Zebrafish models of candidate human epilepsy-associated genes provide evidence of hyperexcitability.

Hundreds of novel candidate human epilepsy-associated genes have been identified thanks to advancements in next-generation sequencing and large genome-wide association studies, but establishing genetic etiology requires functional validation. We generated a list of >2200 candidate epilepsy-associated genes, of which 81 were determined suitable for the generation of loss-of-function zebrafish models via CRISPR/Cas9 gene editing. Of those 81 crispants, 48 were successfully established as stable mutant lines and assessed for seizure-like swim patterns in a primary F2 screen. Evidence of seizure-like behavior was present in 5 (arfgef1, kcnd2, kcnv1, ubr5, wnt8b) of the 48 mutant lines assessed. Further characterization of those 5 lines provided evidence for epileptiform activity via electrophysiology in kcnd2 and wnt8b mutants. Additionally, arfgef1 and wnt8b mutants showed a decrease in the number of inhibitory interneurons in the optic tectum of larval animals. Furthermore, RNAseq revealed convergent transcriptional abnormalities between mutant lines, consistent with their developmental defects and hyperexcitable phenotypes. These zebrafish models provide strongest experimental evidence supporting the role of ARFGEF1, KCND2, and WNT8B in human epilepsy and further demonstrate the utility of this model system for evaluating candidate human epilepsy genes.

Context-dependent environmental associations with endometrial cancer histotype and genotype.

OBJECTIVE: MLH1 loss due to MLH1 methylation, detected during Lynch syndrome screening, is one of the most common molecular changes in endometrial cancer. It is well established that environmental influences such as nutritional state can impact gene methylation, both in the germline and in a tumor. In colorectal cancer and other cancer types, aging is associated with changes in gene methylation. The objective of this study was to determine if there was an association between aging or body mass index on MLH1 methylation in sporadic endometrial cancer. METHODS: A retrospective review of patients with endometrial cancer was performed. Tumors were screened for Lynch syndrome via immunohistochemistry, with MLH1 methylation analysis performed when there was loss of MLH1 expression. Clinical information was abstracted from the medical record. RESULTS: There were 114 patients with mismatch repair deficient tumors associated with MLH1 methylation, and 349 with mismatch repair proficient tumors. Patients with mismatch repair deficient tumors were older than those whose tumors were proficient. Mismatch repair deficient tumors had a higher incidence of lymphatic/vascular space invasion. When stratified by endometrioid grade, associations with body mass index and age became apparent. Patients with endometrioid grades 1 and 2 tumors and somatic mismatch repair deficiency were significantly older, but body mass index was comparable with that of the mismatch repair intact group. For endometrioid grade 3, patient age did not significantly vary between the somatic mismatch repair deficient group and the mismatch repair intact group. In contrast, body mass index was significantly higher in the patients with grade 3 tumors with somatic mismatch repair deficiency. CONCLUSION: The relationship of MLH1 methylated endometrial cancer with age and body mass index is complex and somewhat dependent on tumor grade. As body mass index is modifiable, it is possible that weight loss induces a 'molecular switch' to alter the histologic characteristics of an endometrial cancer.

Trauma-Informed Home Visiting Models in Public Health Nursing: An Evidence-Based Approach.

Traumatic experiences can have significant health effects, particularly when they are experienced during childhood. Structural determinants of health including environmental disasters and limited access to mental health services and affordable housing can contribute additional stress for parents with a personal history of childhood adversity. These factors can directly affect their children, contributing to intergenerational trauma. Pregnant people and families with young children are often referred to public health nursing maternal and child home visiting (HV) programs when there are concerns about historical or evolving childhood trauma. The strict eligibility and participation requirements of existing evidence-based maternal and child HV programs can exclude families that have experienced or are experiencing childhood trauma and its effects and can limit innovation by public health nurses, a hallmark of the field. Therefore, we advocate and describe the implementation of the Trauma Informed Approach in Public Health Nursing (TIA PHN) model, which incorporates a trauma-informed approach into a traditional maternal and child HV program in 3 California counties. TIA PHN, which began enrollment in March 2021, involves public health nurses and community health workers and integrates program evaluations in pursuit of evidence-based status. (Am J Public Health. 2022;112(S3):S298-S305. https://doi.org/10.2105/AJPH.2022.306737).

Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish.

