Reward Behavior Disengagement, a Neuroeconomic Model-Based Objective Measure of Reward Pathology in Depression: Findings from the EMBARC Trial.

The probabilistic reward task (PRT) has identified reward learning impairments in those with major depressive disorder (MDD), as well as anhedonia-specific reward learning impairments. However, attempts to validate the anhedonia-specific impairments have produced inconsistent findings. Thus, we seek to determine whether the Reward Behavior Disengagement (RBD), our proposed economic augmentation of PRT, differs between MDD participants and controls, and whether there is a level at which RBD is high enough for depressed participants to be considered objectively disengaged. Data were gathered as part of the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study, a double-blind, placebo-controlled clinical trial of antidepressant response. Participants included 195 individuals with moderate to severe MDD (Quick Inventory of Depressive Symptomatology (QIDS-SR) score ≥ 15), not in treatment for depression, and with complete PRT data. Healthy controls (n = 40) had no history of psychiatric illness, a QIDS-SR score < 8, and complete PRT data. Participants with MDD were treated with sertraline or placebo for 8 weeks (stage I of the EMBARC trial). RBD was applied to PRT data using discriminant analysis, and classified MDD participants as reward task engaged (n = 137) or reward task disengaged (n = 58), relative to controls. Reward task engaged/disengaged groups were compared on sociodemographic features, reward-behavior, and sertraline/placebo response (Hamilton Depression Rating Scale scores). Reward task disengaged MDD participants responded only to sertraline, whereas those who were reward task engaged responded to sertraline and placebo (F(1293) = 4.33, p = 0.038). Reward task engaged/disengaged groups did not differ otherwise. RBD was predictive of reward impairment in depressed patients and may have clinical utility in identifying patients who will benefit from antidepressants.

Predictors of Mediastinal Exploration While on Extracorporeal Membrane Oxygenation After Pediatric Cardiac Surgery.

Cardiac surgical patients requiring extracorporeal membrane oxygenation (ECMO) are at increased risk for hemorrhage due to necessary anticoagulation, in-situ cannulas, and disturbed hemostasis. We performed a retrospective, cross-sectional study of patients 0-18 years old in our cardiac intensive care unit (CICU) cannulated to ECMO within 48 h of cardiopulmonary bypass. The 69 patients included in the study were divided into three analysis groups based on serial chest tube output per hour: no bleeding (NB) on admission to the CICU (21/69, 30%), bleeding stopped (BS) with medical management (26/69, 38%), bleeding requiring emergent mediastinal exploration (BME) (22/69, 32%). The NB group had a more favorable coagulation profile upon admission to the CICU (PTT 53 s NB, 105 s BS, 83 s BME p < 0.001, ACT 169 s NB, 225 s BS, 211 s BME, p =0.013). Only chest tube output during the first three postcannulation hours remained associated with the need for mediastinal exploration by multivariable analysis. An average chest-tube output of 11.6 mL/kg/h during the first three hours had the highest percentage of patients classified correctly (84%) for requiring mediastinal exploration during their ECMO run (sensitivity 91%, specificity 81%).

Impaired Neurovascular Function Underlies Poor Neurocognitive Outcomes and Is Associated with Nitric Oxide Bioavailability in Congenital Heart Disease.

