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

BackgroundTransition from pediatric to adult health care varies and is resource intensive. Patient-centered health information technology (HIT) interventions are increasingly being developed in partnership with patients. ObjectiveThis study aims to develop an internet-based mobile app intervention for patients with brain-based disabilities to improve transition in care readiness. MethodsThe app was designed for patients aged 15 to 17 years with brain-based disabilities having the ability to use a mobile app. A multidisciplinary team, an industry partner, and a patient and family advisory council was assembled. We hypothesized that existing tools could be migrated into the app to address education, empowerment, and navigation. We used cognitive learning theory to support chapters targeting transition in care skill sets. We used the agile iterative methodology to engage stakeholders. ResultsWe developed a novel MyREADY Transition HIT platform. An electronic mentor supported cognitive learning with messaging, quizzes, rewards, and videos. We used gaming to guide navigation through a fictitious health care city. Adapting existing tools was achieved by the patient and family advisory council requesting personalization. Our iterative design required time-consuming back-end technology management. Developing the platform took 24 months instead of our grant-approved 12 months, impacting the onset of the planned trial within the allotted budget. ConclusionsA novel patient-centered HIT platform to improve health care transition was successfully developed in partnership with patients and industry. Careful resource management was needed to achieve timely delivery of the end product, flagging the cautious planning required to deliver HIT tools in time for the much-needed trials informing their clinical application. Trial RegistrationClinicalTrials.gov NCT03852550; https://clinicaltrials.gov/study/NCT03852550

IntroductionThe model of quantity–to–number word linkage (QNL model) identifies relevant milestones in the process of early numerical acquisition and describes a developmental sequence that can guide the fostering of foundational mathematical abilities in at-risk children. While there is substantial evidence for the predictive value of the quantity-number competencies (QNC) described by the model, evidence supporting the preventive potential of interventions targeting these QNC is so far largely restricted to short-term effects. Findings regarding their long-term preventive impact, especially in terms of transfer to mathematical school achievement, are still limited. This quasi-experimental study aimed to address this gap by evaluating the long-term transfer effects of an intervention program that is strictly derived from the QNL model of mathematical development [QNL training; in German “Mengen, zählen, Zahlen” (MZZ)].MethodsWe assessed the quantity-number competencies of 575 first-graders and identified 119 of them as being at risk for mathematical learning difficulties, who were then assigned to three experimental conditions. Sixty one children received 12 sessions of the QNL training, while 30 underwent training in inductive reasoning. Another 28 children served as a control group, receiving no specific intervention.Results and DiscussionMulti-level analyses confirmed both significant short-and long-term effects in the specifically trained quantity–number competencies as well as transfer effects on subsequent mathematical school achievement. In accordance with previous findings, transfer effects of the QNL training on mathematical school achievement were not yet evident immediately after the intervention but turned out to be significant after a delay of 6 months and remained stable even 15 months after training. Effect sizes ranged from d = 0.32 to d = 1.12. These findings both underscore the preventive potential of interventions that are strictly driven by developmental theory and, conversely, support the theoretical assumptions of the QNL model.

Abstract Background While patient and family engagement in research has become a widespread practice, meaningful and authentic engagement remains a challenge. In the READYorNot™ Brain-Based Disabilities Study, we developed the MyREADY Transition™ Brain-Based Disabilities App to promote education, empowerment, and navigation for the transition from pediatric to adult care among youth with brain-based disabilities, aged 15–17 years old. Our research team created a Patient and Family Advisory Council (PFAC) to engage adolescents, young adults, and parent caregivers as partners throughout our multi-year and multi-stage project. Main body This commentary, initiated and co-authored by members of our PFAC, researchers, staff, and a trainee, describes how we corrected the course of our partnership in response to critical feedback from partners. We begin by highlighting an email testimonial from a young adult PFAC member, which constituted a “critical turning point,” that unveiled feelings of unclear expectations, lack of appreciation, and imbalanced relationships among PFAC members. As a team, we reflected on our partnership experiences and reviewed documentation of PFAC activities. This process allowed us to set three intentions to create a collective goal of authentic and meaningful engagement and to chart the course to get us there: (1) offering clarity and flexibility around participation; (2) valuing and acknowledging partners and their contributions; and (3) providing choice and leveraging individual interests and strengths. Our key recommendations include: (1) charting the course with a plan to guide our work; (2) learning the ropes by developing capacity for patient-oriented research; (3) all hands on deck by building a community of engagement; and (4) making course corrections and being prepared to weather the storms by remaining open to reflection, re-evaluation, and adjustment as necessary. Conclusions We share key recommendations and lessons learned from our experiences alongside examples from the literature to offer guidance for multi-stage research projects partnering with adolescents, young adults, and family partners. We hope that by sharing challenges and lessons learned, we can help advance patient and family engagement in research.

It has become increasingly common for researchers to partner with patients as members of the research team and collaborate to use their lived experiences to shape research priorities, interventions, dissemination, and more. The patient-oriented research (POR) model has been adopted by both adult and pediatric health researchers. This cultural change to conducting pediatric health research brings with it new methodologies, tools, challenges, and benefits. In this review, we aim to provide guidance on how to conduct POR for pediatric populations using examples from the literature. We describe considerations for engagement before the project begins, for engagement across the research cycle, and for measurement and evaluation. We aim to show that conducting POR is feasible, beneficial, and that many common challenges and barriers can be overcome with preparation and usage of specific tools.

