Enhlink infers distal and context-specific enhancer-promoter linkages.

Enhlink is a computational tool for scATAC-seq data analysis, facilitating precise interrogation of enhancer function at the single-cell level. It employs an ensemble approach incorporating technical and biological covariates to infer condition-specific regulatory DNA linkages. Enhlink can integrate multi-omic data for enhanced specificity, when available. Evaluation with simulated and real data, including multi-omic datasets from the mouse striatum and novel promoter capture Hi-C data, demonstrate that Enhlink outperfoms alternative methods. Coupled with eQTL analysis, it identified a putative super-enhancer in striatal neurons. Overall, Enhlink offers accuracy, power, and potential for revealing novel biological insights in gene regulation.

Modified Beer-Lambert algorithm to measure pulsatile blood flow, critical closing pressure, and intracranial hypertension.

We introduce a frequency-domain modified Beer-Lambert algorithm for diffuse correlation spectroscopy to non-invasively measure flow pulsatility and thus critical closing pressure (CrCP). Using the same optical measurements, CrCP was obtained with the new algorithm and with traditional nonlinear diffusion fitting. Results were compared to invasive determination of intracranial pressure (ICP) in piglets (n = 18). The new algorithm better predicted ICP elevations; the area under curve (AUC) from logistic regression analysis was 0.85 for ICP ≥ 20 mmHg. The corresponding AUC for traditional analysis was 0.60. Improved diagnostic performance likely results from better filtering of extra-cerebral tissue contamination and measurement noise.

Age Influence on Total Ankle Arthroplasty Outcomes: A Systematic Review.

Total ankle arthroplasty has gained popularity as advancing technology has resulted in higher survivorship and lower complication rates. In the past, total ankle replacement candidates have been reserved for patients greater than 50 years old with low physical demands and minimal deformity. However, with newer designs, surgeons have begun to expand their patient inclusion criteria. The purpose of this study was to analyze current literature comparing patient outcomes among total ankle replacement patients over and under age 50. A systematic review of the literature was performed comparing the impact of age to total ankle replacement outcomes. 159 articles were reviewed. Seven studies met our inclusion criteria and therefore were included in the synthesis. No statistically significant difference in outcomes was determined for the younger and older age groups in regard to reoperation, complications, and implant survivorship (p = .412, .955, .155, respectively). However, the statistical model is underpowered given the limited number of studies. While the findings of this study infer that total ankle replacement outcomes are not significantly different among older and younger age groups, further research in this area is needed.

Exploring Functional Improvements by Sex in Six-Minute Walk Test, Exertional Angina, and Dyspnea After Enhanced External Counterpulsation Therapy.

PURPOSE: The objective of this study was to explore functional improvements by sex for patients with refractory angina pectoris using a 6-min walk test (6MWT) after enhanced external counterpulsation (EECP) therapy. METHODS: All patients who completed EECP from 2015 to 2023 were identified for analysis retrospectively, utilizing the electronic medical record. Patients completed 35 1-hr EECP sessions 5 d/wk over 7 wk. All baseline and post-EECP intervention 6MWT, exertional angina, and dyspnea measurements were assessed on the first and last sessions, respectively. Paired and unpaired t tests and linear and stepwise multivariable regression analyses were performed. RESULTS: The cohort consisted of 116 patients (24 female) with a mean age of 69 ± 13 yr. After EECP, there was a mean improvement of 128 m (72%) in distance walked during the 6MWT ( P < .001) with 126 ± 91 m improvement in males and 134 ± 73 m in females. The improvement in angina and dyspnea scores was 3.5 ± 2.1 and 4.2 ± 2.4, respectively. There were no differences between the sexes for improvements in 6MWT distance, angina, or dyspnea. Univariate associations for change in 6MWT distance included body mass index (BMI; adjusted R2  = .05) and being a nonsmoker (adjusted R2  = .03). The only independent predictor for increasing distance during 6MWT was BMI (adjusted R2  = .1; P = .001). CONCLUSION: Patients who have refractory angina pectoris can improve their functional capacity while simultaneously decreasing exertional angina and dyspnea using EECP. This study highlights the equal efficacy of EECP therapy for females.

