Genome Sequencing is Critical for Forecasting Outcomes following Congenital Cardiac Surgery.

While genome sequencing has transformed medicine by elucidating the genetic underpinnings of both rare and common complex disorders, its utility to predict clinical outcomes remains understudied. Here, we used artificial intelligence (AI) technologies to explore the predictive value of genome sequencing in forecasting clinical outcomes following surgery for congenital heart defects (CHD). We report results for a cohort of 2,253 CHD patients from the Pediatric Cardiac Genomics Consortium with a broad range of complex heart defects, pre- and post-operative clinical variables and exome sequencing. Damaging genotypes in chromatin-modifying and cilia-related genes were associated with an elevated risk of adverse post-operative outcomes, including mortality, cardiac arrest and prolonged mechanical ventilation. The impact of damaging genotypes was further amplified in the context of specific CHD phenotypes, surgical complexity and extra-cardiac anomalies. The absence of a damaging genotype in chromatin-modifying and cilia-related genes was also informative, reducing the risk for adverse postoperative outcomes. Thus, genome sequencing enriches the ability to forecast outcomes following congenital cardiac surgery.

Accurate prediction of neurologic changes in critically ill infants using pose AI.

Importance: Infant alertness and neurologic changes are assessed by exam, which can be intermittent and subjective. Reliable, continuous methods are needed. Objective: We hypothesized that our computer vision method to track movement, pose AI, could predict neurologic changes. Design: Retrospective observational study from 2021-2022. Setting: A level four urban neonatal intensive care unit (NICU). Participants: Infants with corrected age ≤1 year, comprising 115 patients with 4,705 hours of video data linked to electroencephalograms (EEG), including 46% female and 25.2% white non-Hispanic. Exposures: Pose AI prediction of anatomic landmark position and an XGBoost classifier trained on one-minute variance in pose. Main outcomes and measures: Outcomes were cerebral dysfunction, diagnosed from EEG readings by an epileptologist, and sedation, defined by the administration of sedative medications. Measures of algorithm performance were receiver operating characteristic-area under the curves (ROC-AUCs) on cross-validation and on two test datasets comprised of held-out infants and held-out video frames from infants used in training. Results: Infant pose was accurately predicted in cross-validation, held-out frames, and held-out infants (respective ROC-AUCs 0.94, 0.83, 0.89). Median movement increased with age and, after accounting for age, was lower with sedative medications and in infants with cerebral dysfunction (all P<5×10-3, 10,000 permutations). Sedation prediction had high performance on cross-validation, held-out frames, and held-out infants (ROC-AUCs 0.90, 0.91, 0.87), as did prediction of cerebral dysfunction (ROC-AUCs 0.91, 0.90, 0.76). Conclusions and Relevance: We used pose AI to predict sedation and cerebral dysfunction in 4,705 hours of video from a large, diverse cohort of infants. Pose AI may offer a scalable, minimally invasive method for neuro-telemetry in the NICU.

Early Impairment of Cerebral Bioenergetics After Cardiopulmonary Bypass in Neonatal Swine.

Objectives: We previously demonstrated cerebral mitochondrial dysfunction in neonatal swine immediately following a period of full-flow cardiopulmonary bypass (CPB). The extent to which this dysfunction persists in the postoperative period and its correlation with other markers of cerebral bioenergetic failure and injury is unknown. We utilized a neonatal swine model to investigate the early evolution of mitochondrial function and cerebral bioenergetic failure after CPB. Methods: Twenty piglets (mean weight 4.4 ± 0.5 kg) underwent 3 h of CPB at 34 °C via cervical cannulation and were followed for 8, 12, 18, or 24 h (n = 5 per group). Markers of brain tissue damage (glycerol) and bioenergetic dysfunction (lactate to pyruvate ratio) were continuously measured in cerebral microdialysate samples. Control animals (n = 3, mean weight 4.1 ± 1.2 kg) did not undergo cannulation or CPB. Brain tissue was extracted immediately after euthanasia to obtain ex-vivo cortical mitochondrial respiration and frequency of cortical microglial nodules (indicative of cerebral microinfarctions) via neuropathology. Results: Both the lactate to pyruvate ratio (P < .0001) and glycerol levels (P = .01) increased in cerebral microdialysate within 8 h after CPB. At 24 h post-CPB, cortical mitochondrial respiration was significantly decreased compared with controls (P = .046). The presence of microglial nodules increased throughout the study period (24 h) (P = .01, R2 = 0.9). Conclusion: CPB results in impaired cerebral bioenergetics that persist for at least 24 h. During this period of bioenergetic impairment, there may be increased susceptibility to secondary injury related to alterations in metabolic delivery or demand, such as hypoglycemia, seizures, and decreased cerebral blood flow.

