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Abstract Background As the healthcare of individuals with intellectual and developmental disabilities (IDD) shifts toward community-based services, physicians in all areas of medicine are more likely to care for this population. To ensure that all physicians can provide high-quality care to people with IDD, further understanding and attention to undergraduate medical education related to IDD is needed. Methods A 24-item survey assessed the experiences, attitudes, knowledge, skills, and future interest of Canadian medical students regarding IDD. Descriptive statistics were calculated for questionnaire responses and responses of students who had more in-depth experience were compared to those of students with minimal past experience. Results A total of 443 Canadian medical students completed the survey. Students did not feel competent obtaining clear histories from people with IDD. Most students were not confident they could provide quality care to this population but wanted further learning. Students with prior IDD experiences through family/friends felt more knowledgeable and interested in caring for this population than those with community/clinical and minimal experiences. Discussion Many Canadian medical students lack the knowledge and skills needed to adequately care for people with IDD. Despite this, a majority of students were interested in further learning opportunities to improve care for people with IDD. These findings underscore the necessity of evaluating the current medical curriculum and implementing measures to better prepare students to care for this population.

Abstract Background People with disabilities experience perinatal health disparities. This qualitative study examines disabled people’s experiences of labour and delivery care from a disability justice lens. Methods Semi-structured interviews were conducted between July 2019 and February 2020 with 31 women and transgender people aged 18–45 years with physical, sensory, and/or intellectual/developmental disabilities, who were living in in Ontario, Canada and had given birth in the previous five years. Results People with disabilities described negative experiences of provider-driven, disrespectful, and discriminatory labour and delivery care that can be interpreted as examples of disability injustice and obstetric ableism. People with disabilities also described positive experiences of collaborative, respectful, and disability-affirming labour and delivery care that can be interpreted as examples of disability justice, facilitated by what feminist disability justice scholars and activists call collective access. Conclusions Collective access to labour and delivery care can improve perinatal health care for people with disabilities and promote disability justice. Reimagining care-related decision-making as an interdependent, collaborative, respectful, and disability-affirming process shared between patients and providers can help to facilitate collective access to labour and delivery care.

Introduction Children with medical complexity (CMC) have chronic, intensive care needs managed by many healthcare practitioners. Medical advances have enabled CMC to survive well into adulthood. However, the availability of supports as CMC transition into the adult care system remain suboptimal, contributing to poor care coordination, and discontinuity. Promoting Intensive Transitions for Children and Youth with Medical Complexity from Paediatric to Adult Care (PITCare) aims to assess whether intensive patient and caregiver-oriented transition support beyond age 18 will improve continuity of care for CMC compared with usual care.Methods and analysis This is a pragmatic superiority randomised controlled trial in a parallel group, two-arm design with an embedded qualitative component. CMC turning 17.5 years old will be recruited (n=154), along with their primary caregiver. Participants randomised to the intervention arm will be provided with access to a multidisciplinary transition team who will support patients and caregivers in care planning, integration with an adult primary care provider (PCP), adult subspecialty facilitation and facilitation of resource supports for 2 years. Outcomes will be measured at baseline, 12 and 24 months. The primary outcome measure is successful transfer completion, defined as continuous care in the 2 years after age 18 years old. Secondary outcomes include satisfaction with transitional care, self-management, care coordination, healthcare service use, caregiver fatigue, family distress, utility and cost-effectiveness. Qualitative interviews will be conducted to explore the experiences of patients, caregivers, the transition team, and healthcare providers with the PITCare intervention.Ethics and dissemination Institutional approval was obtained from the Hospital for Sick Children Research Ethics Board. Our findings and resources will be shared with child health policymakers and transitions advocacy groups provincially, nationally, and internationally.Trial registration number ClinicalTrials.gov, US National Library of Medicine, National Institutes of Health, #NCT06093386.

The COVID-19 pandemic has had a detrimental impact on sexual and reproductive health (SRH) and rights globally. However, little is known about the experiences of people with disabilities accessing SRH services during the COVID-19 pandemic. In this community-engaged qualitative study, we examined COVID-related impacts on access to SRH services for people with disabilities. We interviewed 61 women and gender-diverse people in Canada from May 2022 to March 2023. Informed by disability reproductive justice, we identified four major themes through constructivist analysis. First, COVID-related changes to SRH service delivery disrupted access to care and caused disability-related health implications. Second, pandemic response measures changed SRH service accessibility: in-person accessibility barriers were amplified, new in-person accessibility barriers were introduced, and the transition to telehealth exacerbated, as well as mitigated, accessibility barriers. Third, COVID-related social changes (e.g. lockdowns) had disability-related SRH and rights implications. Fourth, disabled people recommended improving SRH services by enhancing funding, provider training, information and communication, disability accommodations, representation, and comprehensive community engagement. Cutting across these themes were disproportionate negative impacts of the COVID-19 pandemic on access to SRH services for racialised women and gender-diverse people with disabilities. Failure to ensure SRH and rights for women and gender-diverse people with disabilities during the COVID-19 pandemic undermined disability reproductive justice. Comprehensive disability community engagement is necessary to inform accessible SRH services and policies, both during and beyond a pandemic.

Background Internationally, stresses related to the COVID-19 pandemic negatively affected the mental health of family caregivers of adults with intellectual and developmental disabilities (IDDs). Aims This cross-sectional study investigated demographic, situational and psychological variables associated with mental wellbeing among family caregivers of adults with IDDs during the COVID-19 pandemic. Method Baseline data from 202 family caregivers participating in virtual courses to support caregiver mental well-being were collected from October 2020 to June 2022 via online survey. Mental well-being was assessed using total scores from the Warwick-Edinburgh Mental Wellbeing Scale. Demographic, situational and psychological contributors to mental well-being were identified using hierarchical regression analysis. Results Variables associated with lower levels of mental well-being were gender (women); age (

Summary: Background: People with disabilities are at elevated risk of adverse short-term outcomes following hospitalization for acute infectious illness. No prior studies have compared long-term healthcare use among this high-risk population. We compared the healthcare use of adults with disabilities in the one year following hospitalization for COVID-19 vs. sepsis vs. influenza. Methods: We performed a population-based cohort study using linked clinical and health administrative databases in Ontario, Canada of all adults with pre-existing disability (physical, sensory, or intellectual) hospitalized for COVID-19 (n = 22,551, median age 69 [IQR 57–79], 47.9% female) or sepsis (n = 100,669, median age 77 [IQR 66–85], 54.8% female) between January 25, 2020, and February 28, 2022, and for influenza (n = 11,216, median age 78 [IQR 67–86], 54% female) or sepsis (n = 49,326, median age 72 [IQR 62–82], 45.8% female) between January 1, 2014 and March 25, 2019. The exposure was hospitalization for laboratory-confirmed SARS-CoV-2 or influenza, or sepsis (not secondary to COVID-19 or influenza). Outcomes were ambulatory care visits, diagnostic testing, emergency department visits, hospitalization, palliative care visits and death within 1 year. Rates of these outcomes were compared across exposure groups using propensity-based overlap weighted Poisson and Cox proportional hazards models. Findings: Among older adults with pre-existing disability, hospitalization for COVID-19 was associated with lower rates of ambulatory care visits (adjusted rate ratio (aRR) 0.88, 95% confidence interval (CI), 0.87–0.90), diagnostic testing (aRR 0.86, 95% CI, 0.84–0.89), emergency department visits (aRR 0.91, 95% CI, 0.84–0.97), hospitalization (aRR 0.74, 95% CI, 0.71–0.77), palliative care visits (aRR 0.71, 95% CI, 0.62–0.81) and low hazards of death (adjusted hazard ratio (aHR) 0.71, 95% 0.68–0.75), compared to hospitalization for sepsis during the COVID-19 pandemic. Rates of healthcare use among those hospitalized for COVID-19 varied compared to those hospitalized for influenza or sepsis prior to the pandemic. Interpretation: This study of older adults with pre-existing disabilities hospitalized for acute infectious illness found that COVID-19 was not associated with higher rates of healthcare use or mortality over the one year following hospital discharge compared to those hospitalized for sepsis. However, hospitalization for COVID-19 was associated with higher rates of ambulatory care use and mortality when compared to influenza. As COVID-19 enters an endemic phase, the associated long-term health resource use and risks in the contemporary era are reassuringly similar to sepsis and influenza, even among people with pre-existing disabilities. Funding: This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. This study also received funding from the Canadian Institutes of Health Research (CIHR GA4-177772).

