Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.

The glioblastoma microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine is elevated in the glioblastoma tumor microenvironment. Exogenous administration of spermidine drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and phenotype. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+T cell number and function.

Matrix Selection for the Visualization of Small Molecules and Lipids in Brain Tumors Using Untargeted MALDI-TOF Mass Spectrometry Imaging.

Matrix-assisted laser desorption/ionization mass spectrometry imaging allows for the study of metabolic activity in the tumor microenvironment of brain cancers. The detectable metabolites within these tumors are contingent upon the choice of matrix, deposition technique, and polarity setting. In this study, we compared the performance of three different matrices, two deposition techniques, and the use of positive and negative polarity in two different brain cancer types and across two species. Optimal combinations were confirmed by a comparative analysis of lipid and small-molecule abundance by using liquid chromatography-mass spectrometry and RNA sequencing to assess differential metabolites and enzymes between normal and tumor regions. Our findings indicate that in the tumor-bearing brain, the recrystallized α-cyano-4-hydroxycinnamic acid matrix with positive polarity offered superior performance for both detected metabolites and consistency with other techniques. Beyond these implications for brain cancer, our work establishes a workflow to identify optimal matrices for spatial metabolomics studies.

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.

Early childhood outcomes of NICU graduates with cytomegalovirus infection in California.

BACKGROUND: To assess demographics and outcomes up to 3 years of age among children with cytomegalovirus (CMV) infection in California neonatal intensive care units (NICUs) during 2010-2021. METHODS: The California Perinatal Quality Care Collaborative (CPQCC) collects data on all very low birth weight (VLBW, birth weight ≤ 1500 g) and acutely ill infants with birth weight > 1500 g across 92% of NICUs in California. VLBW infants and those with neurological conditions are referred to a statewide high-risk infant follow-up (HRIF) program. CMV infection was defined as a positive culture or PCR identified during the NICU hospitalization. RESULTS: During 2010-2021, CMV reporting rates averaged 3.5/1000 VLBW infants (n = 205) and 1.1/1000 infants >1500 g (n = 128). Among all 333 infants with CMV, 314 (94%) were discharged home alive, 271 (86%) were referred for HRIF and 205 (65%) had ≥1 visit. Whereas infants born to mothers <20 years of age had highest CMV reporting rates and those born to Hispanic mothers comprised 49% of all infected infants, they had the highest loss of follow-up. At the 12-month visit (n = 152), 19 (13%) infants with CMV had bilateral blindness and 18 (12%) had hearing loss. At the 24-month visit, 5 (5%) of 103 had severe cerebral palsy. CONCLUSIONS: Among infants admitted to the NICU, those with CMV diagnoses may over represent infants with more severe CMV disease and outcomes. The CPQCC and HRIF program findings may help inform implementation of surveillance for congenital CMV infection in other U.S. states and guide strategies to reduce disparities in access to services.

Rural Residence and Factors Associated with Attendance at the Second High-Risk Infant Follow-up Clinic Visit for Very Low Birth Weight Infants in California.

