimed to examine whether abstinent cannabis users demonstrated abnormal functional activation and connectivity of the bilateral rACC during an emotional inhibitory processing task, and whether gender moderated these relationships. Cannabis-using (N = 34) and non-using (N = 32) participants ages 16-25 underwent at least 2-weeks of monitored substance use abstinence (excluding tobacco) and fMRI scanning while completing a Go/No-go task using fearful and calm emotional faces as non-targets. Multiple linear regression and ANCOVA were used to determine if cannabis group status was related to rACC activation and context-dependent functional connectivity, and whether gender moderated these relationships. Results showed decreased bilateral rACC activation in cannabis users during fearful response inhibition, although groups did not show any context-dependent connectivity differences between the left or right rACC during calm or fearful inhibition. Gender findings revealed that cannabis-using females compared to males did show aberrant connectivity between the right rACC and right cerebellum. These results are consistent with literature demonstrating aberrant structural and functional rACC findings and suggest that chronic cannabis use may disrupt typical rACC development-even after abstinence-potentially conferring risk for later development of mood disorders. Marginal gender-specific connectivity findings bolster continued findings regarding female vulnerability to effects of cannabis on cognition and affect. Findings should be assessed in longitudinal studies to determine causality and timing effects.

Assessment of Withdrawal, Mood, and Sleep Inventories After Monitored 3-Week Abstinence in Cannabis-Using Adolescents and Young Adults.

Introduction: Among adolescents and young adults, cannabis use is prevalent. Prior studies characterizing withdrawal effects in this age range have primarily included treatment seeking or comorbid psychiatric samples; these studies have identified several affected domains, especially sleep, mood, and anxiety. The present study compared a community (i.e., nontreatment seeking) sample of cannabis-using and control participants on mood, anxiety, sleep, and withdrawal inventories during the course of a monitored 3-week cannabis abstinence period. Materials and Methods: Seventy-nine adolescent and young adult participants (cannabis-using group=37 and control group=42) were recruited from the community to undergo 3 weeks of confirmed abstinence (i.e., urine and sweat patch toxicology) and completion of Cannabis Withdrawal Symptom Criteria, State-Trait Anxiety Inventory, Beck's Depression Inventory, and Pittsburgh Sleep Quality Index across the study period. Repeated measures and cross-sectional regressions were used to examine main effects of group and interactions with time (where appropriate), while accounting for recent alcohol use and cotinine levels. Results: Cannabis-using participants reported higher mood (p=0.006), overall withdrawal (p=0.009), and sleep-related withdrawal (p<0.001) symptoms across abstinence compared to controls. Overall withdrawal severity (p=0.04) and sleep-related withdrawal symptoms (p=0.02) demonstrated a quadratic trajectory across the monitored abstinence periods, with an increase from baseline and subsequent decreases in symptom severity. No differences of anxiety scores (p=0.07) or trajectories (p=0.18) were observed. By study completion, groups did not differ among sleep quality components (all p's>.05). Conclusions: These findings revealed that nontreatment-seeking cannabis-using adolescents and young adults reported heightened total withdrawal symptoms during a 3-week sustained abstinence period relative to controls. Cannabis-using participants demonstrated an increase in withdrawal symptom trajectory during the first week followed by decreased symptoms from weeks 2 to 3, which contrasts with prior linear decreases observed in cannabis-using adolescent and young adults. More mood symptoms were observed in the cannabis-using group even while excluding for comorbid psychopathologies-along with significantly more sleep problems during the abstinence period. Implications include the necessity to provide psychoeducation for recreational, nontreatment-seeking cannabis-using individuals about cannabis withdrawal, mood symptoms, and sleep quality difficulties when cannabis cessation is attempted, to improve likelihood of long-term sustained abstinence.

Substance use patterns in 9 to 13-year-olds: Longitudinal findings from the Adolescent Brain Cognitive Development (ABCD) study.

