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Technology-driven interactions are becoming commonplace, particularly as online classes, telecommuting, and virtual meetings across distances and time zones have all increased in popularity. Platforms such as Google Meet, Skype, Webex, and Zoom use synchronous audio-visual communication supported by text-based chat, emoticon responses, and other supplementary functions. Given this uptick in the use of video conferencing with dynamic integrated features, it is important to understand how attention and cognitive resources may be taxed in these environments, and what that may ultimately do to participants' ability to comprehend the target content. In the current study, we investigated the impact of topically-relevant student-initiated text chat frequency on comprehension during an online lecture. The findings revealed that chat involvement alone does not affect learning itself. Chat activity was found to not be a distraction but in fact, a facilitator of increased confidence in learning in an online lecture environment when controlling for other outside distractions. Overall, the findings suggest that relevant chat content is not distracting and can be helpful in reinforcing concepts through supportive examples in adjacent modalities.

Abstract Background Latinos are more likely than non-Latino Whites to develop dementia and be prescribed antipsychotics for dementia-related behavioral symptoms. Antipsychotics have significant risks yet are often overprescribed. Our understanding of how Latino caregivers of Latino older adults living with dementia perceive and address behavioral issues is limited, impeding our ability to address the root causes of antipsychotic overprescribing. Methods We interviewed Latino older adults’ caregivers and community-based organization workers serving older adults with cognitive impairment (key informants), focusing on the management of behavioral symptoms and experiences with health services. Results We interviewed 8 caregivers and 2 key informants. Caregivers were the spouses, children, or grandchildren of the older adult living with cognitive impairment; their ages ranged from 30 to 95. We identified three categories of how caregivers learned about, managed, and coped with behavioral symptoms: caregivers often faced shortcomings with dementia care in the medical system, receiving limited guidance and support; caregivers found community organizations and senior day centers to be lifelines, as they received relevant, timely advice and support, caregivers often devised their own creative strategies to manage behavioral symptoms. Conclusion In-depth interviews suggest that the healthcare system is failing to provide support for behavioral symptoms from dementia; caregivers of Latino older adults rely on community organizations instead.

Abstract Given the persistent challenge of differentiating idiopathic Normal Pressure Hydrocephalus (iNPH) from similar clinical entities, we conducted an in-depth proteomic study of cerebrospinal fluid (CSF) in 28 shunt-responsive iNPH patients, 38 Mild Cognitive Impairment (MCI) due to Alzheimer’s disease, and 49 healthy controls. Utilizing the Olink Explore 3072 panel, we identified distinct proteomic profiles in iNPH that highlight significant downregulation of synaptic markers and cell-cell adhesion proteins. Alongside vimentin and inflammatory markers upregulation, these results suggest ependymal layer and transependymal flow dysfunction. Moreover, downregulation of multiple proteins associated with congenital hydrocephalus (e.g., L1CAM, PCDH9, ISLR2, ADAMTSL2, and B4GAT1) points to a possible shared molecular foundation between congenital hydrocephalus and iNPH. Through orthogonal partial least squares discriminant analysis (OPLS-DA), a panel comprising 13 proteins has been identified as potential diagnostic biomarkers of iNPH, pending external validation. These findings offer novel insights into the pathophysiology of iNPH, with implications for improved diagnosis.

Abstract Rhabdomyosarcoma (RMS) is a pediatric tumor that resembles undifferentiated muscle cells; yet the extent to which cell state heterogeneity is shared with human development has not been described. Using single-cell/nucleus RNA sequencing from patient tumors, patient-derived xenografts, primary in vitro cultures, and cell lines, we identify four dominant muscle-lineage cell states: progenitor, proliferative, differentiated, and ground cells. We stratify these RMS cells/nuclei along the continuum of human muscle development and show that they share expression patterns with fetal/embryonal myogenic precursors rather than postnatal satellite cells. Fusion-negative RMS (FN-RMS) have a discrete stem cell hierarchy that recapitulates fetal muscle development and contain therapy-resistant FN-RMS progenitors that share transcriptomic similarity with bipotent skeletal mesenchymal cells. Fusion-positive RMS have tumor-acquired cells states, including a neuronal cell state, that are not found in myogenic development. This work identifies previously underappreciated cell state heterogeneity including unique treatment-resistant and tumor-acquired cell states that differ across RMS subtypes.

