Recent publications
- Lauren J. Moskowitz
- Elizabeth A. Will
- Conner J. Black
- Jane E. Roberts
Background
Restricted and repetitive behaviors (RRBs) are highly prevalent and reduce function in individuals with fragile X syndrome (FXS). As transdiagnostic features of intellectual disability, elevated rates of RRBs in FXS could represent various underlying known co-occurring conditions in FXS such as anxiety or autism spectrum disorder (ASD), yet this distinction has not been investigated. Further, delineating whether RRBs are more indicative of anxiety or ASD in FXS may clarify phenotypic profiles within FXS and improve differential assessment.
Methods
We longitudinally examined the potentially independent or multiplicative effect of ASD and anxiety symptom severity on RRBs in 60 children with FXS. Anxiety was measured using the Child Behavior Checklist (CBCL), ASD severity was measured using the Childhood Autism Rating Scale (CARS), and RRBs were measured using the Repetitive Behavior Scale – Revised (RBS-R). We estimated a series of moderated regression models with anxiety and ASD symptoms at the initial assessment (Time 1) as predictors of RRBs at the outcome assessment two years later (Time 2), along with an anxiety-by-ASD interaction term to determine the potential multiplicative effect of these co-occurring conditions on RRBs.
Results
Results identified a significant interaction between ASD and anxiety symptom severity at the initial assessment that predicted elevated sensory-motor RRBs two years later. Increased sensory-motor RRBs were predicted by elevated ASD symptoms only when anxiety symptom severity was low. Likewise, increased sensory-motor RRBs were predicted by elevated anxiety symptoms only when ASD symptom severity was low. Interestingly, this relationship was isolated to Sensory-Motor RRBs, with evidence that it could also apply to total RRBs.
Conclusions
Findings suggest that ASD and anxiety exert independent and differential effects on Sensory-Motor RRBs when at high severity levels and a multiplicative effect when at moderate levels, which has important implications for early and targeted interventions.
Rationale
The cornea is a unique structure that maintains its clarity by remaining avascular. Corneal injuries can lead to neovascularisation (CNV) and fibrosis and are the third most common cause of blindness worldwide.
Objective
Corneal injuries induce an immune cell infiltration to initiate reparative processes. However, inflammation caused by sustained immune cell infiltration is known to be detrimental and can delay the healing process. This study was designed to understand the potential role of neutrophil and epithelial cell crosstalk in post‐injury CNV.
Methods and results
Western blotting and immunostaining assays demonstrated that neutrophils infiltrated corneas and underwent pyroptosis following acute alkali injury. In vivo studies showed that genetic ablation of Gasdermin D (GsdmD), a key effector of pyroptosis, enhanced corneal re‐epithelialisation and suppressed post‐injury CNV. In vitro co‐culture experiments revealed that interleukin‐1β (IL‐1β) was released from pyroptotic neutrophils which suppressed migration of murine corneal epithelial cells. Real‐time RT‐PCR and immunostaining assays identified two factors, Wnt5a and soluble fms‐like tyrosine kinase‐1 (sflt‐1), highly expressed in newly healed epithelial cells. sflt‐1 is known to promote corneal avascularity. Bone marrow transplantation, antibody mediated neutrophil depletion, and pharmacological inhibition of pyroptosis promoted corneal wound healing and inhibited CNV in an in vivo murine corneal injury model.
Conclusion
Taken together, our study reveals the importance of neutrophil/epithelium crosstalk and neutrophil pyroptosis in response to corneal injuries. Inhibition of neutrophil pyroptosis may serve as a potential treatment to promote corneal healing without CNV.
Key points
Neutrophil pyroptosis delays re‐epithelialization after corneal injury
Compromised re‐epithelialization promotes corneal neovascularization after injury
Inhibition of post‐injury pyroptosis could be an effective therapy to promote corneal wound healing.
