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In our brains, different neurons make appropriate connections; however, there remain few in vitro models of such circuits. We use an open microfluidic approach to build and study neuronal circuits in vitro in ways that fit easily into existing bio-medical workflows. Dumbbell-shaped circuits are built in minutes in standard Petri dishes; the aqueous phase is confined by fluid walls - interfaces between cell-growth medium and an immiscible fluorocarbon, FC40. Conditions are established that ensure post-mitotic neurons derived from human induced pluripotent stem cells (iPSCs) plated in one chamber of a dumbbell remain where deposited. After seeding cortical neurons on one side, axons grow through the connecting conduit to ramify amongst striatal neurons on the other - an arrangement mimicking unidirectional cortico-striatal connectivity. We also develop a moderate-throughput non-contact axotomy assay. Cortical axons in conduits are severed by a media jet; then, brain-derived neurotrophic factor and striatal neurons in distal chambers promote axon regeneration. As additional conduits and chambers are easily added, this opens up the possibility of mimicking complex neuronal networks, and screening drugs for their effects on connectivity.

Understanding medium spiny neuron (MSN) physiology is essential to understand motor impairments in Parkinson's disease (PD) given the architecture of the basal ganglia. Here, we developed a custom three-chambered microfluidic platform and established a cortico-striato-nigral microcircuit partially recapitulating the striatal presynaptic landscape in vitro using induced pluripotent stem cell (iPSC)-derived neurons. We found that, cortical glutamatergic projections facilitated MSN synaptic activity, and dopaminergic transmission enhanced maturation of MSNs in vitro. Replacement of wild-type iPSC-derived dopamine neurons (iPSC-DaNs) in the striatal microcircuit with those carrying the PD-related GBA-N370S mutation led to a depolarisation of resting membrane potential and an increase in rheobase in iPSC-MSNs, as well as a reduction in both voltage-gated sodium and potassium currents. Such deficits were resolved in late microcircuit cultures, and could be reversed in younger cultures with antagonism of protein kinase A activity in iPSC-MSNs. Taken together, our results highlight the unique utility of modelling striatal neurons in a modular physiological circuit to reveal mechanistic insights into GBA1 mutations in PD., (© 2024. The Author(s).)

Adolescents often experience heightened socioemotional sensitivity warranting their use of regulatory strategies. Yet, little is known about how key socializing agents help regulate teens' negative emotions in daily life and implications for long-term adjustment. We examined adolescent girls' interpersonal emotion regulation (IER) with parents and peers in response to negative social interactions, defined as parent and peer involvement in the teen's enactment of emotion regulation strategies. We also tested associations between rates of daily parental and peer IER and depressive symptoms, concurrently and one year later. Adolescent girls ( N = 112; M age = 12.39) at temperamental risk for depressive disorders completed a 16-day ecological momentary assessment protocol measuring reactivity to negative social interactions, parental and peer IER, and current negative affect. Results indicated that adolescents used more adaptive strategies with peers and more maladaptive strategies with parents in daily life. Both parental and peer IER down-regulated negative affect, reflected by girls' decreased likelihood of experiencing continued negative affect. Higher proportions of parental adaptive IER predicted reduced depressive symptoms one year later. Findings suggest that both parents and peers effectively help adolescent girls down-regulate everyday negative emotions; however, parents may offer more enduring benefits for long-term adjustment.

