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Commonalities and distinctions of pediatric patient and family engagement in clinical care, education, and research contexts: Protocol for a scoping review

Background Pediatric patient and family engagement is an active and collaborative process, that involves children, adolescents, and family members with lived experience contributing to the design, implementation, and evaluation of healthcare services. Prior studies have highlighted the patient engagement methods and impact in clinical care, education, and research. However, gaps remain in understanding the commonalities and distinctions of engagement approaches, patient/family partner roles, and outcomes in clinical care, education, and research contexts. Further, research examining the nuances of pediatric patient and family engagement within healthcare delivery, education, and research in pediatric institutions is needed to streamline efforts. Objective This scoping review will identify the commonalities of and distinctions between pediatric patient and family engagement in clinical care, education, and research contexts in pediatric healthcare institutions. Methods A scoping review, conducted in collaboration with a team of adolescent, young adult, and family partners, will allow us to systematically map out key concepts, evidence, and knowledge gaps regarding pediatric patient and family engagement in clinical care, education, and research. We will follow the Joanna Briggs Institute framework in the design and conduct of the review and guidance on engaging knowledge users within scoping reviews. The protocol for this scoping review has been registered with the Open Science Framework database (https://osf.io/63qx5). Results This study will describe the engagement types, approaches, and outcomes of pediatric patient and family engagement employed within clinical care, education, and research settings, highlighting commonalities and distinctions across contexts. In doing so, it will identify potential opportunities for collaboration and resource-sharing based on the context of engagement and provide needed clarity on streamlining pediatric patient and family engagement approaches within pediatric institutional settings. Conclusions It is anticipated that the results will produce preliminary evidence of relevance to pediatric institutions seeking to consolidate engagement practices across clinical care, education, and research domains.

Increasing the feasibility, impact, and equity of the Medicare Annual Wellness Visit (AWV) with a practice tailored AWV intervention: A stepped wedge clinical trial protocol

Background Older adults vastly underutilize evidence-based preventive health services and screenings that reduce illness, morbidity and mortality. The free-to-patient Medicare Annual Wellness Visit (AWV) is an opportunity to enhance preventive healthcare use, but also is underused. Objectives To evaluate the effect of a practice-tailored intervention on the sustained use of Medicare AWVs and on guideline-recommended preventive services and racial/ethnic disparities in 3 types of practice settings. Methods This is a stepped wedge cluster randomized controlled trial. The intervention will be implemented at the practice level in 24 primary care practices across the country (8 community-based, 8 academic, and 8 serving medically underserved populations). Electronic health record data will be used to assess changes in AWV and preventive service delivery rates and racial, ethnic, and gender disparities. Semi-structured interviews will be conducted with clinicians/staff and patients, and clinicians will be surveyed to assess the process and acceptability of the intervention. The protocol is registered on clinicaltrials.gov (NCT05910736). Results Analyses will determine the effect of the intervention on AWV visit and preventive health services use at 12- and 24-months post-intervention implementation. Additional analyses will evaluate the effect of the intervention on reducing racial/ethnic disparities. Conclusions A practice-tailored intervention has the potential to increase use of AWVs and preventive health services, and reduce racial/ethnic disparities, in diverse practice settings.

Glial reactivity and cognitive decline follow chronic heterochromatin loss in neurons

Abstract In aging cells and animal models of premature aging, heterochromatin loss coincides with transcriptional disruption including the activation of normally silenced endogenous retroviruses (ERVs). Here we show that loss of heterochromatin maintenance and de-repression of ERVs result in a chronic inflammatory environment characterized by neurodegeneration and cognitive decline in mice. We identify distinct roles for HP1 proteins to ERV silencing where HP1γ is necessary and sufficient for H4K20me3 deposition and HP1β deficiency causes aberrant DNA methylation. Combined loss of HP1β and HP1γ results in loss of DNA methylation at ERVK elements. Progressive ERV de-repression in HP1β/γ DKO mice is followed by stimulation of the integrated stress response, an increase of Complement 3+ reactive astrocytes and phagocytic microglia. This chronic inflammatory state coincides with age-dependent reductions in dendrite complexity and cognition. Our results demonstrate the importance of preventing loss of epigenetic maintenance that is necessary for protection of postmitotic neuronal genomes.

