Resource Utilization and Costs Associated with Approaches to Identify Infants with Early-Onset Sepsis.

Objective. To compare resource utilization and costs associated with 3 alternative screening approaches to identify early-onset sepsis (EOS) in infants born at ≥35 wk of gestational age, as recommended by the American Academy of Pediatrics (AAP) in 2018. Study Design. Decision tree-based cost analysis of the 3 AAP-recommended approaches: 1) categorical risk assessment (categorization by chorioamnionitis exposure status), 2) neonatal sepsis calculator (a multivariate prediction model based on perinatal risk factors), and 3) enhanced clinical observation (assessment based on serial clinical examinations). We evaluated resource utilization and direct costs (2022 US dollars) to the health system. Results. Categorical risk assessment led to the greatest neonatal intensive care unit usage (210 d per 1,000 live births) and antibiotic exposure (6.8%) compared with the neonatal sepsis calculator (112 d per 1,000 live births and 3.6%) and enhanced clinical observation (99 d per 1,000 live births and 3.1%). While the per-live birth hospital costs of the 3 approaches were similar-categorical risk assessment cost $1,360, the neonatal sepsis calculator cost $1,317, and enhanced clinical observation cost $1,310-the cost of infants receiving intervention under categorical risk assessment was approximately twice that of the other 2 strategies. Results were robust to variations in data parameters. Conclusion. The neonatal sepsis calculator and enhanced clinical observation approaches may be preferred to categorical risk assessment as they reduce the number of infants receiving intervention and thus antibiotic exposure and associated costs. All 3 approaches have similar costs over all live births, and prior literature has indicated similar health outcomes. Inclusion of downstream effects of antibiotic exposure in the neonatal period should be evaluated within a cost-effectiveness analysis. Highlights: Of the 3 approaches recommended by the American Academy of Pediatrics in 2018 to identify early-onset sepsis in infants born at ≥35 weeks, the categorical risk assessment approach leads to about twice as many infants receiving evaluation to rule out early-onset sepsis compared with the neonatal sepsis calculator and enhanced clinical observation approaches.While the hospital costs of the 3 approaches were similar over the entire population of live births, the neonatal sepsis calculator and enhanced clinical observation approaches reduce antibiotic exposure, neonatal intensive care unit admission, and hospital costs associated with interventions as part of the screening approach compared with the categorical risk assessment approach.

Changes in perceptions of antibiotic stewardship among neonatal intensive care unit providers over the course of a learning collaborative: a prospective, multisite, mixed-methods evaluation.

OBJECTIVE: To assess clinician perceptions towards the value and implementation of antibiotic stewardship (AS) in neonatal intensive care units (NICU). STUDY DESIGN: We performed a mixed-methods study of AS perceptions (prescribing appropriateness, importance, activity, capacity) using surveys and interviews in 30 California NICUs before and after a multicenter collaborative (Optimizing Antibiotic Use in California NICUs [OASCN]). RESULTS: Pre-OASCN, 24% of respondents felt there was "a lot of" or "some" inappropriate prescribing, often driven by fear of a bad outcome or reluctance to change existing practice. Clinicians reported statistically significant increases in AS importance (71 v 79%), perceived AS activity (67 v 87%), and more openness to change after OASCN (59 v 70%). We identified other concerns that lessen AS effort. CONCLUSION: OASCN increased perceived AS activity and openness to change in AS practices among NICU prescribers. Greater attention to subjective concerns should augment AS improvement.

Evaluating Epidemiologic Trends and Variations in NICU Admissions in California, 2008 to 2018.