Abstract Introduction Persons with Parkinson’s disease (PwPD) suffer from motor and non-motor symptoms which significantly affect their quality of life (QoL), and the QoL of their care partners (CP). Tandem cycling reduces PwPD motor symptoms; however, no studies have examined other benefits or included PwPD CP. We conducted an 8-week community virtual reality (VR) tandem cycling intervention to assess the feasibility and efficacy for PwPD and their CP (i.e., PD dyads). We hypothesized that dyadic tandem cycling would improve (1) PwPD motor and non-motor symptoms and (2) dimensions of PD dyads’ QoL and physiologic health. Methods Ten PD dyads were recruited to complete 8 weeks of progressive intensity, bi-weekly tandem cycling. At pre- and post-testing, PwPD were assessed using the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale-III (MDS-UPDRS-III), functional gait assessment (FGA), and 10-m gait speed test. PD dyads also completed emotional and cognitive status questionnaires [e.g., Geriatric Depression Scale-Short Form (GDS-SF)], and wore BodyGuard 2 heart rate (HR) monitors for 48 h to assess surrogate measures of heart rate variability. Statistical analyses were conducted using Student’s t tests with significance set at p ≤ 0.05. Results Eight PD dyads and one PwPD completed the intervention. Retention of PwPD (90%) and CP (80%) was adequate, and PD dyad adherence ranged from 91.67 to 97.91%. PwPD demonstrated significant clinical improvements in MDS-UPDRS-III scores (− 7.38, p

Abstract Background Pediatric acute transverse myelitis (ATM) accounts for 20–30% of children presenting with a first acquired demyelinating syndrome (ADS) and may be the first clinical presentation of a relapsing ADS such as multiple sclerosis (MS). B cells have been strongly implicated in the pathogenesis of adult MS. However, little is known about B cells in pediatric MS, and even less so in pediatric ATM. Our lab previously showed that plasmablasts (PB), the earliest B cell subtype producing antibody, are expanded in adult ATM, and that these PBs produce self-reactive antibodies that target neurons. The goal of this study was to examine PB frequency and phenotype, immunoglobulin selection, and B cell receptor reactivity in pediatric patients presenting with ATM to gain insight to B cell involvement in disease. Methods We compared the PB frequency and phenotype of 5 pediatric ATM patients and 10 pediatric healthy controls (HC) and compared them to previously reported adult ATM patients using cytometric data. We purified bulk IgG from the plasma samples and cloned 20 recombinant human antibodies (rhAbs) from individual PBs isolated from the blood. Plasma-derived IgG and rhAb autoreactivity was measured by mean fluorescence intensity (MFI) in neurons and astrocytes of murine brain or spinal cord and primary human astrocytes. We determined the potential impact of these rhAbs on astrocyte health by measuring stress and apoptotic response. Results We found that pediatric ATM patients had a reduced frequency of peripheral blood PB. Serum IgG autoreactivity to neurons in EAE spinal cord was similar in the pediatric ATM patients and HC. However, serum IgG autoreactivity to astrocytes in EAE spinal cord was reduced in pediatric ATM patients compared to pediatric HC. Astrocyte-binding strength of rhAbs cloned from PBs was dependent on somatic hypermutation accumulation in the pediatric ATM cohort, but not HC. A similar observation in predilection for astrocyte binding over neuron binding of individual antibodies cloned from PBs was made in EAE brain tissue. Finally, exposure of human primary astrocytes to these astrocyte-binding antibodies increased astrocytic stress but did not lead to apoptosis. Conclusions Discordance in humoral immune responses to astrocytes may distinguish pediatric ATM from HC.

