Compromised Cerebral Arterial Perfusion, Altered Brain Tissue Integrity, and Cognitive Impairment in Adolescents with Complex Congenital Heart Disease.

(1) Introduction: Adolescents with complex congenital heart disease (CCHD) show brain tissue injuries in regions associated with cognitive deficits. Alteration in cerebral arterial perfusion (CAP), as measured by arterial transit time (ATT), may lead to perfusion deficits and potential injury. Our study aims to compare ATT values between CCHD patients and controls and assess the associations between ATT values, MD values, and cognitive scores in adolescents with CCHD. (2) Methods: 37 CCHD subjects, 14-18 years of age, who had undergone surgical palliation and 30 healthy controls completed cognitive testing and brain MRI assessments using a 3.0-Tesla scanner. ATT values and regional brain mean diffusivity [MD] were assessed for the whole brain using diffusion tensor imaging. (3) Results: The mean MoCA values [23.1 ± 4.1 vs. 28.1 ± 2.3; p < 0.001] and General Memory Index, with a subscore of WRAML2 [86.8 ± 15.4 vs. 110.3 ± 14.5; p < 0.001], showed significant cognitive deficits in CCHD patients compared to controls. The mean global ATT was significantly higher in CCHD patients versus controls (mean ± SD, s, 1.26 ± 0.11 vs. 1.19 ± 0.11, p = 0.03), respectively. The partial correlations between ATT values, MD values, and cognitive scores (p < 0.005) showed significant associations in areas including the hippocampus, prefrontal cortices, cerebellum, caudate, anterior and mid cingulate, insula, thalamus, and lingual gyrus. (4) Conclusions: Adolescents with CCHD had prolonged ATTs and showed correlation with clinical measurements of cognitive impairment and MRI measurements of brain tissue integrity. This suggests that altered CAP may play a role in brain tissue injury and cognitive impairment after surgical palliation.

A First Insight into the Developability of an Immunoglobulin G3: A Combined Computational and Experimental Approach.

Immunoglobulin G 3 (IgG3) monoclonal antibodies (mAbs) are high-value scaffolds for developing novel therapies. Despite their wide-ranging therapeutic potential, IgG3 physicochemical properties and developability characteristics remain largely under-characterized. Protein-protein interactions elevate solution viscosity in high-concentration formulations, impacting physicochemical stability, manufacturability, and the injectability of mAbs. Therefore, in this manuscript, the key molecular descriptors and biophysical properties of a model anti-IL-8 IgG1 and its IgG3 ortholog are characterized. A computational and experimental framework was applied to measure molecular descriptors impacting their downstream developability. Findings from this approach underpin a detailed understanding of the molecular characteristics of IgG3 mAbs as potential therapeutic entities. This work is the first report examining the manufacturability of IgG3 for high-concentration mAb formulations. While poorer conformational and colloidal stability and elevated solution viscosity were observed for IgG3, future efforts controlling surface potential through sequence-engineering of solvent-accessible patches can be used to improve biophysical parameters that dictate mAb developability.

Electroconvulsive Therapy for Psychogenic Polydipsia and Hyponatremia in Chronic Schizophrenia: A Case Report and Literature Review.

ABSTRACT: Compulsive drinking of excessive quantities of water, called psychogenic polydipsia (PP), is a challenging complication of chronic psychotic disorders, which can lead to hyponatremia and downstream morbidity or mortality. Treatments include behavioral modifications such as free water restriction, medications to modify free water excretion, and psychotropic medications to target psychotic symptoms. However, in many cases, these options remain ineffective and/or intolerable, necessitating chronic institutionalization with poor patient quality of life. Here we report the use of an acute course of 8 sessions of bilateral electroconvulsive therapy (ECT) in a 57-year-old man with chronic schizophrenia, PP, and moderate hyponatremia refractory to standard treatments in an inpatient psychiatric setting. Serum sodium normalized and remained stable during and immediately following his ECT course, despite chronic hyponatremia with high variability for months prior to ECT initiation. A literature review found remarkably few reported cases of ECT for PP in chronic schizophrenia, a surprising result given the use of this modality for patients with psychotic illness in many countries. Our findings support future investigation into the clinical utility and mechanism of ECT for PP in this patient population.

Low pre-albumin but not thiamine predicts cognitive deficits in adolescents post-Fontan and healthy controls.

