L. Steven Brown

The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia

The pathogenesis of bronchopulmonary dysplasia (BPD), a devastating lung disease in preterm infants, includes inflammation, the mechanisms of which are not fully characterized. Here we report that the activation of the NLRP3 inflammasome is associated with the development of BPD. Hyperoxia-exposed neonatal mice have increased caspase-1 activation, IL1β and inflammation, and decreased alveolarization. Nlrp3(-/-) mice have no caspase-1 activity, no IL1β, no inflammatory response and undergo normal alveolarization. Treatment of hyperoxia-exposed mice with either IL1 receptor antagonist to block IL1β or glyburide to block the Nlrp3 inflammasome results in decreased inflammation and increased alveolarization. Ventilated preterm baboons show activation of the NLRP3 inflammasome with increased IL1β:IL1ra ratio. The IL1β:IL1ra ratio in tracheal aspirates from preterm infants with respiratory failure is predictive of the development of BPD. We conclude that early activation of the NLRP3 inflammasome is a key mechanism in the development of BPD, and represents a novel therapeutic target for BPD.

Serial neutrophil values facilitate predicting the absence of neonatal early-onset sepsis.

OBJECTIVE To validate established neonatal neutrophil reference ranges (RRs) and determine the utility of serial measurements of neutrophil values in the first 24 hours to predict the absence of neonatal early-onset sepsis (EOS). STUDY DESIGN Retrospective study of 2073 admissions to the neonatal intensive care unit (2009-2011). Neonates were classified as blood culture-positive, proven EOS (n = 9), blood culture-negative but clinically suspect EOS (n = 292), and not infected (n = 1292). Neutrophil values from 745 not-infected neonates without perinatal complications were selected to validate RR distributions. Positive and negative predictive values were calculated; area under receiver operating characteristic curves (AUCs) were constructed to predict the presence or absence of EOS. Neutrophil value scores were established to determine whether serial neutrophil values predict the absence of EOS. RESULTS Seventy-seven percent of admissions to the neonatal intensive care unit were evaluated for EOS: 9 (0.56%) had proven EOS with positive blood culture ≤ 37 hours; 18% had clinically suspect EOS. Neutropenia occurred in preterm neonates, and nonspecific neutrophilia was common in uninfected neonates. The distribution of neutrophil values differed significantly between study groups. The specificity for absolute total immature neutrophils and immature to total neutrophil proportions was 91% and 94%, respectively, with negative predictive value of 99% for proven and 78% for proven plus suspect EOS. Absolute total immature neutrophils and immature to total neutrophil proportions had the best predictability for EOS >6 hours postnatal with an AUC ∼ 0.8. Neutrophil value scores predicted the absence of EOS with AUC of 0.9 and 0.81 for proven and proven plus suspect EOS, respectively. CONCLUSION Age-dependent neutrophil RRs remain valid. Serial neutrophil values at 0, 12, and 24 hours plus blood culture and clinical evaluation can be used to discontinue antimicrobial therapy at 36-48 hours.

Self-Administered Outpatient Antimicrobial Infusion by Uninsured Patients Discharged from a Safety-Net Hospital: A Propensity- Score-Balanced Retrospective Cohort Study

Background Outpatient parenteral antimicrobial therapy (OPAT) is accepted as safe and effective for medically stable patients to complete intravenous (IV) antibiotics in an outpatient setting. Since, however, uninsured patients in the United States generally cannot afford OPAT, safety-net hospitals are often burdened with long hospitalizations purely to infuse antibiotics, occupying beds that could be used for patients requiring more intensive services. OPAT is generally delivered in one of four settings: infusion centers, nursing homes, at home with skilled nursing assistance, or at home with self-administered therapy. The first three—termed healthcare-administered OPAT (H-OPAT)—are most commonly used in the United States by patients with insurance funding. The fourth—self-administered OPAT (S-OPAT)—is relatively uncommon, with the few published studies having been conducted in the United Kingdom. With multidisciplinary planning, we established an S-OPAT clinic in 2009 to shift care of selected uninsured patients safely to self-administration of their IV antibiotics at home. We undertook this study to determine whether the low-income mostly non-English-speaking patients in our S-OPAT program could administer their own IV antimicrobials at home with outcomes as good as, or better than, those receiving H-OPAT. Methods and Findings Parkland Hospital is a safety-net hospital serving Dallas County, Texas. From 1 January 2009 to 14 October 2013, all uninsured patients meeting criteria were enrolled in S-OPAT, while insured patients were discharged to H-OPAT settings. The S-OPAT patients were trained through multilingual instruction to self-administer IV antimicrobials by gravity, tested for competency before discharge, and thereafter followed at designated intervals in the S-OPAT outpatient clinic for IV access care, laboratory monitoring, and physician follow-up. The primary outcome was 30-d all-cause readmission, and the secondary outcome was 1-y all-cause mortality. The study was adequately powered for readmission but not for mortality. Clinical, sociodemographic, and outcome data were collected from the Parkland Hospital electronic medical records and the US census, constituting a historical prospective cohort study. We used multivariable logistic regression to develop a propensity score predicting S-OPAT versus H-OPAT group membership from covariates. We then estimated the effect of S-OPAT versus H-OPAT on the two outcomes using multivariable proportional hazards regression, controlling for selection bias and confounding with the propensity score and covariates. Of the 1,168 patients discharged to receive OPAT, 944 (81%) were managed in the S-OPAT program and 224 (19%) by H-OPAT services. In multivariable proportional hazards regression models controlling for confounding and selection bias, the 30-d readmission rate was 47% lower in the S-OPAT group (adjusted hazard ratio [aHR], 0.53; 95% CI 0.35–0.81; p = 0.003), and the 1-y mortality rate did not differ significantly between the groups (aHR, 0.86; 95% CI 0.37–2.00; p = 0.73). The S-OPAT program shifted a median 26 d of inpatient infusion per patient to the outpatient setting, avoiding 27,666 inpatient days. The main limitation of this observational study—the potential bias from the difference in healthcare funding status of the groups—was addressed by propensity score modeling. Conclusions S-OPAT was associated with similar or better clinical outcomes than H-OPAT. S-OPAT may be an acceptable model of treatment for uninsured, medically stable patients to complete extended courses of IV antimicrobials at home.