OBJECTIVE: Previous research suggests increasing numbers of and variation in NICU admissions. We explored whether these trends were reflected in California by examining NICU admissions and birth data in aggregate and among patient and hospital subpopulations more susceptible to variations in care. METHODS: In this retrospective cohort study, we evaluated NICU utilization between 2008 and 2018 for all live births at hospitals that provide data to the California Perinatal Quality Care Collaborative. We compared hospital- and admission-level data across birth weight (BW), gestational age (GA), and illness acuity categories. Trends were analyzed by using linear regression models. RESULTS: We identified 472 402 inborn NICU admissions and 3 960 441 live births across 144 hospitals. Yearly trends in NICU admissions remained stable among all births and higher acuity births (mean admission rates 11.9% and 4.1%, respectively). However, analysis of the higher acuity births revealed significant increases in NICU admission rates for neonates with higher BW and GA (BW ≥ 2500g: 1.8% in 2008, 2.1% in 2018; GA ≥ 37 weeks: 1.5% in 2010, 1.8% in 2018). Kaiser hospitals had a decreasing trend of NICU admissions compared to non-Kaiser hospitals (Kaiser: 13.9% in 2008, 10.1% in 2018; non-Kaiser: 11.3% in 2008, 12.3% in 2018). CONCLUSIONS: Overall NICU admission rates in California were stable from 2008-2018. However, trends similar to national patterns emerged when stratified by infant GA, BW, and illness acuity as well as Kaiser or non-Kaiser hospitals, with increasing admission rates for infants born at higher BW and GA and within non-Kaiser hospitals.

Automated Sample Preparation Workflow for Tandem Mass Tag-Based Proteomics.

Although tandem mass tag (TMT)-based isobaric labeling has become a powerful approach for multiplexed protein quantitation, automating the workflow for this technique has not been easy to achieve for widespread adoption. This is because preparation of TMT-labeled peptide samples involves multiple steps ranging from protein extraction, denaturation, reduction, and alkylation to tryptic digestion, desalting, labeling, and cleanup, all of which require a high level of proficiency. The variability resulting from multiple processing steps is inherently problematic, especially with large-scale clinical studies that involve hundreds of samples where reproducibility is critical for quantitation. Here, we sought to compare the performance of a recently introduced platform, AccelerOme, for an automated proteomic workflow employing TMT labeling with the manual processing of samples. Cell pellets were prepared and subjected to a 16-plex experiment using an automated platform and a conventional manual protocol. Single-shot liquid chromatography with tandem mass spectrometry analysis revealed a higher number of proteins and peptides identified using the automated platform. Efficiency of tryptic digestion, alkylation, and TMT labeling were similar in both manual and automated processes. In addition, comparison of quantitation accuracy and precision showed similar performance in an automated workflow compared to manual sample preparation by an expert. Overall, we demonstrated that the automated platform performs at a level similar to a manual process performed by an expert for TMT-based proteomics. We anticipate that this automated workflow will increasingly replace manual pipelines and has the potential to be applied to large-scale TMT-based studies, providing robust results and high sample throughput.

Admission and Care Practices in United States Well Newborn Nurseries.

OBJECTIVES: Late preterm and term infants comprise 97.3% of annual births in the United States. Admission criteria and the availability of medical interventions in well newborn nurseries are key determinants of these infants remaining within a mother-infant dyad or requiring a NICU admission and resultant separation of the dyad. The objective of this study was to identify national patterns for well newborn nursery care practices. METHODS: We surveyed a physician representative from each nursery in the Better Outcomes through Research for Newborns Network. We described the admission criteria and clinical management of common newborn morbidities and analyzed associations with nursery demographics. RESULTS: Of 96 eligible nursery representatives, 69 (72%) completed surveys. Among respondents, 59 (86%) used a minimal birth weight criterion for admission to their well newborn nursery. The most commonly used criteria were 2000 g (n = 29, 49%) and 1800 g (n = 19, 32%), with a range between 1750 and 2500 g. All nurseries used a minimal gestational age criterion for admission; the most commonly used criterion was 35 weeks (n = 55, 80%). Eleven percent of sites required transfer to the NICU for phototherapy. Common interventions in the mother's room included dextrose gel (n = 56, 81%), intravenous antibiotics (n = 35, 51%), opiates for neonatal abstinence syndrome (n = 15, 22%), and an incubator for thermoregulation (n = 14, 20%). CONCLUSIONS: Wide variation in admission criteria and medical interventions exists in well newborn nurseries. Further studies may help identify evidence-based optimal admission criteria to maximize care within the mother-infant dyad.

A proteomic study to unveil lead toxicity-induced memory impairments invoked by synaptic dysregulation.