Introduction Removing a child from their family is the option of last resort for social services. However, decisions to place children into care are occurring more frequently and earlier in children's lives, with newborn discharge to social services being a particular concern due to the effects of mother-newborn separations on child development. Women with disabilities face negative assumptions about their parenting capacity, but little is known about their rates of newborn discharge to social services. Objectives To examine the risk of discharge to social services among newborns of women with and without disabilities. Methods We conducted a population-based cohort study of singleton livebirths in Ontario, Canada, 2008-2019. We used modified Poisson regression to estimate the relative risk (RR) of discharge to social services immediately after the birth hospital stay, comparing newborns of women with physical (n = 114,685), sensory (n = 38,268), intellectual/developmental (n = 2,094), and multiple disabilities (n = 8,075) to newborns of women without a disability (n = 1,221,765). Within each group, we also examined maternal sociodemographic, health, health care, and pregnancy-related characteristics associated with the outcome. Results Compared to newborns of women without disabilities (0.2%), newborns of women with physical (0.5%; aRR 1.53, 95% CI 1.39-1.69), sensory (0.4%; aRR 1.34, 95% CI 1.12-1.59), intellectual/developmental (5.6%; aRR 5.34, 95% CI 4.36-6.53), and multiple disabilities (1.7%; aRR 3.09, 95% CI 2.56-3.72) had increased risk of being discharged to social services after the birth hospital stay. Within each group, the strongest predictors of the outcome were young maternal age, low income quintile, social assistance, maternal mental illness and substance use disorders, inadequate prenatal care, and neonatal morbidity. Conclusions Newborns of women with disabilities are at increased risk of being discharged to social services after the birth hospital stay. These findings can be used to inform the development of tailored supports for new mothers with disabilities and their infants.

Background The COVID-19 pandemic significantly impacted the mental health of adults with intellectual and developmental disabilities (IDD). During this period of uncertainty and need for up-to-date information, various virtual training programmes demonstrated the role of tele-mentoring programmes. Aim The aim of this paper is to describe the educational evaluation of the National Extension for Community Healthcare Outcomes – Adults with Intellectual and Developmental Disabilities (ECHO-AIDD), a programme for service providers working with adults with IDD during COVID-19. Method The programme consisted of six sessions, conducted weekly, over two cycles. Each session included didactic teaching by hub team members, COVID-19 news updates, wellness check-ins and a brief mindfulness activity, followed by a 30 to 45 min case-based discussion. The hub structure had an inter-professional approach to team expertise. Those with lived experience were an integral part of the content experts’ hub. Pre-, post- and follow-up evaluation data were collected. Results Care providers from health and social care sectors (n = 230) participated in the programme. High levels of engagement and satisfaction were reported. Self-efficacy ratings improved from pre- to post-, and were maintained at 8-week follow-up; improvement from pre- to post- was significant (P < 0.0001). Conclusion Exposure to National ECHO-AIDD educational intervention led to improvement in perceived competencies. This study also shows the valuable role of people with lived experience in fostering adaptive expertise in learners. The outreach and scalability support the feasibility of building a national virtual community of practice for IDD service providers. Future studies should focus on studying the impact of these programmes on the health outcomes of people with IDD.

Major urban centers are grappling with challenges related to urban mobility and elevated greenhouse gas emissions. Shared electric bicycles (e-bikes) present a potential solution to these issues. Nonetheless, many ventures of this nature have previously faltered due to high operational costs. This paper aims to assess the optimal decisions for a shared e-bike company serving a university community. To this end, we consider two relocation strategies: one led by the operator and another by the user. Additionally, we examine elements inherent to a smart campus, such as photovoltaic systems and advanced energy tariffs, like time-of-use and real-time tariffs. We modeled the optimization problem as a mixed-integer nonlinear program, further linearized to a mixed-integer linear program using the Big-M method. Our case study focuses on the academic community at Universidade Federal Fluminense in Niterói, Brazil. Findings suggest a trade-off between operator and user relocation tariffs. They also underscore an enhancement in meeting demand, from 51 % to 69 %, when both mechanisms are employed. Lastly, the smart campus influences the operator's decisions, highlighting the importance of considering the interplay between energy and rental tariffs during planning.

Abstract Background In January 2018, the Government of Ontario, Canada, initiated a universal pharmacare program (OHIP+) for all individuals aged 24 years and younger. In April 2019, the program was amended to cover only children and youth without private insurance. Because benzodiazepines are commonly prescribed to children and youth despite their potential hazards, we examined whether changes in publicly-funded drug coverage influenced benzodiazepine dispensing trends in this demographic. Methods We conducted a population-based natural experiment study of benzodiazepine dispensing to children and youth in Ontario between January 2013 and March 2020. We used interventional autoregressive integrated moving average models to estimate the impact of OHIP + and its subsequent modification on these trends. Results The implementation of OHIP + was associated with an immediate increase in the monthly rate of benzodiazepine dispensing of 12.9 individuals per 100,000 population (95% confidence interval [CI]; 7.5 to 18.3 per 100,000). Benzodiazepine dispensing rates rose from 214.2 to 241.5 per 100,000 from December 2017 to March 2019, a 12.8% (95% CI 9.6–16.0%) increase. In stratified analyses, increases were most pronounced among females, children and youth living in the lowest income neighbourhoods and individuals aged 20 to 24. The April 2019 modification to OHIP + was not associated with changes in monthly benzodiazepine dispensing trends (0.39 individuals per 100,000; 95% CI -1.3 to 2.1 per 100,000). However, rates remained elevated relative to the period preceding OHIP + implementation. Conclusions Implementation of a publicly-funded pharmacare program resulted in more children and youth being prescribed benzodiazepines.

BackgroundAtypical sensory reactivity is a cardinal presentation in autism. Within the tactile domain, atypical tactile reactivity (TR) is common, it emerges early, persists into adulthood, and impedes social interaction and daily functioning. Hence, atypical TR is a key target for biological intervention to improve outcomes. Brain mechanisms informing biological interventions for atypical TR remains elusive. We previously reported hyper-plasticity in the motor cortex in autistic adults and found that repetitive transcranial magnetic stimulation (rTMS), designed to strengthen inhibitory processes in the brain, reduced hyper-plasticity. Whether the primary sensory cortex (S1) is characterized by hyper-plasticity, which may underlie atypical TR in autism is unknown.ObjectivesWe aim to test whether hyper-plasticity in the S1 underlies atypical TR in autism, and investigate if a single session of rTMS can safely reduce hyper-plasticity in S1 in autistic adults.MethodPlasticity will be assessed in the left S1 with integrated paired associative stimulation and electroencephalography (PAS-EEG) paradigm in 32 autistic adults and 32 age-, sex-, and intelligence quotient-matched controls. Autistic participants will be further randomized (double-blind, 1:1) to receive a single-session of either sham or active 20 Hz bilateral rTMS over the S1 and the plasticity will be re-assessed over the left S1 on the same day.ConclusionsAtypical TR has been identified as one of the top clinical research priorities that can influence outcome in autistic population. The study findings can be highly valuable to further elucidate the mechanism underlying atypical TR, which in turn can help with developing a mechanism-driven intervention.

Enhancing production of protein cargoes delivered by gene therapies can improve efficacy by reducing the amount of vector or simply increasing transgene expression levels. We explored the utility of a 126-amino acid collagen domain (CD) derived from the C1qTNF3 protein as a fusion partner to chaperone secreted proteins, extracellular “decoy receptor” domains, and single-chain variable fragments (scFvs). Fusions to the CD domain result in multimerization and enhanced levels of secretion of numerous fusion proteins while maintaining functionality. Efficient creation of bifunctional proteins using the CD domain is also demonstrated. Recombinant adeno-associated viral vector delivery of the CD with a signal peptide resulted in high-level expression with minimal biological impact as assessed by whole-brain transcriptomics. As a proof-of-concept in vivo study, we evaluated three different anti-amyloid Aβ scFvs (anti-Aβ scFvs), alone or expressed as CD fusions, following viral delivery to neonatal CRND8 mice. The CD fusion increased half-life, expression levels, and improved efficacy for amyloid lowering of a weaker binding anti-Aβ scFv. These studies validate the potential utility of this small CD as a fusion partner for secretory cargoes delivered by gene therapy and demonstrate that it is feasible to use this CD fusion to create biotherapeutic molecules with enhanced avidity or bifunctionality.

