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The human brain undergoes rapid development during the first years of life. Beginning in utero, a wide array of biological, social, and environmental factors can have lasting impacts on brain structure and function. To understand how prenatal and early life experiences alter neurodevelopmental trajectories and shape health outcomes, several NIH Institutes, Centers, and Offices collaborated to support and launch the HEALthy Brain and Child Development (HBCD) Study. The HBCD Study is a multi-site prospective longitudinal cohort study, that will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Influenced by the success of the ongoing Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®) and in partnership with the NIH Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, the HBCD Study aims to establish a diverse cohort of over 7000 pregnant participants to understand how early life experiences, including prenatal exposure to addictive substances and adverse social environments as well as their interactions with an individuals genes, can affect neurodevelopmental trajectories and outcomes. Knowledge gained from the HBCD Study will help identify targets for early interventions and inform policies that promote resilience and mitigate the neurodevelopmental effects of adverse childhood experiences and environments.

Abstract MYCN-amplified RB1 wild-type (MYCN amp RB1 +/+) retinoblastoma is a rare and aggressive subtype, often resistant to standard therapies. Identifying unique MRI features is crucial for diagnosing this subtype, as biopsy is not recommended. This study aimed to differentiate MYCN amp RB1 +/+ from the most prevalent RB1 -/- retinoblastoma using pretreatment MRI and radiomics. Ninety-eight unilateral retinoblastoma patients (19 MYCN cases and 79 matched controls) were included. Tumors on T2-weighted MR images were manually delineated and validated by experienced radiologists. Radiomics analysis extracted 120 features per tumor. Several combinations of feature selection methods, oversampling techniques and machine learning (ML) classifiers were evaluated in a repeated fivefold cross-validation machine learning pipeline to yield the best-performing prediction model for MYCN. The best model used univariate feature selection, data oversampling (duplicating MYCN cases), and logistic regression classifier, achieving a mean AUC of 0.78 (SD 0.12). SHAP analysis highlighted lower sphericity, higher flatness, and greater gray-level heterogeneity as predictive for MYCN amp RB1 +/+ status, yielding an AUC of 0.81 (SD 0.11). This study shows the potential of MRI-based radiomics to distinguish MYCN amp RB1 +/+ and RB1 -/- retinoblastoma subtypes.

Anxiety and depression are highly prevalent psychiatric disorders, affecting approximately 18% of the United States population. Evidence indicates that central oxytocin mediates social cognition, social bonding, and social anxiety. Although it is well-established that oxytocin ameliorates social deficits, less is known about the therapeutic effects of oxytocin in non-social contexts. We hypothesized that positive effects of oxytocin in social contexts are attributable to intrinsic effects of oxytocin on neural systems that are related to emotion regulation. The present study investigated the effect of intracerebroventricular (ICV) oxytocin administration (i.e., central action) on anxiety- and depression-like behavior in C57Bl/6J mice using non-social tests. Male and female mice received an ICV infusion of vehicle or oxytocin (100, 200, or 500 ng), then were tested in the elevated zero maze (for anxiety-like behavior) and the tail suspension test (for depression-like behavior). Oxytocin dose-dependently increased open zone occupancy and entries in the elevated zero maze and reduced immobility duration in the tail suspension test in both sexes. Oxytocin decreased anxiety and depression-like behavior in male and female mice. The observed effect of oxytocin on anxiolytic-like behavior appeared to be driven by the males. Given the smaller anxiolytic-like effect of oxytocin in the female mice and the established interaction between oxytocin and reproductive hormones (estrogen and progesterone), we also explored whether oxytocin sensitivity in females varies across estrous cycle phases and in ovariectomized females that were or were not supplemented with estrogen or progesterone. Oxytocin reduced anxiety-like behavior in female mice in proestrus/estrus, ovariectomized females (supplemented or not with estrogen or progesterone), but not females in metestrus/diestrus. Additionally, oxytocin reduced depression-like behavior in all groups tested with slight differences across the various hormonal statuses. These results suggest that the effect of oxytocin in depression- and anxiety-like behavior in mice can be influenced by sex and hormonal status.

