Identifying and Characterizing the Transgender and Nonbinary Population Presenting to Pediatric Psychiatry Emergency Services.

Transgender and nonbinary (TGNB) individuals have an increased risk of certain mental health outcomes, such as depression and suicide attempts. This population skews younger in the United States and prior studies have not included TGNB patients for the entire pediatric age range in an emergency department (ED) setting. The present study aimed to examine gender identity documentation in the electronic health record and then use that information to identify and further characterize the pediatric TGNB population presenting to a psychiatric emergency service. Preliminary findings include a greater percentage of TGNB patients compared to non-TGNB individuals who had repeat visits to the ED for high acuity psychiatric concerns. A larger portion of TGNB patients also had at least one evaluation that included suicidal ideation. These results call for increased attention on the quality of mental healthcare for TGNB youth both inside and outside of the ED.

A novel ilarvirus protein CP-RT is expressed via stop codon readthrough and suppresses RDR6-dependent RNA silencing.

Ilarviruses are a relatively understudied but important group of plant RNA viruses that includes a number of crop pathogens. Their genomes comprise three RNA segments encoding two replicase subunits, movement protein, coat protein (CP), and (in some ilarvirus subgroups) a protein that suppresses RNA silencing. Here we report that, in many ilarviruses, RNA3 encodes an additional protein (termed CP-RT) as a result of ribosomal readthrough of the CP stop codon into a short downstream readthrough (RT) ORF. Using asparagus virus 2 as a model, we find that CP-RT is expressed in planta where it functions as a weak suppressor of RNA silencing. CP-RT expression is essential for persistent systemic infection in leaves and shoot apical meristem. CP-RT function is dependent on a putative zinc-finger motif within RT. Replacing the asparagus virus 2 RT with the RT of an ilarvirus from a different subgroup restored the ability to establish persistent infection. These findings open up a new avenue for research on ilarvirus silencing suppression, persistent meristem invasion and vertical transmission.

Implementing a student-centered stroke intervention and prevention education program; evaluating motivation, cognitive load, and performance among middle school students.

Background: In this study, we investigated the association between motivation, cognitive load, difficulty, and performance in a stroke education outreach program implemented for middle school students. Methods: Various interactive instructional activities were developed to engage students throughout the program to assess cognitive and intrinsic load arising from learner implementation of various tasks in a stroke education program for middle school kids. Performance was measured using a post-test to assess knowledge gained by the 6th, 7th, and 8th-grade middle school students. A short questionnaire was also administered to collect data on students' motivation using the ARCS model to asses attention, relevance, confidence, and satisfaction. In addition, we evaluated difficulty level and cognitive load. The relationship between performance and motivation was assessed using Pearson's correlation. Results: In our results, there was no significant difference (p > 0.05) in performance between the 6th, 7th, and 8th-grade students. The difference in performance, cognitive load (mental effort and difficulty), or motivation between the 6th, 7th, and 8 t-grade students was not significant (p > 0.05). The correlation between motivation and performance was significant (r = 0.87, p = 0.001), while the correlation between mental effort and performance was not significant (r = 0.34, p = 0.270). Also, the correlation between difficulty and performance was not significant (r = 0.38, p = 0.361). In the ARCS motivation model, attention, and confidence received the lowest mean scores (3.9), while relevance received the highest score (4.3). Conclusion: Our findings reveal the importance of implementing novel activities to enhance students' motivation to improve performance in the implementation of stroke education outreach programs for middle school students.

A comprehensive meta-analysis and systematic review of breath analysis in detection of COVID-19 through Volatile organic compounds.

