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The purpose of this study was to investigate neo-aortic curvature and diameter variation using the principal component analysis in patients who underwent a Norwood procedure for hypoplastic left heart syndrome. We further assessed whether neo-aortic curvature and diameter features are associated with clinical outcomes, single right ventricle function and flow hemodynamic patterns derived by 4D-Flow MRI. 55 patients with Fontan circulation who underwent a Norwood procedure in infancy underwent cardiac MRI as part of surveillance of their Fontan circulation. Neo-aortic models segmented from the MRI angiography were subjected to principal component analysis. Principal component (PC) score values representing curvature and diameter variability were compared between patients with and without composite clinical event and correlated with standard cardiac hemodynamics. Fourteen patients experienced composite adverse clinical events. The PCs describing the variations in aortic curvature were not associated with cardiac MRI hemodynamics or clinical events. The diameter-based 2nd PC describing the degree of aortic tapering was significantly associated with the end-systolic volume index (R = 0.34, P = 0.011), ejection fraction (R = -0.44, P = 0.001), and viscous energy loss measured in the ascending aorta (R = 0.45, P = 0.009). High 2nd PC score values describing abrupt diameter changes were also associated with worse freedom from clinical events (P = 0.042). Neo-aortic shape variation described by gradual diameter tapering is strongly linked to better clinical and hemodynamic outcomes. Neo-aortic curvature and luminal trajectory seems to have less impact on the overall hemodynamics and long-term outcomes., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the University of Colorado Institutional Review Board with the waived written consent, COMIRB # 19-1420; date of approval: June 20, 2019. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Nitrous oxide (N 2 O) induces rapid and durable antidepressant effects. The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled N 2 O induces rapid and specific activation of layer V (L5) pyramidal neurons in the cingulate cortex of rodents exposed to chronic stress conditions. N 2 O-induced L5 activation rescues a stress-associated hypoactivity state, persists following exposure, and is necessary for its antidepressant-like activity. Although NMDA-receptor antagonism is believed to be a primary mechanism of action for N 2 O, L5 neurons activate even when NMDA-receptor function is attenuated through both pharmacological and genetic approaches. By examining different molecular and circuit targets, we identify N 2 O-induced inhibition of calcium-sensitive potassium (SK2) channels as a key molecular interaction responsible for driving specific L5 activity along with ensuing antidepressant-like effects. These results suggest that N 2 O-induced L5 activation is crucial for its fast antidepressant action and this effect involves novel and specific molecular actions in distinct cortical cell types., Competing Interests: Competing Interests No competing interests. Additional Declarations: There is NO Competing Interest.

Understanding the neurophysiological changes that occur during loss and recovery of consciousness is a fundamental aim in neuroscience and has marked clinical relevance. Here, we utilize multimodal magnetic resonance neuroimaging to investigate changes in regional network connectivity and neurovascular dynamics as the brain transitions from wakefulness to dexmedetomidine-induced unconsciousness, and finally into early-stage recovery of consciousness. We observed widespread decreases in functional connectivity strength across the whole brain, and targeted increases in structure-function coupling (SFC) across select networks-especially the cerebellum-as individuals transitioned from wakefulness to hypnosis. We also observed robust decreases in cerebral blood flow (CBF) across the whole brain-especially within the brainstem, thalamus, and cerebellum. Moreover, hypnosis was characterized by significant increases in the amplitude of low-frequency fluctuations (ALFF) of the resting-state blood oxygen level-dependent signal, localized within visual and somatomotor regions. Critically, when transitioning from hypnosis to the early stages of recovery, functional connectivity strength and SFC-but not CBF-started reverting towards their awake levels, even before behavioral arousal. By further testing for a relationship between connectivity and neurovascular alterations, we observed that during wakefulness, brain regions with higher ALFF displayed lower functional connectivity with the rest of the brain. During hypnosis, brain regions with higher ALFF displayed weaker coupling between structural and functional connectivity. Correspondingly, brain regions with stronger functional connectivity strength during wakefulness showed greater reductions in CBF with the onset of hypnosis. Earlier recovery of consciousness was associated with higher baseline (awake) levels of functional connectivity strength, CBF, and ALFF, as well as female sex. Across our findings, we also highlight the role of the cerebellum as a recurrent marker of connectivity and neurovascular changes between states of consciousness. Collectively, these results demonstrate that induction of, and emergence from dexmedetomidine-induced unconsciousness are characterized by widespread changes in connectivity and neurovascular dynamics.

Preliminary evidence suggests perturbations of the kynurenine pathway (KP) of tryptophan metabolism in infants with single ventricle heart disease (SVHD). In 72 infants with SVHD undergoing stage 2 palliation (S2P) and 41 controls, we quantified serum KP metabolite concentrations via tandem mass spectroscopy pre-S2P and post-S2P at 2, 24, and 48 h and assessed metabolite relationships with post-S2P outcomes (length of stay, hypoxemia burden, and intubation duration). Pre-S2P, SVHD infants had lower tryptophan and serotonin levels and higher kynurenic acid, 3-hydroxykynurenine, and picolinic acid levels than controls. Post-S2P, metabolites peaked at 2 h, with return to baseline by 48 h for all except kynurenic acid, which remained elevated. Metabolite concentrations pre-S2P were poorly associated with outcomes. A lower serotonin peak 2 h post-S2P was associated with longer length of stay and intubation duration. Multiple metabolites at 24 and 48 h correlated with outcomes; notably, elevated kynurenic acid was associated with worse results for all three outcomes. Our results confirm that interstage SVHD infants have altered KP activity compared to controls. Further, the link between outcomes and KP metabolites post-S2P-but not at baseline-demonstrates that acute, perioperative changes in tryptophan catabolism may be more important to tolerating S2P physiology than chronic interstage changes., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Objective Resistance management in psychotherapy remains a foundational skill that is associated with positive client outcomes (Westra, H. A., & Norouzian, N. (2018). Using motivational interviewing to manage process markers of ambivalence and resistance in cognitive behavioral therapy. Cognitive Therapy and Research , 42 (2), 193-203). However, little is known about which therapist characteristics contribute to successful management of resistance. Research has suggested that psychotherapy performance does not improve with experience (Goldberg, S. B., Rousmaniere, T., Miller, S. D., Whipple, J., Nielsen, S. L., Hoyt, W. T., & Wampold, B. E. (2016). Do psychotherapists improve with time and experience? A longitudinal analysis of outcomes in a clinical setting. Journal of Counseling Psychology , 63 (1), 1-11), that psychotherapists lack humility (Macdonald, J., & Mellor-Clark, J. (2015). Correcting psychotherapists' blindsidedness: Formal feedback as a means of overcoming the natural limitations of therapists. Clinical Psychology & Psychotherapy , 22 (3), 249-257), and that difficult therapeutic moments may dysregulate therapist emotions (Muran, J. C., & Eubanks, C. F. (2020). Therapist performance under pressure: Negotiating emotion, difference, and rupture . American Psychological Association). This study aimed to 1) identify whether psychotherapy experience (i.e., training versus no training and number of years of psychotherapy experience) was associated with resistance management skill, and 2) identify whether humility and difficulties regulating emotions among trained individuals were each associated with resistance management. Method: A sample of 76 trained and 98 untrained participants were recruited for the present study. All participants completed the Comprehensive Intellectual Humility Scale (CIHS, Krumrei-Mancuso, E. J., & Rouse, S. V. (2016). The development and validation of the comprehensive intellectual humility scale. Journal of Personality Assessment , 98 (2), 209-221), the Difficulties in Emotion Regulation Scale (DERS; Gratz, K. L., & Roemer, L. (2004). Multidimensional assessment of emotion regulation and dysregulation: Development, factor structure, and initial validation of the difficulties in emotion regulation scale. Journal of Psychopathology and Behavioral Assessment , 26 (1), 41-54), and the Resistance Vignette Task (RVT; Westra, H. A., Nourazian, N., Poulin, L., Hara, K., Coyne, A., Constantino, M. J., Olson, D., & Antony, M. M. (2021). Testing a deliberate practice workshop for developing appropriate responsivity to resistance markers: A randomized clinical trial. Psychotherapy , 58 , 175-185 ) which was used to assess resistance management skill. Results: Trained individuals performed significantly better on resistance management than untrained individuals; however, years of experience within the trained sample were not associated with resistance management. Conversely, lower humility and greater difficulties regulating emotions were each associated with significantly poorer resistance management in trained individuals. Conclusion: These findings suggest the possibility of improving training to focus on key skills, like resistance management, through supporting humility and emotion regulation in training, as opposed to simply acquiring more experience.