BACKGROUND: Low pre-albumin, body mass index, and thiamine levels have been associated with poor nutritional status and cognitive/memory deficits in adult heart failure patients. However, the relationship of these nutritional/dietary intake biomarkers to cognition has not been assessed in adolescents post-Fontan procedure and healthy controls. METHODS: This is a cross-sectional study. Adolescents (14-21 years of age) post-Fontan completion were recruited from paediatric cardiology clinics and controls from the community. The Montreal Cognitive Assessment was administered (normal ≥ 26), and blood draw (thiamine [normal 70-110 nmol/L] and pre-albumin levels [adolescent normal 23-45 mg/dL]) and the Thiamine Food Frequency Questionnaire were completed by all participants. RESULTS: Seventy subjects, 40 post-Fontan (mean age 16 ± 1.6, female 51%, Hispanic 44%, hypoplastic left heart syndrome 26%) and 30 controls (mean age 16.8 ± 1.9, female 52%, Hispanic 66%), were participated. Post-Fontan group had lower median total cognitive scores (23 versus 29, p < 0.001), pre-albumin levels (23 versus 27, p = 0.013), and body mass index (20 versus 24, p = 0.027) than controls. Post-Fontan group had higher thiamine levels than controls (127 versus 103, p = 0.033). Lower pre-albumin levels (< 23) and underweight body mass index were associated with abnormal total cognitive scores (p = 0.030). Low pre-albumin level (p = .038) was an independent predictor of worse cognition. CONCLUSION: Lower pre-albumin was an independent predictor for worse cognition in adolescents post-Fontan. Lower pre-albumin levels may reflect chronic liver changes or protein-losing enteropathy seen in Fontan physiology. These findings highlight the possibility for nutrition-induced cognitive changes.

Longitudinal Follow-Up of Children With HLHS and Association Between Norwood Shunt Type and Long-Term Outcomes: The SVR III Study.

OBJECTIVE: In the SVR trial (Single Ventricle Reconstruction), newborns with hypoplastic left heart syndrome were randomly assigned to receive a modified Blalock-Taussig-Thomas shunt (mBTTS) or a right ventricle-to-pulmonary artery shunt (RVPAS) at Norwood operation. Transplant-free survival was superior in the RVPAS group at 1 year, but no longer differed by treatment group at 6 years; both treatment groups had accumulated important morbidities. In the third follow-up of this cohort (SVRIII [Long-Term Outcomes of Children With Hypoplastic Left Heart Syndrome and the Impact of Norwood Shunt Type]), we measured longitudinal outcomes and their risk factors through 12 years of age. METHODS: Annual medical history was collected through record review and telephone interviews. Cardiac magnetic resonance imaging (CMR), echocardiogram, and cycle ergometry cardiopulmonary exercise tests were performed at 10 through 14 years of age among participants with Fontan physiology. Differences in transplant-free survival and complication rates (eg, arrhythmias or protein-losing enteropathy) were identified through 12 years of age. The primary study outcome was right ventricular ejection fraction (RVEF) by CMR, and primary analyses were according to shunt type received. Multivariable linear and Cox regression models were created for RVEF by CMR and post-Fontan transplant-free survival. RESULTS: Among 549 participants enrolled in SVR, 237 of 313 (76%; 60.7% male) transplant-free survivors (mBTTS, 105 of 147; RVPAS, 129 of 161; both, 3 of 5) participated in SVRIII. RVEF by CMR was similar in the shunt groups (RVPAS, 51±9.6 [n=90], and mBTTS, 52±7.4 [n=75]; P=0.43). The RVPAS and mBTTS groups did not differ in transplant-free survival by 12 years of age (163 of 277 [59%] versus 144 of 267 [54%], respectively; P=0.11), percentage predicted peak Vo2 for age and sex (74±18% [n=91] versus 72±18% [n=84]; P=0.71), or percentage predicted work rate for size and sex (65±20% versus 64±19%; P=0.65). The RVPAS versus mBTTS group had a higher cumulative incidence of protein-losing enteropathy (5% versus 2%; P=0.04) and of catheter interventions (14 versus 10 per 100 patient-years; P=0.01), but had similar rates of other complications. CONCLUSIONS: By 12 years after the Norwood operation, shunt type has minimal association with RVEF, peak Vo2, complication rates, and transplant-free survival. RVEF is preserved among the subgroup of survivors who underwent CMR assessment. Low transplant-free survival, poor exercise performance, and accruing morbidities highlight the need for innovative strategies to improve long-term outcomes in patients with hypoplastic left heart syndrome. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT0245531.

