Automated Vehicles: Future Initiatives for Occupational Therapy Practitioners and Driver Rehabilitation Specialists.

This article addresses a critically important topic for the occupational therapy (OT) profession and driver rehabilitation specialists (DRS), related to the introduction and deployment of personal and public automated vehicles (AVs); and discusses the current and corresponding changing roles for these professionals. Within this commentary, we provide an overview of the relevant literature on AV regulations, policy, and legislation in North America, the various levels of AV technology, and inclusive and universal design principles to consider in AV deployment for people with disabilities. The role of the OT practitioner and DRS is described within the context of the person-environment-occupation-performance model, and within the guidelines of the Association for Driver Rehabilitation Specialists and the American Occupational Therapy Association. The article concludes with considerations for an extended clinical agenda, a new research agenda, and a call for action to OT practitioners and DRS, as well as to educators, certification bodies, professional organizations, and collaborators.

Automated Vehicles: Future Initiatives for Occupational Therapy Practitioners and Driver Rehabilitation SpecialistsThis article discusses a critical practice and scientific area for occupational therapy (OT) practitioners and driver rehabilitation specialists (DRS), namely the deployment of automated vehicles (AVs) in North America and its effect on the OT profession. The article situates driving, including driving AVs, within the context of a credible OT model, discusses the current and changing roles of the OT practitioner and DRS, stipulates the rules and regulations for AVs in North America, expounds on the different levels of AV technology and potential implications, requirements for accessible AVs for people with disabilities, and highlights guidelines from professional organizations pertaining driving as a practice area. The article concludes by suggesting new directions for clinical practice and research, and it calls on OT practitioners, DRS, educators, certification organizations, and collaborators to take action.

Does in-vehicle automation help individuals with Parkinson's disease? A preliminary analysis.

Introduction: PD is a progressive neurodegenerative disorder that affects, according to the ICF, body systems (cognitive, visual, and motor), and functions (e.g., decreased executive functions, decreased visual acuity, impaired contrast sensitivity, decreased coordination)-all which impact driving performance, an instrumental activity of daily living in the domain of "Activity" and "Participation" according to the ICF. Although there is strong evidence of impaired driving performance in PD, few studies have explored the real-world benefits of in-vehicle automation technologies, such as in-vehicle information systems (IVIS) and advanced driver assistance systems (ADAS), for drivers with PD. These technologies hold potential to alleviate driving impairments, reduce errors, and improve overall performance, allowing individuals with PD to maintain their mobility and independence more safely and for longer periods. This preliminary study aimed to fill the gap in the literature by examining the impact of IVIS and ADAS on driving safety, as indicated by the number of driving errors made by people with PD in an on-road study. Methods: Forty-five adults with diagnosed PD drove a 2019 Toyota Camry equipped with IVIS and ADAS features (Toyota Safety Sense 2.0) on a route containing highway and suburban roads. Participants drove half of the route with the IVIS and ADAS systems activated and the other half with the systems deactivated. Results: The results suggest that systems that assume control of the driving task, such as adaptive cruise control, were most effective in reducing driving errors. Furthermore, individual differences in cognitive abilities, particularly memory, were significantly correlated with the total number of driving errors when the systems were deactivated, but no significant correlations were present when the systems were activated. Physical capability factors, such as rigidity and bradykinesia, were not significantly correlated with driving error. Discussion: Taken together, these results show that in-vehicle driver automation systems can benefit drivers with PD and diminish the impact of individual differences in driver cognitive ability.

Contribution of animal models to the mechanistic understanding of Alternative Pathway and Amplification Loop (AP/AL)-driven Complement-mediated Diseases.

This review aimed to capture the key findings that animal models have provided around the role of the alternative pathway and amplification loop (AP/AL) in disease. Animal models, particularly mouse models, have been incredibly useful to define the role of complement and the alternative pathway in health and disease; for instance, the use of cobra venom factor and depletion of C3 provided the initial insight that complement was essential to generate an appropriate adaptive immune response. The development of knockout mice have further underlined the importance of the AP/AL in disease, with the FH knockout mouse paving the way for the first anti-complement drugs. The impact from the development of FB, properdin, and C3 knockout mice closely follows this in terms of mechanistic understanding in disease. Indeed, our current understanding that complement plays a role in most conditions at one level or another is rooted in many of these in vivo studies. That C3, in particular, has roles beyond the obvious in innate and adaptive immunity, normal physiology, and cellular functions, with or without other recognized AP components, we would argue, only extends the reach of this arm of the complement system. Humanized mouse models also continue to play their part. Here, we argue that the animal models developed over the last few decades have truly helped define the role of the AP/AL in disease.

RCT protocol for driving performance in people with Parkinson's using autonomous in-vehicle technologies.