Establishing maladaptive personality traits at a younger age in a developmentally appropriate and clinically tangible way may alert clinicians to dysfunction earlier, and thus reduce the risk of significant impairment later in life. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Alternative Model for Personality Disorders (AMPD) provides a set of traits useful for organizing behavioral and experiential patterns central to daily personality functioning. The goal of the present study was to evaluate manifestations indicative of AMPD traits via ambulatory assessments in the daily lives of adolescent girls. Caregivers and girls ( N = 129; age: M = 12.27, SD = 0.80) provided baseline assessments of girls' trait vulnerabilities (negative affectivity, detachment, antagonism, disinhibition, psychoticism) and girls additionally completed a 16-day ecological momentary assessment protocol ( N = 5,036 observations), rating social behaviors and experiences in their daily lives. Multilevel structural equation models revealed that trait vulnerabilities were linked to more extreme shifts in interpersonal experiences and behaviors from one moment to the next, suggesting that maladaptive personality traits were linked to greater variability. Furthermore, AMPD traits were positively and strongly related to negative affect in daily interpersonal situations. More specifically, girls' trait ratings were associated with elevated mean-levels of boredom, as well as interpersonal tension. Caregiver-reports complemented this perspective of dissatisfying social interactions, suggesting that especially detachment and antagonism accounted for lower levels of social connectedness and more variability in social activities in girls' daily lives. Results are discussed in terms of the short-term dynamics and related intervention targets of developmental personality pathology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective: Anxiety symptoms often increase in late childhood/early adolescence, particularly among girls. However, few studies examine anxiety-relevant gender differences during anticipation and avoidance of naturalistic experiences during adolescence. The current study uses ecological momentary assessment (EMA) to examine associations among clinical anxiety, gender, anticipation, and attempted avoidance of person-specific anxiety-provoking experiences in youth ages 8-18., Method: 124 youth (73 girls) completed 7 consecutive days of EMA. Seventy participants (42 girls) met criteria for one or more anxiety disorders, while the remaining 54 were healthy controls (31 girls). Participants reported the experience that they were "most worried about happening that day" and completed ratings about that event including whether they attempted to avoid that experience. Multilevel models examined whether diagnostic group (anxious, healthy), gender (boys, girls), or their interaction predicted anticipatory ratings or avoidance of these experiences., Results: Analyses revealed significant diagnostic group by gender interactions for anticipatory ratings. Specifically, anxious girls reported greater worry and predicted more negative outcomes related to future experiences. However, only a main effect of diagnostic group emerged for attempted avoidance. Finally, anticipatory worry predicted higher rates of attempted avoidance, but this association did not vary by diagnostic group, gender, or their interaction., Conclusion: These findings extend the literature on the interplay of anticipation and avoidance to person-specific naturalistic experiences in pediatric anxiety. They reveal that anxious girls report more anticipatory anxiety and worry, while avoidance of real-world anxiety-provoking scenarios is a key concern for anxious youth independent of gender. By using EMA to examine person-specific anxiety-inducing experiences we can begin to understand how these processes and experiences unfold in the real world., Competing Interests: The authors have declared that they have no competing or potential conflicts of interest., (© 2022 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objective: We examined risk and protective factors for emotional health problems in adolescent girls during the COVID-19 pandemic. We investigated pre- to early-pandemic changes in symptoms of anxiety and depression, documented daily activities and perceived positive and negative impacts of the pandemic, and linked perceived positive and negative impacts of the pandemic to real-time changes in emotional health., Methods: The study was a 10-day daily diary study with 93 U.S. adolescent girls (aged 12-17; 68% White non-Hispanic) at temperamental risk for anxiety and depression, conducted in April/May 2020 when all participants were under state-issued stay-at-home orders. Girls provided daily reports of positive and negative affect, depressive and anxious symptoms, activities, and positive and negative impacts resulting from the pandemic., Results: Girls reported engaging in many activities that may contribute to well-being. Mixed effects analyses revealed positive impacts associated with improved same-day emotional health such as more time for family and relaxation and reduced pressure from school/activities. Negative impacts associated with poorer same-day emotional health included problems with online schooling, lack of space/privacy, lack of a regular schedule, and family conflict., Conclusion: Findings highlight the importance of providing in-person or quality online schooling, resources and space for learning, promoting daily routines, and spending time with teens while reducing family conflict. The pandemic also appears to have offered many girls a respite from the chronic stress of modern teen life, with time to relax and engage in creative and healthy pursuits showing benefits for daily emotional health, which should be considered following the return to normal life., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Pediatric Psychology.)

