Effects of the use of neuronavigation in patients with supratentorial brain gliomas: a cohort study.

OBJECTIVE: Despite the growing acceptance of neuronavigation in the field of neurosurgery, there is limited comparative research, with contradictory results. This study aimed to compare the effectiveness (tumor resection rate and survival) and safety (frequency of neurological complications) of surgery for brain gliomas with or without neuronavigation. METHODS: This retrospective cohort study evaluated data obtained from electronic records of patients who underwent surgery for gliomas at Dr. Alejandro Dávila Bolaños Military Hospital and the Clinic Hospital of Barcelona between July 2016 and September 2022. The preoperative and postoperative clinical and radiological characteristics were analyzed and compared according to the use of neuronavigation. RESULTS: This study included 110 patients, of whom 79 underwent surgery with neuronavigation. Neuronavigation increased gross total resection by 57% in patients in whom it was used; gross total resection was performed in 56% of patients who underwent surgery with neuronavigation as compared with 35.5% in those who underwent surgery without neuronavigation (risk ratio [RR], 1.57; P = 0.056). The incidence of postoperative neurological deficits (transient and permanent) decreased by 79% with the use of neuronavigation, (12% versus 33.3%; RR, 0.21; P = 0.0003) . Neuronavigation improved survival in patients with grade IV gliomas (15 months versus 13.8 months), but it was not statistically significant (odds ratio, 0.19; P = 0.13). CONCLUSIONS: Neuronavigation improved the effectiveness (greater gross total resection of tumors) and safety (fewer neurological deficits) of brain glioma surgery. However, neuronavigation does not significantly influence the survival of patients with grade IV gliomas.

Strategies to Improve Drug Delivery Across the Blood-Brain Barrier for Glioblastoma.

PURPOSE OF REVIEW: Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed. RECENT FINDINGS: We discuss how the blood-brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody-drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood-brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.

Now it's your turn!: Eye blink rate in a Jenga task modulated by interaction of task wait times, effortful control, and internalizing behaviors.

Dopamine is a versatile neurotransmitter with implications in many domains, including anxiety and effortful control. Where high levels of effortful control are often regarded as adaptive, other work suggests that high levels of effortful control may be a risk factor for anxiety. Dopamine signaling may be key in understanding these relations. Eye blink rate is a non-invasive proxy metric of midbrain dopamine activity. However, much work with eye blink rate has been constrained to screen-based tasks which lack in ecological validity. We tested whether changes in eye blink rate during a naturalistic effortful control task differ as a function of parent-reported effortful control and internalizing behaviors. Children played a Jenga-like game with an experimenter, but for each trial the experimenter took an increasingly long time to take their turn. Blinks-per-second were computed during each wait period. Multilevel modeling examined the relation between duration of wait period, effortful control, and internalizing behaviors on eye blink rate. We found a significant 3-way interaction between effortful control, internalizing behaviors, and duration of the wait period. Probing this interaction revealed that for children with low reported internalizing behaviors (-1 SD) and high reported effortful control (+1 SD), eye blink rate significantly decreased as they waited longer to take their turn. These findings index task-related changes in midbrain dopamine activity in relation to naturalistic task demands, and that these changes may vary as a function of individual differences in effortful control and internalizing behaviors. We discuss possible top-down mechanisms that may underlie these differences.

Interactions among stress, behavioral inhibition, and delta-beta coupling predict adolescent anxiety during the COVID-19 pandemic.