Abstract Background Authentic researcher-youth partnerships in patient-oriented research (POR) where the research responds to the needs expressed by youth themselves are essential to make research meaningful. While patient-oriented research (POR) is increasingly practiced, few training programs exist in Canada and none, to our knowledge, are tailored for youth with neurodevelopmental disabilities (NDD). Our primary objective was to explore the training needs of youth (ages 18–25) with NDD to enhance their knowledge, confidence, and skills as research partners. Our secondary objective was to identify the benefits and challenges of engaging youth with NDD in a POR approach. Methods Our team of four youth and one parent with lived experience [Youth Engagement in Research (YER) partners] and six researchers engaged in POR to investigate the primary objective via two phases: (1) individual interviews with youth living with NDD and (2) a two-day virtual symposium with focus groups with youth and researchers. Collaborative qualitative content analysis was employed to synthesize the data. Our secondary objective was assessed by asking our YER partners to complete the Public and Patient Engagement Evaluation Tool (PPEET) survey and participate in reflective discussions. Results Phase 1 participants (n = 7) identified various barriers and facilitators to their engagement in research and offered suggestions to meet their needs through minimizing barriers and integrating facilitators, which would subsequently enhance their knowledge, confidence, and skills as research partners. Informed by phase 1, phase 2 participants (n = 17) prioritized the following POR training needs: researcher-youth communication, research roles and responsibilities, and finding partnership opportunities. For delivery methods, participants stated the importance of youth representation, using Universal Design for Learning, and co-learning between youth and researchers. Based on the PPEET data and subsequent discussions, YER partners agreed that they were able to express views freely, feel that their views were heard, and that their participation made a meaningful difference. Challenges included scheduling difficulties, ensuring multiple methods for engagement, and working under short timelines. Conclusion This study identified important training needs for youth with NDD and for researchers to engage in meaningful POR, which can subsequently inform the co-production of accessible training opportunities with and for youth.

Gomez-Lopez-Hernandez syndrome (GLHS), also known as cerebello-trigeminal-dermal dysplasia, is a neurocutaneous disorder typically presenting in childhood. GLHS is characterized by rhombencephalosynapsis (RES) and partial alopecia, with or without trigeminal anesthesia. We describe a rare case of GLHS in a paucisymptomatic adult who presented with new-onset seizure-like activity. Magnetic resonance imaging revealed partial midline fusion of the cerebellar hemispheres, incomplete development of vermis, and slight medialization of the dentate nuclei: all consistent with the diagnosis of RES. Radiographic evidence combined with partial alopecia, truncal ataxia, and muscular hypotonia are suggestive GLHS diagnosis. Our report not only highlights the importance of maintaining GLHS on the differential for new-onset seizure-like activity, but also demonstrates how patients with GLHS may be minimally symptomatic and diagnosed in adulthood. Lay Summary: The Gomez-Lopez-Hernandez syndrome (GLHS), or cerebellotrigeminal-dermal dysplasia, is a rare condition that affects both the nervous system and the skin. It involves abnormal development of the brain, partial alopecia [thinning of hair], and loss of sensation in the face. One specific brain malformation, called rhombencephalosynapsis (RES), results from abnormal formation of the cerebellum and is seen in GHLS.Both RES and GLHS present early in childhood, and cases presenting later in life are exceptionally rare. Here we describe a young adult with RES and GLHS whose normal development and mild clumsiness eluded recognition by doctors until early adulthood when she presented with a single seizure.

There is a growing number of youth with healthcare needs such as disabilities or chronic health conditions who require lifelong care. In Canada, transfer to the adult healthcare system typically occurs at age 18 and is set by policy regardless of whether youth and their families are ready. When the transition to adult services is suboptimal, youth may experience detrimental gaps in healthcare resulting in increased visits to the emergency department and poor healthcare outcomes. Despite the critical need to support youth with disabilities and their families to transition to the adult healthcare system, there is limited legislation to ensure a successful transfer or to mandate transition preparation in Canada. This advocacy and policy planning work was conducted in partnership with the Patient and Family Advisory Council (PFAC) within the CHILD-BRIGHT READYorNot™ Brain-Based Disabilities (BBD) Project and the CHILD-BRIGHT Policy Hub. Together, we identified the need to synthesize and better understand existing policies about transition from pediatric to adult healthcare, and to recommend solutions to improve healthcare access and equity as Canadian youth with disabilities become adults. In this perspective paper, we will report on a dialogue with key informants and make recommendations for change in healthcare transition policies at the healthcare/community, provincial and/or territorial, and/or national levels.

Patient and family engagement has become a widely accepted approach in health care research. We recognize that research conducted in partnership with people with relevant lived experience can substantially improve the quality of that research and lead to meaningful outcomes. Despite the benefits of patient-researcher collaboration, research teams sometimes face challenges in answering the questions of how patient and family research partners should be compensated, due to the limited guidance and lack of infrastructure for acknowledging partner contributions. In this paper, we present some of the resources that might help teams to navigate conversations about compensation with their patient and family partners and report how existing resources can be leveraged to compensate patient and family partners fairly and appropriately. We also present some of our first-hand experiences with patient and family compensation and offer suggestions for research leaders, agencies, and organizations so that the health care stakeholders can collectively move toward more equitable recognition of patient and family partners in research.