Dioxins have been suggested to induce inflammation in the intestine and brain and to induce neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), partly due to deficits in parvalbumin-positive neurons in the brain that are sensitive to inflammatory stress. Previously, we reported ADHD traits with increased aggressiveness in children with prenatal exposure to dioxins in Vietnam, whereas dried bonito broth (DBB) has been reported to suppress inflammation and inhibit aggressive behavior in animal and human studies. In the present study, we investigated the association between dioxin exposure and the prevalence of children with highly aggressive behaviors (Study 1), as well as the effects of DBB on the prevalence of children with highly aggressive behaviors (Study 2)., Methods: In Study 1, we investigated the effects of dioxin exposure on the prevalence of children with high aggression scores, which were assessed using the Children's Scale of Hostility and Aggression: Reactive/Proactive (C-SHARP) in dioxin-contaminated areas. The data were analyzed using a logistic regression model after adjusting for confounding factors. In Study 2, we performed nutritional intervention by administering DBB for 60 days to ameliorate the aggressiveness of children with high scores on the C-SHARP aggression scale. The effects of DBB were assessed by comparing the prevalence of children with high C-SHARP scores between the pre- and post-intervention examinations., Results: In Study 1, only the prevalence of children with high covert aggression was significantly increased with an increase in dioxin exposure. In Study 2, in the full ingestion (>80% of goal ingestion volume) group, the prevalence of children with high covert aggression associated with dioxin exposure was significantly lower in the post-ingestion examination compared with in the pre-ingestion examination. However, in other ingestion (<20% and 20-79%) groups and a reference (no intervention) group, no difference in the prevalence of children with high covert aggression was found between the examinations before and after the same experimental period., Conclusions: The findings suggest that DBB ingestion may ameliorate children's aggressive behavior, which is associated with perinatal dioxin exposure.

Social media (SM) use has increasingly changed how adolescents interact with their peers, yet it remains unclear how peer interactions on social media differ from in-person peer interactions. The current study evaluated whether the context (social media or in-person) of adolescent girls' worst and best peer interactions influenced their emotional responses to peer interactions and sustained affect in everyday life. In this study, a total of 110 adolescent girls (11-13 years old; mean age = 12.28 years) completed ecological momentary assessment (EMA) for 16 days following an initial baseline visit. Participants reported their worst (i.e., most negative) and best (i.e., most positive) interactions with peers since the last prompt, the context in which it occurred (social media or in-person), emotional reactivity during the interaction, and momentary affect. Multilevel models indicated that negative peer interactions that occurred on social media were more likely to be associated with sustained negative affect, but not negative emotional reactivity during the interaction. Positive interactions on social media were more likely to be associated with both lower positive emotional reactivity and lower sustained positive affect. Findings indicate that peer interactions on social media may differentially impact girls' emotional reactivity and sustained affect, particularly for positive interactions with peers. Findings highlight that social media and in-person peer interactions may impact how girls experience and respond to positive and negative peer interactions, which may have implications for peer relationships and onset of psychopathology during this vulnerable period.