Abstract Aging enhances numerous processes that compromise homeostasis and pathophysiological processes. Among these, activated HSCs play a pivotal role in advancing liver fibrosis. This research delved into how aging impacts liver fibrosis mechanisms. The study involved 32 albino rats categorized into four groups: Group I (young controls), Group II (young with liver fibrosis), Group III (old controls), and Group IV (old with liver fibrosis). Various parameters including serum ALT, adiponectin, leptin, and cholesterol levels were evaluated. Histopathological analysis was performed, alongside assessments of TGF-β, FOXP3, and CD133 gene expressions. Markers of fibrosis and apoptosis were the highest in group IV. Adiponectin levels significantly decreased in Group IV compared to all other groups except Group II, while cholesterol levels were significantly higher in liver fibrosis groups than their respective control groups. Group III displayed high hepatic expression of desmin, α-SMA, GFAP and TGF- β and in contrast to Group I. Increased TGF-β and FOXP3 gene expressions were observed in Group IV relative to Group II, while CD133 gene expression decreased in Group IV compared to Group II. In conclusion, aging modulates immune responses, impairs regenerative capacities via HSC activation, and influences adipokine and cholesterol levels, elevating the susceptibility to liver fibrosis.

A spectrophotometric method that is sensitive, easy, accurate, exact, reproducible, and verified has been developed for quantifying a new antiepileptic medication called retigabine in both its pure form and pharmaceutical formulations. The techniques employ N-bromosuccinimide (NBS) as an oxidizing agent and three dyes, namely amaranth, methylene blue, and indigo carmine. The three methods rely on the oxidation reaction of retigabine with an excess of N-bromosuccinimide (NBS) in an acidic environment. The unreacted NBS is then quantified by reacting it with fixed amounts of dyes, specifically amaranth, methylene blue, and indigo carmine. The absorbance at 520 nm, 664 nm, and 610 nm is measured for each respective dye. Linear relationships with high correlation coefficients (0.9992-0.9997) were observed under optimal conditions across concentration ranges of 0.5-12, 0.5-16, and 0.5–10 µg/ml. The limit of detection (LOD) for amaranth, methylene blue, and indigo carmine methods were determined to be 0.15, 0.15, and 0.14 µg/ml, respectively. The accuracy and precision of the approaches have been assessed for both intra-day and inter-day measurements. There was no observable interference caused by the typical tablet excipients. The proposed methodologies were verified in compliance with ICH recommendations and effectively utilized for the analysis of retigabine in pharmaceutical formulations. The reliability of the approaches was confirmed by conducting recovery studies employing the usual addition method. The findings produced by the proposed methods were statistically compared to those of the described approach using the student's t-test and F-test, which showed a significant level of agreement.

Uncertainty-identity theory (Hogg, 2000, 2007, 2012) postulates that people strengthen their adherence to, and identification with, extreme ideologies when they undergo an enduring uncertainty regarding their self-definition. Concomitantly, nationalist and extreme right-wing ideologies have been associated with the attribution of a threatening character to immigrant and refugee groups. We propose that self-uncertainty precedes the perceived threat posed by the latter groups, which in turn predicts adherence to nationalist attitudes. In one correlational (Study 1; n = 169) and one experimental study (Study 2; n = 309), we tested the mediational effects of perceived realistic and symbolic threat towards immigrants on the association between self-uncertainty and nationalist attitudes (belief in national superiority, support for anti-immigration laws and intention to vote for an anti-immigration party). In both studies, perceived realistic threat emerged as the most reliable mediator between self-uncertainty and nationalist attitudes. In addition (Study 2), we found a causal effect of self-uncertainty on realistic threat. We discuss the implications of these findings for social inclusion policies based on the reduction of uncertainty generated by immigration.