Evaluate the use of coronary CTA as an initial assessment for determining Right Ventricle Dependent Coronary Circulation (RVDCC) in neonates with Pulmonary Atresia with Intact Ventricular Septum (PA IVS). Retrospective review of cases with coronary CTA and compare with available catheter angiography, pathology, surgical reports, and outcomes from Mar 2015 to May 2022. In our cohort of 16 patients, 3 were positive for RVDCC, confirmed by pathologic evaluation, and there was concordance for presence or absence of RVDCC with catheter angiography in 5 patients (4 negatives for RVDCC, 1 positive). Clinical follow up for the 8 patients that underwent RV decompression had no clinical evidence of myocardial ischemia. Our findings suggest that coronary CTA is reliable as first-line imaging for determination of RVDCC in neonates with PA IVS. These findings, if supported by further prospective study, may reserve invasive coronary angiography for cases with diagnostic uncertainty or at the time of necessary transcatheter interventions., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Despite the high prevalence of disability and the frequency with which people with disabilities encounter the health care system, physicians report inadequate knowledge regarding caring for their patients with disabilities., Objective: To determine the number and type of disability-related competencies in the Accreditation Council for Graduate Medical Education's Milestones 2.0., Design: Cross-sectional analysis of publicly available data to identify, via key word search, the presence of disability-related competencies using disability-related terms derived from the World Health Organization's International Classification of Functioning Disability and Health., Setting: Accreditation Council for Graduate Medical Education's Milestones 2.0., Participants: N/A INTERVENTIONS: N/A MAIN OUTCOME MEASURE: Presence of disability-related competencies., Results: Over one-third (37.5%) of specialties had zero disability-related competencies. Nineteen (59.4%) included an Interpersonal and Communication Skills Milestone that mentions disability as a potential barrier to communication. No specialties had Systems-Based Practice or Practice-Based Learning and Improvement disability-related competencies. Physical medicine and rehabilitation (PM&R) had six disability-related competencies, preventive medicine occupational and environmental medicine had three, and otolaryngology and transition year each had two., Conclusions: A minority of medical and surgical specialties had disability-related competencies outside of the Interpersonal and Communication domain. With the rising prevalence of disability and the lack of physicians with expertise in the care of people with disability, the time is now to integrate disability competencies into residencies, especially for the primary care specialties., (© 2024 The Author(s). PM&R published by Wiley Periodicals LLC on behalf of American Academy of Physical Medicine and Rehabilitation.)

Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic disease of autosomal dominant inheritance, with an estimated prevalence of 3-20/100 000. Its main feature is neuroendocrine neoplasia in the parathyroid glands, the endocrine pancreas, the duodenum, and the pituitary gland. In this article, we review the diagnostic and therapeutic options for MEN1-associated tumors., Methods: We present an analysis and evaluation of retrospective case studies retrieved from PubMed, guidelines from Germany and abroad, and our own experience., Results: The disease is caused by mutations in the MEN1 gene. Mutation carriers should participate in a regular, specialized screening program from their twenties onward. The early diagnosis and individualized treatment of MEN1-associated tumors can prevent the development of life-threatening hormonal syndromes and prolong the expected life span of MEN1 patients from 55 to 70 years, as well as improving their quality of life. Surgical treatment is based on the location, size, growth dynamics, and functional activity of the tumors. The evidence for treatment strategies is derived from retrospective studies only (level III evidence) and the optimal treatment is often a matter of debate. This is a further reason for treatment in specialized centers., Conclusion: MEN1 is a rare disease, and, consequently, the evidence base for its treatment is limited. Carriers of disease-causing mutations in the MEN1 gene should be cared for in specialized interdisciplinary centers, so that any appreciable tumor growth or hormonal activity can be detected early and organ-sparing treatment can be provided.

Functioning pancreatic neuroendocrine neoplasms other than insulinomas and gastrinomas (rf-pNENs) are exceptionally rare tumours. Thus, their characteristics and long-term prognosis have not been well defined. This article aims to present data and experience from a single institution concerning this topic. Twelve of 216 (5.5%) patients with pNENs operated between 2002 and 2022 in the ENETS Centre of Excellence Marburg had rf-pNENs and their data were retrospectively analysed. We identified three vasoactive intestinal polypeptide producing pNENs, four glucagonomas and five calcitoninomas. The tumour could be visualised by preoperative imaging in all 12 patients, and six patients had distant metastases at the time of diagnosis. The tumour was located in the pancreatic tail in nine patients and the median tumour size was 82 (range 12-220) mm. Eleven patients underwent tumour resections (two robotic, nine conventional), nine of which were R0. After a median follow-up of 75 (range 1-247) months, six patients were alive, five of whom had no evidence of disease. All patients who remained disease-free had an initial R0 resection of the primary tumour and no initial liver involvement. This study sheds light on the distinct characteristics and outcomes of these exceedingly rare tumours, offering insights for improved understanding and management., (© 2024. The Author(s).)

