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OBJECTIVE: Relatively few studies have tracked retention effects of stroke education in low- and high-risk groups. Such information is important to improve the design of stroke prevention programs. METHODS: The frequency of risk factors within the sample was defined as 'high' if 30% or more of participants in that group had that risk. Only one stroke risk factor was present at this level in the low-risk group (n=29; all less than 50 years old). The high-risk group was 44 individuals aged 50 years or over, with four stroke risk factors present at this level. Stroke knowledge was tested on three occasions: baseline, post-education, and retention. Education consisted of reading a published stroke brochure. RESULTS: Stroke knowledge improved over time, from baseline to post-education, but not from post-education to retention. The performance of both groups increased, but there was a differential learning effect: low-risk participants learned more than high-risk participants. Important information was learned and included details such when TIA symptoms dissipate. This particular issue was one about which both groups knew little at baseline (less than 15% of combined sample answered this item correctly), but post-education at least 75% of participants got this question correct. CONCLUSION: Both low- and high-risk individuals can learn information about stroke and retain it over the short term. The 'durable' effects in learning observed in this study are important because the benefit of brochure-only approaches to education have not yet been convincingly demonstrated. PRACTICE IMPLICATIONS: Information about stroke from education brochures is retained by at-risk populations for at least 1 week. [ABSTRACT FROM AUTHOR]

Background: We explored carer motivation for seeking participation for a relative in an Alzheimer's disease (AD) clinical drug trial, to assess impressions of the value of trial participation. We also surveyed the carers of patients who did not meet study entry screening criteria to see if our conduct of the screening visit was acceptable and ethical.Method: A retrospective questionnaire was sent to the carers of 36 randomized participants and 22 carers of patients who did not meet study entry screening criteria for an AD clinical treatment trial.Results: Twenty-nine (81%) of the trial participant carers and 15 (68%) of carers of the group who did not meet study entry criteria returned their questionnaires with sufficient information for analysis. The prime motivators in seeking trial participation were to help their relative feel better and live longer, to contribute to medical science, to improve the health of others, and the hope of a cure. Carers of both groups found research staff supportive and would recommend trial participation to others.Conclusions: Even though trial participation is onerous and patients were generally perceived by carers as not having improved, both the screening visit and participation in the trial itself were seen as positive experiences and the expectations of carers were met. [ABSTRACT FROM AUTHOR]

Abstract Background Locomotor training using body weight support and a treadmill as a therapeutic modality for rehabilitation of walking post-stroke is being rapidly adopted into clinical practice. There is an urgent need for a well-designed trial to determine the effectiveness of this intervention. The objective of the Locomotor Experience Applied Post-Stroke (LEAPS) trial is to determine if there is a difference in the proportion of participants who recover walking ability at one year post-stroke when randomized to a specialized locomotor training program (LTP), conducted at 2- or 6-months post-stroke, or those randomized to a home based non-specific, low intensity exercise intervention (HEP) provided 2 months post-stroke. We will determine if the timing of LTP delivery affects gait speed at 1 year and whether initial impairment severity interacts with the timing of LTP. The effect of number of treatment sessions will be determined by changes in gait speed taken pre-treatment and post-12, -24, and -36 sessions. Methods/Design We will recruit 400 adults with moderate or severe walking limitations within 30 days of stroke onset. At two months post stroke, participants are stratified by locomotor impairment severity as determined by overground walking speed and randomly assigned to one of three groups: (a) LTP-Early; (b) LTP-Late or (c) Home Exercise Program -Early. The LTP program includes body weight support on a treadmill and overground training. The LTP and HEP interventions are delivered for 36 sessions over 12 weeks. Primary outcome measure include successful walking recovery defined as the achievement of a 0.4 m/s gait speed or greater by persons with initial severe gait impairment or the achievement of a 0.8 m/s gait speed or greater by persons with initial moderate gait impairment. LEAPS is powered to detect a 20% difference in the proportion of participants achieving successful locomotor recovery between the LTP groups and the HEP group, and a 0.1 m/s mean difference in gait speed change between the two LTP groups. Discussion The goal of this single-blinded, phase III randomized clinical trial is to provide evidence to guide post-stroke walking recovery programs. Trial registration NCT00243919.

Abstract Background The QUALIOST® was designed for use with the SF-36 to measure established osteoporosis-specific quality of life (QoL). The reliability (internal consistency and test-retest) and validity of the questionnaire were established in a stand-alone psychometric validation study. The objective of this paper is to provide additional information on the instrument's responsiveness using clinical trial data, along with the reliability and validity of translated versions. Methods The Spinal Osteoporosis Therapeutic Intervention (SOTI) was an international clinical trial comparing strontium ranelate to placebo on the occurrence of new vertebral fracture in patients with postmenopausal osteoporosis. QoL was a secondary endpoint, assessed using the SF-36 and QUALIOST® at baseline and every six months, with the main analysis at 3-year follow-up. Questionnaire acceptability, analysis of the hypothesised structure, internal consistency reliability and responsiveness to clinical change over time were assessed at the 3-year follow up. Results 1592 patients from 11 countries completed at least one QoL questionnaire. The psychometric properties of the questionnaires were assessed on cross-sectional (N = 1486) and longitudinal (N = 1288) data. Item discriminant validity of the QUALIOST® was excellent, as was item convergent validity, with 100% of item-scale correlations being above the 0.40 level. Internal consistency reliability was also extremely good, with high Cronbach's alpha scores above the 0.70 benchmark. Responsiveness results were consistent for all QUALIOST® scores, indicating that greater decreases in QoL corresponded to greater numbers of fractures experienced. QUALIOST® scores also differed according to the type of fracture suffered. This was demonstrated by increased effect sizes for more severe vertebral fractures (clinical vertebral and painful vertebral). In comparing responsiveness, the QUALIOST® scores were generally more consistent than those of the SF-36. Most notably, the QUALIOST® was more responsive with regard to painful vertebral fractures than the SF-36. Conclusion The QUALIOST® is a reliable and valid tool for measuring QoL in postmenopausal osteoporotic women. Being available in several validated language versions, it is ready to be used in a variety of settings, including international clinical trials.