Evaluation of positive and negative predictors of seizure outcomes among patients with immune-mediated epilepsy: a meta-analysis

Background: The objective of this study was to analyze published literature on autoimmune epilepsy and assess predictors of seizure outcome. Methods: From PubMed and EMBASE databases, two reviewers independently identified publications reporting clinical presentations, management and outcomes of patients with autoimmune epilepsy. A meta-analysis of 46 selected studies was performed. Demographic/clinical variables (sex, age, clinical presentation, epilepsy focus, magnetic resonance imaging [MRI] characteristics, time to diagnosis and initiation of immunomodulatory therapy, and type of immunomodulatory therapy) were compared between two outcome groups (responders and nonresponders). Clinical response was defined as >50% reduction in seizure frequency. Unstandardized effect sizes were collected for the studies for responder and nonresponder groups. Sample size was used as the weight in the meta-analysis. The random effects model was used to account for heterogeneity in the studies. Results: The 46 reports included 186 and 96 patients in responder and nonresponder groups respectively. Mean age of the responders and nonresponders was 43 and 31 years (p < 0.01). Responders were more likely to have cell-surface antibodies (68% versus 39%, p < 0.05), particularly voltage-gated potassium channel complex antibodies (p < 0.01). Mean duration from symptom onset to diagnosis, and symptom onset to initiation of immunomodulation was significantly lower among the responders (75 versus 431 days, p < 0.05, and 80 versus 554, p < 0.01, respectively). There was no outcome difference based on gender, MRI characteristics, seizure type, type of acute immunomodulatory therapy, or use of chronic immunomodulation. Conclusions: Among published cases to date, older age, presence of cell-surface antibodies, early diagnosis and immunomodulatory treatment are associated with better seizure outcomes among patients with autoimmune epilepsy.

Blood biomarker for Parkinson disease: peptoids

Parkinson disease (PD) is the second most common neurodegenerative disease. Because dopaminergic neuronal loss begins years before motor symptoms appear, a biomarker for the early identification of the disease is critical for the study of putative neuroprotective therapies. Brain imaging of the nigrostriatal dopamine system has been used as a biomarker for early disease along with cerebrospinal fluid analysis of α-synuclein, but a less costly and relatively non-invasive biomarker would be optimal. We sought to identify an antibody biomarker in the blood of PD patients using a combinatorial peptoid library approach. We examined serum samples from 75 PD patients, 25 de novo PD patients, and 104 normal control subjects in the NINDS Parkinson’s Disease Biomarker Program. We identified a peptoid, PD2, which binds significantly higher levels of IgG3 antibody in PD versus control subjects (P<0.0001) and is 68% accurate in identifying PD. The PD2 peptoid is 84% accurate in identifying de novo PD. Also, IgG3 levels are significantly higher in PD versus control serum (P<0.001). Finally, PD2 levels are positively correlated with the United Parkinson’s Disease Rating Scale score (r=0.457, P<0001), a marker of disease severity. The PD2 peptoid may be useful for the early-stage identification of PD, and serve as an indicator of disease severity. Additional studies are needed to validate this PD biomarker.