Background: Outside of randomized controlled trials (RCTs), there are limited data regarding the acceptability of injectable long-acting cabotegravir + rilpivirine (LA-CAB+RPV) among persons living with HIV (PLWH). To evaluate acceptability, we describe participant-reported outcomes (PRO) of LA-CAB+RPV among a population underrepresented in RCTs., Setting: Ruth M. Rothstein Core Center (CORE), large urban HIV clinic in Chicago, Illinois, USA., Methods: We interviewed PLWH prescribed LA-CAB+RPV who receive primary care at CORE. PRO endpoints included treatment satisfaction, tolerability of injections, reasons for switching to LA-CAB+RPV, and unexpected effects of LA-CAB+RPV. Mean and standard deviations (mean±SD) and proportions (%) are reported., Results: Among respondents (N=150), 67% identified as Non-Hispanic Black, 24% Hispanic, 56% male; the average age was 43 years (SD:13.2), and 37% were ≥50 years old. Most respondents (93%) completed ≥3 injection appointments at the time of interview. The most common reasons for switching to LA-CAB+RPV were no longer wanting to take pills (89%) and trouble taking their pills daily (58%). Treatment satisfaction was high (6.7±0.5 out of 7). Two-thirds (61%) reported an unexpected aspect of their life improved. Pain from injections was common (98%), with a mean pain score of 4.3 out of 10. Among those reporting pain, half (47%) reported pain decreased after initial injection. Among participants reporting pain score >6 (n=36), most (78%) reported no improvement since initial injection., Conclusions: We found high treatment satisfaction with LA-CAB+RPV in a diverse population. Participants reported moderate injection pain, which improved with time. Results suggest injectable LA-CAB+RPV will be met with acceptability across diverse participant populations., Competing Interests: Conflicts of Interest and Source of Funding: Blake Max discloses that a family member that is employed of ViiV Healthcare. For the remaining authors none were declared. No funding sources utilized in this work., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Repair is preferable for children with mitral valve disease, but mitral valve replacement (MVR) is occasionally necessary. This report presents the results of a multiinstitutional Investigational Device Exemption trial of the 15-mm St Jude (SJM) mechanical mitral valve (Abbott Structural Heart)., Methods: From May 2015 to March 2017, 23 children aged 0.4 to 27.4 months (mean, 7.8 months; 85% <1 year) weighing 2.9 to 10.9 kg (mean, 5.5 kg) at 15 centers underwent MVR with a 15-mm SJM mechanical mitral valve (intraannular, 45%; supraannular, 55%). A total of 21 (91%) of the children had undergone previous cardiac operations. Follow-up until death, valve explantation, or 5 years postoperatively was 100% complete., Results: There were 6 deaths, all in the first 12 months; no death was valve related. Four patients required a pacemaker (2 supraannular, 2 intraannular). Three patients had thrombosis requiring valve explantation at 13, 21, and 35 days postoperatively. Two of these 3 patients were receiving low-molecular-weight heparin for anticoagulation, and the third had factor V Leiden deficiency. There were 5 nonfatal bleeding complications within 4 months of MVR (1-year freedom from bleeding, 71.0%). The 1- and 5-year freedom from death or valve explantation was 71.0%., Conclusions: In small children with severe mitral valve disease requiring MVR, the 15-mm SJM mechanical mitral valve provides satisfactory hemodynamics. Mortality and complications in these patients are not trivial. Low-molecular-weight heparin likely should be avoided as primary anticoagulation. Eventual valve replacement is inevitable., Competing Interests: Disclosures The authors have no conflicts of interest to disclose and have no relationship with Abbott, including any financial, professional, or personal relationship that could be perceived to bias their work consistent with International Committee of Medical Journal Editors standards, as applicable., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Surgical site infections (SSI) following congenital heart surgery (CHS) remain a significant source of morbidity. Delayed sternal closure (DSC) is often required to minimize the potential for hemodynamic instability. The purpose of this study was to determine the incidence of SSI among patients undergoing DSC versus primary chest closure (PCC) and to define a potential inflection point for increased risk of SSI as a function of open chest duration (OCD).A retrospective review of our institutional Society of Thoracic Surgeons dataset is to identify patients undergoing CHS at our institution between 2015 and 2020. Incidences of SSI were compared between DSC and PCC patients. DSC patients were evaluated to determine the association of OCD and the incidence of SSI.2582 operations were performed at our institution between 2015 and 2020, including 195 DSC and 2387 PCC cases. The incidence of SSI within the cohort was 1.8% (47/2,582). DSC patients had significantly higher incidences of SSI (17/195, 8.7%) than PCC patients (30/2387, 1.3%, p < 0.001). Further, patients with an OCD of four or more days had a significantly higher incidence of SSI (11/62, 17.7%, p = 0.006) than patients with an OCD less than 4 days (6/115, 5.3%).The incidence of SSI following CHS is higher in DSC patients compared to PCC patients. Prolonged OCD of 4 days or more significantly increases the risk of SSI and represents a potentially modifiable risk factor for SSI predisposition. These data support dedicated, daily post-operative assessment of candidacy for chest closure to minimize the risk of SSI., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Amino acids (AAs) are modular building blocks which nature uses to synthesize both macromolecules, such as proteins, and small molecule natural products, such as alkaloids and non-ribosomal peptides. While the 20 main proteinogenic AAs display relatively limited side chain diversity, a wide range of non-canonical amino acids (ncAAs) exist that are not used by the ribosome for protein synthesis, but contain a broad array of structural features and functional groups. In this communication, we report the discovery of the biosynthetic pathway for a new ncAA, pazamine, which contains a cyclopropane ring formed in two steps. In the first step, a chlorine is added onto the C 4 position of lysine by a radical halogenase, PazA. The cyclopropane ring is then formed in the next step by a pyridoxal-5'-phosphate-dependent enzyme, PazB, via an S N 2-like attack at C 4 to eliminate chloride. Genetic studies of this pathway in the native host, Pseudomonas azotoformans, show that pazamine potentially inhibits ethylene biosynthesis in growing plants based on alterations in the root phenotype of Arabidopsis thaliana seedlings. We further show that PazB can be utilized to make an alternative cyclobutane-containing AA. These discoveries may lead to advances in biocatalytic production of specialty chemicals and agricultural biotechnology., (© 2024 Wiley-VCH GmbH.)

There is an urgent need for non-invasive imaging-based biomarkers suitable for diagnostic surveillance of cardiac allograft vasculopathy (CAV) in pediatric heart transplant (PHT) patients. The purpose of this study was to comprehensively investigate left ventricular (LV) myocardial deformation in conjunction with electromechanical discoordination in PHT. PHT patients with and without CAV were evaluated for echocardiography derived global longitudinal strain (GLS) and electromechanical discoordination indices including systolic stretch fraction (SSF) and diastolic relaxation fraction (DRF). SSF was increased in CAV(+) patients at the time of CAV diagnosis (median CAV(+) 5.0 vs. median CAV(-) 0.0, P = 0.008) and in the echocardiogram preceding the CAV diagnosis (median CAV(+) 29.0 vs. median CAV(-) 0.0, P < 0.001). DRF was also increased in the echocardiogram that preceded CAV diagnosis in CAV(+) patients (0.31 ± 0.08 vs. 0.25 ± 0.05, P = 0.008). The final model using indices 6-12 months prior to CAV diagnosis included GLS, SSF, and DRF providing AUC of 0.94 with sensitivity 98.5%, specificity 80.0%, positive predictive value 85.0%, and negative predictive value 94.1%. Systolic and diastolic electro-mechanical discoordination indices are significantly worse in PHT patients experiencing CAV. Non-invasive imaging guided surveillance using echocardiographic myocardial deformation indices can be improved by adding SSF and DRF to standard GLS measurements., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Living systems contain a vast network of metabolic reactions, providing a wealth of enzymes and cells as potential biocatalysts for chemical processes. The properties of protein and cell biocatalysts-high selectivity, the ability to control reaction sequence and operation in environmentally benign conditions-offer approaches to produce molecules at high efficiency while lowering the cost and environmental impact of industrial chemistry. Furthermore, biocatalysis offers the opportunity to generate chemical structures and functions that may be inaccessible to chemical synthesis. Here we consider developments in enzymes, biosynthetic pathways and cellular engineering that enable their use in catalysis for new chemistry and beyond., (© 2024. Springer Nature Limited.)