We use a non-invasive MRI proxy of neurovascular function (pnvf) to assess the ability of the vasculature to supply baseline metabolic demand, to compare pediatric and young adult congenital heart disease (CHD) patients to normal referents and relate the proxy to neurocognitive outcomes and nitric oxide bioavailability. In a prospective single-center study, resting-state blood-oxygen-level-dependent (BOLD) and arterial spin labeling (ASL) MRI scans were successfully obtained from 24 CHD patients (age = 15.4 ± 4.06 years) and 63 normal referents (age = 14.1 ± 3.49) years. Pnvf was computed on a voxelwise basis as the negative of the ratio of functional connectivity strength (FCS) estimated from the resting-state BOLD acquisition to regional cerebral blood flow (rCBF) as estimated from the ASL acquisition. Pnvf was used to predict end-tidal CO2 (PETCO2) levels and compared to those estimated from the BOLD data. Nitric oxide availability was obtained via nasal measurements (nNO). Pnvf was compared on a voxelwise basis between CHD patients and normal referents and correlated with nitric oxide availability and neurocognitive outcomes as assessed via the NIH Toolbox. Pnvf was shown as highly predictive of PETCO2 using theoretical modeling. Pnvf was found to be significantly reduced in CHD patients in default mode network (DMN, comprising the ventromedial prefrontal cortex and posterior cingulate/precuneus), salience network (SN, comprising the insula and dorsal anterior cingulate), and central executive network (CEN, comprising posterior parietal and dorsolateral prefrontal cortex) regions with similar findings noted in single cardiac ventricle patients. Positive correlations of Pnvf in these brain regions, as well as the hippocampus, were found with neurocognitive outcomes. Similarly, positive correlations between Pnvf and nitric oxide availability were found in frontal DMN and CEN regions, with particularly strong correlations in subcortical regions (putamen). Reduced Pnvf in CHD patients was found to be mediated by nNO. Mediation analyses further supported that reduced Pnvf in these regions underlies worse neurocognitive outcome in CHD patients and is associated with nitric oxide bioavailability. Impaired neuro-vascular function, which may be non-invasively estimated via combined arterial-spin label and BOLD MR imaging, is a nitric oxide bioavailability dependent factor implicated in adverse neurocognitive outcomes in pediatric and young adult CHD.

Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease.

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease with 30% mortality from heart failure (HF) in the first year of life, but the cause of early HF remains unknown. Induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CM) from patients with HLHS showed that early HF is associated with increased apoptosis, mitochondrial respiration defects, and redox stress from abnormal mitochondrial permeability transition pore (mPTP) opening and failed antioxidant response. In contrast, iPSC-CM from patients without early HF showed normal respiration with elevated antioxidant response. Single-cell transcriptomics confirmed that early HF is associated with mitochondrial dysfunction accompanied with endoplasmic reticulum (ER) stress. These findings indicate that uncompensated oxidative stress underlies early HF in HLHS. Importantly, mitochondrial respiration defects, oxidative stress, and apoptosis were rescued by treatment with sildenafil to inhibit mPTP opening or TUDCA to suppress ER stress. Together these findings point to the potential use of patient iPSC-CM for modeling clinical heart failure and the development of therapeutics.

Do Lower Costs for Applicants Come at the Expense of Program Perception? A Cross-Sectional Survey Study of Virtual Residency Interviews.

Background: Travel costs and application fees make in-person residency interviews expensive, compounding existing financial burdens on medical students. We hypothesized virtual interviews (VI) would be associated with decreased costs for applicants compared to in-person interviews (IPI) but at the expense of gathering information with which to assess the program. Objective: To survey senior medical students and postgraduate year (PGY)-1 residents regarding their financial burden and program perception during virtual versus in-person interviews. Methods: The authors conducted a single center, multispecialty study comparing costs of IPI vs VI from 2020-2021. Fourth-year medical students and PGY-1 residents completed one-time surveys regarding interview costs and program perception. The authors compared responses between IPI and VI groups. Potential debt accrual was calculated for 3- and 7-year residencies. Results: Two hundred fifty-two (of 884, 29%) surveys were completed comprising 75 of 169 (44%) IPI and 177 of 715 (25%) VI respondents. The VI group had significantly lower interview costs compared to the IPI group (median $1,000 [$469-$2,050 IQR] $784-$1,216 99% CI vs $3,200 [$1,700-$5,500 IQR] $2,404-$3,996 99% CI, P<.001). The VI group scored lower for feeling the interview process was an accurate representation of the residency program (3.3 [0.5] vs 4.1 [0.7], P<.001). Assuming interview costs were completely loan-funded, the IPI group will have accumulated potential total loan amounts $2,334 higher than the VI group at 2% interest and $2,620 at 6% interest. These differences were magnified for a 7-year residency. Conclusions: Virtual interviews save applicants thousands of dollars at the expense of their perception of the residency program.

The impact of a smartphone meditation application on anesthesia trainee well-being.

