Benchmarking computational variant effect predictors by their ability to infer human traits.

BACKGROUND: Computational variant effect predictors offer a scalable and increasingly reliable means of interpreting human genetic variation, but concerns of circularity and bias have limited previous methods for evaluating and comparing predictors. Population-level cohorts of genotyped and phenotyped participants that have not been used in predictor training can facilitate an unbiased benchmarking of available methods. Using a curated set of human gene-trait associations with a reported rare-variant burden association, we evaluate the correlations of 24 computational variant effect predictors with associated human traits in the UK Biobank and All of Us cohorts. RESULTS: AlphaMissense outperformed all other predictors in inferring human traits based on rare missense variants in UK Biobank and All of Us participants. The overall rankings of computational variant effect predictors in these two cohorts showed a significant positive correlation. CONCLUSION: We describe a method to assess computational variant effect predictors that sidesteps the limitations of previous evaluations. This approach is generalizable to future predictors and could continue to inform predictor choice for personal and clinical genetics.

Ciliary and non-ciliary functions of Rab34 during craniofacial bone development.

The primary cilium is a hair-like projection that controls cell development and tissue homeostasis. Although accumulated studies identify the molecular link between cilia and cilia-related diseases, the underlying etiology of ciliopathies has not been fully understood. In this paper, we determine the function of Rab34, a small GTPase, as a key regulator for controlling ciliogenesis and type I collagen trafficking in craniofacial development. Mechanistically, Rab34 is required to form cilia that control osteogenic proliferation, survival, and differentiation via cilia-mediated Hedgehog signaling. In addition, Rab34 is indispensable for regulating type I collagen trafficking from the ER to the Golgi. These results demonstrate that Rab34 has both ciliary and non-ciliary functions to regulate osteogenesis. Our study highlights the critical function of Rab34, which may contribute to understanding the novel etiology of ciliopathies that are associated with the dysfunction of RAB34 in humans.

The impact of caregiving on the roles and valued activities of stroke carers: A systematic review of qualitative studies.

OBJECTIVE: To understand the experiences of informal carers and the impact of role and activity changes on their health and wellbeing. METHODS: A systematic search of CINHAL, MEDLINE, Embase, APA PsycInfo, and Web of Science was conducted. Studies were eligible if they included informal stroke carers (≥18 years), used a qualitative methodology, explored the roles and valued activities of stroke carers, and were published in English. The 10-item Critical Appraisal Skills Programme checklist for qualitative studies was used to assess methodological quality. The results of the included studies were thematically synthesised. RESULTS: A total of 36 qualitative studies were included and four overarching themes were identified: (1) Life adjustment; (2) Changing role and identity; (3) Changing activities: From meaningful to purposeful; and (4) Understanding and supporting carers. CONCLUSION: The sudden nature of stroke requires major readjustment in the carers life that has implications on their relationships, roles, and activities, subsequently impacting on their health and wellbeing. Health professionals and researchers should collaborate with stroke carers to identify their valued activities and implement realistic strategies to maintain these activities. Future interventions designed for carers should implement education about the importance of participating in valued activities and strategies to maintain these activities.

Strategies adopted by informal carers to enhance participation in daily activities for persons with dementia.

OBJECTIVE: Carers for people with dementia commonly experience difficulty assisting the care-recipients with their daily activities and may adopt specific strategies to decrease the difficulties experienced. The objective of this qualitative study was to explore and understand the strategies used by carers to assist with daily activities for persons living with dementia. METHODS: Individual semi-structured interviews via face-to-face or telephone mode were conducted with 62 carers of persons living with dementia in Australia. Carers were asked about the strategies they have used previously, or are currently using, to assist with daily activity completion. Data were analysed via constant comparison and thematic analysis. RESULTS: All carers reported the need for strategies to accommodate the varying behaviour and functioning of the care-recipients. Participants reported a total of 207 strategies that fell into four main categories: (i) engage; (ii) adapt; (iii) orientate; and (iv) sense. The most used strategies were reported as those aimed at adapting the activity by using equipment to facilitate completion. CONCLUSIONS: Carers help persons living with dementia complete their daily activities by developing their own strategies based on the care-recipients' needs and personal preferences through a trial-and-error process. Carers can benefit if more advice is provided to them by health/social care professionals regarding what strategies may be helpful. Further studies are needed to develop these strategies into an educational package so that carers can be guided to use these strategies appropriately.