BACKGROUND: Up to fifty percent of alcohol dependent individuals have alexithymia, a personality trait characterised by difficulties identifying and describing feelings, a lack of imagination and an externalised cognitive style. Although studies have examined alexithymia in relation to alcohol dependence, no research exists on mechanisms underlying this relationship. The present study examined the mediational effect of alcohol expectancies on alexithymia and alcohol dependence. METHODS: 230 outpatients completed the Toronto Alexithymia Scale (TAS-20), the Drinking Expectancy Questionnaire (DEQ) and the Alcohol Use Disorder Identification Test (AUDIT). RESULTS: Regression analysis showed that alexithymia and alcohol dependence was, in two of three cases, partially mediated through alcohol expectancy. CONCLUSIONS: Alcohol expectancies of assertion and affective change show promise as mediators of alcohol dependence in individuals with alexithymia. [ABSTRACT FROM AUTHOR]

Objective: To determine whether targeted sampling (TS), which omits biopsy of triple- normal lymph nodes (LNs) on positron emission tomography, computed tomography, and endobronchial ultrasound (EBUS), is noninferior to systematic sampling (SS) of mediastinal LNs during EBUS for staging of patients with early-stage non-small cell lung cancer (NSCLC)., Methods: Patients who are clinical nodal (cN)0-N1 with suspected NSCLC eligible for EBUS based on positron emission tomography/computed tomography were enrolled in this prospective, multicenter trial. During EBUS, all patients underwent TS and then crossed over to SS, whereby at least 3 mediastinal LN stations (4R, 4L, 7) were routinely sampled. Gold standard of comparison was pathologic results. Based on the previous feasibility trial, a noninferiority margin of 6% was established for difference in missed nodal metastasis (MNM) incidence between TS and SS. The McNemar test on paired proportions was used to determine MNM incidence for each sampling method. Analysis was per-protocol using a level of significance of P < .05., Results: Between November 2020 and April 2022, 91 patients were enrolled at 6 high-volume Canadian tertiary care centers. A total of 256 LNs underwent TS and SS. Incidence of MNM was 0.78% in SS and 2.34% in TS, with an absolute difference of 1.56% (95% confidence interval, -0.003% to 4.1%; P = .13). This falls within the noninferiority margin. A total of 6/256 LNs from 4 patients who were not sampled by TS were found to be malignant when sampled by SS., Conclusions: In high-volume thoracic endosonography centers, TS is not inferior to SS in nodal staging of early-stage NSCLC. This results in change of clinical management for a minority of patients., Competing Interests: Conflict of Interest Statement Dr Turner serves on an advisory board and has received speaker honoraria from Astra Zeneca. Dr Yasufuku has received unrestricted grants from Olympus Medical Systems for continuing medical education. Dr Hanna serves on an advisory board for AstraZeneca, data safety committee for Roche/Genentech, and speaker’s bureau for Minogue Medical. Dr Nayak has received speaker honoraria from Merck and Co. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

While the proliferation of data-driven omics technologies has continued to accelerate, methods of identifying relationships among large-scale changes from omics experiments have stagnated. It is therefore imperative to develop methods that can identify key mechanisms among one or more omics experiments in order to advance biological discovery. To solve this problem, here we describe the network-based algorithm MENTOR - Multiplex Embedding of Networks for Team-Based Omics Research. We demonstrate MENTOR's utility as a supervised learning approach to successfully partition a gene set containing multiple ontological functions into their respective functions. Subsequently, we used MENTOR as an unsupervised learning approach to identify important biological functions pertaining to the host genetic architectures in Populus trichocarpa associated with microbial abundance of multiple taxa. Moreover, as open source software designed with scientific teams in mind, we demonstrate the ability to use the output of MENTOR to facilitate distributed interpretation of omics experiments.

With the increasing use of infotainment systems in vehicles, secondary tasks requiring executive demand may increase crash risk, especially for young drivers. Naturalistic driving data were examined to determine if secondary tasks with increasing executive demand would result in increasing crash risk. Data were extracted from the Second Strategic Highway Research Program Naturalistic Driving Study, where vehicles were instrumented to record driving behavior and crash/near-crash data. executive and visual-manual tasks paired with a second executive task (also referred to as dual executive tasks) were compared to the executive and visual-manual tasks performed alone. Crash/near-crash odds ratios were computed by comparing each task condition to driving without the presence of any secondary task. Dual executive tasks resulted in greater odds ratios than those for single executive tasks. The dual visual-manual task odds ratios did not increase from single task odds ratios. These effects were only found in young drivers. The study shows that dual executive secondary task load increases crash/near-crash risk in dual task situations for young drivers. Future research should be conducted to minimize task load associated with vehicle infotainment systems that use such technologies as voice commands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

ABSTRACT: Purpose: Emergency department (ED) visits for suicidal ideation and self-harm are more prevalent in autistic than non-autistic youth. However, providers are typically offered insufficient guidance for addressing suicide risk in autistic youth, likely impacting confidence and care., Methods: In this pilot study, we conducted semi-structured interviews with 17 key members of the autism community (i.e., autistic youth with a history of suicidality, caregivers of autistic youth with a history of suicidality, autism specialist clinicians, ED clinicians) to inform the development of recommendations for modifying ED care for autistic patients, with a focus on suicide risk screening and management., Results: Participants reported on challenges they encountered receiving or providing care and/or recommendations for improving care. Participant perspectives were aligned, and four main categories emerged: accounting for autism features, connection and youth engagement in care, caregiver and family involvement, and service system issues., Conclusion: As research continues in the development of autism-specific suicide risk assessment tools and management strategies, it is essential we better equip providers to address suicide risk in autistic patients, particularly in ED settings., (© 2024. The Author(s).)