Introduction: Driving is an essential facilitator of independence, community participation, and quality of life. Drivers with Parkinson's Disease (PD) make more driving errors and fail on-road evaluations more than healthy controls. In-vehicle technologies may mitigate PD-related driving impairments and associated driving errors. Establishing a rigorous study protocol will increase the internal validity and the transparency of the scientific work. Methods: We present a protocol to assess the efficacy of autonomous in-vehicle technologies (Level 1) on the driving performance of drivers with PD via a randomized crossover design with random allocation. Drivers with a PD diagnosis based on established clinical criteria (N = 105), referred by neurologists, are exposed to two driving conditions (technology activated or not) on a standardized road course as they drove a 2019 Toyota Camry. The researchers collected demographic, clinical, on-road data observational and kinematic, and video data to understand several primary outcome variables, i.e., number of speeding, lane maintenance, signaling, and total driving errors. Discussion: The protocol may enhance participant adherence, decrease attrition, provide early and accurate identification of eligible participants, ensure data integrity, and improve the study flow. One limitation is that the protocol may change due to unforeseen circumstances and assumptions upon implementation. A strength is that the protocol ensures the study team executes the planned research in a systematic and consistent way.Following, adapting, and refining the protocol will enhance the scientific investigation to quantify the nuances of driving among those with PD in the era of automated in-vehicle technologies. Trial registration: ClinicalTrials.gov NCT04660500.

Homodimeric Minimal Factor H: In Vivo Tracking and Extended Dosing Studies in Factor H Deficient Mice.

C3 glomerulopathy (C3G) is associated with dysregulation of the alternative pathway (AP) of complement and treatment options remain inadequate. Factor H (FH) is a potent regulator of the AP. An in-depth analysis of FH-related protein dimerised minimal (mini)-FH constructs has recently been published. This analysis showed that addition of a dimerisation module to mini-FH not only increased serum half-life but also improved complement regulatory function, thus providing a potential treatment option for C3G. Herein, we describe the production of a murine version of homodimeric mini-FH [mHDM-FH (mFH1-5^18-20^R1-2)], developed to reduce the risk of anti-drug antibody formation during long-term experiments in murine models of C3G and other complement-driven pathologies. Our analysis of mHDM-FH indicates that it binds with higher affinity and avidity to WT mC3b when compared to mouse (m)FH (mHDM-FH KD=505 nM; mFH KD=1370 nM) analogous to what we observed with the respective human proteins. The improved binding avidity resulted in enhanced complement regulatory function in haemolytic assays. Extended interval dosing studies in CFH-/- mice (5mg/kg every 72hrs) were partially effective and bio-distribution analysis in CFH-/- mice, through in vivo imaging technologies, demonstrates that mHDM-FH is preferentially deposited and remains fixed in the kidneys (and liver) for up to 4 days. Extended dosing using an AAV- human HDM-FH (hHDM-FH) construct achieved complete normalisation of C3 levels in CFH-/- mice for 3 months and was associated with a significant reduction in glomerular C3 staining. Our data demonstrate the ability of gene therapy delivery of mini-FH constructs to enhance complement regulation in vivo and support the application of this approach as a novel treatment strategy in diseases such as C3G.

Insights Into the Structure-Function Relationships of Dimeric C3d Fragments.

Cleavage of C3 to C3a and C3b plays a central role in the generation of complement-mediated defences. Although the thioester-mediated surface deposition of C3b has been well-studied, fluid phase dimers of C3 fragments remain largely unexplored. Here we show C3 cleavage results in the spontaneous formation of C3b dimers and present the first X-ray crystal structure of a disulphide-linked human C3d dimer. Binding studies reveal these dimers are capable of crosslinking complement receptor 2 and preliminary cell-based analyses suggest they could modulate B cell activation to influence tolerogenic pathways. Altogether, insights into the physiologically-relevant functions of C3d(g) dimers gained from our findings will pave the way to enhancing our understanding surrounding the importance of complement in the fluid phase and could inform the design of novel therapies for immune system disorders in the future.

Investigating Evolutionary Rate Variation in Bacteria.

Rates of molecular evolution are known to vary between species and across all kingdoms of life. Here, we explore variation in the rate at which bacteria accumulate mutations (accumulation rates) in their natural environments over short periods of time. We have compiled estimates of the accumulation rate for over 34 species of bacteria, the majority of which are pathogens evolving either within an individual host or during outbreaks. Across species, we find that accumulation rates vary by over 3700-fold. We investigate whether accumulation rates are associated to a number potential correlates including genome size, GC content, measures of the natural selection and the time frame over which the accumulation rates were estimated. After controlling for phylogenetic non-independence, we find that the accumulation rate is not significantly correlated to any factor. Furthermore, contrary to previous results, we find that it is not impacted by the time frame of which the estimate was made. However, our study, with only 34 species, is likely to lack power to detect anything but large effects. We suggest that much of the rate variation may be explained by differences between species in the generation time in the wild.

Calcium activated nucleotidase 1 (CANT1) is critical for glycosaminoglycan biosynthesis in cartilage and endochondral ossification.

