Live-attenuated Vaccines Prevent Respiratory Syncytial Virus-associated Illness in Young Children.

Rationale: Active immunization is needed to protect infants and young children against respiratory syncytial virus (RSV). Rationally designed live-attenuated RSV vaccines are in clinical development.Objectives: Develop preliminary estimates of vaccine efficacy, assess durability of antibody responses to vaccination and "booster" responses after natural RSV infection, and determine sample sizes needed for more precise estimates of vaccine efficacy.Methods: We analyzed data from seven phase 1 trials of live-attenuated RSV vaccines in 6- to 24-month-old children (n = 239).Measurements and Main Results: The five vaccine regimens that induced neutralizing antibody responses in ≥80% of vaccinees (defined post hoc as "more promising") protected against RSV-associated medically attended acute respiratory illness (RSV-MAARI) and medically attended acute lower respiratory illness (RSV-MAALRI) and primed for potent anamnestic responses upon natural exposure to wild-type RSV. Among recipients of "more promising" RSV vaccines, efficacy against RSV-MAARI was 67% (95% confidence interval [CI], 24 to 85; P = 0.008) and against RSV-MAALRI was 88% (95% CI, -9 to 99; P = 0.04). A greater than or equal to fourfold increase in RSV serum neutralizing antibody following vaccination was strongly associated with protection against RSV-MAARI (odds ratio, 0.26; 95% CI, 0.09 to 0.75; P = 0.014) and RSV-MAALRI; no child with a greater than or equal to fourfold increase developed RSV-MAALRI. Rates of RSV-MAARI and RSV-MAALRI in placebo recipients were 21% and 7%, respectively. Given these rates, a study of 540 RSV-naive children would have 90% power to demonstrate ≥55% efficacy against RSV-MAARI and ≥80% efficacy against RSV-MAALRI; if rates were 10% and 3%, a study of 1,300 RSV-naive children would be needed.Conclusions: Rapid development of a live-attenuated RSV vaccine could contribute substantially to reducing the global burden of RSV disease.

SENTINEL1: Two-Season Study of Respiratory Syncytial Virus Hospitalizations among U.S. Infants Born at 29 to 35 Weeks' Gestational Age Not Receiving Immunoprophylaxis.

OBJECTIVE: The SENTINEL1 observational study characterized confirmed respiratory syncytial virus hospitalizations (RSVH) among U.S. preterm infants born at 29 to 35 weeks' gestational age (wGA) not receiving respiratory syncytial virus (RSV) immunoprophylaxis (IP) during the 2014 to 2015 and 2015 to 2016 RSV seasons. STUDY DESIGN: All laboratory-confirmed RSVH at participating sites during the 2014 to 2015 and 2015 to 2016 RSV seasons (October 1-April 30) lasting ≥24 hours among preterm infants 29 to 35 wGA and aged <12 months who did not receive RSV IP within 35 days before onset of symptoms were identified and characterized. RESULTS: Results were similar across the two seasons. Among infants with community-acquired RSVH (N = 1,378), 45% were admitted to the intensive care unit (ICU) and 19% required invasive mechanical ventilation (IMV). There were two deaths. Infants aged <6 months accounted for 78% of RSVH observed, 84% of ICU admissions, and 91% requiring IMV. Among infants who were discharged from their birth hospitalization during the RSV season, 82% of RSVH occurred within 60 days of birth hospitalization discharge. CONCLUSION: Among U.S. preterm infants 29 to 35 wGA not receiving RSV IP, RSVH are often severe with almost one-half requiring ICU admission and about one in five needing IMV.

Population Pharmacokinetics of Milrinone in Infants, Children, and Adolescents.