Objective
The objectives of this review were to comprehensively identify the best available qualitative evidence about parents’ and guardians’ experiences of barriers and facilitators in accessing autism spectrum disorder (ASD) diagnostic services for their children; and to develop recommendations based on the review for addressing barriers to timely diagnosis and early intervention.
Introduction
Early identification of ASD is a priority because the best chance for improving symptoms occurs through early and intensive intervention. A definitive ASD diagnosis is often a prerequisite for children to access publicly funded services, yet obtaining a diagnosis in itself can be stressful, frustrating, and time-consuming for many families. It is essential to understand the barriers and facilitators parents and guardians face in accessing ASD diagnostic services for their children.
Inclusion criteria
This qualitative systematic review considered studies conducted worldwide that included parents and guardians of children up to 18 years of age who had accessed or who were attempting to access ASD diagnostic services for their children.
Methods
This review was conducted in accordance with the JBI methodology for systematic reviews of qualitative evidence. A literature search included CINAHL (EBSCOhost), CINAHL Plus (EBSCOhost), MEDLINE (EBSCOhost), APA PsycINFO (EBSCOhost), Social Services Abstracts (ProQuest), ERIC (EBSCOhost), and Embase. Gray literature sources included ProQuest Dissertations and Theses, Google Scholar, Google, OpenGrey, other online resources (government and organizational websites), and reference lists of retrieved records. No language, date, or country limits were applied to the searches. Retrieved records from the academic databases, gray literature, and reference lists of retrieved records were screened, with potentially relevant records examined in full against the inclusion criteria. Eligible studies were critically appraised for methodological quality and those included in this review were subjected to data extraction of descriptive details and study findings relevant to the review question. Study findings were synthesized and assigned confidence scores. All reviewers agreed upon the categories and finalized synthesized findings.
Results
The 36 included studies varied in qualitative research designs with high methodological quality. There were approximately 661 eligible participants, and 55 credible and unequivocal research findings. The research findings yielded 6 categories and 3 synthesized findings with moderate confidence scores. Parents’ and guardians’ ability to access ASD diagnostic services for their children is affected by i) encountering health care providers who actively listened to and addressed parents’ and guardians’ concerns instead of dismissing them, providing a sense of support and validation; ii) facing extended waiting times and associated financial burdens resulting in frustration and associated financial impact when delays occurred; and iii) encountering health care providers lacking specialized knowledge about ASD contributing to parents’ and guardians’ confusion due to inaccurate or conflicting diagnoses related to ASD comorbidities.
Conclusion
Many parents described their journey in accessing ASD assessment and diagnostic services for their children as cumbersome. Parents’ and guardians’ experiences were affected by the level of perceived support by and knowledge of health care providers; confusion surrounding inaccurate/mixed diagnoses related to ASD; lengthy delays; and systemic and contextual barriers in navigating the pathway to ASD assessment and diagnosis that included socioeconomic and cultural disparities.
Review registration
PROSPERO CRD42018100127
Background
Self-guided Internet-based cognitive behavior therapy (iCBT) for migraine interventions could improve access to care, but there is poor evidence of their efficacy.
Methods
A three-arm randomized controlled trial compared: iCBT focused on psychoeducation, self-monitoring and skills training (SPHERE), iCBT focused on identifying and managing personal headache triggers (PRISM) and a waitlist control. The primary treatment outcome was a ≥ 50% reduction in monthly headache days at 4 months post-randomization.
Results
428 participants were randomized (mean age = 30.1). 240 participants (56.2%) provided outcome data at 4 months. Intention-to-treat (ITT) analysis with missing data imputed demonstrated that the proportion of responders with a ≥ 50% reduction was similar between combined iCBTs and waitlist (48.5/285, 17% vs. 16.6/143, 11.6%, p = 0.20), but analysis of completers showed both iCBT programs to be superior to the waitlist (24/108, 22.2% vs. 13/113, 11.5%, p = 0.047). ITT analysis with missing data imputed showed no difference between the two iCBTs (SPHERE: 24.8/143, 17.3% vs. PRISM: 23.7/142, 16.7%, p = 0.99). Uptake rates of the iCBTs were high (76.9% and 81.69% logged in at least once into SPHERE and PRISM, respectively), but adherence was low (out of those who logged in at least once, 19.01% [21/110] completed at least 50% modules in SPHERE and 7.76% [9/116] set a goal for trying out a given trigger-specific recommendation in PRISM). Acceptability ratings were intermediate.