Epilepsy is one of the most common neurological disorders. The X-linked gene PCDH19 is associated with sporadic and familial epilepsy in humans, typically with early-onset clustering seizures and intellectual disability in females but not in so-called 'carrier' males, suggesting that mosaic PCDH19 expression is required to produce epilepsy. To characterize the role of loss of PCDH19 function in epilepsy, we generated zebrafish with truncating pcdh19 variants. Evaluating zebrafish larvae for electrophysiological abnormalities, we observed hyperexcitability phenotypes in both mosaic and non-mosaic pcdh19+/- and pcdh19-/- mutant larvae. Thus, we demonstrate that the key feature of epilepsy-network hyperexcitability-can be modeled effectively in zebrafish, even though overt spontaneous seizure-like swim patterns were not observed. Further, zebrafish with non-mosaic pcdh19 mutation displayed reduced numbers of inhibitory interneurons suggesting a potential cellular basis for the observed hyperexcitability. Our findings in both mosaic and non-mosaic pcdh19 mutant zebrafish challenge the prevailing theory that mosaicism governs all PCDH19-related phenotypes and point to interneuron-mediated mechanisms underlying these phenotypes.

Biocatalytic Asymmetric Construction of Secondary and Tertiary Fluorides from ß-Fluoro-α-Ketoacids.

Fluorine is a critical element for the design of bioactive compounds, driving advances in selective and sustainable fluorination. However, stereogenic tertiary fluorides pose a synthetic challenge and are thus present in only a few approved drugs (fluticasone, solithromycin, and sofosbuvir). The aldol reaction of fluorinated donors provides an atom-economical approach to asymmetric C-F motifs via C-C bond formation. We report that the type II pyruvate aldolase HpcH and engineered variants perform addition of ß-fluoro-α-ketoacids (including fluoropyruvate, ß-fluoro-α-ketobutyrate, and ß-fluoro-α-ketovalerate) to diverse aldehydes. The reactivity of HpcH towards these fluoro-donors grants access to enantiopure secondary or tertiary fluorides. In addition to representing the first synthesis of tertiary fluorides via biocatalytic carboligation, the afforded products could improve the diversity of fluorinated building blocks and enable the synthesis of fluorinated drug analogs.

Maculopathy Masquerading as Migraine.

We describe a case of a 23-year-old Caucasian woman with a background history of migraines who presented with bilateral paracentral scotomata. The ophthalmoscopy and MRI head were originally thought to be normal, and the scotomata were attributed to be of migrainous origin: a persistent negative aura. However, persistence of her symptoms prompted further specialist review 10 months later, at which time subtle bilateral perifoveal changes were noted, which had been apparent but overlooked at the initial assessment. Near-infrared reflectance imaging enabled better visualization of the lesions, which were apparent prior to any abnormalities on clinical examination. Spectral-domain optical coherence tomography revealed the early findings of hyperreflectivity in the outer nuclear and outer plexiform layers characteristic of acute macular neuroretinopathy. Our case aims to emphasize the importance of scrutinising ancillary tests of the macula in patients presenting with scotomata or atypical migraine symptoms, and to caution clinicians against diagnosing migraine with persistent negative aura without these investigations.

A randomized controlled trial of exercise on augmenting the effects of cognitive remediation in persons with severe mental illness.

BACKGROUND: Preliminary evidence suggests that aerobic exercise may augment the effects of cognitive remediation on improving cognitive functioning in severe mental illness. It has also been hypothesized that increases in cognitive functioning associated with adding exercise are mediated by increases in brain derived neurotrophic factor (BDNF). However, rigorous controlled trials are lacking. METHODS: A randomized controlled trial was conducted to explore whether adding a 30-h aerobic exercise program over 10 weeks to an equally intensive cognitive remediation program (CR + E) improved cognitive functioning more than cognitive remediation alone (CR-Only). Thirty-four participants with schizophrenia or bipolar disorder were randomly assigned to CR + E or CR-Only, and cognitive functioning was assessed at baseline and post-treatment. Total and mature BDNF were measured in blood serum at baseline, Week-5 pre- and post-exercise, and Week-10 pre- and post-exercise. RESULTS: Participants in both conditions had high levels of engagement in the interventions and improved significantly in cognitive functioning, but did not differ in amount of cognitive change. The groups also did not differ in changes in BDNF from pre-to post-exercise at Weeks 5 or 10, nor in resting BDNF levels. Exploratory analyses indicated that higher body mass index (BMI) significantly predicted attenuated improvement in cognitive functioning for both groups. DISCUSSION: Exercise did not augment the effects of cognitive remediation in persons with severe mental illness, possibly because the cognitive remediation program resulted in strong gains in cognitive functioning. Moderate aerobic exercise does not appear to reliably increase BDNF levels in persons with severe mental illness. CLINICALTRIALS. GOV IDENTIFIER: NCT02326389.