Abstract Background To determine whether restricted diffusion of the callosal splenium is specific for seizure activity in neonates. Methods We performed a retrospective chart review of 123 neonates who had a diagnosis of hypoxic ischemic encephalopathy (HIE) who underwent therapeutic cooling and had magnetic resonance imaging (MRI) within the first 10 days of life. The regions examined for injury include the callosal splenium, cortex, deep gray matter, and subcortical white matter. Neurodevelopmental outcomes were secondarily assessed using the Bayley Scales of Infant Development at 12 to 18 months of age and > 18 months of age. APGAR scores and pH, two important markers of hypoxia/ischemia and encephalopathy, were also analyzed in relation to these outcomes. Results Approximately 41% of the neonates had at least one abnormal region on brain MRI, and 21% had abnormal signal in the splenium. Clinical and/or electrographic seizures were documented in 32%. Changes in the splenium had a sensitivity of 54%, specificity of 94%, and positive predictive value of 81% for seizure presence. The presence of seizures and splenium lesion was associated poor developmental outcomes at 12 to 18 months of age. APGAR scores at 10 minutes, but not lowest pH was associated with splenial changes. Conclusions Restricted diffusion of the callosal splenium is specific for recent seizures in neonates with HIE. Seizures and splenial lesion represent risk factors for poor neurodevelopmental outcomes. Child neurologists and neonatologists should consider splenial signal abnormality in their assessment of neonates at risk for seizures and counsel families about likely outcomes accordingly.

Plain English summary In more and more projects, researchers and young people are working together in partnership; but there is little guidance about how to organize this partnership. In this paper, we share what partnerships in six projects from Canada, Netherlands, and United Kingdom looked like, so that others can be inspired. To do so, a researcher and a young partner from each project were asked to together: (1) describe their project, (2) summarize the practical details about the collaboration and (3) think about things that went well or could be improved. We found that all projects had the same beliefs important to partnerships, like having respect for each other. Young people could work on parts of the project they liked in a way that worked for them. They were supported by staff, could join meetings and were appreciated for their work. Clear communication during and in-between meetings was helpful. Youth were often asked about the role they wanted in the project. While there was often no formal training on how to do research, there were many opportunities to learn. We offer six recommendations to researchers and young people who want to partner together: (1) It is okay to not know what the partnership will look like and there is no single recipe of how to partner; (2) Take your time; (3) Discuss how the partnership is going; (4) Think about who is doing what and why; (5) Consider the diversity of young partners. We hope others will share their experiences.

Plain English summary More and more patients and family members are getting involved in health research studies as partners. However we do not know much about what happens after the research study ends. This article looks at how parents have been involved in research studies at CanChild Centre for Childhood Disability Research at McMaster University in Ontario, Canada. CanChild researchers, staff, students and parents were asked about their experiences of working together on research studies. One of the researchers then pooled together all of these stories, shared them with everyone to get their feedback, and wrote the initial draft of this article. All the people interviewed were invited to read the article and to add their thoughts and opinions until everyone was satisfied with the final product. Our shared stories show that a lot has changed since CanChild was established in 1989. At first, researchers consulted with parents when they were doing a study. Now, many parents are partners and co-principal investigators on research studies. CanChild has also developed opportunities for parents and researchers to get training in patient-family engagement and to network with each other outside of research studies. Researchers, staff, students and parents talked about what makes research partnerships successful, including: being open to learning from each other; taking the time to get to know each other as people; and always trying to do better. They also shared some of the challenges that come up on research studies and suggested strategies for working through them.

ABSTRACT An outstanding question regarding the human gut microbiota is whether and how microbiota-directed interventions influence host phenotypic traits. Here, we employed a dietary intervention to probe this question in the context of lactose intolerance. To assess the effects of dietary dairy product elimination and (re)introduction on the microbiota and host phenotype, we studied 12 self-reported mildly lactose-intolerant adults with triweekly collection of fecal samples over a 12-week study period: 2 weeks of baseline diet, 4 weeks of dairy product elimination, and 6 weeks of gradual whole cow milk (re)introduction. Of the 12 subjects, 6 reported either no dairy or only lactose-free dairy product consumption. A clinical assay for lactose intolerance, the hydrogen breath test, was performed before and after each of these three study phases, and 16S rRNA gene amplicon sequencing was performed on all fecal samples. We found that none of the subjects showed change in a clinically defined measure of lactose tolerance. Similarly, fecal microbiota structure resisted modification. Although the mean fraction of the genus Bifidobacterium, a group known to metabolize lactose, increased slightly with milk (re)introduction (from 0.0125 to 0.0206; Wilcoxon P = 0.068), the overall structure of each subject’s gut microbiota remained highly individualized and largely stable in the face of diet manipulation. IMPORTANCE Lactose intolerance is a gastrointestinal disorder diagnosed with a lactose hydrogen breath test. Lifestyle changes such as diet interventions can impact the gut microbiome; however, the role of the microbiome in lactose intolerance is unclear. Our study assessed the effects of a 12-week dietary dairy product elimination and (re)introduction on the microbiome and clinical lactose intolerance status in 12 adult self-reported lactose-intolerant individuals. We found each subject’s gut microbiome remained highly individualized and largely stable in the face of this diet manipulation. We also report that none of the subjects showed change in a clinically defined measure of lactose tolerance.