Background: Though largely substance-naïve at enrollment, a proportion of the youth in the Adolescent Brain Cognitive Development (ABCD) Study are expected to initiate substance use (SU) as they transition into later adolescence. With annual data from youth 9-13 years-old, this study aims to describe their SU patterns over time. Here, prevalence rates of use are reported, along with predicted odds of use while analyzing common risk-factors associated with youth SU. Methods: The ABCD Study® enrolled 11,876 participants at Baseline (ages 9-10) and has followed them annually. Data through half of the third follow-up visit are available (ages 12-13; n = 6,251). SU descriptives for al psychoactive substances over time are outlined. General estimating equations (GEEs) assessed whether sociodemographic factors, internalizing and externalizing symptoms, and parental SU problems were associated with SU between Baseline and Y2 follow-up. Results: Across time, alcohol and nicotine remain the most used substances. Yearly rates of any SU increased (past year use: 13.9% in Y1; 14% Y2, 18.4% Y3). Cumulatively, by Y3, 39.7% of the cohort reported experimenting (e.g., sipping alcohol) with SU within their lifetime, while 7.4% reported a "full use" (a full alcohol drink, nicotine use, cannabis use, or any other SU) in their lifetime (past-year: 1.9% alcohol, 2.1% nicotine, 1.1% cannabis, 1.2% other substances). GEEs revealed ongoing longitudinal associations between sociodemographic factors, greater externalizing symptoms, and parental drug problems with increased odds of initiating SU. Conclusions: As ABCD participants transition into their teenage years, the cohort is initiating SU at increasing (though still low) rates.

Passive Sensing of Preteens' Smartphone Use: An Adolescent Brain Cognitive Development (ABCD) Cohort Substudy.

BACKGROUND: Concerns abound regarding childhood smartphone use, but studies to date have largely relied on self-reported screen use. Self-reporting of screen use is known to be misreported by pediatric samples and their parents, limiting the accurate determination of the impact of screen use on social, emotional, and cognitive development. Thus, a more passive, objective measurement of smartphone screen use among children is needed. OBJECTIVE: This study aims to passively sense smartphone screen use by time and types of apps used in a pilot sample of children and to assess the feasibility of passive sensing in a larger longitudinal sample. METHODS: The Adolescent Brain Cognitive Development (ABCD) study used passive, objective phone app methods for assessing smartphone screen use over 4 weeks in 2019-2020 in a subsample of 67 participants (aged 11-12 years; 31/67, 46% female; 23/67, 34% White). Children and their parents both reported average smartphone screen use before and after the study period, and they completed a questionnaire regarding the acceptability of the study protocol. Descriptive statistics for smartphone screen use, app use, and protocol feasibility and acceptability were reviewed. Analyses of variance were run to assess differences in categorical app use by demographics. Self-report and parent report were correlated with passive sensing data. RESULTS: Self-report of smartphone screen use was partly consistent with objective measurement (r=0.49), although objective data indicated that children used their phones more than they reported. Passive sensing revealed the most common types of apps used were for streaming (mean 1 hour 57 minutes per day, SD 1 hour 32 minutes), communication (mean 48 minutes per day, SD 1 hour 17 minutes), gaming (mean 41 minutes per day, SD 41 minutes), and social media (mean 36 minutes per day, SD 1 hour 7 minutes). Passive sensing of smartphone screen use was generally acceptable to children (43/62, 69%) and parents (53/62, 85%). CONCLUSIONS: The results of passive, objective sensing suggest that children use their phones more than they self-report. Therefore, use of more robust methods for objective data collection is necessary and feasible in pediatric samples. These data may then more accurately reflect the impact of smartphone screen use on behavioral and emotional functioning. Accordingly, the ABCD study is implementing a passive sensing protocol in the full ABCD cohort. Taken together, passive assessment with a phone app provided objective, low-burden, novel, informative data about preteen smartphone screen use.

Longitudinal Impact of Childhood Adversity on Early Adolescent Mental Health During the COVID-19 Pandemic in the ABCD Study Cohort: Does Race or Ethnicity Moderate Findings?