Background: Infants with single ventricle heart disease (SVHD) suffer morbidity from insufficient pulmonary blood flow, which may be related to impaired arginine metabolism. No prior study has reported quantitative mapping of arginine metabolites to evaluate the relationship between circulating metabolite levels and outcomes., Methods: Prospective cohort study of 75 SVHD cases peri-Stage 2 and 50 healthy controls. We targeted pre- and post-op absolute serum quantification of 9 key members of the arginine metabolism pathway by tandem mass spectrometry. Primary outcomes were length of stay (LOS) and post-Stage 2 hypoxemia., Results: Pre-op cases showed alteration in 6 metabolites including decreased arginine and increased asymmetric dimethyl arginine (ADMA) levels compared to controls. Post-op cases demonstrated decreased arginine and citrulline levels persisting through 48 h. Adjusting for clinical variables, lower pre-op and 2 h post-op concentrations of multiple metabolites, including arginine and citrulline, were associated with longer post-op LOS (p < 0.01). Increased ADMA at 24 h was associated with greater post-op hypoxemia burden (p < 0.05)., Conclusion: Arginine metabolism is impaired in interstage SVHD infants and is further deranged following Stage 2 palliation. Patients with greater metabolite alterations experience greater post-op morbidity. Decreased arginine metabolism may be an important driver of pathology in SVHD., Impact: Interstage infants with SVHD have significantly altered arginine-nitric oxide metabolism compared to healthy children with deficiency of multiple pathway intermediates persisting through 48 h post-Stage 2 palliation. After controlling for clinical covariates and classic catheterization-derived predictors of Stage 2 readiness, both lower pre-operation and lower post-operation circulating metabolite levels were associated with longer post-Stage 2 LOS while increased post-Stage 2 ADMA concentration was associated with greater post-op hypoxemia. Arginine metabolism mapping offers potential for development using personalized medicine strategies as a biomarker of Stage 2 readiness and therapeutic target to improve pulmonary vascular health in infants with SVHD., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Preoxygenation is universally recommended before induction of general anaesthesia to prolong safe apnoea time. The optimal technique for preoxygenation is unclear. We conducted a systematic review to determine the preoxygenation technique associated with the greatest effectiveness in adult patients having general anaesthesia., Methods: We searched six databases for randomised controlled trials of patients aged ≥16 yr, receiving general anaesthesia in any setting and comparing different preoxygenation techniques and methods. Our primary effectiveness outcome was safe apnoea time, and secondary outcomes included incidence of arterial oxygen desaturation; lowest SpO 2 during airway management; time to end-tidal oxygen concentration of 90%; and [Formula: see text] and [Formula: see text] at the end of preoxygenation. We assessed the quality of evidence according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) recommendations., Results: We included 52 studies of 3914 patients. High-flow nasal oxygen with patients in a head-up position was most likely to be associated with a prolonged safe apnoea time when compared with other strategies, with a mean difference (95% credible interval) of 291 (138-456) s and 203 (79-343) s compared with preoxygenation with a facemask in the supine and head-up positions, respectively. Subgroup analysis of studies without apnoeic oxygenation also showed high-flow nasal oxygen in the head-up position as the highest ranked technique, with a statistically significantly delayed mean difference (95% credible interval) safe apnoea time compared with facemask in supine and head-up positions of 222 (63-378) s and 139 (15-262) s, respectively. High-flow nasal oxygen was also the highest ranked technique for increased [Formula: see text] at the end of preoxygenation. However, the incidence of arterial desaturation was less likely to occur when a facemask with pressure support was used compared with other techniques, and [Formula: see text] was most likely to be lowest when preoxygenation took place with patients deep breathing in a supine position., Conclusions: Preoxygenation of adults before induction of general anaesthesia was most effective in terms of safe apnoea time when performed with high-flow nasal oxygen with patients in the head-up position in comparison with facemask alone. Also, high-flow nasal oxygen in the head-up position is likely to be the most effective technique to prolong safe apnoea time among those evaluated. Clinicians should consider this technique and patient position in routine practice., Systematic Review Protocol: PROSPERO CRD42022326046., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Aortic arch measurements provide a framework for surgical decision-making in neonatal aortic coarctation, specifically in the determination of approach for arch repair by lateral thoracotomy vs median sternotomy. The purpose of this study was to evaluate our experience with transthoracic echocardiography (TTE) and computed tomography angiography (CTA) in the preoperative evaluation of infants with aortic coarctation, specifically comparing arch dimensions as a function of imaging modality., Methods: Imaging data were reviewed for all infants undergoing surgical repair of aortic coarctation at our institution from 2012 to 2022. Infants with both TTE and CTA evaluations were included. Aortic measurements were compared at predefined anatomic regions including ascending aorta, proximal arch, distal arch, and isthmus., Results: During the study period, 372 infants underwent surgical coarctation repair; 72 (19.4%) infants had TTE and CTA arch evaluations preoperatively. Significant discrepancies between imaging modalities were defined by poor correlation coefficients and absolute measurement differences and were most prominent in the proximal aortic arch (R 2  = 0.23 [-4.4 to 3.2 mm]) and isthmus regions (R 2  = 0.11 [-4.2 to 1.7 mm]). Improved correlation was demonstrated in the ascending aorta (R 2  = 0.63) and distal aortic arch (R 2  = 0.54)., Conclusions: Significant variability exists between TTE- and CTA-derived aortic measurements in infants with coarctation, with proximal arch measurements demonstrating the poorest correlation. This anatomic location represents a commonly used arch region for the determination of approach for repair of neonatal aortic coarctation. Thus, these findings have important implications for current preoperative surgical decision-making paradigms and future prospective study to minimize the risk of residual or recurrent arch obstruction., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Typhoid is endemic in many low-income countries, including in Papua New Guinea. This study aimed to describe the burden and clinical features of typhoid in children in a provincial hospital, to describe environmental conditions that lead to typhoid, and to document the antibiotic sensitivity of Salmonella spp. in the Eastern Highlands Province., Methods: A combined retrospective and prospective study of children admitted to with clinical features of typhoid to the Goroka Hospital throughout 2022., Results: The study included 98 children, of which 54% were female. The median age was 8 (IQR 5-10.6) years. Over 60% of the patients were from Goroka District, the peri-urban area encompassing the town and surrounds. Ninety-four percent (92) of the patients used a pit latrine as a toilet and only 28% had access to treated water. Neuropsychiatric symptoms were common (60%), as was leukopenia (48%), thrombocytopenia (52%) and anaemia (42%). Thirty-seven patients had positive blood cultures for Salmonella typhi; all isolates were sensitive to third-generation cephalosporins, pefloxacin, ampicillin, trimethoprim and sulfamethoxazole, and only 54% sensitive to chloramphenicol. The median duration of hospitalisation was 6 days (IQR). There were no deaths., Conclusion: Prompt public health actions are needed to reduce the burden of typhoid infection in the Papua New Guinea. The conjugate typhoid vaccine should be considered in the highlands region, where typhoid is most endemic., (© 2024 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Inclusion of photoswitchable azobenzene units as spacers into ditopic bridging ligands L m and L p , containing two chelating pyrazolyl-pyridine termini, allows formation of metal complex assemblies with Co(ii) that undergo a range of light-induced structural transformations. One notable result is the light-induced conversion of a Co 2 (L p ) 3 dinuclear triple helicate (based on the E ligand isomer) to a C 3 -symmetric Co 4 (L p ) 6 assembly, assumed to be an edge-bridged tetrahedral cage, based on the Z ligand isomer. Another is the preparation of a series of Co 4 (L m ) 6 complexes, of which Co 4 ( E -L m ) 6 was crystallographically characterised and consists of a pair of Co 2 (L m ) 2 double helicates connected by an additional two bridging ligands which span the pair of helicate units, giving a cyclic Co 4 array in which one and then two bridging ligands alternate around the periphery. A set of Co 4 (L m ) 6 complexes could be prepared containing different ratios of Z  :  E ligand isomers (0 : 6, 2 : 4, 4 : 2 and 6 : 0) of which Co 4 ( Z -L m ) 2 ( E -L m ) 4 was particularly stable and dominated the speciation behaviour, either during light-induced switching of the ligand geometry in pre-formed complexes, or when ligand isomers were combined in different proportions during the preparation. These examples of (i) interconversion between Co 2 L 3 (helicate) and (ii) Co 4 L 6 (cage) assemblies with L p , and the interconversion between a series of Co 4 L 6 assemblies Co 4 ( Z -L m ) n ( E -L m ) 6- n with L m , constitute significant advances in the field of photoswitchable supramolecular assemblies., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Alcohol use disorder (AUD) is characterized by a set of behavioral, cognitive, nutritional, and physiological phenomena derived from the uncontrolled use of alcoholic beverages. There are cases in which AUD is associated with anxiety disorder, and when untreated, it requires careful pharmacotherapy. Blue Calm® (BC) is a food supplement indicated to aid restorative sleep, which has traces of medicinal plant extracts, as well as myo-inositol, magnesium bisglycinate, taurine, and L-tryptophan as its main chemical constituents. In this context, this study aimed to evaluate the potential of the BC in the treatment alcohol withdrawal-induced anxiety in adult zebrafish (aZF). Initially, BC was submitted to antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl radical. Subsequently, the aZF (n = 6/group) were treated with BC (0.1 or 1 or 10 mg/mL; 20 μL; p.o.), and the sedative effect and acute toxicity (96 h) were evaluated. Then, the anxiolytic-like effect and the possible GABAergic mechanism were analyzed through the Light & Dark Test. Finally, BC action was evaluated for treating alcohol withdrawal-induced anxiety in aZF. Molecular docking was performed to evaluate the interaction of the major chemical constituents of BC with the GABA A receptor. BC showed antioxidant potential, a sedative effect, was not toxic, and all doses of BC had an anxiolytic-like effect and showed potential for the treatment of alcohol withdrawal-induced anxiety in aZF. In addition to the anxiolytic action, the main chemical constituents of BC were confirmed in the molecular docking, thus suggesting that BC is an anxiolytic that modulates the GABAergic system and has pharmacological potential for the treatment of alcohol withdrawal-induced anxiety., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The relationship between sensory stimuli and perceptions is brain-state dependent: in wakefulness, suprathreshold stimuli evoke perceptions; under anesthesia, perceptions are abolished; and during dreaming and in dissociated states, percepts are internally generated. Here, we exploit this state dependence to identify brain activity associated with internally generated or stimulus-evoked perceptions. In awake mice, visual stimuli phase reset spontaneous cortical waves to elicit 3-6 Hz feedback traveling waves. These stimulus-evoked waves traverse the cortex and entrain visual and parietal neurons. Under anesthesia as well as during ketamine-induced dissociation, visual stimuli do not disrupt spontaneous waves. Uniquely, in the dissociated state, spontaneous waves traverse the cortex caudally and entrain visual and parietal neurons, akin to stimulus-evoked waves in wakefulness. Thus, coordinated neuronal assemblies orchestrated by traveling cortical waves emerge in states in which perception can manifest. The awake state is privileged in that this coordination is reliably elicited by external visual stimuli., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Multiple endocrine neoplasia type 1 (MEN1)-associated duodenopancreatic neuroendocrine neoplasms (dpNEN) represent the most frequent syndrome-associated cause of death, but the adequate treatment is sometimes considered controversial., Objective: Presentation of possible diagnostic and therapeutic options for MEN1-associated dpNENs., Material and Methods: In this review article retrospective case studies, expert recommendations, national and international guidelines as well as personal experiences were analyzed and evaluated., Results: Due to early detection programs and the use of the most modern imaging techniques, dpNEN are nowadays diagnosed much earlier. Nonfunctional pNENs currently represent the most frequent dpNENs with about 70%, followed by gastrinomas and insulinomas. Regardless of their functional activity, dpNENs with a size of > 2 cm are generally an indication for surgery. The choice of the optimal treatment strategy, however, in most cases remains the subject of controversial discussions, although nowadays surgery should always be performed in an organ-preserving and minimally invasive way when feasible. Recurrences or new dpNENs are expected in more than 60% of cases, necessitating a reoperation in up to 40% of these cases. Duodenopancreatic resections and reoperations can be carried out safely by experienced practitioners and with an acceptable level of risk., Conclusion: The planning of treatment requires careful consideration of the suitable timing, the extent of the operation, the risk of recurrence and potential morbidities. Furthermore, preserving pancreatic function and the quality of life is of utmost importance. In view of the complexity of the disease, MEN1 patients should be treated in specialized centers., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