Perceived stress and allostatic load: Results from the All of Us Research Program

The rising prevalence of individuals reporting extreme stress has major public health implications as it increases vulnerability to accelerated premature biological aging, thus increasing risk of chronic disease. To examine the impact of stress on premature biological aging, we assessed the association between exposure to increased stress, quantified by the Perceived Stress Scale, and odds of high allostatic load (AL). To illuminate previously unexplored socio-contextual factors, we controlled for self-reported individual and neighborhood social determinants of health that included discrimination, loneliness, food insecurity, neighborhood disorder, and neighborhood social cohesion. We utilized a cross-sectional design to examine the association between perceived stress and AL among 7,415 participants ages 18–65 in the All of Us Research Program, who enrolled from 2017–2022. We used logistic regression to evaluate the association between stress and high AL, controlling for sociodemographic factors and self-reported social determinants of health. Participants who were younger, receiving Medicaid, or Hispanic had increased prevalence of high stress. High stress was associated with elevated odds of high AL in age and sex-adjusted models (OR=2.18, 95%CI = 1.78, 2.66, high stress vs. low), an association which remained significant after adjusting for social determinants of health (OR=1.29, 95%CI = 1.01, 1.65). Using restricted cubic splines, high stress was significantly associated with increased odds of high AL, even after controlling for upstream individual and neighborhood-level determinants of health. While individuals living below the medium poverty-to-income ratio demonstrated little appreciable association between high stress and increased odds of high allostatic load, those living above the median poverty-to-income ratio reporting increased stress appeared to have increased odds of high allostatic load. Through addressing the upstream factors causing undue burdens of stress, which particularly affect marginalized communities and younger generations, we can begin to address premature biological aging and the comorbid conditions it accompanies.

Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer’s disease

Abstract Alzheimer’s disease (AD) often begins with non-cognitive symptoms such as olfactory deficits, which can predict later cognitive decline, though the mechanisms remain unclear. Pathologically, the brainstem locus coeruleus (LC), the main source of the neurotransmitter noradrenalin (NA) modulating olfactory information processing is affected early. Here we show early and distinct loss of noradrenergic input to the olfactory bulb (OB) coinciding with impaired olfaction in an AD mouse model, before appearance of amyloid plaques. Mechanistically, OB microglia recognize and phagocytose LC axons. Reducing phagocytosis genetically preserves LC axons and olfaction. Prodromal AD patients display elevated TSPO-PET signals in the OB, similarly to App NL-G-F mice. We further confirm early LC axon degeneration in post-mortem OBs in patients with early AD. Our findings reveal a mechanism linking early LC damage to hyposmia in AD, suggesting olfactory testing and neurocircuit imaging for early diagnosis and enable timely therapeutic intervention for Alzheimer’s disease.

Psychoeducation Group for Depression (PEG-D): Study protocol for a prospective, randomized, single-blind, crossover trial

Background Considered a leading contributor to the global health burden, depression is characterized by its multifaceted nature. Recognizing the limitations of pharmacological treatments, non-pharmacological alternatives have been suggested to enhance full remission and increase quality of life. Aim To contribute to this field, we aim to develop and investigate the efficacy of a short psychoeducational program as an adjunctive treatment for depression. Methods/design We propose a single-center, prospective, crossover, single blind, randomized controlled trial, with 190 patients diagnosed with Major Depressive Disorder-MDD (DSM-5-TR), and moderate or intense severity by Hamilton Depression Rating Scale -HAMD-17. Participants will be randomly assigned to one of two arms, Treatment as usual (TAU) + Psychoeducation (n = 96) or TAU (n = 96). The psychoeducational program will consist of six weekly group sessions (6–10 participants) with each session lasting 90 minutes, covering information and techniques for identifying and coping with depression. Reduction in depressive levels, measured by the Beck Depression Inventory-BDI-II, and an increase in their level of knowledge on depression will be considered our primary outcome. Secondary outcomes, such as improvement in functionality and quality of life, will be measured by the Global Functioning Rating Scale (GAF), Clinical Global Impression Scale, and cognitive and behavioral factors by the Cognitive and Behavioral Avoidance Scale-CBAS, and Thoughts Scale Depressants-DTS (EPD). Discussion Developing and validating a structured psychoeducational program for depression is crucial for understanding the contribution of psychoeducation for depression and to facilitate the replication of findings, if positive. If our program demonstrates efficacy-superiority compared to TAU treatment, it might present as an interesting, cost-effective alternative as an adjunctive treatment. An expansion to other modalities, including open groups, euthymic patients, and online formats, might be considered, depending on our results. Trial registration NCT06467474