BackgroundThe COVID-19 pandemic has disrupted everyday rehabilitation research. Many academic institutions have halted in-person human research including rehabilitation sciences. Researchers are faced with several barriers to continuing their research programs. The purpose of this perspective article is to report the results of an interdisciplinary workshop aimed at understanding the challenges and corresponding strategies for conducting rehabilitation research during the COVID-19 pandemic.MethodsTwenty-five rehabilitation researchers (17 trainees and eight faculty) attended a 2-h facilitated online workshop in to discuss challenges and strategies they had experienced and employed to conduct rehabilitation research during the COVID-19 pandemic.ResultsRehabilitation researchers reported challenges with (1) pandemic protocol adjustments, (2) participant accessibility, and (3) knowledge dissemination, along with corresponding strategies to these challenges. Researchers experienced disruptions in study outcomes and intervention protocols to adhere to public health guidelines and have suggested implementing novel virtual approaches and study toolkits to facilitate offsite assessment. Participant accessibility could be improved by engaging community stakeholders in protocol revisions to ensure equity, safety, and feasibility. Researchers also experienced barriers to virtual conferences and publication, suggested opportunities for smaller networking events, and revisiting timeframes for knowledge dissemination.ConclusionThis perspective article served as a catalyst for discussion among rehabilitation researchers to identify novel and creative approaches that address the complexities of conducting rehabilitation research during the COVID-19 pandemic and beyond.

While Vietnamese students continue to enrol in international branch university campuses in Vietnam, little is known about the Vietnamese first year transition into these institutions, especially from a cultural perspective. This article presents the findings of four case studies that explored the face strategies used by Vietnamese undergraduate business students in transition to an international branch campus based in Vietnam. The use of collectivist and individualist face strategies was examined in three phases: at commencement, mid-way and at the end of the first year of studies. The findings suggest that collectivist face strategies might not be employed as often as expected by Vietnamese first year students in this context even though they transition from a Confucian heritage culture. Understanding face strategies can help anticipate challenges of Vietnamese students studying in English-medium environments and inform culturally sensitive practices in teaching and learning.

Background: Older patients from nursing homes are commonly exposed to polypharmacy before a hospital admission. Deprescribing has been promoted as a solution to this problem, though systematic reviews have not found benefit. The aim of this study was to understand if in-hospital deprescribing of certain classes of medications is associated with certain benefits or risks. Methods: We conducted a prospective, multicentre, cohort study in 239 medical inpatients ⩾75 years (mean age 87.4 years) who were exposed to polypharmacy (⩾5 medications) prior to admission and discharged to a nursing home for permanent placement. Patients were categorised by whether deprescribing occurred, mortality and readmissions were assessed 30 and 90 days after hospital discharge. The EQ-5D-5 L health survey assessed changes in health-related quality of life (HRQOL) at 90 days, with comparison to EQ-5D-5 L results at day 30. Latent class analysis (LCA) was used to investigate associations between patterns of prescribed and deprescribed medications and mortality. Results: Patients for whom deprescribing occurred had a higher Charlson Index; there were no differences between the groups in principal diagnosis, total or Beers list number of medications on admission. The number of Beers list medications increased in both groups before discharge. Patients who had medications deprescribed had nonsignificantly greater odds of dying within 90 days [odds ration (OR) = 3.23 (95% confidence interval (CI): 0.68, 14.92; p = 0.136]. Deprescribing of certain classes was associated with higher 90-day mortality: antihypertensives (OR = 2.27, 95% CI: 1.004, 5; p = 0.049) and statins (OR = 5, 95% CI: 1.61, 14.28; p = 0.005). Readmissions and 1-year mortality rates were similar. There was no deterioration in HRQOL when medications were deprescribed. LCA showed that patients with the least medication changes had the lowest mortality. Conclusion: Deprescribing certain classes of medications during hospitalisation was associated with worse mortality, but not readmissions or overall HRQOL. Larger controlled deprescribing studies targeting specific medications are warranted to further investigate these findings. This study was registered with the Australian and New Zealand Clinical Trials Registry, ACTRN1 2616001336471. Plain language summary Background: When an older person living in a nursing home is admitted to hospital, does stopping long-term medications help them? Many older people from nursing homes take a large number of medications each day to treat symptoms and prevent adverse events. “Polypharmacy” is a term used to describe taking multiple long-term medications, and it is associated with many negative outcomes such as increased number of falls, cognitive decline, hospital readmission, even death. Deprescribing of nonessential medications – whether stopping or reducing the dose – is promoted as good hospital practice and is assumed to help older frail people live longer and feel better. However, we often don’t fully understand what is and is not essential. We wanted to better understand the effect of deprescribing long-term medications for older frail patients during an unplanned hospital admission as they were going to a nursing home to live. Methods: While admitted to hospital, medications are often reviewed by a clinical pharmacist and specialist physician. Sometimes medications are ceased; sometimes they are not. This gave us the opportunity to study two groups of older frail people from nursing homes: those who had regular, long-term medications ceased or reduced and those who did not. We wanted to see if one group did better. For example, did they feel worse if we stopped certain medications? Did they suffer other bad events compared with those patients for whom no medications were ceased? Were they readmitted to hospital earlier or more often? Results and conclusion: Despite the assumption that stopping medications for this type of patient is good practice, we found no benefit. We were also surprised to find stopping or reducing certain drug classes (e.g. antihypertensives and cholesterol-lowering drugs) was associated with greater mortality. Larger, randomised studies will better answer these important questions.

