N-of-1 medicine.

ABSTRACT: The fields of precision and personalised medicine have led to promising advances in tailoring treatment to individual patients. Examples include genome/molecular alteration-guided drug selection, single-patient gene therapy design and synergy-based drug combination development, and these approaches can yield substantially diverse recommendations. Therefore, it is important to define each domain and delineate their commonalities and differences in an effort to develop novel clinical trial designs, streamline workflow development, rethink regulatory considerations, create value in healthcare and economics assessments, and other factors. These and other segments are essential to recognise the diversity within these domains to accelerate their respective workflows towards practice-changing healthcare. To emphasise these points, this article elaborates on the concept of digital health and digital medicine-enabled N-of-1 medicine, which individualises combination regimen and dosing using a patient's own data. We will conclude with recommendations for consideration when developing novel workflows based on emerging digital-based platforms.

CURATE.AI COR-Tx platform as a digital therapy and digital diagnostic for cognitive function in patients with brain tumour postradiotherapy treatment: protocol for a prospective mixed-methods feasibility clinical trial.

INTRODUCTION: Conventional interventional modalities for preserving or improving cognitive function in patients with brain tumour undergoing radiotherapy usually involve pharmacological and/or cognitive rehabilitation therapy administered at fixed doses or intensities, often resulting in suboptimal or no response, due to the dynamically evolving patient state over the course of disease. The personalisation of interventions may result in more effective results for this population. We have developed the CURATE.AI COR-Tx platform, which combines a previously validated, artificial intelligence-derived personalised dosing technology with digital cognitive training. METHODS AND ANALYSIS: This is a prospective, single-centre, single-arm, mixed-methods feasibility clinical trial with the primary objective of testing the feasibility of the CURATE.AI COR-Tx platform intervention as both a digital intervention and digital diagnostic for cognitive function. Fifteen patient participants diagnosed with a brain tumour requiring radiotherapy will be recruited. Participants will undergo a remote, home-based 10-week personalised digital intervention using the CURATE.AI COR-Tx platform three times a week. Cognitive function will be assessed via a combined non-digital cognitive evaluation and a digital diagnostic session at five time points: preradiotherapy, preintervention and postintervention and 16-weeks and 32-weeks postintervention. Feasibility outcomes relating to acceptability, demand, implementation, practicality and limited efficacy testing as well as usability and user experience will be assessed at the end of the intervention through semistructured patient interviews and a study team focus group discussion at study completion. All outcomes will be analysed quantitatively and qualitatively. ETHICS AND DISSEMINATION: This study has been approved by the National Healthcare Group (NHG) DSRB (DSRB2020/00249). We will report our findings at scientific conferences and/or in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04848935.

Digital game-based interventions for cognitive training in healthy adults and adults with cognitive impairment: protocol for a two-part systematic review and meta-analysis.

INTRODUCTION: Digital game-based training interventions are scalable solutions that may improve cognitive function for many populations. This protocol for a two-part review aims to synthesise the effectiveness and key features of digital game-based interventions for cognitive training in healthy adults across the life span and adults with cognitive impairment, to update current knowledge and impact the development of future interventions for different adult subpopulations. METHODS AND ANALYSIS: This systematic review protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. A systematic search was performed in PubMed, Embase, CINAHL, Cochrane Library, Web of Science, PsycINFO and IEEE Explore on 31 July 2022 for relevant literature published in English from the previous 5 years. Experimental, observational, exploratory, correlational, qualitative and mixed methods studies will be eligible if they report at least one cognitive function outcome and include a digital game-based intervention intended to improve cognitive function. Reviews will be excluded but retained to search their reference lists for other relevant studies. All screening will be done by at least two independent reviewers. The appropriate Joanna Briggs Institute Critical Appraisal Tool, according to the study design, will be applied to perform the risk of bias assessment. Outcomes related to cognitive function and digital game-based intervention features will be extracted. Results will be categorised by adult life span stages in the healthy adult population for part 1 and by neurological disorder in part 2. Extracted data will be analysed quantitatively and qualitatively, according to study type. If a group of sufficiently comparable studies is identified, we will perform a meta-analysis applying the random effects model with consideration of the I2 statistic. ETHICS AND DISSEMINATION: Ethics approval is not applicable for this study since no original data will be collected. The results will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42022351265.