Influence of sunscreen formulation on the transfer of mineral and organic ultraviolet filters from skin to seawater in simulated ocean bathing tests.

OBJECTIVE: Significant research and regulatory attention have been focussed on the potential for some ultraviolet filters (UVFs) to rinse off from beachgoers' skin into seawater leading to exposure to sea life, especially coral reefs. The amount of UVFs potentially rinsed from skin during recreational beach activities has not been well studied, leading to uncertainty about the potential magnitude of aquatic UVF exposure due to changes in sunscreen use patterns. This study quantifies rinse-off of UVFs in sunscreen from skin into synthetic seawater and identifies differences in rinse-off quantity due to formulation type with a goal of informing future modelling efforts aimed at estimating UVF exposure to sea life associated with recreational activities at the beach. METHODS: UVF rinse-off from skin during recreation in seawater was simulated by applying eight different sunscreen products to porcine skin samples followed by three periods of shaking in synthetic seawater totalling 40 min. The rinsed mass of six UVFs - zinc oxide, titanium dioxide, avobenzone, homosalate, octisalate, and octocrylene - was determined analytically in synthetic seawater and in extractant rinsate from glassware for organic UVFs and compared among formulas. RESULTS: Among the 22 UVF-formulation combinations tested, 19 resulted in less than 10% of the applied UVF rinsed from skin. All formulation-UVF combinations where the formula types were water-in-oil (reverse phase) emulsions or anhydrous resulted in 5% or less of the applied UVF rinsed to synthetic seawater. Sunscreens formulated as oil-in-water emulsions yielded higher rinse-off percentages for all UVFs tested, with a maximum of 20% rinse-off of avobenzone in one lotion. CONCLUSION: The potential for sunscreen UVF rinse-off is significantly influenced by formulation and is generally well below the prior assumed rinse-off levels used to estimate risk. Formulation consideration is therefore essential for accurate exposure models used in environmental risk assessment. Anhydrous and reverse phase (water-in-oil) sunscreen formulations tested resulted in lower UVF transfer from skin to synthetic seawater in simulated ocean bathing tests and as a result, are expected to yield lower UVF exposures to sea life. This approach can be used in predictive environmental exposure models to support ecologically safe sunscreen formulation design.

OBJECTIF: Des recherches importantes ont été effectuées et l'attention réglementaire a été portée sur le potentiel de certains filtres ultraviolets (UVF) à être rincés de la peau de baigneurs par l'eau de mer à la plage, entraînant une exposition à la vie marine, en particulier aux récifs coralliens. La quantité d'UVF potentiellement rincée de la peau pendant les activités récréatives sur la plage n'a pas été étudiée de manière approfondie, ce qui entraîne une incertitude quant à l'ampleur potentielle de l'exposition aux UVF dans l'eau en raison des changements dans les habitudes d'utilisation de la crème solaire. Cette étude quantifie le rinçage des UVF contenus dans la crème solaire appliquée sur la peau par de l'eau de mer reconstituée et identifie les différences dans la quantité UVF rinçés selon le type de formulation afin d'éclairer les futurs efforts de modélisation visant à estimer l'exposition des UVF à la vie marine associée aux activités récréatives à la plage. MÉTHODES: Le rinçage des UVF pendant les loisirs en eau de mer a été simulé en appliquant huit produits de protection solaire différents sur des échantillons de peau porcine, suivis de trois périodes d'agitation dans de l'eau de mer reconstituée d'une durée totale de 40 min. La masse rincée de six UVF - oxyde de zinc, dioxyde de titane, avobenzone, homosalate, octisalate et octocrylène - a été déterminée analytiquement dans l'eau de mer reconstituée et en solution pour les UVF organiques, et une comparaison entre les formules a été effectuée. RÉSULTATS: Parmi les 22 combinaisons de formulations UVF testées, 19 ont entraîné le rinçage de moins de 10 % des UVF appliqués sur la peau. Toutes les combinaisons de formulations UVF où les types de formule étaient des émulsions eau dans huile (phase inverse) ou anhydres ont entraîné 5 % ou moins de rinçage des UVF appliquées dans l'eau de mer reconstituée. Les écrans solaires formulés sous forme d'émulsions huile dans l'eau ont produit des pourcentages de rinçage plus élevés pour tous les UVF testés, avec un maximum de 20 % de rinçage pour l'avobenzone pour une lotion. CONCLUSION: Le potentiel de rinçage des UVF de l'écran solaire est significativement influencé par la formulation et est généralement bien inférieur aux niveaux de rinçage précédemment supposés, utilisés pour estimer le risque. La prise en compte de la formulation est donc essentielle pour obtenir des modèles d'exposition exacts utilisés dans l'évaluation des risques environnementaux. Les formulations de crème solaire anhydre et en phase inverse (eau dans l'huile) testées ont entraîné un transfert plus faible des UVF dans l'eau de mer reconstituée dans des tests de simulation de bain de mer et, par conséquent, devraient entrainer une exposition plus faible des UVF à la vie marine. Cette approche peut être utilisée dans des modèles prédictifs d'exposition environnementale pour soutenir une conception de crème solaire écologiquement sûre.