The COVID-19 pandemic brought about unprecedented changes and uncertainty to the daily lives of youth. The range of adjustment in light of a near-universal experience of COVID restrictions highlights the importance of identifying factors that may render some individuals more susceptible to heightened levels of anxiety during stressful life events than others. Two risk factors to consider are temperamental behavioral inhibition (BI) and difficulties in emotion regulation (ER). As such, the current paper focused on BI examined prior to COVID, because of its developmental link to anxiety and ER, as difficulties may be associated with differences in anxiety. We examined a neurocognitive marker of ER processes, delta-beta coupling (DBC). The current paper had two goals: (1) to examine BI in relation to COVID-related worry and social anxiety experienced during the pandemic, and (2) to explore the role of individual differences in early DBC in the relationship between BI and anxiety outcomes 6 months apart during COVID-19 (n = 86; T1 Mage  = 15.95, SD = 1.73; T6 Mage  = 16.43, SD = 1.73). We found support for the moderating role of DBC in the relationship between BI levels and social anxiety disorder (SAD) symptom severity during the pandemic. Here, high BI was predictive of increased SAD symptom levels in adolescents with stronger DBC.

Understanding a Core Pilin of the Type IVa Pili of Acidithiobacillus thiooxidans, PilV.

Pilins are protein subunits of pili. The pilins of type IV pili (T4P) in pathogenic bacteria are well characterized, but anything is known about the T4P proteins in acidophilic chemolithoautotrophic microorganisms such as the genus Acidithiobacillus. The interest in T4P of A. thiooxidans is because of their possible role in cell recruitment and bacterial aggregation on the surface of minerals during biooxidation of sulfide minerals. In this study we present a successful ad hoc methodology for the heterologous expression and purification of extracellular proteins such as the minor pilin PilV of the T4P of A. thiooxidans, a pilin exposed to extreme conditions of acidity and high oxidation-reduction potentials, and that interact with metal sulfides in an environment rich in dissolved minerals. Once obtained, the model structure of A. thiooxidans PilV revealed the core basic architecture of T4P pilins. Because of the acidophilic condition, we carried out in silico characterization of the protonation status of acidic and basic residues of PilV in order to calculate the ionization state at specific pH values and evaluated their pH stability. Further biophysical characterization was done using UV-visible and fluorescence spectroscopy and the results showed that PilV remains soluble and stable even after exposure to significant changes of pH. PilV has a unique amino acid composition that exhibits acid stability, with significant biotechnology implications such as biooxidation of sulfide minerals. The biophysics profiles of PilV open new paradigms about resilient proteins and stimulate the study of other pilins from extremophiles.

Categorical and latent profile approaches to temperamental infant reactivity and early trajectories of socioemotional adjustment.

This article examines the patterns, and consequences, of infant temperamental reactivity to novel sensory input in a large (N = 357; 271 in current analysis) and diverse longitudinal sample through two approaches. First, we examined profiles of reactivity in 4-month-old infants using the traditional theory-driven analytic approach laid out by Jerome Kagan and colleagues, and derived groups characterized by extreme patterns of negative reactivity and positive reactivity. We then used a theory-neutral, data-driven approach to create latent profiles of reactivity from the same infants. Despite differences in sample characteristics and recruitment strategy, we noted similar reactivity groups relative to prior cohorts. The current data-driven approach found four profiles: high positive, high negative, high motor, and low reactive. Follow-up analyses found differential predictions of internalizing, externalizing, dysregulation, and competence trajectories across 12, 18, and 24 months of life based on 4-month reactivity profiles. Findings are discussed in light of the initial formulation of early reactivity by Kagan and the four decades of research that has followed to refine, bolster, and expand on this approach to child-centered individual differences. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Adolescent coping and social media use moderated anxiety change during the COVID-19 pandemic.

INTRODUCTION: Adolescence is a sensitive period during which stressors and social disruptions uniquely contribute to anxiety symptoms. Adolescent's coping strategies (i.e., avoidance and approach) during the coronavirus disease 2019 (COVID-19) pandemic may be differentially related to anxiety symptom changes. Further, social media use (SMU) is ubiquitous and may serve as an avenue to deploy avoidant and/or approach coping. METHOD: Participants included 265 adolescents (ages 12-20 years; 55.8% female, 43.8% male) and one parent per adolescent. At two time points separated by ~6 months, adolescents reported on SMU and coping strategies, and parents and adolescents reported demographic information and adolescents' anxiety symptoms. Data were collected online in the United States, from summer 2020 through spring 2021. RESULTS: Increases in avoidant coping predicted increasing anxiety, particularly when approach coping decreased. Decreases in both avoidant coping and SMU coincided with decreasing anxiety. Older adolescents showed decreasing anxiety when avoidant coping declined and SMU increased. CONCLUSION: Coping strategies and SMU predicted patterns of adolescent anxiety symptom change across 6 months during the COVID-19 pandemic. Results highlight that coping and SMU should be contextualized within the time course of stressors.