BACKGROUND: The COVID-19 pandemic had profound global impacts on daily lives, economic stability, and healthcare systems. Diagnosis of COVID-19 infection via RT-PCR was crucial in reducing spread of disease and informing treatment management. While RT-PCR is a key diagnostic test, there is room for improvement in the development of diagnostic criteria. Identification of volatile organic compounds (VOCs) in exhaled breath provides a fast, reliable, and economically favorable alternative for disease detection. METHODS: This meta-analysis analyzed the diagnostic performance of VOC-based breath analysis in detection of COVID-19 infection. A systematic review of twenty-nine papers using the grading criteria from Newcastle-Ottawa Scale (NOS) and PRISMA guidelines was conducted. RESULTS: The cumulative results showed a sensitivity of 0.92 (95 % CI, 90 %-95 %) and a specificity of 0.90 (95 % CI 87 %-93 %). Subgroup analysis by variant demonstrated strong sensitivity to the original strain compared to the Omicron and Delta variant in detection of SARS-CoV-2 infection. An additional subgroup analysis of detection methods showed eNose technology had the highest sensitivity when compared to GC-MS, GC-IMS, and high sensitivity-MS. CONCLUSION: Overall, these results support the use of breath analysis as a new detection method of COVID-19 infection.

A Web-Based Intervention to Support the Mental Well-Being of Sexual and Gender Minority Young People: Mixed Methods Co-Design of Oneself.

BACKGROUND: Sexual and gender minority youth are at greater risk of compromised mental health than their heterosexual and cisgender peers. This is considered to be due to an increased burden of stigma, discrimination, or bullying resulting in a heightened experience of daily stress. Given the increasing digital accessibility and a strong preference for web-based support among sexual and gender minority youth, digital interventions are a key means to provide support to maintain their well-being. OBJECTIVE: This paper aims to explicate the co-design processes and underpinning logic of Oneself, a bespoke web-based intervention for sexual and gender minority youth. METHODS: This study followed a 6-stage process set out by Hagen et al (identify, define, position, concept, create, and use), incorporating a systematic scoping review of existing evidence, focus groups with 4 stakeholder groups (ie, sexual and gender minority youth, professionals who directly support them, parents, and UK public health service commissioners), a series of co-design workshops and web-based consultations with sexual and gender minority youth, the appointment of a digital development company, and young adult sexual and gender minority contributors to create content grounded in authentic experiences. RESULTS: Oneself features a welcome and home page, including a free accessible to all animation explaining the importance of using appropriate pronouns and the opportunity to create a user account and log-in to access further free content. Creating an account provides an opportunity (for the user and the research team) to record engagement, assess users' well-being, and track progress through the available content. There are three sections of content in Oneself focused on the priority topics identified through co-design: (1) coming out and doing so safely; (2) managing school, including homophobic, biphobic, or transphobic bullying or similar; and (3) dealing with parents and families, especially unsupportive family members, including parents or caregivers. Oneself's content focuses on identifying these as topic areas and providing potential resources to assist sexual and gender minority youth in coping with these areas. For instance, Oneself drew on therapeutic concepts such as cognitive reframing, stress reduction, and problem-solving techniques. There is also a section containing relaxation exercises, a section with links to other recommended support and resources, and a downloads section with more detailed techniques and strategies for improving well-being. CONCLUSIONS: This study contributes to research by opening up the black box of intervention development. It shows how Oneself is underpinned by a logic that can support future development and evaluation and includes diverse co-designers. More interactive techniques to support well-being would be beneficial for further development. Additional content specific to a wider range of intersecting identities (such as care-experienced Asian sexual and gender minority youth from a minority faith background) would also be beneficial in future Oneself developments. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/31036.

Development and Characterization of Hemoglobin Microbubbles for Acoustic Blood Oxygen Level Dependent Imaging.

