Search

Modern in vitro technologies for preclinical research, including organ-on-a-chip, organoids- and assembloid-based systems, have rapidly emerged as pivotal tools for elucidating disease mechanisms and assessing the efficacy of putative therapeutics. In this context, advanced in vitro models of Parkinson's Disease (PD) offer the potential to accelerate drug discovery by enabling effective platforms that recapitulate both physiological and pathological attributes of the in vivo environment. Although these systems often aim at replicating the PD-associated loss of dopaminergic (DA) neurons, only a few have modelled the degradation of dopaminergic pathways as a way to mimic the disruption of downstream regulation mechanisms that define the characteristic motor symptoms of the disease. To this end, assembloids have been successfully employed to recapitulate neuronal pathways between distinct brain regions. However, the investigation and characterization of these connections through neural tracing and electrophysiological analysis remain a technically challenging and time-consuming process. Here, we present a novel bioengineered platform consisting of surface-grown midbrain and striatal organoids at opposite sides of a self-assembled DA pathway. In particular, dopaminergic neurons and striatal GABAergic neurons spontaneously form DA connections across a microelectrode array (MEA), specifically integrated for the real-time monitoring of electrophysiological development and stimuli response. Calcium imaging data showed spiking synchronicity of the two organoids forming the inter-organoid pathways (IOPs) demonstrating that they are functionally connected. MEA recordings confirm a more robust response to the DA neurotoxin 6-OHDA compared to midbrain organoids alone, thereby validating the potential of this technology to generate highly tractable, easily extractable real-time functional readouts to investigate the dysfunctional dopaminergic network of PD patients.

Summary: Contraction of the human sarcomere is the result of interactions between myosin cross-bridges and actin filaments. Pathogenic variants in genes such as MYH7, TPM1, and TNNI3 that encode parts of the cardiac sarcomere cause muscle diseases that affect the heart, such as dilated cardiomyopathy and hypertrophic cardiomyopathy. In contrast, pathogenic variants in homologous genes such as MYH2, TPM2, and TNNI2 that encode parts of the skeletal muscle sarcomere cause muscle diseases affecting skeletal muscle, such as distal arthrogryposis (DA) syndromes and skeletal myopathies. To date, there have been few reports of genes (e.g., MYH7) encoding sarcomeric proteins in which the same pathogenic variant affects skeletal and cardiac muscle. Moreover, none of the known genes underlying DA have been found to contain pathogenic variants that also cause cardiac abnormalities. We report five families with DA because of heterozygous missense variants in the gene actin, alpha, cardiac muscle 1 (ACTC1). ACTC1 encodes a highly conserved actin that binds to myosin in cardiac and skeletal muscle. Pathogenic variants in ACTC1 have been found previously to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction. Our discovery delineates a new DA condition because of variants in ACTC1 and suggests that some functions of ACTC1 are shared in cardiac and skeletal muscle.

PurposeNeurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors.MethodsA total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study.ResultsNone of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del.ConclusionWe demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

A correction has been published to this Article. The PDF and HTML have been updated accordingly.

Background Health care providers’ knowledge and attitudes about vaccines are important determinants of their own vaccine uptake, their intention to recommend vaccines, and their patients’ vaccine uptake. This qualitative study’ objective was to better understand health care providers’ vaccination decisions, their views on barriers to COVID-19 vaccine acceptance and proposed solutions, their opinions on vaccine policies, and their perceived role in discussing COVID-19 vaccination with patients. Methods Semi-structured interviews on perceptions of COVID-19 vaccines were conducted with Canadian health care providers (N = 14) in spring 2021. A qualitative thematic analysis using NVivo was conducted. Results Participants had positive attitudes toward vaccination and were vaccinated against COVID-19 or intended to do so once eligible (two delayed their first dose). Only two were actively promoting COVID-19 vaccination to their patients; others either avoided discussing the topic or only provided answers when asked questions. Participants’ proposed solutions to enhance COVID-19 vaccine uptake in the public were in relation to access to vaccination services, information in multiple languages, and community outreach. Most participants were in favor of mandatory vaccination policies and had mixed views on the potential impact of the Canadian vaccine-injury support program. Conclusions While health care providers are recognized as a key source of information regarding vaccines, participants in our study did not consider it their role to provide advice on COVID-19 vaccination. This is a missed opportunity that could be avoided by ensuring health care providers have the tools and training to feel confident in engaging in vaccine discussions with their patients.