Background Sports concussion (SC) management guidelines have recently been updated. A key focus is the emphasis on rest (immediately postinjury) followed by gradual resumption of activity (active recovery). This study aimed to explore community views on SC management and compared these with the guidelines. Methods A total of 157 volunteers completed an online SC survey, including listing three pieces of advice for a concussed person immediately postinjury, and after 2weeks (subacute). Quantitative data were statistically compared, and qualitative data underwent content analysis. Results Almost all participants offered different immediate versus subacute advice; however, rest featured highly at both timepoints. Commonly expressed themes, consistent with guidelines were immediate rest; safety and reinjury prevention; and symptom monitoring. Two themes were identified in the community advice with limited emphasis in the guidelines: general health advice and psychological and social support. Expert clinical assessment was not always identified in community advice. Conclusion Community members hold some views that align with expert advice for SC, particularly the importance of immediate postinjury rest. However, there is scope to grow public awareness of some recommended practices, including expert clinical assessment following injury and when to engage in active recovery.

Chronic pain is a common problem, with more than one-fifth of adult Americans reporting pain daily or on most days. It adversely affects the quality of life and imposes substantial personal and economic costs. Efforts to treat chronic pain using opioids had a central role in precipitating the opioid crisis. Despite an estimated heritability of 25-50%, the genetic architecture of chronic pain is not well-characterized, in part because studies have largely been limited to samples of European ancestry. To help address this knowledge gap, we conducted a cross-ancestry meta-analysis of pain intensity in 598,339 participants in the Million Veteran Program, which identified 126 independent genetic loci, 69 of which are new. Pain intensity was genetically correlated with other pain phenotypes, level of substance use and substance use disorders, other psychiatric traits, education level and cognitive traits. Integration of the genome-wide association studies findings with functional genomics data shows enrichment for putatively causal genes (n = 142) and proteins (n = 14) expressed in brain tissues, specifically in GABAergic neurons. Drug repurposing analysis identified anticonvulsants, β-blockers and calcium-channel blockers, among other drug groups, as having potential analgesic effects. Our results provide insights into key molecular contributors to the experience of pain and highlight attractive drug targets., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Road trauma is a leading cause of death and disability for young Australians (15-24 years). Young adults are overrepresented in crashes due to sleepiness, with two-thirds of their fatal crashes attributed to sleepy driving. This trial aims to examine the effectiveness of a sleep extension and education program for improved road safety in young adults., Methods: Young adults aged 18-24 years (n = 210) will be recruited for a pragmatic randomised controlled trial employing a placebo-controlled, parallel-groups design. The intervention group will undergo sleep extension and receive education on sleep, whereas the placebo control group will be provided with information about diet and nutrition. The primary outcomes of habitual sleep and on-road driving performance will be assessed via actigraphy and in-vehicle accelerometery. A range of secondary outcomes including driving behaviours (driving simulator), sleep (diaries and questionnaire) and socio-emotional measures will be assessed., Discussion: Sleep is a modifiable factor that may reduce the risk of sleepiness-related crashes. Modifying sleep behaviour could potentially help to reduce the risk of young driver sleepiness-related crashes. This randomised control trial will objectively assess the efficacy of implementing sleep behaviour manipulation and education on reducing crash risk in young adult drivers., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Although sex determination is ubiquitous in vertebrates, mechanisms of sex determination vary from environmentally to genetically influenced. In vertebrates, genetic sex determination is typically accomplished with sex chromosomes. Groups like mammals maintain conserved sex chromosome systems, while sex chromosomes in most vertebrate clades are not conserved across similar evolutionary timescales. One group inferred to have an evolutionarily stable mode of sex determination is Anguimorpha, a clade of charismatic taxa including monitor lizards, Gila monsters, and crocodile lizards. The common ancestor of extant anguimorphs possessed a ZW system that has been retained across the clade. However, the sex chromosome system in the endangered, monotypic family of crocodile lizards (Shinisauridae) has remained elusive. Here, we analyze genomic data to demonstrate that Shinisaurus has replaced the ancestral anguimorph ZW system on LG7 with a novel ZW system on LG3. The linkage group, LG3, corresponds to chromosome 9 in chicken, and this is the first documented use of this syntenic block as a sex chromosome in amniotes. Additionally, this ~1 Mb region harbors approximately 10 genes, including a duplication of the sex-determining transcription factor, Foxl2, critical for the determination and maintenance of sexual differentiation in vertebrates, and thus a putative primary sex-determining gene for Shinisaurus., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE). All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Modifying gut bacteria in children with autism may influence behaviour, with potential to improve family functioning. We conducted a randomised controlled trial to assess the effect of prebiotics on behaviour, gastrointestinal symptoms and downstream effects on parental quality of life., Method: Children with autism (4-10yrs) were randomised to 2.4 g/d of prebiotic (GOS) or placebo for six weeks. Pre and post stools samples were collected, and validated questionnaires used to measure change in social and mealtime behaviours, GI symptoms and pQOL. Linear mixed models evaluated group differences for behavioural variables, and Mann Whitney U tests were used to compare change between-groups for GI symptoms, differential abundance of genera and alpha diversity of the microbiome., Results: Thirty-three parent-child dyads completed the trial. No group difference was seen for behavioural variables but both groups improved significantly from baseline. There was a medium effect size between groups for GI symptoms (d = 0.47) and pQOL (d = 0.44) driven by greater improvements in the prebiotic group. Bifidobacterium increased threefold following prebiotics (1.4-5.9%, p < 0.001) with no change in controls. Supplements were well tolerated, compliance with dose 94%., Conclusion: Prebiotics modify levels of Bifidobacterium and prove well tolerated but in this instance, resulted in only marginal effects on GI symptoms and pQOL. A larger sample of children with more severe symptoms could help to determine the potential of prebiotics in autism., Trial Registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12619000615189 ., (© 2024. The Author(s).)

