AI-based derivation of atrial fibrillation phenotypes in the general and critical care populations.

BACKGROUND: Atrial fibrillation (AF) is the most common heart arrhythmia worldwide and is linked to a higher risk of mortality and morbidity. To predict AF and AF-related complications, clinical risk scores are commonly employed, but their predictive accuracy is generally limited, given the inherent complexity and heterogeneity of patients with AF. By classifying different presentations of AF into coherent and manageable clinical phenotypes, the development of tailored prevention and treatment strategies can be facilitated. In this study, we propose an artificial intelligence (AI)-based methodology to derive meaningful clinical phenotypes of AF in the general and critical care populations. METHODS: Our approach employs generative topographic mapping, a probabilistic machine learning method, to identify micro-clusters of patients with similar characteristics. It then identifies macro-cluster regions (clinical phenotypes) in the latent space using Ward's minimum variance method. We applied it to two large cohort databases (UK-Biobank and MIMIC-IV) representing general and critical care populations. FINDINGS: The proposed methodology showed its ability to derive meaningful clinical phenotypes of AF. Because of its probabilistic foundations, it can enhance the robustness of patient stratification. It also produced interpretable visualisation of complex high-dimensional data, enhancing understanding of the derived phenotypes and their key characteristics. Using our methodology, we identified and characterised clinical phenotypes of AF across diverse patient populations. INTERPRETATION: Our methodology is robust to noise, can uncover hidden patterns and subgroups, and can elucidate more specific patient profiles, contributing to more robust patient stratification, which could facilitate the tailoring of prevention and treatment programs specific to each phenotype. It can also be applied to other datasets to derive clinically meaningful phenotypes of other conditions. FUNDING: This study was funded by the DECIPHER project (LJMU QR-PSF) and the EU project TARGET (10113624).

Perioperative Dexamethasone in Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized, Placebo-Controlled Trials.

BACKGROUND: The perioperative use of dexamethasone in diabetic patients remains controversial due to concerns related to infection and adverse events. This study aimed to determine whether clinical evidence supports withholding dexamethasone in diabetic patients due to concern for infection risk. We hypothesized that there is no difference in infectious outcomes between dexamethasone-treated patients and controls. METHODS: A literature search was performed on November 22, 2022 to identify randomized, placebo-controlled trials investigating short-course (<72 hours), perioperative dexamethasone that explicitly included diabetic patients and measured at least 1 clinical outcome. Pertinent studies were independently searched in PubMed, Embase, and Cochrane. Authors for all identified studies were contacted with the aim of performing quantitative subgroup analyses of diabetic patients. The primary end point was surgical site infection and the secondary end point was a composite of adverse events. Qualitative remarks were reported based on the total available data and a quality assessment tool. Meta-analyses were performed using inverse variance with random effects. Heterogeneity was assessed via standard χ2 and I2 tests. RESULTS: Sixteen unique studies were included, 5 of which were analyzed quantitatively. Of the 2592 diabetic patients, 2344 (1184 randomized to dexamethasone and 1160 to placebo) were analyzed in at least 1 quantitative outcome. Quantitative analysis showed that the use of perioperative dexamethasone had no effect on the risk of surgical site infections (log odds ratio [LOR], -0.10, 95%; 95% confidence interval [CI], -0.64 to 0.44) while significantly reducing the risk of composite adverse events (LOR, -0.33; 95% CI, -0.62 to -0.05). Qualitative analysis reinforced these findings, demonstrating noninferior to superior results across all clinical outcomes. There was high heterogeneity between the included studies. CONCLUSIONS: Current evidence suggests perioperative dexamethasone may be given to diabetic patients without increasing the risk of infectious complications. Prospective investigations aimed at optimizing dose, frequency, and timing are needed, as well as studies aimed explicitly at exploring the use of dexamethasone in patients with poorly controlled diabetes.

Mid-infrared Doppler-free saturation absorption spectroscopy of the Q branch of CH4ν3 = 1 band using a rapid-scanning continuous-wave optical parametric oscillator.

