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Recently, perioperative care has gained attention for its ability to improve outcomes, reduce costs, and enhance patient satisfaction, especially when multidisciplinary support is involved. Despite these benefits, patient compliance remains low due to limited engagement in program design and practical barriers such as transportation, particularly for older adults. Co-designed digital health solutions offer a promising, scalable approach to delivering personalized, accessible perioperative care, with emerging evidence supporting their feasibility and effectiveness in patients who undergo joint replacement. The objectives of this study protocol are to outline the methods to address three study aims: (1) understand gaps and unmet needs, including knowledge, perceptions, barriers, and acceptability, during the perioperative patient journey of hip and knee arthroplasty; (2) co-create a novel patient-centric digital care pathway (DCP) that provides education and systematically captures patient-reported outcomes; and (3) evaluate the feasibility of implementation, appropriateness, and acceptability of the pathway when tested in patients undergoing nontraumatic hip and knee joint arthroplasty. This mixed methods co-design and implementation study will be conducted across 3 phases informed by the generative co-design framework for health care interventions. In phase 1 (predesign), patient interviews and journey mapping will be used to identify perioperative care gaps to be addressed in the DCP. In phase 2 (co-design), care gaps will be collaboratively framed, and iterative prototyping of the DCP will be conducted with consumer feedback and pilot testing. In phase 3 (evaluation), the feasibility of the DCP will be assessed using a previously reported framework. Inclusion criteria will vary across phases, focusing on people with lived experience or undergoing hip or knee joint replacement and relevant clinical or administrative staff. The study was funded in September 2024, with phase 1 commencing in July 2025 and phase 2 in October 2025. Phase 3 is projected to commence before the end of 2025 and conclude 6 months later. As of October 2025, 13 people had been recruited, interviews were completed for phase 1, and recruitment for phase 2 had commenced. This protocol enhances methodological transparency by detailing the co-design approach, strengthening the evidence base, and supporting the development of a credible, transferable DCP. It addresses the lack of patient-centric perioperative programs in joint replacement care by incorporating individual needs and preferences. The digital format helps overcome access barriers, such as transport limitations, enabling patients to engage with the pathway anywhere. Additionally, patient-reported outcome measures collected through the DCP will improve understanding of recovery trajectories following hip and knee replacements. DERR1-10.2196/85701.

Background:Dementia is a major cause of disability and is associated with adverse events such as falls. Physiotherapists play an important role in dementia care. However, symptoms such as cognitive impairment can make delivering treatments more challenging. The overall aim of the thesis is therefore to understand the challenges and needs of physiotherapists and students to ensure they are equipped to provide effective dementia care.Aims:Study 1: Determine the knowledge, confidence, attitudes and beliefs of physiotherapists and students' working with people with dementia.Study 2: 1) Explore physiotherapist students' experiences and their perceived preparedness to work with people with dementia upon graduation. 2) Identify opportunities to improve dementia education from the perspective of students.Study 3: To determine 1) what education is being provided to entry-to-practice physiotherapy students regarding dementia in Australia and Canada and 2) how this education is being delivered.Study 4: 1) Understand what the components of effective physiotherapy care for people with dementia are, and 2) what can be done to ensure effective physiotherapy care is provided.Methods:Study 1. A mixed-methods systematic review following the Joanna Briggs Institute methodology, and a convergent integrated approach for data synthesis.Study 2. Qualitative interviews with 17 physiotherapy students. Data were thematically analysed.Study 3. Survey of lecturers working in Canadian and Australian universities. Descriptive statistics were used for quantitative data and content analysis for qualitative data.Study 4. Qualitative interviews with 16 physiotherapists experienced in dementia care. Data were thematically analysed.Results:Study 1. Physiotherapists and students lack knowledge and confidence in key areas, notably cognition, communication, behavioural and psychological symptoms. Working with people with dementia was considered complex, and dementia care was seen as a specialised area of practice.Study 2. Physiotherapy students' experiences with people with dementia were variable. They experienced many challenges that resulted in a range of emotions. The scope of dementia education opportunities was perceived as mostly inadequate, with students seeking more 'real-life' training opportunities.Study 3. A median of less than four hours of dementia education was provided across courses, with most delivered as lectures and tutorials. There were varying amounts of education on topics such as cognition, communication and behavioural symptoms and strategies. Dementia was acknowledged as a difficult topic to teach.Study 4. Effective physiotherapy dementia care involved engaging the person with dementia and working collaboratively with an interdisciplinary team and care partners. Greater advocacy and opportunities for mentoring and dementia education are needed.ConclusionPhysiotherapists and students lack knowledge and confidence when working with people with dementia. For the physiotherapy profession to provide effective care to people with dementia, physiotherapy students may benefit from more \"real-life\" scenario training at university, and current physiotherapists will benefit from specialised dementia training and mentoring by more experienced physiotherapists, as well as other allied professionals with expertise in cognitive and communication strategies. Further research into the best educational approaches is warranted. In addition, there is a need for physiotherapists and the profession to advocate for their role in dementia care.