Evaluation of an exercise program incorporating an international cycling competition: a multimodal intervention model for physical, psychological, and social wellbeing in residential aged care.

BACKGROUND: The transition into residential aged care is frequently associated with a reduction in physical activity, social engagement, and emotional wellbeing. Our aim was to evaluate the impact of a 26-day international cycling competition (Road Worlds Competition for Seniors), incorporating elements of exercise, audiovisual cycling footage, social engagement, and gamification, on the physical, psychological, and social well-being of aged care residents. We aimed to use findings to inform the development of a multi-modal intervention model to maximise wellbeing for older adults. METHODS: Residents (N = 32) participated in a mixed-methods single-group intervention pilot study that compared pre-and post-competition measures for the following wellbeing domains; physical, psychological, and social. In addition, interviews were conducted with residents (n = 27) and staff (n = 6) to explore their experiences. RESULTS: Measures identified significant improvements across multiple wellbeing domains, including functional fitness, depression, self-efficacy, and social network sizes. Findings from the interview data indicated that the multimodal components involved in the program delivery were valued by staff and residents who enjoyed the gamification, audiovisual cycling footage, social engagement, opportunities for reminiscence, and camaraderie between peers, staff, and volunteers. CONCLUSIONS: Findings highlight a constellation of benefits across physical, psychological, and social domains of wellbeing and inform a model for innovative multidimensional programs in residential aged care. The benefits for residents with varying physical and cognitive abilities support the use of creative strategies that maximise inclusion and engagement for residents.

A severe case of swimmer's itch in Victoria, Australia with bullous eruption.

Abstract: We describe a severe case of swimmer's itch in Victoria with widespread bullous eruption, which is a rare manifestation of this condition and presented a diagnostic challenge. This is the first case reported in Victoria, having been previously reported in more northern parts of Australia; with climate change trends, swimmer's itch is likely to become increasingly common in southern parts of the region.

Effectiveness of Motor Imagery in the Rehabilitation of People With Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVE: With more research completed using Motor imagery (MI) in people with Parkinson's disease, this study gathered and synthesized evidence on the use of MI for Parkinson's disease in improving rehabilitation outcomes. METHODS: Medical Literature Analysis and Retrieval System Online, Embase, Web of Science, The Cochrane Library, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, and Scopus were searched from inception to May 2023. We included randomized controlled trials that examine the effects of MI on individuals with Parkinson's disease. Two reviewers selected articles and extracted study characteristics and results independently. The Physiotherapy Evidence Database scale was used to assess the methodological quality. Mean differences and 95% confidence intervals were calculated. Heterogeneity was assessed using the I2 statistic. RESULTS: Thirteen articles with 12 studies were included, involving 320 individuals with Parkinson's disease, with moderate to high methodological quality (mean = 6.62/10). Compared with the control group, 3 articles reported significant greater improvements in cognitive function, 7 reported significant greater improvement in motor function, 1 article reported significant greater improvement in quality of life, and 1 reported significant greater confidence in daily task performance. No statistically significant effects were found in the meta-analyses. Conclusion. Results of individual articles were in favor of the MI intervention. No statistically significant results were found in the meta-analyses. This might be due to the small number of studies and the heterogeneity of interventions and outcome measures used. MI may be effective in improving some rehabilitation outcomes, but meta-analytic evidence is lacking. More research with larger sample size and less heterogeneous samples, interventions, and outcome measures, is warranted. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42021230556.

