Dynamic Ultrastrong Coupling in a 2 nm Gap Plasmonic Cavity at the Sub-Picosecond Scale.

Localized surface plasmon resonances (LSPRs) can enhance the electromagnetic fields on metallic nanostructures upon light illumination, providing an approach for manipulating light-matter interactions at the sub-wavelength scale. However, currently, there is no thorough investigation of the physical mechanism in the dynamic formation of the strongly coupled LSPRs on sub-5 nm plasmonic cavities at the sub-picosecond scale. In this work, through femtosecond broadband transient absorption spectroscopy, we reveal the dynamic ultrastrong coupling processes in a nanoparticle-in-trench (NPiT) structure containing 2 nm gap cavities, and demonstrate a coherent motional coupling between vibrating AuNPs and the nanogaps. We achieve a maximum Rabi splitting energy of ∼660 meV in the sub-picosecond hot-electron relaxation time scale under the resonant excitation of the nanogap cavity's LSPR, reaching the ultrastrong coupling regime. This leads to a change of global vibration modes for the 2 nm gap cavity, potentially related to the dynamical Casimir effect with nanogap resonators.

Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits. Current treatment options for SSADHD remain supportive, but there are ongoing attempts to develop targeted genetic therapies. This study aimed to create consensus guidelines for the diagnosis and management of SSADHD. Thirty relevant statements were initially addressed by a systematic literature review, resulting in different evidence levels of strength according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. The highest level of evidence (level A), based on randomized controlled trials, was unavailable for any of the statements. Based on cohort studies, Level B evidence was available for 12 (40%) of the statements. Thereupon, through a process following the Delphi Method and directed by the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria, expert opinion was sought, and members of an SSADHD Consensus Group evaluated all the statements. The group consisted of neurologists, epileptologists, neuropsychologists, neurophysiologists, metabolic disease specialists, clinical and biochemical geneticists, and laboratory scientists affiliated with 19 institutions from 11 countries who have clinical experience with SSADHD patients and have studied the disorder. Representatives from parent groups were also included in the Consensus Group. An analysis of the survey's results yielded 25 (83%) strong and 5 (17%) weak agreement strengths. These first-of-their-kind consensus guidelines intend to consolidate and unify the optimal care that can be provided to individuals with SSADHD.

Readmission After Neonatal Intensive Care Unit Discharge: The Importance of Social Drivers of Health.

OBJECTIVE: To determine associations between sociodemographic and medical factors and odds of readmission after discharge from the neonatal intensive care unit for infants with very low birth weight (<1500g). STUDY DESIGN: Cohort study using linked data from the California Perinatal Quality Care Collaborative, California Vital Statistics, and the Child Opportunity Index (COI) 2.0. Infants with very low birth weight born from 2009 through 2018 in California were considered. Odds ratios of readmission within 30 days of discharge adjusting for infant medical factors, maternal sociodemographic factors, and birth hospital were calculated via multivariable logistic regression and fixed-effect logistic regression models. RESULTS: A total of 42 411 infants met inclusion criteria. Also, 8.5% of all infants were readmitted within 30 days of discharge. In addition to traditional medical risk factors, two sociodemographic factors were significantly associated with increased odds of readmission in adjusted models: payor other than private insurance for delivery [aOR = 1.25 (95% CI 1.14-1.36)] and maternal education of less than high school degree [aOR = 1.19 (95% CI 1.06-1.33)]. Neighborhood Child Opportunity Index was not associated with odds of readmission. CONCLUSIONS: Sociodemographic factors, including lack of private insurance and lower maternal educational attainment, are significantly and independently associated with increased odds of readmission after neonatal intensive care unit discharge, in addition to traditional medical risk factors. Socioeconomic deprivation and health literacy may contribute to risk of readmission. Targeted discharge interventions focused on addressing social drivers of health warrant exploration.

Racial and Ethnic Inequities in Therapeutic Hypothermia and Neonatal Hypoxic-Ischemic Encephalopathy: A Retrospective Cohort Study.