Closed-loop stimulation of the pelvic nerve for optimal micturition.

OBJECTIVE: Neural stimulation to restore bladder function has traditionally relied on open-loop approaches that used pre-set parameters, which do not adapt to suboptimal outcomes. The goal of this study was to examine the effectiveness of a novel closed-loop stimulation paradigm for improving micturition or bladder voiding. APPROACH: We compared the voiding efficiency obtained with this closed-loop framework against open-loop stimulation paradigms in anesthetized rats. The bladder pressures that preceded voiding, and the minimum current amplitudes for stimulating the pelvic nerves to evoke bladder contractions, were first calibrated for each animal. An automated closed-loop system was used to initiate voiding upon bladder fullness, adapt the stimulation current by using real-time bladder pressure changes to classify voiding outcomes, and halt stimulation when the bladder had been emptied or when the safe stimulation limit was reached. MAIN RESULTS: In vivo testing demonstrated that the closed-loop system achieved high voiding efficiency or VE (75.7% ± 3.07%, mean ± standard error of the mean) and outperformed open-loop systems with either conserved number of stimulation epochs (63.2% ± 4.90% VE) or conserved charge injected (32.0% ± 1.70% VE). Post-hoc analyses suggest that the classification algorithm can be further improved with data from additional closed-loop experiments. SIGNIFICANCE: This novel approach may be applied to an implantable device for treating underactive bladder (<60% VE), especially in cases where under- or over-stimulation of the nerve is a concern.

Neuromodulatory circuit effects on Drosophila feeding behaviour and metabolism.

Animals have evolved to maintain homeostasis in a changing external environment by adapting their internal metabolism and feeding behaviour. Metabolism and behaviour are coordinated by neuromodulation; a number of the implicated neuromodulatory systems are homologous between mammals and the vinegar fly, an important neurogenetic model. We investigated whether silencing fly neuromodulatory networks would elicit coordinated changes in feeding, behavioural activity and metabolism. We employed transgenic lines that allowed us to inhibit broad cellular sets of the dopaminergic, serotonergic, octopaminergic, tyraminergic and neuropeptide F systems. The genetically-manipulated animals were assessed for changes in their overt behavioural responses and metabolism by monitoring eleven parameters: activity; climbing ability; individual feeding; group feeding; food discovery; both fed and starved respiration; fed and starved lipid content; and fed/starved body weight. The results from these 55 experiments indicate that individual neuromodulatory system effects on feeding behaviour, motor activity and metabolism are dissociated.

Drosophila learn efficient paths to a food source.

Elucidating the genetic, and neuronal bases for learned behavior is a central problem in neuroscience. A leading system for neurogenetic discovery is the vinegar fly Drosophila melanogaster; fly memory research has identified genes and circuits that mediate aversive and appetitive learning. However, methods to study adaptive food-seeking behavior in this animal have lagged decades behind rodent feeding analysis, largely due to the challenges presented by their small scale. There is currently no method to dynamically control flies' access to food. In rodents, protocols that use dynamic food delivery are a central element of experimental paradigms that date back to the influential work of Skinner. This method is still commonly used in the analysis of learning, memory, addiction, feeding, and many other subjects in experimental psychology. The difficulty of microscale food delivery means this is not a technique used in fly behavior. In the present manuscript we describe a microfluidic chip integrated with machine vision and automation to dynamically control defined liquid food presentations and sensory stimuli. Strikingly, repeated presentations of food at a fixed location produced improvements in path efficiency during food approach. This shows that improved path choice is a learned behavior. Active control of food availability using this microfluidic system is a valuable addition to the methods currently available for the analysis of learned feeding behavior in flies.