Outcomes of extremely low gestational age neonates (ELGANs) may be adversely impacted by packed red blood cell (pRBC) transfusions. We investigated the impact of transfusions on neurodevelopmental ...outcome in the Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial population.
This is a post hoc analysis of 936 infants 24-0/6 to 27-6/7 weeks' gestation enrolled in the PENUT Trial. Epo 1000 U/kg or placebo was given every 48 h × 6 doses, followed by 400 U/kg or sham injections 3 times a week through 32 weeks postmenstrual age. Six hundred and twenty-eight (315 placebo, 313 Epo) survived and were assessed at 2 years of age. We evaluated associations between BSID-III scores and the number and volume of pRBC transfusions.
Each transfusion was associated with a decrease in mean cognitive score of 0.96 (95% CI of -1.34, -0.57), a decrease in mean motor score of 1.51 (-1.91, -1.12), and a decrease in mean language score of 1.10 (-1.54, -0.66). Significant negative associations between BSID-III score and transfusion volume and donor exposure were observed in the placebo group but not in the Epo group.
Transfusions in ELGANs were associated with worse outcomes. We speculate that strategies to minimize the need for transfusions may improve outcomes.
Transfusion number, volume, and donor exposure in the neonatal period are associated with worse neurodevelopmental (ND) outcome at 2 years of age, as assessed by the Bayley Infant Scales of Development, Third Edition (BSID-III). The impact of neonatal packed red blood cell transfusions on the neurodevelopmental outcome of preterm infants is unknown. We speculate that strategies to minimize the need for transfusions may improve neurodevelopmental outcomes.
Children born before 28 weeks’ gestation are at increased risk of chronic kidney disease (CKD). Urine biomarkers may shed light on mechanistic pathways and improve the ability to forecast CKD. We ...evaluated whether urinary biomarkers in neonates of low gestational age (GA) are associated with a reduced estimated glomerular filtration rate (eGFR) over time.
A cohort study of neonates with an exploratory case-control study of a subset of the cohort.
327 neonates born at 24-27 weeks’ gestation with 2-year eGFR data from the PENUT (Preterm Erythropoietin Neuroprotection Trial) and the REPaIReD (Recombinant Erythropoietin for Prevention of Infant Renal Disease) study.
11 urinary biomarkers measured at 27, 30, and 34 weeks’ postmenstrual age for the primary cohort study and 10 additional biomarkers for the exploratory case-control study.
eGFR<90mL/min/1.73m2 at 2 years corrected for GA.
Linear mixed models to assess differences in biomarker values between neonates in whom CKD did and did not develop, accounting for multiple comparisons using Bonferroni-Holm correction in the cohort study only. Cohort analyses were adjusted for sex, GA, and body mass index. Cases were matched to controls on these variables in the case-control study.
After adjusting for weeks of GA, urinary levels of α-glutathione-S-transferase (log difference, 0.27; 95% CI, 0.12-0.43), albumin (log difference, 0.13; 95% CI, 0.02-0.25), and cystatin C (log difference, 0.19; 95% CI, 0.04-0.34) were higher in those in whom CKD developed than in those in whom it did not. Urinary albumin and cystatin C levels did not remain significantly different after Bonferroni-Holm correction. In the exploratory case-control analysis, there were no differences in any biomarkers between cases and controls.
Early deaths and a high number of subjects without eGFR at 2 years corrected for GA.
Measurement of urinary biomarkers may assist in monitoring neonates who are at risk for CKD. Additional studies are needed to confirm these findings.
Grants from government (National Institutes of Health).
Registered at ClinicalTrials.gov with study number NCT01378273.
Approximately 15 million neonates worldwide are born prematurely, and 2 million are born before 28 weeks’ gestation. Many of these children go on to experience chronic kidney disease. Urine biomarkers may allow for early recognition of those at risk for the development of kidney disease. In this study of more than 300 children born before 28 weeks’ gestational age, we found higher mean urinary levels of α-glutathione-S-transferase at 27, 30, and 34 weeks in children whose estimated glomerular filtration rate was<90mL/min/1.73m2 at 2 years compared with children whose estimated glomerular filtration rate was>90mL/min/1.73m2 at 2 years. Measurement of urinary biomarkers may assist in monitoring neonates who are at risk for chronic kidney disease. Additional studies are needed to confirm our findings.
To evaluate whether extremely low gestational age neonates (ELGANs) randomized to erythropoietin have better or worse kidney-related outcomes during hospitalization and at 22-26 months of corrected ...gestational age (cGA) compared with those randomized to placebo.
We performed an ancillary study to a multicenter double-blind, placebo-controlled randomized clinical trial of erythropoietin in ELGANs.