STUDY OBJECTIVE: Physician burnout is a pervasive problem in the United States. The goal of this study was to investigate use of the smartphone meditation application Headspace® as a well-being improvement tool in anesthesia trainees. DESIGN: Prospective self-controlled observational study. SETTING: Anesthesia training program in an academic hospital. SUBJECTS: Resident and fellow trainees in the Department of Anesthesiology and Perioperative Medicine at the University of Pittsburgh Medical Center. INTERVENTIONS: Resident and fellow trainees were given a free 1-year subscription to the mindfulness application. Participation was voluntary and included questionnaires at baseline, 1 month, and 4 months for assessment of burnout and well-being. Questionnaires were linked with the use of de-identified codes and completed via REDCap. Questionnaires included the abbreviated Maslach Burnout Inventory, Becks Depression Index, Cohens Stress Score, Pittsburgh Sleep Quality Index, and a Headspace® Self-Reporting Questionnaire. MEASUREMENTS: Depression, stress, sleep quality, emotional exhaustion, depersonalization, and personal achievement. MAIN RESULTS: Of 112 trainees eligible to participate, 71 completed baseline questionnaires, 54 created application accounts, and 29 completed the entire questionnaire protocol with 4 months of app use. Application use was associated with reduced depression scores and increased feelings of personal achievement at both 1 month (p = 0.003, p = 0.066) and 4 months (p = 0.011, p = 0.005). Burnout from feelings of depersonalization and emotional exhaustion did not improve with application use. Over the study period, trainees completed 786 meditation sessions, accounting for 6123 min of app engagement. CONCLUSIONS: Findings of decreased depression scores and improved feelings of personal achievement suggest that Headspace® could serve as a mindfulness tool for incorporating meditation into the daily practice of anesthesia trainees in an effort to improve well-being.

Design and rationale of a clinical trial to increase cardiomyocyte division in infants with tetralogy of Fallot.

BACKGROUND: Patients with Tetralogy of Fallot with pulmonary stenosis (ToF/PS), the most common form of cyanotic congenital heart disease (CHD), develop adverse right ventricular (RV) remodeling, leading to late heart failure and arrhythmia. We recently demonstrated that overactive ß-adrenergic receptor signaling inhibits cardiomyocyte division in ToF/PS infants, providing a conceptual basis for the hypothesis that treatment with the ß-adrenergic receptor blocker, propranolol, early in life would increase cardiomyocyte division. No data are available in ToF/PS infants on the efficacy of propranolol as a possible novel therapeutic option to increase cardiomyocyte division and potentially reduce adverse RV remodeling. METHODS: Using a randomized, double-blind, placebo-controlled trial, we will evaluate the effect of propranolol administration on reactivating cardiomyocyte proliferation to prevent adverse RV remodeling in 40 infants with ToF/PS. Propranolol administration (1 mg/kg po QID) will begin at 1 month of age and last until surgical repair. The primary endpoint is cardiomyocyte division, quantified after 15N-thymidine administration with Multi-isotope Imaging Mass Spectrometry (MIMS) analysis of resected myocardial specimens. The secondary endpoints are changes in RV myocardial and cardiomyocyte hypertrophy. CONCLUSION: This trial will be the first study in humans to assess whether cardiomyocyte proliferation can be pharmacologically increased. If successful, the results could introduce a paradigm shift in the management of patients with ToF/PS from a purely surgical approach, to synergistic medical and surgical management. It will provide the basis for future multi-center randomized controlled trials of propranolol administration in infants with ToF/PS and other types of CHD with RV hypertension. CLINICAL TRIAL REGISTRATION: The trial protocol was registered at clinicaltrials.gov (NCT04713657).

Mucociliary Clearance Scans Show Infants Undergoing Congenital Cardiac Surgery Have Poor Airway Clearance Function.