OBJECTIVE: To investigate racial inequities in the use of therapeutic hypothermia (TH) and outcomes in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: We queried an administrative birth cohort of mother-baby pairs in California from 2010 through 2019 using International Classification of Diseases codes to evaluate the association between race and ethnicity and the application of TH in infants with HIE. We identified 4779 infants with HIE. Log-linear regression was used to calculate risk ratios (RR) for TH, adjusting for hospital transfer, rural location, gestational age between 35 and 37 weeks, and HIE severity. Risk of adverse infant outcome was calculated by race and ethnicity and stratified by TH. RESULTS: From our identified cohort, 1338 (28.0%) neonates underwent TH. White infants were used as the reference sample, and 410 (28.4%) received TH. Black infants were significantly less likely to receive TH with 74 (20.0%) with an adjusted risk ratio (aRR) of 0.7 (95% CI 0.5-0.9). Black infants with any HIE who did not receive TH were more likely to have a hospital readmission (aRR 1.36, 95% CI 1.10-1.68) and a tracheostomy (aRR 3.07, 95% CI 1.19-7.97). Black infants with moderate/severe HIE who did not receive TH were more likely to have cerebral palsy (aRR 2.72, 95% CI 1.07-6.91). CONCLUSIONS: In this study cohort, Black infants with HIE were significantly less likely to receive TH. Black infants also had significantly increased risk of some adverse outcomes of HIE. Possible reasons for this inequity include systemic barriers to care and systemic bias.

Magnesium sulfate and risk of hypoxic-ischemic encephalopathy in a high-risk cohort.

BACKGROUND: Hypoxic-ischemic encephalopathy contributes to morbidity and mortality among neonates ≥36 weeks of gestation. Evidence of preventative antenatal treatment is limited. Magnesium sulfate has neuroprotective properties among preterm fetuses. Hypertensive disorders of pregnancy are a risk factor for hypoxic-ischemic encephalopathy, and magnesium sulfate is recommended for maternal seizure prophylaxis among patients with preeclampsia with severe features. OBJECTIVE: (1) Determine trends in the incidence of hypertensive disorders of pregnancy, antenatal magnesium sulfate, and hypoxic-ischemic encephalopathy; (2) evaluate the association between hypertensive disorders of pregnancy and hypoxic-ischemic encephalopathy; and (3) evaluate if, among patients with hypertensive disorders of pregnancy, the odds of hypoxic-ischemic encephalopathy is mitigated by receipt of antenatal magnesium sulfate. STUDY DESIGN: We analyzed a prospective cohort of live births ≥36 weeks of gestation between 2012 and 2018 within the California Perinatal Quality Care Collaborative registry, linked with the California Department of Health Care Access and Information files. We used Cochran-Armitage tests to assess trends in hypertensive disorders, encephalopathy diagnoses, and magnesium sulfate utilization and compared demographic factors between patients with or without hypertensive disorders of pregnancy or treatment with magnesium sulfate. Hierarchical logistic regression models were built to explore if hypertensive disorders of pregnancy were associated with any severity and moderate/severe hypoxic-ischemic encephalopathy. Separate hierarchical logistic regression models were built among those with hypertensive disorders of pregnancy to evaluate the association of magnesium sulfate with hypoxic-ischemic encephalopathy. RESULTS: Among 44,314 unique infants, the diagnosis of hypoxic-ischemic encephalopathy, maternal hypertensive disorders of pregnancy, and the use of magnesium sulfate increased over time. Compared with patients with hypertensive disorders of pregnancy alone, patients with hypertensive disorders treated with magnesium sulfate represented a high-risk population. They were more likely to be publicly insured, born between 36 and 38 weeks of gestation, be small for gestational age, have lower Apgar scores, require a higher level of resuscitation at delivery, have prolonged rupture of membranes, experience preterm labor and fetal distress, and undergo operative delivery (all P<.002). Hypertensive disorders of pregnancy were associated with hypoxic-ischemic encephalopathy (adjusted odds ratio, 1.26 [95% confidence interval, 1.13-1.40]; P<.001) and specifically moderate/severe hypoxic-ischemic encephalopathy (adjusted odds ratio, 1.26 [95% confidence interval, 1.11-1.42]; P<.001). Among patients with hypertensive disorders of pregnancy, treatment with magnesium sulfate was associated with 29% reduction in the odds of neonatal hypoxic-ischemic encephalopathy (adjusted odds ratio, 0.71 [95% confidence interval, 0.52-0.97]; P=.03) and a 37% reduction in the odds of moderate/severe neonatal hypoxic-ischemic encephalopathy (adjusted odds ratio, 0.63 [95% confidence interval, 0.42-0.94]; P=.03). CONCLUSION: Hypertensive disorders of pregnancy are associated with hypoxic-ischemic encephalopathy and, specifically, moderate/severe disease. Among people with hypertensive disorders, receipt of antenatal magnesium sulfate is associated with a significant reduction in the odds of hypoxic-ischemic encephalopathy and moderate/severe disease in a neonatal cohort admitted to neonatal intensive care unit at ≥36 weeks of gestation. The findings of this observational study cannot prove causality and are intended to generate hypotheses for future clinical trials on magnesium sulfate in term infants.