General anesthesia-a pharmacologically induced reversible state of unconsciousness-enables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females., Competing Interests: Competing interests statement:The authors declare no competing interest.

Introduction: Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). OSA can induce excessive daytime sleepiness (EDS) and is associated with impaired cognition and anxiety. Solriamfetol (SOL) and modafinil (MOD) are widely used wake-promoting agents in OSA patients with EDS., Methods: Male C57Bl/6J mice were exposed to SF along with sleep controls (SC) or to IH and room air (RA) controls during the light (inactive) phase for 4 and 16 weeks, respectively. Both IH and SF exposures were then discontinued to mimic "ideal" continuous positive airway pressure (CPAP) adherence. All groups were then randomly assigned to receive once daily intraperitoneal injections of SOL, MOD, or vehicle (VEH) for 6 days. Sleep/wake activity was assessed along with tests of explicit memory, anxiety and depression were performed before and after treatments., Results: IH and SF exposures increased sleep percentage in the dark phase and reduced wake bouts lengths (i.e., EDS), and induced cognitive deficits and impulsivity in mice. Both SOL and MOD treatments effectively mitigated EDS when combined with recovery, while recovery alone did not improve EDS over the 6-day period. Furthermore, improvements explicit memory emerged only after SOL., Conclusion: Chronic IH and SF induce EDS in young adult mice that is not ameliorated by recovery except when combined with either SOL or MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits. Thus, SOL emerges as a viable adjuvant medication for residual EDS in OSA along with its positive impact on cognition., (Copyright © 2023 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Intracardiac flow hemodynamic patterns have been considered to be an early sign of diastolic dysfunction. In this study we investigated right ventricular (RV) diastolic dysfunction between patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension with chronic lung disease (PH-CLD) via 4D-Flow cardiac MRI (CMR). Patients underwent prospective, comprehensive CMR for function and size including 4D-Flow CMR protocol for intracardiac flow visualization and analysis. RV early filling phase and peak atrial phase vorticity (E-vorticity and A-vorticity) values were calculated in all patients. Patients further underwent comprehensive Doppler and tissue Doppler evaluation for the RV diastolic dysfunction. In total 13 patients with PAH, 15 patients with PH-CLD, and 10 control subjects underwent the 4D-Flow CMR and echocardiography evaluation for RV diastolic dysfunction. Reduced E-vorticity differentiated PAH and PH-CLD from healthy controls (both p  < 0.01) despite the same Doppler E values. E-vorticity was further decreased in PAH patients when compared to PH-CLD group ( p  < 0.05) with similar Doppler and tissue Doppler markers of diastolic dysfunction. A-vorticity was decreased in both PAH and PH-CLD groups compared to controls but with no difference between the disease groups. E-vorticity correlated with ejection fraction ( R  = 0.60, p  < 0.001), end-systolic volume ( R  = 0.50, p  = 0.001), stroke volume ( R  = 0.42, p  = 0.007), and cardiac output ( R  = 0.30, p  = 0.027). Intracardiac flow analysis using 4D-Flow CMR derived vorticity is a sensitive method to differentiate diastolic dysfunction in patients with different PH etiology and similar Doppler echocardiography profile., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Motivated by the need to develop more informative and data-rich patient-specific presurgical planning models, we present a high-resolution method that enables the tangible replication of multimodal medical data. By leveraging voxel-level control of multimaterial three-dimensional (3D) printing, our method allows for the digital integration of disparate medical data types, such as functional magnetic resonance imaging, tractography, and four-dimensional flow, overlaid upon traditional magnetic resonance imaging and computed tomography data. While permitting the explicit translation of multimodal medical data into physical objects, this approach also bypasses the need to process data into mesh-based boundary representations, alleviating the potential loss and remodeling of information. After evaluating the optical characteristics of test specimens generated with our correlative data-driven method, we culminate with multimodal real-world 3D-printed examples, thus highlighting current and potential applications for improved surgical planning, communication, and clinical decision-making through this approach., Competing Interests: N.M.J. is an author of a patent application filed by the University of Colorado Regents that describes methods similar to those described in this article (No. 20783116.5; Filed: April 3, 2020)., (© Nicholas M. Jacobson et al. 2023; Published by Mary Ann Liebert, Inc.)

Introduction: T-wave analysis from standard electrocardiogram (ECG) remains one of the most available clinical and research methods for evaluating myocardial repolarization. T-wave morphology was recently evaluated to aid with diagnosis and characterization of diastolic dysfunction. Unfortunately, PDF stored ECG datasets limit additional numerical post-processing of ECG waveforms. In this study, we apply a simple custom process pipeline to extract and re-digitize T-wave signals and subject them to principal component analysis (PCA) to define primary T-wave shape variations., Methods: We propose simple pre-processing and digitization algorithms programmable as a MATLAB tool using standard thresholding functions without the need for advanced signal analysis. To validate digitized datasets, we compared clinically standard measurements in 20 different ECGs with the original ECG machine interpreted values as a gold standard. Afterwards, we analyzed 212 individual ECGs for T-wave shape analysis using PCA., Results: The re-digitized signal was shown to preserve the original information as evidenced by excellent agreement between original - machine interpreted and re-digitized clinical variables including heart rate: bias ~ 1 bpm (95% CI: -1.0 to 3.5), QT interval: bias ~ 0.000 ms (95% CI: -0.012 to 0.012), PR interval: bias = -0.015 ms (95% CI: -0.015 to 0.003), and QRS duration: bias = -0.001 ms (95% CI: -0.007 to 0.006). PCA revealed that the first principal component universally modulates the T-wave height or amount of repolarization voltage regardless of the investigated ECG lead. The second and third principal components described variation in the T-wave peak onset and the T-wave peak morphology, respectively., Conclusion: This study presents a straightforward method for re-digitizing ECGs stored in the PDF format utilized in many academic electronic medical record systems. This process can yield re-digitized lead specific signals which can be retrospectively analyzed using advanced custom post-processing numerical analysis independent of commercially available platforms., (© 2023. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Background: Superior cavopulmonary connection (SCPC) for stage II palliation of hypoplastic left heart syndrome (HLHS) is achieved most frequently by either a bidirectional Glenn (BDG) or hemi-Fontan (HF) operation. The comparison of flow hemodynamic efficiency at the region of surgical reconstruction and in proximal pulmonary arteries has been evaluated primarily using computational modeling techniques with conflicting reports. The purpose of this descriptive study was to compare flow hemodynamics following stage II (BDG vs HF) using 4-dimensional flow magnetic resonance imaging (4D-Flow MRI) with particular focus on flow-mediated viscous energy loss ( E L ' ) under matched hemodynamic conditions., Methods: Patients with hypoplastic left heart syndrome (HLHS) who underwent either HF or BDG as part of stage II palliation underwent pre-Fontan 4D-Flow MRI. Patients were matched by the pulmonary vascular resistance index, net superior vena cava (SVC) flow, right pulmonary artery (RPA) and left pulmonary artery (LPA) size, and age. Maximum E L ' throughout the cardiac cycle was calculated along the SVC-RPA and SVC-LPA tracts., Results: Eight patients who underwent HF as part of their stage II single ventricle palliation were matched with 8 patients who underwent BDG. There were no differences between the 2 groups in median volumetric indices, including end-diastolic volume ( P  = .278) and end-systolic volume ( P  = .213). Moreover, no differences were observed in ejection fraction ( P  = .091) and cardiac index ( P  = .324). There also were no differences in peak E L ' measured along the SVC-RPA tract (median, 0.05 mW for HF vs 0.04 mW for BDG; P  = .365) or along the SVC-LPA tract (median, 0.05 mW vs 0.04 mW; P  = .741)., Conclusions: The second stage of surgical palliation of HLHS using either HF or BDG results in similar flow-mediated viscous energy loss throughout the SCPC junction. 4D-Flow MRI and computational methods should be applied together to investigate flow hemodynamic patterns throughout the Fontan palliation and overall efficiency of the Fontan circuit., Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2023 The Author(s).)