Background: Infants undergoing congenital cardiac surgery with cardiopulmonary bypass are at high risk for respiratory complications. As impaired airway mucociliary clearance (MCC) can potentially contribute to pulmonary morbidity, our study objective was to measure airway clearance in infants undergoing congenital cardiac surgery and examine correlation with clinical covariables that may impair airway clearance function. Materials and Methods: Airway clearance in infants was measured over 30 min using inhaled nebulized Technetium 99m sulfur colloid administered either via a nasal cannula or the endotracheal tube in intubated infants. This was conducted bedside with a portable gamma camera. No difficulty was encountered in positioning the gamma camera over the patient, and neither the camera nor the MCC scan interfered with routine medical care or caused any adverse events. Patient and perioperative variables were examined relative to the MCC measurements. Results: We prospectively enrolled 57 infants undergoing congenital cardiac surgery and conducted a single MCC scan per patient. MCC data from 42 patients were analyzable, including five pre-operative, 15 (40.5%) in the immediate post-operative period (days 1-2), and 22 (59.5%) were later post-operative (≥3 days). Pre-operative MCC was inversely proportional to days requiring post-operative mechanical ventilation (p = 0.006) and non-invasive positive pressure ventilation (p = 0.017). MCC was higher at later post-operative days (p = 0.002) with immediate post-operative MCC being lower (3%; 0-13%) than either pre-operative (21%; 4-25%) (p = 0.091) or later post-operative MCC (18%; 0-29%) (p = 0.054). Among the infants with low post-operative MCC, significantly more were pre-mature [5/19 (26%) vs. 0/18 (0%); p = 0.046], were intubated [14/19 (75%) vs. only 7/18 (39%); p = 0.033] and were receiving higher FiO2 (40%, 27-47% vs. 26%, 21-37%; p = 0.015). Conclusions: This is the first study to show that infants undergoing congenital cardiac surgery have impaired MCC. MCC appeared lowest in the immediate post-operative period. Worse MCC was associated with pre-maturity, mechanical ventilation, or receiving higher FiO2. These findings suggest MCC scans should be further explored for informing clinical decision making to improve post-surgical respiratory outcomes. The possible therapeutic benefit of airway clearance maneuvers for infants with poor MCC function should also be investigated.

Sugammadex Neuromuscular Blockade Reversal Associated With Lower Postoperative Arterial Carbon Dioxide Levels After Congenital Cardiac Surgery.

OBJECTIVE: To compare postoperative arterial blood gas samples and requirement for respiratory support between patients who received sugammadex versus neostigmine reversal before extubation after congenital cardiac surgery. DESIGN: Retrospective, cross-sectional study. SETTING: Single-center, university-based, tertiary care hospital. PARTICIPANTS: Patients with congenital heart disease undergoing surgery with cardiopulmonary bypass. INTERVENTIONS: Chart review. MEASUREMENTS AND MAIN RESULTS: The first postoperative arterial blood gas measurements were abstracted from electronic medical records, and reintubation or use of positive- pressure respiratory support within the first 24 postoperative hours was documented. Of the 237 charts reviewed, 111 (47%) patients received sugammadex reversal and 126 (53%) received neostigmine. Multivariate models showed that patients with 2-ventricle congenital heart disease who received sugammadex had lower postoperative arterial carbon dioxide partial pressure (PaCO2) values (coefficient -3.1, 95% confidence interval [CI] -5.9 to -0.4; p = 0.026) and required less- noninvasive positive- pressure ventilation (odds ratio 0.3, 95% CI 0.1-0.8; p = 0.021). Single-ventricle congenital heart disease patients who received sugammadex had higher postoperative pH values (coefficient 0.04, 95% CI 0.01-0.06; p = 0.01) and lower PaCO2 values (coefficient -5.2, 95% CI -9.6 to -0.8; p = 0.021). CONCLUSION: Sugammadex reversal was associated with lower postoperative PaCO2 values. In addition, sugammadex reversal was associated with less need for noninvasive positive- pressure ventilation in 2-ventricle patients. The magnitude of the effect appears modest, therefore the clinical significance remains unclear. Additional studies focused on investigating particular patient populations, such as infants, single-ventricle congenital heart disease, or patients with pulmonary hypertension, are needed to identify whether these patients appreciate a greater benefit from sugammadex reversal.

Transesophageal probe placement increases endotracheal tube cuff pressure but is not associated with postoperative extubation failure after congenital cardiac surgery.