Desbuquois dysplasia type 1 (DBQD1) is a chondrodysplasia caused by mutations in CANT1 gene encoding an ER/Golgi calcium activated nucleotidase 1 that hydrolyses UDP. Here, using Cant1 knock-in and knock-out mice recapitulating DBQD1 phenotype, we report that CANT1 plays a crucial role in cartilage proteoglycan synthesis and in endochondral ossification. Specifically, the glycosaminoglycan synthesis was decreased in chondrocytes from Cant1 knock-out mice and their hydrodynamic size was reduced, whilst the sulfation was increased and the overall proteoglycan secretion was delayed. Interestingly, knock-out chondrocytes had dilated ER cisternae suggesting delayed protein secretion and cellular stress; however, no canonical ER stress response was detected using microarray analysis, Xbp1 splicing and protein levels of BiP and ATF4. The observed proteoglycan defects caused deregulated chondrocyte proliferation and maturation in the growth plate resulting in the reduced skeletal growth. In conclusion, the pathogenic mechanism of DBQD1 comprises deregulated chondrocyte performance due to defective intracellular proteoglycan synthesis and altered proteoglycan properties in the extracellular matrix.

The distribution of bacterial doubling times in the wild.

Generation time varies widely across organisms and is an important factor in the life cycle, life history and evolution of organisms. Although the doubling time (DT) has been estimated for many bacteria in the laboratory, it is nearly impossible to directly measure it in the natural environment. However, an estimate can be obtained by measuring the rate at which bacteria accumulate mutations per year in the wild and the rate at which they mutate per generation in the laboratory. If we assume the mutation rate per generation is the same in the wild and in the laboratory, and that all mutations in the wild are neutral, an assumption that we show is not very important, then an estimate of the DT can be obtained by dividing the latter by the former. We estimate the DT for five species of bacteria for which we have both an accumulation and a mutation rate estimate. We also infer the distribution of DTs across all bacteria from the distribution of the accumulation and mutation rates. Both analyses suggest that DTs for bacteria in the wild are substantially greater than those in the laboratory, that they vary by orders of magnitude between different species of bacteria and that a substantial fraction of bacteria double very slowly in the wild.

The aggrecanopathies; an evolving phenotypic spectrum of human genetic skeletal diseases.

The large chondroitin sulphated proteoglycan aggrecan (ACAN) is the most abundant non-collagenous protein in cartilage and is essential for its structure and function. Mutations in ACAN result in a broad phenotypic spectrum of non-lethal skeletal dysplasias including spondyloepimetaphyseal dysplasia, spondyloepiphyseal dysplasia, familial osteochondritis dissecans and various undefined short stature syndromes associated with accelerated bone maturation. However, very little is currently known about the disease pathways that underlie these aggrecanopathies, although they are likely to be a combination of haploinsufficiency and dominant-negative (neomorphic) mechanisms. This review discusses the known human and animal aggrecanopathies in the context of clinical presentation and potential disease mechanisms.

Protection against murine osteoarthritis by inhibition of the 26S proteasome and lysine-48 linked ubiquitination.

OBJECTIVES: To determine whether the process of ubiquitination and/or activity of the 26S proteasome are involved in the induction of osteoarthritis (OA). METHODS: Bovine cartilage resorption assays, chondrocyte cell-line SW1353 and primary human articular chondrocytes were used with the general proteasome inhibitor MG132 or vehicle to identify a role of the ubiquitin-proteasome system (UPS) in cartilage destruction and matrix metalloproteinase-13 (MMP13) expression. In vivo, MG132 or vehicle, were delivered subcutaneously to mice following destabilisation of the medial meniscus (DMM)-induced OA. Subsequently, DMM was induced in Lys-to-Arg (K48R and K63R) mutant ubiquitin (Ub) transgenic mice. Cytokine signalling in SW1353s was monitored by immunoblotting and novel ubiquitinated substrates identified using Tandem Ubiquitin Binding Entities purification followed by mass spectrometry. The ubiquitination of TRAFD1 was assessed via immunoprecipitation and immunoblotting and its role in cytokine signal-transduction determined using RNA interference and real-time RT-PCR for MMP13 and interleukin-6 (IL6). RESULTS: Supplementation with the proteasome inhibitor MG132 protected cartilage from cytokine-mediated resorption and degradation in vivo in mice following DMM-induced OA. Using transgenic animals only K48R-mutated Ub partially protected against OA compared to wild-type or wild-type Ub transgenic mice, and this was only evident on the medial femoral condyle. After confirming ubiquitination was vital for NF-κB signalling and MMP13 expression, a screen for novel ubiquitinated substrates involved in cytokine-signalling identified TRAFD1; the depletion of which reduced inflammatory mediator-induced MMP13 and IL6 expression. CONCLUSIONS: Our data for the first time identifies a role for ubiquitination and the proteasome in the induction of OA via regulation of inflammatory mediator-induced MMP13 expression. These data open avenues of research to determine whether the proteasome, or K48-linked ubiquitination, are potential therapeutic targets in OA.