Oxygen levels in tissues and organs are crucial for their normal functioning, and approaches to monitor them non-invasively have wide biological and clinical applications. In this study, we developed a method of acoustically detecting oxygenation using contrast-enhanced ultrasound (CEUS) imaging. Our approach involved the use of specially designed hemoglobin-based microbubbles (HbMBs) that reversibly bind to oxygen and alter the state-dependent acoustic response. We confirmed that the bioactivity of hemoglobin remained intact after the microbubble shell was formed, and we did not observe any significant loss of heme. We conducted passive cavitation detection (PCD) experiments to confirm whether the acoustic properties of HbMBs vary based on the level of oxygen present. The experiments involved driving the HbMBs with a 1.1 MHz focused ultrasound transducer. Through the PCD data collected, we observed significant differences in the subharmonic and harmonic responses of the HbMBs when exposed to an oxygen-rich environment versus an oxygen-depleted one. We used a programmable ultrasound system to capture high-frame rate B mode videos of HbMBs in both oxy and deoxy conditions at the same time in a two-chambered flow phantom and observed that the mean pixel intensity of deoxygenated HbMB was greater than in the oxygenated state using B-mode imaging. Finally, we demonstrated that HbMBs can circulate in vivo and are detectable by a clinical ultrasound scanner. To summarize, our results indicate that CEUS imaging with HbMB has the potential to detect changes in tissue oxygenation and could be a valuable tool for clinical purposes in monitoring regional blood oxygen levels.

Modulating Nonlinear Acoustic Response of Phospholipid-Coated Microbubbles with pH for Ultrasound Imaging.

Activatable microbubble contrast agents for contrast-enhanced ultrasound have a potential role for measuring physiologic and pathologic states in deep tissues, including tumor acidosis. In this study, we describe a novel observation of increased harmonic oscillation of phosphatidylcholine microbubbles (PC-MBs) in response to lower ambient pH using a clinical ultrasound scanner. MB echogenicity and nonlinear echoes were monitored at neutral and acidic pH using B-mode and Cadence contrast pulse sequencing (CPS), a harmonic imaging technique at 7.0 and 1.5 MHz. A 3-fold increase in harmonic signal intensity was observed when the pH of PC-MB suspensions was decreased from 7.4 to 5.5 to mimic normal and pathophysiological levels that can be encountered in vivo. This pH-mediated activation is tunable based on the chemical structure and length of phospholipids composing the MB shell. It is also reliant on the presence of phosphate groups, as the use of lipids without phosphate instead of phospholipids completely abrogated this phenomenon. The increased harmonic signal likely is the result of increased MB oscillation caused by a decrease of the interfacial tension induced at a lower pH, altering the lipid conformation. While relative signal changes are interpreted clinically as mostly related to blood flow, pH effects could be significant contributors, particularly when imaging tumors. While our observation can be used clinically, it requires further research to isolate the effect of pH from other variables. These findings could pave the way toward for the development of new smart ultrasound contrast agents that expand the clinical utility of contrast-enhanced ultrasound.

Enhanced CD95 and interleukin 18 signalling accompany T cell receptor Vß21.3+ activation in multi-inflammatory syndrome in children.

Multisystem inflammatory syndrome in children is a post-infectious presentation SARS-CoV-2 associated with expansion of the T cell receptor Vß21.3+ T-cell subgroup. Here we apply muti-single cell omics to compare the inflammatory process in children with acute respiratory COVID-19 and those presenting with non SARS-CoV-2 infections in children. Here we show that in Multi-Inflammatory Syndrome in Children (MIS-C), the natural killer cell and monocyte population demonstrate heightened CD95 (Fas) and Interleuking 18 receptor expression. Additionally, TCR Vß21.3+ CD4+ T-cells exhibit skewed differentiation towards T helper 1, 17 and regulatory T cells, with increased expression of the co-stimulation receptors ICOS, CD28 and interleukin 18 receptor. We observe no functional evidence for NLRP3 inflammasome pathway overactivation, though MIS-C monocytes show elevated active caspase 8. This, coupled with raised IL18 mRNA expression in CD16- NK cells on single cell RNA sequencing analysis, suggests interleukin 18 and CD95 signalling may trigger activation of TCR Vß21.3+ T-cells in MIS-C, driven by increased IL-18 production from activated monocytes and CD16- Natural Killer cells.

Reversal of C9orf72 mutation-induced transcriptional dysregulation and pathology in cultured human neurons by allele-specific excision.