The CPLANE protein Fuzzy regulates ciliogenesis by suppressing actin polymerization at the base of the primary cilium via p190A RhoGAP.

The primary cilium decorates most eukaryotic cells and regulates tissue morphogenesis and maintenance. Structural or functional defects of primary cilium result in ciliopathies, congenital human disorders affecting multiple organs. Pathogenic variants in the ciliogenesis and planar cell polarity effectors (CPLANE) genes FUZZY, INTU and WDPCP disturb ciliogenesis, causing severe ciliopathies in humans and mice. Here, we show that the loss of Fuzzy in mice results in defects of primary cilia, accompanied by increased RhoA activity and excessive actin polymerization at the basal body. We discovered that, mechanistically, Fuzzy interacts with and recruits the negative actin regulator ARHGAP35 (also known as p190A RhoGAP) to the basal body. We identified genetic interactions between the two genes and found that a mutant ArhGAP35 allele increases the severity of phenotypic defects observed in Fuzzy-/- mice. Based on our findings, we propose that Fuzzy regulates ciliogenesis by recruiting ARHGAP35 to the basal body, where the latter likely restricts actin polymerization and modifies the actin network. Our study identifies a mechanism whereby CPLANE proteins control both actin polymerization and primary cilium formation.

A simulation framework to determine optimal strength training and musculoskeletal geometry for sprinting and distance running.

Musculoskeletal geometry and muscle volumes vary widely in the population and are intricately linked to the performance of tasks ranging from walking and running to jumping and sprinting. As an alternative to experimental approaches, where it is difficult to isolate factors and establish causal relationships, simulations can be used to independently vary musculoskeletal geometry and muscle volumes, and develop a fundamental understanding. However, our ability to understand how these parameters affect task performance has been limited due to the high computational cost of modelling the necessary complexity of the musculoskeletal system and solving the requisite multi-dimensional optimization problem. For example, sprinting and running are fundamental to many forms of sport, but past research on the relationships between musculoskeletal geometry, muscle volumes, and running performance has been limited to observational studies, which have not established cause-effect relationships, and simulation studies with simplified representations of musculoskeletal geometry. In this study, we developed a novel musculoskeletal simulator that is differentiable with respect to musculoskeletal geometry and muscle volumes. This simulator enabled us to find the optimal body segment dimensions and optimal distribution of added muscle volume for sprinting and marathon running. Our simulation results replicate experimental observations, such as increased muscle mass in sprinters, as well as a mass in the lower end of the healthy BMI range and a higher leg-length-to-height ratio in marathon runners. The simulations also reveal new relationships, for example showing that hip musculature is vital to both sprinting and marathon running. We found hip flexor and extensor moment arms were maximized to optimize sprint and marathon running performance, and hip muscles the main target when we simulated strength training for sprinters. Our simulation results provide insight to inspire future studies to examine optimal strength training. Our simulator can be extended to other athletic tasks, such as jumping, or to non-athletic applications, such as designing interventions to improve mobility in older adults or individuals with movement disorders.

Better translation via collaboration: The MRC National Mouse Genetics Network.

The MRC National Mouse Genetics Network (NMGN) has been established in the UK to bring together researchers from academia and industry across the country from a wide range of disease areas and research backgrounds to rapidly facilitate clinical translation of mouse research findings and foster an environment of interdisciplinary learning.

Student-led activities of daily living group program in a hospital inpatient rehabilitation setting.