Conclusions
Self-guided iCBTs were not found to be superior in our primary ITT analysis. Low adherence could explain the lack of effects as completer analysis showed effects for both interventions. Enhancement of adherence should be a focus of future research.
Introduction
American Indian and Alaska Native People (AI/AN) have experienced discrimination stemming from sustained attempts to erase AI/AN People and their culture or livelihood. Research identifying the types of discrimination experienced by AI/AN People is needed to help individuals recognize discrimination in daily life. We examine experiences of discrimination among an urban AI/AN population using a mixed methods approach.
Methods
Self-identified AI/AN participants (N = 303, n = 294 with complete data; 63% women, mean age = 43 years) were recruited from the Denver-metro area in Colorado. Stress and coping models of discrimination guided our analysis. Exposure to discrimination was quantitatively assessed via the Brief Perceived Ethnic Questionnaire – Community Version (BPEDQ-CV), a self-report measure including four subscales assessing workplace discrimination, social exclusion, physical threat and harassment, and stigmatization. Participants responded to a laboratory recall task in which they described an episode of discrimination and their affective and coping responses. Content analysis was conducted on transcribed responses to illustrate discrimination exposure as reported in the BPEDQ-CV and in prior theoretical work on coping with discrimination.
Results
Repeated measures analyses revealed participants reported experiencing social exclusion more than other forms of discrimination, followed by reports of workplace discrimination, stigmatization, and physical threat. Consistent with these quantitative findings, participants were more likely to recall experiences of social threat (94%), including episodes of workplace discrimination, social exclusion, and stigmatization than physical threat and harassment. Almost half the participants (47%) reported confronting or directly addressing the discrimination, and 38% reported avoiding a direct approach. For 44% of participants, their predominant emotional response included internalizing emotions such as fear/sadness/embarrassment, and another 44% reported experiencing externalizing emotions, including anger.
Conclusion
Our descriptive findings present the experiences of urban AI/AN People who have experienced many forms of unjust and prejudicial treatment. These data can provide useful information to help the general public and AI/AN individuals more readily recognize and prevent discriminatory behavior, and consequently mitigate deleterious effects of discrimination on health.
Objective
The objectives of this review are to identify barriers/facilitators to designing, maintaining, and utilizing rare disease patient registries (RDPRs); determine whether and how these differ among patient partners, other knowledge users (KUs), and researchers; and chart definitions of rare diseases and RDPRs.
Introduction
RDPRs are vital to improving the understanding of the natural histories and predictors of outcomes for rare diseases, assessing interventions, and identifying potential participants for clinical trials. Currently, however, the functionality of RDPRs is not fully optimized. To improve the quality and functionality of RDPRs, it is important to understand the barriers and/or facilitators involved in their design, maintenance, and utilization; how these might differ among patient partners, other KUs, and researchers; and to delineate the range of definitions for rare diseases and RDPRs .
Inclusion criteria
Evidence of any study design or format (including empirical studies, books, manuals, commentaries, editorials, guidance documents, conference abstracts, review documents, and gray literature) referencing barriers/facilitators for designing, maintaining, or utilizing RDPRs will be considered for inclusion.
Methods
The review will follow the JBI methodology for scoping reviews. We will search health science databases, including the Cochrane Library, Embase, MEDLINE, the JBI EBP Database, and PsycINFO, from inception onwards, as well as gray literature using the Canadian Agency for Drugs and Technologies in Health (CADTH) Grey Matters guidance. Two independent reviewers will screen titles and abstracts and full-text documents, as well as abstract data. Disagreements will be resolved through discussion or with a third reviewer. Evidence will be synthesized descriptively and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRIMSA-ScR).