BackgroundThe COVID-19 pandemic was associated with increases in the prevalence of depression, anxiety and behavioural problems among children and youth. Less well understood is the influence of the pandemic on antidepressant and antipsychotic use among children. This is important, as it is possible that antidepressants and antipsychotics were used as a “stop-gap” measure to treat mental health symptoms when in-person access to outpatient care and school-based supportive services was disrupted. Furthermore, antipsychotics and antidepressants have been associated with harm in children and youth. We examined trends in dispensing of these medications two years following the pandemic among children 18 years of age and under in Ontario, Canada.MethodsWe conducted a population-based time-series study of antidepressant and antipsychotic medication dispensing to children and adolescents ≤18 years old between September 1, 2014, and March 31, 2022. We measured monthly population-adjusted rates of antidepressant and antipsychotics obtained from the IQVIA Geographic Prescription Monitor (GPM) database. We used structural break analyses to identify the pandemic month(s) when changes in the dispensing of antidepressants and antipsychotics occurred. We used interrupted time series models to quantify changes in dispensing following the structural break and compare observed and expected use of these drugs.ResultsOverall, we found higher-than-expected dispensing of antidepressants and antipsychotics in children and youth. Specifically, we observed an immediate step decrease in antidepressant dispensing associated with a structural break in April 2020 (−55.8 units per 1,000 individuals; 95% confidence intervals [CI] CI: −117.4 to 5.8), followed by an increased monthly trend in the rate of antidepressant dispensing of 13.0 units per 1,000 individuals (95% CI: 10.2–15.9). Antidepressant dispensing was consistently greater than predicted from September 2020 onward. Antipsychotic dispensing increased immediately following a June 2020 structural break (26.4 units per 1,000 individuals; 95% CI: 15.8–36.9) and did not change appreciably thereafter. Antipsychotic dispensing was higher than predicted at all time points from June 2020 onward.ConclusionWe found higher-than-expected dispensing of antidepressants and antipsychotics in children and youth. These increases were sustained through nearly two years of observation and are especially concerning in light of the potential for harm with the long-term use of antipsychotics in children. Further research is required to understand the clinical implications of these findings.

Objectives Despite young carers (YCs) providing regular and significant care that exceeds what would normally be associated with an adult caregiver, we need to learn more about their experience interacting with the healthcare system. The primary study aims were to (1) describe YC experiences in interacting with the healthcare system and (2) identify types of support YC recognise as potentially helpful to their caring role.Design and setting A mixed-methods qualitative study was conducted between March 2022 and August 2022, comprising two phases of (1) semi-structured interviews and focus groups with YCs living in the community to confirm and expand earlier research findings, and (2) a co-design workshop informed by a generative research approach. We used findings from the interviews and focus groups to inform the brainstorming process for identifying potential solutions.Results Eight YCs completed either a focus group or an interview, and four continued the study and participated in the co-design activity with 12 participants. Phase 1 resulted in three overarching themes: (1) navigating the YC role within the healthcare system; (2) being kept out of the loop; and (3) normalising the transition into caregiving. Phase 2 identified two categories: (1) YC-focused supports and (2) raising awareness and building capacity in the healthcare system.Conclusion Study findings revealed the critical role that YCs play when supporting their families during pivotal interactions in the healthcare system. Like their older caregiver counterparts, YCs struggle to navigate, coordinate and advocate for their family members while juggling their needs as they transition from adolescence to adulthood. This study provides important preliminary insights into YCs encountering professionals, which can be used to design and implement national support structures.

Abstract Background Despite the increasing global population of individuals with intellectual and developmental disabilities (IDD), this population remains especially vulnerable to health disparities through several factors such as a lack of access to sufficient medical care and poor determinants of health. To add, numerous studies have shown that healthcare professionals are still insufficiently prepared to support this population of patients. This review synthesizes the literature on current pre-graduate IDD training programs across healthcare professions with the goal of informing the creation of evidence-based curricula. Methods Four major databases were searched for current pre-graduate IDD training interventions for healthcare professionals. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis flow diagram and the Best Evidence Medical Educations systematic review guide were used to frame our collection and analysis. Results Of the 8601 studies screened, 32 studies were identified, with most studies involving medical students (50%). Of note, 35% of studies were interprofessional. Most interventions utilized multiple pedagogical methods with a majority including clinical experiences (63%) followed by theoretical teaching (59%). Kirkpatrick levels showed 9% were level 0, 6% were level 1, 31% were level 2A, 31% were level 2B, 19% were level 3, 3% were level 4A, and none were level 4B. Conclusions There is a paucity of formally evaluated studies in pre-graduate health professional IDD education. As well, there are a lack of longitudinal learning opportunities and integration into formal curriculum. Strengths identified were the use of multimodal approaches to teaching, including interprofessional approaches to optimize team competencies.

Abstract Background High quality communication is central to effective primary care. The COVID-19 pandemic led to a dramatic increase in virtual care but little is known about how this may affect communication quality. Adults with intellectual and developmental disabilities (IDD) can experience challenges communicating or communicate in non-traditional ways. This study explored how the use of virtual modalities, including telephone and video, affects communication in primary care interactions for patients with IDD. Methods This qualitative descriptive study included semi-structured interviews with a multi-stakeholder sample of 38 participants, including 11 adults with IDD, 13 family caregivers, 5 IDD support staff and 9 primary care physicians. Interviews were conducted in Ontario, Canada between March and November 2021 by video-conference or telephone. A mixed inductive and deductive thematic analysis approach was used to code the data and identify themes. Themes were reviewed and refined with members of each stakeholder group. Results Four elements of communication were identified that were affected by virtual care: (1) patient engagement in the virtual appointment; (2) the ability to hear other participants and have the time and space to be heard; (3) the ability to use nonverbal communication strategies; and (4) the ability to form trusting relationships. In some cases, the virtual platform hindered these elements of communication. Video offered some advantages over telephone to support nonverbal communication, and stimulate engagement; though this could be limited by technical challenges. For adults with IDD who find it difficult to attend in-person appointments, virtual care improved communication quality by allowing them to participate from a space where they were comfortable. Conclusion Though there are circumstances in which virtual delivery can improve communication for patients with IDD, there are also challenges to achieving high quality patient-provider communication over telephone and video. Improved infrastructure and training for providers, patients and caregivers can help improve communication quality, though in some cases it may never be appropriate. A flexible patient-centred approach is needed that includes in-person, telephone and video options for care.

Abstract Background Population-based research examining geographic variability in psychotropic medication dispensing to children and youth and the sociodemographic correlates of such variation is lacking. Variation in psychotropic use could reflect disparities in access to non-pharmacologic interventions and identify potentially concerning use patterns. Methods We conducted a population-based study of all Ontario residents aged 0 to 24 years who were dispensed a benzodiazepine, stimulant, antipsychotic or antidepressant between January 1, 2018, and December 31, 2018. We conducted small-area variation analyses and identified determinants of dispensing using negative binomial generalized estimating equation models. Results The age- and sex-standardized rate of psychotropic dispensing to children and youth was 76.8 (range 41.7 to 144.4) prescriptions per 1000 population, with large variation in psychotropic dispensing across Ontario’s census divisions. Males had higher antipsychotic [rate ratio (RR) 1.40; 95% confidence interval (CI) 1.36 to 1.44) and stimulant (RR 1.75; 95% CI 1.70 to 1.80) dispensing rates relative to females, with less use of benzodiazepines (RR 0.85; 95% CI 0.83 to 0.88) and antidepressants (RR 0.81; 95% CI 0.80 to 0.82). Lower antipsychotic dispensing was observed in the highest income neighbourhoods (RR 0.72; 95% CI 0.70 to 0.75) relative to the lowest. Benzodiazepine (RR 1.12; 95% CI 1.01 to 1.24) and stimulant (RR 1.11; 95% CI 1.01 to 1.23) dispensing increased with the density of mental health services in census divisions, whereas antipsychotic use decreased (RR 0.82; 95% CI 0.73 to 0.91). The regional density of child and adolescent psychiatrists and developmental pediatricians (RR 1.00; 95% CI 0.99 to 1.01) was not associated with psychotropic dispensing. Conclusion We found significant variation in psychotropic dispensing among young Ontarians. Targeted investment in regions with long wait times for publicly-funded non-pharmacological interventions and novel collaborative service models may minimize variability and promote best practices in using psychotropics among children and youth.