Glymphatic dysfunction coincides with lower GABA levels and sleep disturbances in succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ-aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction. This study aimed to determine whether indices of the hyperGABAergic state characteristic of SSADHD coincide with glymphatic dysfunction and sleep disturbances and to explicate the modulatory effect that GABA may have on the glymphatic system. The study included 42 individuals (21 with SSADHD; 21 healthy controls) who underwent brain MRIs and magnetic resonance spectroscopy (MRS) for assessment of glymphatic dysfunction and cortical GABA, plasma GABA measurements, and circadian clock gene expression. The SSADHD subjects responded to an additional Children's Sleep Habits Questionnaire (CSHQ). Compared with the control group, SSADHD subjects did not differ in sex and age but had a higher severity of enlarged perivascular spaces in the centrum semiovale (p < 0.001), basal ganglia (p = 0.01), and midbrain (p = 0.001), as well as a higher MRS-derived GABA/NAA peak (p < 0.001). Within the SSADHD group, the severity of glymphatic dysfunction was specific for a lower MRS-derived GABA/NAA (p = 0.04) and lower plasma GABA (p = 0.004). Additionally, the degree of their glymphatic dysfunction correlated with the CSHQ-estimated sleep disturbances scores (R = 5.18, p = 0.03). In the control group, EPVS burden did not correlate with age or cerebral and plasma GABA values. The modulatory effect that GABA may exert on the glymphatic system has therapeutic implications for sleep-related disorders and neurodegenerative conditions associated with glymphatic dysfunction.

Gene replacement therapies for inherited disorders of neurotransmission: Current progress in succinic semialdehyde dehydrogenase deficiency.

Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction. However, practical challenges for gene replacement therapy remain major hurdles for its translation from bench to bedside. We discuss key considerations for the development of gene replacement therapies for IDNT. As an example, we describe our ongoing work on gene replacement therapy for succinic semialdehyde dehydrogenase deficiency, a GABA catabolic disorder.

Burden of illness in patients with pulmonary hypertension due to interstitial lung disease: a real-world analysis.

BACKGROUND: Pulmonary hypertension due to interstitial lung disease (PH-ILD) is associated with high rates of respiratory failure and death. Healthcare resource utilization (HCRU) and cost data are needed to characterize PH-ILD disease burden. METHODS: A retrospective cohort analysis of the Truven Health MarketScan® Commercial Claims and Encounters Database and Medicare Supplemental Database between June 2015 to June 2019 was conducted. Patients with ILD were identified and indexed based on their first claim with a PH diagnosis. Patients were required to be 18 years of age on the index date and continuously enrolled for 12-months pre- and post-index. Patients were excluded for having a PH diagnosis prior to ILD diagnosis or the presence of other non-ILD, PH-associated conditions. Treatment patterns, HCRU, and healthcare costs were compared between the 12 months pre- versus 12 months post-index date. RESULTS: In total, 122 patients with PH-ILD were included (mean [SD] age, 63.7 [16.6] years; female, 64.8%). The same medication classes were most frequently used both pre- and post-index (corticosteroids: pre-index 43.4%, post-index 53.5%; calcium channel blockers: 25.4%, 36.9%; oxygen: 12.3%, 25.4%). All-cause hospitalizations increased 2-fold, with 29.5% of patients hospitalized pre-index vs. 59.0% post-index (P < 0.0001). Intensive care unit (ICU) utilization increased from 6.6 to 17.2% (P = 0.0433). Mean inpatient visits increased from 0.5 (SD, 0.9) to 1.1 (1.3) (P < 0.0001); length of stay (days) increased from 5.4 (5.9) to 7.5 (11.6) (P < 0.0001); bed days from 2.5 (6.6) to 8.0 (16.3) (P < 0.0001); ICU days from 3.8 (2.3) to 7.0 (13.2) (P = 0.0362); and outpatient visits from 24.5 (16.8) to 32.9 (21.8) (P < 0.0001). Mean (SD) total all-cause healthcare costs increased from $43,201 ($98,604) pre-index to $108,387 ($190,673) post-index (P < 0.0001); this was largely driven by hospitalizations (which increased from a mean [SD] of $13,133 [$28,752] to $63,218 [$75,639] [P < 0.0001]) and outpatient costs ($16,150 [$75,639] to $25,604 [$93,964] [P < 0.0001]). CONCLUSION: PH-ILD contributes to a high HCRU and cost burden. Timely identification, management, and treatment are needed to mitigate the clinical and economic consequences of PH-ILD development and progression.