Regional heterogeneity of the blood-brain barrier

Abstract The blood-brain barrier (BBB), formed by specialized endothelial cells (ECs), regulates the extracellular composition of the central nervous system (CNS). Little is known about whether there are regional specializations of the BBB that may control the function of specific neural circuits. We use single cell RNA-seq to characterize ECs from nine CNS regions in male mice: cortex, hippocampus, cerebellum, spinal cord, striatum, thalamus, hypothalamus, midbrain, and medulla/pons. Although there is a core BBB transcriptional profile, there are significant regional specializations. Stra6, a retinoid transporter, is highly enriched in the BBB of the nucleus accumbens shell (ShNAc) and ventral cochlear nucleus, and is controlled by dietary vitamin A, through endothelial RARƔ. EC Stra6 regulates the deposition of retinoids specifically in the ShNAc and cochlear nucleus, and is required for the function of the ShNAc, in a retinoid-dependent manner. Thus regional specializations of the BBB can regulate the function of local brain regions.

Proximal and distal middle cerebral artery diameter ratio and lenticulostriate artery infarction

Background Lipohyalinotic degeneration (LD) and branch atheromatous disease (BAD) can contribute to subcortical infarctions in the lenticulostriate artery (LSA) territory. This study aimed to identify the association between the proximal and distal middle cerebral artery (MCA) diameter ratio and the two different pathomechanisms of LSA infarction. Methods Patients with acute LSA infarctions categorized as small vessel occlusive disease were included. Demographic and clinical data, along with MCA geometrical variables, were collected. LD and BAD were differentiated based on the length of the infarction diameter and number of axial slices. The proximal/distal M1 diameter ratio was calculated. MCA geometrics between LD and BAD were compared. Independent factors associated with LD were investigated. Computational fluid dynamics (CFD) analysis was used to evaluate hemodynamic parameters. Results A total of 117 patients were included, of whom 64 (54.7%) and 53 (45.3%) were classified as BAD and LD, respectively. LD was associated with hypertension and favorable prognosis. MCA geometric variables revealed that LD had a higher proximal/distal M1 diameter ratio, indicating a potential distinguishing factor. Multivariate analysis confirmed the independent association between LD and the proximal/distal M1 diameter ratio. The proximal/distal M1 diameter ratio also showed a positive correlation with the number of ipsilesional lacunes. CFD analysis showed that the LD model had faster, greater blood influx into LSAs and higher wall shear stress and pressure gradient compared with the BAD model. Conclusions This study suggests MCA geometry, particularly the proximal/distal M1 diameter ratio, may serve as an independent factor for identifying LD.

Development of conformation-selective antibodies targeting human SLC15A4

Prevalence and determinants of violent disciplinary practices for children in Bangladesh: Evidence from a nationally representative survey

Violent discipline, characterized by the use of physical force resulting in bodily pain, discomfort, or resorting to scolding and emotional abuse to correct children’s misbehavior, has gathered considerable attention due to its negative impact on children’s development. This study aims to identify the prevalence and factors associated with different violent disciplinary practices toward children of 1–14 years age in Bangladesh. Utilizing data from the Multiple Indicator Cluster Surveys (MICS) conducted in 2019, this analysis, based on interviews with parents of 70027 children, focuses on three dependent variables measuring violent disciplinary practices: psychological aggression, physical punishment and any violent discipline. The independent variables considered include the child’s age, sex, type of residence (rural or urban), division, education of mothers, child disability, ethnicity and wealth index. Logistic regression models were employed to find the relationships between these variables and different forms of violent discipline, including psychological aggression, physical punishment and any violent discipline (psychological aggression, physical punishment or both), among children in Bangladesh. The results reveal several significant associations with these disciplinary practices. Younger male children, with functional difficulties, those from urban residence and poorer households, residing in the central and southern regions of the country (Khulna, Chattogram), having primary educated mothers and belonging to the Bengali households are at higher risk of any form of violent discipline including psychological aggression, physical punishment. Significantly, our study unveils a strong correlation between any violent discipline and psychological aggression, highlighting that Bangladeshi parents predominantly employ psychological aggression as their primary mode of disciplinary practice. The findings underscore the importance of activating child protection laws and implementing continuous training programs for parents to promote positive parenting practices. To mitigate the use of violent discipline in Bangladesh, the study suggests focusing on improving parental education levels and addressing economic conditions.

