Retinopathy of prematurity and neurodevelopmental outcome and quality of life at 10 years of age.

Objective: In a cohort of 10-year-old children born extremely preterm, we evaluated the hypothesis that increasing severity of retinopathy of prematurity (ROP) is associated with increasing frequency of unfavorable neurodevelopmental and quality of life outcomes. Study Design: Study participants were classified according to the severity of ROP. At 10 years of age, their neurocognitive abilities, academic achievement, and gross motor function were assessed, and they were evaluated for autism spectrum disorder, anxiety, depression, and quality of life. Results: After adjustment for sample attrition and confounders, only the association with lower quality of life persisted. Increasing severity of visual impairment was associated with worse neurodevelopmental outcomes and lower quality of life. Conclusion: Among extremely preterm children, severity of visual impairment, but not severity of ROP, was associated with adverse neurodevelopmental outcomes at 10 years of age. Both severe ROP and more severe visual impairment were associated with lower quality of life.

Cerebral Palsy and Motor Impairment After Extreme Prematurity: Prediction of Diagnoses at Ages 2 and 10 Years.

OBJECTIVE: To identify perinatal factors in children born extremely preterm (EP) that were associated with motor impairment (MI) at 2 and 10 years of age and develop a predictive algorithm to estimate the risk of MI during childhood. STUDY DESIGN: Participants of the Extremely Low Gestational Age Newborns Study (ELGANS) were classified as: no MI, MI only at 2 years, MI only at 10 years, and MI at both 2 and 10 years, based on a standardized neurological examination at 2 and the Gross Motor Function Classification System (GMFCS) at 10 years of age. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to develop the final predictive model. RESULTS: Of the 849 study participants, 64 (7.5%) had a diagnosis of MI at both 2 and 10 years and 63 (7.4%) had a diagnosis of MI at 1 visit but not the other. Of 22 total risk factors queried, 4 variables most reliably and accurately predicted MI: gestational age, weight z-score growth trajectory during neonatal intensive care unit (NICU) stay, ventriculomegaly, and cerebral echolucency on head ultrasound. By selecting probability thresholds of 3.5% and 7.0% at ages 2 and 10, respectively, likelihood of developing MI can be predicted with a sensitivity and specificity of 71.2%/72.1% at age 2 and 70.7%/70.7% at age 10. CONCLUSION: In our cohort, the diagnosis of MI at 2 years did not always predict a diagnosis of MI at 10 years. Specific risk factors are predictive of MI and can estimate an individual infant's risk at NICU discharge of MI at age 10 years.

Association of Growth During Infancy with Neurodevelopment and Obesity in Children Born Very Preterm: The Environmental Influences on Child Health Outcomes Cohort.

OBJECTIVE: To evaluate associations between change in weight z score after neonatal intensive care unit (NICU) discharge and neurodevelopmental outcomes and obesity at 12-48 months of age among individuals born very preterm. STUDY DESIGN: This secondary analysis used data from infants born very preterm participating in the Environmental influences on Child Health Outcomes cohort (n = 1400). Growth during infancy was calculated as change in weight z score between NICU discharge and follow-up at a mean of 27 months of age. Very low weight gain was defined as a change in weight z score <-1.67; very high weight gain was a change in weight z score >1.67. Neurodevelopmental outcomes included the Bayley Scales of Infant and Toddler Development, Child Behavior Checklist 1.5-5 years, and Modified Checklist for Autism in Toddlers. Multivariable linear regression was used to estimate associations between increase in weight z score and neurodevelopmental outcomes. RESULTS: Very low weight gain between NICU discharge and follow-up (experienced by 6.4% of participants) was associated with lower scores on cognitive (adjusted mean difference: -4.26; 95% CI: -8.55, -0.04) and language (adjusted mean difference: -4.80; 95% CI: -9.70, -0.11) assessments. Very high weight gain (experienced by 13.6% of participants) was associated with an increased obesity risk (adjusted relative risk: 6.20; 95% CI: 3.99, 9.66) but not with neurodevelopmental outcomes. CONCLUSIONS: Very high weight gain in the first 12-48 months after NICU discharge was associated with a higher risk of obesity at follow-up; very low weight gain was associated with lower scores on cognitive and language assessments.