Children with single ventricle heart disease (SVHD) experience morbidity due to inadequate pulmonary blood flow. Using proteomic screening, our group previously identified members of the matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP), and fibroblast growth factor (FGF) families as potentially dysregulated in SVHD. No prior study has taken a targeted approach to mapping circulating levels of these protein families or their relationship to pulmonary vascular outcomes in SVHD. We performed a prospective cohort study of 70 SVHD infants pre-Stage 2 palliation and 24 healthy controls. We report targeted serum quantification of 39 proteins in the MMP, TIMP, and FGF families using the SomaScan platform. Clinical variables were extracted from the medical record. Twenty of 39 tested proteins (7/14 MMPs, 2/4 TIMPs, and 11/21 FGFs) differed between cases and controls. On single variable testing, 6 proteins and no clinical covariates were associated with both post-Stage 2 hypoxemia and length of stay. Multiple-protein modeling identified increased circulating MMP 7 and MMP 17, and decreased circulating MMP 8 and FGFR2 as most associated with post-Stage 2 hypoxemia; increased MMP 7 and TIMP 4 and decreased circulating MMP 1 and MMP 8 were most associated with post-operation length of stay. The MMP, TIMP, and FGF families are altered in SVHD. Pre-Stage 2 imbalance of extracellular matrix (ECM) proteins-increased MMP 7 and decreased MMP 8-was associated with multiple adverse post-operation outcomes. Maintenance of the ECM may be an important pathophysiologic driver of Stage 2 readiness in SVHD., (© 2023. Springer Nature Limited.)

The host-guest chemistry of O , O '-diisopropyl fluorophosphate (DFP), a phosphonofluoridate G-series chemical warfare agent simulant, was investigated in the presence of a number of octanuclear cubic coordination cage hosts. The aim was to demonstrate cage-catalysed hydrolysis of DFP at near neutral pH: however, two octanuclear coordination cages, H PEG (containing water-solubilising PEG groups) and H W (containing water-solubilising hydroxymethyl groups), were actually found to increase the lifetime of DFP in aqueous buffer solution (pH 8.7). Crystallographic analysis of DFP with a structurally related host cage revealed that DFP binds to windows in the cage surface, not in the internal cavity. The phosphorus-fluorine bond is directed into the cavity rather than towards the external environment, with the cage/DFP association protecting DFP from hydrolysis. Initial studies with the chemical warfare agent (CWA) sarin (GB) with H PEG cage in a buffered solution also showed a drastically reduced rate of hydrolysis for sarin when bound in the host cage. The ability of these cages to inhibit hydrolysis of these P-F bond containing organophosphorus guests, by encapsulation, may have applications in forensic sample preservation and analysis.

Myocardial deformation analysis by cardiac MRI (CMR) yielding global circumferential and longitudinal strain (GCS and GLS) is an increasingly utilized method to accurately quantify systolic function and predict clinical events in patients with Fontan circulation. The purpose of this study was to use principal component analysis (PCA) to investigate myocardial temporal deformation patterns derived from strain-time curves to learn about latent strain features beyond peak values. We conducted the study with specific attention to dominant single left or right ventricle (SLV and SRV) morphologies. Methods and Results: Patients remote from Fontan operation who underwent follow-up CMR were analyzed for standard volumetric and function hemodynamics including myocardial deformation parameters including GCS and GLS. We applied PCA to investigate in an unbiased fashion the strain-time curve morphology and to calculate patient specific shape scores. All variables were subjected to single variable Cox regression analysis to detect composite clinical outcome including death, heart transplant, protein losing enteropathy and plastic bronchitis. A total of 122 patients, (SLV = 67, SRV = 55) with a mean age of 12.7 years underwent comprehensive CMR analysis. The PCA revealed 3 primary modes of strain-curve variation regardless of single ventricle morphology and type of strain investigated. Principle components (PCs) described changes in (1) strain-time curve amplitude, (2) time-to-peak strain, and (3) post-systolic slope of the strain-time curve. Considering only SLV patients, GCS was only CMR variable predictive of clinical events (HR 1.46, p = 0.020). In the SRV group, significant CMR predictors of clinical events were derived indexed end-diastolic (HR 1.02, p = 0.023) and end-systolic (HR 1.03, p = 0.022) volumes, GCS (HR 1.91, p = 0.003) and its related first component score (HR 1.20, p = 0.005), GLS (HR 1.32, p = 0.029) and its third component score (HR 1.58, p = 0.017). CMR derived global strain measures are sensitive markers of clinical outcomes in patients with Fontan circulation, particularly in patients with the SRV morphology. Myocardial strain-time curve morphology specific to SLV and SRV patients inspired by unbiased PCA technique can further aid with predicting clinical outcomes., (© 2023. The Author(s).)