Lipid-mediated gating of a miniature mechanosensitive MscS channel from Trypanosoma cruzi

Abstract The mechanosensitive channel of small conductance (MscS) from E. coli (EcMscS) has served as the prevailing model system for understanding mechanotransduction in ion channels. Trypanosoma cruzi, the protozoan parasite causing Chagas disease, encodes a miniature MscS ortholog (TcMscS) critical for parasite development and infectivity. TcMscS contains a minimal portion of the canonical EcMscS fold yet maintains mechanosensitive channel activity, thus presenting a unique model system to assess the essential molecular determinants underlying mechanotransduction. Using cryo-electron microscopy and molecular dynamics simulations, we show that TcMscS contains two short membrane-embedded helices that would not fully cross an intact lipid bilayer. Consequently, drastic membrane deformation is induced at the protein-lipid interface, resulting in a funnel-shaped bilayer surrounding the channel. Resident lipids within the central pore lumen block ion permeation pathway, and their departure driven by lateral membrane tension is required for ion conduction. Together with electrophysiology and mutagenesis studies, our results support a direct lipid-mediated mechanical gating transition. Moreover, these findings provide a foundation for the development of alternative treatment of Chagas disease by inhibition of the TcMscS channel.

Developmental differences in perceiving arousal and valence from dynamically unfolding emotional expressions

The development of emotion perception has predominantly been studied using static, unimodal stimuli featuring the faces of young adults. Most findings indicate a processing advantage for positive emotions in children (positivity bias) and a negativity bias in adults, although these results are usually task-dependent. We created a new stimulus database comprising digital avatars from four age groups, dynamically expressing happiness, happy-surprise, anger, and sadness in visual (face only) and visual-verbal (face and voice) conditions. To determine whether previously found biases would re-emerge with this new database, we tested the arousal and valence perception of positive and negative emotions in 6- and 7-year-old children and young adults. Our results revealed high correlations between children’s and adults’ responses but also significant differences: children rated negative expressions as more arousing compared to adults and positive emotions as more positive than adults. Additionally, visual-verbal presentations were perceived as more arousing than visual across both age groups. In terms of valence, all participants found positive emotions as more positive in the visual condition, whereas negative emotions were perceived as more negative in the visual-verbal condition. As one of the first studies to employ dynamically multimodal emotional expressions, our findings underscore the relevance of studying developmental differences in emotion perception using naturalistic stimuli.

Real-time prediction of intensive care unit patient acuity and therapy requirements using state-space modelling

A qualitative study on barriers and facilitators of COVID-19 vaccination during pregnancy among pregnant women in Malaysia

Background COVID-19 vaccination is crucial for pregnant women to protect against severe complications during pregnancy. However, vaccine hesitancy and refusal can affect acceptance rates among this vulnerable group, posing risks to both maternal and fetal health. This research was conducted to explore the barriers and facilitators influencing COVID-19 vaccination among Malaysian pregnant women. Methods This qualitative study adopted a hermeneutic phenomenological design. Nineteen pregnant women receiving antenatal care at three clinics in Kelantan between February 2024 and June 2024 were purposively selected to participate in in-depth interviews. The interviews were audio-recorded, transcribed verbatim, and analyzed using NVivo software alongside manual coding. Thematic analysis, incorporating both inductive and deductive approaches, was conducted to identify key themes. Results Most pregnant women expressed hesitancy toward COVID-19 vaccination during pregnancy due to various concerns. Our findings identified four key themes as barriers to vaccination: (i) Fear of side effects, (ii) Negative social influences, (iii) Perception of returning to normalcy, and (iv) Vaccine scepticism and prejudice. Conversely, three themes emerged as facilitators of vaccine acceptance: (i) Concerns about the effects of COVID-19 infection, (ii) Trust in the vaccine, and (iii) Personal and shared vaccination experiences. Conclusion This study identified key factors influencing COVID-19 vaccine hesitancy. These findings highlight the importance of addressing both personal and social dimensions of vaccine hesitancy. Public health interventions should focus on building trust, countering misinformation, and leveraging positive community experiences to encourage vaccine uptake, particularly in populations where hesitancy remains a concern.