Abstract Background Effective provider-patient communication is a key element of quality health care, including perinatal care. What constitutes “effective communication” in perinatal care may vary according to the population seeking care, such as women with intellectual and developmental disabilities (IDD) and sensory disabilities. Research broadly indicates that communication issues are among the barriers to perinatal care experienced by women with disabilities. However, few studies have explicitly explored their communication experiences in this context. The purpose of this study was to understand the communication experiences of birthing people with IDD and/or sensory disabilities in perinatal care. Methods We conducted semi-structured interviews with 17 people with IDD (e.g., autism, cognitive delay) and/or sensory disabilities (e.g., d/Deaf, blind) in Ontario, Canada, who had recently given birth, to explore barriers to and facilitators of effective communication in perinatal care. A combination of deductive and inductive thematic analysis guided data analysis. Results We found that birthing people with IDD and/or sensory disabilities encountered multiple barriers to effective communication in perinatal care, namely, lack of policies and guidelines, lack of provider experience, lack of provider effort, as well as ableism and provider assumptions. Facilitators included knowledgeable, aware, and supportive providers; access to communication aids and services; tailoring information to patients’ disability-related communication needs; empathic communication; and, communication among providers. Conclusion Unmet communication needs may contribute to negative health and social outcomes for birthing people with disabilities and their newborns. Accessibility policy implementation and practice change are needed to meet the communication needs of people with IDD and/or sensory disabilities in perinatal care to ensure positive experiences and outcomes.

Abstract Single domain antibodies (VHHs) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHHs have not been widely used in the central nervous system (CNS), largely because of their restricted blood–brain barrier (BBB) penetration. Here, we propose a gene transfer strategy based on BBB‐crossing adeno‐associated virus (AAV)‐based vectors to deliver VHH directly into the CNS. As a proof‐of‐concept, we explored the potential of AAV‐delivered VHH to inhibit BACE1, a well‐characterized target in Alzheimer’s disease. First, we generated a panel of VHHs targeting BACE1, one of which, VHH‐B9, shows high selectivity for BACE1 and efficacy in lowering BACE1 activity in vitro. We further demonstrate that a single systemic dose of AAV‐VHH‐B9 produces positive long‐term (12 months plus) effects on amyloid load, neuroinflammation, synaptic function, and cognitive performance, in the AppNL‐G‐F Alzheimer’s mouse model. These results constitute a novel therapeutic approach for neurodegenerative diseases, which is applicable to a range of CNS disease targets.

BackgroundIn 2011, the Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA) published guidelines for the metabolic monitoring of antipsychotic-treated children and youth. Population-based studies examining adherence to these guidelines are needed to ensure the safe use of antipsychotics in children and youth.MethodsWe conducted a population-based study of all Ontario residents aged 0 to 24 who were newly dispensed an antipsychotic between April 1, 2018, and March 31, 2019. We estimated prevalence ratios (PRs) and 95% confidence intervals (CI) associating sociodemographic characteristics with the receipt of baseline and follow-up (3- and 6-month) laboratory testing using log-Poisson regression models.ResultsOverall, 6,505 of 27,718 (23.5%) children and youth newly dispensed an antipsychotic received at least one guideline-recommended baseline test. Monitoring was more prevalent among individuals aged 10 to 14 years (PR 1.20; 95% CI 1.04 to 1.38), 15 to 19 years (PR 1.60; 95% CI 1.41 to 1.82), and 20 to 24 years (PR 1.71; 95% CI 1.50 to 1.94) compared to children under the age of 10. Baseline monitoring was associated with mental health-related hospitalizations or emergency department visits in the year preceding therapy (PR 1.76; 95% CI 1.65 to 1.87), a prior diagnosis of schizophrenia (PR 1.20; 95% CI 1.14 to 1.26) or diabetes (PR 1.35; 95% CI 1.19 to 1.54), benzodiazepine use (PR 1.13; 95% CI 1.04 to 1.24), and receipt of a prescription from a child and adolescent psychiatrist or developmental pediatrician versus a family physician (PR 1.41; 95% CI 1.34 to 1.48). Conversely, monitoring was less frequent in individuals co-prescribed stimulants (PR 0.83; 95% CI 0.75 to 0.91). The prevalence of any 3- and 6-month follow-up monitoring among children and youth receiving continuous antipsychotic therapy at these time points was 13.0% (1,179 of 9,080) and 11.4% (597 of 5,261), respectively. Correlates of follow-up testing were similar to those of baseline monitoring.ConclusionMost children initiating antipsychotic therapy do not receive guideline-recommended metabolic laboratory monitoring. Further research is needed to understand reasons for poor guideline adherence and the role of clinician training and collaborative service models in promoting best monitoring practices.

Background: Autism is not always considered for girls and women until later along their clinical diagnostic pathways. Misdiagnosis or late diagnosis can pose significant disadvantages with respect to accessing timely health and autism-related services and supports. Understanding what contributes to roadblocks and detours along clinical pathways to an autism diagnosis can shed light on missed opportunities for earlier recognition. Objective: Our objective was to examine what contributed to roadblocks, detours, and missed opportunities for earlier recognition and clinical diagnosis of autism for girls and women. Design: We conducted a qualitative secondary analysis using data from a Canadian primary study that examined the health and healthcare experiences of autistic girls and women through interviews and focus groups. Methods: Transcript data of 22 girls and women clinically diagnosed with autism and 15 parents were analysed, drawing on reflexive thematic analysis procedures. Techniques included coding data both inductively based on descriptions of roadblocks and detours and deductively based on conceptualizations of sex and gender. Patterns of ideas were categorized into themes and the ‘story’ of each theme was refined through writing and discussing analytic memos, reflecting on sex and gender assumptions, and creating a visual map of clinical pathways. Results: Contributing factors to roadblocks, detours, and missed opportunities for earlier recognition and diagnosis were categorized as follows: (1) age of pre-diagnosis ‘red flags’ and ‘signals’; (2) ‘non-autism’ mental health diagnoses first; (3) narrow understandings of autism based on male stereotypes; and (4) unavailable and unaffordable diagnostic services. Conclusion: Professionals providing developmental, mental health, educational, and/or employment supports can be more attuned to nuanced autism presentations. Research in collaboration with autistic girls and women and their childhood caregivers can help to identify examples of nuanced autistic features and how context plays a role in how these are experienced and navigated.

Severe behavioral problems (SBPs) are common contributors to morbidity and reduced quality of life for adults with intellectual and developmental disabilities (IDD) and their families. Current medications for SBPs show equivocal effectiveness and are associated with a high risk of side effects. New and safe treatments are urgently needed. While preliminary studies suggest that medical cannabinoids, particularly the synthetic cannabinoid nabilone, are plausible treatment options for SBPs in adults with IDD, data on the tolerability, safety and efficacy of nabilone in this population has never been investigated. Thus, we propose this first-ever Phase I pre-pilot open-label clinical trial to obtain preliminary data on the adherence, tolerability and safety profiles of nabilone in adults with IDD, and explore changes in SBPs pre- to post-treatment. We hypothesize that nabilone has favorable tolerability and safety profile for adults with IDD. The preliminary results will inform the next-stage pilot randomized controlled trials, followed by fully powered clinical trials eventually. This research helps fill the evidence gap in the use of cannabinoids in individuals with IDD to meet the needs of patients, families, and service providers.

Background: Autistic women experience life differently than autistic men. For example, autistic women tend to be diagnosed significantly later than autistic men, they experience a higher number of traumas, and are at increased risk for mental health conditions. Given gender-specific life experiences, autistic women may benefit from gender-specific group-based supports. Virtual mindfulness has been shown to be helpful in improving well-being among autistic adults; however, limited research has explored the impact of virtual mindfulness when it is delivered to a group of autistic women only. Objectives: The aim of this article is to describe a preliminary evaluation of a virtual mindfulness group piloted for autistic women. Five key areas of feasibility were assessed in the current study: demand, implementation, acceptability, practicality, and limited efficacy testing. Methods: Twenty-eight women participated in a 6-week virtual autism-informed mindfulness program and were asked to complete measures assessing psychological distress, self-compassion, and mindfulness at pre and post. Participants were also asked to complete a satisfaction survey after the program. Results: Results showed that the program was feasible in terms of demand, implementation, practicality, and acceptability. While quantitative results showed there were no changes in psychological distress, self-compassion, and mindfulness from pre- to post-program, qualitative results showed some benefits. Conclusion: Given the unique challenges that some autistic women experience, offering groups to autistic women may have some value and it would be important to continue exploring this topic area.

