Influence of Eat, Sleep, and Console on Infants Pharmacologically Treated for Opioid Withdrawal: A Post Hoc Subgroup Analysis of the ESC-NOW Randomized Clinical Trial.

Importance: The function-based eat, sleep, console (ESC) care approach substantially reduces the proportion of infants who receive pharmacologic treatment for neonatal opioid withdrawal syndrome (NOWS). This reduction has led to concerns for increased postnatal opioid exposure in infants who receive pharmacologic treatment. However, the effect of the ESC care approach on hospital outcomes for infants pharmacologically treated for NOWS is currently unknown. Objective: To evaluate differences in opioid exposure and total length of hospital stay (LOS) for pharmacologically treated infants managed with the ESC care approach vs usual care with the Finnegan tool. Design, Setting, and Participants: This post hoc subgroup analysis involved infants pharmacologically treated in ESC-NOW, a stepped-wedge cluster randomized clinical trial conducted at 26 US hospitals. Hospitals maintained pretrial practices for pharmacologic treatment, including opioid type, scheduled opioid dosing, and use of adjuvant medications. Infants were born at 36 weeks' gestation or later, had evidence of antenatal opioid exposure, and received opioid treatment for NOWS between September 2020 and March 2022. Data were analyzed from November 2022 to January 2024. Exposure: Opioid treatment for NOWS and the ESC care approach. Main Outcomes and Measures: For each outcome (total opioid exposure, peak opioid dose, time from birth to initiation of first opioid dose, length of opioid treatment, and LOS), we used generalized linear mixed models to adjust for the stepped-wedge design and maternal and infant characteristics. Results: In the ESC-NOW trial, 463 of 1305 infants were pharmacologically treated (143/603 [23.7%] in the ESC care approach group and 320/702 [45.6%] in the usual care group). Mean total opioid exposure was lower in the ESC care approach group with an absolute difference of 4.1 morphine milligram equivalents per kilogram (MME/kg) (95% CI, 1.3-7.0) when compared with usual care (4.8 MME/kg vs 8.9 MME/kg, respectively; P = .001). Mean time from birth to initiation of pharmacologic treatment was 22.4 hours (95% CI, 7.1-37.7) longer with the ESC care approach vs usual care (75.4 vs 53.0 hours, respectively; P = .002). No significant difference in mean peak opioid dose was observed between groups (ESC care approach, 0.147 MME/kg, vs usual care, 0.126 MME/kg). The mean length of treatment was 6.3 days shorter (95% CI, 3.0-9.6) in the ESC care approach group vs usual care group (11.8 vs 18.1 days, respectively; P < .001), and mean LOS was 6.2 days shorter (95% CI, 3.0-9.4) with the ESC care approach than with usual care (16.7 vs 22.9 days, respectively; P < .001). Conclusion and Relevance: When compared with usual care, the ESC care approach was associated with less opioid exposure and shorter LOS for infants pharmacologically treated for NOWS. The ESC care approach was not associated with a higher peak opioid dose, although pharmacologic treatment was typically initiated later. Trial Registration: ClinicalTrials.gov Identifier: NCT04057820.

Eat, Sleep, Console Approach or Usual Care for Neonatal Opioid Withdrawal.

BACKGROUND: Although clinicians have traditionally used the Finnegan Neonatal Abstinence Scoring Tool to assess the severity of neonatal opioid withdrawal, a newer function-based approach - the Eat, Sleep, Console care approach - is increasing in use. Whether the new approach can safely reduce the time until infants are medically ready for discharge when it is applied broadly across diverse sites is unknown. METHODS: In this cluster-randomized, controlled trial at 26 U.S. hospitals, we enrolled infants with neonatal opioid withdrawal syndrome who had been born at 36 weeks' gestation or more. At a randomly assigned time, hospitals transitioned from usual care that used the Finnegan tool to the Eat, Sleep, Console approach. During a 3-month transition period, staff members at each hospital were trained to use the new approach. The primary outcome was the time from birth until medical readiness for discharge as defined by the trial. Composite safety outcomes that were assessed during the first 3 months of postnatal age included in-hospital safety, unscheduled health care visits, and nonaccidental trauma or death. RESULTS: A total of 1305 infants were enrolled. In an intention-to-treat analysis that included 837 infants who met the trial definition for medical readiness for discharge, the number of days from birth until readiness for hospital discharge was 8.2 in the Eat, Sleep, Console group and 14.9 in the usual-care group (adjusted mean difference, 6.7 days; 95% confidence interval [CI], 4.7 to 8.8), for a rate ratio of 0.55 (95% CI, 0.46 to 0.65; P<0.001). The incidence of adverse outcomes was similar in the two groups. CONCLUSIONS: As compared with usual care, use of the Eat, Sleep, Console care approach significantly decreased the number of days until infants with neonatal opioid withdrawal syndrome were medically ready for discharge, without increasing specified adverse outcomes. (Funded by the Helping End Addiction Long-term (HEAL) Initiative of the National Institutes of Health; ESC-NOW ClinicalTrials.gov number, NCT04057820.).