INTRODUCTION: Occupational therapists have vital roles in inpatient rehabilitation to focus on independence in activities of daily living. Occupational therapy interventions are uniquely designed to address goals of service users and can be delivered individually or in group formats. Group interventions promote service users' mutual support and enable therapists to increase frequency and intensity of service provision. Student-led programs have become an attractive model, benefiting students while providing positive treatment outcomes for service users. There is an emerging body of literature that explores service users' and students' satisfaction with student-led group models of practice within inpatient rehabilitation and occupational performance outcomes of service users participating in student-led programs. This study aimed to explore the satisfaction of service users and students in addition to the self-reported occupational performance outcomes of a student-led activities of daily living group program in inpatient rehabilitation. METHODS: Data from 33 service users and seven students were collected retrospectively. The intervention involved a student-led activities of daily living group program, consisting of three groups: breakfast, morning tea, and home readiness group. All service users and students completed unique satisfaction surveys at the conclusion of their participation in the student-led program. Service users completed a self-reported activities of daily living performance measure pre- and post-program. Findings were reported in descriptive statistics, and pre- and post-program data were compared with the Wilcoxon signed-rank test. RESULTS: All students were satisfied with the student-led program. Majority of service users were satisfied with all components of the student-led program. Median scores for self-reported performance increased significantly following the student-led program (P < 0.001). CONCLUSION: This study highlighted that service users and students were satisfied with the service delivery of a student-led activities of daily living group program. The program was effective in addressing self-reported performance for service users in inpatient rehabilitation. The findings from this study have potential to inform clinical practice on the implementation of student-led programs in occupational therapy settings.

Cranial suture lineage and contributions to repair of the mouse skull.

The cranial sutures are proposed to be a stem cell niche, harbouring skeletal stem cells that are directly involved in development, homeostasis and healing. Like the craniofacial bones, the sutures are formed from both mesoderm and neural crest. During cranial bone repair, neural crest cells have been proposed to be key players; however, neural crest contributions to adult sutures are not well defined, and the relative importance of suture proximity is unclear. Here, we use genetic approaches to re-examine the neural crest-mesoderm boundaries in the adult mouse skull. These are combined with calvarial wounding experiments suggesting that suture proximity improves the efficiency of cranial repair. Furthermore, we demonstrate that Gli1+ and Axin2+ skeletal stem cells are present in all calvarial sutures examined. We propose that the position of the defect determines the availability of neural crest-derived progenitors, which appear to be a key element in the repair of calvarial defects.

The Fuzzy planar cell polarity protein (FUZ), necessary for primary cilium formation, is essential for pituitary development.

The primary cilium is an essential organelle that is important for normal cell signalling during development and homeostasis but its role in pituitary development has not been reported. The primary cilium facilitates signal transduction for multiple pathways, the best-characterised being the SHH pathway, which is known to be necessary for correct pituitary gland development. FUZ is a planar cell polarity (PCP) effector that is essential for normal ciliogenesis, where the primary cilia of Fuz-/- mutants are shorter or non-functional. FUZ is part of a group of proteins required for recruiting retrograde intraflagellar transport proteins to the base of the organelle. Previous work has reported ciliopathy phenotypes in Fuz-/- homozygous null mouse mutants, including neural tube defects, craniofacial abnormalities, and polydactyly, alongside PCP defects including kinked/curly tails and heart defects. Interestingly, the pituitary gland was reported to be missing in Fuz-/- mutants at 14.5 dpc but the mechanisms underlying this phenotype were not investigated. Here, we have analysed the pituitary development of Fuz-/- mutants. Histological analyses reveal that Rathke's pouch (RP) is initially induced normally but is not specified and fails to express LHX3, resulting in hypoplasia and apoptosis. Characterisation of SHH signalling reveals reduced pathway activation in Fuz-/- mutant relative to control embryos, leading to deficient specification of anterior pituitary fate. Analyses of the key developmental signals FGF8 and BMP4, which are influenced by SHH, reveal abnormal patterning in the ventral diencephalon, contributing further to abnormal RP development. Taken together, our analyses suggest that primary cilia are required for normal pituitary specification through SHH signalling.

Public Mixed Funding for Residential Aged Care Facilities Residents' Needs in the Asia-Pacific Region: A Scoping Review.