The work of the Gulf War Illness (GWI) Consortium and that of basic and clinical researchers across the USA have resulted in a better understanding in recent years of the pathological basis of GWI, as well as of the mechanisms underlying the disorder. Among the most concerning symptoms suffered by veterans with GWI are cognitive decrements including those related to memory functioning. These decrements are not severe enough to meet dementia criteria, but there is significant concern that the mild cognitive impairment of these veterans will progress to dementia as they become older. Recent studies on GWI using human brain organoids as well as a rat model suggest that one potential cause of the cognitive problems may be elevated levels of tau in the brain, and this is supported by high levels of tau autoantibodies in the blood of veterans with GWI. There is urgency in finding treatments and preventive strategies for these veterans before they progress to dementia, with added value in doing so because their current status may represent an early phase of tauopathy common to many neurodegenerative diseases., (© 2023 Wiley Periodicals LLC.)

Cardinal features of lupus include elevated B cell activation and autoantibody production with a female sex preponderance. We quantified interactions of sex and genetic variation on the development of autoimmune B-cell phenotypes and autoantibodies in the BXD2 murine model of lupus using a cohort of backcrossed progeny (BXD2 x C57BL/6J) x BXD2. Sex was the key factor leading to increased total IgG, IgG2b, and autoantibodies. The percentage of T-bet + CD11c + IgD + activated naive B cells (aNAV) was higher in females and was associated with increased T-bet + CD11c + IgD - age-related B cells, Fas + GL7 + germinal center B cells, Cxcr5 - Icos + peripheral T-helper cells, and Cxcr5 + Icos + follicular T-helper cells. IFN-β was elevated in females. Variation in aNAV cells was mapped to Chr 7 in a locus that shows significant interactions between the female sex and heterozygous B/D variant. Our results suggest that activation of naive B cells forms the basis for the female-predominant development of autoantibodies in lupus-susceptible BXD2 mice., Competing Interests: Declaration of Competing Interest The Authors declare that there is no conflict of interest., (Published by Elsevier Inc.)

This research is an integrative review of the literature on social factors in TBI outcomes. It examines how such factors have been framed in TBI models, the social experience of people post-injury, and the evidence for effective social interventions. Evidence suggests that even when physical functioning has improved after injury, there is a lingering social distress that leaves individuals isolated and functionally impaired. A novel hypothesis is proposed to explain why these difficulties persist. This hypothesis draws from existing biopsychosocial models of TBI recovery, including those prominent in neuropsychology. It is argued that the social component of several TBI outcome models is too narrowly defined. This potentially has the effect of focusing efforts on the individual and their social skills or abilities as opposed to the seeking improvements at the level of the community. Evidence for and against this hypothesis is considered. This evaluation supports the idea that TBI outcomes are subject to a wider range of post injury social factors than is typically recognized, and that these factors are dynamic rather than static. Inspired by this hypothesis, this review proposes that social interventions for TBI should be adjusted to suit the stage of recovery.

Polyploid cells contain more than two copies of each chromosome. Polyploidy has important roles in development, evolution, and tissue regeneration/repair, and can arise as a programmed polyploidization event or be triggered by stress. Cancer cells are often polyploid. C. elegans nematodes are typically diploid, but stressors such as heat shock and starvation can trigger the production of tetraploid offspring. In this study, we utilized a recently published protocol to generate stable tetraploid strains of C. elegans and compared their physiological traits and sensitivity to two DNA-damaging chemotherapeutic drugs, cisplatin and doxorubicin. As prior studies have shown, tetraploid worms are approximately 30% longer, shorter-lived, and have a smaller brood size than diploids. We investigated the reproductive defect further, determining that tetraploid worms have a shorter overall germline length, a higher rate of germ cell apoptosis, more aneuploidy in oocytes and offspring, and larger oocytes and embryos. We also found that tetraploid worms are modestly protected from growth delay from the chemotherapeutics but are similarly or more sensitive to reproductive toxicity. Transcriptomic analysis revealed differentially expressed pathways that may contribute to sensitivity to stress. This study reveals phenotypic consequences of whole-animal tetraploidy that make C. elegans an excellent model for ploidy differences., (© 2023. Springer Nature Limited.)