Implementation of a multi-site neonatal simulation improvement program: a cost analysis.

BACKGROUND: To improve patient outcomes and provider team practice, the California Perinatal Quality Care Collaborative (CPQCC) created the Simulating Success quality improvement program to assist hospitals in implementing a neonatal resuscitation training curriculum. This study aimed to examine the costs associated with the design and implementation of the Simulating Success program. METHODS: From 2017-2020, a total of 14 sites participated in the Simulating Success program and 4 of them systematically collected resource utilization data. Using a micro-costing approach, we examined costs for the design and implementation of the program occurring at CPQCC and the 4 study sites. Data collection forms were used to track personnel time, equipment/supplies, space use, and travel (including transportation, food, and lodging). Cost analysis was conducted from the healthcare sector perspective. Costs incurred by CPQCC were allocated to participant sites and then combined with site-specific costs to estimate the mean cost per site, along with its 95% confidence interval (CI). Cost estimates were inflation-adjusted to 2022 U.S. dollars. RESULTS: Designing and implementing the Simulating Success program cost $228,148.36 at CPQCC, with personnel cost accounting for the largest share (92.2%), followed by program-related travel (6.1%), equipment/supplies (1.5%), and space use (0.2%). Allocating these costs across participant sites and accounting for site-specific resource utilizations resulted in a mean cost of $39,210.69 per participant site (95% CI: $34,094.52-$44,326.86). In sensitivity analysis varying several study assumptions (e.g., number of participant sites, exclusion of design costs, and useful life span of manikins), the mean cost per site changed from $35,645.22 to $39,935.73. At all four sites, monthly cost of other neonatal resuscitation training was lower during the program implementation period (mean = $1,112.52 per site) than pre-implementation period (mean = $2,504.01 per site). In the 3 months after the Simulating Success program ended, monthly cost of neonatal resuscitation training was also lower than the pre-implementation period at two of the four sites. CONCLUSIONS: Establishing a multi-site neonatal in situ simulation program requires investment of sufficient resources. However, such programs may have financial and non-financial benefits in the long run by offsetting the need for other neonatal resuscitation training and improving practice.

Identification of skeletal remains in Croatia and Bosnia and Herzegovina, including the homeland war - a 30-year review.

Over the past 30 years, forensic experts from Croatia and Bosnia and Herzegovina have embraced advanced technologies and innovations to enable great efficacy and proficiency in the identification of war victims. The wartime events in the countries of former Yugoslavia greatly influenced the application of the selected DNA analyses as routine tools for the identification of skeletal remains, especially those from mass graves. Initially, the work was challenging because of the magnitude of the events, technical aspects, and political aspects. Collaboration with reputable foreign forensic experts helped tremendously in the efforts to start applying DNA analysis routinely and with increasing success. In this article, we reviewed the most significant achievements related to the application of DNA analysis in identifying skeletal remains in situations where standard identification methods were insufficient.

Quality improvement efforts directed at optimal umbilical cord management in delivery room.

Delayed or deferred cord clamping (DCC) and umbilical cord milking (UCM) benefit all infants by optimizing fetal-neonatal transition and placental transfusion. Even though DCC is recommended by almost all maternal and neonatal organizations, it has not been universally implemented. There is considerable variation in umbilical cord management practices across institutions. In this article, we provide examples of successful quality improvement (QI) initiatives to implement optimal cord management in the delivery room. We discuss a number of key elements that should be considering among those undertaking QI efforts to implement DCC and UCM including, multidisciplinary team collaboration, development of theory for change, mapping of the current and ideal process and workflow for cord management, and creation of a unit-specific evidence-based protocol for cord management. We also examine important strategies for implementation and provide suggestions for developing a system for measurement and benchmarking.