Efforts to genetically reverse C9orf72 pathology have been hampered by our incomplete understanding of the regulation of this complex locus. We generated five different genomic excisions at the C9orf72 locus in a patient-derived induced pluripotent stem cell (iPSC) line and a non-diseased wild-type (WT) line (11 total isogenic lines), and examined gene expression and pathological hallmarks of C9 frontotemporal dementia/amyotrophic lateral sclerosis in motor neurons differentiated from these lines. Comparing the excisions in these isogenic series removed the confounding effects of different genomic backgrounds and allowed us to probe the effects of specific genomic changes. A coding single nucleotide polymorphism in the patient cell line allowed us to distinguish transcripts from the normal vs. mutant allele. Using digital droplet PCR (ddPCR), we determined that transcription from the mutant allele is upregulated at least 10-fold, and that sense transcription is independently regulated from each allele. Surprisingly, excision of the WT allele increased pathologic dipeptide repeat poly-GP expression from the mutant allele. Importantly, a single allele was sufficient to supply a normal amount of protein, suggesting that the C9orf72 gene is haplo-sufficient in induced motor neurons. Excision of the mutant repeat expansion reverted all pathology (RNA abnormalities, dipeptide repeat production, and TDP-43 pathology) and improved electrophysiological function, whereas silencing sense expression did not eliminate all dipeptide repeat proteins, presumably because of the antisense expression. These data increase our understanding of C9orf72 gene regulation and inform gene therapy approaches, including antisense oligonucleotides (ASOs) and CRISPR gene editing.

Retrospective consecutive controlled case series of outcomes for functional analyses of severe destructive behavior.

Functional analysis methods allow clinicians to determine the variable(s) that maintain destructive behavior. Previous reviews of functional analysis outcomes have included large samples of published and unpublished data sets (i.e., clinical samples). The purpose of this review was to conduct a large retrospective consecutive controlled case series of clinical functional analyses. We sought to identify the prevalence of differentiation, procedural modifications for undifferentiated and differentiated cases, and identified function(s) of destructive behavior. In addition, we extended the existing literature by determining whether functional analysis differentiation and function varied when single or multiple behavior topographies were consequated in the functional analysis. We discuss our findings considering previously published functional analysis reviews, provide avenues for future research, and offer suggestions for clinical practice.

Stimulus Avoidance Assessment: A Systematic Literature Review.

Board certified behavior analysts are ethically required to first address destructive behavior using reinforcement-based and other less intrusive procedures before considering the use of restrictive or punishment-based procedures (ethics standard 2.15; Behavior Analyst Certification Board, 2020). However, the inclusion of punishment in reinforcement-based treatments may be warranted in some cases of severe forms of destructive behavior that poses risk of harm to the client or others. In these cases, behavior analysts are required to base the selection of treatment components on empirical assessment results (ethics standard 2.14; Behavior Analyst Certification Board, 2020). One such preintervention assessment is the stimulus avoidance assessment (SAA), which allows clinicians to identify a procedure that is likely to function as a punisher. Since the inception of this assessment approach, no studies have conducted a systematic literature review of published SAA cases. These data may be pertinent to examine the efficacy, generality, and best practices for the SAA. The current review sought to address this gap by synthesizing findings from peer-reviewed published literature including (1) the phenomenology and epidemiology of the population partaking in the SAA; (2) procedural variations of the SAA across studies (e.g., number of series, session length); (3) important quality indicators of the SAA (i.e., procedural integrity, social validity); and (4) how the SAA informed final treatment efficacy. We discuss findings in the context of the clinical use of the SAA and suggest several avenues for future research.

Logistic burdens of cancer care: A qualitative study.

Cancer treatment often creates logistic conflicts with everyday life priorities; however, these challenges and how they are subjectively experienced have been largely unaddressed in cancer care. Our goal was to describe time and logistic requirements of cancer care and whether and how they interfered with daily life and well-being. We conducted interviews with 20 adults receiving cancer-directed treatment at a single academic cancer center. We focused on participants' perception of the time, effort, and energy-intensiveness of cancer care activities, organization of care requirements, and preferences in how to manage the logistic burdens of their cancer care. Participant interview transcripts were analyzed using an inductive thematic analysis approach. Burdens related to travel, appointment schedules, healthcare system navigation, and consequences for relationships had roots both at the system-level (e.g. labs that were chronically delayed, protocol-centered rather than patient-centered bureaucratic requirements) and in individual circumstances (e.g. greater stressors among those working and/or have young children versus those who are retired) that determined subjective burdensomeness, which was highest among patients who experienced multiple sources of burdens simultaneously. Our study illustrates how objective burdens of cancer care translate into subjective burden depending on patient circumstances, emphasizing that to study burdens of care, an exclusive focus on objective measures does not capture the complexity of these issues. The complex interplay between healthcare system factors and individual circumstances points to clinical opportunities, for example helping patients to find ways to meet work and childcare requirements while receiving care.