Adolescence is a sensitive period for the development of adaptive social behaviors and social anxiety, possibly due to aspects of brain development. However, research is needed to examine interactions among age, social anxiety, and social dynamics previously shown to influence neural responding. The current functional magnetic resonance imaging (fMRI) study examines brain function in 8-18 year-olds with varying levels of social anxiety. Interactions are examined among age, social anxiety, and two key task factors: valence and predictability of social interactions. Results demonstrate age, social anxiety severity, and each of the two key task-based factors interact to predict neural response in the caudate, middle and superior temporal gyri. In particular, among adolescents less-than 13 years of age, higher social anxiety predicted greater responding to unpredictable negative evaluations. However, in this same age group, the opposite pattern emerged during receipt of unpredictable positive evaluations, with less neural response in more anxious youth. Adolescents aged 13 and older overall showed less robust effects. We discuss these findings in terms of age- and anxiety-related differences in socioemotional processing., Competing Interests: Declaration of Competing Interest None, (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Clinical researchers face challenges when trying to quantify diverse processes engaged during social interactions. We report results from two studies, each demonstrating the potential utility of tools for examining processes engaged during social interactions., Method: In the first study, youth (n = 57) used a smartphone-based tool to rate mood and responses to social events. A subset (n = 20) completed the second, functional magnetic resonance imaging study. This second study related anxiety to error-evoked brain responses in two social conditions-while being observed and when alone. We also combined these tools to bridge clinical, social-contextual, and neural levels of measurement., Results: Results from the first study showed an association between negatively-perceived social experiences and a range of negative emotions. In the second study there was a positive correlation during error monitoring between social-anxiety severity and context-specific activation of the pregenual anterior cingulate cortex. Finally, during imaging, the perceived quality of peer interactions as assessed using the smartphone-based tool, interacted with social context to predict levels of activation in the hippocampus and superior frontal gyrus., Conclusions: By improving measurement, enhanced tools may provide new means for studying relationships among anxiety, brain function, and social interactions., (© 2019 Wiley Periodicals, Inc.)

Rapidly progressing development of optogenetic tools, particularly genetically encoded optical indicators, enables monitoring activities of neuronal circuits of identified cell populations in longitudinal in vivo studies. Recently developed advanced transgenic approaches achieve high levels of indicator expression. However, targeting non-sparse cell populations leads to dense expression patterns such that optical signals from neuronal processes cannot be allocated to individual neurons. This issue is particularly pertinent for the use of genetically encoded voltage indicators whose membrane-delimited signals arise largely from the neuropil where dendritic and axonal membranes of many cells intermingle. Here we address this need for sparse but strong expression of genetically encoded optical indicators using a titratable recombination-activated transgene transcription to achieve a Golgi staining-type indicator expression pattern in vivo. Using different transgenic strategies, we also illustrate that co-expression of genetically encoded voltage and calcium indicators can be achieved in vivo for studying neuronal circuit input-output relationships., Competing Interests: The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Objective: The use of antiplatelet drugs to treat acute myocardial infarction, unstable angina, acute coronary syndrome and secondary prevention following percutaneous coronary interventions is well accepted. However, it constitutes a serious risk of bleeding for patients undergoing coronary artery bypass grafting surgery (CABG). We evaluated the effect of aspirin and clopidogrel (CPDG), both irreversible platelet aggregation inhibitors, on operative bleeding and determined the optimal timing for their discontinuation before surgery., Method: Between July 2001 and December 2004, we reviewed our experience with 453 patients undergoing off-pump CABG surgery (OPCAB) who received CPDG (n=101) or not (n=352) preoperatively, and compared the intraoperative and postoperative bleeding to determine risks factors associated with blood or platelet transfusions., Results: Clopidogrel in OPCAB surgery is associated with higher intraoperative (702.24 ml vs 554.13 ml, p=0.03) and postoperative bleeding (864.93 ml vs 603.75 ml, p=0.03). The mean operative blood loss is higher in patients still on CPDG at the time of surgery compared to patients off CPDG at least 72 h before surgery (802 ml vs 554.13 ml, p<0.0001). Blood loss in the later subgroup of patients is comparable to the control group without CPDG (p=NS). Clopidogrel is associated with more platelet transfusions (OR=11.79, [1.48; 93.86])., Conclusion: Blood loss is higher in OPCAB patients receiving clopidogrel before surgery. However, discontinuation of clopidogrel three days (72 h) prior to the operation demonstrated a similar blood loss pattern compared to a control group. Clopidogrel is associated with more platelets, but not red blood cell transfusions following OPCAB surgery.