Systematic review and meta-analysis of intraventricular antibiotics for neonatal meningitis and ventriculitis.

PURPOSE: We aimed to determine the safety and effectiveness of intraventricular antibiotics in neonates with meningitis and/or ventriculitis and analyze the quality of available evidence. METHODS: DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, EMBASE, LILACS, and SCOPUS up to 17 February 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomized experimental and observational studies were included. The Cochrane methodology was used for systematic reviews. RESULTS: Twenty-six observational studies and one randomized clinical trial involving 272 patients were included. The risk of bias in both pediatric and neurosurgical studies was high, and the quality of evidence was low (evidence level C). In the pediatric studies, no significant differences in mortality were found between intraventricular antibiotics and only systemic antibiotic [25.4% vs 16.1%, OR = 0.96 (0.42-2.24), P = 0.93]. However, when analyzing the minimum administered doses, we found a lower mortality when a minimum duration of 3 days for intraventricular antibiotics was used compared to only systemic antibiotic [4.3% vs 17%, OR = 0.22 (0.07-0.72), P = 0.01]. In the neurosurgical studies, the use of intraventricular antibiotics in ventriculitis generally results in a mortality of 5% and a morbidity of 25%, which is lower than that in cases where intraventricular antibiotics were not used, with an average mortality of 37.3% and a morbidity of 50%. CONCLUSION: Considering the low quality of evidence in pediatric and neurosurgical studies, we can conclude with a low level of certainty that intraventricular antibiotics may not significantly impact mortality in neonatal meningitis and ventriculitis. However, reduced mortality was observed in cases treated with a minimum duration of 3 days of intraventricular antibiotic, particularly the multidrug-resistant or treatment-refractory infections. Higher-quality studies are needed to improve the quality of evidence and certainty regarding the use of intraventricular antibiotics for treating neonatal meningitis and ventriculitis.

Intraventricular endoscopy and intraventricular antibiotics in the treatment of multiloculated hydrocephalus with ventriculitis in a neonate and an infant: Two case reports.

Background: We present two pediatric cases, a neonate and an infant, who presented with treatment-refractory ventriculitis and multiloculated hydrocephalus treated with simultaneous intraventricular endoscopy and antibiotics. This is the first report of this combined therapy in children. Case Description: Using intraventricular endoscopic surgery and antibiotics, hydrocephalus was treated with a minimum number of ventricular shunt systems. In addition, treatment-refractory ventriculitis was treated in both patients using intraventricular antibiotics. Conclusion: Endoscopic surgery and intraventricular antibiotic administration are useful strategies for treating multiloculated hydrocephalus and ventriculitis in children.

Disorder and amino acid composition in proteins: their potential role in the adaptation of extracellular pilins to the acidic media, where Acidithiobacillus thiooxidans grows.

There are few biophysical studies or structural characterizations of the type IV pilin system of extremophile bacteria, such as the acidophilic Acidithiobacillus thiooxidans. We set out to analyze their pili-comprising proteins, pilins, because these extracellular proteins are in constant interaction with protons of the acidic medium in which At. thiooxidans grows. We used the web server Operon Mapper to analyze and identify the cluster codified by the minor pilin of At. thiooxidans. In addition, we carried an in-silico characterization of such pilins using the VL-XT algorithm of PONDR® server. Our results showed that structural disorder prevails more in pilins of At. thiooxidans than in non-acidophilic bacteria. Further computational characterization showed that the pilins of At. thiooxidans are significantly enriched in hydroxy (serine and threonine) and amide (glutamine and asparagine) residues, and significantly reduced in charged residues (aspartic acid, glutamic acid, arginine and lysine). Similar results were obtained when comparing pilins from other Acidithiobacillus and other acidophilic bacteria from another genus versus neutrophilic bacteria, suggesting that these properties are intrinsic to pilins from acidic environments, most likely by maintaining solubility and stability in harsh conditions. These results give guidelines for the application of extracellular proteins of acidophiles in protein engineering.