Community assessment of methods to deconvolve cellular composition from bulk gene expression.

We evaluate deconvolution methods, which infer levels of immune infiltration from bulk expression of tumor samples, through a community-wide DREAM Challenge. We assess six published and 22 community-contributed methods using in vitro and in silico transcriptional profiles of admixed cancer and healthy immune cells. Several published methods predict most cell types well, though they either were not trained to evaluate all functional CD8+ T cell states or do so with low accuracy. Several community-contributed methods address this gap, including a deep learning-based approach, whose strong performance establishes the applicability of this paradigm to deconvolution. Despite being developed largely using immune cells from healthy tissues, deconvolution methods predict levels of tumor-derived immune cells well. Our admixed and purified transcriptional profiles will be a valuable resource for developing deconvolution methods, including in response to common challenges we observe across methods, such as sensitive identification of functional CD4+ T cell states.

Saccades, pupil response and blink abnormalities in Huntington's disease patients during free viewing.

OBJECTIVE: Video-based eye tracking was used to investigate saccade, pupil, and blink abnormalities among patients with Huntington's disease (HD) who watched sequences of short videos. HD, an autosomal dominant neurodegenerative disorder resulting from a CAG mutation on chromosome 4, produces motor and cognitive impairments including slow or irregular eye movements, which have been studied using structured tasks. METHODS: To explore how HD affects eye movements under instruction free conditions, we assessed 22 HD patients and their age matched controls in a 10-minute video-based free viewing task. RESULTS: Patients with HD experienced a significant reduction in saccade exploration rate following video clip transitions, an increase in pupil reactions to luminance changes after clip transitions, and a significant higher blink rate throughout the task compared to the control group. CONCLUSIONS: These results show that HD has a significant impact on how patients visually explore and respond to their environment under unconstrained and ecologically natural conditions. SIGNIFICANCE: Eye tracking in HD patients revealed saccadic, pupil, and blink abnormalities in early HD patients, suggestive of brain circuitry abnormalities that probably involve brain stem deficits. Further research should explore the impact of these changes on the quality of life of the patients affected by the disease.

Chassis-based fiber-coupled optical probe design for reproducible quantitative diffuse optical spectroscopy measurements.

Advanced optical neuromonitoring of cerebral hemodynamics with hybrid diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS) methods holds promise for non-invasive characterization of brain health in critically ill patients. However, the methods' fiber-coupled patient interfaces (probes) are challenging to apply in emergent clinical scenarios that require rapid and reproducible attachment to the head. To address this challenge, we developed a novel chassis-based optical probe design for DOS/DCS measurements and validated its measurement accuracy and reproducibility against conventional, manually held measurements of cerebral hemodynamics in pediatric swine (n = 20). The chassis-based probe design comprises a detachable fiber housing which snaps into a 3D-printed, circumferential chassis piece that is secured to the skin. To validate its reproducibility, eight measurement repetitions of cerebral tissue blood flow index (BFI), oxygen saturation (StO2), and oxy-, deoxy- and total hemoglobin concentration were acquired at the same demarcated measurement location for each pig. The probe was detached after each measurement. Of the eight measurements, four were acquired by placing the probe into a secured chassis, and four were visually aligned and manually held. We compared the absolute value and intra-subject coefficient of variation (CV) of chassis versus manual measurements. No significant differences were observed in either absolute value or CV between chassis and manual measurements (p > 0.05). However, the CV for BFI (mean ± SD: manual, 19.5% ± 9.6; chassis, 19.0% ± 10.8) was significantly higher than StO2 (manual, 5.8% ± 6.7; chassis, 6.6% ± 7.1) regardless of measurement methodology (p<0.001). The chassis-based DOS/DCS probe design facilitated rapid probe attachment/re-attachment and demonstrated comparable accuracy and reproducibility to conventional, manual alignment. In the future, this design may be adapted for clinical applications to allow for non-invasive monitoring of cerebral health during pediatric critical care.