OBJECTIVE: This study was aimed to determine factors associated with attendance at the second high-risk infant follow-up (HRIF) visit (V2) by 20 months of corrected age after a successful first visit (V1), and the impact of rural residence on attendance rates in a statewide population of very low birth weight (VLBW; <1,500 g) infants. STUDY DESIGN: Data linked from the California Perinatal Quality of Care Collaborative (CPQCC) Neonatal Intensive Care Unit (NICU) database and CPQCC-California Children's Services (CCS) HRIF database. Multivariable logistic regression evaluated independent associations of sociodemographic, maternal, family, neonatal clinical, and individual HRIF program differences (factors) with successful V2 in VLBW infants born in 2010 to 2012. RESULTS: Of 7,295 eligible VLBW infants, 75% (5,475) attended V2. Sociodemographic factors independently associated with nonattendance included maternal race of Black (adjusted odds ratio [aOR] = 0.61; 95% confidence interval [CI]: 0.5-0.75), public insurance (aOR = 0.79; 95% CI: 0.69-0.91), and rural residence (aOR = 0.74; 95% CI: 0.61-0.9). Factors identified at V1that were associated with V2 attendance included attending V1 within the recommended window (aOR = 2.34; 95% CI: 1.99-2.75) and early intervention enrollment (aOR = 1.39; 95% CI: 1.12-1.61). Neonatal factors associated with attendance included birth weight ≤750 g (aOR = 1.83; 95% CI: 1.48-2.5). There were significant program differences with risk-adjusted rates ranging from 43.7 to 99.7%. CONCLUSION: Sociodemographic disparities and HRIF program factors are associated with decreased attendance at V2 among VLBW infants. These findings highlight opportunities for quality and process improvement interventions starting in the NICU and continuing through transition to home and community to assure participation in HRIF. KEY POINTS: · Only 75% of VLBW infants attended the second HRIF visit.. · Those less likely to attend were Black or had rural residence.. · Infants in early intervention or attending first visit within recommended ages were more likely to attend..

Delayed Cord Clamping Uptake and Outcomes for Infants Born Very Preterm in California.

OBJECTIVE: The aim of this study is to investigate whether the purported benefits of delayed cord clamping (DCC) translate into a reduction in mortality and intraventricular hemorrhage (IVH) among preterm neonates in practice. STUDY DESIGN: This was a prospective cohort study of very preterm infants constructed from data from the California Perinatal Quality Care Collaborative for infants admitted into 130 California neonatal intensive care units (NICUs) within the first 28 days of life from 2016 through 2020. Individual-level analyses were conducted using log-binomial regression models controlling for confounders and allowing for correlation within hospitals to examine the relationship of DCC to the outcomes of mortality and IVH. Hospital-level analyses were conducted using Poisson regression models with robust variance controlling for confounders. RESULTS: Among 13,094 very preterm infants included (5,856 with DCC and 7,220 without), DCC was associated with a 43% lower risk of mortality (adjusted risk ratio [aRR]: 0.57; 95% confidence interval [CI]: 0.47-0.66). Furthermore, every 10% increase in the hospital rate of DCC among preterm infants was associated with a 4% lower hospital mortality rate among preterm infants (aRR: 0.96; 95% CI: 0.96-0.99). DCC was associated with severe IVH at the individual level, but not at the hospital level. CONCLUSION: At the individual level and hospital level, the use of DCC was associated with lower mortality among preterm infants admitted to NICUs in California. These findings are consistent with clinical trial results, suggesting that the effects of DCC seen in clinical trials are translating to improved survival in practice. KEY POINTS: · DCC was associated with lower mortality among very preterm newborns in California.. · Hospitals using DCC more often had lower very preterm mortality.. · DCC was not associated with IVH at the hospital level..

Active Treatment of Infants Born at 22-25 Weeks of Gestation in California, 2011-2018.

OBJECTIVE: To determine the rate and trend of active treatment in a population-based cohort of infants born at 22-25 weeks of gestation and to examine factors associated with active treatment. STUDY DESIGN: This observational study evaluated 8247 infants born at 22-25 weeks of gestation at hospitals in the California Perinatal Quality Care Collaborative between 2011 and 2018. Multivariable logistic regression was used to relate maternal demographic and prenatal factors, fetal characteristics, and hospital level of care to the primary outcome of active treatment. RESULTS: Active treatment was provided to 6657 infants. The rate at 22 weeks was 19.4% and increased with each advancing week, and was significantly higher for infants born between days 4 and 6 at 22 or 23 weeks of gestation compared with those born between days 0 and 3 (26.2% and 78.3%, respectively, vs 14.1% and 65.9%, respectively; P < .001). The rate of active treatment at 23 weeks increased from 2011 to 2018 (from 64.9% to 83.4%; P < .0001) but did not change significantly at 22 weeks. Factors associated with increased odds of active treatment included maternal Hispanic ethnicity and Black race, preterm premature rupture of membranes, obstetrical bleeding, antenatal steroids, and cesarean delivery. Factors associated with decreased odds included lower gestational age and small for gestational age birth weight. CONCLUSIONS: In California, active treatment rates at 23 weeks of gestation increased between 2011 and 2018, but rates at 22 weeks did not. At 22 and 23 weeks, rates increased during the latter part of the week. Several maternal and infant factors were associated with the likelihood of active treatment.