Internal states such as arousal, attention and motivation modulate brain-wide neural activity, but how these processes interact with learning is not well understood. During learning, the brain modifies its neural activity to improve behavior. How do internal states affect this process? Using a brain–computer interface learning paradigm in monkeys, we identified large, abrupt fluctuations in neural population activity in motor cortex indicative of arousal-like internal state changes, which we term ‘neural engagement.’ In a brain–computer interface, the causal relationship between neural activity and behavior is known, allowing us to understand how neural engagement impacted behavioral performance for different task goals. We observed stereotyped changes in neural engagement that occurred regardless of how they impacted performance. This allowed us to predict how quickly different task goals were learned. These results suggest that changes in internal states, even those seemingly unrelated to goal-seeking behavior, can systematically influence how behavior improves with learning. Hennig et al. study how changes in internal state interact with learning in primates. They report stereotyped activity fluctuations in the motor cortex that reflect the animal’s level of engagement and predict how quickly the animals learned.

During learning, the new patterns of neural population activity that develop are constrained by the existing network structure so that certain patterns can be generated more readily than others. Neural activity pattern generation during learning In a study of the extent to which new patterns of neural activity can be generated through learning, Aaron Batista and colleagues examine neuronal network reorganization in Rhesus macaques learning to control a computer cursor using different patterns of activity in motor cortex. Some new neural activity patterns were more easily generated than others — corresponding to more easily learned tasks — and these could be predicted mathematically from the network topology at the beginning of the experiment. The authors speculate that the results provide a basis for a neural explanation for the balance between adaptability and persistence in action and thought. Learning, whether motor, sensory or cognitive, requires networks of neurons to generate new activity patterns. As some behaviours are easier to learn than others 1 , 2 , we asked if some neural activity patterns are easier to generate than others. Here we investigate whether an existing network constrains the patterns that a subset of its neurons is capable of exhibiting, and if so, what principles define this constraint. We employed a closed-loop intracortical brain–computer interface learning paradigm in which Rhesus macaques ( Macaca mulatta ) controlled a computer cursor by modulating neural activity patterns in the primary motor cortex. Using the brain–computer interface paradigm, we could specify and alter how neural activity mapped to cursor velocity. At the start of each session, we observed the characteristic activity patterns of the recorded neural population. The activity of a neural population can be represented in a high-dimensional space (termed the neural space), wherein each dimension corresponds to the activity of one neuron. These characteristic activity patterns comprise a low-dimensional subspace (termed the intrinsic manifold) within the neural space. The intrinsic manifold presumably reflects constraints imposed by the underlying neural circuitry. Here we show that the animals could readily learn to proficiently control the cursor using neural activity patterns that were within the intrinsic manifold. However, animals were less able to learn to proficiently control the cursor using activity patterns that were outside of the intrinsic manifold. These results suggest that the existing structure of a network can shape learning. On a timescale of hours, it seems to be difficult to learn to generate neural activity patterns that are not consistent with the existing network structure. These findings offer a network-level explanation for the observation that we are more readily able to learn new skills when they are related to the skills that we already possess 3 , 4 .

Behavior is driven by coordinated activity across a population of neurons. Learning requires the brain to change the neural population activity produced to achieve a given behavioral goal. How does population activity reorganize during learning? We studied intracortical population activity in the primary motor cortex of rhesus macaques during short-term learning in a brain–computer interface (BCI) task. In a BCI, the mapping between neural activity and behavior is exactly known, enabling us to rigorously define hypotheses about neural reorganization during learning. We found that changes in population activity followed a suboptimal neural strategy of reassociation: animals relied on a fixed repertoire of activity patterns and associated those patterns with different movements after learning. These results indicate that the activity patterns that a neural population can generate are even more constrained than previously thought and might explain why it is often difficult to quickly learn to a high level of proficiency.

BackgroundCoformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS).ObjectiveDetermine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial.MethodsAdults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation.ResultsRisk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO.ConclusionsEarly PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.Trial registration number NCT03127514; NCT03488524.