Background: Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH). Excessive daytime sleepiness (EDS) is a common consequence of OSA and is associated with cognitive deficits and anxiety. Modafinil (MOD) and Solriamfetol (SOL) are potent wake-promoting agents clinically used to improve wakefulness in OSA patients with EDS., Methods: Male C57Bl/6J mice were exposed to either IH or room air (RA) controls during the light phase for 16 weeks. Both groups were then randomly assigned to receive once-daily intraperitoneal injections of SOL (200 mg/kg), MOD (200 mg/kg) or vehicle (VEH) for 9 days while continuing IH exposures. Sleep/wake activity was assessed during the dark (active) phase. Novel object recognition (NOR), elevated-plus maze test (EPMT), and forced swim test (FST) were performed before and after drug treatment., Results: IH exposure increased dark phase sleep percentage and reduced wake bouts lengths and induced cognitive deficits and anxiogenic effects. Both SOL and MOD treatments decreased sleep propensity under IH conditions, but only SOL promoted improvements in NOR performance (explicit memory) and reduced anxiety-like behaviors., Conclusion: Chronic IH, a hallmark feature of OSA, induces EDS in young adult mice that is ameliorated by both SOL and MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits and promotes anxiolytic effects. Thus, SOL could potentially benefit OSA patients beyond EDS management., Competing Interests: Declaration of competing interest The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. The authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Tectal plate gliomas are rare, slow-growing tumors of the midbrain that are discovered predominantly in the pediatric population. Because of their indolent nature, treatment mainly consists of observation and management of hydrocephalus. Unfortunately, a subset of tectal gliomas may exhibit tumor enlargement and disease progression. Currently, there are no established guidelines for predicting future progression of tectal gliomas or the need for tumor-directed treatment. In this paper, the authors present a large case series of tectal plate gliomas with the aim of determining early indicators of tumor progression and the need for tumor-directed treatment in a pediatric population, along with providing their experience in treating progressive tumors., Methods: A retrospective chart review of 170 patients diagnosed with tectal plate glioma from a single institution, of whom 67 were pediatric patients (≤ 18 years of age), was performed. Univariate analysis was used to determine statistically significant predictors of symptomatic disease progression requiring eventual tumor-directed therapy., Results: The median patient age of the full cohort was 24 years (range 0-73 years). Compared with the pediatric population, the adult population had more instances of incidental lesions (p < 0.001) and lower rates of hydrocephalus (50% vs 84%, p < 0.001). Of the pediatric patients who had ≥ 5 years of follow-up (n = 51), 12 (24%) experienced radiological progression and 13 (25%) required treatment for their tumor. The 1-year, 5-year, and 10-year radiographic progression-free survival (PFS) rates were 98%, 90%, and 86%, respectively. In univariate analysis, lesion involvement of the pons, moderate T1 hypointensity, and moderate contrast enhancement on baseline radiology were significantly associated with worse radiographic PFS. Alternatively, significant predictors of requiring tumor-directed treatment included extraocular eye movement abnormalities at presentation, involvement of the lesion beyond the tectum on baseline radiology, moderate T1 hypointensity, moderate contrast enhancement, and an increase in total lesion size during progression. At the most recent follow-up, 94% of the patients had stable/nonprogressive disease, 2% had progressive disease, and 4% died of tumor progression., Conclusions: Patients who demonstrate radiographic progression may not necessarily experience clinical/symptomatic progression or require tumor-directed treatment. Certain patient presentation characteristics and baseline radiographic features may be predictive of worse radiographic PFS or the need for future tumor-directed treatment in the pediatric population. Typically, the natural history of these lesions lends to excellent long-term survival, even in patients who experience clinical progression, should appropriate treatment be initiated.

Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). In murine models, chronic SF can impair endothelial function and induce cognitive declines. These deficits are likely mediated, at least in part, by alterations in Blood-brain barrier (BBB) integrity. Male C57Bl/6J mice were randomly assigned to SF or sleep control (SC) conditions for 4 or 9 weeks and in a subset 2 or 6 weeks of normal sleep recovery. The presence of inflammation and microglia activation were evaluated. Explicit memory function was assessed with the novel object recognition (NOR) test, while BBB permeability was determined by systemic dextran-4kDA-FITC injection and Claudin 5 expression. SF exposures resulted in decreased NOR performance and in increased inflammatory markers and microglial activation, as well as enhanced BBB permeability. Explicit memory and BBB permeability were significantly associated. BBB permeability remained elevated after 2 weeks of sleep recovery ( p < 0.01) and returned to baseline values only after 6 weeks. Chronic SF exposures mimicking the fragmentation of sleep that characterizes patients with OSA elicits evidence of inflammation in brain regions and explicit memory impairments in mice. Similarly, SF is also associated with increased BBB permeability, the magnitude of which is closely associated with cognitive functional losses. Despite the normalization of sleep patterns, BBB functional recovery is a protracted process that merits further investigation.

Obstructive sleep apnea (OSA) is a highly prevalent condition characterized by episodes of partial or complete breath cessation during sleep that induces sleep fragmentation (SF). One of the frequent manifestations of OSA is the presence of excessive daytime sleepiness (EDS) associated with cognitive deficits. Solriamfetol (SOL) and modafinil (MOD) are wake-promoting agents commonly prescribed to improve wakefulness in OSA patients with EDS. This study aimed to assess the effects of SOL and MOD in a murine model of OSA characterized by periodic SF. Male C57Bl/6J mice were exposed to either control sleep (SC) or SF (mimicking OSA) during the light period (06:00 h to 18:00 h) for 4 weeks, which consistently induces sustained excessive sleepiness during the dark phase. Both groups were then randomly assigned to receive once-daily intraperitoneal injections of SOL (200 mg/kg), MOD (200 mg/kg), or vehicle for 1 week while continuing exposures to SF or SC. Sleep/wake activity and sleep propensity were assessed during the dark phase. Novel Object Recognition test, Elevated-Plus Maze Test, and Forced Swim Test were performed before and after treatment. SOL or MOD decreased sleep propensity in SF, but only SOL induced improvements in explicit memory, while MOD exhibited increased anxiety behaviors. Chronic SF, a major hallmark of OSA, induces EDS in young adult mice that is mitigated by both SOL and MOD. SOL, but not MOD, significantly improves SF-induced cognitive deficits. Increased anxiety behaviors are apparent in MOD-treated mice. Further studies aiming to elucidate the beneficial cognitive effects of SOL are warranted., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Photoaffinity ligands are best known as tools used to identify the specific binding sites of drugs to their molecular targets. However, photoaffinity ligands have the potential to further define critical neuroanatomic targets of drug action. In the brains of WT male mice, we demonstrate the feasibility of using photoaffinity ligands in vivo to prolong anesthesia via targeted yet spatially restricted photoadduction of azi- m -propofol (aziPm), a photoreactive analog of the general anesthetic propofol. Systemic administration of aziPm with bilateral near-ultraviolet photoadduction in the rostral pons, at the border of the parabrachial nucleus and locus coeruleus, produced a 20-fold increase in the duration of sedative and hypnotic effects compared with control mice without UV illumination. Photoadduction that missed the parabrachial-coerulean complex also failed to extend the sedative or hypnotic actions of aziPm and was indistinguishable from nonadducted controls. Paralleling the prolonged behavioral and EEG consequences of on target in vivo photoadduction, we conducted electrophysiologic recordings in rostral pontine brain slices. Using neurons within the locus coeruleus to further highlight the cellular consequences of irreversible aziPm binding, we demonstrate transient slowing of spontaneous action potentials with a brief bath application of aziPm that becomes irreversible on photoadduction. Together, these findings suggest that photochemistry-based strategies are a viable new approach for probing CNS physiology and pathophysiology. SIGNIFICANCE STATEMENT Photoaffinity ligands are drugs capable of light-induced irreversible binding, which have unexploited potential to identify the neuroanatomic sites of drug action. We systemically administer a centrally acting anesthetic photoaffinity ligand in mice, conduct localized photoillumination within the brain to covalently adduct the drug at its in vivo sites of action, and successfully enrich irreversible drug binding within a restricted 250 µm radius. When photoadduction encompassed the pontine parabrachial-coerulean complex, anesthetic sedation and hypnosis was prolonged 20-fold, thus illustrating the power of in vivo photochemistry to help unravel neuronal mechanisms of drug action., (Copyright © 2023 McKinstry-Wu, Wasilczuk et al.)

Chromatin regulation and alternative splicing are both critical mechanisms guiding gene expression. Studies have demonstrated that histone modifications can influence alternative splicing decisions, but less is known about how alternative splicing may impact chromatin. Here, we demonstrate that several genes encoding histone-modifying enzymes are alternatively spliced downstream of T cell signaling pathways, including HDAC7, a gene previously implicated in controlling gene expression and differentiation in T cells. Using CRISPR-Cas9 gene editing and cDNA expression, we show that differential inclusion of HDAC7 exon 9 controls the interaction of HDAC7 with protein chaperones, resulting in changes to histone modifications and gene expression. Notably, the long isoform, which is induced by the RNA-binding protein CELF2, promotes expression of several critical T cell surface proteins including CD3, CD28, and CD69. Thus, we demonstrate that alternative splicing of HDAC7 has a global impact on histone modification and gene expression that contributes to T cell development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The Gumbel-max trick is a method to draw a sample from a categorical distribution, given by its unnormalized (log-)probabilities. Over the past years, the machine learning community has proposed several extensions of this trick to facilitate, e.g., drawing multiple samples, sampling from structured domains, or gradient estimation for error backpropagation in neural network optimization. The goal of this survey article is to present background about the Gumbel-max trick, and to provide a structured overview of its extensions to ease algorithm selection. Moreover, it presents a comprehensive outline of (machine learning) literature in which Gumbel-based algorithms have been leveraged, reviews commonly-made design choices, and sketches a future perspective.