Treatment Response Biomarkers: Working Toward Personalized Radiotherapy for Lung Cancer.

Owing to major advances in the field of radiation oncology, patients with lung cancer can now receive technically individualized radiotherapy treatments. Nevertheless, in the era of precision oncology, radiotherapy-based treatment selection needs to be improved as many patients do not benefit or are not offered optimum therapies. Cost-effective robust biomarkers can address this knowledge gap and lead to individuals being offered more bespoke treatments leading to improved outcome. This narrative review discusses some of the current achievements and challenges in the realization of personalized radiotherapy delivery in patients with lung cancer.

Contrasting somatic mutation patterns in aging human neurons and oligodendrocytes.

Characterizing somatic mutations in the brain is important for disentangling the complex mechanisms of aging, yet little is known about mutational patterns in different brain cell types. Here, we performed whole-genome sequencing (WGS) of 86 single oligodendrocytes, 20 mixed glia, and 56 single neurons from neurotypical individuals spanning 0.4-104 years of age and identified >92,000 somatic single-nucleotide variants (sSNVs) and small insertions/deletions (indels). Although both cell types accumulate somatic mutations linearly with age, oligodendrocytes accumulated sSNVs 81% faster than neurons and indels 28% slower than neurons. Correlation of mutations with single-nucleus RNA profiles and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed across the genome similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These stark differences suggest an assortment of active mutagenic processes in oligodendrocytes and neurons.

Whole systems approaches to diet and healthy weight: A scoping review of reviews.

BACKGROUND: Obesity is a global epidemic affecting all age groups, populations, and income levels across continents, though is known to disproportionately affect socioeconomically disadvantaged populations. The causes of obesity are complex, informed by diet and weight practices, but shaped by social, commercial, and environmental factors and government policy. Consequently, a Whole System Approach (WSA)-which considers the many causes of obesity and shifts the focus away from individuals as points of intervention and puts an emphasis on understanding and improving the system in which people live-is required. This scoping review of reviews aims to: determine how WSAs to diet and healthy weight have been implemented and evaluated nationally and internationally; to determine what models or theories have been used to implement WSAs; describe how WSAs have been evaluated; determine if WSAs are effective; and to identify the contribution of the public and/or service users in the development of WSAs. METHOD: Systematic searches were carried out using CINAHL, Scopus, PsycINFO (ProQuest), the Cochrane Library, and MEDLINE. Included review papers were those that focused on the application of a whole system approach to diet and/or healthy weight, and/or reported the theory/model used to implement or simulate this approach. Databases were searched from 1995 to March 2022 using a combination of text and Medical Subject Headings (MeSH terms). In addition, reference sections of identified articles were examined for additional relevant articles. Covidence software was used to screen titles and abstracts from the electronic databases and resolve conflicts. RESULTS: A total of 20,308 articles were initially retrieved; after duplicate removal 7,690 unique title and abstracts were reviewed, and 110 articles were selected for full text review. On completion of full text review, 8 review articles were included for data extraction. These included: one umbrella review, four systematic reviews, a rapid review, and two literature reviews (one of which was on strategic reports written for government and public health policy). Evaluations of WSA were mainly process evaluations although health outcomes were assessed in some studies. Several conceptual frameworks or mathematical modelling approaches have been applied to WSAs for diet, healthy weight, and obesity to inform their planning or delivery, and to understand/map the associated systems. Common mathematical approaches include agent based or System Dynamic Modelling. Underlying both conceptual and mathematical models is an understanding how the elements of the complex systems impact each other to affect diet, healthy weight, and obesity. WSA implementations have reported some success in positively impacting health outcomes including reducing Body Mass Index, reducing sugary food intake, and increasing physical activity. Public and user involvement in WSA was not widely reported. CONCLUSION: The application of WSA to diet and healthy weight shows promise, yet the research is lagging behind their implementation. Further robust evidence for using WSA to address diet and healthy weight are required, including incorporating process and outcome evaluations (perhaps using established approaches such as Systems Dynamic Modelling). Furthermore, the analysis of epidemiological data alongside longitudinal process and outcome evaluation regarding the implementation of a WSA is required.