Genomic testing and molecular diagnosis among infants with congenital heart disease in the neonatal intensive care unit.

OBJECTIVE: To evaluate patterns of genetic testing among infants with CHD at a tertiary care center. STUDY DESIGN: We conducted a retrospective observational cohort study of infants in the NICU with suspicion of a genetic disorder. 1075 of 7112 infants admitted to BCH had genetic evaluation including 329 with CHD and 746 without CHD. 284 of 525 infants with CHD admitted to CMHH had genetic evaluation. Patterns of testing and diagnoses were compared. RESULTS: The rate of diagnosis after testing was similar for infants with or without CHD (38% [121/318] vs. 36% [246/676], p = 0.14). In a multiple logistic regression, atrioventricular septal defects were most high associated with genetic diagnosis (odds ratio 29.99, 95% confidence interval 2.69-334.12, p < 0.001). CONCLUSIONS: Infants with suspicion of a genetic disorder with CHD had similar rates of molecular diagnosis as those without CHD. These results support a role for genetic testing among NICU infants with CHD.

Can the MIRACLE2 Score Be Used in the Prehospital Environment and Is It Useful? An Observational Study.

OBJECTIVE: The MIRACLE2 score has been developed for use in a primary percutaneous coronary intervention center. It is unclear if it is feasible in the helicopter emergency medical service (HEMS) setting. METHODS: The computerized system at 1 UK HEMS was interrogated between December 1, 2020, and May 1, 2022, for the components of the MIRACLE2 score (recorded contemporaneously) plus demographics and outcomes in all post-return of spontaneous circulation patients conveyed to the hospital. pH was excluded because of no point-of-care testing resulting in a modified MIRACLE2 score (maximum score of 9). Data were analyzed using the chi-square test; P < .05 was statistically significant. RESULTS: Three hundred thirty patients (240 males) with out-of-hospital cardiac arrests were reviewed. Ninety-two adult patients with nontraumatic out-of-hospital cardiac arrests had sustained return of spontaneous circulation and a median MIRACLE2 score of 4 (range, 0-7). Forty-seven patients died before hospital discharge; the median MIRACLE2 score was higher in those who died (4) than those who survived (1.5, P < .01); 90.3% of those with a score ≥ 5 were triaged to an emergency department rather than directly to a catheterization laboratory. CONCLUSION: A modified MIRACLE2 score can be calculated in the HEMS setting. The benefit of point-of-care testing pH requires investigation. There may be a benefit in predicting outcomes in this nondifferentiated group, but additional research is required.

Pediatric Intubations in a Semiurban Helicopter Emergency Medicine Service: A Retrospective Review.

OBJECTIVE: Although a small proportion of helicopter emergency medical service (HEMS) missions are for pediatric patients, it is recognized that children do present unique challenges. This case series aims to evaluate the intubation first-pass success rate in HEMS pediatric patients for both medical and trauma patients in a UK semiurban environment. METHODS: A retrospective review of the computerized records system was performed from January 1, 2015, to July 31, 2022, at 1 UK HEMS. Anonymous data relating to advanced airway interventions in patients < 16 years of age were extracted. Primary analysis related to the first-pass success rate was performed; secondary analysis relating to the initial Glasgow Coma Scale (GCS) of the pediatric patients requiring prehospital anesthesia (rapid sequence induction with drugs) and first-pass success rates by clinician group was also performed. RESULTS: Of the pediatric patients, 15.8% required intubation. The overall first-pass success rate for intubation (including in cardiac arrest) was 83.5%; for prehospital anesthesia (drugs administered), it was 98.4%. First-pass success rates were lowest for those under 2 years of age (45.2% without drugs and 87.5% with drugs). There was no difference between physician background in the first-pass success rate. The median GCS for pediatric prehospital anesthesia was 7 versus 5 for adults (P = .012). No children with an initial GCS of 15 had prehospital anesthesia. CONCLUSION: The overall intubation first-pass success rates for pediatric patients is high at 83.5% and higher still for prehospital anesthesia (98.4%). However, it remains a rare intervention for clinicians, and children under 2 years of age require special consideration.