BACKGROUND: During the COVID-19 pandemic in the United States, mental health among youth has been negatively affected. Youth with a history of adverse childhood experiences (ACEs), as well as youth from minoritized racial-ethnic backgrounds, may be especially vulnerable to experiencing COVID-19-related distress. The aims of this study are to examine whether exposure to pre-pandemic ACEs predicts mental health during the COVID-19 pandemic in youth and whether racial-ethnic background moderates these effects. METHODS: From May to August 2020, 7983 youths (mean age, 12.5 years; range, 10.6-14.6 years) in the Adolescent Brain Cognitive Development (ABCD) Study completed at least one of three online surveys measuring the impact of the pandemic on their mental health. Data were evaluated in relation to youths' pre-pandemic mental health and ACEs. RESULTS: Pre-pandemic ACE history significantly predicted poorer mental health across all outcomes and greater COVID-19-related stress and impact of fears on well-being. Youths reported improved mental health during the pandemic (from May to August 2020). While reporting similar levels of mental health, youths from minoritized racial-ethnic backgrounds had elevated COVID-19-related worry, stress, and impact on well-being. Race and ethnicity generally did not moderate ACE effects. Older youths, girls, and those with greater pre-pandemic internalizing symptoms also reported greater mental health symptoms. CONCLUSIONS: Youths who experienced greater childhood adversity reported greater negative affect and COVID-19-related distress during the pandemic. Although they reported generally better mood, Asian American, Black, and multiracial youths reported greater COVID-19-related distress and experienced COVID-19-related discrimination compared with non-Hispanic White youths, highlighting potential health disparities.

Cannabis Use and Brain Volume in Adolescent and Young Adult Cannabis Users: Effects Moderated by Sex and Aerobic Fitness.

OBJECTIVES: Studies examining the impact of adolescent and young adult cannabis use on structural outcomes have been heterogeneous. One already-identified moderator is sex, while a novel potential moderator is extent of aerobic fitness. Here, we sought to investigate the associations of cannabis use, sex, and aerobic fitness levels on brain volume. Second, we explored brain-behavior relationships to interpret these findings. METHODS: Seventy-four adolescents and young adults (36 cannabis users and 38 controls) underwent 3 weeks of monitored cannabis abstinence, aerobic fitness testing, structural neuroimaging, and neuropsychological testing. Linear regressions examined cannabis use and its interaction with sex and aerobic fitness on whole-brain cortical volume and subcortical regions of interests. RESULTS: No main-effect differences between cannabis users and nonusers were observed; however, cannabis-by-sex interactions identified differences in frontal, temporal, and paracentral volumes. Female cannabis users generally exhibited greater volume while male users exhibited less volume compared to same-sex controls. Positive associations between aerobic fitness and frontal, parietal, cerebellum, and caudate volumes were observed. Cannabis-by-fitness interaction was linked with left superior temporal volume. Preliminary brain-behavior correlations revealed that abnormal volumes were not advantageous in either male or female cannabis users. CONCLUSIONS: Aerobic fitness was linked with greater brain volume and sex moderated the effect of cannabis use on volume; preliminary brain-behavior correlations revealed that differences in cannabis users were not linked with advantageous cognitive performance. Implications of sex-specific subtleties and mechanisms of aerobic fitness require large-scale investigation. Furthermore, present findings and prior literature on aerobic exercise warrant examinations of aerobic fitness interventions that aimed at improving neurocognitive health in substance-using youth.

Association between brain morphometry and aerobic fitness level and sex in healthy emerging adults.

OBJECTIVE: Aerobic fitness may be beneficial for neuroanatomical structure. However, few have investigated this in emerging adults while also accounting for potential sex differences. Here we examine aerobic fitness level, sex, and their interaction in relation to cortical thickness, surface area, and volume. METHOD: Sixty-three young adults between the ages of 16-26 were balanced for sex and demonstrated a wide range of aerobic fitness levels. Exclusion criteria included left-handedness, past-year independent Axis-I disorders, major medical/neurologic disorders, prenatal medical issues, prenatal alcohol/illicit drug exposure, or excessive substance use. Participants completed an MRI scan and a graded exercise test to volitional fatigue (VO2 max). Data analyses were run in Freesurfer and data was corrected for multiple comparisons with Monte Carlo simulations at .05. RESULTS: Males demonstrated higher VO2 values. Higher VO2 values were statistically independently related to thinner lateral occipital, superior parietal, cuneus, precuneus, and inferior parietal regions, smaller lateral occipital volume, and larger inferior parietal surface area. Compared to females, males had larger volume in rostral anterior cingulate, lateral occipital, and superior frontal regions, and greater surface area in fusiform, inferior parietal, rostral and caudal anterior cingulate, and superior parietal regions. VO2*Sex interactions revealed higher-fit females had higher inferior parietal, paracentral, and supramarginal surface area, while lower-fit males showed larger surface area in these same regions. CONCLUSIONS: Individuals with higher aerobic fitness performance had thinner cortices, lower volume, and larger surface area in sensorimotor regions than lower fit individuals, perhaps suggesting earlier neuromaturation in higher fit individuals. Larger surface area was associated with higher-fit females and lower-fit males. Thus both sex and aerobic fitness are important in shaping brain health in emerging adults.