Racial Disparities in Breastmilk Receipt and Extremely Low Gestational Age Neonatal Morbidities in an Asian Pacific Islander Population.

BACKGROUND: Racial disparities in breastmilk provision and neonatal morbidities of extreme prematurity have been documented in previous studies but are not as well-documented in Asian and Pacific Islander (API) infants. The objectives of this study were to evaluate a predominantly API neonatal intensive care unit (NICU) population for racial disparities in (1) the receipt of breastmilk within 24 h of admission and at discharge and (2) neonatal morbidities among infants ≤ 28 weeks gestational age. METHODS: A retrospective chart review of 2528 infants from 2018 to 2020 born at the largest level 3 NICU in Honolulu, Hawai'i, was conducted. Multivariable logistic regression analysis was performed on NICU outcomes to calculate adjusted odds ratios (aOR) and confidence intervals (CI). RESULTS: Native Hawaiian (NH) (aOR 0.73 [0.54, 0.98]), Pacific Islander (PI) (aOR 0.57 [0.41, 0.79]), and Filipino infants (aOR 0.66 [0.49, 0.89]) were less likely to receive breastmilk at discharge compared to Asian infants. PI infants were also more likely to experience necrotizing enterocolitis (aOR 7.89 [1.07, 58.10]) and intraventricular hemorrhage (aOR 3.86 [1.15, 13.02]) compared to Asian infants. CONCLUSION: In a predominantly API population, disparities in breastmilk receipt and neonatal morbidities exist among NH, PI, and Filipino infants in the NICU. Our findings call for better understanding of the underlying inequities to guide directed efforts, including standardization of care through staff trainings on implicit biases and trauma-informed care, as well as provision of culturally sensitive education and lactation support for these patients.

Infant Body Composition in an Asian Pacific Islander Population.

BACKGROUND: Normative infant body composition data using air displacement plethysmography (ADP) are from primarily Caucasian populations. Racial differences may exist. OBJECTIVES: To describe body composition in Asian and Pacific Islander infants and compare them to previously published data on Caucasian infants. DESIGN: Body composition was measured using ADP with the PEA POD® Infant Body Composition System in 249 healthy full-term newborns in a predominately Asian and Pacific Islander population in Hawaii within the first 3 days of life and compared to published data on Caucasian infants with multiple t-tests adjusted for false discovery rate. RESULTS: There were no differences in percent body fat between Asian, Pacific Islander, or mixed race Asian Pacific Islander infants. Both Asian and Pacific Islander infants had significantly higher percent body fat than Caucasians from Italy in Europe (13.2% and 11.8% vs 8.9%, p < 0.01 among males, 15.3% and 15.6% vs 8.7%, p < 0.01 among females) but not when compared to Caucasians from New York. CONCLUSIONS: Racial and geographical differences in body composition exist at birth between Asian and Pacific Islanders and other Caucasian cohorts. Previously published ADP nomograms must be interpreted with caution. Future studies are needed to investigate the impact of environmental, perinatal, and genetic factors on infant body composition and its relationship to future cardiometabolic morbidity. Efforts to address racial disparities in cardiometabolic disease measures must also address pre-conceptual maternal health, which may have long-term implications on future body composition in offspring.

Advocating For a Culture of Support for Lactating Medical Residents in Hawai'i.

Lactating medical residents face unique barriers due to intense clinical work schedules, limited support in the clinic and hospital workspaces, and competing pressures between career development and childcare. The objective of this project was to explore the perceived culture of breastfeeding support among medical trainees and design an action plan to improve support for lactating residents in Hawai'i. Resident and faculty representatives from the Hawai'i Residency Programs and the University of Hawai'i John A Burns School of Medicine participated in an 8 month national learning collaborative to review the existing resident lactation policy and resident perception of lactation support. In a pre-survey, the majority of residents (88%) agreed that 20-30 minutes every 2-3 hours should be allowed to express milk but only 18% felt comfortable asking for a change in schedule to accommodate time to pump. An action plan was created with the following objectives: (1) revamping the existing policy to address protected pumping times, lactation spaces, and responsibilities of administration, faculty, and residents; (2) improving lactation space through uniform provision of educational material on available facilities and efficiency tips for new parents, and (3) improving awareness of the unique challenges lactating residents face and empowering faculty and trainees to advocate for lactating residents through department and educational presentations. Medical residents in Hawai'i recognize the importance of breastfeeding but perceive a lack of support in the workplace. A comprehensive action plan to revamp the resident lactation policy and improve faculty and resident education may foster an increased culture of lactation support and healthy development of the physician workforce.