Genetics and etiology of congenital heart disease.

Congenital heart disease (CHD) is the most common severe birth anomaly, affecting almost 1% of infants. Most CHD is genetic, but only 40% of patients have an identifiable genetic risk factor for CHD. Chromosomal variation contributes significantly to CHD but is not readily amenable to biological follow-up due to the number of affected genes and lack of evolutionary synteny. The first CHD genes were implicated in extended families with syndromic CHD based on the segregation of risk alleles in affected family members. These have been complemented by more CHD gene discoveries in large-scale cohort studies. However, fewer than half of the 440 estimated human CHD risk genes have been identified, and the molecular mechanisms underlying CHD genetics remains incompletely understood. Therefore, model organisms and cell-based models are essential tools for improving our understanding of cardiac development and CHD genetic risk. Recent advances in genome editing, cell-specific genetic manipulation of model organisms, and differentiation of human induced pluripotent stem cells have recently enabled the characterization of developmental stages. In this chapter, we will summarize the latest studies in CHD genetics and the strengths of various study methodologies. We identify opportunities for future work that will continue to further CHD knowledge and ultimately enable better diagnosis, prognosis, treatment, and prevention of CHD.

Functional dissection of human cardiac enhancers and noncoding de novo variants in congenital heart disease.

Rare coding mutations cause ∼45% of congenital heart disease (CHD). Noncoding mutations that perturb cis-regulatory elements (CREs) likely contribute to the remaining cases, but their identification has been problematic. Using a lentiviral massively parallel reporter assay (lentiMPRA) in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we functionally evaluated 6,590 noncoding de novo variants (ncDNVs) prioritized from the whole-genome sequencing of 750 CHD trios. A total of 403 ncDNVs substantially affected cardiac CRE activity. A majority increased enhancer activity, often at regions with undetectable reference sequence activity. Of ten DNVs tested by introduction into their native genomic context, four altered the expression of neighboring genes and iPSC-CM transcriptional state. To prioritize future DNVs for functional testing, we used the MPRA data to develop a regression model, EpiCard. Analysis of an independent CHD cohort by EpiCard found enrichment of DNVs. Together, we developed a scalable system to measure the effect of ncDNVs on CRE activity and deployed it to systematically assess the contribution of ncDNVs to CHD.

Cardiorespiratory consequences of attenuated fentanyl and augmented rocuronium dosing during protocolised prehospital emergency anaesthesia at a regional air ambulance service: a retrospective study.

BACKGROUND: Pre-Hospital Emergency Anaesthesia (PHEA) has undergone significant developments since its inception. However, optimal drug dosing remains a challenge for both medical and trauma patients. Many prehospital teams have adopted a drug regimen of 3 mcg/kg fentanyl, 2 mg/kg ketamine and 1 mg/kg rocuronium ('3:2:1'). At Essex and Herts Air Ambulance Trust (EHAAT) a new standard dosing regimen was introduced in August 2021: 1 mcg/kg fentanyl, 2 mg/kg ketamine and 2 mg/kg rocuronium (up to a maximum dose of 150 mg) ('1:2:2'). The aim of this study was to evaluate the cardiorespiratory consequences of a new attenuated fentanyl and augmented rocuronium dosing regimen. METHODS: A retrospective study was conducted at EHAAT as a service evaluation. Anonymized records were reviewed from an electronic database to compare the original ('3:2:1') drug dosing regimen (December 2019-July 2021) and the new ('1:2:2') dosing regimen (September 2021-May 2023). The primary outcome was the incidence of absolute hypotension within ten minutes of induction. Secondary outcomes included immediate hypertension, immediate hypoxia and first pass success (FPS) rates. RESULTS: Following exclusions (n = 121), 720 PHEA cases were analysed (360 new vs. 360 original, no statistically significant difference in demographics). There was no difference in the rate of absolute hypotension (24.4% '1:2:2' v 23.8% '3:2:1', p = 0.93). In trauma patients, there was an increased first pass success (FPS) rate with the new regimen (95.1% v 86.5%, p = 0.01) and a reduced incidence of immediate hypoxia (7.9% v 14.8%, p = 0.05). There was no increase in immediate hypertensive episodes (22.7% vs. 24.2%, p = 0.73). No safety concerns were identified. CONCLUSION: An attenuated fentanyl and augmented rocuronium dosing regimen showed no difference in absolute hypotensive episodes in a mixed cohort of medical and trauma patients. In trauma patients, the new regimen was associated with an increased FPS rate and reduced episodes of immediate hypoxia. Further research is required to understand the impact of such drug dosing in the most critically ill and injured subpopulation.