Review registration
Open Science Framework https://osf.io/mvf9r
Purpose
Individuals diagnosed with cancer experience multiple inter-related short- and long-term side effects. Chief among such symptomology is cancer-related fatigue (CRF), which, if left unmanaged, can become chronic and result in increased disability and healthcare utilization. A growing number of self-report scales have been developed to measure CRF symptoms based on various theoretical conceptualizations with the aim of promoting targeted assessment and intervention efforts. It may be, however, unwise to assume that the various measures are conceptually similar (i.e., that they assess for the same constructs). Accordingly, we aimed to characterize item content among nine self-report scales, using a Jaccard index to quantify content overlap among scales.
Methods
We characterized construct assessment among nine self-report scales recommended to assess CRF by a recent clinical practice guideline, and used a Jaccard index to quantify content overlap among scales.
Results
Analysis of 208 items across nine rating scales resulted in 20 distinct symptoms of CRF assessed. The most common symptoms were energy level (captured in all nine scales), cognitive function, impaired task performance (in eight scales), sleepiness, and physical function (in seven scales). Mean overlap among all scales was low (Jaccard index = 0.455). Only one construct (duration of fatigue; 5.0%) was captured by a single scale, and one symptom (energy level; 5.0%) was common across all scales. The PFS, MFSI, and BFI each captured at least one symptom from each of the NCCN domains of CRF.
Conclusion
CRF scales are heterogeneous in the content they measure, critically impairing integration of knowledge across studies using disparate scales. Future work is urgently needed to build more integrated theoretical and/or computational models of CRF based on relevant mechanisms.
Objective
Data-driven methodologies in healthcare necessitate labeled data for effective decision-making. However, medical data, particularly in unstructured formats, such as clinical notes, often lack explicit labels, making manual annotation challenging and tedious.
Methods
This paper introduces a novel deep active learning framework designed to facilitate the annotation process for multiclass text classification, specifically using the SOAP (subjective, objective, assessment, plan) framework, a widely recognized medical protocol. Our methodology leverages transformer-based deep learning techniques to automatically annotate clinical notes, significantly easing the manual labor involved and enhancing classification performance. Transformer-based deep learning models, with their ability to capture complex patterns in large datasets, represent a cutting-edge approach for advancing natural language processing tasks.
Results
We validate our approach through experiments on a diverse set of clinical notes from publicly available datasets, comprising over 426 documents. Our model demonstrates superior classification accuracy, with an F1 score improvement of 4.8% over existing methods but also provides a practical tool for healthcare professionals, potentially improving clinical documentation practices and patient care.
Conclusions
The research underscores the synergy between active learning and advanced deep learning, paving the way for future exploration of automatic text annotation and its implications for clinical informatics. Future studies will aim to integrate multimodal data and large language models to enhance the richness and accuracy of clinical text analysis, opening new pathways for comprehensive healthcare insights.
Brain cancer is regarded as one of the most life-threatening forms of cancer worldwide. Oxidative stress acts to derange normal brain homeostasis, thus is involved in carcinogenesis in brain. The Nrf2/Keap1/ARE pathway is an important signaling cascade responsible for the maintenance of redox homeostasis, and regulation of anti-inflammatory and anticancer activities by multiple downstream pathways. Interestingly, Nrf2 plays a somewhat, contradictory role in cancers, including brain cancer. Nrf2 has traditionally been regarded as a tumor suppressor since its cytoprotective functions are considered to be the principle cellular defense mechanism against exogenous and endogenous insults, such as xenobiotics and oxidative stress. However, hyperactivation of the Nrf2 pathway supports the survival of normal as well as malignant cells, protecting them against oxidative stress, and therapeutic agents. Plants possess a pool of secondary metabolites with potential chemotherapeutic/chemopreventive actions. Modulation of Nrf2/ARE and downstream activities in a Keap1-dependant manner, with the aid of plant-derived secondary metabolites exhibits promise in the management of brain tumors. Current article highlights the effects of Nrf2/Keap1/ARE cascade on brain tumors, and the potential role of secondary metabolites regarding the management of the same.