Assessing the Role of Cannabis Use on Cortical Surface Structure in Adolescents and Young Adults: Exploring Gender and Aerobic Fitness as Potential Moderators.

Cannabis use in adolescents and young adults is linked with aberrant brain structure, although findings to date are inconsistent. We examined whether aerobic fitness moderated the effects of cannabis on cortical surface structure and whether gender may play a moderating role. Seventy-four adolescents and young adults completed three-weeks of monitored abstinence, aerobic fitness testing, and structural magnetic resonance imaging (sMRI). Whole-sample linear regressions examined the effects of gender, VO2 max, cannabis use, and their interactions on the surface area (SA) and local gyrification index (LGI). Cannabis use was associated with greater cuneus SA. Gender-by-cannabis predicted precuneus and frontal SA, and precentral, supramarginal, and frontal LGI; female cannabis users demonstrated greater LGI, whereas male cannabis users demonstrated decreased LGI compared to non-users. Aerobic fitness was positively associated with various SA and LGI regions. Cannabis-by-aerobic fitness predicted cuneus SA and occipital LGI. These findings demonstrate that aerobic fitness moderates the impact of cannabis on cortical surface structure, and gender differences are evident. These moderating factors may help explain inconsistencies in the literature and warrant further investigation. Present findings and aerobic fitness literature jointly suggest aerobic intervention may be a low-cost avenue for improving cortical surface structure, although the impact may be gender-specific.

Meta-analysis of aberrant post-error slowing in substance use disorder: implications for behavioral adaptation and self-control.

Individual with substance use disorders have well-recognized impairments in cognitive control, including in behavioral adaptation after mistakes. One way in which this impairment manifests is via diminished post-error slowing, the increase in reaction time following a task-related error that is posited to reflect cautionary or corrective behavior. Yet, in the substance use disorder literature, findings with regard to post-error slowing have been inconsistent, and thus could benefit from quantitative integration. Here, we conducted a meta-analysis of case-control studies examining post-error slowing in addiction. Twelve studies with 15 unique comparisons were identified, comprising 567 substance users and 384 healthy controls across three broad types of inhibitory control paradigms (go-no/go, conflict resolution, and stop signal tasks, respectively). Results of the random-effects meta-analysis revealed a moderate group difference across all studies (Cohen's d = 0.31), such that the individuals with substance use disorder had diminished post-error slowing compared with controls. Despite this omnibus effect, there was also large variability in the magnitude of the effects, explained in part by differences between studies in task complexity. These findings suggest that post-error slowing may serve as a promising and easy-to-implement measure of cognitive control impairment in substance use disorder, with potential links to aberrant brain function in cognitive control areas such as the anterior cingulate cortex.

Measures of behavioral function predict duration of video game play: Utilization of the Video Game Functional Assessment - Revised.

Background Internet gaming disorder (IGD) was introduced in the DSM-5 as a way of identifying and diagnosing problematic video game play. However, the use of the diagnosis is constrained, as it shares criteria with other addictive orders (e.g., pathological gambling). Aims Further work is required to better understand IGD. One potential avenue of investigation is IGD's relationship to the primary reinforcing behavioral functions. This study explores the relationship between duration of video game play and the reinforcing behavioral functions that may motivate or maintain video gaming. Methods A total of 499 video game players began the online survey, with complete data from 453 participants (85% white and 28% female), were analyzed. Individuals were placed into five groups based on self-reported hours of video gaming per week, and completed the Video Game Functional Assessment - Revised (VGFA-R). Results The results demonstrated the escape and social attention function were significant in predicting duration of video game play, whereas sensory and tangible were not significant. Conclusion Future implications of the VGFA-R and behaviorally based research are discussed.

Delay Discounting of Video Game Players: Comparison of Time Duration Among Gamers.

Video game addiction or Internet game disorder, as proposed by the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), has similar criterion characteristics to other impulse control disorders. There is limited research examining video game addiction within a behavioral economic framework using delay discounting. The current study evaluated delay-discounting patterns of money and video game play by usual weekly hours of video game play. A total of 104 participants were split into 1 of 3 groups of video game players (low, medium, and high) and were asked to complete a monetary and video game discounting procedure through an online survey. Results showed significant differences between groups within both the monetary (p = 0.003) and video game discounting procedures (p = 0.004). Additionally, a positive linear relationship was noted between the groups across both procedures. The results of the current article reinforce previous findings that more hours of video game use are associated with greater impulsivity and provide implications for future research.