Predicting the electronic density response of condensed-phase systems to electric field perturbations.

We present a local and transferable machine-learning approach capable of predicting the real-space density response of both molecules and periodic systems to homogeneous electric fields. The new method, Symmetry-Adapted Learning of Three-dimensional Electron Responses (SALTER), builds on the symmetry-adapted Gaussian process regression symmetry-adapted learning of three-dimensional electron densities framework. SALTER requires only a small, but necessary, modification to the descriptors used to represent the atomic environments. We present the performance of the method on isolated water molecules, bulk water, and a naphthalene crystal. Root mean square errors of the predicted density response lie at or below 10% with barely more than 100 training structures. Derived polarizability tensors and even Raman spectra further derived from these tensors show good agreement with those calculated directly from quantum mechanical methods. Therefore, SALTER shows excellent performance when predicting derived quantities, while retaining all of the information contained in the full electronic response. Thus, this method is capable of predicting vector fields in a chemical context and serves as a landmark for further developments.

Narrowing the translational research gap by aligning replication concepts in basic and clinical neuroscience.

Replicability and reproducibility are widely considered to be cornerstones of valid scientific research. Yet, the elements of replication in fundamental neuroscience studies do not fully overlap with the process of replication in clinical neuroscience involving patients. Here we discuss how better aligning the concept of replication across this translational spectrum might enhance the rate at which basic findings in the organization and function of the nervous system are leveraged to develop new treatments for psychiatric and neurological disorders.

Effects of repeated developmental GLP-1R agonist exposure on adult behavior and hippocampal structure in mice.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are common type 2 diabetes medications that have been repurposed for adult chronic weight management. Clinical trials suggest this class may also be beneficial for obesity in pediatric populations. Since several GLP-1R agonists cross the blood-brain barrier, it is important to understand how postnatal developmental exposure to GLP-1R agonists might affect brain structure and function in adulthood. Toward that end, we systemically treated male and female C57BL/6 mice with the GLP-1R agonist exendin-4 (0.5 mg/kg, twice daily) or saline from postnatal day 14 to 21, then allowed uninterrupted development to adulthood. Beginning at 7 weeks of age, we performed open field and marble burying tests to assess motor behavior and the spontaneous location recognition (SLR) task to assess hippocampal-dependent pattern separation and memory. Mice were sacrificed, and we counted ventral hippocampal mossy cells, as we have recently shown that most murine hippocampal neuronal GLP-1R is expressed in this cell population. We found that GLP-1R agonist treatment did not alter P14-P21 weight gain, but modestly reduced adult open field distance traveled and marble burying. Despite these motor changes, there was no effect on SLR memory performance or time spent investigating objects. Finally, we did not detect any changes in ventral mossy cell number using two different markers. These data suggest developmental exposure to GLP-1R agonists might have specific rather than global effects on behavior later in life and that extensive additional study is necessary to clarify how drug timing and dose affect distinct constellations of behavior in adulthood.