The Representations of science in mass media have shown a significant increase in the last years. However, mass media dissemination activities can extend to pseudoscience due to the fact that not all scientific news are published with the same rigour. Thus, we aimed to develop two theoretical-practical interventions among first-year university students with the purpose of improving their knowledge about scientific studies and original scientific sources, as well as to critically analyze dissemination of scientific research in media. The interventions had a positive impact on knowledge about scientific information sources, particularly Pubmed, in addition to reducing the number of incorrect features linked to both scientific and dissemination articles, suggesting the importance of interventions focused on misconceptions. However, students showed knowledge of correct features of scientific articles, independently of our intervention, and they made more mistakes when attributing incorrect features to scientific articles when compared to dissemination ones.

Objective: Investigators should return study results to patients and families facing cancer to honor their research contributions. We created a found poem from transcripts of sexual and gender minority (SGM) couples facing cancer and returned it to study participants. Methods: Participants were randomized to receive the found poem in text, text and audio, audio, or video format, completed dissemination preferences and emotion questionnaires, and open-ended questions about their experience receiving the poem. Results: Participants preferred the format they received (n = 15, 75.0%), with text-only and combined text and audio formats evoking the greatest number of emotions (n = 13 each). The following categories and subcategories were identified: dyadic experiences (support, strength, depth, durability); dissemination preferences (timing, method); emotion (positive, negative); utility of the found poem (affirming; fostering reflection; not useful or inaccurate, and sense of community). SGM participants utilized positive emotion, affirming, and a sense of community with greater frequency than non-SGM participants. Conclusion: Innovative approaches to dissemination are acceptable; providing choices in how and when participants receive results may increase engagement; and SGM versus non-SGM groups may describe dyadic experiences differently. Innovation: Returning study results via found poetry is an innovative way to honor research participants facing cancer.

ObjectivesThe paediatric gut microbiota is a reservoir of antimicrobial resistance genes. Environmental factors such as a child's exposure to faecal contamination and antimicrobial resistance genes of animal origin likely shape the resistome of infants and children. This study measured how different levels of exposure to domestic or food animals affect the structure of the intestinal resistome in children between 1 and 7 years of age.MethodsOne hundred nineteen faecal samples from 39 children were analysed according to the level of exposure to domestic or food animals and categorized into three risk groups. Using high-throughput sequencing with an Illumina NovaSeq 6000 SP platform, we performed faecal resistome analyses using the ResFinder database. Additionally, ResistoXplorer was used to characterize the resistomes of children differentially exposed to domestic animals.ResultsOur data indicated that specific antimicrobial resistance genes such as those that confer resistance to MATFPR (macrolide, aminoglycoside, tetracycline, fluoroquinolone, phenicol, and rifamycin) and tetracyclines were statistically less abundant in the group of children without exposure to animals (group 2), compared with the groups exposed to domestic and food animals (groups 1 and 3). However, the overall resistome structure among the children was not affected by the different levels of exposure to animals.ConclusionsThis study suggests that animal exposure is a risk factor for young children acquiring specific antimicrobial resistance genes from domestic animals or animal production areas. However, the overall resistome structure was not affected.

With the growth of online courses, moderators can play a significant role in engaging and supporting learners in asynchronous online discussions (AODs). However, a synthesis of the research on moderators has not been performed in the 40 years since the term was first used in reference to online learning. We examined 76 studies to determine key concepts, characteristics, and factors that researchers have identified regarding moderation in educational AODs. We found disparate perspectives regarding moderator definitions, identities, roles, duties, and training approaches. Based on a comparative analysis of four conceptual frameworks on moderation, we developed a taxonomy that delineates moderator duties into managerial, monitoring, pedagogical, technical, and social roles. Understanding how moderation can be used effectively in AODs could direct future research and applications to practice by informing the development of supportive resources and training. We conclude by defining protocols applicable to a future systematic review in this area.

Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, and fast-progressive neurodegenerative disease characterized by the degeneration of motor neurons. ALS patients often experience an initial misdiagnosis or a diagnostic delay due to the current unavailability of an efficient biomarker. Since impaired speech is typical in ALS, we hypothesized that functional differences between healthy and ALS participants during speech tasks can be explained by cortical pattern changes, thereby leading to the identification of a neural biomarker for ALS. In this pilot study, we collected magnetoencephalography (MEG) recordings from three early-diagnosed patients with ALS and three healthy controls during imagined (covert) and overt speech tasks. First, we computed sensor correlations, which showed greater correlations for speakers with ALS than healthy controls. Second, we compared the power of the MEG signals in canonical bands between the two groups, which showed greater dissimilarity in the beta band for ALS participants. Third, we assessed differences in functional connectivity, which showed greater beta band connectivity for ALS than healthy controls. Finally, we performed single-trial classification, which resulted in highest performance with beta band features (∼ 98%). These findings were consistent across trials, phrases, and participants for both imagined and overt speech tasks. Our preliminary results indicate that speech-evoked beta oscillations could be a potential neural biomarker for diagnosing ALS. To our knowledge, this is the first demonstration of the detection of ALS from single-trial neural signals.

The use of data-driven technologies such as Artificial Intelligence (AI) and Machine Learning (ML) is growing in healthcare. However, the proliferation of healthcare AI tools has outpaced regulatory frameworks, accountability measures, and governance standards to ensure safe, effective, and equitable use. To address these gaps and tackle a common challenge faced by healthcare delivery organizations, a case-based workshop was organized, and a framework was developed to evaluate the potential impact of implementing an AI solution on health equity. The Health Equity Across the AI Lifecycle (HEAAL) is co-designed with extensive engagement of clinical, operational, technical, and regulatory leaders across healthcare delivery organizations and ecosystem partners in the US. It assesses 5 equity assessment domains-accountability, fairness, fitness for purpose, reliability and validity, and transparency-across the span of eight key decision points in the AI adoption lifecycle. It is a process-oriented framework containing 37 step-by-step procedures for evaluating an existing AI solution and 34 procedures for evaluating a new AI solution in total. Within each procedure, it identifies relevant key stakeholders and data sources used to conduct the procedure. HEAAL guides how healthcare delivery organizations may mitigate the potential risk of AI solutions worsening health inequities. It also informs how much resources and support are required to assess the potential impact of AI solutions on health inequities.

Background: Phthalate exposure may contribute to hypertensive disorders of pregnancy (HDP), including preeclampsia/eclampsia (PE/E), but epidemiologic studies are lacking. Objectives: To evaluate associations of pregnancy phthalate exposure with development of PE/E and HDP. Methods: Using data from 3,430 participants in eight Environmental influences on Child Health Outcomes (ECHO) Program cohorts (enrolled from 1999 to 2019), we quantified concentrations of 13 phthalate metabolites (8 measured in all cohorts, 13 in a subset of four cohorts) in urine samples collected at least once during pregnancy. We operationalized outcomes as PE/E and composite HDP (PE/E and/or gestational hypertension). After correcting phthalate metabolite concentrations for urinary dilution, we evaluated covariate-adjusted associations of individual phthalates with odds of PE/E or composite HDP via generalized estimating equations, and the phthalate mixture via quantile-based g-computation. We also explored effect measure modification by fetal sex using stratified models. Effect estimates are reported as odds ratios (OR) with 95% confidence intervals (95% CIs). Results: In adjusted analyses, a doubling of mono-benzyl phthalate (MBzP) and of mono (3-carboxypropyl) phthalate (MCPP) concentrations was associated with higher odds of PE/E as well as composite HDP, with somewhat larger associations for PE/E. For example, a doubling of MCPP was associated with 1.12 times the odds of PE/E (95%CI 1.00, 1.24) and 1.02 times the odds of composite HDP (95%CI 1.00, 1.05). A quartile increase in the phthalate mixture was associated with 1.27 times the odds of PE/E (95%CI 0.94, 1.70). A doubling of mono-carboxy isononyl phthalate (MCiNP) and of mono-carboxy isooctyl phthalate (MCiOP) concentrations were associated with 1.08 (95%CI 1.00, 1.17) and 1.11 (95%CI 1.03, 1.19) times the odds of PE/E. Effect estimates for PE/E were generally larger among pregnancies carrying female fetuses. Discussion: In this study, multiple phthalates were associated with higher odds of PE/E and HDP. Estimates were precise and some were low in magnitude. Interventions to reduce phthalate exposures during pregnancy may help mitigate risk of these conditions.