Objectives: The purpose of this study was to assess the patients' hemodynamics during off-pump coronary artery bypass graft (OPCABG) surgery., Methods: Continuous monitoring of the mean systemic arterial pressure (SAP), mean pulmonary arterial pressure (PAP), mixed venous oxygen saturation (SvO(2)) and cardiac output index (COI) was done on 55 patients undergoing complete OPCAB revascularization. Hemodynamic changes were recorded at the completion of the anastomosis before releasing coronary snaring and stabilization and compared to baseline., Results: The mean age of the patients was 66.4+/-9.2 years, and on average 3.3+/-0.8 grafts per patient were performed. The average SAP drop after manipulations was -8.3+/-16.9 mmHg for the left anterior descending artery (LAD), -13.5+/-19.6 mmHg for the diagonal artery (DG), -14.6+/-13 mmHg for the optuse marginal artery (OM), and -14.2+/-13.5 mmHg for the right coronary artery. This was significant for all territories (P<0.01). The PAP significantly increased in all territories except OM (LAD: 3.7+/-6.3 mmHg, DG: 4.3+/-8.6 mmHg, OM: 1.1+/-7.2 mmHg, posterior descending artery: 2.7+/-5.6 mmHg; P<0.05). Variations in COI were significant in all territories (P<0.01) but more significantly in LAD and DG territories (-15+/-3% and -13+/-9%, respectively). The SvO(2) variations were <10% for all territories and reached only borderline significance (P=0.05) in all territories except OM. All these hemodynamic changes were well tolerated by all patients., Conclusions: Manipulation of the beating heart during OPCABG surgery brings significant fluctuations in the patients' hemodynamics. Mean PAP increase and COI drop were more significant during manipulation of the anterior territories suggesting a more severe diastolic restrictive disease during anterior wall manipulation.

The purpose of this study was to examine the early and late results in 29 patients who underwent 32 (6 mechanical and 26 bioprostheses) isolated tricuspid valve replacement (TVR) from a total of 79 TVR and 375 tricuspid annuloplasties performed at the Montréal Heart Institute, between January 1978 and January 1998. Patients' ages ranged from 25 to 70 years (mean 48 years), and 62% were females. Twenty-seven patients (84%) were in New York Heart Association (NYHA) functional class III and IV. Previous valve surgery had been performed in 22 patients (69%) of which 9 had undergone TVR. Postoperatively, permanent pacemaker was implanted in 9 patients (28%), and immediate reoperation was required in 2 patients because of bleeding. Mean follow-up period was 67.7 months (93% complete). Serial echocardiography showed 3 prosthesis dysfunctions, leading to a second replacement in 2 patients at 12.8 and 7.7 years after initial surgery. All but three patients showed an improvement of their NYHA class. Hospital mortality occurred in 6 patients (19%) and 7 patients died during late follow-up: mean 38.1 months after surgery, including one valve-related death (mechanical valve thrombosis). Actuarial survival rate of all patients was 63% after 5 years, and 47% after 10 years. Isolated TVR remains a high-risk procedure. Most survivors, however, should expect a better quality of life with improvement in their NYHA class.

Objective: To examine the early and late results of isolated tricuspid valve replacement (TVR)., Design and Setting: All isolated TVRs performed at the Montreal Heart Institute, Montreal, Quebec between January 1978 and January 1998 were retrospectively reviewed. Follow-up data on patients were obtained through the valve clinic., Participants: From a total of 79 TVR and 375 tricuspid annuloplasties performed during the study period, 29 patients who underwent 32 isolated TVRs (six mechanical valves and 26 bioprostheses) were included. Patient age ranged from 25 to 70 years (mean 48), and 62% were female. Twenty-seven patients (84%) were in New York Heart Association (NYHA) functional classes III and IV. Previous valve surgery had been performed in 22 patients (69%) among whom nine had undergone TVR., Results: Postoperatively, a permanent pacemaker was implanted in nine patients (28%), and reoperation because of bleeding was required in two patients. Mean follow-up was 67.7 months (93% complete). Serial echocardiography showed prosthesis dysfunction in three patients, requiring two valve re-replacements at 12.8 and 7.7 years after initial surgery. All patients, except three, showed an improvement of their NYHA class. Six patients (19%) died in hospital and seven patients died during late follow-up at a mean of 38.1 months after surgery, including one valve-related death (mechanical valve thrombosis). The actuarial survival rate of all patients was 63% after five years and 47% after 10 years., Conclusion: Isolated TVR remains a high risk procedure. Most survivors, however, should expect a better quality of life by the improvement in their NYHA class.