Clinical Correlates of Cholestasis in Preterm Infants with Surgical Necrotizing Enterocolitis.

Background: We sought to investigate the clinical determinants and outcomes of cholestasis in preterm infants with surgical necrotizing enterocolitis (sNEC). Methods: Retrospective comparison of clinical information in preterm infants who developed cholestasis vs those who did not. Results: Sixty-two (62/91, 68.1%) infants with NEC developed cholestasis at any time following the onset of illness. Cholestasis was seen more frequently in those who had received ionotropic support at 24 hours following sNEC diagnosis (87.1% vs 58.6%; p = 0.002), had higher mean C-reactive protein levels 2 weeks after NEC diagnosis (p = 0.009), had blood culture-positive sepsis [25 (40.3%) vs 4 (13.8%); p = 0.011], received parenteral nutrition (PN) for longer durations (108.4 ± 56.63 days vs 97.56 ± 56.05 days; p = 0.007), had higher weight-for-length z scores at 36 weeks' postmenstrual age [-1.0 (-1.73, -0.12) vs -1.32 (-1.76, -0.76); p = 0.025], had a longer length of hospital stay (153.7 ± 77.57 days vs 112.51 ± 85.22 days; p = 0.024), had intestinal failure more often (61% vs 25.0%, p = 0.003), had more surgical complications (50% vs 27.6%; p = 0.044), and had >1 complication (21% vs 3.4%; p = 0.031). Using linear regression, the number of days after surgery when feeds could be started [OR 15.4; confidence interval (CI) 3.71, 27.13; p = 0.009] and the postoperative ileus duration (OR 11.9, CI 1.1, 22.8; p = 0.03) were independently associated with direct bilirubin between 2 and 5 mg/dL (mild-moderate cholestasis) at 2 months of age. The duration of PN was independently associated with direct bilirubin >5 mg/dL (severe cholestasis) at 2 months of age in these patients. Conclusion: Cholestasis was seen in 68% of infants following surgical NEC. The most likely contributive factors are intestinal failure and subsequent PN dependence for longer periods. Our data suggest that identification and prevention of risk factors such as sepsis and surgical complications and early feeds following NEC surgery may improve outcomes.

Comparing autism phenotypes in children born extremely preterm and born at term.

Children born preterm are at increased risk for autism spectrum disorder (ASD). There is limited knowledge about whether ASD phenotypes in children born preterm differ from children born at term. The objective of this study was to compare ASD core symptoms and associated characteristics among extremely preterm (EP) and term-born children with ASD. EP participants (n = 59) from the Extremely Low Gestational Age Newborn Study who met diagnostic criteria for ASD at approximately 10 years of age were matched with term-born participants from the Simons Simplex Collection on age, sex, spoken language level, and nonverbal IQ. Core ASD symptomatology was evaluated with the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). Developmental milestones, anthropometrics, seizure disorder, and psychiatric symptoms were also investigated. The EP group had lower parent-reported symptom scores on ADI-R verbal communication, specifically stereotyped language, and restricted, repetitive behaviors. There were no between-group differences on ADI-R nonverbal communication and ADI-R reciprocal social interaction or with direct observation on the ADOS-2. The EP group was more likely to have delayed speech milestones and lower physical growth parameters. Results from female-only analyses were similar to those from whole-group analyses. In sum, behavioral presentation was similar between EP and IQ- and sex-matched term-born children assessed at age 10 years, with the exception of less severe retrospectively reported stereotyped behaviors, lower physical growth parameters, and increased delays in language milestones among EP-born children with ASD.

Child and family factors associated with positive outcomes among youth born extremely preterm.