Abstract Background Children with medical complexity (CMC) comprise

Abstract Pathological fibrosis is a significant complication of surgical procedures resulting from the accumulation of excess collagen at the site of repair which can compromise the tissue architecture and severely impede the function of the affected tissue. Few prophylactic treatments exist to counteract this process; however, the use of amniotic membrane allografts has demonstrated promising clinical outcomes. This study aimed to identify the underlying mechanism of action by utilizing relevant models that accurately represent the pathophysiology of the disease state. This study employed a pro-fibrotic in vitro system using TGFβ1 stimulation and macromolecular crowding techniques to evaluate the mechanism by which amniotic membrane allografts regulate collagen biosynthesis and deposition. Following treatment with dehydrated human amnion chorion membrane (DHACM), subsequent RNA sequencing and functional enrichment with Reactome pathway analysis indicated that amniotic membranes are indeed capable of regulating genes associated with the composition and function of the extracellular matrix. Furthermore, macromolecular crowding was used in vitro to expand the evaluation to include both the effects of DHACM and a lyophilized human amnion/chorion membrane (LHACM). DHACM and LHACM regulate the TGFβ pathway and myofibroblast differentiation. Additionally, both DHACM and LHACM modulate the production, secretion, and deposition of collagen type I, a primary target for pathological fibrosis. These observations support the hypothesis that amniotic membranes may interrupt pathological fibrosis by regulating collagen biosynthesis and associated pathways.

Abstract The Addictions Neuroclinical Assessment (ANA) is a neurobiologically-informed framework designed to understand the etiology and heterogeneity of Alcohol Use Disorder (AUD). Previous studies validated the three neurofunctional domains of ANA: Incentive Salience (IS), Negative Emotionality (NE) and Executive Function (EF) using secondary data. The present cross-sectional observational study assessed these domains in an independent, prospective clinical sample. Adults across the drinking spectrum (N = 300) completed the ANA battery, a standardized collection of behavioral tasks and self-report assessments. Factor analyses were used to identify latent factors underlying each domain. Associations between identified domain factors were evaluated using structural equation models. Receiver operating characteristics analyses were used to determine factors with the strongest ability to classify individuals with problematic drinking and AUD. We found (1) two factors underlie the IS domain: alcohol motivation and alcohol insensitivity. (2) Three factors were identified for the NE domain: internalizing, externalizing, and psychological strength. (3) Five factors were found for the EF domain: inhibitory control, working memory, rumination, interoception, and impulsivity. (4) These ten factors showed varying degrees of cross-correlations, with alcohol motivation, internalizing, and impulsivity exhibiting the strongest correlations. (5) Alcohol motivation, alcohol insensitivity, and impulsivity showed the greatest ability in classifying individuals with problematic drinking and AUD. Thus, the present study identified unique factors underlying each ANA domain assessed using a standardized assessment battery. These results revealed additional dimensionality to the ANA domains, bringing together different constructs from the field into a single cohesive framework and advancing the field of addiction phenotyping. Future work will focus on identifying neurobiological correlates and identifying AUD subtypes based on these factors.

Background: We examined trends in mental health service utilization before, during, and in the immediate return to in-person learning throughout the COVID-19 pandemic. Methods: Retrospective chart review was assessed for changes in odds of any visit being a mental health encounter from five school-based health centers from the 2018-2019 to the 2021-2022 school years. Data are limited to the in-person school year from mid-August to early June. Results: Data were assessed from 1239 students seen through 2256 visits over the 4 school years (M[subscript age] = 12.93). The odds of any visit being related to a mental health encounter increased each school year, with the 2020 to 2021 and 2021 to 2022 school years having significant increases in odds (both compared to the first and to the antecedent school year). In addition, during the 2019 to 2020 and 2020 to 2021 school years, the odds of a repeated mental health encounter significantly increased from year to year. Conclusions: Findings indicate a steadily increasing number of mental health service utilization needs among adolescent students that was significantly exponentiated throughout the COVID-19 pandemic.

In the present study, we examined how the relevance of potentially distracting information modulates the interplay of target and distractor processing in conflict tasks. Specifically, we manipulated the degree to which distracting information is relevant for performing the overall task by varying the proportion of trials in which a response to the distractor(s) (Experiments 1a and 1b: location in a Simon task; Experiment 2: flankers in an Eriksen flanker task) instead of to the target was required. Across all experiments, the congruency effect on mean RT was larger with the increasing relevance of the distractor(s). Critically, the slopes of the delta plot were more strongly increasing when the distractors were potentially relevant (as opposed to completely irrelevant), suggesting that cognitive control affects the timing of suppressing distractor-based activation. In addition, delta plot and diffusion model analyses revealed that the strength of suppressing distractor processing and the efficiency of target processing were enhanced when the distractors were less relevant. Overall, the present study dissociated multiple and time-dependent adjustments of control processes (i.e., target processing enhancement plus timing and strength of distractor suppression) in environments that encourage either a more stable or more flexible processing mode.