Patients' subjective well-being: Determinants and its usage as a metric of healthcare service quality.

It is commonly suggested that patients' subjective well-being (SWB) can be affected by pre-treatment conditions and treatment experiences, and hence SWB can be used to measure and improve healthcare quality. With data collected in a hospital in the UK (N = 446), we investigated the determinants of patients' SWB and evaluated its use in healthcare research. Our findings showed strong relationships between pre-treatment conditions and patients' SWB: anxiety and depression negatively predicted SWB across all three domains, mobility positively predicted the life satisfaction and happiness domains, while the ability to self care and pain and discomfort also predicted SWB in some domains. In contrast, patients' satisfaction with the treatment only played minor roles in determining SWB, much less so the characteristics of their nurses. The general lack of associations between treatment experiences and patient's SWB highlighted the challenges of using SWB to measure healthcare quality and inform policy making.

Changes in the Treatment and Outcomes of Different Severities of Neonatal Hypoxic Ischemic Encephalopathy in California: A Retrospective Cohort Study.

Objective: Evaluate the changes in management and outcomes of Californian infants with hypoxic ischemic encephalopathy (HIE). Study Design: Infants with HIE were identified from a California administrative birth cohort using ICD codes and divided into two epochs, Epoch 1 (2010-2015) and Epoch 2 (2016-2019). Risk ratios (RR) for therapeutic hypothermia (TH) in each epoch and their outcomes were calculated using log-linear regression. Results: In this cohort, 4779 infants with HIE were identified. Incidence of HIE in California increased yearly from 0.5/1,000 California births to a peak of 1.5/1,000 births in 2018. The use of TH in infants with mild HIE increased in Epoch 2 compared to Epoch 1. There was no significant difference in outcomes between epochs for infants with mild HIE that received TH. Conclusion: Significantly more infants with mild HIE received TH since 2015 in California, but no difference in outcomes was found for these patients.

Risk factors, incidence, and outcomes of neonatal respiratory extracorporeal membrane oxygenation including association with therapeutic hypothermia in California during 2013-2020.

OBJECTIVE: To evaluate the incidence, indications and outcomes with neonatal extracorporeal membrane oxygenation (ECMO) and its association with therapeutic hypothermia (TH) among infants undergoing invasive mechanical ventilation (IMV) in California during 2013-2020. STUDY DESIGN: We analyzed data on neonates ≥34 weeks gestation with ≥4 h of IMV over an 8-year period (2013-2020) from the California Perinatal Quality Care Collaborative (CPQCC) database. RESULTS: Between 2013 and 2020, the ranges for utilization of iNO (13.9 to 17.2%), ECMO (2.1 to 2.5%), TH (10.2 to 15.7%) and TH + ECMO (0.4 to 0.8%) were observed. The most common association with neonatal ECMO was TH (148 cases, OR 3.2, 95% CI 2.6-4.3, p < 0.01). The combination of meconium aspiration syndrome (MAS) and hypoxic ischemic encephalopathy (HIE) increased risk of iNO and ECMO use (OR 11.3, 1.5-86.9), p = 0.02). CONCLUSION: Ventilated infants ≥34 weeks gestational age undergoing TH are at risk for iNO/ECMO use and need close monitoring.

Racial and Ethnic Disparities in Cervical Insufficiency, Cervical Cerclage, and Preterm Birth.

Background: The frequency of cervical insufficiency differs among the major racial and ethnic groups, with limited data specific to Asian American and Native Hawaiian/Pacific Islander (AANHPI) subpopulations. We assessed cervical insufficiency diagnoses and related outcomes across 10 racial and ethnic groups, including disaggregated AANHPI subgroups, in a large population-based cohort. Study Design: We performed a retrospective cohort study of all singleton births between 20-42 weeks' gestation in California from 2007 to 2018. Logistic regression models were performed to estimate the odds of cervical insufficiency and, among people with cervical insufficiency, the odds of cerclage and preterm birth according to self-reported race and ethnicity. Results: Among 5,114,470 births, 38,605 (0.8%) had a diagnosis code for cervical insufficiency. Compared with non-Hispanic White people, non-Hispanic Black people had the highest odds of cervical insufficiency (adjusted odds ratio [aOR] 3.07; 95% confidence interval [CI], 2.97, 3.18), for cerclage placement and higher odds for preterm birth. Disaggregating AANHPI subgroups showed that Indian people had the highest odds (aOR 1.94; 95% CI, 1.82, 2.07) of cervical insufficiency and had significantly higher odds of cerclage without increased odds of preterm birth; Southeast Asian people had the highest odds of preterm birth. Conclusion: Within a large, diverse population-based cohort, non-Hispanic Black people experienced the highest rates of cervical insufficiency, and among those with cervical insufficiency, had among the highest rates of cerclage and preterm birth. Among AANHPI subgroups specifically, Indian people had the highest rates of cervical insufficiency and cerclage placement, without increased rates of preterm birth; Southeast Asian people had the highest rates of preterm birth, without increased rates of cerclage. Disaggregating AANHPI subgroups identifies important differences in obstetric risk factors and outcomes.