BACKGROUND: To analyze the relationship of child behavioral and communication disorders, and adverse family events, to later-in-life child health and cognitive function among youth born extremely preterm. METHODS: The study participants were 694 children enrolled in the Extremely Low Gestational Age Newborn Study. At ages 2 and 10, we assessed internalizing and externalizing behaviors, and at age 10, we assessed adverse life events within the family. Associations were evaluated between these child and family factors and positive child health at age 10 years, and global health and cognitive function at age 15 years. RESULTS: Lower T-scores for internalizing or externalizing behaviors at age 2 were associated with more positive health at age 10. The absence of internalizing behaviors at age 10 was associated with better global child health and better cognitive function at age 15. The absence of communication deficits at age 10 was associated with better cognitive function at age 15. The absence of parent job loss was associated with better global child health at age 15. CONCLUSION: Among individuals born extremely preterm, child health and cognitive outcomes might be improved by timely interventions to address child behavioral symptoms and the impact of adverse life events in the family. IMPACT: The absence of child behavioral and communication disorders, and adverse family events, were associated with more positive health, higher global health, and better cognitive function among youth born extremely preterm. Interventions to address behavioral disorders in early childhood, and to reduce the impact of adverse life events on the family, might promote improved health and developmental outcomes for adolescents born extremely preterm.

Growth During Infancy After Extremely Preterm Birth: Associations with Later Neurodevelopmental and Health Outcomes.

OBJECTIVE: To evaluate associations between changes in weight, length, and weight/length ratio during infancy and outcomes later in life among individuals born extremely preterm. STUDY DESIGN: Among participants in the Extremely Low Gestational Age Newborn (ELGAN) study, we measured weight and length at discharge from the neonatal intensive care unit (NICU) and at age 2 years and evaluated neurocognitive, psychiatric, and health outcomes at age 10 years and 15 years. Using multivariable logistic regression, we estimated associations between gains in weight, length, and weight/length ratio z-scores between discharge and 2 years and outcomes at 10 and 15 years. High gain was defined as the top quintile of change; low gain, as the bottom quintile of change. RESULTS: High gains in weight and weight/length were associated with greater odds of obesity at 10 years, but not at 15 years. These associations were found only for females. High gain in length z-score was associated with lower odds of obesity at 15 years. The only association found between high gains in growth measures and more favorable neurocognitive or psychiatric outcomes was between high gain in weight/length and lower odds of cognitive impairment at age 10 years. CONCLUSIONS: During the 2 years after NICU discharge, females born extremely preterm with high gains in weight/length or weight have greater odds of obesity at 10 years, but not at 15 years. Infants with high growth gains in the 2 years after NICU discharge have neurocognitive and psychiatric outcomes in middle childhood and adolescence similar to those of infants with lower gains in weight and weight/length.

Clinical Correlates of Cerebellar Injury in Preterm Infants with Surgical Necrotizing Enterocolitis.

Objective: Determine the risk factors of cerebellar injury in infants with surgical necrotizing enterocolitis (NEC). Methods: Retrospective study compared clinical/pathological information between surgical NEC infants with and those without cerebellar injury. Results: Infants with cerebellar injury (21/65, 32.3%) had significantly more hemorrhagic and the reparative lesions on the intestinal histopathology, had patent ductus arteriosus (PDA) more often, received red cell transfusion frequently, had blood culture positive sepsis and grew gram positive organisms more often and had cholestasis frequently following NEC than those without cerebellar injury. On multilogistic regression, the positive blood culture sepsis (OR 3.9, CI 1.1-13.7, p = 0.03), PDA (OR 4.5, CI 1.0-19.9, p = 0.04) and severe hemorrhage (grade 3-4)(OR 16.9, CI 2.1-135.5, p = 0.007) were independently associated with higher risk of cerebellar injury. Conclusion: The cerebellar injury was most likely associated with positive blood culture sepsis following NEC, PDA, and severe hemorrhage lesions (grade 3-4) in infants with surgical NEC.

Analysis of Neurodevelopment in Children Born Extremely Preterm Treated With Acid Suppressants Before Age 2 Years.