We have developed a mid-infrared Doppler-free saturation absorption spectroscopy apparatus that employs a commercial continuous-wave optical parametric oscillator (CW OPO), complemented by a home-built automation and wavelength scanning system. Here, we report a comprehensive spectral scan of the Q branch transitions of the ν3 = 1 band of methane (CH4) with an average linewidth (FWHM) of 4.5 MHz. The absolute frequency calibration was achieved using previously reported transition frequencies determined using optical frequency combs, while a Fabry-Perot etalon was used for the relative frequency calibration. We report 15 transitions with improved accuracies of 1.13 MHz (3.76 × 10-5 cm-1).

Association of Occupational Dysfunction and Hospital Admissions With Different Polygenic Profiles in Bipolar Disorder.

OBJECTIVE: Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles. Here, polygenic scores (PGSs) for major psychiatric disorders and educational attainment were assessed for associations with occupational functioning and psychiatric hospital admissions in bipolar disorder. METHODS: A total of 4,782 patients with bipolar disorder and 2,963 control subjects were genotyped and linked to Swedish national registers. Longitudinal measures from at least 10 years of registry data were used to derive percentage of years without employment, percentage of years with long-term sick leave, and mean number of psychiatric hospital admissions per year. Ordinal regression was used to test associations between outcomes and PGSs for bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and educational attainment. Replication analyses of hospital admissions were conducted with data from the Bipolar Disorder Research Network cohort (N=4,219). RESULTS: Long-term sick leave and unemployment in bipolar disorder were significantly associated with PGSs for schizophrenia, ADHD, major depressive disorder, and educational attainment, but not with the PGS for bipolar disorder. By contrast, the number of hospital admissions per year was associated with higher PGSs for bipolar disorder and schizophrenia, but not with the other PGSs. CONCLUSIONS: Bipolar disorder severity (indexed by hospital admissions) was associated with a different polygenic profile than long-term occupational dysfunction. These findings have clinical implications, suggesting that mitigating occupational dysfunction requires interventions other than those deployed to prevent mood episodes.

Complete Blood Count Ratios Predict Adverse Events After Total Joint Arthroplasty.

INTRODUCTION: Complete blood count-based ratios (CBRs), including neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), platelet-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) are biomarkers associated with the proinflammatory surgical stress response. This study sought to determine whether preoperative CBRs are associated with postoperative complications, protracted hospital length of stay (LOS), and mortality after total joint arthroplasty, as well as establish threshold values for these outcomes for use in future investigations. METHODS: The Premier Healthcare Database was retrospectively queried for adult patients who underwent primary elective total hip arthroplasty or total knee arthroplasty (TKA). Approximate cut-point values for CBRs were identified by bootstrap simulation using the Youden index. Multivariable adjusted restricted cubic spline models using the predicted cut-point value as the threshold for odds of outcomes were created to identify a final threshold value associated with increased adjusted odds ratio (aOR) of study outcomes. RESULTS: A total of 32,868 total joint arthroplasties (THA: 12,807, TKA: 20,061) were identified. All measures predicted odds of aggregate postoperative complications (THA: NLR TV: 4.60 [aOR = 2.35], PLR TV: 163.4 [aOR = 1.32], MLR TV: 0.40 [aOR = 2.02], SII TV: 977.00 [aOR = 1.54]; TKA: NLR TV: 3.7 [aOR = 1.69], MLR TV: 0.41 [aOR = 1.62], PLR TV: 205.10 [aOR = 1.43], SII TV: 1,013.10 [aOR = 1.62]; all P < 0.05). A MLR > 0.40 [aOR = 1.54] P < 0.001) was associated with LOS ≥3 days after total hip arthroplasty while an NLR > 13.1 [aOR = 1.38] and an MLR > 0.41[aOR = 1.29] were associated with LOS ≥3 days after total knee arthroplasty (both P < 0.001). No association between inflammatory markers and inpatient mortality was observed. CONCLUSION: Given CBRs' ability to both predict outcomes and identify patients with a proinflammatory phenotype, the findings of this study provide a framework for future investigations aimed at identifying and treating high-risk patients with immune-modulating therapies. Continued work to validate these findings by applying TVs to interventional clinical trials is needed before wide clinical adoption.

Methods of identifying surgical Necrotizing Enterocolitis-a systematic review and meta-analysis.