Disparities and Early Engagement Associated with the 18- to 36-Month High-Risk Infant Follow-Up Visit among Very Low Birthweight Infants in California.

OBJECTIVE: To determine follow-up rates for the high-risk infant follow-up (HRIF) visit at 18-36 months among infants with very low birthweights and identify factors associated with completion. STUDY DESIGN: We completed a retrospective cohort study using linked California Perinatal Quality of Care Collaborative neonatal intensive care unit, California Perinatal Quality of Care Collaborative California Children's Services HRIF, and Vital Statistics Birth Cohort databases. We identified maternal, sociodemographic, neonatal, clinical, and HRIF program level factors associated with the 18- to 36-month follow-up using multivariable Poisson regression. RESULTS: From 2010 to 2015, among 19 284 infants with very low birthweight expected to attend at least 1 visit at 18-36 months, 10 249 (53%) attended. On multivariable analysis, factors independently associated with attendance at an 18- to 36-month visit included estimated gestational age (relative risk [RR], 1.21; 95% CI, 1.15-1.26; <26 weeks vs ≥31 weeks), maternal education (RR, 1.09; 95% CI, 1.06-1.12; college degree or more vs high school), distance from clinic (RR, 0.92; 95% CI, 0.89-0.97; fourth quartile vs first quartile), and Black non-Hispanic race vs White race (RR, 0.88; 95% CI, 0.84-0.92). However, completion of an initial HRIF visit within the first 12 months was the factor most strongly associated with completion of an 18- to 36-month visit (RR, 6.47; 95% CI, 5.91-7.08). CONCLUSIONS: In a California very low birthweight cohort, maternal education, race, and distance from the clinic were associated with sustained HRIF participation, but attendance at a visit by 12 months was the most significantly associated factor. These findings highlight the importance of early engagement with all families to ensure equitable follow-through for children born preterm.

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.

Does active treatment in infants born at 22-23 weeks correlate with outcomes of more mature infants at the same hospital? An analysis of California NICU data, 2015-2019.

OBJECTIVE: To investigate whether hospital rates of active treatment for infants born at 22-23 weeks is associated with survival of infants born at 24-27 weeks. STUDY DESIGN: We included all liveborn infants 22-27 weeks of gestation delivered at California Perinatal Quality Care Collaborative hospitals from 2015 to 2019. We assessed (1) the correlation of active treatment (e.g., endotracheal intubation, epinephrine) in 22-23 week infants and survival until discharge for 24-27 week infants and (2) the association of active treatment with survival using multilevel models. RESULT: The 22-23 week active treatment rate was associated with infant outcomes at 22-23 weeks but not 24-27 weeks. A 10% increase in active treatment did not relate to 24-25 week (adjusted OR: 1.00 [95% CI: 0.95-1.05]), or 26-27 week survival (aOR: 1.02 [0.95-1.09]). CONCLUSION: The hospital rate of active treatment for infants born at 22-23 weeks was not associated with improved survival for 24-27 week infants.

Neonates with mild hypoxic-ischaemic encephalopathy receiving supportive care versus therapeutic hypothermia in California.