Due to population aging and sociodemographic change, there is an increasing reliance on residential aged care facilities in the Asia-Pacific region. Most countries have adopted taxation as the primary means to levy capital for funding universal health services and means-testing of benefits may be further incorporated as a policy balance between horizontal equity and fiscal sustainability. It was hypothesized that residential care needs are evaluated by assessments relating to funding; this scoping review seeks to synthesize how such assessments relate to the care needs of residents. Searches were conducted in concordance with a priori protocol for English-language literature published since 2008 in Embase, CINAHL, PubMed, Scopus, JBI, TROVE, and four peak international organizations for studies and reports that describe the assessment of residents' needs in Asia-Pacific countries that used a mixture of taxation and means-testing to publicly fund residential aged care. One paper and 47 reports were included. Australia, New Zealand, and Singapore utilize a taxation and means-tested user charge approach to fund residential aged care needs. The common care needs assessed include health conditions, daily activities, cognition, psychiatric, and behavioral needs. While essential care needs are publicly funded, other holistic care needs, such as spirituality and autonomy-based needs, still need to be covered for meaningful occupation by the residents.

A Semantic-Based Cognitive Training Programme on Everyday Activities: A Feasibility and Acceptability Study among Cognitively Healthy Older Adults.

Background: During the normal ageing process, a person's cognitive functions and memory gradually decline, which can affect their ability to perform everyday activities including cooking, cleaning, managing finances, and shopping. Semantic memory encoding strategies benefit older adults' cognitive and functional performance. Such strategies can be taught by an accessible, cost-effective, and flexible app-based programme. Currently, no studies examine such an app-based programme focussed on everyday activities. Objectives: To determine if an app-based programme constructed on the principles of semantic memory encoding strategies, targeted towards older adults, called Enhancing Memory in Daily Life (E-MinD Life) is (1) feasible by examining acceptance, engagement, and attendance and (2) acceptable by examining the perceived effectiveness, relevancy, clarity, and convenience. Methods: Eleven participants were recruited to a nine-week (18 sessions) programme using E-MinD Life. Feasibility was measured by collecting data on recruitment and retention rates, attendance, and duration of sessions. Acceptability was measured via a Likert scale questionnaire and free comments. Likert scale responses were analysed using descriptive statistics; open-ended responses were categorised qualitatively via constant comparative approach. Results: Nine participants completed the programme. Overall, most participants found the programme relevant, convenient, logical, and easy to understand and perceived it to be effective to address functional cognitive problems impacting performance of everyday activities. The results from the qualitative analysis showed that participants found the programme enjoyable and the interaction with the research team throughout the intervention beneficial. Conclusion: E-MinD Life shows promise as the focus of further research to determine the effectiveness of the programme and sematic-based cognitive strategies in maintaining cognition and performance in everyday activities among older adults with and without cognitive impairment.

GSK3 and lamellipodin balance lamellipodial protrusions and focal adhesion maturation in mouse neural crest migration.

Neural crest cells are multipotent cells that delaminate from the neuroepithelium, migrating throughout the embryo. Aberrant migration causes developmental defects. Animal models are improving our understanding of neural crest anomalies, but in vivo migration behaviors are poorly understood. Here, we demonstrate that murine neural crest cells display actin-based lamellipodia and filopodia in vivo. Using neural crest-specific knockouts or inhibitors, we show that the serine-threonine kinase glycogen synthase kinase-3 (GSK3) and the cytoskeletal regulator lamellipodin (Lpd) are required for lamellipodia formation while preventing focal adhesion maturation. Lpd is a substrate of GSK3, and phosphorylation of Lpd favors interactions with the Scar/WAVE complex (lamellipodia formation) at the expense of VASP and Mena interactions (adhesion maturation and filopodia formation). This improved understanding of cytoskeletal regulation in mammalian neural crest migration has general implications for neural crest anomalies and cancer.

Simulating the effect of ankle plantarflexion and inversion-eversion exoskeleton torques on center of mass kinematics during walking.