Scaling Up Behavioral Skills Training: Effectiveness of Large-Scale and Multiskill Trainings.

We used behavioral skills training (BST) to teach multiple skills to 2 cohorts of 18 participants. BST consisted of the standard 4 components: (a) didactic instruction, (b) modeling, (c) role-play, and (d) feedback, modified to be delivered in a large-group format. All components were provided by 1 trainer, simultaneously to all participants, with peers delivering feedback during role-plays. Across 4 targeted skills (e.g., discrete-trial teaching), the average performance of Cohort 1 improved from less than 60% correct implementation in baseline to a performance of between 85% and 100% correct, across participants, following BST. We used social validity data collected from Cohort 1 to modify the length of instruction across skills for Cohort 2. BST was similarly effective for Cohort 2, with a decrease in the additional training required for trainees to demonstrate the skill in a novel role-play scenario or with a client. Implications for effectively scaling up BST are discussed.

Acute kidney injury, stroke and death after cardiopulmonary bypass surgery: the role of perfusion flow and pressure.

INTRODUCTION: Acute kidney injury after cardiopulmonary bypass surgery is associated with morbidity and mortality. This study aims to evaluate the role of low perfusion flow and pressure in the development of cardiopulmonary bypass-associated acute kidney injury, stroke and death, using multicentre registry data. METHODS: We identified patients from the Australian and New Zealand Collaborative Perfusion Registry who underwent coronary artery bypass grafting and/or valvular surgery between 2008 and 2018. Primary predictor variables were the length of time the perfusion flow was <1.6 L/min/m2 and the length of time perfusion pressure was < 50mmHg. The primary outcome was new postoperative acute kidney injury defined by the risk-injury-failure-loss-end stage criteria. Secondary outcomes were stroke and in-hospital death. The influence of perfusion flow and pressure during cardiopulmonary bypass on the primary and secondary outcomes was estimated using separate multivariate models. RESULTS: A total of 16,356 patients were included. The mean age was 66 years and 75% were male. Acute kidney injury was observed in 1,844 patients (11%), stroke in 204 (1.3%) and in-hospital death in 286 (1.8%). Neither the duration of the time spent for perfusion flow (<1.6 L/minute/m2) nor the duration of the time spent for perfusion pressure (<50 mmHg) was associated with postoperative acute kidney injury, stroke or death in adjusted models. CONCLUSIONS: Neither low perfusion pressure nor low perfusion flow during cardiopulmonary bypass were predictive of postoperative acute kidney injury, stroke or death.

Membership Trends in the Academic Pediatric Association From 2009 to 2018.

OBJECTIVE: To describe changes in the racial and ethnic diversity of the membership of a national academic health professional organization, the Academic Pediatric Association (APA) from 2009 to 2018. METHODS: Administrative data from the APA was used for the study. Our sample was limited to dues-paying members of the APA with complete profile information. Data on race/ethnicity was collected by self-report and categorized as White, Hispanic, Black, Asian, or other. Gender was obtained by self-report (male/female). Membership type included physician, non-physician, or trainee and was provided by self-report. Age was calculated by subtracting the dues year from the year of birth. Descriptive statistics were used. Log-linear models were used to describe changes in membership race/ethnicity and expressed as relative risk. RESULTS: Three thousand one hundred and ninety-six unique individuals were included. Enrollment in the APA increased from 1429 in 2009 to 1803 in 2018. Females represented 68% of the sample. Six percent of the sample identified as Black, 5% as Hispanic, 12% as Asian, and 74% as White. Using log-linear models, the proportion of members identifying as Black increased from 4% to 6% (P < .001), Asian 8% to 13% (P < .001) and Hispanic increased 4% to 5% (P = .17). CONCLUSIONS: The APA has increased the representation of underrepresented racial and ethnic minorities in medicine within its membership. The APA and other academic pediatric professional organizations, can build on these current trends by continuing to invest in programming focused on increasing racial/ethnic minority groups underrepresented in medicine.

COVID Intensive Care Unit Through the Eyes of Ophthalmologists.