Effects of repeated developmental GLP-1R agonist exposure on young adult behavior and hippocampal structure in mice.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are common type 2 diabetes medications that have been repurposed for adult chronic weight management. Clinical trials suggest this class may also be beneficial for obesity in pediatric populations. Since several GLP-1R agonists cross the blood-brain barrier, it is important to understand how postnatal developmental exposure to GLP-1R agonists might affect brain structure and function later in life. Toward that end, we systemically treated male and female C57BL/6 mice with the GLP-1R agonist exendin-4 (0.5 mg/kg, twice daily) or saline from postnatal day 14 to 21, then allowed uninterrupted development to young adulthood. Beginning at 7 weeks of age, we performed open field and marble burying tests to assess motor behavior and the spontaneous location recognition (SLR) task to assess hippocampal-dependent pattern separation and memory. Mice were sacrificed, and we counted ventral hippocampal mossy cells, as we have recently shown that most murine hippocampal neuronal GLP-1R is expressed in this cell population. We found that GLP-1R agonist treatment did not alter P14-P21 weight gain, but modestly reduced young adult open field distance traveled and marble burying. Despite these motor changes, there was no effect on SLR memory performance or time spent investigating objects. Finally, we did not detect any changes in ventral mossy cell number using two different markers. These data suggest developmental exposure to GLP-1R agonists might have specific rather than global effects on behavior later in life and that extensive additional study is necessary to clarify how drug timing and dose affect distinct constellations of behavior in young adulthood.

An Empirical Analysis of the Effectiveness of Daycare Centers in Improving the Well-Being of Older People.

In 2021 the State Council set out a plan to address the challenges posed by China's aging population, particularly through the consolidation of community home care services, including the provision of daycare centers. This study focuses on the provision of daycare centers in Dalian, a key city in Northeast China, and utilizes Mary Shaw's "housing and health" model to conceptualize daycare centers as elements in a network that encompasse home and neighborhood. Furthermore, the study considers how daycare centers may affect this network, particularly when it comes to contributing to the well-being of older people and how they adapt to the local culture. A survey was conducted across 19 daycare centers to determine the services they provide. Semi-structured interviews were conducted with 8 older people living in Dalian, and their homes were surveyed using the EVOLVE Tool. Additional interviews were conducted with 11 people in outdoor neighborhood spaces and daycare centers. The interviewees were asked to provide insights about their homes, neighborhoods, and daycare centers. The interview and survey data uncovered themes around socialization, nutrition, and personal hygiene by employing the thematic analysis method. The results revealed that daycare centers theoretically compensated for the missing functions in the community; however, residents' cultural awareness and consumption habits prevented daycare centers from being used optimally, thereby failing to improve the well-being of older people. Thus, in the process of improving the socialist market economy, the government should enhance the publicity of these facilities and retain welfare as much as possible. Funds should also be allocated to protect older people's basic needs.

Electronic-Structure Properties from Atom-Centered Predictions of the Electron Density.

The electron density of a molecule or material has recently received major attention as a target quantity of machine-learning models. A natural choice to construct a model that yields transferable and linear-scaling predictions is to represent the scalar field using a multicentered atomic basis analogous to that routinely used in density fitting approximations. However, the nonorthogonality of the basis poses challenges for the learning exercise, as it requires accounting for all the atomic density components at once. We devise a gradient-based approach to directly minimize the loss function of the regression problem in an optimized and highly sparse feature space. In so doing, we overcome the limitations associated with adopting an atom-centered model to learn the electron density over arbitrarily complex data sets, obtaining very accurate predictions using a comparatively small training set. The enhanced framework is tested on 32-molecule periodic cells of liquid water, presenting enough complexity to require an optimal balance between accuracy and computational efficiency. We show that starting from the predicted density a single Kohn-Sham diagonalization step can be performed to access total energy components that carry an error of just 0.1 meV/atom with respect to the reference density functional calculations. Finally, we test our method on the highly heterogeneous QM9 benchmark data set, showing that a small fraction of the training data is enough to derive ground-state total energies within chemical accuracy.

Glucagon-like peptide-1 receptor differentially controls mossy cell activity across the dentate gyrus longitudinal axis.