Addressing Native Hawaiian and Pacific Islander Data Deficiencies Through a Community-based Collaborative Response to the COVID-19 Pandemic.

Early evidence of disproportionate COVID-19 infection and death rates in Native Hawaiian and Pacific Islander communities in the continental US raised concerns for similar disparities in Hawai'i, where these communities make up 25% of the state's population. Representatives from more than 40 different government, academic, institutional and community-based organizations partnered to form the Hawai'i Native Hawaiian and Pacific Islander COVID-19 Response, Recovery, and Resilience Team. The team consists of 5 committees including the Data & Research Committee. This committee is tasked with examining issues regarding the acquisition, quality, public reporting, and utilization of race/ethnicity-related health data used to inform priorities and guide resource allocation. Problems addressed by this committee include: inconsistency across agencies in the use of race identifiers, defaulting to the Office of Management and Budget standards which aggregated Native Hawaiian and Pacific Islanders, and methods of data collection and reporting by the Department of Health. Outcomes include: 2 forms with race categories that reflect the population of Hawai'i; the reporting of disaggregated data by the Department of Health; and conversations with testing sites, laboratories, and health institutions urging a standardized form for race/ethnicity data collection. The collection and reporting of disaggregated race/ethnicity data is critical to guiding organizations in addressing underlying inequities in chronic disease and social determinants of health that can exacerbate the adverse effects of COVID-19. The Data and Research Committee's network offers a community-based model for collaborative work that honors culture and ensures Native Hawaiian, Pacific Islander, and other minority populations are recognized and counted.

A Comparison of Length of Hospitalization and Costs in Obese and Non-Obese Pediatric Patients at a Single Hospital in Honolulu.

The association of obesity with increased hospital costs and length of stay among hospitalized pediatric patients identified by ICD-9 coding may be underestimated due to underreporting of appropriate ICD-9 coding for obesity status. The objective of this study was to compare these lengths of stay and hospital costs. A retrospective chart review was conducted of pediatric patients admitted from May 2009 to January 2012 at Kapi'olani Medical Center, Honolulu, Hawai'i, with the 20 most common primary admission diagnosis ICD-9 codes. Length of hospital stay and total hospital costs were compared for obese, overweight, and normal-weight patients based on body mass index (BMI), controlling for age, sex, ethnicity, insurance type, diagnosis, and calendar year using logistic regression. Analysis of 730 patients showed 1% of overweight patients and 35% of obese patients were correctly coded with the corresponding ICD-9 code for weight status. Obese patients had 15% longer hospital stays and 19% higher hospital costs than normal weight patients, when controlled for age, sex, ethnicity, insurance type, calendar year, and primary diagnosis. Subgroup analyses of the top 3 most common primary admission diagnoses showed obese patients with asthma had significantly higher hospital costs than normal weight patients. Obesity is an independent risk factor for increasing hospital resource utilization in hospitalized pediatric patients. Documentation of ICD-9 codes for overweight and obesity in this cohort drastically underrepresented the true prevalence of obesity and overweight status in this sample of hospitalized children. Further research is needed to better understand the complex role of obesity in pediatric inpatients, particularly among those with asthma.

Distinct transcriptomic profiles of early-onset atopic dermatitis in blood and skin of pediatric patients.