BACKGROUND: Current data suggests potential benefit of earlier surgery for necrotizing enterocolitis (NEC) however this requires accurate prognostication early in the disease course. This study aims to identify and determine the effectiveness of previously reported methods or tests for the identification of surgical NEC. METHODS: Systematic review and meta-analysis with registration on PROSPERO including articles describing a method of identifying surgical NEC. Outcomes of interest were effectiveness and repeatability of index test. RESULTS: Of the 190 full-text articles screened, 90 studies were included which contained 114 methods of identifying surgical NEC in 9546 infants. Of these methods, 44 were a scoring system, 37 a single biomarker, 24 an imaging method, and 9 an invasive method. Sensitivity and specificity ranged from 12.8-100% to 13-100%, respectively. Some methods (9.6%) provided insufficient methods for repeatability within clinical practice or research. Meta-analyses were possible for only 2 methods, the metabolic derangement 7 score and abdominal ultrasound. CONCLUSIONS: A range of methods for identifying surgical NEC have been identified with varying overall performance and uncertainties about reproducibility and superiority of any method. External validation in large multicentre datasets should allow direct comparison of accuracy and prospective study should evaluate impact on clinical outcomes. IMPACT: Earlier identification of need for surgery in necrotizing enterocolitis (NEC) has the potential to improve the unfavourable outcomes in this condition. As such, many methods have been developed and reported to allow earlier identification of surgical NEC. This study is the first synthesis of the literature which identifies previously reported methods and the effectiveness of these. Many methods, including scoring systems and biomarkers, appear effective for prognostication in NEC and external validation is now required in multicentre datasets prior to clinical utility.

Interacting impacts of hydrological changes and air temperature warming on lake temperatures highlight the potential for adaptive management.

Globally, climate warming is increasing air temperatures and changing river flows, but few studies have explicitly considered the consequences for lake temperatures of these dual effects, or the potential to manage lake inflows to mitigate climate warming impacts. Using a one-dimensional model, we tested the sensitivity of lake temperatures to the separate and interacting effects of changes in air temperature and inflow on a small, short-residence time (annual average ≈ 20 days), temperate lake. Reducing inflow by 70% increased summer lake surface temperatures 1.0-1.2 °C and water column stability by 11-19%, equivalent to the effect of 1.2 °C air temperature warming. Conversely, similar increases in inflow could result in lake summer cooling, sufficient to mitigate 0.75 °C air temperature rise, increasing to more than 1.1 °C if inflow temperature does not rise. We discuss how altering lake inflow volume and temperature could be added to the suite of adaptation measures for lakes.

Transcriptomic analysis of the effect of remote ischaemic conditioning in an animal model of necrotising enterocolitis.

Necrotising enterocolitis (NEC) has a complex pathophysiology but the common end-point is ischaemia reperfusion injury (IRI) and intestinal necrosis. We have previously reported that RIC significantly reduces the intestinal injury in a rat model of NEC. Here we describe the changes in intestinal mRNA occurring in the intestine of animals exposed to IRI, both with and without RIC. Related rat-pups were randomly assigned to four groups: SHAM, IRI only, RIC only and RIC + IRI. IRI animals, underwent 40 min of intestinal ischaemia, and 90 min of reperfusion. Animals that underwent RIC had three cycles of 5 min of alternating ischaemia/reperfusion by means of a ligature applied to the hind limb. Samples from the terminal ileum were immediately stored in RNA-preserving media for later next generation sequencing and transciptome analysis using R v 3.6.1. Differential expression testing showed that 868 genes differentially expressed in animals exposed to RIC alone compared to SHAM and 135 in the IRI and RIC group compared to IRI alone. Comparison between these two sets showed that 25 genes were differentially expressed in both groups. Pro-inflammatory molecules: NF-ĸß2, Cxcl1, SOD2 and Map3k8 all show reduced expression in response to RIC. Targeted gene analysis revealed increased expression in PI3K which is part of the so-called RISK-pathway which is a key part of the protective mechanisms of RIC in the heart. Overall, this transcriptomic analysis shows that RIC provides a protective effect to the intestine via anti-inflammatory pathways. This could be particularly relevant to treating and preventing NEC.

Insights from multi-omic modeling of neurodegeneration in xeroderma pigmentosum using an induced pluripotent stem cell system.