Understanding the role of dentate gyrus (DG) mossy cells (MCs) in learning and memory has rapidly evolved due to increasingly precise methods for targeting MCs and for in vivo recording and activity manipulation in rodents. These studies have shown MCs are highly active in vivo, strongly remap to contextual manipulation, and that their inhibition or hyperactivation impairs pattern separation and location or context discrimination. Less well understood is how MC activity is modulated by neurohormonal mechanisms, which might differentially control the participation of MCs in cognitive functions during discrete states, such as hunger or satiety. In this study, we demonstrate that glucagon-like peptide-1 (GLP-1), a neuropeptide produced in the gut and the brain that regulates food consumption and hippocampal-dependent mnemonic function, might regulate MC function through expression of its receptor, GLP-1R. RNA-seq demonstrated that most, though not all, Glp1r in hippocampal principal neurons is expressed in MCs, and in situ hybridization revealed strong expression of Glp1r in hilar neurons. Glp1r-ires-Cre mice crossed with Ai14D reporter mice followed by co-labeling for the MC marker GluR2/3 revealed that almost all MCs in the ventral DG expressed Glp1r and that almost all Glp1r-expressing hilar neurons were MCs. However, only ~60% of dorsal DG MCs expressed Glp1r, and Glp1r was also expressed in small hilar neurons that were not MCs. Consistent with this expression pattern, peripheral administration of the GLP-1R agonist exendin-4 (5 µg/kg) increased cFos expression in ventral but not dorsal DG hilar neurons. Finally, whole-cell patch-clamp recordings from ventral MCs showed that bath application of exendin-4 (200 nM) depolarized MCs and increased action potential firing. Taken together, this study adds to known MC activity modulators a neurohormonal mechanism that may preferentially affect ventral DG physiology and may potentially be targetable by several GLP-1R pharmacotherapies already in clinical use.

Distal femur versus humeral or tibial IO, access in adult out of hospital cardiac resuscitation.

BACKGROUND: Intraosseous (IO) vascular access is a well-established method for fluid and drug administration in the critically ill. The Food and Drug Administration has approved adult IO access at the proximal humerus, proximal tibia, and the sternum; all three sites have significant limitations. The Distal Femur is away from the chest, with high flow rates. The objective of this study was to evaluate the distal femur site during resuscitation of adult out-of-hospital cardiac arrest. METHODS: A retrospective analysis of adult out of hospital cardiac arrest patients treated by the San Antonio Fire Department. IO access was obtained by first-responders (paramedics or EMT-basic) or EMS paramedics. All resuscitation attempts from 2017 to 2018 data were analyzed. The protocol did not dictate the preference of IO site. The primary measure: number of OHCA patients in each subgroup: IO femur, IO humerus, IO tibia. Secondary measures: paramedic or basic operator, dislodgement rate, and total fluid infused. RESULTS: There were 2,198 patients meeting inclusion criteria: 888 femur, 696 humerus, 432 tibia. Distal femur increased 2.5 times in the 2018 cohort compared to the 2017 cohort, with a corresponding decrease in humerus (factor of 0.29). Proximal tibia remained unchanged. Dislodgement rates and total infusion (ml) remained unchanged. CONCLUSIONS: The distal femur IO was feasible and associated with similar measured performance parameters as other IO sites in adult OHCA for both advanced and basic life support personnel.

Cumulative In-Hospital Costs Associated With Single-Ventricle Palliation.

Background: In the SVR (Single Ventricle Reconstruction) Trial, 1-year survival in recipients of right ventricle to pulmonary artery shunts (RVPAS) was superior to that in those receiving modified Blalock-Taussig-Thomas shunts (MBTTS), but not in subsequent follow-up. Cost analysis is an expedient means of evaluating value and morbidity. Objectives: The purpose of this study was to evaluate differences in cumulative hospital costs between RVPAS and MBTTS. Methods: Clinical data from SVR and costs from Pediatric Health Information Systems database were combined. Cumulative hospital costs and cost-per-day-alive were compared serially at 1, 3, and 5 years between RVPAS and MBTTS. Potential associations between patient-level factors and cost were explored with multivariable models. Results: In total, 303 participants (55% of the SVR cohort) from 9 of 15 sites were studied (48% MBTTS). Observed total costs at 1 year were lower for MBTTS ($701,260 ± 442,081) than those for RVPAS ($804,062 ± 615,068), a difference that was not statistically significant (P = 0.10). Total costs were also not significantly different at 3 and 5 years (P = 0.21 and 0.32). Similarly, cost-per-day-alive did not differ significantly for either group at 1, 3, and 5 years (all P > 0.05). In analyses of transplant-free survivors, total costs and cost-per-day-alive were higher for RVPAS at 1 year (P = 0.05 for both) but not at 3 and 5 years (P > 0.05 for all). In multivariable models, aortic atresia and prematurity were associated with increased cost-per-day-alive across follow-up (P < 0.05). Conclusions: Total costs do not differ significantly between MBTTS and RVPAS. The magnitude of longitudinal costs underscores the importance of efforts to improve outcomes in this vulnerable population.