BACKGROUND: Atopic dermatitis (AD) predominantly affects young children, but our understanding of AD pathogenesis is based on skin and blood samples from long-standing adult AD. Genomic biopsy profiling from early pediatric AD showed significant Th2 and Th17/Th22-skewing, without the characteristic adult Th1 up-regulation. Because obtaining pediatric biopsies is difficult, blood gene expression profiling may provide a surrogate for the pediatric skin signature. OBJECTIVE: To define the blood profile and associated biomarkers of early moderate-to-severe pediatric AD. METHODS: We compared microarrays and reverse transcription polymerase chain reaction (RT-PCR) of blood cells from 28 AD children (<5 years and within 6 months of disease onset) to healthy control blood cells. Differentially expressed genes (DEGs) in blood (fold change [FCH] > 1.2 and false discovery rate [FDR] < 0.05) were then compared with skin DEGs. RESULTS: Eosinophil and Th2 markers (IL5RA, IL1RL1/ST2, HRH4, CCR3, SIGLEC8, PRSS33, CLC from gene arrays; IL13/IL4/CCL22 from RT-PCR) were up-regulated in early pediatric AD blood, whereas IFNG/Th1 was decreased. Th1 markers were negatively correlated with clinical severity (EASI, pruritus, transepidermal water loss [TEWL]), whereas Th2/Th17-induced interleukin (IL)-19 was positively correlated with SCORAD. Although a few RT-PCR-defined immune markers (IL-13/CCL22) were increased in blood, as previously also reported for skin, minimal overlap based on gene array DEGs was seen. CONCLUSION: The whole blood signature of early moderate-to-severe pediatric AD blood cells show predominantly a Th2/eosinophil profile; however, markers largely differ from the skin profile. Given their complementarity, pooling of biomarkers from blood and skin may improve profiling and predictions, providing insight regarding disease course, allergic comorbidity development, and response to systemic medications.

The Major Orphan Forms of Ichthyosis Are Characterized by Systemic T-Cell Activation and Th-17/Tc-17/Th-22/Tc-22 Polarization in Blood.

The ichthyoses are rare skin disorders with immune and barrier aberrations. Identifying blood phenotypes may advance targeted therapeutics. We aimed to compare frequencies of skin homing/cutaneous lymphocyte antigen (+) versus systemic/cutaneous lymphocyte antigen (-) "polar" CD4+/CD8+ and activated T-cell subsets in ichthyosis versus atopic dermatitis, psoriasis, and control blood, with appropriate clinical correlations. Flow cytometry was used to measure IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4+/CD8+ T cells, with inducible co-stimulator molecule and HLA-DR defining mid- and long-term T-cell activation, respectively. We compared peripheral blood from 47 patients with ichthyosis (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic ichthyosis, and Netherton syndrome) with 43 patients with atopic dermatitis and 24 patients with psoriasis and 59 age-matched controls. Clinical measures included the ichthyosis severity score, with subsets for erythema and scaling, transepidermal water loss, and pruritus. All ichthyoses had excessive inducible co-stimulator molecule activation (P < 0.001), particularly epidermolytic ichthyosis. Significantly elevated IL-17- (P < 0.05) and IL-22-producing (P < 0.01) T cells characterized ichthyoses, mainly Netherton syndrome and congenital ichthyosiform erythroderma (P < 0.05). Increased T helper 2/cytotoxic T cell 2/T helper 9 (P < 0.05) and similar IFN-γ frequencies (P > 0.1) versus controls were also noted. IL-17/IL-22-producing cells clustered with clinical measures, whereas IFN-γ clustered with age. Our data show peripheral blood IL-17/IL-22 activation across the ichthyoses, correlating with clinical measures. Targeted therapies should dissect the relative contribution of polar cytokines to disease pathogenesis.

Amyloid ß concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis.

INTRODUCTION: Cerebrospinal fluid analysis and other measurements of amyloidosis, such as amyloid-binding positron emission tomography studies, are limited by cost and availability. There is a need for a more practical amyloid ß (Aß) biomarker for central nervous system amyloid deposition. METHODS: We adapted our previously reported stable isotope labeling kinetics protocol to analyze the turnover kinetics and concentrations of Aß38, Aß40, and Aß42 in human plasma. RESULTS: Aß isoforms have a half-life of approximately 3 hours in plasma. Aß38 demonstrated faster turnover kinetics compared with Aß40 and Aß42. Faster fractional turnover of Aß42 relative to Aß40 and lower Aß42 and Aß42/Aß40 concentrations in amyloid-positive participants were observed. DISCUSSION: Blood plasma Aß42 shows similar amyloid-associated alterations as we have previously reported in cerebrospinal fluid, suggesting a blood-brain transportation mechanism of Aß. The stability and sensitivity of plasma Aß measurements suggest this may be a useful screening test for central nervous system amyloidosis.

The perinatal presentation of cardiofaciocutaneous syndrome.