Object: To study the effect of surgical manipulations on patient hemodynamics during beating-heart CABG surgery., Methods: We continuously monitored the systemic arterial pressure (SAP, n = 31), the pulmonary arterial pressure (PAP, n = 31) and the mixed venous oxygen saturation (SvO2, n = 6) using an Oxymetrix catheter., Results: Patients age ranged from 53 to 85 years old (mean 66.4 +/- 8.5) to whom 3.0 +/- 0.8 distal anastomoses were performed per patient. Stabilization of the heart were done using a "fork-type" stabilizator in all patients, and the target coronaries were clamped proximally and distally to the anastomosis site without pre-conditioning. A SAP decrease was found during the procedure and differed on the coronary territory being worked on: left anterior descending (LAD) (-11 +/- 19%), diagonal (Diag) (-13 +/- 27%), circumflex marginal (CM) (-19 +/- 17%) and right coronary (RC) or posterior descending artery (PDA) (-17 +/- 14%). PAP increase was maximal with the Diag (+47 +/- 84%) and was more important during LAD (+30 +/- 36%) and CM (+21 +/- 48%) than RC/PDA revascularization (+10 +/- 24%). On the other hand, SvO2 changes were found unchanged with any coronary territory. These changes occurred during the stabilization period before vessel occlusion, and were well tolerated by all patients, whom rarely needed inotropic support. No correlation between SvO2, SAP, PAP and occlusion time was found., Conclusion: The mobilization and stabilization of the heart using a "fork-type" stabilizator, rather than clamping the coronaries, during beating-heart CABG surgery were responsible for a decreased in SvO2, the SAP and an increase of the PAP. The marked elevation of PAP during revascularization of the diagonal and LAD territory may be explained by a compression of the left ventricle outflow tract. The Trendelenburg maneuver used during revascularization of the marginal and PDA territories may improve hemodynamics by relieving such pressure on the outflow tract and improve venous return.

Although neuronal cell bodies have been identified in the upper part of the atrial septum, the functional anatomy of its autonomic innervation remains unknown. To study parasympathetic inputs to the atrial septum, we performed isointegral distribution mapping using a 64-electrode balloon array inserted in the right atrium under cardiopulmonary bypass in 9 anesthetized mongrel dogs. Unipolar electrograms were recorded during stimulation of either the right or left vagus nerve or right atrialpulmonary vein ganglionated plexus before and after surgical ablation of tissues along the superior vena cava, of the right atrial-pulmonary vein ganglionated plexus, the aorto-pulmonary tissues and the inferior vena cava fat pad. Local neural effects were estimated from integral changes of each electrogram which were plotted on a septal grid to generate isointegral distribution maps. Changes were considered significant whenever integral differences exceeded twice the standard deviation of control values. Stimulation of the right and left vagi induced significant effects in the high atrial septum in 5 preparations and in the low septum in 6. These effects were suppressed by the dissection of tissues around the superior vena cava and ablation of the right atrial-pulmonary vein ganglionated plexus, but not by that of the inferior vena cava or the aorto-pulmonary tissues. Direct stimulation of the right atrial-pulmonary vein ganglionated plexus produced effects in the high and low septum in 8 and 4 preparations, respectively, which persisted after dissection around the superior vena cava, suggesting the existence of local circuit neural elements. We conclude that the canine atrial septum is innervated by axons from both vagi which course near the superior vena cava and converge through the right atrial-pulmonary vein ganglionated plexus and also by intrinsic neural elements independent of central parasympathetic efferents.