Prospective evaluation of acute neurological events after paediatric cardiac surgery.

OBJECTIVES: Children with CHD are at heightened risk of neurodevelopmental problems; however, the contribution of acute neurological events specifically linked to the perioperative period is unclear. AIMS: This secondary analysis aimed to quantify the incidence of acute neurological events in a UK paediatric cardiac surgery population, identify risk factors, and assess how acute neurological events impacted the early post-operative pathway. METHODS: Post-operative data were collected prospectively on 3090 consecutive cardiac surgeries between October 2015 and June 2017 in 5 centres. The primary outcome of analysis was acute neurological event, with secondary outcomes of 6-month survival and post-operative length of stay. Patient and procedure-related variables were described, and risk factors were statistically explored with logistic regression. RESULTS: Incidence of acute neurological events after paediatric cardiac surgery in our population occurred in 66 of 3090 (2.1%) consecutive cardiac operations. 52 events occurred with other morbidities including renal failure (21), re-operation (20), cardiac arrest (20), and extracorporeal life support (18). Independent risk factors for occurrence of acute neurological events were CHD complexity 1.9 (1.1-3.2), p = 0.025, longer operation times 2.7 (1.6-4.8), p < 0.0001, and urgent surgery 3.4 (1.8-6.3), p < 0.0001. Unadjusted comparison found that acute neurological event was linked to prolonged post-operative hospital stay (median 35 versus 9 days) and poorer 6-month survival (OR 13.0, 95% CI 7.2-23.8). CONCLUSION: Ascertainment of acute neurological events relates to local measurement policies and was rare in our population. The occurrence of acute neurological events remains a suitable post-operative metric to follow for quality assurance purposes.

Recommendations for accelerating open preprint peer review to improve the culture of science.

Peer review is an important part of the scientific process, but traditional peer review at journals is coming under increased scrutiny for its inefficiency and lack of transparency. As preprints become more widely used and accepted, they raise the possibility of rethinking the peer-review process. Preprints are enabling new forms of peer review that have the potential to be more thorough, inclusive, and collegial than traditional journal peer review, and to thus fundamentally shift the culture of peer review toward constructive collaboration. In this Consensus View, we make a call to action to stakeholders in the community to accelerate the growing momentum of preprint sharing and provide recommendations to empower researchers to provide open and constructive peer review for preprints.

Metastatic gastric adenocarcinoma to the cutaneous neck and chest wall.

This case describes an atypical cutaneous presentation of metastatic gastric carcinoma in a patient initially presenting with dysphagia and a sclerotic red plaque overlying the anterior neck and chest. Skin biopsy revealed metastatic adenocarcinoma from the upper gastrointestinal tract. Esophagogastroduodenoscopy revealed stage IV metastatic gastric adenocarcinoma. Treatment with chemotherapy was initiated.

Updated Recommendations for Reinforcement Schedule Thinning following Functional Communication Training.

Schedule thinning is a necessary treatment procedure following the acquisition of a communication response during functional communication training. In this article, we update and extend the Hagopian et al. Behavior Analysis in Practice, 4, 4-16, (2011) review and recommendations on schedule-thinning procedures following functional communication training. Since their publication, substantial research has been published on the efficacy, efficiency, and social validity of schedule-thinning methods. We provide updated recommendations for schedule thinning based on contemporary literature that has been published since 2011, as well as discuss key areas for future research.