Evaluation of give kids a boost: A school-based program to increase booster seat use among urban children in economically disadvantaged areas

ABSTRACT Objective: This study evaluated the effectiveness of a series of 1-year multifaceted school-based programs aimed at increasing booster seat use among urban children 4–7 years of age in economically disadvantaged areas. Methods: During 4 consecutive school years, 2011–2015, the Give Kids a Boost (GKB) program was implemented in a total of 8 schools with similar demographics in Dallas County. Observational surveys were conducted at project schools before project implementation (P0), 1–4 weeks after the completion of project implementation (P1), and 4–5 months later (P2). Changes in booster seat use for the 3 time periods were compared for the 8 project and 14 comparison schools that received no intervention using a nonrandomized trial process. The intervention included (1) train-the-trainer sessions with teachers and parents; (2) presentations about booster seat safety; (3) tailored communication to parents; (4) distribution of fact sheets/resources; (5) walk-around education; and (6) booster seat inspections. The association between the GKB intervention and proper booster seat use was determined initially using univariate analysis. The association was also estimated using a generalized linear mixed model predicting a binomial outcome (booster seat use) for those aged 4 to 7 years, adjusted for child-level variables (age, sex, race/ethnicity) and car-level variables (vehicle type). The model incorporated the effects of clustering by site and by collection date to account for the possibility of repeated sampling. Results: In the 8 project schools, booster seat use for children 4–7 years of age increased an average of 20.9 percentage points between P0 and P1 (P0 = 4.8%, P1 = 25.7%; odds ratio [OR] = 6.9; 95% confidence interval [CI], 5.5, 8.7; P < .001) and remained at that level in the P2 time period (P2 = 25.7%; P < .001, for P0 vs. P2) in the univariate analysis. The 14 comparison schools had minimal change in booster seat use. The multivariable model showed that children at the project schools were significantly more likely to be properly restrained in a booster seat after the intervention (OR = 2.7; 95% CI, 2.2, 3.3) compared to the P0 time period and compared to the comparison schools. Conclusion: Despite study limitations, the GKB program was positively associated with an increase in proper booster seat use for children 4–7 years of age in school settings among diverse populations in economically disadvantaged areas. These increases persisted into the following school year in a majority of the project schools. The GKB model may be a replicable strategy to increase booster seat use among school-age children in similar urban settings.

Lenticulostriate vasculopathy in preterm infants: a new classification, clinical associations and neurodevelopmental outcome

ObjectiveTo examine the inter-rater reliability for the diagnosis of LSV on cranial ultrasound (cUS), determine the risk factors associated with LSV and its progression, and examine neurodevelopmental outcome.Study designProspective case–control study of neonates ≤32wks of gestation assessed for LSV by serial cUS (n = 1351) between 2012 and 2014 and their neurodevelopment at 18–36mon-corrected age compared to controls.ResultsAgreement for LSV on cUS improved from Κappa 0.4–0.7 after establishing definitive criteria and guidelines. BPD was the only variable associated with the occurrence and the progression of LSV. Cytomegalovirus (CMV) infection occurred in one neonate (1.5%). Neurodevelopmental outcome of neonates with LSV did not differ from controls.ConclusionsEstablishment of well-defined stages of LSV improves the reliability of the diagnosis and allows identification of neonates with progression of LSV. Although LSV was associated with BPD, it was not associated with congenital CMV infection.

Valid serial length measurements in preterm infants permit characterization of growth patterns

Background:The lack of a valid and safe method for measuring length in critically ill preterm neonates has led to a primary focus on weight gain.Local problem:Paucity of valid length measurements, precluding the accurate analysis of growth patterns.Methods:Quality improvement project among infants < 29 weeks or small for gestational age < 35 weeks with embedded validation of (1) a caliper (infantometer) for length measurements and (2) length measurements during the first week to estimate birth length.Intervention:Implementation of valid methods to measure length.Results:We validated infantometer measurements and first week length measurements. The percentage of neonates with valid measurements during the first week rose from 10% to 78%, resulting in increased identification of classifiable growth patterns from < 10% to 89%.Conclusions:By increasing the percentage of neonates with valid length measurements in the first week postnatal, we identified an increased number of neonates with classifiable growth abnormalities.

Electrogastrography, Near-infrared Spectroscopy and Acoustics to Measure Gastrointestinal Development in Preterm Babies

Objectives: The aim of the study was to obtain objective measures indicative of gastrointestinal maturity using 3 noninvasive technologies. Methods: Electrogastrography (EGG), abdominal near-infrared spectroscopy (NIRS), and bowel sound/acoustics (AC) monitoring were used simultaneously to obtain physiologic measures of the gastrointestinal system of 18 preterm and 5 term neonates who were tolerating enteral feedings. Measures of EGG slow wave voltage (EGG dominant power) and AC signal amplitude (AC dominant power) were obtained after spectral density analysis. Mean abdominal regional saturations (A-rSO2) were obtained directly from NIRS. The relationship of these 3 measures with postmenstrual age (PMA) was assessed. Results: The results of the 3 methods differed depending on whether the measurements were pre- or postprandial. Postprandial EGG dominant power increases with PMA (r = 0.67, P = 0.003), both pre- and postprandial abdominal NIRS mean regional saturation increase with PMA (r = 0.73, P < 0.001 and r = 0.55, P = 0.009), and postprandial AC dominant power (at 300–500 Hz) increases with PMA (r = −0.48, P = 0.025). Conclusions: EGG, abdominal NIRS, and AC, whenever used simultaneously, can provide objective and synergistic measures that correlate with PMA. These findings may be helpful in the assessment of feeding readiness because they reveal quantitative measures suggestive of the developmental process of the gut.