Xeroderma pigmentosum (XP) is caused by defective nucleotide excision repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We show substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find that the endoplasmic reticulum stress response is upregulated and reversal of the mutant genotype is associated with phenotypic rescue. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity in XP neuronal models improves phenotypes, albeit inadequately. Although more work is required, this study presents insights with intervention potential.

Intraretinal Hyper-Reflective Foci Are Almost Universally Present and Co-Localize With Intraretinal Fluid in Diabetic Macular Edema.

Purpose: In diabetic macular edema (DME), hyper-reflective foci (HRF) has been linked to disease severity and progression. Using an automated approach, we aimed to investigate the baseline distribution of HRF in DME and their co-localization with cystoid intraretinal fluid (IRF). Methods: Baseline spectral-domain optical coherence tomography (SD-OCT) volume scans (N = 1527) from phase III clinical trials YOSEMITE (NCT03622580) and RHINE (NCT03622593) were segmented using a deep-learning-based algorithm (developed using B-scans from BOULEVARD NCT02699450) to detect HRF. The HRF count and volume were assessed. HRF distributions were analyzed in relation to best-corrected visual acuity (BCVA), central subfield thickness (CST), and IRF volume in quartiles, and Diabetic Retinopathy Severity Scores (DRSS) in groups. Co-localization of HRF with IRF was calculated in the central 3-mm diameter using the en face projection. Results: HRF were present in most patients (up to 99.7%). Median (interquartile range [IQR]) HRF volume within the 3-mm diameter Early Treatment Diabetic Retinopathy Study ring was 1964.3 (3325.2) pL, and median count was 64.0 (IQR = 96.0). Median HRF volumes were greater with decreasing BCVA (nominal P = 0.0109), and increasing CST (nominal P < 0.0001), IRF (nominal P < 0.0001), and DRSS up to very severe nonproliferative diabetic retinopathy (nominal P < 0.0001). HRF co-localized with IRF in the en face projection. Conclusions: Using automated HRF segmentation of full SD-OCT volumes, we observed that HRF are a ubiquitous feature in DME and exhibit relationships with BCVA, CST, IRF, and DRSS, supporting a potential link to disease severity. The spatial distribution of HRF closely followed that of IRF.

A conserved molecular logic for neurogenesis to gliogenesis switch in the cerebral cortex.

During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons. During this process, cortical RGCs generate intermediate progenitor cells that express critical gliogenesis genes Ascl1, Egfr, and Olig2. The increased Ascl1 expression and appearance of Egfr+ and Olig2+ cortical progenitors are concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Furthermore, the transcriptional regulation of Olig2 and Egfr has not been explored. Here, we show that in cortical progenitor cells, multiple regulatory programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between the mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.

A targeted single mutation in influenza A virus universal epitope transforms immunogenicity and protective immunity via CD4+ T cell activation.

CD4+ T cells are central to adaptive immunity. Their role in cross-protection in viral infections such as influenza and severe acute respiratory syndrome (SARS) is well documented; however, molecular rules governing T cell receptor (TCR) engagement of peptide-human leukocyte antigen (pHLA) class II are less understood. Here, we exploit an aspect of HLA class II presentation, the peptide-flanking residues (PFRs), to "tune" CD4+ T cell responses within an in vivo model system of influenza. Using a recombinant virus containing targeted substitutions at immunodominant HLA-DR1 epitopes, we demonstrate limited weight loss and improved clinical scores after heterosubtypic re-challenge. We observe enhanced protection linked to lung-derived influenza-specific CD4+ and CD8+ T cells prior to re-infection. Structural analysis of the ternary TCR:pHLA complex identifies that flanking amino acids influence side chains in the core 9-mer peptide, increasing TCR affinity. Augmentation of CD4+ T cell immunity is achievable with a single mutation, representing a strategy to enhance adaptive immunity that is decoupled from vaccine modality.

The PRC2.1 Subcomplex Opposes G1 Progression through Regulation of CCND1 and CCND2.