Walking balance is central to independent mobility, and falls due to loss of balance are a leading cause of death for people 65 years of age and older. Bipedal gait is typically unstable, but healthy humans use corrective torques to counteract perturbations and stabilize gait. Exoskeleton assistance could benefit people with neuromuscular deficits by providing stabilizing torques at lower-limb joints to replace lost muscle strength and sensorimotor control. However, it is unclear how applied exoskeleton torques translate to changes in walking kinematics. This study used musculoskeletal simulation to investigate how exoskeleton torques applied to the ankle and subtalar joints alter center of mass kinematics during walking. We first created muscle-driven walking simulations using OpenSim Moco by tracking experimental kinematics and ground reaction forces recorded from five healthy adults. We then used forward integration to simulate the effect of exoskeleton torques applied to the ankle and subtalar joints while keeping muscle excitations fixed based on our previous tracking simulation results. Exoskeleton torque lasted for 15% of the gait cycle and was applied between foot-flat and toe-off during the stance phase, and changes in center of mass kinematics were recorded when the torque application ended. We found that changes in center of mass kinematics were dependent on both the type and timing of exoskeleton torques. Plantarflexion torques produced upward and backward changes in velocity of the center of mass in mid-stance and upward and smaller forward velocity changes near toe-off. Eversion and inversion torques primarily produced lateral and medial changes in velocity in mid-stance, respectively. Intrinsic muscle properties reduced kinematic changes from exoskeleton torques. Our results provide mappings between ankle plantarflexion and inversion-eversion torques and changes in center of mass kinematics which can inform designers building exoskeletons aimed at stabilizing balance during walking. Our simulations and software are freely available and allow researchers to explore the effects of applied torques on balance and gait.

The feasibility and acceptability of an app-based cognitive strategy training programme for older people.

BACKGROUND: Increasing numbers of people are living with mild cognitive impairment in later life and seeking therapy to maintain cognition to remain as independent as possible in daily life. Based on a review of the literature, an app-based programme using perceptual-encoding strategies called Enhancing Memory in Daily Life (E-MinD Life) was developed. An expert panel reviewed the programme's appropriateness for older people with and without mild cognitive impairment. As part of the design process, the feasibility and acceptability of the E-MinD Life programme were then assessed in relation to its use by healthy older adults, with findings informing the application of the programme to older people with mild cognitive impairment in the future. METHODS: Phase 1: The E-MinD Life programme was reviewed by an expert panel of occupational therapists. Experts rated the programme on a Likert scale and answered open-ended questions in relation to feasibility, clarity, and relevancy. Phase 2 involved field-testing the 9-week programme with a sample of nine healthy older people. Participants rated the acceptability of the programme on a Likert scale questionnaire. Data on recruitment rates and retention, and adherence and duration of sessions were collected to determine the feasibility of the programme. Responses to the Likert scale were analysed using descriptive statistics. Open-ended responses were categorised qualitatively using a constant comparative approach. RESULTS: Phase 1: Experts indicated that the E-MinD Life programme was feasible and included relevant activities for community living. Although experts felt that an older user with mild NCD would be able to independently complete the programme, the qualitative analysis suggests formatting changes in future iterations of the programme to enhance visual clarity. Phase 2: All participants completed the 9-week programme. The average number of self-administered sessions attempted over the 9-week period was 13.44 (SD = 6.73) out of 18 scheduled sessions. Overall, most participants found the programme relevant, logical and easy to understand, and perceived it to be effective for functional cognitive problems. CONCLUSION: The E-MinD Life programme shows promise for inclusion into trial designs to determine the effectiveness of the cognitive strategy programme for older people with and without cognitive impairment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03430401. Registered 1 February 2018.

PROTOCOL: The effectiveness of sensory interventions targeted at improving occupational outcomes, quality of life, well-being and behavioural and psychological symptoms for older adults living with dementia: A systematic review and meta-analysis.

This is the protocol for a Campbell systematic review. The objectives are as follows: The primary objective is to systematically review the available evidence of the effects of sensory interventions on quality of life, well-being, occupational participation, and behavioural and psychological symptoms of older adults living with dementia.