A Pan-Cancer Patient-Derived Xenograft Histology Image Repository with Genomic and Pathologic Annotations Enables Deep Learning Analysis.

Patient-derived xenografts (PDX) model human intra- and intertumoral heterogeneity in the context of the intact tissue of immunocompromised mice. Histologic imaging via hematoxylin and eosin (H&E) staining is routinely performed on PDX samples, which could be harnessed for computational analysis. Prior studies of large clinical H&E image repositories have shown that deep learning analysis can identify intercellular and morphologic signals correlated with disease phenotype and therapeutic response. In this study, we developed an extensive, pan-cancer repository of >1,000 PDX and paired parental tumor H&E images. These images, curated from the PDX Development and Trial Centers Research Network Consortium, had a range of associated genomic and transcriptomic data, clinical metadata, pathologic assessments of cell composition, and, in several cases, detailed pathologic annotations of neoplastic, stromal, and necrotic regions. The amenability of these images to deep learning was highlighted through three applications: (i) development of a classifier for neoplastic, stromal, and necrotic regions; (ii) development of a predictor of xenograft-transplant lymphoproliferative disorder; and (iii) application of a published predictor of microsatellite instability. Together, this PDX Development and Trial Centers Research Network image repository provides a valuable resource for controlled digital pathology analysis, both for the evaluation of technical issues and for the development of computational image-based methods that make clinical predictions based on PDX treatment studies. Significance: A pan-cancer repository of >1,000 patient-derived xenograft hematoxylin and eosin-stained images will facilitate cancer biology investigations through histopathologic analysis and contributes important model system data that expand existing human histology repositories.

Automated Analysis Pipeline for Extracting Saccade, Pupil, and Blink Parameters Using Video-Based Eye Tracking.

The tremendous increase in the use of video-based eye tracking has made it possible to collect eye tracking data from thousands of participants. The traditional procedures for the manual detection and classification of saccades and for trial categorization (e.g., correct vs. incorrect) are not viable for the large datasets being collected. Additionally, video-based eye trackers allow for the analysis of pupil responses and blink behaviors. Here, we present a detailed description of our pipeline for collecting, storing, and cleaning data, as well as for organizing participant codes, which are fairly lab-specific but nonetheless, are important precursory steps in establishing standardized pipelines. More importantly, we also include descriptions of the automated detection and classification of saccades, blinks, "blincades" (blinks occurring during saccades), and boomerang saccades (two nearly simultaneous saccades in opposite directions where speed-based algorithms fail to split them), This is almost entirely task-agnostic and can be used on a wide variety of data. We additionally describe novel findings regarding post-saccadic oscillations and provide a method to achieve more accurate estimates for saccade end points. Lastly, we describe the automated behavior classification for the interleaved pro/anti-saccade task (IPAST), a task that probes voluntary and inhibitory control. This pipeline was evaluated using data collected from 592 human participants between 5 and 93 years of age, making it robust enough to handle large clinical patient datasets. In summary, this pipeline has been optimized to consistently handle large datasets obtained from diverse study cohorts (i.e., developmental, aging, clinical) and collected across multiple laboratory sites.

Spatial nonstationarity of image noise in widefield optical imaging and its effects on cluster-based inference for resting-state functional connectivity.