Background: As children and adolescents with a chronic health condition (CHC) age and transition to adulthood, many will increasingly assume responsibilities for the management of their healthcare. For individuals with CHCs, family members including siblings often provide significant and varied supports. There are a range of resources in Canada to support siblings of individuals with a CHC, but these resources are not synthesized and the extent to which they relate to healthcare management remains unclear.Purpose: The purpose of this document review was to identify, describe, and synthesize the types of resources currently available to provide general information and healthcare management information about how siblings can provide support to individuals with CHCs in Canada.Methods: Print and electronic resources were systematically identified and retrieved from the websites of organizations, treatment centers, and children's hospitals that are part of Children's Healthcare Canada. Each unique resource was treated as a text document. Documents that met the following inclusion criteria were included: addressed the topic of siblings of individuals with a CHC and written in English. Data were extracted from included documents and qualitative conventional content analysis was conducted. Throughout the process of this review, we partnered with a Sibling Youth Advisory Council.Results: The systematic search yielded 1,628 non-duplicate documents, of which 163 documents met the inclusion criteria. Of the total of 163 documents, they were delivered in the following formats: 17 (10%) general informational products (e.g., booklets, videos) about a CHC and sibling relationships, 39 about support programs and workshops (24%), 34 news articles (21%) that described the roles of siblings, and 6 (3%) healthcare management informational products (e.g., toolkit, tipsheets), 31 blogs (19%) and 39 interviews (24%) with parents and siblings. In the blogs and interviews, siblings and parents described how siblings developed knowledge and skills for healthcare management, as well as their role and identity over time.Significance: This study identified that there are limited resources available about healthcare management for siblings of CHC in Canada. Resources are needed to facilitate conversations in the family about the role of siblings with healthcare management of their sibling with a CHC.

Abstract Background Some individuals who sustain traumatic brain injuries (TBIs) continue to experience significant cognitive impairments chronically (months to years post injury). Many tests of executive function are insensitive to these executive function impairments, as such impairments may only appear during complex daily life conditions. Daily life often requires us to divide our attention and focus on abstract goals. In the current study, we compare the effects of two 1-month electronic cognitive rehabilitation programs for individuals with chronic TBI. The active program (Expedition: Strategic Advantage) focuses on improving goal-directed executive functions including working memory, planning, long-term memory, and inhibitory control by challenging participants to accomplish life-like cognitive simulations. The challenge level of the simulations increases in accordance with participant achievement. The control intervention (Expedition: Informational Advantage) is identical to the active program; however, the cognitive demand level is capped, preventing participants from advancing beyond a set level. We will evaluate these interventions with a military veteran TBI population. Methods/design One hundred individuals will be enrolled in this double-blinded clinical trial (all participants and testers are blinded to condition). Each individual will be randomly assigned to one of two interventions. The primary anticipated outcomes are improvement of daily life cognitive function skills and daily life functions. These are measured by a daily life performance task, which tests cognitive skills, and a survey that evaluates daily life functions. Secondary outcomes are also predicted to include improvements in working memory, attention, planning, and inhibitory control as measured by a neuropsychological test battery. Lastly, neuroimaging measures will be used to evaluate changes in brain networks supporting cognition pre and post intervention. Discussion We will test whether electronically delivered cognitive rehabilitation aimed at improving daily life functional skills will provide cognitive and daily life functional improvements for individuals in the chronic phase of TBI recovery (greater than 3 months post injury). We aim to better understand the cognitive processes involved in recovery and the characteristics of individuals most likely to benefit. This study will also address the potential to observe generalizability or to transfer from a software-based cognitive training tool toward daily life improvement. Trial registration ClinicalTrials.gov, NCT03704116. Retrospectively registered on 12 Oct 2018.

Introduction Siblings share a lifelong bond in their relationship, and they may choose to provide support to their brother or sister with a neurodisability. Previous reviews summarised programmes that only focused on the behavioural, emotional and psychological outcomes of the siblings. There is a need to synthesise existing evidence and enhance our understanding about programmes for siblings to acquire knowledge, develop skills and become empowered that can help them to provide support to their brother or sister with a neurodisability. The objective of this review is to identify and map the characteristics and outcomes of programmes designed to prepare siblings in their future roles to support their brother or sister with a neurodisability.Methods and analysis This review will be conducted using the Joanna Briggs Institute methodology for scoping reviews. An integrated knowledge translation approach will be used by partnering with the Sibling Youth Advisory Council comprised of siblings of individuals with a disability throughout all review phases. Databases to be searched include PsycINFO, Cumulative Index of Nursing and Allied Health Literature, Sociological Abstracts, Education Resources Information Center, EMBASE, Web of Science, MEDLINE (Ovid) and SPORTDiscus, from date of inception to November 2020. Studies of programmes designed for siblings of individuals with neurodisabilities, with no exclusion on the age of siblings or context, and published in English will be included. Extracted data will include details of programme structure and content, eligibility criteria and participants, context, study methods and outcomes. A summary of the results will be presented in a tabular form to provide an overview of the programmes with an accompanying narrative summary to address the research questions of this review.Dissemination Findings from this review will be shared using dissemination strategies in partnership with the Sibling Youth Advisory Council. We will share the findings with key stakeholders such as healthcare providers, researchers, and patient and family advocacy groups.