Context: The concomitant use of cuffed endotracheal tubes (ETT) and transesophageal echocardiography (TEE) probes increases ETT cuff pressures (CP), which may contribute to mucosal ischemia and perioperative complications such as failed extubation. Aims: To assess changes in ETT CP after TEE insertion in patients of different age groups undergoing congenital heart surgery and examine the relationship between ETT CP and postoperative extubation failure. Settings and Design: Single-center quality improvement project. Subjects and Methods: ETT CP was measured with a manometer following intubation and again after TEE insertion. Tracheal perfusion pressure was then calculated and postoperative extubation failures were recorded. Statistical Analysis: Chi-square testing, Fisher's-exact testing, one-way analysis of variance testing or Kruskal-Wallis testing with Dunn's pairwise, and student's t-test or Wilcoxon rank-sum testing were used to analyze the data. Results: Median ETT CP increased significantly after TEE insertion in each age group, with infants showing a smaller magnitude of increase (+2 [1-6] cm H2O, P < 0.001) than adults (+12 [8-14] cm H2O, P = 0.008) (intergroup comparison P = 0.002). Five patients (9%) failed extubation, all of which were infants. Within the infant subgroup, no significant difference existed between failed vs successful extubation regarding ETT CP during bypass (15 ± 1 vs 16 ± 2 mmHg, P = 0.206) or tracheal perfusion pressure pre-bypass (34 ± 9 vs 38 ± 11 mmHg, P = 0.518), during bypass (20 ± 9 vs 22 ± 6 mmHg, P = 0.697), or post-bypass (42 ± 9 vs 41 ± 9 mmHg, P = 0.923). There was a significant difference in cardiopulmonary bypass duration (151 ± 29 vs 85 ± 32 min, P < 0.001). Conclusion: Factors beyond intraoperative ETT CP likely play a larger role in postoperative extubation failure.

Wellness Principles Correlate With More Favorable Burnout Scores in Junior Anesthesiology Residents.

BACKGROUND: Strategies to prevent or reduce burnout for anesthesiology residents remain relatively unexplored. We aimed to determine if participation in a wellness course would be associated with lower burnout. METHODS: A prospective, case-control survey/questionnaire study was implemented within a single anesthesiology residency in a large academic medical center program. One class participated in an inaugural wellness course (n = 15) promoting particular wellness principles 4 months into their postgraduate year (PGY)-1, while another class with no course participation served as controls (n = 13). Both groups completed the Maslach Burnout Inventory (MBI) 6 months into their PGY-2 year. In addition, a survey measuring their perceived ability to implement wellness principles (regardless of course participation) as well as validated questionnaires measuring stress, depression, and sleep quality were administered. RESULTS: Course participants had a trend toward lower MBI depersonalization scores; however, this was not statistically significant (MBI score 7 versus 12, P = .078, Cohen d 0.71). In a multivariable model, course participation yielded lower exhaustion scores (P = .011) whereas higher stress yielded higher exhaustion scores (P = .013), and higher depression scores yielded higher depersonalization scores (P = .019). A higher perceived ability to implement the wellness principles resulted in significantly better scores in all 3 burnout components (exhaustion P = .049, depersonalization P = .004 achievement P = .001). CONCLUSION: Residents who felt they could implement wellness principles had lower burnout, regardless of course participation. Our brief course exposure had only marginal independent effects, suggesting that more longitudinal and repeated exposures to wellness training are likely required to produce a more effective outcome for mitigating burnout.

Effect of Intrinsic Patterns of Functional Brain Connectivity in Moderating Antidepressant Treatment Response in Major Depression.

OBJECTIVE: Major depressive disorder is associated with aberrant resting-state functional connectivity across multiple brain networks supporting emotion processing, executive function, and reward processing. The purpose of this study was to determine whether patterns of resting-state connectivity between brain regions predict differential outcome to antidepressant medication (sertraline) compared with placebo. METHODS: Participants in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study underwent structural and resting-state functional MRI at baseline. Participants were then randomly assigned to receive either sertraline or placebo treatment for 8 weeks (N=279). A region of interest-based approach was utilized to compute functional connectivity between brain regions. Linear mixed-model intent-to-treat analyses were used to identify brain regions that moderated (i.e., differentially predicted) outcomes between the sertraline and placebo arms. RESULTS: Prediction of response to sertraline involved several within- and between-network connectivity patterns. In general, higher connectivity within the default mode network predicted better outcomes specifically for sertraline, as did greater between-network connectivity of the default mode and executive control networks. In contrast, both placebo and sertraline outcomes were predicted (in opposite directions) by between-network hippocampal connectivity. CONCLUSIONS: This study identified specific functional network-based moderators of treatment outcome involving brain networks known to be affected by major depression. Specifically, functional connectivity patterns of brain regions between and within networks appear to play an important role in identifying a favorable response for a drug treatment for major depressive disorder.

Reward related ventral striatal activity and differential response to sertraline versus placebo in depressed individuals.