Establishing a neonatology consultation program: extending care beyond the neonatal intensive care unit.

Neonates can be cared for in neonatal, pediatric, or cardiac intensive care units, and general and subspecialty pediatric units. Disposition is based on phase of care, gestational and postnatal age, birth weight, specific cardiac or surgical diagnoses, and co-existing medical morbidities. In addition, neonates may transfer between the neonatal intensive care unit (NICU) and other units several times throughout their hospitalization. As such, care for high-risk infants with ongoing neonatal morbidities (often related to prematurity or congenital anomalies) is provided in units with varying neonatal expertise. In this perspective, we provide a framework for the design and implementation of a neonatology consultation service for infants cared for in clinical units outside the NICU. We describe the core principles of effective neonatology consultation and focus on understanding hospital/unit workflow, team composition, patient selection, billing and compliance, and offer suggestions for research initiatives and educational opportunities.

Distribution of dim light melatonin offset (DLMOff) and phase relationship to waketime in healthy adults and associations with chronotype.

OBJECTIVES: Dim light melatonin onset, or the rise in melatonin levels representing the beginning of the biological night, is the gold standard indicator of circadian phase. Considerably less is known about dim light melatonin offset, or the decrease in melatonin to low daytime levels representing the end of the biological night. In the context of insufficient sleep, morning circadian misalignment, or energy intake after waketime but before dim light melatonin offset, is linked to impaired insulin sensitivity, suggesting the need to characterize dim light melatonin offset and identify risk for morning circadian misalignment. METHODS: We examined the distributions of dim light melatonin offset clock hour and the phase relationship between dim light melatonin offset and waketime, and associations between dim light melatonin offset, phase relationship, and chronotype in healthy adults (N = 62) who completed baseline protocols measuring components of the circadian melatonin rhythm and chronotype. RESULTS: 74.4% demonstrated dim light melatonin offset after waketime, indicating most healthy adults wake up before the end of biological night. Later chronotype (morningness-eveningness, mid-sleep on free days corrected, and average mid-sleep) was associated with later dim light melatonin offset clock hour. Later chronotype was also associated with a larger, positive phase relationship between dim light melatonin offset and waketime, except for morningness-eveningness. CONCLUSIONS: These findings suggest morning circadian misalignment risk among healthy adults, which would not be detected if only dim light melatonin onset were assessed. Chronotype measured by sleep timing may better predict this risk in healthy adults keeping a consistent sleep schedule than morningness-eveningness preferences. Additional research is needed to develop circadian biomarkers to predict dim light melatonin offset and evaluate appropriate dim light melatonin offset timing to promote health.

Comparative Effectiveness of Alternative Treatment Approaches to Secondary Hyperparathyroidism in Patients Receiving Maintenance Hemodialysis: An Observational Trial Emulation.