Description The disproportionate impact of COVID on the mortality and morbidity of people of black, Asian and minority ethnic (BAME) backgrounds has been recognised and is under investigation. Here we present a different impact: that on the psyche. As three doctors of BAME heritage, we shared an experience of being redeployed from ophthalmology to the COVID Intensive Care Unit. We share our reflections on the experience and lessons learned.

Improving body functions through participation in community activities among young people with physical disabilities.

AIM: To examine the impact of engagement in a self-chosen community-based activity on three relevant body functions (motor, cognitive, and affective) as well as on the performance of the selected activity. METHOD: An individual-based interrupted time series design with multiple baselines was used. Seven young people (four males, three females) aged 15 to 25 years (median 18y; interquartile range 17-20y) with physical disabilities participated in an 8-week community activity of choice (e.g. swimming, playing piano). Change in three relevant body functions, underpinning the specific chosen activity, including motor (e.g. Functional Reach Test, Trunk Impairment Scale, dynamometers), cognitive and affective (Behavior Assessment System for Children), as well as activity performance (Canadian Occupational Performance Measure) were measured repeatedly, providing individual outcome trajectories. Linear and mixed-effects models were used. RESULTS: Significant improvements in at least one aspect of motor function (6 out of 6), cognition (3 out of 3), affect (5 out of 7), and performance (7 out of 7) were observed. Specifically, the intervention had a moderate to large effect on hyperactivity (1.45, 95% confidence interval [CI] 1.0-1.9) with a smaller effect on anxiety (0.21, 95% CI 0.10-0.32) and inadequacy (0.21, 95% CI 0.02-0.39). Concurrently, a notable effect size for activity performance (4.61, 95% CI 0.76-8.46) was observed. Average change across motor outcomes was substantial (3.7 SDs from baseline), yet non-significant. INTERPERTATION: Findings provide initial evidence of the benefits resulting from participation-based interventions, emphasizing the merit of meaningful 'real-life' young people-engaging therapy. WHAT THIS PAPER ADDS: Participation-based interventions can impact body-function level outcomes. Significant improvements in the performance of chosen activities were observed. Significant improvements were also seen in cognitive and affective body functions. Improvements in motor-related outcomes were substantial but not statistically significant.

Trauma informed public health nursing visits to parents and children.

Adverse Childhood Experiences (ACEs) research has demonstrated a strong correlation between a traumatic childhood and poor health and social status in adulthood. Maternal/child Public Health Nursing (PHN) home visiting teams frequently encounter families experiencing trauma, thus offering a unique opportunity to assist parents in recognizing the potential harm such stress may have for their child. The Sonoma County Field Nursing team developed a trauma-informed model utilizing ACEs education in a self-reflective approach with parents to increase family resilience and reduce the risk for future childhood trauma. This paper presents the supporting research used to develop the trauma-informed approach and describes the execution of the model by the Sonoma County Field Nursing team.

Parkinson's Disease and Driving Cessation: a Journey Influenced by Anxiety.

OBJECTIVES: In addition to the motor and cognitive symptoms that people with Parkinson's disease (PD) typically experience, psychiatric symptoms such as anxiety are also commonly experienced by people with PD. The overall purpose of the current study was to explore driving and driving cessation for people with PD and their families. METHODS: A descriptive phenomenological approach was employed using semi-structured interviews and 34 interviews were conducted overall (22 participants with PD and 12 family members). RESULTS: Experiences of anxiety and worry that had an impact on driving and driving cessation arose from the data, and this article specifically captured the lived experience of anxiety with driving and driving cessation for people with PD and their families. CONCLUSIONS: Findings reveal that the experience of anxiety while driving, as well as anticipatory anxiety and/or worry related to driving cessation, affect the driving experiences and wellbeing of people with PD. CLINICAL IMPLICATIONS: Implications of the study findings are outlined and aim to provide information about the needs to enable future clinical directions to be developed.

Young people have their say: What makes a youth-friendly general practice?

BACKGROUND: The health of young people can be considered an indicator of the health of Australia's future population. To improve access to healthcare, the perspectives of adolescents on the design and delivery of services need to be championed. The objective of this study was to identify what young people in north-west Tasmania value when seeking healthcare at general practices. METHODS: The study was conducted at a single high school in rural Tasmania. Students aged 16-18 years were invited to participate in an electronic survey seeking their views and preferences for presenting to their general practitioner (GP). RESULTS: One hundred and fifty-five students, with a mean age of 17 years, were surveyed. GPs were the usual healthcare providers for 98.4% of participants, and 86% stated that they would like to discuss mental health, substance use and sexual health with their GP. DISCUSSION: GPs can improve access to care for young people through good communications skills and treating young people as young adults.

