Restoration of Visual Function by Enhancing Conduction in Regenerated Axons.

Although a number of repair strategies have been shown to promote axon outgrowth following neuronal injury in the mammalian CNS, it remains unclear whether regenerated axons establish functional synapses and support behavior. Here, in both juvenile and adult mice, we show that either PTEN and SOCS3 co-deletion, or co-overexpression of osteopontin (OPN)/insulin-like growth factor 1 (IGF1)/ciliary neurotrophic factor (CNTF), induces regrowth of retinal axons and formation of functional synapses in the superior colliculus (SC) but not significant recovery of visual function. Further analyses suggest that regenerated axons fail to conduct action potentials from the eye to the SC due to lack of myelination. Consistent with this idea, administration of voltage-gated potassium channel blockers restores conduction and results in increased visual acuity. Thus, enhancing both regeneration and conduction effectively improves function after retinal axon injury.

2023 American Heart Association and American Academy of Pediatrics Focused Update on Neonatal Resuscitation: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

This 2023 focused update to the neonatal resuscitation guidelines is based on 4 systematic reviews recently completed under the direction of the International Liaison Committee on Resuscitation Neonatal Life Support Task Force. Systematic reviewers and content experts from this task force performed comprehensive reviews of the scientific literature on umbilical cord management in preterm, late preterm, and term newborn infants, and the optimal devices and interfaces used for administering positive-pressure ventilation during resuscitation of newborn infants. These recommendations provide new guidance on the use of intact umbilical cord milking, device selection for administering positive-pressure ventilation, and an additional primary interface for administering positive-pressure ventilation.

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.

Infants Born at Late Preterm Gestation: Management During the Birth Hospitalization.

OBJECTIVE: To examine the admission practices, frequency of common clinical morbidities, and rates of medical intervention in infants born at 34-36 weeks gestational age (GA, late preterm). STUDY DESIGN: This retrospective, single institution, cohort study analyzed electronic health records of infants born late preterm from 2019 through 2021. Infants with anomalies necessitating neonatal intensive care unit admission were excluded. Analysis included descriptive and inferential statistics. RESULTS: The study included 1022 infants: 209 (21%) 34 weeks GA; 263 (26%) 35 weeks GA; and 550 (54%) 36 weeks GA. Sixty-three percent of infants at 35 weeks GA and 78% of infants of 36 weeks GA remained in well newborn care throughout the birth hospitalization; infants born at 34 weeks GA were ineligible for well newborn care. The need for respiratory support was 32%, 18% and 11% in infants of 34, 35, and 36 weeks GA, respectively. Supplemental tube feeds were administered in 55%, 24%, and 8% of infants of 34, 35, and 36 weeks GA, respectively. Most infants born at 34 weeks GA (91%) were placed in an incubator; this was less frequent in infants at 35 (37%) and 36 weeks (16%). Tachypnea, hypoglycemia, and hypothermia were noted in 40%, 61%, and 57% of infants, respectively. A subset of these infants (30% with tachypnea, 23% with hypoglycemia, 46% with hypothermia) required medical intervention for these abnormalities. CONCLUSION: This single center study provides an outlook on the care of infants born late preterm. Multi-center studies can contextualize these findings in order to develop clinical benchmarks and quality markers for this large population of infants.

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.

Cohort selection and the estimation of racial disparity in mortality of extremely preterm neonates.

BACKGROUND: Racial disparities in preterm neonatal mortality are long-standing. We aimed to assess how cohort selection influences mortality rates and racial disparity estimates. METHODS: With 2014-2018 California data, we compared neonatal mortality rates among Black and non-Hispanic White very low birth weight (VLBW, <1500 g) or very preterm infants (22-29 weeks gestational age). Relative risks were estimated by different cohort selection criteria. Blinder-Oaxaca decomposition quantified factors contributing to mortality differential. RESULTS: Depending upon standard selection criteria, mortality ranged from 6.2% (VLBW infants excluding first 12-h deaths) to 16.0% (22-29 weeks' gestation including all deaths). Black observed neonatal mortality was higher than White infants only for delivery room deaths in VLBW infants (5.6 vs 4.2%). With risk adjustment accounting for higher rate of low gestational age, low Apgar score and other factors, White infant mortality increased from 15.9 to 16.6%, while Black infant mortality decreased from 16.7 to 13.7% in the 22-29 weeks cohort. Across varying cohort selection, risk adjusted survival advantage among Black infants ranged from 0.70 (CL 0.61-0.80) to 0.84 (CL 0.76-0.93). CONCLUSIONS: Standard cohort selection can give markedly different mortality estimates. It is necessary to reduce prematurity rates and perinatal morbidity to improve outcomes for Black infants. IMPACT: In this population-based observational cohort study that encompassed very low birth weight infant hospitalizations in California, varying standard methods of cohort selection resulted in neonatal mortality ranges from 6.2 to 16.0%. Across all cohorts, the only significant observed Black-White disparity was for delivery room deaths in Very Low Birth Weight births (5.6 vs 4.2%). Across all cohorts, we found a 16-30% survival advantage for Black infants. Cohort selection can result in an almost three-fold difference in estimated mortality but did not have a meaningful impact on observed or adjusted differences in neonatal mortality outcomes by race and ethnicity.