RATIONALE & OBJECTIVE: Optimal approaches to treat secondary hyperparathyroidism (SHPT) in patients on maintenance hemodialysis (HD) have yet to be established in randomized controlled trials (RCTs). STUDY DESIGN: Two observational clinical trial emulations. SETTING & PARTICIPANTS: Both emulations included adults receiving in-center HD from a national dialysis organization. The patients who had SHPT in the period between 2009 and 2014, were insured for≥180 days by Medicare as primary payer, and did not have contraindications or poor health status limiting theoretical trial participation. EXPOSURE: The parathyroid hormone (PTH) Target Trial emulation included patients with new-onset SHPT (first PTH 300-600pg/mL), with 2 arms defined as up-titration of either vitamin D sterols or cinacalcet within 30 days (lower target) or no up-titration (higher target). The Agent Trial emulation included patients with a PTH≥300 pg/mL while on≥6µg weekly of vitamin D sterol (paricalcitol equivalent dose) and no prior history of cinacalcet. The 2 arms were defined by the first dose or agent change within 30 days (vitamin D-favoring [vitamin-D was up-titrated] vs cinacalcet-favoring [cinacalcet was added] vs nondefined [neither applies]). Multiple trials per patient were allowed in trial 2. OUTCOME: The primary outcome was all-cause death over 24 months; secondary outcomes included cardiovascular (CV) hospitalization or the composite of CV hospitalization or death. ANALYTICAL APPROACH: Pooled logistic regression. RESULTS: There were 1,152 patients in the PTH Target Trial (635 lower target and 517 higher target). There were 2,726 unique patients with 6,727 patient trials in the Agent Trial (6,268 vitamin D-favoring trials and 459 cinacalcet-favoring trials). The lower PTH target approach was associated with reduced adjusted hazard of death (HR, 0.71 [95% CI, 0.52-0.93]), CV hospitalization (HR, 0.78 [95% CI, 0.63-0.98]), and their composite (HR, 0.74 [95% CI, 0.61-0.89]). The cinacalcet-favoring approach demonstrated lower adjusted hazard of death compared to the vitamin D-favoring approach (HR, 0.79 [95% CI, 0.62-0.99]), but not of CV hospitalization or the composite outcome. LIMITATIONS: Potential for residual confounding; low use of cinacalcet with low power. CONCLUSIONS: SHPT management that is focused on lower PTH targets may lower mortality and CV disease in patients receiving HD. These findings should be confirmed in a pragmatic randomized trial. PLAIN-LANGUAGE SUMMARY: Optimal approaches to treat secondary hyperparathyroidism (SHPT) have not been established in randomized controlled trials. Data from a national dialysis organization was used to identify patients with SHPT in whom escalated treatment may be indicated. The approach to treatment was defined based on observed upward titration of SHPT-controlling medications: earlier titration (lower target) versus delayed titration (higher target); and the choice of medication (cinacalcet vs vitamin D sterols). In the first trial emulation, we estimated a 29% lower rate of death and 26% lower rate of cardiovascular disease or death for patients managed with a lower versus higher target approach. Cinacalcet versus vitamin D-favoring approaches were not consistently associated with outcomes in the second trial emulation. This observational study suggests the need for additional clinical trials of SHPT treatment intensity.

Association of genetic and sulcal traits with executive function in congenital heart disease.

OBJECTIVE: Persons with congenital heart disease (CHD) are at increased risk of neurodevelopmental disabilities, including impairments to executive function. Sulcal pattern features correlate with executive function in adolescents with single-ventricle heart disease and tetralogy of Fallot. However, the interaction of sulcal pattern features with genetic and participant factors in predicting executive dysfunction is unknown. METHODS: We studied sulcal pattern features, participant factors, and genetic risk for executive function impairment in a cohort with multiple CHD types using stepwise linear regression and machine learning. RESULTS: Genetic factors, including predicted damaging de novo or rare inherited variants in neurodevelopmental disabilities risk genes, apolipoprotein E genotype, and principal components of sulcal pattern features were associated with executive function measures after adjusting for age at testing, sex, mother's education, and biventricular versus single-ventricle CHD in a linear regression model. Using regression trees and bootstrap validation, younger participant age and larger alterations in sulcal pattern features were consistently identified as important predictors of decreased cognitive flexibility with left hemisphere graph topology often selected as the most important predictor. Inclusion of both sulcal pattern and genetic factors improved model fit compared to either alone. INTERPRETATION: We conclude that sulcal measures remain important predictors of cognitive flexibility, and the model predicting executive outcomes is improved by inclusion of potential genetic sources of neurodevelopmental risk. If confirmed, measures of sulcal patterning may serve as early imaging biomarkers to identify those at heightened risk for future neurodevelopmental disabilities.

Insufficient sleep and weekend recovery sleep: classification by a metabolomics-based machine learning ensemble.

Although weekend recovery sleep is common, the physiological responses to weekend recovery sleep are not fully elucidated. Identifying molecular biomarkers that represent adequate versus insufficient sleep could help advance our understanding of weekend recovery sleep. Here, we identified potential molecular biomarkers of insufficient sleep and defined the impact of weekend recovery sleep on these biomarkers using metabolomics in a randomized controlled trial. Healthy adults (n = 34) were randomized into three groups: control (CON: 9-h sleep opportunities); sleep restriction (SR: 5-h sleep opportunities); or weekend recovery (WR: simulated workweek of 5-h sleep opportunities followed by ad libitum weekend recovery sleep and then 2 days with 5-h sleep opportunities). Blood for metabolomics was collected on the simulated Monday immediately following the weekend. Nine machine learning models, including a machine learning ensemble, were built to classify samples from SR versus CON. Notably, SR showed decreased glycerophospholipids and sphingolipids versus CON. The machine learning ensemble showed the highest G-mean performance and classified 50% of the WR samples as insufficient sleep. Our findings show insufficient sleep and recovery sleep influence the plasma metabolome and suggest more than one weekend of recovery sleep may be necessary for the identified biomarkers to return to healthy adequate sleep levels.