Background: Lung cancer resection is associated with high rates of prolonged hospital stay. It is presumed that preconditioning with aerobic exercise can shorten the postoperative duration of hospital stay, but this has not yet been demonstrated in trials after lung cancer surgery. The aim of this study was to perform a RCT to determine whether Move For Surgery (MFS), a home-based and wearable technology-enhanced preconditioning program before lung cancer surgery, is associated with a lower incidence of prolonged hospital stay when compared to usual preoperative care., Methods: Patients undergoing lung resection for early-stage non-small cell lung cancer were enrolled before surgery into this blinded, single-site RCT, and randomized to either the MFS or control group in a 1 : 1 ratio. Patients in the MFS group were given a wearable activity tracker, and education about deep breathing exercises, nutrition, sleep hygiene, and smoking cessation. Participants were motivated/encouraged to reach incrementally increasing fitness goals remotely. Patients in the control group received usual preoperative care. The primary outcome was the difference in proportion of patients with hospital stay lasting more than 5 days between the MFS and control groups., Results: Of 117 patients screened, 102 (87.2 per cent) were eligible, enrolled, and randomized (51 per trial arm). The majority (95 of 102, 93.1 per cent) completed the trial. Mean(s.d.) age was 67.2(8.8) years and there were 55 women (58 per cent). Type of surgery and rates of thoracotomy were not different between arms. The proportion of patients with duration of hospital stay over 5 days was 3 of 45 (7 per cent) in the MFS arm compared to 12 of 50 (24 per cent) in the control arm (P = 0.021)., Conclusion: MFS, a home-based and wearable technology-enhanced preconditioning program before lung cancer surgery, decreased the proportion of patients with a prolonged hospital stay. Registration number: NCT03689634 (http://www.clinicaltrials.gov)., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Epileptogenesis is characterized by intrinsic changes in neuronal firing, resulting in hyperactive neurons and the subsequent generation of seizure activity. These alterations are accompanied by changes in gene transcription networks, first with the activation of early-immediate genes and later with the long-term activation of genes involved in memory. Our objective was to engineer a promoter containing binding sites for activity-dependent transcription factors upregulated in chronic epilepsy (EpiPro) and validate it in multiple rodent models of epilepsy. First, we assessed the activity dependence of EpiPro: initial electrophysiology studies found that EpiPro-driven GFP expression was associated with increased firing rates when compared with unlabeled neurons, and the assessment of EpiPro-driven GFP expression revealed that GFP expression was increased ~150× after status epilepticus. Following this, we compared EpiPro-driven GFP expression in two rodent models of epilepsy, rat lithium/pilocarpine and mouse electrical kindling. In rodents with chronic epilepsy, GFP expression was increased in most neurons, but particularly in dentate granule cells, providing in vivo evidence to support the "breakdown of the dentate gate" hypothesis of limbic epileptogenesis. Finally, we assessed the time course of EpiPro activation and found that it was rapidly induced after seizures, with inactivation following over weeks, confirming EpiPro's potential utility as a gene therapy driver for epilepsy.

Objective: Existing TBI misconception measures are critiqued for failing to measure postinjury social experiences. This study developed a social subscale for the Common Misconceptions about TBI (CM-TBI) questionnaire for use in the general public., Methods: Seven experts independently review items drawn from the literature. Shortlisted items were administered online to 158 adults (aged ≥18 years; 51% postschool educated; 60% no TBI experience), the CM-TBI, and a measure of construct validity (a published TBI-adaptation of the Community Attitudes Towards the Mentally Ill; CAMI-TBI). One week later, the new items were redeployed ( n  = 46)., Results: Expert review and iterative correlations identified a 10-item social subscale (internal consistency, test-retest reliability, α's>.80). When added to the CM-TBI (ie. CM-TBI-II), the internal consistency was .71. The social subscale was significantly correlated with CAMI-TBI measures (p's <.05, r's > .3). There was no significant difference on the social subscale for education subgroups (school vs post-school, p  = 0.056) or previous TBI experience; but there was a difference for the CM-TBI-II (post-school>school; Cohen's d = 7.83, large effect)., Conclusion: This study found strong preliminary psychometric support for a new social subscale, administered as the CM-TBI-II. This subscale shows promise as a measure of misconceptions about social functioning post-TBI. The CM-TBI-II could support evaluations of programs aiming to improve social engagement and community participation for people with TBI.

Context: This study investigated individual sociocognitive factors from the theory of planned behavior and their relationship to exercise for postconcussion recovery., Design and Methods: Four hundred and fifty-nine Australian adults, two-thirds of whom had no concussion history (66%), completed an online survey of their beliefs and attitudes toward exercise for postconcussion recovery. Secondary questions evaluated program design features that could affect engagement (eg, session frequency)., Results: Structured equation modeling found that subjective norms were the strongest significant predictor of intention to participate in exercise for postconcussion recovery. Perceived behavioral control was also a significant predictor of intention to participate but to a lesser extent. Attitude did not predict participation intention. The design features identified as key were personalization and being supervised during the program., Conclusions: This study found that people's intention to participate in a program of exercise postconcussion recovery is shaped by individual psychological factors and identified program design features that could be adjusted for increased engagement. Program success could be maximized through strategies such as supporting individuals to have a stronger sense of control over their participation through the choice of session timing or frequency and harnessing the influence of significant others via supportive messaging from key professionals.

Introduction: Despite a recent global decrease in suicide rates, death by suicide has increased in the United States. It is therefore imperative to identify the risk factors associated with suicide attempts to combat this growing epidemic. In this study, we aim to identify potential risk factors of suicide attempt using geospatial features in an Artificial intelligence framework., Methods: We use iterative Random Forest, an explainable artificial intelligence method, to predict suicide attempts using data from the Million Veteran Program. This cohort incorporated 405,540 patients with 391,409 controls and 14,131 attempts. Our predictive model incorporates multiple climatic features at ZIP-code-level geospatial resolution. We additionally consider demographic features from the American Community Survey as well as the number of firearms and alcohol vendors per 10,000 people to assess the contributions of proximal environment, access to means, and restraint decrease to suicide attempts. In total 1,784 features were included in the predictive model., Results: Our results show that geographic areas with higher concentrations of married males living with spouses are predictive of lower rates of suicide attempts, whereas geographic areas where males are more likely to live alone and to rent housing are predictive of higher rates of suicide attempts. We also identified climatic features that were associated with suicide attempt risk by age group. Additionally, we observed that firearms and alcohol vendors were associated with increased risk for suicide attempts irrespective of the age group examined, but that their effects were small in comparison to the top features., Discussion: Taken together, our findings highlight the importance of social determinants and environmental factors in understanding suicide risk among veterans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (At least a portion of this work is authored by David W. Oslin, Jean C. Beckham and Nathan A. Kimbrel on behalf of the U.S. Government and as regards Dr Oslin, Dr. Beckham, Dr. Kimbrel and the U.S. Government, is not subject to copyright protection in the United States. Foreign and other copyrights may apply.)