Medications to treat major depressive disorder (MDD) are not equally effective across patients. Given that neural response to rewards is altered in MDD and given that reward-related circuitry is modulated by dopamine and serotonin, we examined, for the first time, whether reward-related neural activity moderated response to sertraline, an antidepressant medication that targets these neurotransmitters. A total of 222 unmedicated adults with MDD randomized to receive sertraline (n = 110) or placebo (n = 112) in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study completed demographic and clinical assessments, and pretreatment functional magnetic resonance imaging while performing a reward task. We tested whether an index of reward system function in the ventral striatum (VS), a key reward circuitry region, moderated differential response to sertraline versus placebo, assessed with the Hamilton Rating Scale for Depression (HSRD) over 8 weeks. We observed a significant moderation effect of the reward index, reflecting the temporal dynamics of VS activity, on week-8 depression levels (Fs ≥ 9.67, ps ≤ 0.002). Specifically, VS responses that were abnormal with respect to predictions from reinforcement learning theory were associated with lower week-8 depression symptoms in the sertraline versus placebo arms. Thus, a more abnormal pattern of pretreatment VS dynamic response to reward expectancy (expected outcome value) and prediction error (difference between expected and actual outcome), likely reflecting serotonergic and dopaminergic deficits, was associated with better response to sertraline than placebo. Pretreatment measures of reward-related VS activity may serve as objective neural markers to advance efforts to personalize interventions by guiding individual-level choice of antidepressant treatment.

Multicenter evaluation of the cobas® HIV-1 quantitative nucleic acid test for use on the cobas® 4800 system for the quantification of HIV-1 plasma viral load.

BACKGROUND AND OBJECTIVES: Measurement of HIV-1 viral load (VL) is necessary to monitor treatment efficacy in patients receiving antiretroviral therapy. We evaluated the performance of the cobas® HIV-1 quantitative nucleic acid test for use on the cobas® 4800 system ("cobas 4800 HIV-1"). METHODS: Limit of detection, linearity, accuracy, precision, and specificity of cobas 4800 HIV-1, COBAS® AmpliPrep/COBAS® Taqman® HIV-1 version 2.0 (CAP/CTM HIV-1 v2) and Abbott RealTime HIV-1 were determined in one or two out of three sites. RESULTS: The limit of detection of the cobas 4800 HIV-1 for 400 µL and 200 µL input volumes was 14.2 copies/mL (95% CI: 12.5-16.6 copies/mL) and 43.9 copies/mL (37.7-52.7 copies/mL), respectively. Cobas 4800 HIV-1 demonstrated 100% specificity, and results were linear for all analyzed group M HIV-1 subtypes. Precision was high (SD < 0.19 log10) across all measured ranges, reagent lots and input volumes. Correlation between cobas 4800 HIV-1 and CAP/CTM HIV-1 v2 or RealTime HIV-1 was high (R2 ≥ 0.95). Agreement between cobas 4800 HIV-1 and CAP/CTM HIV-1 v2 was 96.5% (95.0%-97.7%) at a threshold of 50 copies/mL, and 97.2% (95.8%-98.3%) at 200 copies/mL. Agreement between cobas 4800 HIV-1 and RealTime HIV-1 was 96.6% (93.4%-98.5%) at 50 copies/mL, and 97.0% (94.0%-98.8%) at 200 copies/mL. The mean difference between cobas 4800 HIV-1 and CAP/CTM HIV-1 v2 or RealTime HIV-1 was -0.10 log10 or 0.01 log10, respectively. CONCLUSIONS: The cobas 4800 HIV-1 test is highly sensitive, accurate and correlated well with other assays, including agreement around clinically relevant thresholds, indicating minimal overall VL quantification differences between tested platforms.

Deposition studies of aerosol delivery by nasal cannula to infants.