Importance: Children born preterm are at increased risk of adverse neurodevelopmental outcomes and may be particularly vulnerable to the effects of gastric acid suppression during infancy. Objective: To assess whether early acid suppressant use in infants born extremely preterm is associated with poorer neurodevelopmental outcomes. Design, Setting, and Participants: The Extremely Low Gestational Age Newborn study was a multicenter, longitudinal cohort study of infants born before 28 weeks' gestational age between March 22, 2002, and August 31, 2004. The current analyses were performed from September 12, 2020, through September 22, 2022. Of the 1506 infants enrolled, 284 died before discharge and 22 died before 24 months of age. An additional 2 died before age 10 years, leaving 1198 (79.5%) eligible for a visit. Of these, 889 (74%) participated in the visit at age 10. At age 10 years, the association of early-life acid suppressant use with neurocognitive, neurodevelopmental, and psychiatric symptomatology was assessed. Exposures: Acid suppressant use before 24 months of age was determined from medical records and from questionnaires administered to mothers. Main Outcomes and Measures: Neurodevelopmental assessments at age 10 years included the School-Age Differential Ability Scales-II, the Developmental Neuropsychological Assessment-II, the Autism Diagnostic Observation Schedule-2, the Social Responsiveness Scale-2, and the Child Symptom Inventory-4 for attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety. Results: Of the 889 participants assessed at age 10 years (mean [SD] age, 9.97 [0.67] years; mean [SD] gestational age at birth, 26.1 [1.3] weeks; 455 [51.2%] male), 368 (41.4%) had received acid suppressants by 24 months of age. Associations were observed between acid suppressant use and decreased full-scale IQ z score (adjusted ß, -0.29; 95% CI, -0.45 to -0.12), verbal IQ z score (adjusted ß, -0.34; 95% CI, -0.52 to -0.15), nonverbal IQ z score (adjusted ß, -0.22; 95% CI to -0.39 to -0.05), working memory z score (adjusted ß, -0.26; 95% CI to -0.45, -0.08), autism spectrum disorder (adjusted relative risk, 1.84; 95% CI, 1.15-2.95), and epilepsy (adjusted relative risk, 2.07; 95% CI, 1.31 to 3.35). Results were robust to multiple sensitivity analyses. Use of acid suppressants was not associated with inhibitory control, ADHD, anxiety, or depression. Conclusions and Relevance: The results of this cohort study suggest that early-life use of acid suppressants in extremely preterm infants may be associated with poorer neurodevelopmental outcomes and add to evidence indicating caution in use of these agents.

Long-Term Outcome of Necrotizing Enterocolitis and Spontaneous Intestinal Perforation.

OBJECTIVES: Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are complications in preterm infants associated with high morbidity, mortality, impaired growth, and neurodevelopmental (ND) outcomes. Few studies have reported growth or ND outcomes of infants born extremely preterm with NEC/SIP beyond early childhood. Here, we compared anthropometric and ND outcomes, at 10 and 15 years, for children with medical NEC, surgical NEC, SIP, and neither NEC nor SIP. METHODS: Participants from the prospective longitudinal extremely low gestational age newborns study were evaluated at ages 10 and 15 years for anthropometrics, neurocognition, attention-deficit/hyperactivity disorder, epilepsy, and gross motor function. RESULTS: At age 10 years, 889 children were followed-up (medical NEC = 138, surgical NEC = 33, SIP = 29, no NEC/SIP = 689), and 694 children were followed up-at 15 years. Children with medical NEC had similar weight, BMI, height, and head circumference compared with controls at both 10 and 15 years. At 15 years, children with surgical NEC had lower weight z-score (adjusted ß: -0.75, 95% confidence interval [CI]: -1.25 to -0.25), lower BMI z-score (adjusted ß: -0.55, 95% CI: -1.09 to -0.01), and lower height z-score (adjusted ß: -0.65, 95% CI: -1.16 to -0.14). Children with SIP had lower weight and height z-scores at age 10 years when adjusted for sample attrition, but these differences were not significant when adjusted for confounders. We observed no differences in long-term ND outcomes. CONCLUSIONS: Surgical NEC- and SIP-associated growth impairment may persist through late childhood. ND outcomes among school-aged children born extremely preterm with any NEC or SIP are no different from children without NEC/SIP.

The Association of Selective Serotonin Reuptake Inhibitors With Delirium in Critically Ill Adults: A Secondary Analysis of the Bringing to Light the Risk Factors and Incidence of Neuropsychologic Dysfunction in ICU Survivors ICU Study.