Lead (Pb2+), a ubiquitously present heavy metal toxin, has various detrimental effects on memory and cognition. However, the molecular processes affected by Pb2+ causing structural and functional anomalies are still unclear. To explore this, we employed behavioral and proteomic approaches using rat pups exposed to lead acetate through maternal lactation from postnatal day 0 (P0) until weaning. Behavioral results from three-month-old rats clearly emphasized the early life Pb2+ exposure induced impairments in spatial cognition. Further, proteomic analysis of synaptosomal fractions revealed differential alteration of 289 proteins, which shows functional significance in elucidating Pb2+ induced physiological changes. Focusing on the association of Small Ubiquitin-like MOdifier (SUMO), a post-translational modification, with Pb2+ induced cognitive abnormalities, we identified 45 key SUMO target proteins. The significant downregulation of SUMO target proteins such as metabotropic glutamate receptor 3 (GRM3), glutamate receptor isoforms 2 and 3 (GRIA 2 and GRIA3) and flotilin-1 (FLOT1) indicates SUMOylation at the synapses could contribute to and drive Pb2+ induced physiological imbalance. These findings identify SUMOylation as a vital protein modifier with potential roles in hippocampal memory consolidation and regulation of cognition. Data availbility: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD034212".

Epidemiology and trends in neonatal early onset sepsis in California, 2010-2017.

OBJECTIVE: This study evaluated patterns of neonatal early onset sepsis (EOS) disease burden to guide approaches to EOS management. STUDY DESIGN: Retrospective cohort. RESULT: A total of 1535 EOS cases were identified amongst 2,872,964 neonates born between 2010 and 2017 at 136 NICUs within the California Perinatal Quality Care Collaborative. EOS incidence was 7.4 per 1000 (E coli: 4.3, GBS: 1.1) in preterm, 0.76 per 1000 (E coli: 0.29, GBS: 0.22) in late preterm, and 0.31 per 1000 (E coli: 0.07, GBS 0.13) in term neonates. There was no significant change in overall incidence, though an increase in E coli (p < 0.001) and decrease in GBS (p = 0.04) incidence were noted. After adjusting for gestational age, there was no difference in the odds of death by pathogen (p > 0.2). CONCLUSION: The overall EOS incidence remained steady in California NICUs from 2010-2017, though an increase in E coli and decrease in GBS EOS incidence was noted.

Proteomic Signatures of Diffuse and Intestinal Subtypes of Gastric Cancer.

Gastric cancer is a leading cause of death from cancer globally. Gastric cancer is classified into intestinal, diffuse and indeterminate subtypes based on histology according to the Laurén classification. The intestinal and diffuse subtypes, although different in histology, demographics and outcomes, are still treated in the same fashion. This study was designed to discover proteomic signatures of diffuse and intestinal subtypes. Mass spectrometry-based proteomics using tandem mass tags (TMT)-based multiplexed analysis was used to identify proteins in tumor tissues from patients with diffuse or intestinal gastric cancer with adjacent normal tissue control. A total of 7448 or 4846 proteins were identified from intestinal or diffuse subtype, respectively. This quantitative mass spectrometric analysis defined a proteomic signature of differential expression across the two subtypes, which included gremlin1 (GREM1), bcl-2-associated athanogene 2 (BAG2), olfactomedin 4 (OLFM4), thyroid hormone receptor interacting protein 6 (TRIP6) and melanoma-associated antigen 9 (MAGE-A9) proteins. Although GREM1, BAG2, OLFM4, TRIP6 and MAGE-A9 have all been previously implicated in tumor progression and metastasis, they have not been linked to intestinal or diffuse subtypes of gastric cancer. Using immunohistochemical labelling of a tissue microarray comprising of 124 cases of gastric cancer, we validated the proteomic signature obtained by mass spectrometry in the discovery cohort. Our findings should help investigate the pathogenesis of these gastric cancer subtypes and potentially lead to strategies for early diagnosis and treatment.

A Feasibility Study of a Novel Delayed Cord Clamping Cart.