Mannose-Binding Lectin Levels in Critically Ill Children With Severe Infections.

OBJECTIVES: Low mannose-binding lectin levels and haplotypes associated with low mannose-binding lectin production have been associated with infection and severe sepsis. We tested the hypothesis that mannose-binding lectin levels would be associated with severe infection in a large cohort of critically ill children. DESIGN: Prospective cohort study. SETTING: Medical and Surgical PICUs, Boston Children's Hospital. PATIENTS: Children less than 21 years old admitted to the ICUs from November 2009 to November 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured mannose-binding lectin levels in 479 of 520 consecutively admitted children (92%) with severe or life-threatening illness. We genotyped 213 Caucasian children for mannose-binding lectin haplotype tagging variants and assigned haplotypes. In the univariate analyses of mannose-binding lectin levels with preadmission characteristics, levels were higher in patients with preexisting renal disease. Patients who received greater than 100 mL/kg of fluids in the first 24 hours after admission had markedly lower mannose-binding lectin, as did patients who underwent spinal fusion surgery. Mannose-binding lectin levels had no association with infection status at admission, or with progression from systemic inflammatory response syndrome to sepsis or septic shock. Although mannose-binding lectin haplotypes strongly influenced mannose-binding lectin levels in the predicted relationship, low mannose-binding lectin-producing haplotypes were not associated with increased risk of infection. CONCLUSIONS: Mannose-binding lectin levels are largely genetically determined. This relationship was preserved in children during critical illness, despite the effect of large-volume fluid administration on mannose-binding lectin levels. Previous literature evaluating an association between mannose-binding lectin levels and severe infection is inconsistent; we found no relationship in our PICU cohort. We found that mannose-binding lectin levels were lower after aggressive fluid resuscitation and suggest that studies of mannose-binding lectin in critically ill patients should assess mannose-binding lectin haplotypes to reflect preillness levels.

Critically Ill Children Have Low Vitamin D-Binding Protein, Influencing Bioavailability of Vitamin D.

RATIONALE: Vitamin D deficiency, often defined by total serum 25-hydroxyvitamin D (25[OH]D) <20 ng/ml, is common in critically ill patients, with associations with increased mortality and morbidity in the intensive care unit. Correction of vitamin D deficiency in critical illness has been recommended, and ongoing clinical trials are investigating the effect of repletion on patient outcome. The biologically active amount of 25(OH)D depends on the concentration and protein isoform of vitamin D-binding protein (VDBP), which is also an acute-phase reactant affected by inflammation and injury. OBJECTIVES: We performed a secondary analysis of a cohort of critically ill children in which we reported a high rate of vitamin D deficiency, to examine how VDBP level and genotype would impact vitamin D status. METHODS: We prospectively enrolled 511 children admitted to the pediatric intensive care unit over a 12-month period. MEASUREMENTS AND MAIN RESULTS: We measured serum VDBP in 479 children. We genotyped single nucleotide polymorphisms rs7041 and rs4588 in the VDBP gene (GC) to determine haplotypes GC1F, GC1S, and GC2 in 178 subjects who consented, then calculated bioavailable 25(OH)D from serum 25(OH)D, VDBP, albumin, and GC haplotype. The median serum VDBP level was 159 µg/ml (interquartile range, 108-221), lower than has been reported in healthy children. Factors predicting lower levels in multivariate analysis included age <1 year, nonwhite race, being previously healthy, 25(OH)D <20 ng/ml and greater illness severity. In the subgroup that was genotyped, GC haplotype had the strongest association with VDBP level; carriage of one additional copy of GC1S was associated with a 37.5% higher level (95% confidence interval, 31.9-44.8; P < 0.001). Bioavailable 25(OH)D was also inversely associated with illness severity (r = -0.24, P < 0.001), and ratio to measured total 25(OH)D was variable and related to haplotype. CONCLUSIONS: Physiologic deficiency of 25(OH)D in critical illness may be more difficult to diagnose, given that lower VDBP levels increase bioavailability. Treatment studies conducted on the basis of total 25(OH)D level, without consideration of VDBP concentration and genotype, may increase the risk of falsely negative results.