OBJECTIVES: To assess the association between selective serotonin reuptake inhibitors (SSRI) and delirium in the subsequent 24 hours after drug administration in critically ill adults. DESIGN: Retrospective cohort study utilizing the Bringing to Light the Risk Factors and Incidence of Neuropsychologic Dysfunction in ICU Survivors dataset. SETTING: Two large U.S. ICUs. PATIENTS: Critically ill adults admitted to a medical or surgery ICU between March 2007 and May 2010 with respiratory failure or shock. INTERVENTIONS: Our primary outcome was the occurrence rate of delirium or coma during each day in the ICU. Our exposure variable was SSRI administration on the prior day in the ICU. As a secondary question, we assessed the association of SSRI administration and delirium the same day of SSRI administration in the ICU. MEASUREMENTS AND MAIN RESULTS: We analyzed 821 patients. The median age was 61.2 years old (interquartile range, 50.9-70.7), and 401 (48.8%) were female. A total of 233 patients (28.4%) received prescribed SSRIs at least once during their ICU admission. Delirium was present in 606 (74%) of the patients at some point during hospitalization in the ICU. Coma was present in 532 (64.8%) of the patients at some point during hospitalization in the ICU. After adjusting for multiple potential confounding factors, we found that SSRI administration in the ICU was associated with lower odds of delirium/coma (odds ratio [OR], 0.75; 95% CI, 0.57-1.00) the next day. An SSRI administered on the same day reduced the odds of delirium/coma as well (OR, 0.66; 95% CI, 0.50-0.87). CONCLUSIONS: SSRI administration is associated with decreased risk of delirium/coma in 24 hours and on the same day of administration in critically ill patients in a medical or surgical ICU.

Use of Capstone Experiences in Pharmacy Education to Synthesize and Apply Students' Knowledge and Skills.

Objective. To investigate capstone experiences in pharmacy education with the broad aim of better understanding how they are designed, used, and sustained.Methods. Capstones were defined as culminating experiences that required Doctor of Pharmacy (PharmD) students to apply their knowledge and skills and demonstrate their ability to integrate, extend, and apply multiple components of their academic experience. This study was conducted in two phases. Phase one was a mapping review, which provided insight into the design of pharmacy capstone experiences, including the purpose they served and their associated outcomes. Phase two consisted of conducting follow-up interviews to explore the current status and sustainability of those capstone experiences. Qualitative methods with multiple coders were used to analyze the data.Results. Five distinct purposes for capstone experiences were identified: preparation for advanced pharmacy practice experiences (APPEs), pharmacotherapy education, research, reflection on pharmacy school experiences, and immersive learning through an external organization. Wide variability was found in the design, purpose, and outcomes of capstone experiences. Study authors described the capstone experiences at their institution in terms of the viability, feasibility, desirability, and challenges faced.Conclusion. Capstones can play an important role in assessing student progress and practice readiness in pharmacy education. The findings of this study can be used to help pharmacy schools design capstone experiences that are effective and sustainable.

In vitro Expansion of Natural Regulatory T Lymphocytes Useful for Cell Therapy in Allotransplantation

Immunotherapy with regulatory T lymphocytes is considered to be an attractive new therapeutic modality to prevent allograft rejection. The success of this new therapy is critically dependent on the preparation of highly effective and enough number of regulatory T cells. Here, we tried to establish a proper strategy for the ex vivo expansion of regulatory T cells and evaluated their characteristics. CD4+CD25h+CD62L+ T cells were isolated from the recipient mice and weekly stimulated with various stimuli in the presence of IL-2. The most efficient protocol for the expansion of regulatory T cells maintaining Foxp3 expression and regulatory activity was the three cycles stimulation with donor bone marrow-derived dendritic cells (BM-DCs) which yielded around 400 fold expansion of regulatory T cells. The in vitro-expanded regulatory T cells expressing lymph node homing receptors on their cell surface, were composed of polyclonal population, and did not acquire the ability to produce effector cytokines. Importantly, these expanded regulatory T cells induced a modest prolongation of skin allograft survival when combined with transient T cell depletion in recipient mice. These data indicate that our protocol could be used to obtain an effective population of natural regulatory T cells available for the regulatory T cell therapy to prevent allograft rejection.