Introduction: Recurrence of splenic volvulus after splenopexy in children is rare. A consensus on the optimal surgical strategy in splenic volvulus is lacking. Case Presentation: An 11-year-old female presented left upper quadrant abdominal pain for 24 hours following a short-lived appearance of an epigastric bulge. A CT-scan demonstrated findings consistent with splenic volvulus, without distal arterial flow. She underwent an exploratory laparoscopy, splenic detorsion, and splenopexy to the abdominal wall using two non-resorbable, knotless, unidirectional barbed sutures. The patient was discharged on day 2 after the procedure. A 6-month follow-up ultrasound showed a normally perfused spleen. Then months after the operation she presented with the same abdominal symptoms. A CT scan confirmed the recurrence of the splenic volvulus. She underwent a second laparoscopy, splenic detorsion, and splenopexy with a tailor-made mesh bag anchored to the abdominal wall. She recovered well from that operation. At 10 months of follow up she has had no recurrent of symptoms and the spleen is well vascularized by ultrasound. Conclusion: Simple splenopexy using direct sutures to abdominal wall may not be sufficient to create adequate adhesions and prevent recurrence. The use of a mesh may have a higher success rate.

The human brain undergoes rapid development during the first years of life. Beginning in utero, a wide array of biological, social, and environmental factors can have lasting impacts on brain structure and function. To understand how prenatal and early life experiences alter neurodevelopmental trajectories and shape health outcomes, several NIH Institutes, Centers, and Offices collaborated to support and launch the HEALthy Brain and Child Development (HBCD) Study. The HBCD Study is a multi-site prospective longitudinal cohort study, that will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Influenced by the success of the ongoing Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®) and in partnership with the NIH Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, the HBCD Study aims to establish a diverse cohort of over 7000 pregnant participants to understand how early life experiences, including prenatal exposure to addictive substances and adverse social environments as well as their interactions with an individual’s genes, can affect neurodevelopmental trajectories and outcomes. Knowledge gained from the HBCD Study will help identify targets for early interventions and inform policies that promote resilience and mitigate the neurodevelopmental effects of adverse childhood experiences and environments.

Abstract The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake in male rats and modifies the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. We use RNA-sequencing to show that GHSR-KO rats have upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity.

ABSTRACTMultiple myeloma (MM) is an incurable malignancy of the B-cell lineage. Remarkable progress has been made in the treatment of MM with anti-CD38 monoclonal antibodies such as daratumumab and isatuximab, which can kill MM cells by inducing complement-dependent cytotoxicity (CDC). We showed that the CDC efficacy of daratumumab and isatuximab is limited by membrane complement inhibitors, including CD46 and CD59, which are upregulated in MM cells. We recently developed a small recombinant protein, Ad35K++, which is capable of transiently removing CD46 from the cell surface. We also produced a peptide inhibitor of CD59 (rILYd4). In this study, we tested Ad35K++ and rILYd4 in combination with daratumumab and isatuximab in MM cells as well as in cells from two other B-cell malignancies. We showed that Ad35K++ and rILYd4 increased CDC triggered by daratumumab and isatuximab. The combination of both inhibitors had an additive effect in vitro in primary MM cells as well as in vivo in a mouse xenograft model of MM. Daratumumab and isatuximab treatment of MM lines (without Ad35K++ or rILYd4) resulted in the upregulation of CD46/CD59 and/or survival of CD46high/CD59high MM cells that escaped the second round of daratumumab and isatuximab treatment. The escape in the second treatment cycle was prevented by the pretreatment of cells with Ad35K++. Overall, our data demonstrate that Ad35K++ and rILYd4 are efficient co-therapeutics of daratumumab and isatuximab, specifically in multi-cycle treatment regimens, and could be used to improve treatment of multiple myeloma.