AIM: Nasal cannulas are used to provide oxygen support for infants and have been considered as a means for delivering aerosols to the lungs. To measure mucociliary clearance in the lungs of infants with congenital heart defects, we delivered radiopharmaceutical aerosols via a nasal cannula. Here we report on the pulmonary and nasal deposition of these aerosols. METHOD: A total of 18 infants (median age = 26 days; quartiles = 11-74 days) performed clearance measurements soon before or after corrective cardiac surgery. The regional aerosol deposition was assessed using gamma camera imaging. RESULTS: Cannula flow rate significantly affected pulmonary dosing. Flow rates useful for oxygen support were associated with low pulmonary deposition (2 L/min; mean, 4.5% of deposited dose; range, 2%-9%; n = 7) and high nasal deposition. Much lower cannula flow rates increased the pulmonary deposition (0.2 L/min; mean, 33.5% of deposited dose; range, 15%-51%; n = 5; P = 0.005 vs 2 L/min). The ratio of nose/lung dosing was approximately 26:1 at 2 L/min and 2:1 at 0.2 L/min. Bench studies demonstrated cannula output rates of 10.2 ± 1.7% (2 L/min) and 3.3 ± 0.4% (0.2 L/min) of the loaded nebulizer dose during a 2-minute delivery. Combining in vitro and in vivo results, we estimate that 0.46% of the loaded nebulizer dose reaches the lungs at 2 L/min vs 1.10% at 0.2 L/min during a 2-minute delivery. CONCLUSION: With the delivery system used here, pulmonary aerosol delivery via nasal cannula was very inefficient at the flow rates required to provide oxygen support. Even at low flows, nasal deposition was substantial and local toxicity must be considered.

A Review of Clinical Poster Presentations at the Sixth Biennial Pediatric Anesthesia Neurodevelopment Assessment (PANDA) Symposium.

Clinical researchers studying the long-term neurocognitive effects of anesthetic and sedative agents on children continue to struggle with identifying a phenotype for anesthetic neurotoxicity, the window of vulnerability, and the toxicity threshold in terms of concentration and duration. The Sixth Biennial Pediatric Anesthesia Neurodevelopment Assessment (PANDA) symposium at Columbia University included a moderated poster presentation session where 4 investigators presented their latest contributions to the landscape of clinical anesthetic neurotoxicity research. A lack of standardization in the design of clinical studies in terms of age at exposure, duration and type of exposure, and outcome measures assessed were highlighted by all the investigators. Suggestions for the future direction of clinical trials included the implementation of more consistent study parameters and the employment of standardized neurocognitive testing and imaging before and after exposure to general anesthesia. Presentations covered a broad range of topics including the valid translation of preclinical studies to human subjects, the quantification of real-world exposures to anesthetic and sedative medications, and possible alternatives to these exposures.

Academic faculty demonstrate higher well-being than residents: Pennsylvania anesthesiology programs' results of the 2017-2018 ACGME well-being survey.

STUDY OBJECTIVE: Physician burnout and suicide are at epidemic proportions. There is very little data directly comparing resident versus faculty well-being. The 2017-2018 ACGME resident and faculty surveys mark the first time that well-being questions were included. The purpose of this study was to determine whether responses to ACGME well-being questions would differ significantly between anesthesiology residents and academic anesthesiology faculty. DESIGN: 2017-2018 ACGME well-being survey responses. SETTING: All eight Pennsylvania anesthesiology residency programs. PATIENTS: None. INTERVENTIONS: None. MEASUREMENTS: The authors compared the 5-point Likert scale responses (1 = Never through 5 = Very Often) between residents (371/384 responses, 97%) and faculty (277/297 responses, 93%) for each of the twelve well-being questions. Responses were also dichotomized as being ≥4 versus <4 for categorical comparisons. MAIN RESULTS: Faculty responded higher than residents both by mean scores and percent of scores ≥ 4 for 6/12 questions (questions 1 (p < 0.001), 2 (p < 0.001), 4 (p < 0.001), 5 (p < 0.001), 8 (p < 0.001), and 11 (p = 0.001)). Residents responded categorically higher for question 9 (p = 0.022) although this was not considered statistically significant. Residents responded lowest for "Reflected on how your work helps make the world a better place" (question 1), whereas the lowest faculty responses were for questions 1, 9, and 10. Both had high responses for "Had an enjoyable interaction with a patient" (question 11). CONCLUSIONS: Pennsylvania academic anesthesiology faculty survey responses demonstrated a higher level of well-being compared to their residents. The variation in scoring suggests that anesthesiology residents and faculty have differing perceptions of various well-being domains. Information from well-being surveys can help provide programs with focus areas that they can intervene on to improve physician well-being.

Associations of Perioperative Renal Oximetry Via Near-Infrared Spectroscopy, Urinary Biomarkers, and Postoperative Acute Kidney Injury in Infants After Congenital Heart Surgery: Should Creatinine Continue to Be the Gold Standard?