BACKGROUND: Resting-state functional connectivity (RSFC) analysis with widefield optical imaging (WOI) is a potentially powerful tool to develop imaging biomarkers in mouse models of disease before translating them to human neuroimaging with functional magnetic resonance imaging (fMRI). The delineation of such biomarkers depends on rigorous statistical analysis. However, statistical understanding of WOI data is limited. In particular, cluster-based analysis of neuroimaging data depends on assumptions of spatial stationarity (i.e., that the distribution of cluster sizes under the null is equal at all brain locations). Whether actual data deviate from this assumption has not previously been examined in WOI. NEW METHOD: In this manuscript, we characterize the effects of spatial nonstationarity in WOI RSFC data and adapt a "two-pass" technique from fMRI to correct cluster sizes and mitigate spatial bias, both parametrically and nonparametrically. These methods are tested on multi-institutional data. RESULTS AND COMPARISON WITH EXISTING METHODS: We find that spatial nonstationarity has a substantial effect on inference in WOI RSFC data with false positives much more likely at some brain regions than others. This pattern of bias varies between imaging systems, contrasts, and mouse ages, all of which could affect experimental reproducibility if not accounted for. CONCLUSIONS: Both parametric and nonparametric corrections for nonstationarity result in significant improvements in spatial bias. The proposed methods are simple to implement and will improve the robustness of inference in optical neuroimaging data.

Rapid and sensitive detection of genome contamination at scale with FCS-GX.

Assembled genome sequences are being generated at an exponential rate. Here we present FCS-GX, part of NCBI's Foreign Contamination Screen (FCS) tool suite, optimized to identify and remove contaminant sequences in new genomes. FCS-GX screens most genomes in 0.1-10 min. Testing FCS-GX on artificially fragmented genomes demonstrates high sensitivity and specificity for diverse contaminant species. We used FCS-GX to screen 1.6 million GenBank assemblies and identified 36.8 Gbp of contamination, comprising 0.16% of total bases, with half from 161 assemblies. We updated assemblies in NCBI RefSeq to reduce detected contamination to 0.01% of bases. FCS-GX is available at https://github.com/ncbi/fcs/ or https://doi.org/10.5281/zenodo.10651084 .

Attentional modulation of eye blinking is altered by sex, age, and task structure.

Spontaneous eye blinking is gaining popularity as a proxy for higher cognitive functions, as it is readily modulated by both environmental demands and internal processes. Prior studies were impoverished in sample size, sex representation and age distribution, making it difficult to establish a complete picture of the behavior. Here we present eye-tracking data from a large cohort of normative participants (n=604, 393 F, aged 5-93 years) performing two tasks: one with structured, discrete trials (interleaved pro/anti-saccade task; IPAST) and one with a less structured, continuous organization in which participants watch movies (free-viewing; FV). Sex- and age-based analyses revealed that females had higher blink rates between the ages of 22 and 58 years in the IPAST, and 22 and 34 years in FV. We derived a continuous measure of blink probability to reveal behavioral changes driven by stimulus appearance in both paradigms. In the IPAST, blinks were suppressed near stimulus appearance, particularly on correct anti-saccade trials, which we attribute to the stronger inhibitory control required for anti-saccades compared to pro-saccades. In FV, blink suppression occurred immediately after scene changes, and the effect was sustained on scenes where gaze clustered among participants (indicating engagement of attention). Females were more likely than males to blink during appearance of novel stimuli in both tasks, but only within the age bin of 18-44 years. The consistency of blink patterns in each paradigm endorses blinking as a sensitive index for changes in visual processing and attention, while sex and age differences drive interindividual variability.Significance Statement Eye-tracking is becoming useful as a non-invasive tool for detecting preclinical markers of neurological and psychiatric disease. Blinks are understudied despite being an important supplement to saccade and pupil eye-tracking metrics. The present study is a crucial step in developing a healthy baseline for blink behavior to compare to clinical groups. While many prior blink studies suffered from small sample sizes with relatively low age- and sex-diversity (review by Jongkees & Colzato, 2016), our large cohort of healthy participants has permitted a more detailed analysis of sex and age effects in blink behavior. Furthermore, our analysis techniques are robust to temporal changes in blink probability, greatly clarifying the relationship between blinking, visual processing, and inhibitory control mechanisms on visual tasks.

New Picture Stimuli for the NIH Stroke Scale: A Validation Study.