There is limited information available related to the perinatal course of cardiofaciocutaneous syndrome (CFC) compared to other syndromes within the Ras-MAP kinase pathway (rasopathies) such as Noonan and Costello syndrome. Retrospective chart review revealed four cases of CFC with molecular confirmation between 2005 and 2012 at Hawaii's largest obstetric and pediatric referral center. We report on details of the prenatal, neonatal, and infancy course and long-term follow-up beyond infancy in two patients. This report includes novel features including systemic hypertension, hyponatremia, and chronic respiratory insufficiency, not previously reported in CFC. We provide pathologic diagnosis of loose anagen hair in one patient. Some of these findings have been reported in the other rasopathies, documenting further clinical overlap among these conditions. Molecular testing can be useful to differentiate CFC from other rasopathies and in counseling families about potential complications and prognosis. We recommend a full phenotypic evaluation including echocardiogram, renal ultrasound, brain imaging, and ophthalmology examination. We additionally recommend close follow-up of blood pressure, pulmonary function, and monitoring for electrolyte disturbance and extra-vascular fluid shifts.

Diagnosis of intussusception using bedside ultrasound by a pediatric resident in the emergency department.

The use of bedside ultrasound in the emergency department has been gaining favor among emergency medicine physicians and can be invaluable in the prompt diagnosis and treatment of acutely ill patients, especially when radiology evaluation is unavailable or delayed. Although pediatric ultrasound examinations are taught in some pediatric residency programs, they are not part of the required pediatric residency curriculum in the United States. This is the first case report of a pediatric resident diagnosing intussusception by bedside ultrasound in a 4-year-old boy under the guidance of a pediatric emergency attending with ultrasound training. This report illustrates the ease of using bedside ultrasound even among early learners and highlights its potential importance in medical education for fellows and residents.

Perspectives of Chuukese patients and their health care providers on the use of different sources of interpreters.

BACKGROUND: Immigrants from Chuuk, a Pacific Island nation in Micronesia, are a growing population of limited-English speakers in Hawai'i. The purpose of this study was to examine the perspectives of Chuukese patients and their physicians in Honolulu, Hawai'i on interpreter services. METHODS: An anonymous multiple choice survey was distributed to potential patients through a Chuukese community group and to physicians through the Hawai'i Residency Programs to examine the following sources of interpreters: Family member or friend, telephone interpreter, or professional in-person interpreter. Statistical significance of cross-tabulated responses was analyzed using Fisher's exact test. RESULTS: 114 surveys from health care providers and 95 surveys from Chuukese community members were analyzed after exclusion criteria. Using a family member or friend was the method most frequently used by physicians (78%) and Chuukese patients (71%). Telephone interpreters were used the least by physicians (6%) and Chuukese patients (2%) and both rated it poorly in terms of comfort and ease of use. Physicians rated professional in-person interpreters as the best method (67%) while Chuukese patients rated using a family member or friend as the best method (61%), especially among those who reported a lower English proficiency (P = .04) and who lived in Hawai'i for fewer years (P > .01). DISCUSSION: The preference of Chuukese patients for using a family member or friend as interpreter differs from national standards which promote the use of a professional interpreter. Given the preference of both physicians and Chuukese patients for in-person interpreters over telephone interpreters, there is a need for increased training and hiring of in-person interpreters.

PAC-1 activates procaspase-3 in vitro through relief of zinc-mediated inhibition.

The direct induction of apoptosis has emerged as a powerful anticancer strategy, and small molecules that either inhibit or activate certain proteins in the apoptotic pathway have great potential as novel chemotherapeutic agents. Central to apoptosis is the activation of the zymogen procaspase-3 to caspase-3. Caspase-3 is the key "executioner" caspase, catalyzing the hydrolysis of a multitude of protein substrates within the cell. Interestingly, procaspase-3 levels are often elevated in cancer cells, suggesting a compound that directly stimulates the activation of procaspase-3 to caspase-3 could selectively induce apoptosis in cancer cells. We recently reported the discovery of a compound, PAC-1, which enhances procaspase-3 activity in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Described herein is the mechanism by which PAC-1 activates procaspase-3 in vitro. We show that zinc inhibits the enzymatic activity of procaspase-3 and that PAC-1 strongly activates procaspase-3 in buffers that contain zinc. PAC-1 and zinc form a tight complex with one another, with a dissociation constant of approximately 42 nM. The combined data indicate that PAC-1 activates procaspase-3 in vitro by sequestering inhibitory zinc ions, thus allowing procaspase-3 to autoactivate itself to caspase-3. The small-molecule-mediated activation of procaspases has great therapeutic potential and thus this discovery of the in vitro mechanism of action of PAC-1 is critical to the development and optimization of other procaspase-activating compounds.