Retrospective study of preterm infants exposed to inhaled nitric oxide in Kaiser Permanente Southern California: morbidity, mortality and follow-up.

OBJECTIVE: Describe characteristics of preterm infants exposed to inhaled nitric oxide (iNO) in Kaiser Permanente Southern California. STUDY DESIGN: Case review of preterm infants <34-weeks exposed to iNO during 2010-2020 including respiratory and echocardiographic status, NICU course, and 12-month follow-up. RESULTS: 270 infants, 2.63% of births<34 weeks, (median, range: 26.1, 225/7-336/7 weeks gestation) were exposed to iNO. Median FiO2 at iNO initiation was 1.0 (IQR 0.94-1.0). Pulmonary hypertension (PH) was not associated with risk-adjusted 2 h oxygenation response or improved survival. Mortality to NICU discharge was 37.4%. Median cost of iNO was $7,695/patient. Discharged survivors experienced frequent rehospitalization (34.9%), use of supplemental oxygen, sildenafil, diuretics, bronchodilators, and steroids. Four infants had persistent PH. Five infants died after NICU discharge. CONCLUSIONS: Preterm infants receiving iNO have high mortality and 1st year morbidity. As currently used, iNO may be an indicator of respiratory disease severity rather than mediator of improved outcomes.

Institutional and Regional Variation in Opioid Prescribing for Hospitalized Infants in the US.

Importance: High-risk infants, defined as newborns with substantial neonatal-perinatal morbidities, often undergo multiple procedures and require prolonged intubation, resulting in extended opioid exposure that is associated with poor outcomes. Understanding variation in opioid prescribing can inform quality improvement and best-practice initiatives. Objective: To examine regional and institutional variation in opioid prescribing, including short- and long-acting agents, in high-risk hospitalized infants. Design, Setting, and Participants: This retrospective cohort study assessed high-risk infants younger than 1 year from January 1, 2016, to December 31, 2022, at 47 children's hospitals participating in the Pediatric Health Information System (PHIS). The cohort was stratified by US Census region (Northeast, South, Midwest, and West). Variation in cumulative days of opioid exposure and methadone treatment was examined among institutions using a hierarchical generalized linear model. High-risk infants were identified by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes for congenital heart disease surgery, medical and surgical necrotizing enterocolitis, extremely low birth weight, very low birth weight, hypoxemic ischemic encephalopathy, extracorporeal membrane oxygenation, and other abdominal surgery. Infants with neonatal opioid withdrawal syndrome, in utero substance exposure, or malignant tumors were excluded. Exposure: Any opioid exposure and methadone treatment. Main Outcomes and Measures: Regional and institutional variations in opioid exposure. Results: Overall, 132 658 high-risk infants were identified (median [IQR] gestational age, 34 [28-38] weeks; 54.5% male). Prematurity occurred in 30.3%, and 55.3% underwent surgery. During hospitalization, 76.5% of high-risk infants were exposed to opioids and 7.9% received methadone. Median (IQR) length of any opioid exposure was 5 (2-12) cumulative days, and median (IQR) length of methadone treatment was 19 (7-46) cumulative days. There was significant hospital-level variation in opioid and methadone exposure and cumulative days of exposure within each US region. The computed intraclass correlation coefficient estimated that 16% of the variability in overall opioid prescribing and 20% of the variability in methadone treatment was attributed to the individual hospital. Conclusions and Relevance: In this retrospective cohort study of high-risk hospitalized infants, institution-level variation in overall opioid exposure and methadone treatment persisted across the US. These findings highlight the need for standardization of opioid prescribing in this vulnerable population.