Delaying umbilical cord clamping (DCC) for 1 min or longer following a neonate's birth has now been recommended for preterm and term newborns by multiple professional organizations. DCC has been shown to decrease rates of iron deficiency anemia, intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and blood transfusion. Despite these benefits, clinicians typically cut the umbilical cord without delay in neonates requiring resuscitation and move them to a radiant warmer for further care; this effectively prevents these patients from receiving any benefits from DCC. This study evaluated the feasibility of a delayed cord clamping cart (DCCC) in low-risk neonates born via Cesarean section (CS). The DCCC is a small, sterile cart designed to facilitate neonatal resuscitation while the umbilical cord remains intact. The cart is cantilevered over the operating room (OR) table during a CS, allowing the patient to be placed onto it immediately after birth. For this study, a sample of 20 low-risk CS cases were chosen from the non-emergency Labor and Delivery surgical case list. The DCCC was utilized for 1 min of DCC in all neonates. The data collected included direct observation by research team members, recorded debriefings and surveys of clinicians as well as surveys of patients. Forty-four care team members participated in written surveys; of these, 16 (36%) were very satisfied, 12 (27%) satisfied, 13 (30%) neutral, and 3 (7%) were somewhat dissatisfied with use of the DCCC in the OR. Feedback was collected from all 20 patients, with 18 (90%) reporting that they felt safe with the device in use. This study provides support that utilizing a DCCC can facilitate DCC with an intact umbilical cord.

Sustainability of a Clinical Examination-Based Approach for Ascertainment of Early-Onset Sepsis in Late Preterm and Term Neonates.

We demonstrated the sustained impact over a 5-year period of a clinical examination-based approach to identification of early-onset sepsis in late preterm and term neonates at our hospital. To date, more than 20 000 neonates have been safely managed using this approach, resulting in a 63% reduction in antibiotic use.

Management of Chorioamnionitis-Exposed Infants in the Newborn Nursery Using a Clinical Examination-Based Approach.

BACKGROUND: Antibiotic use in well-appearing late preterm and term chorioamnionitis-exposed (CE) infants was reduced by 88% after the adoption of a care approach that was focused on clinical monitoring in the intensive care nursery to determine the need for antibiotics. However, this approach continued to separate mothers and infants. We aimed to reduce maternal-infant separation while continuing to use a clinical examination-based approach to identify early-onset sepsis (EOS) in CE infants. METHODS: Within a quality improvement framework, well-appearing CE infants ≥35 weeks' gestation were monitored clinically while in couplet care in the postpartum unit without laboratory testing or empirical antibiotics. Clinical monitoring included physician examination at birth and nurse examinations every 30 minutes for 2 hours and then every 4 hours until 24 hours of life. Infants who developed clinical signs of illness were further evaluated and/or treated with antibiotics. Antibiotic use, laboratory testing, and clinical outcomes were collected. RESULTS: Among 319 initially well-appearing CE infants, 15 (4.7%) received antibiotics, 23 (7.2%) underwent laboratory testing, and 295 (92.5%) remained with their mothers in couplet care throughout the birth hospitalization. One infant had group B Streptococcus EOS identified and treated at 24 hours of age based on new-onset tachypnea and had an uncomplicated course. CONCLUSIONS: Management of well-appearing CE infants by using a clinical examination-based approach during couplet care in the postpartum unit maintained low rates of laboratory testing and antibiotic use and markedly reduced mother-infant separation without adverse events. A framework for repeated clinical assessments is an essential component of identifying infants with EOS.

Clinical Monitoring of Well-Appearing Infants Born to Mothers With Chorioamnionitis.

