"Extracorporeal membrane oxygenation outcomes in multisystem inflammatory syndrome of childhood - An extracorporeal life support organization registry study".

Multisystem inflammatory disease in childhood (MIS-C) is a novel pediatric syndrome after a COVID-19 infection that causes systemic injury, with potential life-threatening hemodynamic compromise requiring Extracorporeal Membrane Oxygenation (ECMO) support. We performed an observational retrospective cohort study in children aged 0-18 years with MIS-C and non-MIS-C myocarditis on ECMO between January 2020 and December 2021, using the ELSO Registry database. We aimed to compare the outcomes of both populations and to identify factors for decreased survival in MIS-C patients on ECMO. The Extracorporeal Life Support Organization (ELSO) Registry reported 310 pediatric ECMO patients with MIS-C (56.1%) and non-MIS-C myocarditis (43.9%). No difference was found in survival to hospital discharge between groups (67.2% for MIS-C vs 69.1% for non-MIS-C myocarditis, p 0.725). Multivariable analysis demonstrated that ECPR and co-infection were significantly associated with decreased survival to hospital discharge in MIS-C patients (OR 0.138, p 0.01 and OR 0.44, p 0.02, respectively). Outcomes of children with MIS-C on ECMO support are similar to those of non-MIS-C myocarditis despite higher infectious, multiorgan dysfunction and respiratory complications accompanying COVID-19 infections. The use of ECMO for MIS-C patients seems to be feasible and safe. Prospective studies on the use of ECMO support in MIS-C patients may improve outcomes in this pediatric population.

Social threat alters the behavioral structure of social motivation and reshapes functional brain connectivity.

Traumatic social experiences redefine socially motivated behaviors to enhance safety and survival. Although many brain regions have been implicated in signaling a social threat, the mechanisms by which global neural networks regulate such motivated behaviors remain unclear. To address this issue, we first combined traditional and modern behavioral tracking techniques in mice to assess both approach and avoidance, as well as sub-second behavioral changes, during a social threat learning task. We were able to identify previously undescribed body and tail movements during social threat learning and recognition that demonstrate unique alterations into the behavioral structure of social motivation. We then utilized inter-regional correlation analysis of brain activity after a mouse recognizes a social threat to explore functional communication amongst brain regions implicated in social motivation. Broad brain activity changes were observed within the nucleus accumbens, the paraventricular thalamus, the ventromedial hypothalamus, and the nucleus of reuniens. Inter-regional correlation analysis revealed a reshaping of the functional connectivity across the brain when mice recognize a social threat. Altogether, these findings suggest that reshaping of functional brain connectivity may be necessary to alter the behavioral structure of social motivation when a social threat is encountered.

Regional and cellular organization of the autism-associated protein UBE3A/E6AP and its antisense transcript in the brain of the developing rhesus monkey.

Angelman syndrome (AS) is a neurogenetic disorder caused by mutations or deletions in the maternally-inherited UBE3A allele, leading to a loss of UBE3A protein expression in neurons. The paternally-inherited UBE3A allele is epigenetically silenced in neurons during development by a noncoding transcript (UBE3A-ATS). The absence of neuronal UBE3A results in severe neurological symptoms, including speech and language impairments, intellectual disability, and seizures. While no cure exists, therapies aiming to restore UBE3A function-either by gene addition or by targeting UBE3A-ATS-are under development. Progress in developing these treatments relies heavily on inferences drawn from mouse studies about the function of UBE3A in the human brain. To aid translational efforts and to gain an understanding of UBE3A and UBE3A-ATS biology with greater relevance to human neurodevelopmental contexts, we investigated UBE3A and UBE3A-ATS expression in the developing brain of the rhesus macaque, a species that exhibits complex social behaviors, resembling aspects of human behavior to a greater degree than mice. Combining immunohistochemistry and in situ hybridization, we mapped UBE3A and UBE3A-ATS regional and cellular expression in normal prenatal, neonatal, and adolescent rhesus macaque brains. We show that key hallmarks of UBE3A biology, well-known in rodents, are also present in macaques, and suggest paternal UBE3A silencing in neurons-but not glial cells-in the macaque brain, with onset between gestational day 48 and 100. These findings support proposals that early-life, perhaps even prenatal, intervention is optimal for overcoming the maternal allele loss of UBE3A linked to AS.

Maltodextrin Consumption Impairs the Intestinal Mucus Barrier and Accelerates Colitis Through Direct Actions on the Epithelium.