Milrinone is a type 3 phosphodiesterase inhibitor used to improve cardiac output in critically ill infants and children. Milrinone is primarily excreted unchanged in the urine, raising concerns for toxic accumulation in the setting of renal dysfunction of critical illness. We developed a population pharmacokinetic model of milrinone using nonlinear mixed-effects modeling in NONMEM to perform dose-exposure simulations in children with variable renal function. We included children aged <21 years who received intravenous milrinone per clinical care. Plasma milrinone concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay (range 1-5000 ng/mL). We performed dose-exposure simulations targeting steady-state therapeutic concentrations of 100-300 ng/mL previously established in adults and children with cardiac dysfunction. We simulated concentrations over 48 hours in typical subjects with decreasing creatinine clearance (CrCl), estimated using the updated bedside Schwartz equation. Seventy-four patients contributed 111 plasma samples (concentration range, 4-634 ng/mL). The median (range) postmenstrual age (PMA) was 3.7 years (0-18), and median weight (WT) was 13.1 kg (2.6-157.7). The median serum creatinine and CrCl were 0.5 mg/dL (0.1-3.1) and 117.2 mL/min/1.73 m2 (13.1-261.3), respectively. A 1-compartment model characterized the pharmacokinetic data well. The final model parameterization was: Clearance (L/h) = 15.9*(WT [kg] / 70)0.75 * (PMA1.12 / (67.71.12 +PMA1.12 )*(CrCl / 117)0.522 ; and Volume of Distribution (L) = 32.2*(WT [kg] / 70). A loading dose of 50 µg/kg followed by a continuous infusion of 0.5 µg/kg/min resulted in therapeutic concentrations, except when CrCl was severely impaired at ≤30 mL/min/1.73 m2 . In this setting, a 25 µg/kg loading dose and 0.25 µg/kg/min continuous infusion resulted in therapeutic exposures.

Population Pharmacokinetics of Intramuscular and Intravenous Ketamine in Children.

Ketamine is an N-methyl D-aspartate receptor antagonist used off-label to facilitate dissociative anesthesia in children undergoing invasive procedures. Available for both intravenous and intramuscular administration, ketamine is commonly used when vascular access is limited. Pharmacokinetic (PK) data in children are sparse, and the bioavailability of intramuscular ketamine in children is unknown. We performed 2 prospective PK studies of ketamine in children receiving either intramuscular or intravenous ketamine and combined the data to develop a pediatric population PK model using nonlinear mixed-effects methods. We applied our model by performing dosing simulations targeting plasma concentrations previously associated with analgesia (>100 ng/mL) and anesthesia awakening (750 ng/mL). A total of 113 children (50 intramuscular and 63 intravenous ketamine) with a median age of 3.3 years (range 0.02 to 17.6 years), and median weight of 14 kg (2.4 to 176.1) contributed 275 plasma samples (149 after intramuscular, 126 after intravenous ketamine). A 2-compartment model with first-order absorption following intramuscular administration and first-order elimination described the data best. Allometrically scaled weight was included in the base model for central and peripheral volume of distribution (exponent 1) and for clearance and intercompartmental clearance (exponent 0.75). Model-estimated bioavailability of intramuscular ketamine was 41%. Dosing simulations suggest that doses of 2 mg/kg intravenously and 8 mg/kg or 6 mg/kg intramuscularly, depending on age, provide adequate sedation (plasma ketamine concentrations >750 ng/mL) for procedures lasting up to 20 minutes.

Live-Attenuated Respiratory Syncytial Virus Vaccine Candidate With Deletion of RNA Synthesis Regulatory Protein M2-2 is Highly Immunogenic in Children.