Progression through the G1 phase of the cell cycle is the most highly regulated step in cellular division. We employed a chemogenomics approach to discover novel cellular networks that regulate cell cycle progression. This approach uncovered functional clusters of genes that altered sensitivity of cells to inhibitors of the G1/S transition. Mutation of components of the Polycomb Repressor Complex 2 rescued growth inhibition caused by the CDK4/6 inhibitor palbociclib, but not to inhibitors of S phase or mitosis. In addition to its core catalytic subunits, mutation of the PRC2.1 accessory protein MTF2, but not the PRC2.2 protein JARID2, rendered cells resistant to palbociclib treatment. We found that PRC2.1 (MTF2), but not PRC2.2 (JARID2), was critical for promoting H3K27me3 deposition at CpG islands genome-wide and in promoters. This included the CpG islands in the promoter of the CDK4/6 cyclins CCND1 and CCND2, and loss of MTF2 lead to upregulation of both CCND1 and CCND2. Our results demonstrate a role for PRC2.1, but not PRC2.2, in promoting G1 progression.

Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derived C9orf72-associated ALS/FTD motor neurons.

A hexanucleotide repeat expansion (HRE) in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, patients with the HRE exhibit a wide disparity in clinical presentation and age of symptom onset suggesting an interplay between genetic background and environmental stressors. Neurotrauma as a result of traumatic brain or spinal cord injury has been shown to increase the risk of ALS/FTD in epidemiological studies. Here, we combine patient-specific induced pluripotent stem cells (iPSCs) with a custom-built device to deliver biofidelic stretch trauma to C9orf72 patient and isogenic control motor neurons (MNs) in vitro. We find that mutant but not control MNs exhibit selective degeneration after a single incident of severe trauma, which can be partially rescued by pretreatment with a C9orf72 antisense oligonucleotide. A single incident of mild trauma does not cause degeneration but leads to cytoplasmic accumulation of TDP-43 in C9orf72 MNs. This mislocalization, which only occurs briefly in isogenic controls, is eventually restored in C9orf72 MNs after 6 days. Lastly, repeated mild trauma ablates the ability of patient MNs to recover. These findings highlight alterations in TDP-43 dynamics in C9orf72 ALS/FTD patient MNs following traumatic injury and demonstrate that neurotrauma compounds neuropathology in C9orf72 ALS/FTD. More broadly, our work establishes an in vitro platform that can be used to interrogate the mechanistic interactions between ALS/FTD and neurotrauma.

Characteristics and Health Care Utilization of Patients With Housing Insecurity in the ED.

Importance: Unstable housing and homelessness can exacerbate adverse health outcomes leading to increased risk of chronic disease, injury, and disability. However, emergency departments (EDs) have no universal method to identify those at risk of or currently experiencing homelessness. Objective: To describe the extent of housing insecurity among patients who seek care in an urban ED, including chief concerns, demographics, and patterns of health care utilization. Design, Setting, and Participants: This cross-sectional study included all adult patients presenting to the ED at Vanderbilt University Medical Center (VUMC), an urban tertiary care, level I trauma center in the Southeast US, from January 5 to May 16, 2023. Main Outcomes and Measures: The primary outcome was the proportion of ED visits at which patients screened positive for housing insecurity. Secondary outcomes included prevalence of insecurity by chief concerns, demographics, and patterns of health care utilization. Results: Of all 23 795 VUMC ED visits with screenings for housing insecurity (12 465 visits among women [52%]; median age, 47 years [IQR, 32-48 years]), in 1185 (5%), patients screened positive for current homelessness or housing insecurity (660 unique patients); at 22 610 visits (95%), the screening result was negative. Of visits with positive results, the median age of patients was 46 years (IQR, 36-55 years) and 829 (70%) were among male patients. Suicide and intoxication were more common chief concerns among visits at which patients screened positive (132 [11%] and 118 [10%], respectively) than among those at which patients screened negative (220 [1%] and 335 [2%], respectively). Visits with positive results were more likely to be among patients who were uninsured (395 [33%] vs 2272 [10%]) and had multiple visits during the study period. A higher proportion of positive screening results occurred between 8 pm and 6 am. The social work team assessed patients at 919 visits (78%) with positive screening results. Conclusions and Relevance: In this cross-sectional study of 23 795 ED visits, at 5% of visits, patients screened positive for housing insecurity and were more likely to present with a chief concern of suicide, to be uninsured, and to have multiple visits during the study period. This analysis provides a call for other institutions to introduce screening and create tailored care plans for patients experiencing housing insecurity to achieve equitable health care.