Perceived discrimination and mental health outcomes in college students: the mediating effect of preventive health behaviors and social support.

Objective: To examine the role of social support and health behaviors in the association between discrimination and mental health (e.g., anxiety/depressive symptoms, suicidal ideation) among college students experiencing various forms of discrimination. Participants: Data were collected from 709 college students (42.8% White; 72.2% female) at a large urban university in Fall 2017. Methods: Students completed an online survey assessing perceived discrimination, anxiety/depressive symptoms, suicidal behavior, health behaviors, and social support. Moderation and parallel mediation analyses were conducted in PROCESS SPSS. Results: Results indicated that preventive health behaviors and social support partially mediated associations between discrimination and mental health outcomes. Conclusions: Findings highlight the need to increase awareness regarding engaging in preventive health behaviors on college campuses. For students experiencing discrimination, prevention, and social support might be key factors in improving mental health.

Mutations in genes related to myocyte contraction and ventricular septum development in non-syndromic tetralogy of Fallot.

Objective: Eighty percent of patients with a diagnosis of tetralogy of Fallot (TOF) do not have a known genetic etiology or syndrome. We sought to identify key molecular pathways and biological processes that are enriched in non-syndromic TOF, the most common form of cyanotic congenital heart disease, rather than single driver genes to elucidate the pathogenesis of this disease. Methods: We undertook exome sequencing of 362 probands with non-syndromic TOF and their parents within the Pediatric Cardiac Genomics Consortium (PCGC). We identified rare (minor allele frequency <1 × 10-4), de novo variants to ascertain pathways and processes affected in this population to better understand TOF pathogenesis. Pathways and biological processes enriched in the PCGC TOF cohort were compared to 317 controls without heart defects (and their parents) from the Simons Foundation Autism Research Initiative (SFARI). Results: A total of 120 variants in 117 genes were identified as most likely to be deleterious, with CHD7, CLUH, UNC13C, and WASHC5 identified in two probands each. Gene ontology analyses of these variants using multiple bioinformatic tools demonstrated significant enrichment in processes including cell cycle progression, chromatin remodeling, myocyte contraction and calcium transport, and development of the ventricular septum and ventricle. There was also a significant enrichment of target genes of SOX9, which is critical in second heart field development and whose loss results in membranous ventricular septal defects related to disruption of the proximal outlet septum. None of these processes was significantly enriched in the SFARI control cohort. Conclusion: Innate molecular defects in cardiac progenitor cells and genes related to their viability and contractile function appear central to non-syndromic TOF pathogenesis. Future research utilizing our results is likely to have significant implications in stratification of TOF patients and delivery of personalized clinical care.

Human Paenibacillus Infections: A Systematic Review with Comparison of Adult and Infant Cases.

Neonatal infections due to Paenibacillus species have increasingly been reported over the last few years. We performed a structured literature review of human Paenibacillus infections in infants and adults to compare the epidemiology of infections between these distinct patient populations. Thirty-nine reports describing 176 infections met our inclusion criteria and were included. There were 37 Paenibacillus infections occurring in adults caused by 23 species. The clinical presentations of infections were quite variable. In contrast, infections in infants were caused by only 3 species: P. thiaminolyticus (112/139, 80%), P. alvei (2/139, 1%) and P. dendritiformis (2/139, 1%). All of the infants with Paenibacillus infection presented with a sepsis syndrome or meningitis, often complicated by extensive cerebral destruction and hydrocephalus. Outcomes were commonly poor with 17% (24/139) mortality. Cystic encephalomalacia due to brain destruction was common in both Ugandan and American cases and 92/139 (66%) required surgical management of hydrocephalus following their infection. Paenibacillus infections are likely underappreciated in infants and effective treatments are urgently needed.

Association of cerebral metabolic rate following therapeutic hypothermia with 18-month neurodevelopmental outcomes after neonatal hypoxic ischemic encephalopathy.

