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Dopamine (DA) neurons are thought to encode reward prediction error (RPE), in addition to other signals, such as salience. While RPE is known to support learning, the role of salience in learning remains less clear. To address this, we recorded and manipulated VTA DA neurons in mice during fear extinction. We applied deep learning to classify mouse freezing behavior, eliminating the need for human scoring. Our fiber photometry recordings showed DA neurons in medial and lateral VTA have distinct activity profiles during fear extinction: medial VTA activity more closely reflected RPE, while lateral VTA activity more closely reflected a salience-like signal. Optogenetic inhibition of DA neurons in either region slowed fear extinction, with the relevant time period for inhibition differing across regions. Our results indicate salience-like signals can have similar downstream consequences to RPE-like signals, although with different temporal dependencies.

While there is emerging evidence of sex differences in decision-making behavior, the neural substrates that underlie such differences remain largely unknown. Here we demonstrate that in mice performing a value-based decision-making task, while choices are similar between the sexes, motivation to engage in the task is modulated by action value more strongly in females than in males. Inhibition of activity in anterior cingulate cortex (ACC) neurons that project to the dorsomedial striatum (DMS) preferentially disrupts this relationship between value and motivation in females, without affecting choice in either sex. In line with these effects, in females compared to males, ACC–DMS neurons have stronger representations of negative outcomes and more neurons are active when the value of the chosen option is low. By contrast, the representation of each choice is similar between the sexes. Thus, we identify a neural substrate that contributes to sex-specific modulation of motivation by value. The authors show that action value modulates motivation to perform a decision-making task more strongly in females than in males. Anterior cingulate cortex neurons that project to the striatum contribute to this sex difference.

BackgroundThere are sparse patient-level data available for children with novel coronavirus disease (COVID-19). Therefore, there is an urgent need for an updated systematic literature review that analyzes individual children rather than aggregated data in broad age groups.MethodsSix databases (MEDLINE, Scopus, Web of Science, CINAHL, Google Scholar, medRxiv) were searched for studies indexed from January 1 to May 15, 2020, with MeSH terms: children, pediatrics, COVID-19, SARS-CoV-2. 1241 records were identified, of which only unique papers in English with individual patient information and documented COVID-19 testing were included. This review of 22 eligible studies followed Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data guidelines.ResultsA total of 123 patients from five countries were identified. 46% were females. The median age was 5 years (IQR = 8). At presentation, 62% had a fever, 32% had a cough, 58% had a single symptom, and 21% were asymptomatic. Abnormal chest imaging was seen in 62% (65/105) of imaged and 76.9% (20/26) of asymptomatic children. A minority of children had elevated platelets, CRP, lactate dehydrogenase, and d-dimer.ConclusionData from this independent participant data systematic review revealed that the majority of children with COVID-19 presented with either no symptoms or a single, non-respiratory symptom.ImpactThis systematic review revealed that the majority of children with COVID-19 presented with either no symptoms or a single, non-respiratory symptom.By using an independent participant data approach, this analysis underscores the challenge of diagnosing COVID-19 in pediatric patients due to the wide variety of symptoms and seemingly poor correlation of imaging findings with symptomatic disease.The data presented from individual patients from case series or cohort studies add more granularity to the current description of pediatric COVID-19.

Guided by the theoretical frameworks of communication accommodation theory and conflict management, this study examines U.S. older participants’ (65 or older) written conflict scenario either with a grandchild or a nonfamily young adult. Using content analysis approach, we analyzed these written conflict scenarios to uncover major conflict initiating factors and conflict management styles. Results revealed that intergenerational conflict initiated by old-to-young criticism (more frequently reported in conflicts with nonfamily young adults) or disagreement/generation gap (more frequently reported in conflicts with grandchildren) was reported most frequently followed by young-to-old rebuff, cumulative annoyance, and young-to-old criticism. Additionally, results indicated that older adults used the problem-solving style most frequently when disagreement/generation gap initiated the conflict, especially in the family contexts; both young and older adults used the competing style most frequently when old-to-young criticism initiated the conflict, especially in nonfamily contexts. Furthermore, the use of the competing and problem-solving styles by young adults was significantly associated with the use of the same styles by older adults and vice versa, indicating both positive and negative reciprocation in intergenerational conflict. Results in general show that young and older adults manage intergenerational conflicts in different ways in family versus nonfamily contexts.