Over a third of patients with temporal lobe epilepsy (TLE) are not effectively treated with current anti-seizure drugs, spurring the development of gene therapies. The injection of adeno-associated viral vectors (AAV) into the brain has been shown to be a safe and viable approach. However, to date, AAV expression of therapeutic genes has not been regulated. Moreover, a common property of antiepileptic drugs is a narrow therapeutic window between seizure control and side effects. Therefore, a long-term goal is to develop drug-inducible gene therapies that can be regulated by clinically relevant drugs. In this study, a first-generation doxycycline-regulated gene therapy that delivered an engineered version of the leak potassium channel Kcnk2 (TREK-M) was injected into the hippocampus of male rats. Rats were electrically stimulated until kindled. EEG was monitored 24/7. Electrical kindling revealed an important side effect, as even low expression of TREK M in the absence of doxycycline was sufficient to cause rats to develop spontaneous recurring seizures. Treating the epileptic rats with doxycycline successfully reduced spontaneous seizures. Localization studies of infected neurons suggest seizures were caused by expression in GABAergic inhibitory neurons. In contrast, doxycycline increased the expression of TREK-M in excitatory neurons, thereby reducing seizures through net inhibition of firing. These studies demonstrate that drug-inducible gene therapies are effective in reducing spontaneous seizures and highlight the importance of testing for side effects with pro-epileptic stressors such as electrical kindling. These studies also show the importance of evaluating the location and spread of AAV-based gene therapies in preclinical studies.

The intracellular cholesterol transporter NPC1 functions in late endosomes and lysosomes to efflux unesterified cholesterol, and its deficiency causes Niemann-Pick disease Type C, an autosomal recessive lysosomal disorder characterized by progressive neurodegeneration and early death. Here, we use single-nucleus RNA-seq on the forebrain of Npc1 -/- mice at P16 to identify cell types and pathways affected early in pathogenesis. Our analysis uncovers significant transcriptional changes in the oligodendrocyte lineage during developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. We identify upregulation of genes associated with neurogenesis and synapse formation in Npc1 -/- oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3. Npc1 -/- oligodendrocyte progenitor cells reproduce impaired maturation in vitro, and this phenotype is rescued by treatment with GSK-J4, a small molecule inhibitor of H3K27 demethylases. Moreover, mobilizing stored cholesterol in Npc1 -/- mice by a single administration of 2-hydroxypropyl-β-cyclodextrin at P7 rescues myelination, epigenetic marks, and oligodendrocyte gene expression. Our findings highlight an important role for NPC1 in oligodendrocyte lineage maturation and epigenetic regulation, and identify potential targets for therapeutic intervention., (© 2023. The Author(s).)

Objectives: The disclosure of an Alzheimer's disease diagnosis poses challenges for health care professionals, patients, and their families. Past research has shown that people favour disclosure, but it is uncertain if this situation has changed., Method: We used a cross-sectional online survey to explore disclosure preferences in a sample of young adults ( n  = 229; 66.7% aged 18 - 25 years, 79.5% Australian born). Factors contributing to preferences were also examined (knowledge, experience, close experience, age, relationship to diagnosis recipient). Established measures were used to assess knowledge (the Alzheimer's Disease Knowledge Test) and preferences (the Reasons for Wanting to Know Questionnaire)., Results: Most (95%) but not all participants favoured disclosure, whilst recognising as important at least one reason against it. Only age was a significant determinant of preferences (older people were more likely to prefer disclosure). Those against disclosure cited the fear of suicide as a key reason., Conclusion: The right to know remains a primary reason for preferring disclosure. Health care professionals should use pre-diagnostic interviewing to discuss overall preference and the underpinning reasons both for and against disclosure. Focus should be on developing a person-centred approach that responds to concerns, with further research to evaluate this approach.

Suicidal thoughts and behaviors (STB) and emergency department (ED) utilization are prevalent in autistic youth. The current study surveyed clinicians in a pediatric psychiatric ED to examine differences in attitudes on suicide-related care for autistic and non-autistic patient populations. While clinicians rated addressing STB in ASD as important and adaptations to care as necessary, less than half identified ASD as a suicide risk factor and confidence ratings were significantly lower for autistic patients. Previous ASD training predicted confidence and accounted for approximately 25% of the variance in confidence scores. Findings highlight the urgency to develop and disseminate ED clinician training, and address the lack of validated assessment tools, adapted suicide prevention practices, and evidence-based treatments for STB in autistic youth., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The COVID-19 pandemic led to unprecedented changes in care delivery across the pregnancy care continuum. Our primary objective with this research was to characterize the range of ways that the early months of the COVID-19 pandemic affected pregnancy, childbirth, and postpartum care experiences., Methods: Pregnant and recently pregnant patients (n = 20) from obstetrics and gynecology clinical sites associated with Massachusetts General Hospital were interviewed about their experiences with prenatal care, childbirth, and postpartum care during the first wave of the COVID-19 pandemic. Interview transcripts were analyzed for emergent themes., Results: This sample included 20 pregnant and postpartum people, including 11 individuals who tested positive for COVID-19 during pregnancy or postpartum and nine with suspected infection. The ways in which COVID-19 or suspected COVID-19 affected experiences of prenatal care, childbirth, and postpartum care were complex and varied. Three themes were identified across narratives of pregnancy, birth, and postpartum care: patient perceptions of diminished access to care, stigma due to COVID-19 infection, and limited capacity of providers to honor patient preferences., Conclusions: A better understanding of pregnant and recently pregnant people's experiences during the early months of the COVID-19 pandemic can inform infection control policies and clinical care delivery practices that are more congruent with the needs and values of pregnant, birthing, and postpartum people as institutions craft responses to future pandemics. Approaches that maximize meaningful access across the pregnancy care continuum, center patients' priorities within adapted care models, and honor patient preferences as much as possible are important aspects of an appropriate response to future waves of COVID-19 and other pandemics., (Copyright © 2022 Jacobs Institute of Women's Health, George Washington University. Published by Elsevier Inc. All rights reserved.)