Background: Live respiratory syncytial virus (RSV) candidate vaccine LIDΔM2-2 is attenuated by deletion of the RSV RNA regulatory protein M2-2, resulting in upregulated viral gene transcription and antigen expression but reduced RNA replication. Methods: RSV-seronegative children ages 6-24 months received a single intranasal dose of 105 plaque forming units (PFU) of LIDΔM2-2 (n = 20) or placebo (n = 9) (NCT02237209, NCT02040831). RSV serum antibodies, vaccine infectivity, and reactogenicity were assessed. During the following RSV season, participants were monitored for respiratory illness and pre- and post-RSV season serum antibodies. Results: Vaccine virus was shed by 95% of vaccinees (median peak titers of 3.8 log10 PFU/mL by quantitative culture and 6.3 log10 copies/mL by PCR); 90% had ≥4-fold rise in serum neutralizing antibodies. Respiratory symptoms and fever were common in vaccine (95%) and placebo (78%). One vaccinee had grade 2 rhonchi concurrent with vaccine shedding, rhinovirus, and enterovirus. Eight of 19 vaccinees versus 2 of 9 placebo recipients had substantially increased RSV antibody titers after the RSV season without medically attended RSV disease, indicating anamnestic vaccine responses to wild-type RSV without significant illness. Conclusion: LIDΔM2-2 had excellent infectivity and immunogenicity, encouraging further study of vaccine candidates attenuated by M2-2 deletion. Clinical Trials Registration: NCT02237209, NCT02040831.

Live Respiratory Syncytial Virus (RSV) Vaccine Candidate Containing Stabilized Temperature-Sensitivity Mutations Is Highly Attenuated in RSV-Seronegative Infants and Children.

Background: Respiratory syncytial virus (RSV) is the most important viral cause of severe respiratory illness in young children and lacks a vaccine. RSV cold-passage/stabilized 2 (RSVcps2) is a modification of a previously evaluated vaccine candidate in which 2 major attenuating mutations have been stabilized against deattenuation. Methods: RSV-seronegative 6-24-month-old children received an intranasal dose of 105.3 plaque-forming units (PFU) of RSVcps2 (n = 34) or placebo (n = 16) (International Maternal Pediatric Adolescent AIDS Clinical Trials protocol P1114 and companion protocol CIR285). RSV serum neutralizing antibody titers before and 56 days after vaccination, vaccine virus infectivity (defined as vaccine virus shedding detectable in nasal wash and/or a ≥4-fold rise in serum antibodies), reactogenicity, and genetic stability were assessed. During the following RSV transmission season, participants were monitored for respiratory illness, with serum antibody titers measured before and after the season. Results: A total of 85% of vaccinees were infected with RSVcps2 (median peak titer, 0.5 log10 PFU/mL by culture and 2.9 log10 copies/mL by polymerase chain reaction analysis); 77% shed vaccine virus, and 59% developed a ≥4-fold rise in RSV-serum neutralizing antibody titers. Respiratory tract and/or febrile illness occurred at the same rate (50%) in the vaccine and placebo groups. Deattenuation was not detected at either of 2 stabilized mutation sites. Conclusions: RSVcps2 was well tolerated and moderately immunogenic and had increased genetic stability in 6-24-month-old RSV-seronegative children. Clinical Trials Registration: NCT01852266 and NCT01968083.

Protecting the Community Through Child Vaccination.

The direct impact of vaccines on children is well described, but the major public health impact of indirect protection provided to the community by vaccines is underappreciated. Community protection occurs when vaccinated persons block the chain of transmission, protecting undervaccinated or unvaccinated susceptible community members by preventing exposure and limiting the spread of the pathogen through the community. Substantial declines in disease incidence have occurred shortly after implementing new childhood vaccines, including declines among vaccine-ineligible children, adolescents, and adults. Protection of susceptible community members depends on maintaining high vaccination rates. Improved recognition of community protection will strengthen childhood vaccination strategies that will protect our communities into the future.

A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data.

Amiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature. Both study data and literature data were predominantly from infants < 2 years old, so our analysis was restricted to this group. The final combined dataset consisted of 266 plasma drug concentrations in 45 subjects with a median (interquartile range) postnatal age of 40.1 (11.0-120.4) days and weight of 3.9 (3.1-5.1) kg. Since the median sampling time after the first dose was short (study: 95 h; literature: 72 h) relative to the terminal half-life estimated in adult PopPK studies, values of the deep compartment volume and flow were fixed to literature values. A 3-compartment model best described the data and was validated by visual predictive checks and non-parametric bootstrap analysis. The final model included body weight as a covariate on all volumes and on both inter-compartmental and elimination clearances. The empiric Bayesian estimates for clearance (CL), volume of distribution at steady state, and terminal half-life were 0.25 (90% CL 0.14-0.36) L/kg/h, 93 (68-174) L/kg, and 266 (197-477) h, respectively. These studies will provide useful information for future PopPK studies of amiodarone in infants and children that could improve dosage regimens.

Vital signs analysis algorithm detects inflammatory response in premature infants with late onset sepsis and necrotizing enterocolitis.

BACKGROUND: Nonspecific clinical signs and suboptimal diagnostic tests limit accurate identification of late onset sepsis (LOS) and necrotizing enterocolitis (NEC) in premature infants, resulting in significant morbidity and antibiotic overuse. An infant's systemic inflammatory response may be identified earlier than clinical suspicion through analysis of multiple vital signs by a computerized algorithm (RALIS). AIM: To evaluate the revised RALIS algorithm for detection of LOS and NEC in preterm infants. METHODS: In this nested case-control study, VS data (heart rate, respiratory rate, temperature, desaturations, bradycardias) were extracted from medical records of infants 23-32 weeks gestation. RALIS generated an output, with score ≥ 5 triggering an alert. Patient episodes were classified based on culture, radiograph, and antibiotic data into categories: LOS, expanded LOS, NEC, and controls. Paired t-tests, linear regression and cross-validation analyses were used to evaluate the relationship between RALIS alert and LOS/NEC. RESULTS: Among 155 infants with 161 episodes, there were 41 expanded LOS (+blood, CSF, urine, respiratory culture), 31 LOS (+blood, CSF, urine), 9 NEC, and 93 controls. RALIS alert was 43.1 ±â€¯79 h before culture in LOS (p = .012). There was a significant association between RALIS alert and LOS/NEC (ß = 0.72, p < .0001). Sensitivity and specificity for LOS/NEC were 84% and 80%, (PPV = 63%; NPV = 93%). The regression model demonstrated an AUC of 89.9%. CONCLUSIONS: For infants ≤32 weeks, RALIS detects systemic inflammatory responses in LOS and NEC in the first month of life. The algorithm can identify infection earlier than clinical suspicion, even for NEC with negative cultures. RALIS has high NPV to rule-out LOS and NEC, and may, after prospective validation, aid in antibiotic treatment decisions.

Comparative Analysis of Ampicillin Plasma and Dried Blood Spot Pharmacokinetics in Neonates.

BACKGROUND: Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated. METHODS: An open-label, multicenter, opportunistic, prospective study was conducted in neonates. Ampicillin concentrations from plasma and DBS (CONCPlasma and CONCDBS) were measured by liquid chromatographic tandem mass spectrometry and analyzed using pop-PK and statistical (including transformation) approaches. RESULTS: A total of 29 paired plasma and DBS samples from 18 neonates were analyzed. The median (range) gestational age and postnatal age were 37 (27-41) weeks and 8 (1-26) days, respectively. The geometric mean of CONCDBS to CONCPlasma ratio was 0.56. Correlation analysis demonstrated strong association between CONCPlasma and CONCDBS (r = 0.902, analysis of variance P < 0.001). Using linear regression transformation, the estimated CONCPlasma (eCONCPlasma) was derived using (CONCDBS - 3.223)/0.51. The median bias and geometric mean ratio improved to -11% and 0.88 (Wilcoxon signed-rank test, P < 0.001), respectively, when comparing eCONCPlasma to CONCPlasma. Furthermore, using pop-PK modeling, the median bias (interquartile range) for clearance and individual predicted concentrations improved to 8% (-11 to 50) and -8% (-34 to 11), respectively, when eCONCPlasma was used. CONCLUSIONS: After transformation, DBS sampling accurately predicted ampicillin exposure in neonates.

Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children.

Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii infections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children. Separate population PK models were developed for TMP and SMX administered by the enteral route using nonlinear mixed-effects modeling. Optimal dosing was determined on the basis of the matching adult TMP exposure and attainment of the surrogate pharmacodynamic (PD) target for efficacy, a free TMP concentration above the MIC over 50% of the dosing interval. Data for a total of 153 subjects (240 samples for PK analysis) with a median postnatal age of 8 years (range, 0.1 to 20 years) contributed to the analysis for both drugs. A one-compartment model with first-order absorption and elimination characterized the TMP and SMX PK data well. Weight was included in the base model for clearance (CL/F) and volume of distribution (V/F). Both TMP and SMX CL/F increased with age. In addition, TMP and SMX CL/F were inversely related to the serum creatinine and albumin concentrations, respectively. The exposure achieved in children after oral administration of TMP-SMX at 8/40 mg/kg of body weight/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 320/1,600 mg/day divided into administration every 12 h and achieved the PD target for bacteria with an MIC of 0.5 mg/liter in >90% of infants and children. The exposure achieved in children after oral administration of TMP-SMX at 12/60 and 15/75 mg/kg/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 640/3,200 mg/day divided into administration every 12 h in subjects 6 to <21 years and 0 to <6 years of age, respectively, and was optimal for bacteria with an MIC of up to 1 mg/liter.

Multisite Evaluation of the BD Max Extended Enteric Bacterial Panel for Detection of Yersinia enterocolitica, Enterotoxigenic Escherichia coli, Vibrio, and Plesiomonas shigelloides from Stool Specimens.

The purpose of this study was to perform a multisite evaluation to establish the performance characteristics of the BD Max extended enteric bacterial panel (xEBP) assay directly from unpreserved or Cary-Blair-preserved stool specimens for the detection of Yersinia enterocolitica, enterotoxigenic Escherichia coli (ETEC), Vibrio, and Plesiomonas shigelloides The study included prospective, retrospective, and prepared contrived specimens from 6 clinical sites. BD Max xEBP results were compared to the reference method, which included standard culture techniques coupled with alternate PCR and sequencing, except for ETEC, for which the reference method was two alternate PCRs and sequencing. Alternate PCR was also used to confirm the historical results for the retrospective specimens and for discrepant result analysis. A total of 2,410 unformed, deidentified stool specimens were collected. The prevalence in the prospective samples as defined by the reference method was 1.2% ETEC, 0.1% Vibrio, 0% Y. enterocolitica, and 0% P. shigelloides Compared to the reference method, the positive percent agreement (PPA) (95% confidence interval [CI]), negative percent agreement (NPA) (95% CI), and kappa coefficient (95% CI) for the BD Max xEBP assay for all specimens combined were as follows: ETEC, 97.6% (87.4 to 99.6), 99.8% (99.5 to 99.9), and 0.93 (0.87 to 0.99); Vibrio, 100% (96.4 to 100), 99.7% (99.4 to 99.8), and 0.96 (0.93 to 0.99); Y. enterocolitica, 99.0% (94.8 to 99.8), 99.9% (99.8 to 99.9), and 0.99 (0.98 to 1); P. shigelloides, 100% (96.4 to 100), 99.8% (99.5 to 99.9), and 0.98 (0.95 to 1), respectively. In this multicenter study, the BD Max xEBP showed a high correlation (kappa, 0.97; 95% CI, 0.95 to 0.98) with the conventional methods for the detection of ETEC, Vibrio, Y. enterocolitica, and P. shigelloides in stool specimens from patients suspected of acute gastroenteritis, enteritis, or colitis.

Effectiveness of Palivizumab in High-risk Infants and Children: A Propensity Score Weighted Regression Analysis.