Background Individuals with intellectual and developmental disability (IDD) can have a high prevalence of pain, which can be managed with prescription opioids. However, the prevalence of substance use disorder is also high in this population, raising concern about opioid-related adverse events. Aims To assess the risk of opioid-related adverse events following opioid initiation among adults with versus without IDD. Method We conducted a population-based, propensity score matched cohort study on all adults starting prescription opioid therapy in Ontario, Canada, between January 2013 and December 2018. The outcomes of interest were opioid toxicity, new opioid use disorder (OUD) diagnosis and dose escalation (≥90 mg morphine or equivalent) in the year after opioid initiation. We used Cox proportional hazards models to assess the association between IDD diagnosis and each outcome. Results The hazards of opioid toxicity and OUD were significantly higher in those with IDD compared with those without IDD in unmatched analyses (opioid toxicity hazard ratio 3.19, 95% CI 2.81–5.18; OUD hazard ratio 2.36, 95% CI 2.10–2.65), whereas the hazard of dose escalation was significantly lower (hazard ratio 0.76, 95% CI 0.66–0.88). Findings were no longer significant in propensity score matched models for opioid toxicity and dose escalation, whereas the hazard of OUD diagnosis was attenuated substantially in those with IDD (hazard ratio 0.79, 95% CI 0.68–0.91). Conclusions IDD diagnosis is not a driver of opioid-related harm. The increased risk we observed is likely driven by various risk factors often present in this population.

Abstract Introduction Passive immunotherapies targeting Aβ continue to be evaluated as Alzheimer’s disease (AD) therapeutics, but there remains debate over the mechanisms by which these immunotherapies work. Besides the amount of preexisting Aβ deposition and the type of deposit (compact or diffuse), there is little data concerning what factors, independent of those intrinsic to the antibody, might influence efficacy. Here we (i) explored how constitutive priming of the underlying innate activation states by Il10 and Il6 might influence passive Aβ immunotherapy and (ii) evaluated transcriptomic data generated in the AMP-AD initiative to inform how these two cytokines and their receptors’ mRNA levels are altered in human AD and an APP mouse model. Methods rAAV2/1 encoding EGFP, Il6 or Il10 were delivered by somatic brain transgenesis to neonatal (P0) TgCRND8 APP mice. Then, at 2 months of age, the mice were treated bi-weekly with a high-affinity anti-Aβ1–16 mAb5 monoclonal antibody or control mouse IgG until 6 months of age. rAAV mediated transgene expression, amyloid accumulation, Aβ levels and gliosis were assessed. Extensive transcriptomic data was used to evaluate the mRNA expression levels of IL10 and IL6 and their receptors in the postmortem human AD temporal cortex and in the brains of TgCRND8 mice, the later at multiple ages. Results Priming TgCRND8 mice with Il10 increases Aβ loads and blocks efficacy of subsequent mAb5 passive immunotherapy, whereas priming with Il6 priming reduces Aβ loads by itself and subsequent Aβ immunotherapy shows only a slightly additive effect. Transcriptomic data shows that (i) there are significant increases in the mRNA levels of Il6 and Il10 receptors in the TgCRND8 mouse model and temporal cortex of humans with AD and (ii) there is a great deal of variance in individual mouse brain and the human temporal cortex of these interleukins and their receptors. Conclusions The underlying immune activation state can markedly affect the efficacy of passive Aβ immunotherapy. These results have important implications for ongoing human AD immunotherapy trials, as they indicate that underlying immune activation states within the brain, which may be highly variable, may influence the ability for passive immunotherapy to alter Aβ deposition.

BackgroundThe COVID-19 pandemic has led to an unprecedented increase in the delivery of virtual primary care. Adults with intellectual and developmental disabilities (IDDs) have complex health care needs, and little is known about the value and appropriateness of virtual care for this patient population. ObjectiveThe aim of this study was to explore the accessibility of virtual primary care for patients with IDDs during the pandemic. MethodsWe conducted semistructured interviews with 38 participants in Ontario, Canada between March and November 2021. A maximum variation sampling strategy was used to achieve a diverse sample including 11 adults with IDDs, 13 family caregivers, 5 IDD support staff members, and 9 primary care physicians. An iterative mixed inductive and deductive thematic analysis approach was used to code the data and synthesize higher-level themes. The analysis was informed by the Levesque Patient-Centered Access to Health Care Framework. ResultsWe identified themes related to 4 of 5 access-to-care dimensions that highlighted both the benefits and challenges of virtual care for adults with IDDs. The benefits included saving time spent traveling and waiting; avoiding anxiety and challenging behavior for patients who struggle to attend in-person visits; allowing caregivers who live far away from their loved ones to participate; reducing illness transmission; and allowing health care providers to see patients in their home environments. The challenges included lack of access to necessary technology, lack of comfort or skill using technology, and lack of nonverbal communication; difficulty engaging and establishing rapport; patient exclusion from the health care encounter; and concerns about privacy and confidentiality. An overarching theme was that “one size does not fit all,” and the accessibility of virtual care was dependent on the interaction between the following 5 categories of factors: patient characteristics, patient context, caregiver characteristics, service context, and reason for a particular primary care visit. Though virtual care was not always appropriate, in some cases, it dramatically improved patients’ abilities to access necessary health care. ConclusionsThis study suggests that a flexible patient-centered system including multiple delivery modalities is needed to ensure all patients have access to primary care. Implementing this system will require improved virtual care platforms, access to technology for patients and caregivers, training for primary care providers, and appropriately aligned primary care funding models.

Objectives Equitable vaccine distribution was essential in supporting Ontario’s COVID-19 response, particularly for persons with intellectual and developmental disabilities (IDD), who have been disproportionately impacted by the pandemic. An Applied Health Research Question (AHRQ) request through ICES, sought to report on COVID-19 vaccination uptake in adults with and without IDD. Approach To examine the proportion of adults with IDD vaccinated for COVID-19, a request from the Ministry of Children, Community and Social Services (MCCSS) was approved by the ICES-AHRQ team. A secondary goal was to explore if vaccinated individuals with IDD experienced similar levels of protection from COVID-19 infection, to the general population. The open cohort was derived by linking vaccination events reported in Ontario COVID-19 Vaccine Data, between December 2020 to December 2021, to several administrative health databases. An algorithm was used to define IDD by a series of inpatient hospitalizations, emergency department and/or physician visits, with IDD diagnostic codes. Results The proportion who received at least two doses was similar between both groups (82% (IDD); 83% (non-IDD)). However, despite emerging evidence suggesting that high-risk populations should receive a third dose, a lower proportion of people with IDD (25%), compared to the general population without IDD (30%), had done so. The IDD subpopulation is generally younger, and partially explained the third dose findings when examined by age. Withal, adults with IDD vaccinated with at least two doses were mostly male (62% vs 48%), 18-29 years of age (44% vs 17%), and from the lowest neighborhood income quintile (26% vs 18%), compared to the non-IDD population, respectively. Cumulatively, adults with IDD had comparable rates of confirmed breakthrough case infections following vaccination (17%), to those without IDD (19%). Conclusion/Implications Administrative health data and analytics through the ICES-AHRQ program were used in responding to COVID-19, and providing public health guidance, for those with IDD. To inform decision making and policy actions related to immediate vaccination strategies, MCCSS used such findings to target vaccination efforts in specific IDD subpopulations, across Ontario.

The COVID-19 pandemic has impacted the lives and well-being of all people globally, with consequences being observed across all domains from physical and mental health, to education and employment outcomes, to access to community supports and services. However, the disproportionate impact of the COVID-19 pandemic and its associated public health restrictions on individuals with intellectual and developmental disabilities (IDD) has largely been overlooked. Not only do people with IDD have a greater risk of severe complications and death from the virus as shown in large-scale studies, but they also face significant short- and long-term consequences of COVID-related public health measures on their mental health and well-being. At a time when this vulnerable population is already feeling undervalued, ignored, and forgotten, it is imperative that the risks facing adults and children with IDD—as well as their families and caregivers—are recognized, valued, and addressed through a disability-inclusive approach to Canada’s pandemic policy response planning. This requires both a mainstreaming of disability inclusion into all COVID-19 response and recovery policies as well as disability-specific policies to address the unique barriers and challenges encountered by people with IDD during the pandemic. The recommendations in this policy briefing aim to achieve a more inclusive, accessible, and sustainable Canada for people with IDD both during and after the pandemic—an approach that will result in benefits for all of society.