Introduction Youth with brain-based disabilities (BBDs), as well as their parents/caregivers, often feel ill-prepared for the transfer from paediatric to adult healthcare services. To address this pressing issue, we developed the MyREADY TransitionTM BBD App, a patient-facing e-health intervention. The primary aim of this randomised controlled trial (RCT) was to determine whether the App will result in greater transition readiness compared with usual care for youth with BBD. Secondary aims included exploring the contextual experiences of youth using the App, as well as the interactive processes of youth, their parents/caregivers and healthcare providers around use of the intervention.Methods and analysis We aimed to randomise 264 youth with BBD between 15 and 17 years of age, to receive existing services/usual care (control group) or to receive usual care along with the App (intervention group). Our recruitment strategy includes remote and virtual options in response to the current requirements for physical distancing due to the COVID-19 pandemic. We will use an embedded experimental model design which involves embedding a qualitative study within a RCT. The Transition Readiness Assessment Questionnaire will be administered as the primary outcome measure. Analysis of covariance will be used to compare change in the two groups on the primary outcome measure; analysis will be intention-to-treat. Interviews will be conducted with subsets of youth in the intervention group, as well as parents/caregivers and healthcare providers.Ethics and dissemination The study has been approved by the research ethics board of each participating site in four different regions in Canada. We will leverage our patient and family partnerships to find novel dissemination strategies. Study findings will be shared with the academic and stakeholder community, including dissemination of teaching and training tools through patient associations, and patient and family advocacy groups.Trial registration number NCT03852550.

Plain English summary In Canada, and internationally, there is an increased demand for patient engagement in health care research. Patients are being involved throughout the research process in a variety of roles that extend beyond the traditional passive participant role. These practices, referred to collectively as ‘patient engagement’, have raised questions about how to engage patients in the research process. Specifically, researchers have noted a lack of theory underpinning patient engagement and are looking for guidance on how to select patients and engage patients throughout the research process. In this commentary, we draw on qualitative research perspectives to generate theoretical and methodological ideas that novice or experienced researchers can apply to facilitate patient engagement in research. Abstract Despite the recent advancements in patient engagement in health care research, there is limited research evidence regarding the best strategies for developing and supporting research partnerships with patients and caregivers. Three particular outstanding concerns that have been reported in the literature and that we will explore in this commentary are: (i) the lack of theoretical underpinning to inform the practice of patient engagement in research; (ii) the lack of knowledge regarding how to select patients to engage in research; and (iii) the lack of clear guidance about the best methods for engaging patients in research. We draw on qualitative research perspectives to reflect on these three areas of concern and propose insights into the theory and methods that we believe are useful for engaging patients in research.

Abstract Background In the management of hypertonicity in children with cerebral palsy (CP), goals should be clearly identified in order to evaluate the effectiveness of botulinum toxin A (BoNT-A) treatment, specifically in non-ambulatory children and adolescents, Gross Motor Function Classification System (GMFCS), level IV or V. A retrospective chart review (Mesterman et al., 2013) identified the need for the development of a set of specific and meaningful goals linked to the International Classification of Functioning, Disability and Health (ICF) for future goal setting and evaluation in this population. Our objective is to create an inventory of goals based on the ICF framework that captures the needs and values of families with children with CP. Methods This cross-sectional observational study recruited parents of twenty children and youths with CP in GMFCS levels IV or V (mean age 11.2 years, SD 4.3, 13 males) who were assessed for BoNT-A treatment at the Spasticity Management Clinic at McMaster Children’s Hospital (Hamilton, ON). A previous inventory of goals was developed by a group of experts at a national botulinum toxin conference held in January 2014 (Montreal, Canada). The inventory of goals was further refined by asking the parents to select goals from the inventory list that they would like their child to accomplish after receiving BoNT-A treatment, and asking healthcare professionals for clarity and phrasing of goals in the inventory list. Results All parents identified body structure and function goals, with more than 75% of parents selecting reduction in muscle tone and increased range of movements in the upper and lower extremities. More than 50% of parents identified activity goals related to ease of caregiving. Two activity goals and three participation goals were missing from the inventory. Participation goals were identified by less than 5% of parents. Conclusion The inventory may be a helpful tool to facilitate a discussion about goal setting between healthcare professionals and families in the context of BoNT-A treatment. A future study is needed to conduct qualitative interviews to better understand the information that families may require about setting goals during BoNT-A treatment and to evaluate the usefulness of the inventory.

Abstract Transcription factor NF-κB plays a central role in immunity from fruit flies to humans, and NF-κB activity is altered in many human diseases. To investigate a role for NF-κB in immunity and disease on a broader evolutionary scale we have characterized NF-κB in a sea anemone (Exaiptasia pallida; called Aiptasia herein) model for cnidarian symbiosis and dysbiosis (i.e., “bleaching”). We show that the DNA-binding site specificity of Aiptasia NF-κB is similar to NF-κB proteins from a broad expanse of organisms. Analyses of NF-κB and IκB kinase proteins from Aiptasia suggest that non-canonical NF-κB processing is an evolutionarily ancient pathway, which can be reconstituted in human cells. In Aiptasia, NF-κB protein levels, DNA-binding activity, and tissue expression increase when loss of the algal symbiont Symbiodinium is induced by heat or chemical treatment. Kinetic analysis of NF-κB levels following loss of symbiosis show that NF-κB levels increase only after Symbiodinium is cleared. Moreover, introduction of Symbiodinium into naïve Aiptasia larvae results in a decrease in NF-κB expression. Our results suggest that Symbiodinium suppresses NF-κB in order to enable establishment of symbiosis in Aiptasia. These results are the first to demonstrate a link between changes in the conserved immune regulatory protein NF-κB and cnidarian symbiotic status.