Cable-driven soft robots hold significant potential for surgical and industrial applications, yet their performance and maneuverability can be further enhanced through design optimization. By optimizing the design, factors such as bending angles, manipulator deformation, and overall functionality can be directly influenced, leading to improved interaction with the environment and more accurate task performance. This article presents a physics-based design optimization approach for cable-driven soft robotic manipulators, aiming to enhance bending performance through structural design enhancements. Four design criteria, namely, cross-sectional shape, material, gap shape, and gap size, are considered in the optimization process. Given the inherent nonlinearity of soft materials, finite element modeling techniques are employed to analyze the effects of modifying each design parameter on displacement and bending angle. The manipulator’s design is evaluated using ABAQUS/CAE, and an analysis of variance test is conducted to identify significant performance differences among the design parameters. The results reveal that material variation has the most substantial impact, followed by gap shape and gap size. Based on subsequent parameter optimization, Dragon Skin 10 is determined to be the optimal material for bending motion, while a trapezoidal gap shape is preferred. In addition, a genetic algorithm is utilized to select a maximum gap size of 8.87 mm. These findings provide valuable insights into key design principles for cable-driven soft manipulators, aiming to enhance flexibility and reduce actuation forces. By establishing a fundamental understanding of the relationship between morphology and motion capability, this methodology demonstrates an effective simulation-driven optimization approach that incorporates the nonlinear elastic behavior of materials to improve performance. Overall, this work establishes a framework for optimizing cable-driven architectures to suit various applications in the field of soft robotics.

Introduction: Although health systems increasingly integrate social needs screening and referrals into routine care, the effectiveness of these interventions and for whom they work remains unclear. Methods: Patients (N=4,608) seen in the emergency department were screened for social needs (e.g., transportation, housing, food) and offered an opportunity to receive outreach from community service specialists. Results: Among 453 patients with 1 or more social needs who requested assistance, outreach specialists connected with 95 (21.0%). Patients preferred to be contacted through their telephone (n=21, 60.2%), email (n=126, 28.0%), someone else's telephone (n=30, 6.7%), or first by telephone followed by email (n=23, 5.1%). Preferred contact method varied by patient age; endorsement of unmet transportation, housing, and utility needs; receipt of service outreach; and differences in emergency department utilization from the 6 months before the index visit to the 6 months after. Conclusions: Because limited access to a stable telephone or internet connection may prevent patients from connecting with resource referrals, social needs interventions may not benefit the most underserved populations who are at the highest risk of negative health outcomes. Future research should investigate whether communication preferences are an important indicator of needs and how to adapt social needs screening and referral processes so that they are more accessible to populations who may experience more frequent disruptions in methods utilized for digital communication.