The prevalence of severe (stage 2 or 3) acute kidney injury (AKI) was 18.2%. We did not find a statistically significant difference between those randomized to erythropoietin vs placebo for in-hospital primary (severe AKI) or secondary outcomes (any AKI and serum creatinine/cystatin C values at days 0, 7, 9, and 14). At 22-26 months of cGA, 16% of the cohort had an estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m2, 35.8% had urine albumin/creatinine ratio >30 mg/g, 23% had a systolic blood pressure (SBP) >95th percentile for age, and 40% had a diastolic blood pressure (DBP) >95th percentile for age. SBP >90th percentile occurred less often among recipients of erythropoietin (P < .04). This association remained even after controlling for gestational age, site, and sibship (aOR 0.6; 95% CI 0.39-0.92). We did not find statistically significant differences between treatment groups in eGFR, albumin/creatinine ratio, rates of SBP >95th percentile, or DBP >90th or >95th percentiles at the 2 year follow-up visit.
ELGANs have high rates of in-hospital AKI and kidney-related problems at 22-26 months of cGA. Recombinant erythropoietin may protect ELGANs against long-term elevated SBP but does not appear to protect from AKI, low eGFR, albuminuria, or elevated DBP at 22-26 months of cGA.
To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 240/7-276/7 weeks of gestational age and to ...assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age.
The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models.
One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age.
Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.
The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD).
A secondary analysis of the PENUT Trial dataset was conducted. ...The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization.
Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD.
We find no support for an increased risk of BPD with iron supplementation.
NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT: Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.
IMPORTANCE: Understanding why and how extremely preterm infants die is important for practitioners caring for these infants. OBJECTIVE: To examine risk factors, causes, timing, and circumstances of ...death in a modern cohort of extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort review of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial between December 13, 2013, and September 26, 2016, was conducted. A total of 941 infants born between 24 0/7 and 27 6/7 weeks of gestation enrolled at 19 US sites comprising 30 neonatal intensive care units were included. Data analysis was performed from October 16, 2020, to December 1, 2021. MAIN OUTCOMES AND MEASURES: Risk factors, proximal causes, timing, and circumstances of in-hospital death. RESULTS: Of the 941 enrolled infants, 108 died (11%) before hospital discharge: 38% (n = 41) at 24 weeks’ gestation, 30% (n = 32) at 25 weeks’ gestation, 19% (n = 20) at 26 weeks’ gestation, and 14% (n = 15) at 27 weeks’ gestation. An additional 9 infants (1%) died following hospital discharge. In descending order, the primary causes of death included respiratory distress or failure, pulmonary hemorrhage, necrotizing enterocolitis, catastrophic intracranial hemorrhage, sepsis, and sudden unexplained death. Fifty percent of deaths occurred within the first 10 days after birth. The risk of death decreased with day of life and postmenstrual age such that an infant born at 24 weeks’ gestation who survived 14 days had the same risk of death as an infant born at 27 weeks’ gestation: conditional proportional risk of death, 0.08 (95% CI, 0.03-0.13) vs 0.06 (95% CI, 0.01-0.11). Preterm labor was associated with a decreased hazard of death (hazard ratio HR, 0.45; 95% CI, 0.31-0.66). Infant clinical factors associated with death included birth weight below the tenth percentile for gestational age (HR, 2.11; 95% CI, 1.38-3.22), Apgar score less than 5 at 5 minutes (HR, 2.19; 95% CI, 1.48-3.24), sick appearance at birth (HR, 2.49; 95% CI, 1.69-3.67), grade 2b-3 necrotizing enterocolitis (HR, 7.41; 95% CI, 5.14-10.7), pulmonary hemorrhage (HR, 10.0; 95% CI, 6.76-18.8), severe intracranial hemorrhage (HR, 4.60; 95% CI, 3.24-5.63), and severe sepsis (HR, 4.93; 95% CI, 3.67-7.21). Fifty-one percent of the infants received comfort care before death. CONCLUSIONS AND RELEVANCE: In this cohort study, an association between mortality and gestational age at birth was noted; however, for each week that an infant survived, their risk of subsequent death approximated the risk observed in infants born 1 to 2 weeks later, suggesting the importance of an infant’s postmenstrual age. This information may be useful to include in counseling of families regarding prognosis of survival.