Background: Dysregulation of receptor tyrosine kinase c-MET is known to promote tumor development by stimulating oncogenic signaling pathways in different cancers, including pediatric neuroblastoma (NB). NB is an extracranial solid pediatric cancer that accounts for almost 15% of all pediatric cancer-related deaths, with less than a 50% long-term survival rate. Results: In this study, we analyzed a large cohort of primary NB patient data and revealed that high MET expression strongly correlates with poor overall survival, disease progression, relapse, and high MYCN levels in NB patients. To determine the effects of c-MET in NB, we repurposed a small molecule inhibitor, tivantinib, and found that c-MET inhibition significantly inhibits NB cellular growth. Tivantinib significantly blocks NB cell proliferation and 3D spheroid tumor formation and growth in different MYCN-amplified and MYCN-non-amplified NB cell lines. Furthermore, tivantinib blocks the cell cycle at the G2/M phase transition and induces apoptosis in different NB cell lines. As expected, c-MET inhibition by tivantinib inhibits the expression of multiple genes in PI3K, STAT, and Ras cell signaling pathways. Conclusions: Overall, our data indicate that c-MET directly regulates NB growth and 3D spheroid growth, and c-MET inhibition by tivantinib may be an effective therapeutic approach for high-risk NB. Further developing c-MET targeted therapeutic approaches and combining them with current therapies may pave the way for effectively translating novel therapies for NB and other c-MET-driven cancers.
Across the developed democracies, there has been a rise in populist nationalism and anti-globalization sentiment aimed at reasserting sovereignty through the state. This article develops the concept of discursive power as an alternative basis for citizens to project their voice and influence into global politics. Discursive power arises from the framing role of ideas in orienting citizen judgements to the possibilities for acting beyond the state, as a precursor to deliberative forms of persuasion and agreement. Discursive power is ‘democratic’, we argue, when it enables those affected by global issues and problems to conceive of themselves as collective agents capable of responding. Generating discursive power outside the state, however, requires informal representatives to serve as interlocutors. Drawing on recent theories of representation, we describe how the claims of non-state actors could support the production and mobilization of citizens' discursive powers across borders. Our analysis underscores the importance of claim-making for progressive responses to globalization centred on the judgements of citizens. We conclude by surveying several challenges for democratic discursive power at the transnational and global levels and suggest some background institutions and practices to enhance this power.
Associations between adversity and youth psychopathology likely vary based on the types and timing of experiences. Major theories suggest that the impact of childhood adversity may either be cumulative in type (the more types of adversity, the worse outcomes) or in timing (the longer exposure, the worse outcomes) or, alternatively, specific concerning the type (e.g., parenting, home, neighborhood) or the timing of adversity (e.g., specific developmental periods). In a longitudinal sample from the Future of Families and Wellbeing Study ( N = 4,210), we evaluated these competing hypotheses using a data-driven structured life-course modeling approach using risk factors examined at child age 1 (infancy), 3 (toddlerhood), 5 (early childhood), and 9 (middle childhood). Results showed that exposures to more types of adversity for longer durations (i.e., cumulative in both type and timing) best predicted youth psychopathology. Adversities that occurred at age 9 were better predictors of youth psychopathology as compared to those experienced earlier, except for neglect, which was predictive of internalizing symptoms when experienced at age 3. Throughout childhood (across ages 1–9), aside from the accumulation of all adversities, parental stress and low collective efficacy were the strongest predictors of internalizing symptoms, whereas psychological aggression was predictive of externalizing symptoms.