BACKGROUND: The National Institutes of Health Stroke Scale is a widely accepted tool for structured graded neurological examination of stroke or suspected stroke in the hyperacute setting. Concerns have arisen about the use of its picture stimuli in a contemporary and global health context. Here, we present new stimuli prepared to serve the needs of stroke providers worldwide: the precarious painter image description and updated objects for naming. METHODS: This was a validation study of 101 healthy fluent English speakers. Participants were reached by the Johns Hopkins Outpatient Center, the University of South Carolina, and Prisma Health from 2022 to 2023 and included residents of the United States, Germany, Canada, the United Kingdom, Australia, and Zambia. Participants were recorded in person or via video conferencing when asked to describe the new picture, while a subset named seven illustrations. Multivariate analyses of variance were used for primary analyses. In a complementary investigation, 299 attendees of the 2023 International Stroke Conference were asked about their preference for the existing or new stimuli and why. RESULTS: Each of the 44 content units from the picture description was included by at least 5% of respondents in the demographically representative subsample. Performance was similar across healthy participants irrespective of age, sex, race, ethnicity, or education. Typical descriptions were characterized by an average of 23 content units (SD=5) conveyed with 167 syllables (SD=79). The new naming stimuli were recognized by 100% of participants from many countries as being familiar and identifiable, and names provided in response to the task were highly convergent. The majority of stroke health care providers preferred both the precarious painter and naming stimuli. CONCLUSIONS: The description of the new National Institutes of Health Stroke Scale picture, the precarious painter, results in rich samples among healthy speakers that will provide an appropriate basis for the detection of language deficits.

Role of continuous pulse oximetry and capnography monitoring in the prevention of postoperative respiratory failure, postoperative opioid-induced respiratory depression and adverse outcomes on hospital wards: A systematic review and meta-analysis.

OBJECTIVE: The current standards of postoperative respiratory monitoring on medical-surgical floors involve spot-pulse oximetry checks every 4-8 h, which can miss the opportunity to detect prolonged hypoxia and acute hypercapnia. Continuous respiratory monitoring can recognize acute respiratory depression episodes; however, the existing evidence is limited. We sought to review the current evidence on the effectiveness of continuous pulse oximetry (CPOX) with and without capnography versus routine monitoring and their effectiveness for detecting postoperative respiratory failure, opioid-induced respiratory depression, and preventing downstream adverse events. METHODS: We performed a systematic literature search on Ovid Medline, Embase, and Cochrane Library databases for articles published between 1990 and April 2023. The study protocol was registered in Prospero (ID: 439467), and PRISMA guidelines were followed. The NIH quality assessment tool was used to assess the quality of the studies. Pooled analysis was conducted using the software R version 4.1.1 and the package meta. The stability of the results was assessed using sensitivity analysis. DESIGN: Systematic Review and Meta-Analysis. SETTING: Postoperative recovery area. PATIENTS: 56,538 patients, ASA class II to IV, non-invasive respiratory monitoring, and post-operative respiratory depression. INTERVENTIONS: Continuous pulse oximetry with or without capnography versus routine monitoring. MEASUREMENTS: Respiratory rate, oxygen saturation, adverse events, and rescue events. RESULTS: 23 studies (17 examined CPOX without capnography and 5 examined CPOX with capnography) were included in this systematic review. CPOX was better at recognizing desaturation (SpO2 < 90%) OR: 11.94 (95% CI: 6.85, 20.82; p < 0.01) compared to standard monitoring. No significant differences were reported for ICU transfer, reintubation, and non-invasive ventilation between the two groups. CONCLUSIONS: Oxygen desaturation was the only outcome better detected with CPOX in postoperative patients in hospital wards. These comparisons were limited by the small number of studies that could be pooled for each outcome and the heterogeneity between the studies.

The impact of fentanyl on state- and county-level psychostimulant and cocaine overdose death rates by race in Ohio from 2010 to 2020: a time series and spatiotemporal analysis.