Smart grid refers to the advancement of the current electric grid with the help of information and communication technologies. In such scenarios, an efficient and secure smart grid communication system is essential. Accordingly, Software-Defined Networks (SDN) have been gaining more prominence for smart grids in recent years, as this paradigm allows monitoring and managing these communication networks efficiently. An example is the Autonomic and Resilient Framework for Smart Grids (ARES). ARES allows integration between the supervisory system and the SDN controller, allowing for better energy applications. Although ARES emphasizes the need for security as a premise for its implementation, it does not provide a concrete implementation of this aspect. In this work, we provide an extensive review of the related literature about Authentication, Authorization, and Accountability (AAA) for smart grids, classifying approaches according to several relevant characteristics. We further propose 3AS, extending the ARES framework with a security component based on the IEEE 802.1X standard. 3AS has been implemented on the Ryu SDN controller and evaluated in an emulated environment. Results indicate 3AS successfully provides authentication, authorization, and accountability with low control load and delay, thus being suitable for diverse smart grid scenarios.

Sensing and monitoring electrical signals and power device parameters within the smart grid network infrastructure plays a fundamental role in assessing the smart devices’ proper functioning. Nevertheless, a key challenge for academic teaching and researching purposes is the elevated cost of real electronic devices, such as current and potential transformers, or even intelligent electronic devices. Therefore, traffic emulators are a valuable solution for the evaluation of new smart grid communication proposals. In this work, we propose TITAN, a tool to support the evaluation of automation systems’ communication networks. TITAN enables the emulation of IEC 61850 communication, ranging from data sensing to data acquisition, thus supporting extensive research and development on this fundamental smart grid domain. This tool can interact and communicate with real elements, such as intelligent electronic devices. It enables the emulation of voltage and current data sensing communication, as well as the implementation of different data acquisition schemes by an emulated supervisory system. Our main contributions are: (i) TITAN, a tool with a distributed microservices architecture to execute communication traffic generation tasks; (ii) a user-friendly interface to integrate and manage all components; and (iii) a proof of concept testbed using TITAN and real teleprotection devices. Real case studies using TITAN reveal its feasibility in supporting low-cost testbeds for research, teaching, and testing purposes in sensing and acquisition for automation systems.

Abstract Background Self-assembly of the amyloid-β (Aβ) peptide into aggregates, from small oligomers to amyloid fibrils, is fundamentally linked with Alzheimer’s disease (AD). However, it is clear that not all forms of Aβ are equally harmful and that linking a specific aggregate to toxicity also depends on the assays and model systems used (Haass et al., J Biol. Chem 269:17741–17748, 1994; Borchelt et al., Neuron 17:1005–1013, 1996). Though a central postulate of the amyloid cascade hypothesis, there remain many gaps in our understanding regarding the links between Aβ deposition and neurodegeneration. Methods In this study, we examined familial mutations of Aβ that increase aggregation and oligomerization, E22G and ΔE22, and induce cerebral amyloid angiopathy, E22Q and D23N. We also investigated synthetic mutations that stabilize dimerization, S26C, and a phospho-mimetic, S8E, and non-phospho-mimetic, S8A. To that end, we utilized BRI2-Aβ fusion technology and rAAV2/1-based somatic brain transgenesis in mice to selectively express individual mutant Aβ species in vivo. In parallel, we generated PhiC31-based transgenic Drosophila melanogaster expressing wild-type (WT) and Aβ40 and Aβ42 mutants, fused to the Argos signal peptide to assess the extent of Aβ42-induced toxicity as well as to interrogate the combined effect of different Aβ40 and Aβ42 species. Results When expressed in the mouse brain for 6 months, Aβ42 E22G, Aβ42 E22Q/D23N, and Aβ42WT formed amyloid aggregates consisting of some diffuse material as well as cored plaques, whereas other mutants formed predominantly diffuse amyloid deposits. Moreover, while Aβ40WT showed no distinctive phenotype, Aβ40 E22G and E22Q/D23N formed unique aggregates that accumulated in mouse brains. This is the first evidence that mutant Aβ40 overexpression leads to deposition under certain conditions. Interestingly, we found that mutant Aβ42 E22G, E22Q, and S26C, but not Aβ40, were toxic to the eye of Drosophila. In contrast, flies expressing a copy of Aβ40 (WT or mutants), in addition to Aβ42WT, showed improved phenotypes, suggesting possible protective qualities for Aβ40. Conclusions These studies suggest that while some Aβ40 mutants form unique amyloid aggregates in mouse brains, they do not exacerbate Aβ42 toxicity in Drosophila, which highlights the significance of using different systems for a better understanding of AD pathogenicity and more accurate screening for new potential therapies.

Abstract Background There is a growing recognition of sex and gender influences in autism. Increasingly, studies include comparisons between sexes or genders, but few have focused on clarifying the characteristics of autistic girls’/women’s physical health. Methods A scoping review was conducted to determine what is currently known about the physical health of autistic girls/women. We screened 1112 unique articles, with 40 studies meeting the inclusion criteria. We used a convergent iterative process to synthesize this content into broad thematic areas. Results Autistic girls/women experience more overall physical health challenges compared to non-autistic girls/women and to autistic boys/men. Emerging evidence suggests increased prevalence of epilepsy in autistic girls/women compared to non-autistic girls/women and to autistic boys/men. The literature also suggests increased endocrine and reproductive health conditions in autistic girls/women compared to non-autistic girls/women. Findings regarding gastrointestinal, metabolic, nutritional, and immune-related conditions are preliminary and inconsistent. Limitations The literature has substantial heterogeneity in how physical health conditions were assessed and reported. Further, our explicit focus on physical health may have constrained the ability to examine interactions between mental and physical health. The widely differing research aims and methodologies make it difficult to reach definitive conclusions. Nevertheless, in keeping with the goals of a scoping review, we were able to identify key themes to guide future research. Conclusions The emerging literature suggests that autistic girls/women have heightened rates of physical health challenges compared to non-autistic girls/women and to autistic boys/men. Clinicians should seek to provide holistic care that includes a focus on physical health and develop a women’s health lens when providing clinical care to autistic girls/women.

Abstract The Src family non-receptor tyrosine kinase Fyn has been implicated in neurodegeneration of Alzheimer’s disease through interaction with amyloid β (Aβ). However, the role of Fyn in the pathogenesis of primary tauopathies such as FTDP-17, where Aβ plaques are absent, is poorly understood. In the current study, we used AAV2/8 vectors to deliver tauP301L to the brains of WT and Fyn KO mice, generating somatic transgenic tauopathy models with the presence or absence of Fyn. Although both genotypes developed tau pathology, Fyn KO developed fewer neurofibrillary tangles on Bielschowsky and Thioflavin S stained sections and showed lower levels of phosphorylated tau. In addition, tauP301L-induced behavior abnormalities and depletion of synaptic proteins were not observed in the Fyn KO model. Our work provides evidence for Fyn being a critical protein in the disease pathogenesis of FTDP-17.

Abstract A hallmark pathology of Alzheimer’s disease (AD) is the formation of amyloid β (Aβ) deposits that exhibit diverse localization and morphologies, ranging from diffuse to cored-neuritic deposits in brain parenchyma, with cerebral vascular deposition in leptomeningeal and parenchymal compartments. Most AD brains exhibit the full spectrum of pathologic Aβ morphologies. In the course of studies to model AD amyloidosis, we have generated multiple transgenic mouse models that vary in the nature of the transgene constructs that are expressed; including the species origin of Aβ peptides, the levels and length of Aβ that is deposited, and whether mutant presenilin 1 (PS1) is co-expressed. These models recapitulate features of human AD amyloidosis, but interestingly some models can produce pathology in which one type of Aβ morphology dominates. In prior studies of mice that primarily develop cored-neuritic deposits, we determined that Aβ deposition is associated with changes in cytosolic protein solubility in which a subset of proteins become detergent-insoluble, indicative of secondary proteome instability. Here, we survey changes in cytosolic protein solubility across seven different transgenic mouse models that exhibit a range of Aβ deposit morphologies. We find a surprisingly diverse range of changes in proteome solubility across these models. Mice that deposit human Aβ40 and Aβ42 in cored-neuritic plaques had the most robust changes in proteome solubility. Insoluble cytosolic proteins were also detected in the brains of mice that develop diffuse Aβ42 deposits but to a lesser extent. Notably, mice with cored deposits containing only Aβ42 had relatively few proteins that became detergent-insoluble. Our data provide new insight into the diversity of biological effects that can be attributed to different types of Aβ pathology and support the view that fibrillar cored-neuritic plaque pathology is the more disruptive Aβ pathology in the Alzheimer’s cascade.