The Measure of DAMPs and a role for S100A8 in recruiting suppressor cells in breast cancer lung metastasis.

To determine whether there was a relationship between damage associated molecular pattern molecule (DAMP) expression and recruitment of suppressor cells to sites of metastasis we measured relative expression of DAMPs, regulatory T cells (Tregs), and myeloid derived suppressor cells (MDSC) in mice at various stages of breast cancer progression using the 4T1 model. Although S100A8 was expressed at relatively low levels in the tumor cells, expression was 100-fold higher in the lung and liver which are common sites of metastasis for this tumor. Despite the relatively high level of S100A8 expression in the lungs of naïve mice, the level of expression increased further and was significantly elevated after only 7 days of tumor growth. The same pattern was observed for MDSC, and both S100A8 and MDSC expression peaked in the lungs of mice following 21 days of tumor growth. Characterization of MDSC from the lungs revealed expression of RAGE, and the cells were capable of migrating in a dose-dependent manner toward S100A8. In addition, the MDSC expressed low levels of MHC Class I, MHC Class II, CD80, and secreted TGF-ß. Taken together, these data suggest that expression of S100A8 in the lungs may facilitate recruitment of MDSC, which may in turn aid in establishing a metastatic niche capable of suppressing a localized immune response.

Effectiveness of influenza vaccine against life-threatening RT-PCR-confirmed influenza illness in US children, 2010-2012.

BACKGROUND: No studies have examined the effectiveness of influenza vaccine against intensive care unit (ICU) admission associated with influenza virus infection among children. METHODS: In 2010-2011 and 2011-2012, children aged 6 months to 17 years admitted to 21 US pediatric intensive care units (PICUs) with acute severe respiratory illness and testing positive for influenza were enrolled as cases; children who tested negative were PICU controls. Community controls were children without an influenza-related hospitalization, matched to cases by comorbidities and geographic region. Vaccine effectiveness was estimated with logistic regression models. RESULTS: We analyzed data from 44 cases, 172 PICU controls, and 93 community controls. Eighteen percent of cases, 31% of PICU controls, and 51% of community controls were fully vaccinated. Compared to unvaccinated children, children who were fully vaccinated were 74% (95% CI, 19% to 91%) or 82% (95% CI, 23% to 96%) less likely to be admitted to a PICU for influenza compared to PICU controls or community controls, respectively. Receipt of 1 dose of vaccine among children for whom 2 doses were recommended was not protective. CONCLUSIONS: During the 2010-2011 and 2011-2012 US influenza seasons, influenza vaccination was associated with a three-quarters reduction in the risk of life-threatening influenza illness in children.

Vitamin D deficiency in critically ill children.

OBJECTIVE: Vitamin D influences cardiovascular and immune function. We aimed to establish the prevalence of vitamin D deficiency in critically ill children and identify factors influencing admission 25-hydroxy vitamin D (25(OH)D) levels. We hypothesized that levels would be lower with increased illness severity and in children with serious infections. METHODS: Participants were 511 severely or critically ill children admitted to the PICU from November 2009 to November 2010. Blood was collected near PICU admission and analyzed for 25(OH)D concentration by using Diasorin radioimmunoassay. RESULTS: We enrolled 511 of 818 (62.5%) eligible children. The median 25(OH)D level was 22.5 ng/mL; 40.1% were 25(OH)D deficient (level <20 ng/mL). In multivariate analysis, age and race were associated with 25(OH)D deficiency; summer season, vitamin D supplementation, and formula intake were protective; 25(OH)D levels were not lower in the 238 children (46.6%) admitted with a life-threatening infection, unless they had septic shock (n = 51, 10.0%) (median 25(OH)D level 19.2 ng/mL; P = .0008). After adjusting for factors associated with deficiency, lower levels were associated with higher admission day illness severity (odds ratio 1.19 for a 1-quartile increase in Pediatric Risk of Mortality III score per 5 ng/mL decrease in 25(OH)D, 95% confidence interval 1.10-1.28; P < .0001). CONCLUSIONS: We found a high rate of vitamin D deficiency in critically ill children. Given the roles of vitamin D in bone development and immunity, we recommend screening of those critically ill children with risk factors for vitamin D deficiency and implementation of effective repletion strategies.