Abstract Background Despite efforts by professional societies to reduce low value care, many reports indicate that unnecessary tests, such as nuclear myocardial perfusion imaging (MPI), are commonly used in contemporary practice. The degree to which lack of awareness and professional liability concerns drive these behaviors warrants further study. We sought to investigate patient and provider perceptions about MPI in asymptomatic patients, the Choosing Wisely (CW) campaign, and professional liability concerns. Methods We administered an anonymous, paper-based survey with both discrete and open-response queries to subjects in multiple outpatient settings at our facilities. The survey was completed by 456 respondents including 342 patients and 114 physicians and advanced practice providers between May and August 2014. Our outcome was to compare patient and provider perceptions about MPI in asymptomatic patients and related factors. Results Patients were more likely than providers to report that MPI was justified for asymptomatic patients (e.g. asymptomatic with family history of heart disease 75% versus 9.2%, p

The aim of this pilot study was to assess: (1) the feasibility and acceptability of a Mindfulness-Based Virtual Reality (MBVR) intervention among children and young adults with Inflammatory Bowel Disease (IBD), and (2) the preliminary efficacy of MBVR on key psychological (anxiety) and physical (pain) outcomes. Participants were 62 children to young adults with IBD (M = 15.6 years; 69.4% Crohn’s disease; 58% male) recruited from an outpatient pediatric IBD clinic. Participants completed a baseline assessment, underwent the 6-min MBVR intervention, completed a post-intervention assessment and study satisfaction survey, and provided qualitative feedback. Results suggest strong feasibility and acceptability. Participants reported high levels of satisfaction with MBVR including high levels of enjoyment (M = 4.38; range 1–5) and relaxation (M = 4.35; range 1–5). Qualitative data revealed several key themes including participants interest in using MBVR in IBD medical settings (e.g., hospitalizations, IBD procedures, IBD treatments), as well as in their daily lives to support stress and symptom management. Preliminary analyses demonstrated improvements in anxiety (t = 4.79, p = 0.001) and pain (t = 3.72, p < 0.001) following MBVR. These findings provide initial support for the feasibility and acceptability of MBVR among children and young adults with IBD. Results also suggest MBVR may improve key IBD outcomes (e.g., anxiety, pain) and highlight the importance of conducting a randomized controlled trial and more rigorous research to determine intervention efficacy.

Gastroparesis (GP) is a chronic, gastric dysmotility disorder with significant morbidity and mortality. The hallmark of GP is the delayed emptying of the contents of the stomach in the absence of any mechanical obstruction. Patients most commonly report chronic symptoms of nausea, vomiting, feeling full quickly when eating, bloating, and abdominal pain. Treatments are limited with relatively poor efficacy. As such, children with GP are at significant risk for the development of psychological co-morbidities. In this paper, we provide a topical review of the scientific literature on the psychological, social, and emotional impacts of gastroparesis in pediatric patients. We aim to document the current state of research, identify gaps in our knowledge with appropriate recommendations for future research directions, and highlight the unique challenges pediatric patients with GP and their families may face as they manage this disease. Based on the current review, research into the psychosocial impacts in children with GP is essentially non-existent. However, when considering research in children with other chronic digestive diseases, children with GP are likely to face multiple psychosocial challenges, including increased risk for anxiety and depression, stigma, and reduced quality of life. These significant gaps in the current understanding of effects of GP across domains of childhood functioning allow for ample opportunities for future studies to address psychosocial outcomes.

IntroductionIndividuals with diabetes are at increased risk for complications, including gastroparesis. Type 1 diabetes mellitus (T1DM) is an autoimmune disorder resulting in decreased beta-cell function. Glutamic acid decarboxylase-65 antibody (GADA) is the most commonly used test to assess autoimmunity while C-peptide level is used to assess beta-cell function. Patients with type 2 diabetes mellitus (T2DM), who are GADA positive, are labeled latent autoimmune diabetes in adults (LADA).ObjectiveTo characterize patients with T1 and T2DM who have symptoms of gastroparesis using GADA and C-peptide levels and to look for association with the presence of gastroparesis and its symptom severity.Design113 T1DM and 90 T2DM patients with symptoms suggestive of gastroparesis were studied. Symptom severity was assessed using Gastroparesis Cardinal Symptom Index (GCSI). Serum samples were analyzed for GADA and C-peptide.ResultsDelayed gastric emptying was present in 91 (81%) of T1DM and 60 (67%) of T2DM patients (p = 0.04). GADA was present in 13% of T2DM subjects [10% in delayed gastric emptying and 20% in normal gastric emptying (p = 0.2)]. Gastric retention and GCSI scores were mostly similar in GADA positive and negative T2DM patients. GADA was present in 45% of T1DM subjects [46% in delayed gastric emptying and 41% in normal gastric emptying (p = 0.81)]. Low C-peptide levels were seen in 79% T1DM patients and 8% T2DM. All seven T2DM patients with low C-peptide were taking insulin compared to 52% of T2DM with normal C-peptide.ConclusionGADA was present in 13% while low C-peptide was seen in 8% of our T2DM patients with symptoms of gastroparesis. Neither did correlate with degree of delayed gastric emptying or symptom severity.ClinicalTrials.gov IdentifierNCT01696747.