OBJECTIVES: Examine the relationship between perioperative renal regional tissue oximetry, urinary biomarkers, and acute kidney injury in infants after congenital cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective, observational. SETTING: Cardiac operating room and cardiac ICU. PATIENTS: Neonates and infants without history of kidney injury or anatomic renal abnormality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Renal regional tissue oximetry was measured intraoperatively and for 48 hours postoperatively. Urinary levels of neutrophil gelatinase-associated lipocalin and tissue inhibitor of metalloproteinases 2 together with insulin-like growth factor-binding protein 7 were measured preoperatively, 2, 12, and 24 hours postoperatively. Patients were categorized as no acute kidney injury, stage 1, or Stage 2-3 acute kidney injury using the Kidney Disease: Improving Global Outcomes criteria with 43 of 70 (61%) meeting criteria for any stage acute kidney injury. Stage 2-3 acute kidney injury patients had higher tissue inhibitor of metalloproteinases 2, insulin-like growth factor-binding protein 7 at 2 hours (0.3 vs 0.14 for stage 1 acute kidney injury and 0.05 for no acute kidney injury; p = 0.052) and 24 hours postoperatively (1.71 vs 0.27 for stage 1 acute kidney injury and 0.19 for no acute kidney injury, p = 0.027) and higher neutrophil gelatinase-associated lipocalin levels at 24 hours postoperatively (10.3 vs 3.4 for stage 1 acute kidney injury and 6.2 for no acute kidney injury, p = 0.019). Stage 2-3 acute kidney injury patients had lower mean cardiac ICU renal regional tissue oximetry (66% vs 79% for stage 1 acute kidney injury and 84% for no acute kidney injury, p = 0.038). Regression analyses showed that tissue inhibitor of metalloproteinases 2, insulin-like growth factor-binding protein 7 at 2 hours postoperatively and nadir intraoperative renal regional tissue oximetry to be independent predictors of postoperative kidney damage as measured by urinary neutrophil gelatinase-associated lipocalin. CONCLUSIONS: We observed modest differences in perioperative renal regional tissue oximetry and urinary biomarker levels compared between acute kidney injury groups classified by creatinine-dependent Kidney Disease: Improving Global Outcomes criteria, but there were significant correlations between renal regional tissue oximetry, tissue inhibitor of metalloproteinases 2, insulin-like growth factor-binding protein 7, and postoperative neutrophil gelatinase-associated lipocalin levels. Kidney injury after infant cardiac surgery may be undetectable by functional assessment (creatinine) alone, and continuous monitoring of renal regional tissue oximetry may be more sensitive to important subclinical acute kidney injury.

Pretreatment and early-treatment cortical thickness is associated with SSRI treatment response in major depressive disorder.

To date, there are no biomarkers for major depressive disorder (MDD) treatment response in clinical use. Such biomarkers could allow for individualized treatment selection, reducing time spent on ineffective treatments and the burden of MDD. In search of such a biomarker, multisite pretreatment and early-treatment (1 week into treatment) structural magnetic resonance (MR) images were acquired from 184 patients with MDD randomized to an 8-week trial of the selective serotonin reuptake inhibitor (SSRI) sertraline or placebo. This study represents a large, multisite, placebo-controlled effort to examine the association between pretreatment differences or early-treatment changes in cortical thickness and treatment-specific outcomes. For standardization, a novel, robust site harmonization procedure was applied to structural measures in a priori regions (rostral and caudal anterior cingulate, lateral orbitofrontal, rostral middle frontal, and hippocampus), chosen based on previously published reports. Pretreatment cortical thickness or volume did not significantly associate with SSRI response. Thickening of the rostral anterior cingulate cortex in the first week of treatment was associated with better 8-week responses to SSRI (p = 0.010). These findings indicate that frontal lobe structural alterations in the first week of treatment may be associated with long-term treatment efficacy. While these associational findings may help to elucidate the specific neural targets of SSRIs, the predictive accuracy of pretreatment or early-treatment structural alterations in classifying treatment remitters from nonremitters was limited to 63.9%. Therefore, in this large sample of adults with MDD, structural MR imaging measures were not found to be clinically translatable biomarkers of treatment response to SSRI or placebo.