Food additives are common components of processed foods consumed in a Western diet. In inflammatory bowel disease patients, some diets that exclude food additives improved clinical disease parameters, suggesting a link between food additives and disease pathogenesis. Food additives also enhanced disease severity in mouse colitis models through incompletely described mechanisms. This study examined the mechanisms by which the food additive maltodextrin (MDX) alters the development of colitis in a murine model. Interleukin-10 knockout (IL10KO) mice were fed diets supplemented with MDX or carboxymethyl cellulose (CMC) to determine their impact on colitis onset and severity; microbiome composition, function, and location; colonic immune cell infiltrates; and mucus layer integrity. Primary IL10KO colonic epithelial monolayers were used to dissect the impact of MDX directly on epithelial differentiation and mucus production. MDX or CMC consumption increased the incidence and severity of colitis, as well as decreased microbiome diversity, altered microbial composition, and decreased fecal acetic acid levels. The number of mucus producing cells were decreased in food additive fed mice and resulted in increased microbial proximity to the intestinal epithelium. Additionally, MDX supplementation resulted in crypt hyperplasia and expansion of the HopX+ injury renewal stem cell niche. In primary intestinal epithelial-derived monolayers devoid of microbes and immune cells, MDX exposure decreased goblet cell number and mucus production in association with downregulated expression of the transcription factor Klf4, a marker of terminally differentiated goblet cells. These results suggest MDX disrupts the balance of epithelial cell differentiation and proliferation to contribute to disease pathogenesis through direct and indirect actions on the intestinal epithelial barrier.

Clinical Insights Into Heritable Cardiomyopathies.

Cardiomyopathies (CMs) encompass a heterogeneous group of structural and functional abnormalities of the myocardium. The phenotypic characteristics of these myocardial diseases range from silent to symptomatic heart failure, to sudden cardiac death due to malignant tachycardias. These diseases represent a leading cause of cardiovascular morbidity, cardiac transplantation, and death. Since the discovery of the first locus associated with hypertrophic cardiomyopathy 30 years ago, multiple loci and molecular mechanisms have been associated with these cardiomyopathy phenotypes. Conversely, the disparity between the ever-growing landscape of cardiovascular genetics and the lack of awareness in this field noticeably demonstrates the necessity to update training curricula and educational pathways. This review summarizes the current understanding of heritable CMs, including the most common pathogenic gene variants associated with the morpho-functional types of cardiomyopathies: dilated, hypertrophic, arrhythmogenic, non-compaction, and restrictive. Increased understanding of the genetic/phenotypic associations of these heritable diseases would facilitate risk stratification to leveraging appropriate surveillance and management, and it would additionally provide identification of family members at risk of avoidable cardiovascular morbidity and mortality.

Dual-isoform hUBE3A gene transfer improves behavioral and seizure outcomes in Angelman syndrome model mice.

Loss of the maternal UBE3A allele causes Angelman syndrome (AS), a debilitating neurodevelopmental disorder. Here, we devised an AS treatment strategy based on reinstating dual-isoform expression of human UBE3A (hUBE3A) in the developing brain. Kozak sequence engineering of our codon-optimized vector (hUBE3Aopt) enabled translation of both short and long hUBE3A protein isoforms at a near-endogenous 3:1 (short/long) ratio, a feature that could help to support optimal therapeutic outcomes. To model widespread brain delivery and early postnatal onset of hUBE3A expression, we packaged the hUBE3Aopt vector into PHP.B capsids and performed intracerebroventricular injections in neonates. This treatment significantly improved motor learning and innate behaviors in AS mice, and it rendered them resilient to epileptogenesis and associated hippocampal neuropathologies induced by seizure kindling. hUBE3A overexpression occurred frequently in the hippocampus but was uncommon in the neocortex and other major brain structures; furthermore, it did not correlate with behavioral performance. Our results demonstrate the feasibility, tolerability, and therapeutic potential for dual-isoform hUBE3A gene transfer in the treatment of AS.

Economic elasticities of input substitution using data envelopment analysis.

The use of elasticities of substitution between inputs is a standard method for addressing the effect of a change in the mix of inputs used for production from a technical or cost standpoint. Most estimation methods use parametric production or cost functions or frontiers to estimate these elasticities. A potentially useful nonparametric alternative is data envelopment analysis (DEA). The purpose of this paper is to derive elasticities of input substitution for both technical and cost frontiers using DEA, extending the use of this approach in the field of economics and associated fields. The paper provides derivations for both Hicksian (production and cost frontier) and Morishima (cost frontier) elasticities of input substitution, as well as a parsimonious method for estimating them using DEA. The derivations are presented using an agricultural example form Kansas, USA.

Hormonal gain control of a medial preoptic area social reward circuit.

Neural networks that control reproduction must integrate social and hormonal signals, tune motivation, and coordinate social interactions. However, the neural circuit mechanisms for these processes remain unresolved. The medial preoptic area (mPOA), an essential node for social behaviors, comprises molecularly diverse neurons with widespread projections. Here we identify a steroid-responsive subset of neurotensin (Nts)-expressing mPOA neurons that interface with the ventral tegmental area (VTA) to form a socially engaged reward circuit. Using in vivo two-photon imaging in female mice, we show that mPOANts neurons preferentially encode attractive male cues compared to nonsocial appetitive stimuli. Ovarian hormone signals regulate both the physiological and cue-encoding properties of these cells. Furthermore, optogenetic stimulation of mPOANts-VTA circuitry promotes rewarding phenotypes, social approach and striatal dopamine release. Collectively, these data demonstrate that steroid-sensitive mPOA neurons encode ethologically relevant stimuli and co-opt midbrain reward circuits to promote prosocial behaviors critical for species survival.