Towards a Competency-Based, Ethical, and Socially Valid Approach to the Supervision of Applied Behavior Analytic Trainees.

Competency-based supervision of trainees has recently come to the forefront of behavior analytic practice; however, there are minimal data to support the effectiveness of various supervision practices on trainee outcomes. Accordingly, this paper is intended to spark further discussion and research activity regarding the supervision of those seeking to become Board Certified Behavior Analysts (BCBA). We present a practice model and considerations for supervising applied behavior analytic trainees consistent with the Behavior Analyst Certification Board (BACB) Supervisor Training Curriculum Outline (Behavior Analyst Certification Board, 2012b), the Professional and Ethical Compliance Code for Behavior Analysts (Behavior Analyst Certification Board, 2014), and extant literature from behavior analysis and related fields. Inherent to the current model is a focus on bi-directional feedback and collaboration between the supervisor and trainee to frequently evaluate the acceptability of the procedures, process, outcomes, and effectiveness of supervision. We present a Supervision Monitoring and Evaluation Form consistent with the current model and discuss the assumed importance of objective and subjective self-assessment of supervisor competence to the ultimate advancement of the practice of applied behavior analysis.

The Benefits and Challenges of Preconsent in a Multisite, Pediatric Sickle Cell Intervention Trial.

Enrollment of patients in sickle cell intervention trials has been challenging due to difficulty in obtaining consent from a legal guardian and lack of collaboration between emergency medicine and hematology. We utilized education and preconsent in a pediatric multisite sickle cell intervention trial to overcome these challenges. Overall, 48 patients were enrolled after being preconsented. Variable Institutional Review Board policies related to preconsent validity and its allowable duration decreased the advantages of preconsent at some sites. The utility of preconsent for future intervention trials largely depends on local Institutional Review Board policies. Preeducation may also benefit the consent process, regardless of site differences.

SEPT8 modulates ß-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1.

Dysfunction and loss of synapses are early pathogenic events in Alzheimer's disease. A central step in the generation of toxic amyloid-ß (Aß) peptides is the cleavage of amyloid precursor protein (APP) by ß-site APP-cleaving enzyme (BACE1). Here, we have elucidated whether downregulation of septin (SEPT) protein family members, which are implicated in synaptic plasticity and vesicular trafficking, affects APP processing and Aß generation. SEPT8 was found to reduce soluble APPß and Aß levels in neuronal cells through a post-translational mechanism leading to decreased levels of BACE1 protein. In the human temporal cortex, we identified alterations in the expression of specific SEPT8 transcript variants in a manner that correlated with Alzheimer's-disease-related neurofibrillary pathology. These changes were associated with altered ß-secretase activity. We also discovered that the overexpression of a specific Alzheimer's-disease-associated SEPT8 transcript variant increased the levels of BACE1 and Aß peptides in neuronal cells. These changes were related to an increased half-life of BACE1 and the localization of BACE1 in recycling endosomes. These data suggest that SEPT8 modulates ß-amyloidogenic processing of APP through a mechanism affecting the intracellular sorting and accumulation of BACE1.

Focusing on the Environment to Improve Youth Participation: Experiences and Perspectives of Occupational Therapists.

The environment plays a key role in supporting children's participation and can serve as a focus of intervention. This study aimed to elicit the perceptions and experiences of occupational therapists who had applied the PREP approach--Pathways and Resources for Engagement and Participation. PREP is a novel 12-week intervention for youth with physical disabilities, aimed at improving participation in leisure community-based activities by modifying aspects of the environment. Using a qualitative post-intervention only design, 12 therapists took part in individual semi-structured interviews, in which the therapists reflected on their experience using PREP to enable participation. A thematic analysis was conducted. Four themes emerged from the data; two of which were informative in nature, describing elements of the PREP intervention that target multi-layered composition of the environment and use strategies that involve leveraging resources and problem solving. The two remaining themes were reflective in nature, illustrating a new take on the Occupational Therapy role and re-positioning the concept of participation in therapy practices. Results emphasize aspects of the environment that can serve as effective targets of intervention, guided by the PREP approach. Findings can broaden the scope and focus of occupational therapy practice by redefining views on participation and the environment.