BACKGROUND: Over the past decade in the USA, increases in overdose rates of cocaine and psychostimulants with opioids were highest among Black, compared to White, populations. Whether fentanyl has contributed to the rise in cocaine and psychostimulant overdoses in Ohio is unknown. We sought to measure the impact of fentanyl on cocaine and psychostimulant overdose death rates by race in Ohio. METHODS: We conducted time series and spatiotemporal analyses using data from the Ohio Public Health Information Warehouse. Primary outcomes were state- and county-level overdose death rates from 2010 to 2020 for Black and White populations. Measures of interest were overdoses consisting of four drug involvement classes: (1) all cocaine overdoses, (2) cocaine overdoses not involving fentanyl, (3) all psychostimulant overdoses, and (4) psychostimulant overdoses not involving fentanyl. We fit a time series model of log standardized mortality ratios (SMRs) using a Bayesian generalized linear mixed model to estimate posterior median rate ratios (RR). We conducted a spatiotemporal analysis by modeling the SMR for each drug class at the county level to characterize county-level variation over time. RESULTS: In 2020, the greatest overdose rates involved cocaine among Black (24.8 deaths/100,000 people) and psychostimulants among White (10.1 deaths/100,000 people) populations. Annual mortality rate ratios were highest for psychostimulant-involved overdoses among Black (aRR = 1.71; 95% CI (1.43, 2.02)) and White (aRR = 1.60, 95% CI (1.39, 1.80)) populations. For cocaine not involving fentanyl, annual mortality rate ratios were similar among Black (aRR = 1.04; 95% CI (0.96,1.16)) and White (aRR = 1.02; 95% CI (0.87, 1.20)) populations. Within each drug category, change over time was similar for both racial groups. The spatial models highlighted county-level variation for all drug categories. CONCLUSIONS: Without the involvement of fentanyl, cocaine overdoses remained constant while psychostimulant overdoses increased. Tailored harm reduction approaches, such as distribution of fentanyl test strips and the removal of punitive laws that influence decisions to contact emergency services, are the first steps to reduce cocaine overdose rates involving fentanyl among urban populations in Ohio. In parallel, harm reduction policies to address the increase in psychostimulant overdoses are warranted.

Cardiac magnetic resonance predictors for successful primary biventricular repair of unbalanced complete common atrioventricular canal.

BACKGROUND: Patients with unbalanced common atrioventricular canal can be difficult to manage. Surgical planning often depends on pre-operative echocardiographic measurements. We aimed to determine the added utility of cardiac MRI in predicting successful biventricular repair in common atrioventricular canal. METHODS: We conducted a retrospective cohort study of children with common atrioventricular canal who underwent MRI prior to repair. Associations between MRI and echocardiographic measures and surgical outcome were tested using logistic regression, and models were compared using area under the receiver operator characteristic curve. RESULTS: We included 28 patients (median age at MRI: 5.2 months). The optimal MRI model included the novel end-diastolic volume index (using the ratio of left ventricular end-diastolic volume to total end-diastolic volume) and the left ventricle-right ventricle angle in diastole (area under the curve 0.83, p = 0.041). End-diastolic volume index ≤ 0.18 and left ventricle-right ventricle angle in diastole ≤ 72° yield a sensitivity of 83% and specificity of 81% for successful biventricular repair. The optimal multimodality model included the end-diastolic volume index and the echocardiographic atrioventricular valve index with an area under the curve of 0.87 (p = 0.026). CONCLUSIONS: Cardiac MRI can successfully predict successful biventricular repair in patients with unbalanced common atrioventricular canal utilising the end-diastolic volume index alone or in combination with the MRI left ventricle-right ventricle angle in diastole or the echocardiographic atrioventricular valve index. A prospective cardiac MRI study is warranted to better define the multimodality characteristic predictive of successful biventricular surgery.

Patent ductus arteriosus and coarctation of the aorta in association with PRDM6 variants.

Patent ductus arteriosus (PDA) and coarctation of the aorta (CoA) are relatively common congenital heart defects. Pathogenic variants in PRDM6, which encodes a smooth-muscle-cell-specific transcription factor, have now been etiologically associated with non-syndromic PDA. We present three patients with PDA and CoA found to harbor PRDM6 variants, including a novel, likely-pathogenic variant.