Prader–Willi syndrome (PWS) and Angelman syndrome (AS) are oppositely imprinted autism-spectrum disorders with known genetic bases, but complex epigenetic mechanisms underlie their pathogenesis. The PWS/AS locus on 15q11–q13 is regulated by an imprinting control region that is maternally methylated and silenced. The PWS imprinting control region is the promoter for a one megabase paternal transcript encoding the ubiquitous protein-coding Snrpn gene and multiple neuron-specific noncoding RNAs, including the PWS-related Snord116 repetitive locus of small nucleolar RNAs and host genes, and the antisense transcript to AS-causing ubiquitin ligase encoding Ube3a (Ube3a-ATS). Neuron-specific transcriptional progression through Ube3a-ATS correlates with paternal Ube3a silencing and chromatin decondensation. Interestingly, topoisomerase inhibitors, including topotecan, were recently identified in an unbiased drug screen for compounds that could reverse the silent paternal allele of Ube3a in neurons, but the mechanism of topotecan action on the PWS/AS locus is unknown. Here, we demonstrate that topotecan treatment stabilizes the formation of RNA:DNA hybrids (R loops) at G-skewed repeat elements within paternal Snord116, corresponding to increased chromatin decondensation and inhibition of Ube3a-ATS expression. Neural precursor cells from paternal Snord116 deletion mice exhibit increased Ube3a-ATS levels in differentiated neurons and show a reduced effect of topotecan compared with wild-type neurons. These results demonstrate that the AS candidate drug topotecan acts predominantly through stabilizing R loops and chromatin decondensation at the paternally expressed PWS Snord116 locus. Our study holds promise for targeted therapies to the Snord116 locus for both AS and PWS.

Meiotic chromosome segregation relies on synapsis and crossover (CO) recombination between homologous chromosomes. These processes require multiple steps that are coordinated by the meiotic cell cycle and monitored by surveillance mechanisms. In diverse species, failures in chromosome synapsis can trigger a cell cycle delay and/or lead to apoptosis. How this key step in ‘homolog engagement’ is sensed and transduced by meiotic cells is unknown. Here we report that in C. elegans , recruitment of the Polo-like kinase PLK-2 to the synaptonemal complex triggers phosphorylation and inactivation of CHK-2, an early meiotic kinase required for pairing, synapsis, and double-strand break (DSB) induction. Inactivation of CHK-2 terminates DSB formation and enables CO designation and cell cycle progression. These findings illuminate how meiotic cells ensure CO formation and accurate chromosome segregation. Most animals, plants, and fungi reproduce sexually, meaning that the genetic information from two parents combines during fertilization to produce offspring. This parental genetic information is carried within the reproductive cells in the form of chromosomes. Reproductive cells in the ovaries or testes first multiply through normal cell division, but then go through a unique type of cell division called meiosis. During meiosis, pairs of chromosomes – the two copies inherited from each parent – must find each other and physically line up from one end to the other. As they align side-by-side with their partners, chromosomes also go through a mixing process called recombination, during which regions of one chromosome cross over to the paired chromosome to exchange information. Scientists are still working to understand how this process of chromosome alignment and crossing-over is controlled. If chromosomes fail to line up or cross over during meiosis, eggs or sperm can end up with too many or too few chromosomes. If these faulty reproductive cells combine during fertilization this can lead to birth defects and developmental problems. To minimize this problem, reproductive cells have a quality control mechanism during meiosis called “crossover assurance”, which limits how often mistakes occur. Zhang et al. have investigated how cells can tell if their chromosomes have accomplished this as they undergo meiosis. They looked at egg cells of the roundworm C. elegans , whose meiotic processes are similar to those in humans. In C. elegans , a protein called CHK-2 regulates many of the early events during meiosis. During successful meiosis, CHK-2 is active for only a short amount of time. But if there are problems during recombination, CHK-2 stays active for longer and prevents the cell division from proceeding. Zhang et al. uncovered another protein that affects for how long CHK-2 stays switched on. When chromosomes align with their partners, a protein called PLK-2 sticks to other proteins at the interface between the aligned chromosomes. A combination of microscopy and test tube experiments showed that when PLK-2 is bound to this specific location, it can turn off CHK-2. However, if the chromosome alignment fails, PLK-2 is not activated to switch off CHK-2. Therefore, CHK-2 is only switched off when the chromosomes are properly aligned and move on to the next step in crossing-over, which then allows meiosis to proceed. Thus, PLK-2 and CHK-2 work together to detect errors and to slow down meiosis if necessary. Further experiments in mammalian reproductive cells will reveal how similar the crossover assurance mechanism is in different organisms. In the future, improved understanding of quality control during meiosis may eventually lead to improvements in assisted reproduction.

Purpose Pediatric cerebral palsy patients carry frequent medical comorbidities and disproportionately consume hospital resources after neurosurgical procedures. We implemented an institutional pre-operative gastrointestinal (GI) optimization protocol to improve outcomes and decrease resource utilization. Methods All 323 intrathecal baclofen surgeries from 2000 to 2023 were categorized relative to protocol implementation on July 1, 2017. Outcomes and resource utilization were compared. Results The protocol change resulted in significantly fewer hospital readmissions ( p  = 0.001) for constipation, eliminating them and GI-related emergency visits. There was a reduction of 27 hospital days for constipation-related readmission (median 1 day per patient, IQR 1, 2 days). No differences were reported between the experimental groups including demographics or GI comorbidities. Post-operative complications within 30 days were comparable between groups regarding urinary tract infections, surgical-site infections, and spinal fluid leak. There were no differences in post-operative length of stay between groups. Conclusion A GI optimization protocol can eliminate a frequent source of hospital readmissions and GI-related emergency department visits after baclofen pump surgery, even accounting for baseline GI comorbidities. Preventing readmissions and emergency visits translates to lower hospital resource utilization and improves quality of care. Future efforts are warranted to improve outcomes and care efficiency for our most complex and resource-intensive patients.