TCR-sequencing (for polymerase chain reaction primers, see Table E3 in this article's Online Repository at www.jacionline.org) revealed that, compared with other lineages, type A IELps used more ...proximal TCRα variable (TRAV/Trav) and joining (TRAJ/Traj) gene segments in human subjects (Fig 1, C) and mice (Fig 1, D),4 indicating that type A IELps tend to receive a TCR signal early after initiating TCRα recombination.5 Compared with CD4+ Tconv cells, Treg cells are enriched in hydrophobic amino acid doublets at positions 6 and 7 of the CDR3 in the TCRβ chain (CDR3β), a biomarker of self-reactivity.3 The frequency of sequences carrying these position 6 and 7 doublets (hydrophobic index) was greater in the TCRα and/or TCRβ repertoires of type A IELps than in thymic and peripheral Treg cells and CD4+ and CD8+ Tconv cells in human subjects (Fig 1, E) and mice (Fig 1, F). In patients with RAG mutations, the hydrophobic index was not significantly altered in CDR3α, but it was increased in CDR3β (Fig 2, A, and see Table E2 in this article's Online Repository at www.jacionline.org). Because the cysteine index was also not significantly altered in CDR3α but was increased in the CDR3β repertoire of Treg cells from patients with RAG mutations, subsequent analyses were confined to CDR3β (Fig 2, B). The hydrophobic index appears more sensitive for detection of a self-tolerance defect but is not specific for either cortical or medullary tolerance mechanisms. ...the cysteine and hydrophobic indices provide complementary information in the diagnosis and classification of T-cell self-tolerance defects.Supplementary data Online Repository textTable E1Table E2Table E3Fig E1Fig E2
The genus Stenella is comprised of five species occurring in all oceans. Despite its wide distribution, genetic diversity information on these species is still scarce especially in the Southwest ...Atlantic Ocean. Some features of this genus can enhance opportunities for potential introgressive hybridization, e.g. sympatric distibution along the Brazilian coast, mixed known associations among species, karyotype uniformity and genome permeability. In this study we analyzed three genes of the mitochondrial genome to investigate the genetic diversity and occurrence of genetic mixture among eighty specimens of Stenella. All species exhibited moderate to high levels of genetic diversity (h = 0.833 to h = 1.000 and qi = 0.006 to qi = 0.015). Specimens of S. longirostris, S. attenuata and S. frontalis were clustered into differentiated haplogroups, in contrast, haplotypes of S. coeruleoalba and S. clymene were clustered together. We detected phylogenetic structure of mixed clades for S. clymene and S. coeruleoalba specimens, in the Southwest Atlantic Ocean, and also between S. frontalis and S. attenuata in the Northeast Atlantic Ocean, and between S. frontalis and S. longirostris in the Northwest Atlantic Ocean. These specimes were morphologically identified as one species but exhibited the maternal lineage of another species, by mitochondrial DNA. Our results demonstrate that ongoing gene flow is occurring among species of the genus Stenella reinforcing that this process could be one of the reasons for the confusing taxonomy and difficulties in elucidating phylogenetic relationships within this group.
Pre-exposure prophylaxis (PrEP) is underused in the southern United States (US), a region with high HIV incidence. Clinical decision support (CDS) tools could increase PrEP prescriptions. We explored ...barriers to PrEP delivery and views of CDS tools to identify refinements for implementation strategies for PrEP prescribing and PrEP CDS tools. We conducted focus groups with health care providers from two federally qualified health centers in Alabama and analyzed the results using rapid qualitative methods. Barriers to PrEP included providers’ lack of training in PrEP, competing priorities and time constraints during clinical visits, concerns about side effects, and intensive workload. We identified refinements to the planned implementation strategies to address the barriers, including training all clinic staff in PrEP and having CDS PrEP alerts in electronic health records sent to all staff. Development and deployment of CDS tools in collaboration with providers has potential to increase PrEP prescribing in high-priority jurisdictions.
Immunostimulatory sequences (ISS) are short DNA sequences containing unmethylated CpG dimers that have multiple effects on the host immune system, including the ability to stimulate antigen-specific ...cytotoxic T lymphocytes (CTLs) and drive Th1-type immune responses. Listeriolysin O (LLO)-containing pH-sensitive liposomes have been shown to efficiently deliver macromolecules to the cytosol of APCs and efficiently stimulate CTLs. We hypothesized that encapsulating ISS-oligodeoxyribonucleotides (ODNs) in this delivery system would enhance the cell-mediated immune response and skew Th1-type responses in protein antigen-based vaccination utilizing LLO-liposomes. In vitro studies indicated that coencapsulation of ISS in LLO-liposomes engendered activation of the NF-κB pathway while maintaining the efficient cytosolic delivery of antigen mediated by the coencapsulated LLO. Antigen-specific CTL responses monitored by using the model antigen ovalbumin (OVA) in mice were enhanced when mice were immunized with OVA and ISS-ODN-containing LLO-liposomes compared with those immunized with OVA-containing LLO-liposomes. The enhanced immune responses were of the Th1-type as monitored by the robust OVA-specific IgG2a induction and the OVA CD8 peptide-stimulated IFN-γ secretion. Our study suggests that including ISS-ODN in LLO-containing pH-sensitive liposomes yields a vaccine delivery system that enhances the cell-mediated immune response and skews this response toward the Th1-type.
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