Hypocretin/Orexin (HCRT) is a neuropeptide that is associated with both stress and reward systems in humans and rodents. The different contributions of signaling at hypocretin-receptor 1 (HCRT-R1) and hypocretin-receptor 2 (HCRT-R2) to compulsive alcohol drinking are not yet fully understood. Thus, the current studies used pharmacological and viral-mediated targeting of HCRT to determine participation in compulsive alcohol drinking and measured HCRT-receptor mRNA expression in the extended amygdala of both alcohol-dependent and non-dependent male rats. Rats were made dependent through chronic intermittent exposure to alcohol vapor and were tested for the acute effect of HCRT-R1-selective (SB-408124; SB-R1), HCRT-R2-selective (NBI-80713; NB-R2), or dual HCRT-R1/2 (NBI-87571; NB-R1/2) antagonism on alcohol intake. NB-R2 and NB-R1/2 antagonists each dose-dependently decreased overall alcohol drinking in alcohol-dependent rats, whereas, SB-R1 decreased alcohol drinking in both alcohol-dependent and non-dependent rats at the highest dose (30 mg/kg). SB-R1, NB-R2, and NB-R1/2 treatment did not significantly affect water drinking in either alcohol-dependent or non-dependent rats. Additional PCR analyses revealed a significant decrease in Hcrtr1 mRNA expression within the central amygdala (CeA) of dependent rats under acute withdrawal conditions compared to nondependent rats. Lastly, a shRNA-encoding adeno-associated viral vector with retrograde function was used to knockdown HCRT in CeA-projecting neurons from the lateral hypothalamus (LH). LH-CeA HCRT knockdown significantly attenuated alcohol self-administration in alcohol-dependent rats. These observations suggest that HCRT signaling in the CeA is necessary for alcohol-seeking behavior during dependence. Together, these data highlight a role for both HCRT-R1 and -R2 in dependent alcohol-seeking behavior.

Abstract Mood and anxiety disorders are leading causes of disability worldwide and are major contributors to the global burden of diseases. Neuropeptides, such as oxytocin and opioid peptides, are important for emotion regulation. Previous studies have demonstrated that oxytocin reduced depression- and anxiety-like behavior in male and female mice, and opioid receptor activation reduced depression-like behavior. However, it remains unclear whether the endogenous opioid system interacts with the oxytocin system to facilitate emotion regulation in male and female mice. We hypothesized that opioid receptor blockade would inhibit the anxiolytic- and antidepressant-like effects of oxytocin. In this study, we systemically administered naloxone, a preferential μ−opioid receptor antagonist, and then intracerebroventricularly administered oxytocin. We then tested mice on the elevated zero maze and the tail suspension tests, respective tests of anxiety- and depression-like behavior. Contrary to our initial hypothesis, naloxone potentiated the anxiolytic-like, but not the antidepressant-like, effect of oxytocin. Using a selective μ−opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, and a selective κ−opioid receptor antagonist, norbinaltorphimine, we demonstrate that μ−opioid receptor blockade potentiated the anxiolytic-like effect of oxytocin, whereas κ−opioid receptor blockade inhibited the oxytocin-induced anxiolytic-like effects. The present results suggest that endogenous opioids can regulate the oxytocin system to modulate anxiety-like behavior. Potential clinical implications of these findings are discussed.

ObjectiveTo assess the accuracy of corpus callosum (CC) biometry, including sub-segments, using 3D super-resolution fetal brain MRI (SR) compared to 2D or 3D ultrasound (US) and clinical low-resolution T2-weighted MRI (T2WS).MethodFetal brain biometry was conducted by two observers on 57 subjects [21–35 weeks of gestational age (GA)], including 11 cases of partial CC agenesis. Measures were performed by a junior observer (obs1) on US, T2WS and SR and by a senior neuroradiologist (obs2) on T2WS and SR. CC biometric regression with GA was established. Statistical analysis assessed agreement within and between modalities and observers.ResultsThis study shows robust SR to US concordance across gestation, surpassing T2WS. In obs1, SR aligns with US, except for genu and CC length (CCL), enhancing splenium visibility. In obs2, SR closely corresponds to US, differing in rostrum and CCL. The anterior CC (rostrum and genu) exhibits higher variability. SR’s regression aligns better with literature (US) for CCL, splenium and body than T2WS. SR is the method with the least missing values.ConclusionSR yields CC biometry akin to US (excluding anterior CC). Thanks to superior 3D visualization and better through plane spatial resolution, SR allows to perform CC biometry more frequently than T2WS.

Abstract In recent years, several novel agents have become available to treat individuals with type 2 diabetes (T2D), such as sodium-glucose cotransporter-2 inhibitors (SGLT-2i), tirzepatide, which is a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP RA)/glucagon-like peptide-1 receptor agonist (GLP-1 RA), and finerenone, a non-steroidal mineralocorticoid receptor antagonist (MRA) that confers significant renal and cardiovascular benefits in individuals with (CKD). New medications have the potential to improve the lives of individuals with diabetes. However, clinicians are challenged to understand the benefits and potential risks associated with these new and emerging treatment options. In this article, we discuss how use of network meta-analyses (NMA) can fill this need.