Methodologic considerations in estimating racial disparity of mortality among very preterm infants.

This review explores methodological considerations in estimating racial disparities in mortality among very preterm infants (VPIs). Significant methodological variations are evident across studies, potentially affecting the estimated mortality rates of VPIs across racial groups and influencing the perceived direction and magnitude of racial disparities. Key methodological approaches include the birth-based approach versus the fetuses-at-risk approach, with each offering distinct insights depending on the specific research questions posed. Cohort selection and the decision for crude versus adjusted comparison are also critical elements that shape the outcomes and interpretations of these studies. This review underscores the importance of careful methodological planning and highlights that no single approach is definitively superior; rather, each has its strengths and limitations depending on the research objectives. The findings suggest that adjusting the methodological approach to align with specific research questions and contexts is essential for accurately assessing and addressing racial disparities in neonatal mortality. IMPACT: Elucidates the impact of methodological choices on perceived racial disparities in neonatal mortality. Offers a comprehensive comparison of birth-based vs. fetuses-at-risk approaches in the context of racial disparity research. Provides guidance on the cohort selection and adjustment criteria critical for interpreting studies on racial disparities in very preterm infant mortality.

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.

The Cost of Opioid Use in High-Risk Hospitalized Infants.

INTRODUCTION: Hospitalizations of high-risk infants are among the most expensive in the United States, with many requiring surgery and months of intensive care. Healthcare costs and resource use associated with hospitalized infant opioid exposure are less well known. METHODS: A retrospective cohort of high-risk infants aged <1 y admitted from 47 children's hospitals from 2010 to 2020 was identified from Pediatric Healthcare Information System. High-risk infants were identified by International Classification of Diseases 9/10 codes for congenital heart disease procedures, medical and surgical necrotizing enterocolitis, extremely low birth weight, very low birth weight, hypoxemic ischemic encephalopathy, extracorporeal membrane oxygenation, and gastrointestinal tract malformations. Healthcare resource utilization was estimated using standardized unit costs (SUCs). The impact of opioid use on SUC was examined using general linear models and an instrumental variable. RESULTS: Overall, 126,897 high-risk infants were identified. The cohort was majority White (57.1%), non-Hispanic (72.0%), and male (55.4%). Prematurity occurred in 26.4% and a majority underwent surgery (77.9%). Median SUC was $120,585 (interquartile range: $57,602-$276,562) per infant. On instrumental variable analysis, each day of opioid use was associated with an increase of $4406 in SUC. When adjusting for biologic sex, race, ethnicity, insurance type, diagnosis category, number of comorbidities, mechanical ventilation, and total parental nutrition use, each day of opioid use was associated with an increase of $2177 per infant. CONCLUSIONS: Prolonged opioid use is significantly associated with healthcare utilization and costs for high-risk infants, even when accounting for comorbidities, intensive care, ventilation, and total parental nutrition use. Future studies are needed to estimate the long-term complications and additional costs resulting from prolonged opioid exposures in high-risk infants.

N-acetylcysteine treatment mitigates loss of cortical parvalbumin-positive interneuron and perineuronal net integrity resulting from persistent oxidative stress in a rat TBI model.

Traumatic brain injury (TBI) increases cerebral reactive oxygen species production, which leads to continuing secondary neuronal injury after the initial insult. Cortical parvalbumin-positive interneurons (PVIs; neurons responsible for maintaining cortical inhibitory tone) are particularly vulnerable to oxidative stress and are thus disproportionately affected by TBI. Systemic N-acetylcysteine (NAC) treatment may restore cerebral glutathione equilibrium, thus preventing post-traumatic cortical PVI loss. We therefore tested whether weeks-long post-traumatic NAC treatment mitigates cortical oxidative stress, and whether such treatment preserves PVI counts and related markers of PVI integrity and prevents pathologic electroencephalographic (EEG) changes, 3 and 6 weeks after fluid percussion injury in rats. We find that moderate TBI results in persistent oxidative stress for at least 6 weeks after injury and leads to the loss of PVIs and the perineuronal net (PNN) that surrounds them as well as of per-cell parvalbumin expression. Prolonged post-TBI NAC treatment normalizes the cortical redox state, mitigates PVI and PNN loss, and - in surviving PVIs - increases per-cell parvalbumin expression. NAC treatment also preserves normal spectral EEG measures after TBI. We cautiously conclude that weeks-long NAC treatment after TBI may be a practical and well-tolerated treatment strategy to preserve cortical inhibitory tone post-TBI.