BACKGROUND: Therapeutic hypothermia (TH) is standard of care for moderate to severe neonatal hypoxic ischemic encephalopathy (HIE) but many survivors still suffer lifelong disabilities and benefits of TH for mild HIE are under active debate. Development of objective diagnostics, with sensitivity to mild HIE, are needed to select, guide, and assess response to treatment. The objective of this study was to determine if cerebral oxygen metabolism (CMRO2) in the days after TH is associated with 18-month neurodevelopmental outcomes as the first step in evaluating CMRO2's potential as a diagnostic for HIE. Secondary objectives were to compare associations with clinical exams and characterise the relationship between CMRO2 and temperature during TH. METHODS: This was a prospective, multicentre, observational, cohort study of neonates clinically diagnosed with HIE and treated with TH recruited from the tertiary neonatal intensive care units (NICUs) of Boston Children's Hospital, Brigham and Women's Hospital, and Beth Israel Deaconess Medical Center between December 2015 and October 2019 with follow-up to 18 months. In total, 329 neonates ≥34 weeks gestational age admitted with perinatal asphyxia and suspected HIE were identified. 179 were approached, 103 enrolled, 73 received TH, and 64 were included. CMRO2 was measured at the NICU bedside by frequency-domain near-infrared and diffuse correlation spectroscopies (FDNIRS-DCS) during the late phases of hypothermia (C), rewarming (RW) and after return to normothermia (NT). Additional variables were body temperature and clinical neonatal encephalopathy (NE) scores, as well as findings from magnetic resonance imaging (MRI) and spectroscopy (MRS). Primary outcome was the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at 18 months, normed (SD) to 100 (15). FINDINGS: Data quality for 58 neonates was sufficient for analysis. CMRO2 changed by 14.4% per °C (95% CI, 14.2-14.6) relative to its baseline at NT while cerebral tissue oxygen extraction fraction (cFTOE) changed by only 2.2% per °C (95% CI, 2.1-2.4) for net changes from C to NT of 91% and 8%, respectively. Follow-up data for 2 were incomplete, 33 declined and 1 died, leaving 22 participants (mean [SD] postnatal age, 19.1 [1.2] month; 11 female) with mild to moderate HIE (median [IQR] NE score, 4 [3-6]) and 21 (95%) with BSID-III scores >85 at 18 months. CMRO2 at NT was positively associated with cognitive and motor composite scores (ß (SE) = 4.49 (1.55) and 2.77 (1.00) BSID-III points per 10-10 moL/dl × mm2/s, P = 0.009 and P = 0.01 respectively; linear regression); none of the other measures were associated with the neurodevelopmental outcomes. INTERPRETATION: Point of care measures of CMRO2 in the NICU during C and RW showed dramatic changes and potential to assess individual response to TH. CMRO2 following TH outperformed conventional clinical evaluations (NE score, cFTOE, and MRI/MRS) at predicting cognitive and motor outcomes at 18 months for mild to moderate HIE, providing a promising objective, physiologically-based diagnostic for HIE. FUNDING: This clinical study was funded by an NIH grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States (R01HD076258).

Exploring the Therapeutic Potential of Phosphorylated Cis-Tau Antibody in a Pig Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) results in the generation of tau. As hyperphosphorylated tau (p-tau) is one of the major consequences of TBI, targeting p-tau in TBI may lead to the development of new therapy. Twenty-five pigs underwent a controlled cortical impact. One hour after TBI, pigs were administered either vehicle (n = 13) or PNT001 (n = 12), a monoclonal antibody for the cis conformer of tau phosphorylated at threonine 231. Plasma biomarkers of neural injury were assessed for 14 days. Diffusion tensor imaging was performed at day 1 and 14 after injury, and these were compared to historical control animals (n = 4). The fractional anisotropy data showed significant white matter injury for groups at 1 day after injury in the corona radiata. At 14 days, the vehicle-treated pigs, but not the PNT001-treated animals, exhibited significant white matter injury compared to sham pigs in the ipsilateral corona radiata. The PNT001-treated pigs had significantly lower levels of plasma glial fibrillary acidic protein (GFAP) at day 2 and day 4. These findings demonstrate a subtle reduction in the areas of white matter injury and biomarkers of neurological injury after treatment with PNT001 following TBI. These findings support additional studies for PNT001 as well as the potential use of this agent in clinical trials in the near future.