In response to the COVID-19 public health emergency, state and local mental health authorities rapidly developed and disseminated guidance to community mental health agencies. While tailored communication is effective to reach target audiences under usual circumstances, strategies to facilitate the implementation of guidance amidst a rapidly evolving public health emergency are not well understood. This project sought to understand factors informing decision-making about adaptations to guidance, and strategies used to disseminate and facilitate guidance implementation among system-level community partners in OnTrackNY Coordinated Specialty Care (CSC) programs for early psychosis. Semi-structured interviews were conducted with New York State Office of Mental Health (NYS OMH) state and local mental health authorities including state leaders (n = 3) and NYS OMH field office directors (n = 4), OnTrackNY program directors (n = 4), and leadership and trainers of an intermediary organization, OnTrack Central (n = 12). Interviews were analyzed using content analysis. Code reports relevant to guidance decision-making and dissemination were reviewed to identify emerging themes. For state and local mental health authorities, decision-making was influenced by changing COVID-19 risk levels, need for alignment between federal and local guidance, and balancing support for workforce capacity and mental health service continuity. For OnTrackNY program directors, decision-making was influenced by internal infrastructure and processes (e.g., program autonomy), availability of resources (e.g., technology), and perspective on managing risk and uncertainty (e.g., COVID-19, regulatory waiver expiration). For OnTrack Central, decision-making focused on balancing CSC model fidelity with OnTrackNY team capacity and resources. Dissemination of guidance consisted of mass and targeted strategies. Information flow was bidirectional such that top-down dissemination of guidance (e.g., from state mental health authorities to providers) was informed and refined with bottom-up feedback (e.g., from providers to state leadership) through surveys and professional forums (e.g., COVID-19 town halls, provider learning collaboratives). Unlike a planned approach to disseminate new policies, public health emergencies create variable landscapes that may warrant a deeper understanding of how guidance may be adapted to fit rapidly evolving community partner needs. Findings may inform efforts to identify processes that contribute to adaptation and dissemination of guidance for mental health during future public health emergencies.
Pulmonary emphysema involves progressive destruction of alveolar walls, leading to enlarged air spaces and impaired gas exchange. While the precise mechanisms responsible for these changes remain unclear, there is growing evidence that the extracellular matrix plays a critical role in the process. An essential feature of pulmonary emphysema is damage to the elastic fiber network surrounding the airspaces, which stores the energy needed to expel air from the lungs. The degradation of these fibers disrupts the mechanical forces involved in respiration, resulting in distension and rupture of alveolar walls. While the initial repair process mainly consists of elastin degradation and resynthesis, continued alveolar wall injury may be associated with increased collagen deposition, resulting in a mixed pattern of emphysema and interstitial fibrosis. Due to the critical role of elastic fiber injury in pulmonary emphysema, preventing damage to this matrix component has emerged as a potential therapeutic strategy. One treatment approach involves the intratracheal administration of hyaluronan, a polysaccharide that prevents elastin breakdown by binding to lung elastic fibers. In clinical trials, inhalation of aerosolized HA decreased elastic fiber injury, as measured by the release of the elastin-specific cross-linking amino acids, desmosine, and isodesmosine. By protecting elastic fibers from enzymatic and oxidative damage, aerosolized HA could alter the natural history of pulmonary emphysema, thereby reducing the risk of respiratory failure.
Over-the-air computation (OAC) can effectively support rapid data aggregation from a plethora of devices, exploiting the inherent superposition property of wireless multiple access channels. The key challenge in OAC is the synchronization of multiple devices, which are handled through either the coherent approach using the beacon transmissions by the fusion center or the non-coherent approach based on random sequences. Motivated by the lack of a fair comparison in prior arts, we derive the closed-form expressions of their mean squared errors (MSEs), which provides an explicit guideline on which approach to use and how we improve one compared to the other by adjusting their key design factors. Thus, this paper provides design insights into the OAC synchronization method depending on the system requirements in terms of MSE.
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