Background: The posterior dominant rhythm (PDR) was the first oscillatory pattern noted in the EEG. Evoked by wakeful eyelid closure, these oscillations dissipate over seconds during loss of arousal. The peak frequency of the PDR maintains stability over years, suggesting utility as a state biomarker in the surveillance of acute cognitive impairments. This EEG signature has not been systematically investigated for tracking cognitive dysfunction after anaesthetic-induced loss of consciousness., Methods: This substudy of Reconstructing Consciousness and Cognition (NCT01911195) investigated the PDR and cognitive function in 60 adult volunteers randomised to either 3 h of isoflurane general anaesthesia or resting wakefulness. Serial measurements of EEG power and cognitive task performance were assessed relative to pre-intervention baseline. Mixed-effects models allowed quantification of PDR and neurocognitive trajectories after return of responsiveness (ROR)., Results: Individuals in the control group showed stability in the PDR peak frequency over several hours (median difference/inter-quartile range [IQR] of 0.02/0.20 Hz, P=0.39). After isoflurane general anaesthesia, the PDR peak frequency was initially reduced at ROR (median difference/IQR of 0.88/0.65 Hz, P<0.001). PDR peak frequency recovered at a rate of 0.20 Hz h -1 . After ROR, the PDR peak frequency correlated with reaction time and accuracy on multiple cognitive tasks (P<0.001)., Conclusion: The temporal trajectory of the PDR peak frequency could be a useful perioperative marker for tracking cognitive dysfunction on the order of hours after surgery, particularly for cognitive domains of working memory, visuomotor speed, and executive function., Clinical Trial Registration: NCT01911195., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

α,β-Unsaturated carbonyls are a common motif in environmental toxins (e.g. acrolein) as well as therapeutic drugs, including dimethylfumarate (DMFU) and monomethylfumarate (MMFU), which are used to treat multiple sclerosis and psoriasis. These compounds form adducts with protein Cys residues as well as other nucleophiles. The specific targets ('adductome') that give rise to their therapeutic or toxic activities are poorly understood. This is due, at least in part, to the absence of antigens or chromophores/fluorophores in these compounds. We have recently reported click-chemistry probes of DMFU and MMFU (Redox Biol., 2022, 52, 102299) that allow adducted proteins to be visualized and enriched for further characterization. In the current study, we hypothesized that adducted proteins could be 'clicked' to agarose beads and thereby isolated for LC-MS analysis of DMFU/MMFU targets in primary human coronary artery smooth muscle cells. We show that the probes react with thiols with similar rate constants to the parent drugs, and give rise to comparable patterns of gene induction, confirming similar biological actions. LC-MS proteomic analysis identified ∼2970 cellular targets of DMFU, ∼1440 for MMFU, and ∼140 for the control (succinate-probe) treated samples. The most extensively modified proteins were galectin-1, annexin-A2, voltage dependent anion channel-2 and vimentin. Other previously postulated DMFU targets, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), cofilin, p65 (RELA) and Keap1 were also identified as adducted species, though at lower levels with the exception of GAPDH. These data demonstrate the utility of the click-chemistry approach to the identification of cellular protein targets of both exogenous and endogenous compounds., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The Ross-Konno (RK) operation is a well-established surgical treatment for combined left ventricular outflow tract obstruction and aortic valve pathology in children. Prior study has demonstrated that mechanical and electrical dyssynchrony exist post-RK compared to normal controls. The purpose of this study was to evaluate myocardial function pre- and post-RK as defined by echocardiography. Patients undergoing the RK operation (n = 13; median age: 1.3 years; range: 0.5-13.3 years) were evaluated by echocardiography at defined timepoints: pre-RK, post-RK, 1-year post-RK, and 2 years post-RK. Defined parameters of left ventricular performance were analyzed: systolic mechanical dyssynchrony (M-Dys), global left ventricular circumferential strain (GCS), and diastolic relaxation fraction (DRF). Patients with post-operative atrioventricular block (n = 6) were analyzed separately. No pre- versus post-RK differences existed in M-Dys, GCS, or DRF in patients both with and without post-RK atrioventricular block. Further, 1- and 2-year follow-up post-RK demonstrated significant heterogeneity in evaluated parameters of function with no pre- and post-RK differences in M-Dys, GCS, or DRF. Mechanical dyssynchrony exists post-RK reconstruction in both short- and long-term follow-up yet these echocardiographic parameters of ventricular performance are independent of the RK operation. Further study is, therefore, warranted to define causal relationships for observed short- and long-term ventricular dysfunction post-RK as the findings of the present study suggest a deleterious mechanism apart from the technical RK reconstruction., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The brain can become transiently disconnected from the environment while maintaining vivid, internally generated experiences. This so-called 'dissociated state' can occur in pathological conditions and under the influence of psychedelics or the anesthetic ketamine (KET). The cellular and circuit mechanisms producing the dissociative state remain poorly understood. We show in mice that KET causes spontaneously active neurons to become suppressed while previously silent neurons become spontaneously activated. This switch occurs in all cortical layers and different cortical regions, is induced by both systemic and cortical application of KET and is mediated by suppression of parvalbumin and somatostatin interneuron activity and inhibition of NMDA receptors and HCN channels. Combined, our results reveal two largely non-overlapping cortical neuronal populations-one engaged in wakefulness, the other contributing to the KET-induced brain state-and may lay the foundation for understanding how the brain might become disconnected from the surrounding environment while maintaining internal subjective experiences., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

To determine how different pioneer transcription factors form a targeted, accessible nucleosome within compacted chromatin and collaborate with an ATP-dependent chromatin remodeler, we generated nucleosome arrays in vitro with a central nucleosome containing binding sites for the hematopoietic E-Twenty Six (ETS) factor PU.1 and Basic Leucine Zipper (bZIP) factors C/EBPα and C/EBPβ. Our long-read sequencing reveals that each factor can expose a targeted nucleosome on linker histone-compacted arrays, but with different nuclease sensitivity patterns. The DNA binding domain of PU.1 binds mononucleosomes, but requires an additional intrinsically disordered domain to bind and open compacted chromatin. The canonical mammalian SWI/SNF (cBAF) remodeler was unable to act upon two forms of locally open chromatin unless cBAF was enabled by a separate transactivation domain of PU.1. cBAF potentiates the PU.1 DNA binding domain to weakly open chromatin in the absence of the PU.1 disordered domain. Our findings reveal a hierarchy by which chromatin is opened and show that pioneer factors can provide specificity for action by nucleosome remodelers., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Infants with SVHD experience morbidity related to pulmonary vascular inadequacy. Metabolomic analysis involves a systems biology approach to identifying novel biomarkers and pathways in complex diseases. The metabolome of infants with SVHD is not well understood and no prior study has evaluated the relationship between serum metabolite patterns and pulmonary vascular readiness for staged SVHD palliation., Objectives: The purpose of this study was to evaluate the circulating metabolome of interstage infants with single ventricle heart disease (SVHD) and determine whether metabolite levels were associated with pulmonary vascular inadequacy., Methods: This was a prospective cohort study of 52 infants with SVHD undergoing Stage 2 palliation and 48 healthy infants. Targeted metabolomic phenotyping (175 metabolites) was performed by tandem mass spectrometry on SVHD pre-Stage 2, post-Stage 2, and control serum samples. Clinical variables were extracted from the medical record., Results: Random forest analysis readily distinguished between cases and controls and preoperative and postoperative samples. Seventy-four of 175 metabolites differed between SVHD and controls. Twenty-seven of 39 metabolic pathways were altered including pentose phosphate and arginine metabolism. Seventy-one metabolites differed in SVHD patients between timepoints. Thirty-three of 39 pathways were altered postoperatively including arginine and tryptophan metabolism. We found trends toward increased preoperative methionine metabolites in patients with higher pulmonary vascular resistance and higher postoperative tryptophan metabolites in patients with greater postoperative hypoxemia., Conclusions: The circulating metabolome of interstage SVHD infants differs significantly from controls and is further disrupted after Stage 2. Several metabolites showed trends toward association with adverse outcomes. Metabolic dysregulation may be an important factor in early SVHD pathobiology.