Structural and systemic inequalities can contribute to susceptibility to COVID-19 disease and limited access to vaccines. Recognizing that Racialized and Indigenous Peoples may experience unique barriers to COVID-19 vaccination, this study explored early COVID-19 vaccine accessibility, including barriers and potential solutions to vaccine access, for these communities in Canada. We conducted semi-structured interviews about challenges to accessing COVID-19 vaccination with Racialized and Indigenous Peoples, including linguistic minorities and newcomers, in Spring 2021, just as COVID-19 vaccines were becoming more widely available in Canada. Participants were purposely selected from respondents to a Canadian national online survey. Three researchers analyzed the interviews for emergent themes using a descriptive content analysis approach in NVivo. At the time of the interview, interview participants (N = 27) intended to receive (n = 15) or had received (n = 11) at least one vaccine dose, or did not state their status (n = 1). Participants described multiple barriers to COVID-19 vaccination that they personally experienced and/or anticipated they or others could experience – including technology requirements, language barriers, lack of identification documentation, and travel challenges – as well as related solutions. These were organized into three broad categories: 1) COVID-19 disease and vaccination information, 2) vaccination booking procedures, and 3) vaccination sites. These structural and systemic barriers during the initial months of vaccine rollout substantially restricted participants’ COVID-19 vaccination access, even when they were eager to get vaccinated, and should be addressed early in vaccine rollouts to facilitate optimal uptake for everyone everywhere

BackgroundThe COVID-19 pandemic has generated an explosion in the amount of information shared on the internet, including false and misleading information on SARS-CoV-2 and recommended protective behaviors. Prior to the pandemic, web-based misinformation and disinformation were already identified as having an impact on people’s decision to refuse or delay recommended vaccination for themselves or their children. ObjectiveThe overall aims of our study are to better understand the influence of web-based misinformation and disinformation on COVID-19 vaccine decisions and investigate potential solutions to reduce the impact of web-based misinformation and disinformation about vaccines. MethodsBased on different research approaches, the study will involve (1) the use of artificial intelligence techniques, (2) a web-based survey, (3) interviews, and (4) a scoping review and an environmental scan of the literature. ResultsAs of September 1, 2022, data collection has been completed for all objectives. The analysis is being conducted, and results should be disseminated in the upcoming months. ConclusionsThe findings from this study will help with understanding the underlying determinants of vaccine hesitancy among Canadian individuals and identifying effective, tailored interventions to improve vaccine acceptance among them. International Registered Report Identifier (IRRID)DERR1-10.2196/41012

The presence of multiple dysmorphic features in some children with autism spectrum disorder (ASD) might identify distinct ASD phenotypes and serve as potential markers for understanding causes and prognoses. To evaluate dysmorphology in ASD, children aged 3-6 years with ASD and non-ASD population controls (POP) from the Study to Explore Early Development were evaluated using a novel, systematic dysmorphology review approach. Separate analyses were conducted for non-Hispanic White, non-Hispanic Black, and Hispanic children. In each racial/ethnic group, ~ 17% of ASD cases were Dysmorphic compared with ~ 5% of POP controls. The ASD-POP differential was not explained by known genetic disorders or birth defects. In future epidemiologic studies, subgrouping ASD cases as Dysmorphic vs. Non-dysmorphic might help delineate risk factors for ASD.

Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies. [ABSTRACT FROM AUTHOR]

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.

This paper reports on a pilot project that involved the incorporation of Community Service-Learning (CSL) into a large Introductory Sociology class by drawing on the critical reflections of the six graduate student instructors and the primary instructor who taught the course. Graduate student instructors individually facilitated weekly seminars for about 30 undergraduate students, half of which participated in CSL, completing 20 hours of volunteer work with a local non-profit community organization. We discuss the benefits of incorporating CSL into a large Introductory Sociology class and speculate on the value of our particular course format for the professional development of graduate student instructors. A main finding was the critical importance to graduate students of formal and informal training and collaboration prior to and during the delivery of the course. Graduate students found useful exposure to CSL as pedagogical theory and practice, and appreciated the hands-on teaching experience. Challenges with this course structure include the difficulty of seamlessly incorporating CSL student experiences into the class, dealing with the “CSL”/ “non CSL” student division, and the nature of some of the CSL placements. We conclude by discussing possible methods for dealing with these challenges.