Promoting Empathy and Affiliation in Relationships (PEAR) study: protocol for a longitudinal study investigating the development of early childhood callous-unemotional traits.

INTRODUCTION: Children with callous-unemotional (CU) traits are at high lifetime risk of antisocial behaviour. Low affiliation (ie, social bonding difficulties) and fearlessness (ie, low threat sensitivity) are proposed risk factors for CU traits. Parenting practices (eg, harshness and low warmth) also predict risk for CU traits. However, few studies in early childhood have identified attentional or physiological markers of low affiliation and fearlessness. Moreover, no studies have tested whether parenting practices are underpinned by low affiliation or fearlessness shared by parents, which could further shape parent-child interactions and exacerbate risk for CU traits. Addressing these questions will inform knowledge of how CU traits develop and isolate novel parent and child targets for future specialised treatments for CU traits. METHODS AND ANALYSIS: The Promoting Empathy and Affiliation in Relationships (PEAR) study aims to establish risk factors for CU traits in children aged 3-6 years. The PEAR study will recruit 500 parent-child dyads from two metropolitan areas of the USA. Parents and children will complete questionnaires, computer tasks and observational assessments, alongside collection of eye-tracking and physiological data, when children are aged 3-4 (time 1) and 5-6 (time 2) years. The moderating roles of child sex, race and ethnicity, family and neighbourhood disadvantage, and parental psychopathology will also be assessed. Study aims will be addressed using structural equation modelling, which will allow for flexible characterisation of low affiliation, fearlessness and parenting practices as risk factors for CU traits across multiple domains. ETHICS AND DISSEMINATION: Ethical approval was granted by Boston University (#6158E) and the University of Pennsylvania (#850638). Results will be disseminated through conferences and open-access publications. All study and task materials will be made freely available on lab websites and through the Open Science Framework (OSF).

The Inhibition of the FGFR/PI3K/Akt Axis by AZD4547 Disrupts the Proangiogenic Microenvironment and Vasculogenic Mimicry Arising from the Interplay between Endothelial and Triple-Negative Breast Cancer Cells.

Vasculogenic mimicry (VM), a process in which aggressive cancer cells form tube-like structures, plays a crucial role in providing nutrients and escape routes. Highly plastic tumor cells, such as those with the triple-negative breast cancer (TNBC) phenotype, can develop VM. However, little is known about the interplay between the cellular components of the tumor microenvironment and TNBC cells' VM capacity. In this study, we analyzed the ability of endothelial and stromal cells to induce VM when interacting with TNBC cells and analyzed the involvement of the FGFR/PI3K/Akt pathway in this process. VM was corroborated using fluorescently labeled TNBC cells. Only endothelial cells triggered VM formation, suggesting a predominant role of paracrine/juxtacrine factors from an endothelial origin in VM development. Via immunocytochemistry, qPCR, and secretome analyses, we determined an increased expression of proangiogenic factors as well as stemness markers in VM-forming cancer cells. Similarly, endothelial cells primed by TNBC cells showed an upregulation of proangiogenic molecules, including FGF, VEGFA, and several inflammatory cytokines. Endothelium-dependent TNBC-VM formation was prevented by AZD4547 or LY294002, strongly suggesting the involvement of the FGFR/PI3K/Akt axis in this process. Given that VM is associated with poor clinical prognosis, targeting FGFR/PI3K/Akt pharmacologically may hold promise for treating and preventing VM in TNBC tumors.

Examining transactional associations between maternal internalizing symptoms, infant negative emotionality, and infant respiratory sinus arrhythmia.