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.

On the interdependence of ketone body oxidation, glycogen content, glycolysis and energy metabolism in the heart.

In heart, glucose and glycolysis are important for anaplerosis and potentially therefore for d-ß-hydroxybutyrate (ßHB) oxidation. As a glucose store, glycogen may also furnish anaplerosis. We determined the effects of glycogen content on ßHB oxidation and glycolytic rates, and their downstream effects on energetics, in the isolated rat heart. High glycogen (HG) and low glycogen (LG) containing hearts were perfused with 11 mM [5-3 H]glucose and/or 4 mM [14 C]ßHB to measure glycolytic rates or ßHB oxidation, respectively, then freeze-clamped for glycogen and metabolomic analyses. Free cytosolic [NAD+ ]/[NADH] and mitochondrial [Q+ ]/[QH2 ] ratios were estimated using the lactate dehydrogenase and succinate dehydrogenase reaction, respectively. Phosphocreatine (PCr) and inorganic phosphate (Pi ) concentrations were measured using 31 P-nuclear magnetic resonance spectroscopy. Rates of ßHB oxidation in LG hearts were half that in HG hearts, with ßHB oxidation directly proportional to glycogen content. ßHB oxidation decreased glycolysis in all hearts. Glycogenolysis in glycogen-replete hearts perfused with ßHB alone was twice that of hearts perfused with ßHB and glucose, which had significantly higher levels of the glycolytic intermediates fructose 1,6-bisphosphate and 3-phosphoglycerate, and higher free cytosolic [NAD+ ]/[NADH]. ßHB oxidation increased the Krebs cycle intermediates citrate, 2-oxoglutarate and succinate, the total NADP/H pool, reduced mitochondrial [Q+ ]/[QH2 ], and increased the calculated free energy of ATP hydrolysis (∆GATP ). Although ßHB oxidation inhibited glycolysis, glycolytic intermediates were not depleted, and cytosolic free NAD remained oxidised. ßHB oxidation alone increased Krebs cycle intermediates, reduced mitochondrial Q and increased ∆GATP . We conclude that glycogen facilitates cardiac ßHB oxidation by anaplerosis. KEY POINTS: Ketone bodies (d-ß-hydroxybutyrate, acetoacetate) are increasingly recognised as important cardiac energetic substrates, in both healthy and diseased hearts. As 2-carbon equivalents they are cataplerotic, causing depletion of Krebs cycle intermediates; therefore their utilisation requires anaplerotic supplementation, and intra-myocardial glycogen has been suggested as a potential anaplerotic source during ketone oxidation. It is demonstrated here that cardiac glycogen does indeed provide anaplerotic substrate to facilitate ß-hydroxybutyrate oxidation in isolated perfused rat heart, and this contribution was quantified using a novel pulse-chase metabolic approach. Further, using metabolomics and 31 P-MR, it was shown that glycolytic flux from myocardial glycogen increased the heart's ability to oxidise ßHB, and ßHB oxidation increased the mitochondrial redox potential, ultimately increasing the free energy of ATP hydrolysis.

Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants.

To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders.

Association of Primary Language with Very Low Birth Weight Outcomes in Hispanic Infants in California.

OBJECTIVE: To determine the association of Spanish as a primary language for a family with the health outcomes of Hispanic infants with very low birth weight (VLBW, <1500g). STUDY DESIGN: Data from the California Perinatal Quality Care Collaborative (CPQCC) linked to hospital discharge records were analyzed. Hispanic infants with VLBW born between 2009 and 2018 with a primary language of English or Spanish were included. Outcomes selected were hypothesized to be sensitive to language barriers. Multivariable logistic regression models and mixed models estimated associations between language and outcomes. RESULTS: Of 18 364 infants meeting inclusion criteria, 27% (n = 4976) were born to families with Spanish as a primary language. In unadjusted analyses, compared with infants of primarily English-speaking families, these infants had higher odds of hospital readmission within 1 year (OR 1.11 [95% CI 1.02-1.21]), higher odds to receive human milk at discharge (OR 1.32 [95% CI 1.23-1.42]), and lower odds of discharge home with oxygen (OR 0.83 [95% CI 0.73-0.94]). In multivariable analyses, odds of readmission and home oxygen remained significant when adjusting for infant but not maternal and hospital characteristics. Higher odds for receipt of any human milk at discharge were significant in all models. Remaining outcomes did not differ between groups. CONCLUSIONS: Significant differences exist between Hispanic infants with VLBW of primarily Spanish-vs English-speaking families. Exploration of strategies to prevent readmissions of infants of families with Spanish as a primary language is warranted.