Objective: Athletes perceive sports fans as a source of concussion nondisclosure pressure. Sports fans are exposed to injury depictions from the media that could lead them to underestimate its seriousness. This study examined the concussion knowledge of non-sports fans, sports fans, and wagering sports fans, as knowledge is a modifiable factor that can influence injury disclosure., Setting and Participants: A convenience sample of 443 Australian adults completed an online survey., Design: Cross-sectional., Main Measures: Self-rated and actual concussion knowledge (the Rosenbaum Concussion Knowledge and Attitudes Survey; RoCKAS)., Results: There was no significant difference in the concussion knowledge of self-identified sports ( n = 157) and non-sports ( n = 286) fans; but sports fans rated their knowledge as significantly higher than non-sports fans ( p < .05). Wagering sports fans ( n = 24) had significantly less concussion knowledge than non-wagering sports fans (η 2 = .03, small effect)., Discussion: Athletes who feel nondisclosure pressure from sports fans may be influenced by people with incomplete concussion knowledge, particularly wagering sports fans. Sports fans over-estimated their knowledge, and this could contribute to the nondisclosure pressure felt by athletes. Programmes to increase injury disclosure by athletes should take these factors into consideration.

Objective: This qualitative study aimed to identify the service and support needs of people with a recent history of traumatic brain injury (TBI) living in the community., Methods: A postal survey was sent to 662 people 6-18 months after hospital admission for a mild-to-severe TBI. The survey included an open-ended item ('wish-basket') for collecting ideas about important unmet needs., Results: Responses from 53 individuals were coded and processed using thematic analysis. Five themes ( n = 39) were identified, three of which were related to personal needs. These personal wishes were about being symptom-free, independent and emotionally supported by, and connected to, loved ones. The remaining themes were about the wished-for changes to the health system and society, such as wishing for health care continuity (as opposed to being abandoned), and for greater understanding and support by society., Conclusions: There is scope to improve the services and support for people living with TBI in the community. This includes reconsidering the way that discharge occurs, addressing the personal needs that remain when living in the community and promoting greater social awareness of TBI to counteract disadvantage.

Chemotherapy remains a mainstay in the treatment of many types of cancer even though it is associated with debilitating behavioral side effects referred to as "chemobrain," including difficulty concentrating and memory impairment. The predominant hypothesis in the field is that systemic inflammation drives these cognitive impairments, although the brain mechanisms by which this occurs remain poorly understood. Here, we hypothesized that microglia are activated by chemotherapy and drive chemotherapy-associated cognitive impairments. To test this hypothesis, we treated female C57BL/6 mice with a clinically-relevant regimen of a common chemotherapeutic, paclitaxel (6 i.p. doses at 30 mg/kg), which impairs memory of an aversive stimulus as assessed via a contextual fear conditioning (CFC) paradigm. Paclitaxel increased the percent area of IBA1 staining in the dentate gyrus of the hippocampus. Moreover, using a machine learning random forest classifier we identified immunohistochemical features of reactive microglia in multiple hippocampal subregions that were distinct between vehicle- and paclitaxel-treated mice. Paclitaxel treatment also increased gene expression of inflammatory cytokines in a microglia-enriched population of cells from mice. Lastly, a selective inhibitor of colony stimulating factor 1 receptor, PLX5622, was employed to deplete microglia and then assess CFC performance following paclitaxel treatment. PLX5622 significantly reduced hippocampal gene expression of paclitaxel-induced proinflammatory cytokines and restored memory, suggesting that microglia play a critical role in the development of chemotherapy-associated neuroinflammation and cognitive impairments. This work provides critical evidence that microglia drive paclitaxel-associated cognitive impairments, a key mechanistic detail for determining preventative and intervention strategies for these burdensome side effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

T-helper cytokines interferon gamma (IFNɣ), interleukin 17 (IL-17) and IL-10 impact systemic lupus erythematosus (SLE) directly and indirectly via modulation of autoAb production. We determined the separate and combined effects on clinical manifestations of SLE (N = 62). IFNɣ, IL-17 but not IL-10 were significantly elevated in patients with SLE. IFNɣ positively correlated with anti-DNA and anti-SSA. IL-17 positively correlated with anti-SSA and was significantly higher in patients with discoid rash and class V LN. IL-10 did not correlate with circulating autoantibodies but was significantly elevated in patients with LN. Patients with LN had elevated plasma levels of anti-DNA and anti-Sm/ribonuclear protein (RNP). Anti-Sm/RNP levels were decreased in patients with acute mucocutaneous manifestations, including photosensitivity and/or malar rash. The study provides critical insights into pathological mechanisms of LN, which could help guide future diagnoses and therapies., Competing Interests: Declaration of Competing Interest None. The authors declare that there is no conflict of interest., (Published by Elsevier Inc.)

Objective: Persistent postconcussion symptoms (PPCS) are challenging to diagnose. An improved diagnostic process could consider typical and atypical postconcussion symptoms. This study examined the structure of a modified Rivermead Post-concussion Symptoms Questionnaire (mRPQ) with both symptom types., Method: 298 adult volunteers were randomized into groups: honest responders, mild traumatic brain injury (mTBI) simulators (MS), and biased mTBI simulators (BMS). Both mTBI simulating groups were coached about mTBI and primed about the simulation context (compensation evaluation). The BMS group was also encouraged to bias (exaggerate) symptoms. The participants completed an online battery of tests, including the mRPQ., Results: An exploratory factor analysis of the mRPQ (full sample) revealed a three-factor solution, including a separate dimension for atypical symptoms (all item loadings >0.45, ~4% of explained variance). The overall and group analyses of the standard RPQ items (typical symptoms) found a one- or two-factor solution, as did the analyses of atypical symptoms., Conclusions: Consistent with prior RPQ research, a unidimensional or bifactor structure was measurable from standard RPQ symptoms. Whilst this study did not find support for domain-level symptom scores for either typical or atypical symptoms, the findings support the use of an overall atypical symptoms score.