BACKGROUND: Infants with premature birth ≤35 weeks gestational age, chronic lung disease of prematurity and congenital heart disease are at an increased risk for lower respiratory tract infections and hospitalization from respiratory syncytial virus (RSV), which has been shown in randomized trials to be prevented by palivizumab. However, palivizumab effectiveness (PE) has not been studied in a large clinical setting. METHODS: A multicenter study among high-risk US and Canadian children younger than 24 months hospitalized with lower respiratory tract infection and whose nasopharyngeal aspirates were tested for human metapneumovirus (HMPV) and RSV were the subjects of the trial. We conducted a test-negative case-control study in these subjects to determine PE. We used an inverse propensity score weighted (IPSW) multiple logistic regression model to adjust PE. RESULTS: Palivizumab was used in 434 (51%) of 849 eligible children. RSV was identified in 403 (47%) children. The unadjusted PE was 43% [95% confidence interval (CI), 34%-51%)]. After IPSW adjustment, the adjusted PE was 58% (95% CI, 43%-69%). Palivizumab prevented intensive care unit admissions (PE, 62%; 95% CI, 35%-78%). PE for 29-35 weeks gestational age and ≤6 months of chronologic age without chronic lung disease of prematurity or congenital heart disease was 74% (95% CI, 56%-85%). CONCLUSIONS: Using a test-negative case-control design with RSV molecular detection, palivizumab is shown to prevent RSV hospitalizations and intensive care unit admissions in high-risk infants.

Long-term pulmonary complications in perinatally HIV-infected youth.

BACKGROUND: Increased incidence and prevalence of asthma have been documented for perinatally HIV-infected youth 10 to 21 years of age compared with HIV-exposed uninfected (HEU) youth. OBJECTIVE: We sought to perform objective pulmonary function tests (PFTs) in HIV-infected and HEU youth with and without diagnosed asthma. METHOD: Asthma was determined in 370 participants (218 HIV-infected and 152 HEU participants) by means of chart review and self-report at 13 sites. Interpretable PFTs (188 HIV-infected and 132 HEU participants) were classified as obstructive, restrictive, or normal, and reversibility was determined after bronchodilator inhalation. Values for HIV-1 RNA, CD4 and CD8 T cells, eosinophils, total IgE, allergen-specific IgE, and urinary cotinine were measured. Adjusted prevalence ratios (PRs) of asthma and PFT outcomes were determined for HIV-infected participants relative to HEU participants, controlling for age, race/ethnicity, and sex. RESULTS: Current asthma was identified in 75 (34%) of 218 HIV-infected participants and 38 (25%) of 152 HEU participants (adjusted PR, 1.33; P = .11). The prevalence of obstructive disease did not differ by HIV status. Reversibility was less likely in HIV-infected youth than in HEU youth (17/183 [9%] vs 21/126 [17%]; adjusted PR, 0.47; P = .020) overall and among just those with obstructive PFT results (adjusted PR, 0.46; P = .016). Among HIV-infected youth with current asthma, serum IgE levels were inversely correlated with CD8 T-cell counts and positively correlated with eosinophil counts and not associated with CD4 T-cell counts. HIV-infected youth had lower association of specific IgE levels to several inhalant and food allergens compared with HEU participants and significantly lower CD4/CD8 T-cell ratios (suggesting immune imbalance). CONCLUSION: Compared with HEU youth, HIV-infected youth demonstrated decreased reversibility of obstructive lung disease, which is atypical of asthma. This might indicate an early stage of chronic obstructive pulmonary disease. Follow-up into adulthood is warranted to further define their pulmonary outcomes.

Pharmacokinetics of Clindamycin in Obese and Nonobese Children.

Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size. The final model included TBW and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (liters/hour) = 13.8 × (TBW/70)0.75 × [PMA2.83/(39.52.83+PMA2.83)]; volume of distribution (V) was associated with TBW, albumin (ALB), and alpha-1 acid glycoprotein (AAG): V (liters) = 63.6 × (TBW/70) × (ALB/3.3)-0.83 × (AAG/2.4)-0.25 After accounting for differences in TBW, obesity status did not explain additional interindividual variability in model parameters. Our findings support TBW-based dosing for obese and nonobese children.