Abstract Background Recombinant adeno-associated virus (rAAV) is widely used in the neuroscience field to manipulate gene expression in the nervous system. However, a limitation to the use of rAAV vectors is the time and expense needed to produce them. To overcome this limitation, we evaluated whether unpurified rAAV vectors secreted into the media following scalable PEI transfection of HEK293T cells can be used in lieu of purified rAAV. Methods We packaged rAAV2-EGFP vectors in 30 different wild-type and mutant capsids and subsequently collected the media containing secreted rAAV. Genomic titers of each rAAV vector were assessed and the ability of each unpurified virus to transduce primary mixed neuroglial cultures (PNGCs), organotypic brain slice cultures (BSCs) and the mouse brain was evaluated. Results There was ~ 40-fold wide variance in the average genomic titers of the rAAV2-EGFP vector packaged in the 30 different capsids, ranging from a low ~ 4.7 × 1010 vector genomes (vg)/mL for rAAV2/5-EGFP to a high of ~ 2.0 × 1012 vg/mL for a capsid mutant of rAAV2/8-EGFP. In PNGC studies, we observed a wide range of transduction efficiency among the 30 capsids evaluated, with the rAAV2/6-EGFP vector demonstrating the highest overall transduction efficiency. In BSC studies, we observed robust transduction by wild-type capsid vectors rAAV2/6, 2/8 and 2/9, and by capsid mutants of rAAV2/1, 2/6, and 2/8. In the in vivo somatic brain transgenesis (SBT) studies, we found that intra-cerebroventricular injection of media containing unpurified rAAV2-EGFP vectors packaged with select mutant capsids resulted in abundant EGFP positive neurons and astrocytes in the hippocampus and forebrain of non-transgenic mice. We demonstrate that unpurified rAAV can express transgenes at equivalent levels to lysate-purified rAAV both in vitro and in vivo. We also show that unpurified rAAV is sufficient to drive tau pathology in BSC and neuroinflammation in vivo, recapitulating previous studies using purified rAAV. Conclusions Unpurified rAAV vectors secreted into the media can efficiently transduce brain cells in vitro and in vivo, providing a cost-effective way to manipulate gene expression. The use of unpurified virus will greatly reduce costs of exploratory studies and further increase the utility of rAAV vectors for standard laboratory use.

Background: Seeding of pathology related to Alzheimer’s disease (AD) and Lewy body disease (LBD) by tissue homogenates or purified protein aggregates in various model systems has revealed prion-like properties of these disorders. Typically, these homogenates are injected into adult mice stereotaxically. Injection of brain lysates into newborn mice represents an alternative approach of delivering seeds that could direct the evolution of amyloid-β (Aβ) pathology co-mixed with either tau or α-synuclein (αSyn) pathology in susceptible mouse models. Methods: Homogenates of human pre-frontal cortex were injected into the lateral ventricles of newborn (P0) mice expressing a mutant humanized amyloid precursor protein (APP), human P301L tau, human wild type αSyn, or combinations thereof. The homogenates were prepared from AD and AD/LBD cases displaying variable degrees of Aβ pathology and co-existing tau and αSyn deposits. Behavioral assessments of APP transgenic mice injected with AD brain lysates were conducted. For comparison, homogenates of aged APP transgenic mice that preferentially exhibit diffuse or cored deposits were similarly injected into the brains of newborn APP mice. Results: We observed that lysates from the brains with AD (Aβ+, tau+), AD/LBD (Aβ+, tau+, αSyn+), or Pathological Aging (Aβ+, tau-, αSyn-) efficiently seeded diffuse Aβ deposits. Moderate seeding of cerebral amyloid angiopathy (CAA) was also observed. No animal of any genotype developed discernable tau or αSyn pathology. Performance in fear-conditioning cognitive tasks was not significantly altered in APP transgenic animals injected with AD brain lysates compared to nontransgenic controls. Homogenates prepared from aged APP transgenic mice with diffuse Aβ deposits induced similar deposits in APP host mice; whereas homogenates from APP mice with cored deposits induced similar cored deposits, albeit at a lower level. Conclusions: These findings are consistent with the idea that diffuse Aβ pathology, which is a common feature of human AD, AD/LBD, and PA brains, may arise from a distinct strain of misfolded Aβ that is highly transmissible to newborn transgenic APP mice. Seeding of tau or αSyn comorbidities was inefficient in the models we used, indicating that additional methodological refinement will be needed to efficiently seed AD or AD/LBD mixed pathologies by injecting newborn mice.

BackgroundPeople with intellectual and developmental disabilities are at increased health-related risk due to the COVID-19 pandemic. Virtual training programs that support providers in caring for the physical and mental health needs of this population, as well provide psychological support to the providers themselves, are needed during the pandemic. ObjectiveThis paper describes the design, delivery, and evaluation of a virtual educational COVID-19–focused Extension for Community Healthcare Outcomes program to support providers during the COVID-19 pandemic in caring for the mental health of people with intellectual and developmental disabilities. MethodsA rapid design thinking approach was used to develop a 6-session program that incorporates mindfulness practice, a wellness check, COVID-19–related research and policy updates, a didactic presentation on a combination mental health and COVID-19 related topic, and a case-based discussion to encourage practical learning. We used the first 5 outcome levels of Moore’s evaluation framework—focusing on participation, satisfaction, learning, self-efficacy, and change in practice—which were rated (out of 5) by care providers from health and disability service sectors, as well as additional reflection measures about innovations to the program. Qualitative feedback from open-text responses from participants were analyzed using modified manifest content analysis. ResultsA total of 104 care providers from health and disability service sectors participated in the program. High levels of engagement (81 participants per session on average) and satisfaction (overall satisfaction score: mean 4.31, SD 0.17) were observed. Self-efficacy (score improvement: 19.8%), support, and coping improved. Participants also rated the newly developed COVID-19 program and its innovative components highly. Open text feedback showed participants felt that the Extension for Community Healthcare Outcomes program expanded their knowledge and competency and created a sense of being part of a community of practice; provided value for the COVID-19 innovations; supported resource-sharing within and beyond program participants; and facilitated changes to participants’ approaches to client care in practice and increased participants’ confidence in supporting clients and families. ConclusionsThe Extension for Community Healthcare Outcomes program is an effective model for capacity-building programs with a shared-learning approach. Future iterations should include targeted evaluation of long-term outcomes such as staff burnout.

Abstract α-synuclein (αS) is the major component of several types of brain pathological inclusions that define neurodegenerative diseases termed synucleinopathies. Central nervous system (CNS) inoculation studies using either in vitro polymerized αS fibrils or in vivo derived lysates containing αS aggregates to induce the progressive spread of αS inclusion pathology in animal disease models have supported the notion that αS mediated progressive neurodegeneration can occur by a prion-like mechanism. We have previously shown that neonatal brain inoculation with preformed αS fibrils in hemizygous M20+/− transgenic mice expressing wild type human αS and to a lesser extent in non-transgenic mice can result in a concentration-dependent progressive induction of CNS αS pathology. Recent studies using brain lysates from patients with multiple system atrophy (MSA), characterized by αS inclusion pathology in oligodendrocytes, indicate that these may be uniquely potent at inducing αS pathology with prion-like strain specificity. We demonstrate here that brain lysates from MSA patients, but not control individuals, can induce αS pathology following neonatal brain inoculation in transgenic mice expressing A53T human αS (M83 line), but not in transgenic expressing wild type human αS (M20 line) or non-transgenic mice within the timeframe of the study design. Further, we show that neuroanatomical and immunohistochemical properties of the pathology induced by MSA brain lysates is very similar to what is produced by the neonatal brain injection of preformed human αS fibrils in hemizygous M83+/− transgenic mice. Collectively, these findings reinforce the idea that the intrinsic traits of the M83 mouse model dominates over any putative prion-like strain properties of MSA αS seeds that can induce pathology.

Summary: We present a consensus atlas of the human brain transcriptome in Alzheimer’s disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington’s disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.