OBJECTIVE: The use of therapeutic hypothermia (TH) for mild hypoxic-ischaemic encephalopathy (HIE) remains controversial and inconsistent. We analysed trends in TH and maternal and infant characteristics associated with short-term outcomes of infants with mild HIE. DESIGN: Retrospective cohort analysis of the California Perinatal Quality Care Collaborative database 2010-2018. E-value analysis was conducted to determine the potential impact of unmeasured confounding. SETTING: California neonatal intensive care units. PATIENTS: 1364 neonates with mild HIE. INTERVENTIONS: Supportive care versus TH. MAIN OUTCOME MEASURES: Factors associated with TH and mortality. RESULTS: The proportion of infants receiving TH increased from 46% in 2010 to 79% in 2018. TH was more likely in the setting of singleton birth (OR 2.69, 95% CI 1.21 to 5.39), no major birth defects (OR 2.18, 95% CI 1.42 to 3.30), operative vaginal delivery (OR 3.04, 95% CI 1.80 to 5.10) and 5-minute Apgar score ≤5 (OR 3.17, 95% CI 2.43 to 4.13). Mortality was associated with small for gestational age (OR 5.79, 95% CI 1.90 to 18.48), <38 weeks' gestation (OR 7.31 95% CI 2.39 to 24.93), major birth defects (OR 11.62, 95% CI 3.97 to 38.00), inhaled nitric oxide (OR 12.73, 95% CI 4.00 to 44.53) and nosocomial infection (OR 7.98, 95% CI 1.15 to 47.03). E-value analyses suggest that unmeasured confounding may have contributed to some of the observed effects. CONCLUSIONS: Variation in management of mild HIE persists, but therapeutic drift has become more prevalent over time. Further studies are needed to assess long-term outcomes alongside resource utilisation to inform evidence-based practice.

Factors associated with follow-up of infants with hypoxic-ischemic encephalopathy in a high-risk infant clinic in California.

OBJECTIVE: To determine the rates of high-risk infant follow-up (HRIF) attendance and the characteristics associated with follow-up among infants with hypoxic-ischemic encephalopathy (HIE) in California. STUDY DESIGN: Using population-based datasets, 1314 infants with HIE born in 2010-2016 were evaluated. The characteristics associated with follow-up were identified through multivariable logistic regression. RESULTS: 73.9% of infants attended HRIF by age 1. Follow-up rates increased and variation in follow-up by clinic decreased over time. Female infants; those born to African-American, single, less than college-educated, or publicly insured caregivers; and those referred to high-volume or regional programs had lower follow-up rates. In multivariable analysis, Asian and Pacific Islander race/ethnicity had lower odds of follow-up; infants with college- or graduate school-educated caregivers or referred to mid-volume HRIF programs had greater odds. CONCLUSION: Sociodemographic and program-level characteristics were associated with lack of follow-up among HIE infants. Understanding these characteristics may improve the post-discharge care of HIE infants.

Racial and Ethnic Disparities in Human Milk Intake at Neonatal Intensive Care Unit Discharge among Very Low Birth Weight Infants in California.

OBJECTIVES: To examine how infant and maternal factors, hospital factors, and neighborhood-level factors impact or modify racial/ethnic disparities in human milk intake at hospital discharge among very low birth weight infants. STUDY DESIGN: We studied 14 422 infants from 119 California Perinatal Quality Care Collaborative neonatal intensive care units born from 2008 to 2011. Maternal addresses were linked to 2010 census tract data, representing neighborhoods. We tested for associations with receiving no human milk at discharge, using multilevel cross-classified models. RESULTS: Compared with non-Hispanic whites, the adjusted odds of no human milk at discharge was higher among non-Hispanic blacks (aOR 1.33 [1.16-1.53]) and lower among Hispanics (aOR 0.83 [0.74-0.93]). Compared with infants of more educated white mothers, infants of less educated white, black, and Asian mothers had higher odds of no human milk at discharge, and infants of Hispanic mothers of all educational levels had similar odds as infants of more educated white mothers. Country of birth and neighborhood socioeconomic was also associated with disparities in human milk intake at discharge. CONCLUSIONS: Non-Hispanic blacks had the highest and Hispanic infants the lowest odds of no human milk at discharge. Maternal education and country of birth were the biggest drivers of disparities in human milk intake, suggesting the need for targeted approaches of breastfeeding support.