To determine the burden of disease among subjects at risk of developing stroke or dementia, brain health indexes (BHI) tend to rely on anatomical features. Recent definitions emphasize the need of a broader perspective that encompasses cardiovascular risk factors (CVRFS) and lifestyle components which can be considered partial contributors to optimal brain health. In this study, we aimed to establish the association and risk detected by a Brain Health Index and the risk of possible vascular dementia (PVD) using data from the Mexican Health and Aging Study (MHAS) 2012-2015. The MHAS is a longitudinal study of adults aged ≥ 50 years. We analyzed the data obtained between 2012 and 2015. CVRFS included in the index were diabetes mellitus, hypertension, myocardial infarction, depression, obesity, physical inactivity, and smoking history. A PVD diagnosis was established when scores in the Cross-Cultural Cognitive Examination were below reference norms and limitations in ≥1 instrumental activities of daily living and a history of stroke were present. A multinomial regression model was developed to determine the association between BHI scores and PVD. In 2015, 75 PVD cases were identified. Mean age was 67.1 ±13.2 years, 35.8% were female, and the mean educational level was 5.8 ±5.5 years. In cases with a higher score in the BHI, the model revealed a hazards ratio of 1.63 (95% CI: 1.63-1.64, p< 0.001) for PVD. In this longitudinal study, with the use of a feasible multifactorial BHI in the Mexican population, a greater score was associated with a 1.63-fold risk of developing PVD during the 3-year follow-up, while the risk for stroke was 1.75. This index could potentially be used to predict the risk of PVD in adults with modifiable CVRFS.

Backgroundfalls and fall-related injuries are common in older adults, have negative effects on functional independence and quality of life and are associated with increased morbidity, mortality and health related costs. Current guidelines are inconsistent, with no up-to-date, globally applicable ones present.Objectivesto create a set of evidence- and expert consensus-based falls prevention and management recommendations applicable to older adults for use by healthcare and other professionals that consider: (i) a person-centred approach that includes the perspectives of older adults with lived experience, caregivers and other stakeholders; (ii) gaps in previous guidelines; (iii) recent developments in e-health and (iv) implementation across locations with limited access to resources such as low- and middle-income countries.Methodsa steering committee and a worldwide multidisciplinary group of experts and stakeholders, including older adults, were assembled. Geriatrics and gerontological societies were represented. Using a modified Delphi process, recommendations from 11 topic-specific working groups (WGs), 10 ad-hoc WGs and a WG dealing with the perspectives of older adults were reviewed and refined. The final recommendations were determined by voting.Recommendationsall older adults should be advised on falls prevention and physical activity. Opportunistic case finding for falls risk is recommended for community-dwelling older adults. Those considered at high risk should be offered a comprehensive multifactorial falls risk assessment with a view to co-design and implement personalised multidomain interventions. Other recommendations cover details of assessment and intervention components and combinations, and recommendations for specific settings and populations.Conclusionsthe core set of recommendations provided will require flexible implementation strategies that consider both local context and resources.

Abstract Activation of oncogenic gene expression from long-range enhancers is initiated by the assembly of DNA-binding transcription factors (TF), leading to recruitment of co-activators such as CBP/p300 to modify the local genomic context and facilitate RNA-Polymerase 2 (Pol2) binding. Yet, most TF-to-coactivator recruitment relationships remain unmapped. Here, studying the oncogenic fusion TF PAX3-FOXO1 (P3F) from alveolar rhabdomyosarcoma (aRMS), we show that a single cysteine in the activation domain (AD) of P3F is important for a small alpha helical coil that recruits CBP/p300 to chromatin. P3F driven transcription requires both this single cysteine and CBP/p300. Mutants of the cysteine reduce aRMS cell proliferation and induce cellular differentiation. Furthermore, we discover a profound dependence on CBP/p300 for clustering of Pol2 loops that connect P3F to its target genes. In the absence of CBP/p300, Pol2 long range enhancer loops collapse, Pol2 accumulates in CpG islands and fails to exit the gene body. These results reveal a potential novel axis for therapeutic interference with P3F in aRMS and clarify the molecular relationship of P3F and CBP/p300 in sustaining active Pol2 clusters essential for oncogenic transcription.

The free energy of ion solvation can be decomposed into enthalpic and entropic contributions. This helps one to understand the connection between the dielectric properties and the underlying forces. We present a simple linear-response model of screened charge interactions that provides an alternative understanding of solvation barriers. Moreover, it explains the “anti-Coulomb” interactions (attraction between like-charged ions and repulsion between opposite-charged ions) observed in both simulations and experiments. We show that this is a universal behavior associated to the nonlocal response function of any dielectric or metallic systems.