Individuals with Down syndrome (DS) are among the groups with the highest risk for severe COVID-19. Better understanding of the efficacy and risks of COVID-19 vaccines for individuals with DS may help improve uptake of vaccination. The T21RS COVID-19 Initiative launched an international survey to obtain information on safety and efficacy of COVID-19 vaccines for individuals with DS. De-identified survey data collected between March and December 2021 were analyzed. Of 2172 individuals with DS, 1973 (91%) had received at least one vaccine dose (57% BNT162b2), 107 (5%) were unvaccinated by choice, and 92 (4%) were unvaccinated for other reasons. Most participants had either no side effects (54%) or mild ones such as pain at the injection site (29%), fatigue (12%), and fever (7%). Severe side effects occurred in

Introduction: Adults with intellectual and developmental disabilities (IDD) have high rates of morbidity and are less likely to receive preventive care. Emergency departments and primary care clinics are important entry points into the health care system. Improving care in these settings can lead to increased prevention activities, early disease identification, and ongoing management. We studied barriers and facilitators to improving the care of patients with IDD in three primary and three emergency care sites in Ontario. Methods: Data sources included structured implementation logs at each site, focus groups (n = 5) and interviews (n = 8). Barriers and facilitators were coded deductively based on the Consolidated Framework for Implementation Research (CFIR). Synthesis to higher level themes was achieved through review and discussion by the research team. Focus was given to differences between higher and lower implementing sites. Results: All sites were challenged to prioritize care improvement for a small, complex population and varied levels of implementation were achieved. Having national guidelines, using local data to demonstrate need and sharing evidence on value were important engagement strategies. Factors present at higher implementing sites included strong champions, alignment with site mandate, and use of electronic prompts/reminders. Lower implementing sites showed more passive endorsement of the innovation and had lower capacity to implement. Conclusion: Providing effective care for small, complex groups, such as adults with IDD, is critical to improving long-term health outcomes but is challenging to achieve. At a systemic level, funding incentives, access to expertise and improved electronic record systems may enhance capacity.

Introduction. Les adultes souffrant d’une déficience intellectuelle ou développementale(DID) présentent des taux de morbidité élevés et risquent davantage de ne pas recevoir de soins préventifs. Les services d’urgence des hôpitaux et les cliniques de soins primaires sont d’importants points d’entrée dans le système de soins de santé. Améliorer les soins dans ces lieux est susceptible d’améliorer les activités préventives, le dépistage précoce des maladies et la gestion courante. Nous avons étudié les éléments qui favorisent ou freinent l’amélioration des soins de santé destinés aux patients souffrant d’une DID dans trois établissements de soins primaires et trois services d’urgences de l’Ontario. Méthodologie. Les sources de données consistaient notamment en des journaux de mise en oeuvre structurée sur chacun des sites, des discussions de groupe (n=5) et des entrevues (n=8). Les éléments qui favorisent ou freinent l’amélioration des soins de santé ont été codés par déduction à partir du Consolidated Framework for Implementation Research (CFIR). Les thèmes de plus haut niveau ont été obtenus en faisant la synthèse des discussions et des examens de l’équipe de recherche. L’accent a été mis sur les différences entre les sites de mise en oeuvre de haut et de bas niveau. Résultats. Mis au défi de privilégier l’amélioration des soins destinés à une population complexe de petite taille, les sites ont atteint divers niveaux de mise en oeuvre. Disposer de lignes directrices à l’échelle nationale, utiliser des données locales pour montrer les besoins et mettre en commun les données probantes sur l’intérêt du projet ont constitué des stratégies de mobilisation importantes. Les sites de mise en oeuvre de haut niveau ont présenté des facteurs particuliers, comme la présence de fervents partisans, la conformité avec la mission du site et l’utilisation d’invitations ou de rappels électroniques. Les sites de mise en oeuvre de bas niveau ont accueilli l’innovation plus passivement et ont présenté des capacités de mise en oeuvre inférieures. Conclusion. Il est indispensable de permettre aux groupes complexes de petite taille, comme celui les adultes souffrant d’une DID, de recevoir des soins efficaces afin de voir leur état de santé s’améliorer à long terme, mais cet objectif est difficile à atteindre. À l’échelle du système, des mesures d’incitation au financement, des moyens d’accès à l’expertise et l’amélioration des systèmes de dossiers électroniques pourraient améliorer les choses.

Abstract Tauopathies are a group of neurodegenerative disorders, including Alzheimer’s disease, defined by the presence of brain pathological inclusions comprised of abnormally aggregated and highly phosphorylated tau protein. The abundance of brain tau aggregates correlates with disease severity and select phospho-tau epitopes increase at early stages of disease. We generated and characterized a series of novel monoclonal antibodies directed to tau phosphorylated at several of these phospho-epitopes, including Ser396/Ser404, Ser404 and Thr205. We also generated phosphorylation independent antibodies against amino acid residues 193–211. We show that most of these antibodies are highly specific for tau and strongly recognize pathological inclusions in human brains and in a transgenic mouse model of tauopathy. They also reveal epitope-specific differences in the biochemical properties of Alzheimer’s disease sarkosyl-insoluble tau. These new reagents will be useful for investigating the progression of tau pathology and further as tools to target the cellular transmission of tau pathology.

Objectives To describe factors associated with initiating antipsychotics and patterns of persistence to antipsychotic therapy in a large cohort of adults with intellectual and developmental disabilities.Design Population-based cohort study.Setting Ontario, Canada.Participants Adults with intellectual and developmental disabilities (IDD) in Ontario.Outcome measures We used multivariable logistic regression to investigate patient characteristics associated with antipsychotic initiation. Patient characteristics studied included sociodemographic characteristics, measures of clinical comorbidity and health service use.Results Among 39 244 individuals eligible for this study, 6924 (17.6%) initiated an antipsychotic over the accrual window, of whom 1863 (26.9%) had no psychiatric diagnosis in the prior 2 years. A number of factors were significantly associated with antipsychotic initiation, including male gender, residence in a group home, prior use of benzodiazepines, antidepressants or cognitive enhancers, a recent emergency department visit or mental health hospitalisation and a visit to a psychiatrist or family physician in the prior 90 days. In a secondary analysis, the association between antipsychotic initiation and age, prior diagnosis of diabetes or myocardial infarction and polypharmacy differed slightly on the basis of whether an individual had a previously diagnosed psychiatric disorder.Conclusions Factors associated with the initiation of an antipsychotic differ according to the presence of a psychiatric diagnosis. Given the long duration of antipsychotic use in this population, future research is needed to understand the appropriateness of antipsychotic initiation among adults with IDD and the safety implications of long-term use of these products.

BackgroundWhile up to 45% of individuals with intellectual and developmental disabilities (IDD) have a comorbid psychiatric disorder, and antipsychotics are commonly prescribed, gender differences in the safety of antipsychotics have rarely been studied in this population.AimsTo compare men and women with IDD on medical outcomes after antipsychotic initiation.MethodOur population-based study in Ontario, Canada, compared 1457 women and 1951 men with IDD newly initiating antipsychotic medication on risk for diabetes mellitus, hypertension, venous thromboembolism, myocardial infarction, stroke and death, with up to 4 years of follow-up.ResultsWomen were older and more medically complex at baseline. Women had higher risks for venous thromboembolism (HR 1.72, 95% CI 1.15–2.59) and death (HR 1.46, 95% CI 1.02–2.10) in crude analyses; but only thromboembolism risk was greater for women after covariate adjustment (aHR 1.58, 95% CI 1.05–2.38).ConclusionsGender should be considered in decision-making around antipsychotic medications for individuals with IDD.

BackgroundAttention to research and planning are increasingly being devoted to newcomer health, but the needs of newcomers with disabilities remain largely unknown. This information is difficult to determine since population-level data are rarely available on newcomers or on people with intellectual and developmental disabilities (IDD), although in Ontario, Canada these databases are accessible. This study compared the prevalence of IDD among first generation adult newcomers to adult non-newcomers in Ontario, and assessed how having IDD affected the health profile and health service use of newcomers.MethodsThis population-based retrospective cohort study of adults aged 19-65 in 2010 used linked health and social services administrative data. Prevalence of IDD among newcomers (n = 1,649,633) and non-newcomers (n = 6,880,196) was compared. Among newcomers, those with IDD (n = 2,830) and without IDD (n = 1,646,803) were compared in terms of health conditions, and community and hospital service use.ResultsPrevalence of IDD was lower in newcomers than non-newcomers (171.6 versus 898.3 per 100,000 adults, pConclusionFirst generation adult newcomers have lower rates of IDD than non-newcomers. How much of this difference is attributable to admission policies that exclude people expected to be high health service users versus how much is attributable to our methodological approach is unknown. Finding more medical and psychiatric comorbidity, and more health service use among newcomers with IDD compared to newcomers without IDD is consistent with patterns observed in adults with IDD more generally. To inform polices that support newcomers with IDD future research should investigate reasons for the prevalence finding, barriers and facilitators to timely health care access, and pathways to care.