Factors Associated with Successful First High-Risk Infant Clinic Visit for Very Low Birth Weight Infants in California.

OBJECTIVES: To determine rates of at least 1 high-risk infant follow-up (HRIF) visit by 12 months corrected age, and factors associated with successful first visit among very low birth weight (VLBW) infants in a statewide population-based setting. STUDY DESIGN: We used the linked California Perinatal Quality of Care Collaborative and California Perinatal Quality of Care Collaborative-California Children's Services HRIF databases. Multivariable logistic regression examined independent associations of maternal, sociodemographic, neonatal clinical, and HRIF program factors with a successful first HRIF visit among VLBW infants born in 2010-2011. RESULTS: Among 6512 VLBW children referred to HRIF, 4938 (76%) attended a first visit. Higher odds for first HRIF visit attendance was associated with older maternal age (OR, 1.48; 95% CI, 1.27-1.72; 30-39 vs 20-29 years), lower birth weight (OR, 2.11; 95% CI, 1.69-2.65; ≤750 g vs 1251-1499 g), private insurance (OR, 1.65; 95% CI, 1.19-2.31), a history of severe intracranial hemorrhage (OR, 1.61; 95% CI, 1.12-2.30), 2 parents as primary caregivers (OR, 1.18, 95% CI 1.03-1.36), and higher HRIF program volume (OR, 2.62; 95% CI, 1.88-3.66; second vs lowest quartile); and lower odds with maternal race African American or black (OR, 0.65; 95% CI, 0.54-0.78), and greater distance to HRIF program (OR, 0.69; 95% CI, 0.57-0.83). Rates varied substantially across HRIF programs, which remained after risk adjustment. CONCLUSIONS: In a population-based California VLBW cohort, maternal, sociodemographic, and home- and program-level disparities were associated with HRIF non-attendance. These findings underscore the need to identify challenges in access and resource risk factors during hospitalization in the neonatal intensive care unit, provide enhanced education about the benefits of HRIF, and create comprehensive neonatal intensive care unit-to-home transition approaches.

Home Oxygen Use for Preterm Infants with Bronchopulmonary Dysplasia in California.

OBJECTIVES: To identify predictors of home oxygen use in preterm infants with bronchopulmonary dysplasia (BPD) in a statewide cohort, identify hospital variation in home oxygen use, and determine the relationship between home oxygen use and neonatal intensive care unit discharge timing. STUDY DESIGN: This was a secondary analysis of California Perinatal Quality Care Collaborative data. Infants were born <32 weeks of gestation, diagnosed with BPD based on respiratory support at 36 weeks postmenstrual age (PMA), and discharged home. Risk factors for home oxygen use were identified using a logistic mixed model with center as random effect. Estimates were used to calculate each center's observed to expected ratio of home oxygen use, and a Spearman coefficient between center median PMA at discharge and observed and expected proportions of home oxygen use. RESULTS: Of 7846, 3672 infants (47%) with BPD were discharged with home oxygen. Higher odds of home oxygen use were seen with antenatal steroids, maternal hypertension, earlier gestational age, male sex, ductus arteriosus ligation, more ventilator days, nitric oxide, discharge from regional hospitals, and PMA at discharge (receiver operating characteristic area under the curve 0.85). Of 92 hospitals, home oxygen use ranged from 7% to 95%; 42% of observed home oxygen use was significantly higher or lower than expected given patient characteristics. The 67 community hospitals with higher observed rates of home oxygen had earlier median PMA at discharge (correlation -0.27, P = .024). CONCLUSIONS: Clinical and hospital factors predict home oxygen use. Home oxygen use varies across California, with community centers using more home oxygen having a shorter length of stay.