Millions of neurons drive the activity of hundreds of muscles, meaning many different neural population activity patterns could generate the same movement. Studies have suggested that these redundant (i.e. behaviorally equivalent) activity patterns may be beneficial for neural computation. However, it is unknown what constraints may limit the selection of different redundant activity patterns. We leveraged a brain-computer interface, allowing us to define precisely which neural activity patterns were redundant. Rhesus monkeys made cursor movements by modulating neural activity in primary motor cortex. We attempted to predict the observed distribution of redundant neural activity. Principles inspired by work on muscular redundancy did not accurately predict these distributions. Surprisingly, the distributions of redundant neural activity and task-relevant activity were coupled, which enabled accurate predictions of the distributions of redundant activity. This suggests limits on the extent to which redundancy may be exploited by the brain for computation. When you swing a tennis racket, muscles in your arm contract in a specific sequence. For this to happen, millions of neurons in your brain and spinal cord must fire to make those muscles contract. If you swing the racket a second time, the same muscles in your arm will contract again. But the firing pattern of the underlying neurons will probably be different. This phenomenon, in which different patterns of neural activity generate the same outcome, is called neural redundancy. Neural redundancy allows a set of neurons to perform multiple tasks at once. For example, the same neurons may drive an arm movement while simultaneously planning the next activity. But does performing a given task constrain how often different patterns of neural activity can be produced? If so, this would limit whether other tasks could be carried out at the same time. To address this, Hennig et al. trained macaque monkeys to use a brain-computer interface (BCI). This is a device that reads out electrical brain activity and converts it into signals that can be used to control another device. The key advantage of a BCI is that the redundant activity patterns are precisely known. The monkeys learned to use their brain activity, via the BCI, to move a cursor on a computer screen in different directions. The results revealed that monkeys could only produce a limited number of different patterns of brain activity for a given BCI cursor movement. This suggests that the ability of a group of neurons to multitask is restricted. For example, if the same set of neurons is involved in both planning and performing movements, then an animal’s ability to plan a future movement will depend on the one it is currently performing. BCIs can help patients who have suffered stroke or paralysis. They enable patients to use their brain activity to control a computer or even robotic limbs. Understanding how the brain controls BCIs will help us improve their performance and deepen our knowledge of how the brain plans and performs movements. This might include designing BCIs that allow users to multitask more effectively.

Two drugs, miconazole and clobetasol, have functions that modulate differentiation of oligodendrocyte progenitor cells directly, enhance remyelination, and significantly reduce disease severity in mouse models of multiple sclerosis. Remyelination in multiple sclerosis Multiple sclerosis is characterized by an autoimmune response and failure of remyelination in the brain due to defects in differentiation of myelin-producing cells from oligodendrocyte progenitor cells. Most current treatments target the immune system. Paul Tesar and colleagues screened for compounds that can enhance oligodendrocyte maturation from mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitors. They found two drugs — miconazole (an antifungal) and clobetasol (a steroid) — that enhance myelin production in vivo in mouse models of multiple sclerosis and enhanced the differentiation of human oligodendrocytes progenitors in vitro . Mechanistically, these compounds appear to target both the immune response and oligodendrocyte progenitor cells. Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes 1 . These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention 2 . To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells 3 , 4 , 5 . Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro . Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro . Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.

Sodium phenylbutyrate combined with taurursodiol reduces neuronal endoplasmic reticulum stress and mitochondrial dysfunction in experimental models. In a randomized trial, the combination slowed the rate of progression of ALS but did not affect the slow vital capacity or isometric muscle strength.

Combat military and civilian law enforcement personnel may be exposed to repetitive low-intensity blast events during training and operations. Persons who use explosives to gain entry (i.e., breach) into buildings are known as “breachers” or dynamic entry personnel. Breachers operate under the guidance of established safety protocols, but despite these precautions, breachers who are exposed to low-level blast throughout their careers frequently report performance deficits and symptoms to healthcare providers. Although little is known about the etiology linking blast exposure to clinical symptoms in humans, animal studies demonstrate network-level changes in brain function, alterations in brain morphology, vascular and inflammatory changes, hearing loss, and even alterations in gene expression after repeated blast exposure. To explore whether similar effects occur in humans, we collected a comprehensive data battery from 20 experienced breachers exposed to blast throughout their careers and 14 military and law enforcement controls. This battery included neuropsychological assessments, blood biomarkers, and magnetic resonance imaging measures, including cortical thickness, diffusion tensor imaging of white matter, functional connectivity, and perfusion. To better understand the relationship between repetitive low-level blast exposure and behavioral and imaging differences in humans, we analyzed the data using similarity-driven multi-view linear reconstruction (SiMLR). SiMLR is specifically designed for multiple modality statistical integration using dimensionality-reduction techniques for studies with high-dimensional, yet sparse, data (i.e., low number of subjects and many data per subject). We identify significant group effects in these data spanning brain structure, function, and blood biomarkers.