Background: Obesity rates have significantly increased globally, affecting up to 40% of women of childbearing age in the United States. While prenatal repair of open fetal spina bifida has shown improved outcomes, most fetal surgery centers exclude patients with a body mass index (BMI) ≥ 35 kg/m2 based on criteria from the Management of Myelomeningocele Study (MOMS) trial. This exclusion raises concerns about healthcare equity and highlights a significant knowledge gap regarding the safety and efficacy of fetal spina bifida repair in patients with obesity. Objective: To review the current state of knowledge regarding open fetal surgery for fetal spina bifida in patients with obesity, focusing on safety, efficacy, and clinical considerations. Methods: A comprehensive literature search was conducted using the PubMed and EMBASE databases, covering articles from the inception of the databases to April 2024. Studies discussing fetal surgery for neural tube defects and documenting BMI measurements and their impact on surgical outcomes, published in peer-reviewed journals, and available in English were included. Quantitative data were extracted into an Excel sheet, and data synthesis was conducted using the R programming language (version 4.3.3). Results: Three retrospective studies examining outcomes of prenatal open spina bifida repair in a total of 43 patients with a BMI ≥ 35 kg/m2 were identified. These studies did not report significant adverse maternal or fetal outcomes compared to patients with lower BMIs. Our pooled analysis revealed a perinatal mortality rate of 6.1% (95% CI: 1.76–18.92%), with 28.0% (95% CI: 14.0–48.2%) experiencing the premature rupture of membranes and 82.0% (95% CI: 29.2–98.0%) delivering preterm (<37 weeks). Membrane separation was reported in 10.3% of cases (95% CI: 3.3–27.7%), the mean gestational age at birth was 34.3 weeks (95% CI: 32.3–36.3), and the average birth weight was 2651.5 g (95% CI: 2473.7–2829.4). Additionally, 40.1% (95% CI: 23.1–60.0%) required a ventriculoperitoneal shunt. Conclusion: While current evidence suggests that fetal spina bifida repair may be feasible in patients with obesity, significant limitations in the existing body of research were identified. These include small sample sizes, retrospective designs, and a lack of long-term follow-up data. There is an urgent need for large-scale, prospective, multicenter studies to definitively establish the safety and efficacy of fetal spina bifida repair in patients with obesity. Such research is crucial for developing evidence-based guidelines, improving clinical outcomes, and addressing healthcare disparities in this growing patient population with obesity.

The COVID-19 pandemic will leave an indelible mark on the careers of current medical trainees. Given the disruptions to medical education, economic impact on institutions, and the uncertainties around future job prospects, trainees are facing unprecedented challenges. This situation is especially concerning for futures of pediatric physician-scientist trainees, where concerns regarding maintaining the pipeline were well documented prior to the emergence of COVID-19. In this Perspectives article, we leverage the unique expertise of our workgroup to address concerns of physician-scientist trainees and to provide suggestions on how to navigate career trajectories in the post-COVID-19 era. We identified and addressed four major areas of concern: lack of in-person conferences and the associated decrease access to mentors and networking activities, decreased academic productivity, diminished job prospects, and mental health challenges. We also suggest actions for trainees, mentors and educational leaders, and institutions to help support trainees during the pandemic, with a goal of maintaining the pediatric physician-scientist pipeline. Impact The advice in this article will provide guidance to pediatric physician-scientist trainees on sustaining and developing their career during the continued challenges presented by COVID-19. We also provide suggestions for mentors, educational leaders, institutions, and professional societies on ways to help support the pediatric physician-scientist pipeline.

IntroductionCellular circadian rhythms regulate immune pathways and inflammatory responses that mediate human disease such as asthma. Circadian rhythms in the lung may also contribute to exacerbations of chronic diseases such as asthma by regulating observed rhythms in mucus production, bronchial reactivity, airway inflammation and airway resistance. Primary human airway epithelial cells (AECs) are commonly used to model human lung diseases, such as asthma, with circadian symptoms, but a method for synchronising circadian rhythms in AECs has not been developed, and the presence of circadian rhythms in human AECs remains uninvestigated.MethodsWe used temperature cycling to synchronise circadian rhythms in undifferentiated and differentiated primary human AECs. Reverse transcriptase-quantitative PCR was used to measure expression of the core circadian clock genes ARNTL, CLOCK, CRY1, CRY2, NR1D1, NR1D2, PER1 and PER2.ResultsFollowing temperature synchronisation, the core circadian genes ARNTL, CRY1, CRY2, NR1D1, NR1D2, PER1 and PER2 maintained endogenous 24-hour rhythms under constant conditions. Following serum shock, the core circadian genes ARNTL, NR1D1 and NR1D2 demonstrated rhythmic expression. Following temperature synchronisation, CXCL8 demonstrated rhythmic circadian expression.ConclusionsTemperature synchronised circadian rhythms in AECs differentiated at an air–liquid interface can serve as a model to investigate circadian rhythms in pulmonary diseases.