Development of a versatile chassis for the efficient production of diverse type II polyketides

Expression of human A53T alpha-synuclein without endogenous rat alpha-synuclein fails to elicit Parkinson’s disease-related phenotypes in a novel humanized rat model

Alpha-synuclein (aSyn) is linked to Parkinson’s disease (PD) through SNCA genetic mutations, phosphorylated aSyn in Lewy bodies and Lewy neurites, and most recently through evidence of aSyn aggregation in patient spinal fluid using the aSyn seed amplification assay. Therefore, understanding the biology of this protein and developing therapeutic interventions targeting pathological processing of aSyn are a key area of focus for novel treatments to slow or stop PD. Reliable preclinical models are imperative for these efforts. To this end, we developed a novel model using CRISPR/Cas9 to humanize the regions surrounding the naturally occurring threonine 53 amino acid in the Sprague Dawley rat to generate a humanized A53T aSyn rat model (aSyn A53T KI). We also generated an Snca knockout (aSyn KO) line to pair with the humanized A53T aSyn rat line to confirm that phenotypes were not due to loss of endogenous rat aSyn protein. A systematic phenotyping study was performed on these lines, assessing PD-related pathology and phenotypes at multiple timepoints. The aSyn KO rat line was profiled at 6 and 12 months of age, revealing successful aSyn protein knockout. The aSyn A53T KI model was profiled at 4, 8, 12, and 18 months of age for motor and non-motor phenotypes, nigrostriatal degeneration, and brain pathology. We confirmed the aSyn A53T KI rat expresses human aSyn while lacking endogenous rat aSyn. Motor function and non-motor function remain largely unaffected in this model, and no overt nigrostriatal degeneration or brain pathology are observed up to 18 months of age. Although the aSyn A53T KI rat lacks the ability to model PD pathology and phenotypes at baseline, it is an ideal model for investigating the impact of exogenous synuclein aggregates or environmental triggers on human aSyn in an in vivo model system.

Reaction-induced regioselective reconstruction of Ni-doped Ce(OH)3/CeO2 enables exceptional activity and selectivity for reverse water-shift reaction

Teaching fish new tricks: Repeated exposure to a velocity barrier improves passage performance

Instream structures like culverts and dams can impede upstream fish migration, acting as environmental filters that only allow onward migration of individuals that can successfully pass them. Cognition and learning ability may be an important factor in determining if a fish can successfully traverse such structures. This study investigated the effect of repeated exposure on passage performance of juvenile Galaxias maculatus through an experimental raceway. Over five consecutive days, individual fish were subjected to the same high-speed (0.45–0.5 m s-1) conditions within the raceway, and performance on each day was recorded. The proportion of fish successfully passing the barrier increased significantly from 40% on Day 1–63% on Day 5. Time-to-event analysis further revealed that by Day 5, fish successfully passed the barrier at a significantly faster rate compared to Day 1. However, repeated exposure did not significantly improve approach or entry rates into the raceway. Fish length influenced approach rates, but not entry or passage rates. These findings suggest that cognition and spatial memory play a role in improving passage performance through velocity barriers, but other factors such as attraction flows may also play an important role in successful passage outcomes.

ATP allosterically regulates an acyl-CoA oxidase

Scenario-based Kaya identity analysis for city-level carbon dioxide emissions

Many countries worldwide have committed to reduce their carbon dioxide emissions in response to climate change. In China, cities are striving to achieve their 2030 peak carbon emission targets. In this study, we developed a scenario-based Kaya identity analysis methodology to explore the notable uncertainty inherent in future carbon dioxide emissions. Using the case of Changning City, Hunan province, China, we found that under the business-as-usual scenario, the city’s carbon dioxide emissions of 3,839.1 thousand tons in 2022 are projected to reach 4,674.3 thousand tons in 2031. Changning is unlikely to achieve its carbon peak target. In a more challenging future scenario of rapid economic growth, carbon dioxide emissions are expected to rise from 3,839.1 thousand tons in 2022–5,447 thousand tons in 2031. Under the environmentalist scenario, Changning could achieve its carbon peak target before 2030 (carbon dioxide emissions would peak at 3,922 thousand tons in 2028). Under a slowed economic development scenario, Changning could also achieve a carbon peak in 2028 (carbon dioxide emissions would peak at 3,980.2 thousand tons in 2028). However, without sufficient energy-saving and emissions-reduction measures, annual increases in carbon dioxide emissions are likely to resurge during periods of rapid economic development.