Lower total and regional grey matter brain volumes in youth with perinatally-acquired HIV infection: Associations with HIV disease severity, substance use, and cognition.

Despite improved survival due to combination antiretroviral therapy (cART), youth with perinatally-acquired HIV (PHIV) show cognitive deficits and developmental delay at increased rates. HIV affects the brain during critical periods of development, and the brain may be a persistent reservoir for HIV due to suboptimal blood brain barrier penetration of cART. We conducted structural magnetic resonance imaging (sMRI) and cognitive testing in 40 PHIV youth (mean age=16.7years) recruited from the NIH Pediatric HIV/AIDS Cohort Study (PHACS) who are part of the first generation of PHIV youth surviving into adulthood. Historical and current HIV disease severity and substance use measures were also collected. Total and regional cortical grey matter brain volumes were compared to a group of 334 typically-developing, HIV-unexposed and uninfected youth (frequency-matched for age and sex) from the Pediatric Imaging, Neurocognition, and Genetics (PING) study (mean age=16.1years). PHIV youth had smaller (2.8-5.1%) total and regional grey matter volumes than HIV-unexposed and uninfected youth, with smallest volumes seen among PHIV youth with higher past peak viral load (VL) and recent unsuppressed VL. In PHIV youth, worse cognitive performance correlated with smaller volumes. This pattern of smaller grey matter volumes suggests that PHIV infection may influence brain development and underlie cognitive dysfunction seen in this population. Among PHIV youth, smaller volumes were also linked to substance use (alcohol use: 9.0-13.4%; marijuana use: 10.1-16.0%). In this study, collection of substance use information was limited to the PHIV cohort; future studies should also collect substance use information in controls to further address interactions between HIV and substance use on brain volume.

Cord Blood Acute Phase Reactants Predict Early Onset Neonatal Sepsis in Preterm Infants.

BACKGROUND: Early onset sepsis (EOS) is a major cause of morbidity and mortality in preterm infants, yet diagnosis remains inadequate resulting in missed cases or prolonged empiric antibiotics with adverse consequences. Evaluation of acute phase reactant (APR) biomarkers in umbilical cord blood at birth may improve EOS detection in preterm infants with intrauterine infection. METHODS: In this nested case-control study, infants (29.7 weeks gestation, IQR: 27.7-32.2) were identified from a longitudinal cohort with archived cord blood and placental histopathology. Patients were categorized using culture, laboratory, clinical, and antibiotic treatment data into sepsis groups: confirmed sepsis (cEOS, n = 12); presumed sepsis (PS, n = 30); and no sepsis (controls, n = 30). Nine APRs were measured in duplicate from cord blood using commercially available multiplex immunoassays (Bio-Plex Pro™). In addition, placental histopathologic data were linked to biomarker results. RESULTS: cEOS organisms were Escherichia coli, Streptococcus agalactiae, Proteus mirabilis, Haemophilus influenzae and Listeria monocytogenes. C-reactive protein (CRP), serum amyloid A (SAA), haptoglobin (Hp), serum amyloid P and ferritin were significantly elevated in cEOS compared to controls (p<0.01). SAA, CRP, and Hp were elevated in cEOS but not in PS (p<0.01) and had AUCs of 99%, 96%, and 95% respectively in predicting cEOS. Regression analysis revealed robust associations of SAA, CRP, and Hp with EOS after adjustment for covariates. Procalcitonin, fibrinogen, α-2-macroglobulin and tissue plasminogen activator were not significantly different across groups. Placental acute inflammation was associated with APR elevation and was present in all cEOS, 9 PS, and 17 control infants. CONCLUSION: This study shows that certain APRs are elevated in cord blood of premature infants with EOS of intrauterine origin. SAA, CRP, and Hp at birth have potential diagnostic utility for risk stratification and identification of infants with EOS.