Cerebral microhemorrhages in children with congenital heart disease: Prevalence, risk factors, and impact on neurodevelopmental outcomes.

Background: Infants with complex congenital heart disease (CHD) require life-saving corrective/palliative heart surgery in the first weeks of life. These infants are at risk for brain injury and poor neurodevelopmental outcomes. Cerebral microhemorrhages (CMH) are frequently seen after neonatal bypass heart surgery, but it remains unknown if CMH are a benign finding or constitute injury. Herein, we investigate the risk factors for developing CMH and their clinical significance. Methods: 192 infants with CHD undergoing corrective cardiac surgery with cardiopulmonary bypass (CPB) at a single institution were prospectively evaluated with pre-(n = 183) and/or postoperative (n = 162) brain magnetic resonance imaging (MRI). CMH severity was scored based on total number of microhemorrhages. Antenatal, perioperative, and postoperative candidate risk factors for CMH and neurodevelopmental (ND) outcomes were analyzed. Eighteen-month neurodevelopmental outcomes were assessed using the Bayley-III Scales of Infants and Toddler Development in a subset of patients (n = 82). Linear regression was used to analyze associations between risk factors or ND outcomes and presence/number of CMH. Results: The most common CHD subtypes were hypoplastic left heart syndrome (HLHS) (37%) and transposition of the great arteries (TGA) (33%). Forty-two infants (23%) had CMH present on MRI before surgery and 137 infants (85%) post-surgery. No parameters evaluated were significant risk factors for preoperative CMH. In multivariate analysis, cardiopulmonary bypass (CPB) duration (p < 0.0001), use of extracorporeal membrane oxygenation (ECMO) support (p < 0.0005), postoperative seizure(s) (p < 0.03), and lower birth weight (p < 0.03) were associated with new or worsened CMH postoperatively. Higher CMH number was associated with lower scores on motor (p < 0.03) testing at 18 months. Conclusion: CMH is a common imaging finding in infants with CHD with increased prevalence and severity after CPB and adverse impact on neurodevelopmental outcomes starting at a young age. Longer duration of CPB and need for postoperative ECMO were the most significant risk factors for developing CMH. However, presence of CMH on preoperative scans indicates non-surgical risk factors that are yet to be identified. Neuroprotective strategies to mitigate risk factors for CMH may improve neurodevelopmental outcomes in this vulnerable population.

Diffuse Optical Monitoring of Cerebral Hemodynamics and Oxygen Metabolism during and after Cardiopulmonary Bypass: Hematocrit Correction and Neurological Vulnerability.

Cardiopulmonary bypass (CPB) provides cerebral oxygenation and blood flow (CBF) during neonatal congenital heart surgery, but the impacts of CPB on brain oxygen supply and metabolic demands are generally unknown. To elucidate this physiology, we used diffuse correlation spectroscopy and frequency-domain diffuse optical spectroscopy to continuously measure CBF, oxygen extraction fraction (OEF), and oxygen metabolism (CMRO2) in 27 neonatal swine before, during, and up to 24 h after CPB. Concurrently, we sampled cerebral microdialysis biomarkers of metabolic distress (lactate-pyruvate ratio) and injury (glycerol). We applied a novel theoretical approach to correct for hematocrit variation during optical quantification of CBF in vivo. Without correction, a mean (95% CI) +53% (42, 63) increase in hematocrit resulted in a physiologically improbable +58% (27, 90) increase in CMRO2 relative to baseline at CPB initiation; following correction, CMRO2 did not differ from baseline at this timepoint. After CPB initiation, OEF increased but CBF and CMRO2 decreased with CPB time; these temporal trends persisted for 0-8 h following CPB and coincided with a 48% (7, 90) elevation of glycerol. The temporal trends and glycerol elevation resolved by 8-24 h. The hematocrit correction improved quantification of cerebral physiologic trends that precede and coincide with neurological injury following CPB.