Erratic blood glucose levels can be a cause and consequence of delayed gastric emptying in patients with diabetes. It is unknown if better glycemic control increases risks of hypoglycemia or improves hemoglobin A1c levels and gastrointestinal symptoms in diabetic gastroparesis. This study investigated the safety and potential efficacy of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) in poorly controlled diabetes with gastroparesis. Forty-five type 1 or 2 patients with diabetes and gastroparesis and hemoglobin A1c >8% from the NIDDK Gastroparesis Consortium enrolled in a 24 week open-label pilot prospective study of CSII plus CGM. The primary safety outcome was combined numbers of mild, moderate, and severe hypoglycemic events at screening and 24 weeks treatment. Secondary outcomes included glycemic excursions on CGM, hemoglobin A1c, gastroparesis symptoms, quality-of-life, and liquid meal tolerance. Combined mild, moderate, and severe hypoglycemic events occurred similarly during the screening/run-in (1.9/week) versus treatment (2.2/week) phases with a relative risk of 1.18 (95% CI 0.85-1.64, P = 0.33). CGM time in hypoglycemia (300 mg/dL) decreased from 14.2% to 7.0% (P = 0.005), and hemoglobin A1c decreased from 9.4±1.4% to 8.3±1.3% (P = 0.001) on CSII plus CGM. Symptom scores decreased from 29.3±7.1 to 21.9±10.2 with lower nausea/vomiting, fullness/early satiety, and bloating/distention scores (P≤0.001). Quality-of-life scores improved from 2.4±1.1 to 3.1±1.1 (P

Neurodegenerative diseases with distinct genetic etiologies and pathological phenotypes appear to share common mechanisms of neuronal cellular dysfunction, including excitotoxicity, calcium dysregulation, oxidative damage, ER stress and mitochondrial dysfunction. Glial cells, including microglia and astrocytes, play an increasingly recognized role in both the promotion and prevention of neurodegeneration. Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. These receptors therefore represent compelling putative targets for pharmacologically treating neurodegenerative disorders. In this review, we provide an overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function. In addition, we speculate on their therapeutic potential in the treatment of various neurodegenerative disorders.

Pediatric traumatic brain injury (TBI) and autism spectrum disorder (ASD) are two serious conditions that affect youth. Recent data, both preclinical and clinical, show that pediatric TBI and ASD share not only similar symptoms but also some of the same biologic mechanisms that cause these symptoms. Prominent symptoms for both disorders include gastrointestinal problems, learning difficulties, seizures, and sensory processing disruption. In this review, we highlight some of these shared mechanisms in order to discuss potential treatment options that might be applied for each condition. We discuss potential therapeutic and pharmacologic options as well as potential novel drug targets. Furthermore, we highlight advances in understanding of brain circuitry that is being propelled by improved imaging modalities. Going forward, advanced imaging will help in diagnosis and treatment planning strategies for pediatric patients. Lessons from each field can be applied to design better and more rigorous trials that can be used to improve guidelines for pediatric patients suffering from TBI or ASD.

Dextromethorphan is an antitussive with a high margin of safety that has been hypothesized to display rapid-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. In addition to binding to NMDA receptors, dextromethorphan binds to sigma-1 (σ1) receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine whether dextromethorphan elicits antidepressant-like effects and the involvement of σ1 receptors in mediating its antidepressant-like actions. The antidepressant-like effects of dextromethorphan were assessed in male, Swiss Webster mice using the forced swim test. Next, σ1 receptor antagonists (BD1063 and BD1047) were evaluated in conjunction with dextromethorphan to determine the involvement of σ receptors in its antidepressant-like effects. Quinidine, a cytochrome P450 (CYP) 2D6 inhibitor, was also evaluated in conjunction with dextromethorphan to increase the bioavailability of dextromethorphan and reduce exposure to additional metabolites. Finally, saturation binding assays were performed to assess the manner in which dextromethorphan interacts at the σ1 receptor. Our results revealed dextromethorphan displays antidepressant-like effects in the forced swim test that can be attenuated by pretreatment with σ1 receptor antagonists, with BD1063 causing a shift to the right in the dextromethorphan dose response curve. Concomitant administration of quinidine potentiated the antidepressant-like effects of dextromethorphan. Saturation binding assays revealed that a Ki concentration of dextromethorphan reduces both the Kd and the Bmax of [(3)H](+)-pentazocine binding to σ1 receptors. Taken together, these data suggest that dextromethorphan exerts some of its antidepressant actions through σ1 receptors.

Screening a library of drugs with known safety profiles in humans yielded 30 drugs that reliably protected mammalian neurons against glucose toxicity. Subsequent screening demonstrated that 6 of these 30 drugs increase lifespan in C. elegans: caffeine, ciclopirox olamine, tannic acid, acetaminophen, bacitracin, and baicalein. Every drug significantly reduced the age-dependent acceleration of mortality rate. These protective effects were blocked by RNAi inhibition of cbp-1 in adults only, which also blocks protective effects of dietary restriction. Only 2 drugs, caffeine and tannic acid, exhibited a similar dependency on DAF-16. Caffeine, tannic acid, and bacitracin also reduced pathology in a transgenic model of proteotoxicity associated with Alzheimer's disease. These results further support a key role for glucose toxicity in driving age-related pathologies and for CBP-1 in protection against age-related pathologies. These results also provide novel lead compounds with known safety profiles in human for treatment of age-related diseases, including Alzheimer's disease and diabetic complications.