Learning Electron Densities in the Condensed Phase.

We introduce a local machine-learning method for predicting the electron densities of periodic systems. The framework is based on a numerical, atom-centered auxiliary basis, which enables an accurate expansion of the all-electron density in a form suitable for learning isolated and periodic systems alike. We show that, using this formulation, the electron densities of metals, semiconductors, and molecular crystals can all be accurately predicted using symmetry-adapted Gaussian process regression models, properly adjusted for the nonorthogonal nature of the basis. These predicted densities enable the efficient calculation of electronic properties, which present errors on the order of tens of meV/atom when compared to ab initio density-functional calculations. We demonstrate the key power of this approach by using a model trained on ice unit cells containing only 4 water molecules to predict the electron densities of cells containing up to 512 molecules and see no increase in the magnitude of the errors of derived electronic properties when increasing the system size. Indeed, we find that these extrapolated derived energies are more accurate than those predicted using a direct machine-learning model. Finally, on heterogeneous data sets SALTED can predict electron densities with errors below 4%.

Modeling intrahippocampal effects of anterior hippocampal hyperactivity relevant to schizophrenia using chemogenetic excitation of long axis-projecting mossy cells in the mouse dentate gyrus.

BACKGROUND: The anterior hippocampus of individuals with early psychosis or schizophrenia is hyperactive, as is the ventral hippocampus in many rodent models for schizophrenia risk. Mossy cells (MCs) of the ventral dentate gyrus (DG) densely project in the hippocampal long axis, targeting both dorsal DG granule cells and inhibitory interneurons. Mossy cells are responsive to stimulation throughout hippocampal subfields, and thus may be suited to detect hyperactivity in areas where it originates such as CA1. Here we tested the hypothesis that hyperactivation of ventral MCs activates dorsal DG granule cells to influence dorsal hippocampal function. METHODS: In CD-1 mice, we targeted dorsal DG-projecting ventral MCs using an adeno-associated virus intersectional strategy. In vivo fiber photometry recording of ventral MCs was performed during exploratory behaviors. We used excitatory chemogenetic constructs to test the effects of ventral MC hyperactivation on long-term spatial memory during an object location memory task. RESULTS: Photometry revealed ventral MCs were activated during exploratory rearing. Ventral MCs made functional monosynaptic inputs to dorsal DG granule cells, and chemogenetic activation of ventral MCs modestly increased activity of dorsal DG granule cells measured by c-Fos. Finally, chemogenetic activation of ventral MCs during the training phase of an object location memory task impaired test performance 24 hours later, without effects on locomotion or object exploration. CONCLUSIONS: These data suggest that ventral MC activation can directly excite dorsal granule cells and interfere with dorsal DG function, supporting future study of their in vivo activity in animal models for schizophrenia featuring ventral hyperactivity.

Public Baseline and shared response structures support the theory of antibody repertoire functional commonality.

The naïve antibody/B-cell receptor (BCR) repertoires of different individuals ought to exhibit significant functional commonality, given that most pathogens trigger an effective antibody response to immunodominant epitopes. Sequence-based repertoire analysis has so far offered little evidence for this phenomenon. For example, a recent study estimated the number of shared ('public') antibody clonotypes in circulating baseline repertoires to be around 0.02% across ten unrelated individuals. However, to engage the same epitope, antibodies only require a similar binding site structure and the presence of key paratope interactions, which can occur even when their sequences are dissimilar. Here, we search for evidence of geometric similarity/convergence across human antibody repertoires. We first structurally profile naïve ('baseline') antibody diversity using snapshots from 41 unrelated individuals, predicting all modellable distinct structures within each repertoire. This analysis uncovers a high (much greater than random) degree of structural commonality. For instance, around 3% of distinct structures are common to the ten most diverse individual samples ('Public Baseline' structures). Our approach is the first computational method to find levels of BCR commonality commensurate with epitope immunodominance and could therefore be harnessed to find more genetically distant antibodies with same-epitope complementarity. We then apply the same structural profiling approach to repertoire snapshots from three individuals before and after flu vaccination, detecting a convergent structural drift indicative of recognising similar epitopes ('Public Response' structures). We show that Antibody Model Libraries derived from Public Baseline and Public Response structures represent a powerful geometric basis set of low-immunogenicity candidates exploitable for general or target-focused therapeutic antibody screening.