Design of dual peptide-conjugated hydrogels for proliferation and differentiation of human pluripotent stem cells.

Completely synthetic cell cultivation materials for human pluripotent stem cells (hPSCs) are important for the future clinical use of hPSC-derived cells. Currently, cell culture materials conjugated with extracellular matrix (ECM)-derived peptides are being prepared using only one specific integrin-targeting peptide. We designed dual peptide-conjugated hydrogels, for which each peptide was selected from different ECM sites: the laminin ß4 chain and fibronectin or vitronectin, which can target α6ß1 and α2ß1 or αVß5. hPSCs cultured on dual peptide-conjugated hydrogels, especially on hydrogels conjugated with peptides obtained from the laminin ß4 chain and vitronectin with a low peptide concentration of 200 µg/mL, showed high proliferation ability over the long term and differentiated into cells originating from 3 germ layers in vivo as well as a specific lineage of cardiac cells. The design of grafting peptides was also important, for which a joint segment and positive amino acids were added into the designed peptide. Because of the designed peptides on the hydrogels, only 200 µg/mL peptide solution was sufficient for grafting on the hydrogels, and the hydrogels supported hPSC cultures long-term; in contrast, in previous studies, greater than 1000 µg/mL peptide solution was needed for the grafting of peptides on cell culture materials.

Virtual simulation training for postpartum hemorrhage in low-to-moderate-volume hospitals in the US.

Background: Maternal mortality in the United States is rising and many deaths are preventable. Emergencies, such as postpartum hemorrhage, occur less frequently in non-teaching, rural, and urban low-birth volume hospitals. There is an urgent need for accessible, evidence-based, and sustainable inter-professional education that creates the opportunity for clinical teams to practice their response to rare, but potentially devastating events. Objective: To assess the feasibility of virtual simulation training for the management of postpartum hemorrhage in low-to-moderate-volume delivery hospitals. Study design: The study occurred between December 2021 and March 2022 within 8 non-academic hospitals in the United States with low-to-moderate-delivery volumes, randomized to one of two models: direct simulation training and train-the-trainer. In the direct simulation training model, simulation faculty conducted a virtual simulation training program with participants. In the train-the-trainer model, simulation faculty conducted virtual lessons with new simulation instructors on how to prepare and conduct a simulation course. Following this training, the instructors led their own simulation training program at their respective hospitals. The direct simulation training participants and students trained by new instructors from the train-the-trainer program were evaluated with a multiple-choice questionnaire on postpartum hemorrhage knowledge and a confidence and attitude survey at 3 timepoints: prior to, immediately after, and at 3 months post-training. Paired t-tests were performed to assess for changes in knowledge and confidence within teaching models across time points. ANOVA was performed to test cross-sectionally for differences in knowledge and confidence between teaching models at each time point. Results: Direct simulation training participants (n=22) and students of the train-the-trainer instructors (n=18) included nurses, certified nurse midwives and attending physicians in obstetrics, family practice or anesthesiology. Mean pre-course knowledge and confidence scores were not statistically different between direct simulation participants and the students of the instructors from the train-the-trainer course (79%+/-13 versus 75%+/-14, respectively, P-value=.45). Within the direct simulation group, knowledge and confidence scores significantly improved from pre- to immediately post-training (knowledge score mean difference 9.81 [95% CI 3.23-16.40], P-value<.01; confidence score mean difference 13.64 [95% CI 6.79-20.48], P-value<.01), which were maintained 3-months post-training. Within the train-the-trainer group, knowledge and confidence scores immediate post-intervention were not significantly different compared with pre-course or 3-month post-course scores. Mean knowledge scores were significantly greater for the direct simulation group compared to the train-the-trainer group immediately post-training (89%+/-7 versus 74%+/-8, P-value<.01) and at 3-months (88%+/-7 versus 76%+/-12, P-value<.01). Comparisons between groups showed no difference in confidence and attitude scores at these timepoints. Both direct simulation participants and train-the-trainer instructors preferred virtual education, or a hybrid structure, over in-person education. Conclusion: Virtual education for obstetric simulation training is feasible, acceptable, and effective. Utilizing a direct simulation model for postpartum hemorrhage management resulted in enhanced knowledge acquisition and retention compared to a train-the-trainer model.