The current study examined transactional associations between maternal internalizing symptoms, infant negative emotionality, and infant resting respiratory sinus arrhythmia (RSA). We used data from the Longitudinal Attention and Temperament Study (N = 217) to examine the associations between maternal internalizing symptoms, infant negative emotionality, and infant resting RSA from 4-months to 18-months using a random-intercepts cross-lagged panel model. We found that mothers with higher average internalizing symptoms have infants with higher levels of resting RSA. However, there were no stable, between-individual differences in infant negative emotionality across time. Additionally, we found significant negative within-dyad cross-lagged associations from maternal internalizing symptoms to subsequent measures of infant negative emotionality, as well as a significant negative cross-lagged association from maternal internalizing symptoms to child resting RSA after 12-months of age. Lastly, we find evidence for infant-directed effects of negative emotionality and resting RSA to maternal internalizing symptoms. Results highlight the complex, bidirectional associations in maternal-infant dyads during the first two years of life, and the importance of considering the co-development of infant reactivity and regulatory processes in the context of maternal internalizing symptoms.

Molecular Dynamics Simulations of HPr Proteins from a Thermophilic and a Mesophilic Organism: A Comparative Thermal Study.

The histidine-containing phosphocarrier (HPr) is a monomeric protein conserved in Gram-positive bacteria, which may be of mesophilic or thermophilic nature. In particular, the HPr protein from the thermophilic organism B. stearothermophilus is a good model system for thermostability studies, since experimental data, such as crystal structure and thermal stability curves, are available. However, its unfolding mechanism at higher temperatures is yet unclear at a molecular level. Therefore, in this work, we researched the thermal stability of this protein using molecular dynamics simulations, subjecting it to five different temperatures during a time span of 1 µs. The analyses of the structural parameters and molecular interactions were compared with those of the mesophilic homologue HPr protein from B. subtilis. Each simulation was run in triplicate using identical conditions for both proteins. The results showed that the two proteins lose stability as the temperature increases, but the mesophilic structure is more affected. We found that the salt bridge network formed by the triad of Glu3-Lys62-Glu36 residues and the salt bridge made up of Asp79-Lys83 ion pair are key factors to keep stable the thermophilic protein, maintaining the hydrophobic core protected and the structure packed. In addition, these molecular interactions neutralize the negative surface charge, acting as "natural molecular staples".

Ordered-domain unfolding of thermophilic isolated ß subunit ATP synthase.

The flexibility of the ATP synthase's ß subunit promotes its role in the ATP synthase rotational mechanism, but its domains stability remains unknown. A reversible thermal unfolding of the isolated ß subunit (Tß) of the ATP synthase from Bacillus thermophilus PS3, tracked through circular dichroism and molecular dynamics, indicated that Tß shape transits from an ellipsoid to a molten globule through an ordered unfolding of its domains, preserving the ß-sheet residual structure at high temperature. We determined that part of the stability origin of Tß is due to a transversal hydrophobic array that crosses the ß-barrel formed at the N-terminal domain and the Rossman fold of the nucleotide-binding domain (NBD), while the helix bundle of the C-terminal domain is the less stable due to the lack of hydrophobic residues, and thus the more flexible to trigger the rotational mechanism of the ATP synthase.

Frontal alpha asymmetry in anxious school-aged children during completion of a threat identification task.

Asymmetry of EEG alpha power in the frontal lobe has been extensively studied over the past 30 years as a potential marker of emotion and motivational state. However, most studies rely on time consuming manipulations in which participants are placed in anxiety-provoking situations. Relatively fewer studies have examined alpha asymmetry in response to briefly presented emotionally evocative stimuli. If alpha asymmetry can be evoked in those situations, it would open up greater methodological possibilities for examining task-driven changes in neural activation. Seventy-seven children, aged 8-12 years old (36 of whom were high anxious), completed three different threat identification tasks (faces, images, and words) while EEG signal was recorded. Alpha power was segmented and compared across trials in which participants viewed threatening vs. neutral stimuli. Threatening images and faces, but not words, induced lower right vs. left alpha power (greater right asymmetry) that was not present when viewing neutral images or faces. Mixed results are reported for the effect of anxiety symptomatology on asymmetry. In a similar manner to studies of state- and trait-level withdrawal in adults, frontal neural asymmetry can be induced in school-aged children using presentation of brief emotional stimuli.