Varicose veins represent a common cause of cardiovascular morbidity, with limited available medical therapies. Although varicose veins are heritable and epidemiologic studies have identified several candidate varicose vein risk factors, the molecular and genetic basis remains uncertain. Here we analyzed the contribution of common genetic variants to varicose veins using data from the Veterans Affairs Million Veteran Program and four other large biobanks. Among 49,765 individuals with varicose veins and 1,334,301 disease-free controls, we identified 139 risk loci. We identified genetic overlap between varicose veins, other vascular diseases and dozens of anthropometric factors. Using Mendelian randomization, we prioritized therapeutic targets via integration of proteomic and transcriptomic data. Finally, topological enrichment analyses confirmed the biologic roles of endothelial shear flow disruption, inflammation, vascular remodeling and angiogenesis. These findings may facilitate future efforts to develop nonsurgical therapies for varicose veins., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: Response distortions in the reporting of postconcussion symptoms can occur for many reasons. The Rivermead Post-concussion Symptoms Questionnaire (RPQ) was recently modified to include an embedded symptom validity indicator to test for atypical symptoms. The present study used a simulation design to investigate the psychometric properties of the modified RPQ (mRPQ)., Method: 298 adult volunteers were randomised into three groups: honest responding (Controls, C) who reported actual, current symptoms; mild traumatic brain injury (mTBI) simulators (MS) who role played being injured, and; biased mTBI simulators (BMS) who role played being injured and were asked to bias (exaggerate) their response. The MS and BMS participants received instructions to support the simulation. All participants completed the mRPQ and a modified Neurobehavioral Symptom Inventory (mNSI)., Results: A 2 × 3 mixed ANOVA with one within-group variable (Symptom type: Standard or Atypical) and one between-group variable (Instruction type: C, MS, BMS) found a significant two-way interaction (p < .05, ηp2 = .08)., Conclusions: The BMS group had score elevations for both standard and atypical postconcussion symptoms; therefore, both symptom types should be considered when evaluating for biased responding. The mRPQ has promising psychometric properties and should be further developed.

For plants, distinguishing between mutualistic and pathogenic microbes is a matter of survival. All microbes contain microbe-associated molecular patterns (MAMPs) that are perceived by plant pattern recognition receptors (PRRs). Lysin motif receptor-like kinases (LysM-RLKs) are PRRs attuned for binding and triggering a response to specific MAMPs, including chitin oligomers (COs) in fungi, lipo-chitooligosaccharides (LCOs), which are produced by mycorrhizal fungi and nitrogen-fixing rhizobial bacteria, and peptidoglycan in bacteria. The identification and characterization of LysM-RLKs in candidate bioenergy crops including Populus are limited compared to other model plant species, thus inhibiting our ability to both understand and engineer microbe-mediated gains in plant productivity. As such, we performed a sequence analysis of LysM-RLKs in the Populus genome and predicted their function based on phylogenetic analysis with known LysM-RLKs. Then, using predictive models, molecular dynamics simulations, and comparative structural analysis with previously characterized CO and LCO plant receptors, we identified probable ligand-binding sites in Populus LysM-RLKs. Using several machine learning models, we predicted remarkably consistent binding affinity rankings of Populus proteins to CO. In addition, we used a modified Random Walk with Restart network-topology based approach to identify a subset of Populus LysM-RLKs that are functionally related and propose a corresponding signal transduction cascade. Our findings provide the first look into the role of LysM-RLKs in Populus -microbe interactions and establish a crucial jumping-off point for future research efforts to understand specificity and redundancy in microbial perception mechanisms., Competing Interests: None. The funding agency [DOE BER] had no involvement on the study design, data collection and analysis or interpretation of results reported here., (© 2023 The Authors.)

Robotic-assisted thoracoscopic surgery (RTS) is safe and effective, but is associated with high capital and operating costs that are not reimbursed by the Canadian government. Currently, patients have access to RTS only when it is supported by research or philanthropic funds. In a recent study, we assessed the extent of patient-reported satisfaction with RTS, whether patients would have been willing to pay out of pocket for it, and what factors were associated with patients' willingness to pay. Many patients (290 of 411 [70.56%]) stated that they would have paid the additional $2000 to supplement the government health care coverage to have access to RTS. Factors found to be significantly associated with participants' willingness to pay were an annual income of $60 000 or more ( p = 0.034), private insurance coverage ( p = 0.007), overall experience with RTS rated as 8 or higher out of 10 ( p < 0.001), and overall postoperative postdischarge experience rated as satisfying or very satisfying ( p = 0.004)., Competing Interests: Competing interests: W. Hanna reports a grant and stock or stock options from Intuitive Surgical, consulting fees from AstraZeneca, and honoraria from Minogue Medical. He also participates on the advisory board of Roche/Genentech. No other competing interests were declared., (© 2022 CMA Impact Inc. or its licensors.)

Objectives: Increasing concussion knowledge could contribute to improving injury outcomes. Understanding the predictors of concussion knowledge could determine the areas of educational need. This study examined whether individual factors, prior brain injury, prior concussion education, and contact-sports participation predicted concussion knowledge., Design and Setting: Cross-sectional study with recruitment of community volunteers., Participants: An online survey was completed by 525 adults, 443 of whom provided useable responses., Main Measures: The respondents provided background information and completed the Concussion Knowledge Index from the Rosenbaum Concussion Knowledge and Attitudes Survey (RoCKAS)., Results: On average, the participants answered 19.8 out of 25 items correctly. A multiple regression model with demographic, injury, and sport-related variables did not significantly predict concussion knowledge., Conclusion: This community sample had higher than expected concussion knowledge (restricted range), but some important misconceptions were still present. The model reflecting a combination of self-reported factors did not predict concussion knowledge. The implications for concussion education are discussed, including the need for targeted education to address specific misconceptions., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)