Environmentally dependent and independent control of 3D cell shape.

How cancer cells determine their shape in response to three-dimensional (3D) geometric and mechanical cues is unclear. We develop an approach to quantify the 3D cell shape of over 60,000 melanoma cells in collagen hydrogels using high-throughput stage-scanning oblique plane microscopy (ssOPM). We identify stereotypic and environmentally dependent changes in shape and protrusivity depending on whether a cell is proximal to a flat and rigid surface or is embedded in a soft environment. Environmental sensitivity metrics calculated for small molecules and gene knockdowns identify interactions between the environment and cellular factors that are important for morphogenesis. We show that the Rho guanine nucleotide exchange factor (RhoGEF) TIAM2 contributes to shape determination in environmentally independent ways but that non-muscle myosin II, microtubules, and the RhoGEF FARP1 regulate shape in ways dependent on the microenvironment. Thus, changes in cancer cell shape in response to 3D geometric and mechanical cues are modulated in both an environmentally dependent and independent fashion.

Effectiveness and cost-effectiveness of a web-based cardiac rehabilitation programme for people with chronic stable angina: protocol for the ACTIVATE (Angina Controlled Trial Investigating the Value of the 'Activate your heart' Therapeutic E-intervention) randomised controlled trial.

INTRODUCTION: Chronic stable angina is common and disabling. Cardiac rehabilitation is routinely offered to people following myocardial infarction or revascularisation procedures and has the potential to help people with chronic stable angina. However, there is insufficient evidence of effectiveness and cost-effectiveness for its routine use in this patient group. The objectives of this study are to compare the effectiveness and cost-effectiveness of the 'Activate Your Heart' cardiac rehabilitation programme for people with chronic stable angina compared with usual care. METHODS AND ANALYSIS: ACTIVATE is a multicentre, parallel-group, two-arm, superiority, pragmatic randomised controlled trial, with recruitment from primary and secondary care centres in England and Wales and a target sample size of 518 (1:1 allocation; allocation sequence by minimisation programme with built-in random element). The study uses secure web-based allocation concealment. The two treatments will be optimal usual care (control) and optimal usual care plus the 'Activate Your Heart' web-based cardiac rehabilitation programme (intervention). Outcome assessment and statistical analysis will be performed blinded; participants will be unblinded. Outcomes will be measured at baseline and at 6 and 12 months' follow-up. Primary outcome will be the UK version of Seattle Angina Questionnaire (SAQ-UK), physical limitations domain at 12 months' follow-up. Secondary outcomes will be the remaining two domains of SAQ-UK, dyspnoea, anxiety and depression, health utility, self-efficacy, physical activity and the incremental shuttle walk test. All safety events will be recorded, and serious adverse events assessed to determine whether they are related to the intervention and expected. Concurrent economic evaluation will be cost-utility analysis from health service perspective. An embedded process evaluation will determine the mechanisms and processes that explain the implementation and impacts of the cardiac rehabilitation programme. ETHICS AND DISSEMINATION: North of Scotland National Health Service Research Ethics Committee approval, reference 21/NS/0115. Participants will provide written informed consent. Results will be disseminated by peer-reviewed publication. TRIAL REGISTRATION NUMBER: ISRCTN10054455.

An implantable device for wireless monitoring of diverse physio-behavioral characteristics in freely behaving small animals and interacting groups.

Comprehensive, continuous quantitative monitoring of intricately orchestrated physiological processes and behavioral states in living organisms can yield essential data for elucidating the function of neural circuits under healthy and diseased conditions, for defining the effects of potential drugs and treatments, and for tracking disease progression and recovery. Here, we report a wireless, battery-free implantable device and a set of associated algorithms that enable continuous, multiparametric physio-behavioral monitoring in freely behaving small animals and interacting groups. Through advanced analytics approaches applied to mechano-acoustic signals of diverse body processes, the device yields heart rate, respiratory rate, physical activity, temperature, and behavioral states. Demonstrations in pharmacological, locomotor, and acute and social stress tests and in optogenetic studies offer unique insights into the coordination of physio-behavioral characteristics associated with healthy and perturbed states. This technology has broad utility in neuroscience, physiology, behavior, and other areas that rely on studies of freely moving, small animal models.