Neural Predictors of Improvement With Cognitive Behavioral Therapy for Adolescents With Depression: An Examination of Reward Responsiveness and Emotion Regulation.

Earlier depression onsets are associated with more debilitating courses and poorer life quality, highlighting the importance of effective early intervention. Many youths fail to improve with evidence-based treatments for depression, likely due in part to heterogeneity within the disorder. Multi-method assessment of individual differences in positive and negative emotion processing could improve predictions of treatment outcomes. The current study examined self-report and neurophysiological measures of reward responsiveness and emotion regulation as predictors of response to cognitive-behavioral therapy (CBT). Adolescents (14-18 years) with depression (N = 70) completed monetary reward and emotion regulation tasks while electroencephalogram (EEG) was recorded, and self-report measures of reward responsiveness, emotion regulation, and depressive symptoms at intake. Adolescents then completed a 16-session group CBT program, with depressive symptoms and clinician-rated improvement assessed across treatment. Lower reward positivity amplitudes, reflecting reduced neural reward responsiveness, predicted lower depressive symptoms with treatment. Larger late positive potential residuals during reappraisal, potentially reflecting difficulty with emotion regulation, predicted greater clinician-rated improvement. Self-report measures were not significant predictors. Results support the clinical utility of EEG measures, with impairments in positive and negative emotion processing predicting greater change with interventions that target these processes.

Developmental trajectories of behavioral inhibition from infancy to age seven: The role of genetic and environmental risk for psychopathology.

The present study leveraged data from a longitudinal adoption study of 361 families recruited between 2003 and 2010 in the United States. We investigated how psychopathology symptoms in birth parents (BP; Mage  = 24.1 years; 50.5-62.9% completed high school) and adoptive parents (AP; Mage  = 37.8 years; 80.9% completed college; 94% mother-father couples) influenced children's behavioral inhibition (BI) trajectories. We used latent growth models of observed BI at 18 and 27 months, and 4.5 and 7 years in a sample of adopted children (Female = 42%, White = 57%, Black = 11%, Multi-racial = 21%, Latinx = 9%). BI generally decreased over time, yet there was substantial variability in these trajectories. Neither BP nor AP psychopathology symptoms independently predicted systematic differences in BI trajectories. Instead, we found that AP internalizing symptoms moderated the effects of BP psychopathology on trajectories of BI, indicating a gene by environment interaction.

Relations Between Executive Functioning and Internalizing Symptoms Vary as a Function of Frontoparietal-amygdala Resting State Connectivity.

The prefrontal cortex and the frontoparietal network are associated with a variety of regulatory behaviors. Functional connections between these brain regions and the amygdala are implicated in risk for anxiety disorders. The prefrontal cortex and frontoparietal network are also linked to executive functioning, or behaviors that help orient action towards higher order goals. Where much research has been focused on deleterious effects of under-controlled behavior, a body of work suggests that over-controlled behavior may also pose a risk for internalizing problems. Indeed, while work suggests that high levels of attention shifting may still be protective against internalizing problems, there is evidence that high levels of inhibitory control may be a risk factor for socioemotional difficulties. In the ABCD sample, which offers large sample sizes as well as sociodemographic diversity, we test the interaction between frontoparietal network-amygdala resting state functional connectivity and executive functioning behaviors on longitudinal changes in internalizing symptoms from approximately 10 to 12 years of age. We found that higher proficiency in attention shifting indeed predicts fewer internalizing behaviors over time. In addition, higher proficiency in inhibitory control predicts fewer internalizing symptoms over time, but only for children showing resting state connectivity moderately above the sample average between the frontoparietal network and amygdala. This finding supports the idea that top-down control may not be adaptive for all children, and relations between executive functioning and anxiety risk may vary as a function of trait-level regulation.