BACKGROUND: The risk of early-onset sepsis is low in well-appearing late-preterm and term infants even in the setting of chorioamnionitis. The empirical antibiotic strategies for chorioamnionitis-exposed infants that are recommended by national guidelines result in antibiotic exposure for numerous well-appearing, uninfected infants. We aimed to reduce unnecessary antibiotic use in chorioamnionitis-exposed infants through the implementation of a treatment approach that focused on clinical presentation to determine the need for antibiotics. METHODS: Within a quality-improvement framework, a new treatment approach was implemented in March 2015. Well-appearing late-preterm and term infants who were exposed to chorioamnionitis were clinically monitored for at least 24 hours in a level II nursery; those who remained well appearing received no laboratory testing or antibiotics and were transferred to the level I nursery or discharged from the hospital. Newborns who became symptomatic were further evaluated and/or treated with antibiotics. Antibiotic use, laboratory testing, culture results, and clinical outcomes were collected. RESULTS: Among 277 well-appearing, chorioamnionitis-exposed infants, 32 (11.6%) received antibiotics during the first 15 months of the quality-improvement initiative. No cases of culture result-positive early-onset sepsis occurred. No infant required intubation or inotropic support. Only 48 of 277 (17%) patients had sepsis laboratory testing. The implementation of the new approach was associated with a 55% reduction (95% confidence interval 40%-65%) in antibiotic exposure across all infants ≥34 weeks' gestation born at our hospital. CONCLUSIONS: A management approach using clinical presentation to determine the need for antibiotics in chorioamnionitis-exposed infants was successful in reducing antibiotic exposure and was not associated with any clinically relevant delays in care or adverse outcomes.

Physician Preferences Surrounding Urinary Tract Infection Management in Neonates.

OBJECTIVES: Variability exists in the treatment of neonates with urinary tract infection (UTI), potentially reflecting an overuse of resources. A cross-sectional vignette survey was designed to examine variability in physician preferences for intravenous (IV) antibiotic duration, genitourinary imaging, and prophylactic antibiotics and to evaluate drivers of resource use. METHODS: The survey was administered to a random sample of pediatricians through the American Medical Association's Physician Masterfile. Respondents were provided with a case vignette of a 2-week-old neonate with a febrile UTI and asked to indicate preferences for IV antibiotic duration and rank drivers of this decision. Respondents were also asked whether they would obtain a voiding cystourethrogram (VCUG) and, regardless of preference, randomly presented with a normal result or bilateral grade II vesicoureteral reflux. The survey was delivered electronically to facilitate skip logic and randomization. RESULTS: A total of 279 surveys were completed. Preference for total IV antibiotic duration differed significantly (P < .001) across specialty, with a median duration of 2 days for general pediatricians/hospitalists, 7 days for neonatologists, and 5 days for infectious disease pediatricians. For the 47% (n = 131) who did not want a VCUG, 24/61 (39%) wanted prophylactic antibiotics when presented with grade II vesicoureteral reflux (P < .001). CONCLUSIONS: Subspecialty status appeared to be the most influential driver of IV antibiotic duration in the treatment of UTI. A substantial proportion of pediatricians who initially expressed a preference against ordering a VCUG wished to prescribe prophylactic antibiotics when results were abnormal, which suggests that even unwanted diagnostic test results drive treatment decisions.

Epidemiology of cryptococcal infection in hospitalized children.

BACKGROUND: Cryptococcus neoformans is a common opportunistic infection in adults with acquired immunodeficiency syndrome (AIDS), but cryptococcal infection (CI) has also been recognized in HIV-negative patients. Despite the fact that many studies were conducted in adults, limited data exist for pediatric patients. METHODS: The Pediatric Health Information System, a database containing administrative information from 42 United States children's hospitals, was used to identify children admitted for the treatment of CI between 2003 and 2008. All pediatric inpatients less than 19 years of age who received an ICD-9 code for cryptococcosis or cryptococcal meningitis (CM) were included. Data regarding presence of underlying medical conditions, antifungal therapies administered, and hospital discharge disposition were evaluated. RESULTS: A total of 63 cases of CI were identified, for a CI admission frequency of 6.2 cases per million hospitalizations. Most patients (63.5%) had an underlying immunocompromising medical condition, whereas 21% were immunocompetent and 16% were infected with HIV. Cryptococcosis not involving the central nervous system was more common than CM (62% vs. 38%). Most patients received a combination of fluconazole, amphotericin, and flucytosine in their treatment regimen; however, 9 patients received no antifungal medications. The overall in-hospital case fatality rate was 9.5%. CONCLUSIONS: The majority of pediatric cryptococcosis occurred in non-HIV-infected patients. However, most patients had other immunocompromising medical conditions. Patients with CM usually received therapy in accordance with the Infectious Disease Society of America guidelines for adults, but patients with non-CM were more likely to receive therapies not supported by these guidelines.