Motif discovery in hospital ward vital signs observation networks.

Vital signs observations are regular measurements used by healthcare staff to track a patient's overall health status on hospital wards. We look at the potential in re-purposing aggregated and anonymised hospital data sources surrounding vital signs recording to provide new insights into how care is managed and delivered on wards. In this paper, we conduct a retrospective longitudinal observational study of 770,720 individual vital signs recordings across 20 hospital wards in South Wales (UK) and present a network modelling framework to explore and extract behavioural patterns via analysis of the resulting network structures at a global and local level. Self-loop edges, dyad, triad, and tetrad subgraphs were extracted and evaluated against a null model to determine individual statistical significance, and then combined into ward-level feature vectors to provide the means for determining notable behaviours across wards. Modelling data as a static network, by aggregating all vital sign observation data points, resulted in high uniformity but with the loss of important information which was better captured when modelling the static-temporal network, highlighting time's crucial role as a network element. Wards mostly followed expected patterns, with chains or stand-alone supplementary observations by clinical staff. However, observation sequences that deviate from this are revealed in five identified motif subgraphs and 6 anti-motif subgraphs. External ward characteristics also showed minimal impact on the relative abundance of subgraphs, indicating a 'superfamily' phenomena that has been similarly seen in complex networks in other domains. Overall, the results show that network modelling effectively captured and exposed behaviours within vital signs observation data, and demonstrated uniformity across hospital wards in managing this practice.

Incorporation of Calcimimetics into ESRD Bundle: Changes in Etelcalcetide Utilization and PTH Control Following End of TDAPA Designation.

INTRODUCTION: Calcimimetics, including intravenous etelcalcetide and oral cinacalcet, are often prescribed to hemodialysis patients to prevent complications of elevated parathyroid hormone (PTH) levels. In January 2021, US dialysis reimbursement policy switched from the transitional drug add-on payment adjustment (TDAPA) to an increased bundled payment, with $10.09 per session added for all hemodialysis patients to cover the expense for calcimimetics, whether or not patients are administered etelcalcetide. We leveraged this natural experiment to investigate the impact of this policy change. METHODS: This analysis included 713 US in-center hemodialysis patients enrolled in the United States Dialysis Outcomes and Practice Patterns Study (US-DOPPS) who discontinued etelcalcetide during the TDAPA transition period (December 2020 - April 2021). Within a self-matched longitudinal design, within-patient changes in mean PTH, calcium, and phosphorus were assessed in the six months pre- vs. post- etelcalcetide discontinuation, using linear regression adjusted for potential confounders. RESULTS: Etelcalcetide use in US-DOPPS decreased 58%, from 12% to 5% from July 2020 to July 2021; 73% of etelcalcetide discontinuers switched to cinacalcet within six months. Comparing the six months pre- vs. post- etelcalcetide discontinuation, mean PTH levels increased by 107 (95% CI: 80, 133) pg/mL, and the prevalence of PTH >600 pg/mL increased by 15% (95% CI: 11%, 19%), from 28% to 43% overall, and increased from 26% to 49% among Black patients. Mean serum calcium and phosphorus levels increased by 0.42 and 0.16 mg/dL, respectively. CONCLUSION: Etelcalcetide use decreased substantially after TDAPA ended in January 2021, with most patients switching to cinacalcet. The subsequent increase in PTH levels was swift and sustained, and especially pronounced among Black patients, raising concerns about disparities and potential downstream impact on clinical outcomes. Despite the spirit of the policy change, the flat per-treatment increased payment may have inadvertently created a financial incentive to restrict patient access to a more effective therapy, and potentially stifle drug innovation.

The effect of home-based neuromuscular electrical stimulation-resistance training and protein supplementation on lean mass in persons with spinal cord injury: A pilot study.

In persons with a spinal cord injury (SCI), resistance training using neuromuscular electrical stimulation (NMES-RT) increases lean mass in the lower limbs. However, whether protein supplementation in conjunction with NMES-RT further enhances this training effect is unknown. In this randomized controlled pilot trial, 15 individuals with chronic SCI engaged in 3 times/week NMES-RT, with (NMES+PRO, n = 8) or without protein supplementation (NMES, n = 7), for 12 weeks. Before and after the intervention, whole body and regional body composition (DXA) and fasting glucose and insulin concentrations were assessed in plasma. Adherence to the intervention components was ≥96%. Thigh lean mass was increased to a greater extent after NMES+PRO compared to NMES (0.3 (0.2, 0.4) kg; p < 0.001). Furthermore, fasting insulin concentration and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were decreased similarly in both groups (fasting insulin: 1 [-9, 11] pmol∙L-1; HOMA-IR: 0.1 [-0.3, 0.5] AU; both p ≥ 0.617). Twelve weeks of home-based NMES-RT increased thigh lean mass, an effect that was potentiated by protein supplementation. In combination with the excellent adherence and apparent improvement in cardiometabolic health outcomes, these findings support further investigation through a full-scale randomized controlled trial.

Simulation of bench-scale CO2 injection using a coupled continuum-discrete approach.

Unintended releases of CO2 from carbon capture and storage operations presents the risk of atmospheric emissions and groundwater or surface water quality impacts. Given the potential impacts, it is valuable to have tools capable of predicting groundwater concentrations and likely pathways of CO2 migration in the subsurface. Traditional multiphase flow models struggle to simulate the discontinuous flow expected at leakage sites. This work applied a coupled continuum-discrete model, ET-MIP, to simulate a bench-scale injection of CO2. Results demonstrate the capability of ET-MIP to accurately capture gas fingering behaviour, and the complexity of multicomponent mass transfer observed in the experiment. Simulations were computationally efficient, allowing for the use of multiple displacement pressure realizations. CO2 migration in the subsurface was shown to be sensitive to mass transfer, as i) increased groundwater velocity can dissolve leaked CO2 prior to reaching the surface and ii) background dissolved gases in the subsurface can impact the rate of upwards gas movement, gas distribution, and the composition and persistence of the gas phase. The sensitivity to mass transfer suggests it may be preferable to monitor for low-solubility gases in the source mixture rather than CO2. These findings are applicable to other gases in the subsurface, such as hydrogen or methane migrating from geoenergy wells.

Prescribing strength training for stroke recovery: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To examine the effects of strength training on patient-important outcomes of stroke recovery and to quantify the influence of the exercise prescription on treatment effects. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Eight electronic databases (MEDLINE, EMBASE, EMCARE, AMED, PsycINFO, CINAHL, SPORTDiscus, and Web of Science) and two clinical trial registries (ClinicalTrials.gov and WHO International Clinical Trials Registry Platform) were searched from inception to 19 June 2024. ELIGIBILITY CRITERIA: Randomised controlled trials were eligible if they examined the effects of strength training compared with no exercise or usual care and reported at least one exercise prescription parameter. An advisory group of community members with lived experience of stroke helped inform outcomes most relevant to stroke recovery. RESULTS: Forty-two randomised trials (N=2204) were included. Overall risk of bias was high across most outcomes. Strength training improved outcomes rated as 'critical for decision-making' by the advisory group, including walking capacity (standardised mean difference (SMD)=0.95 (95% CI 0.34-1.56)), balance (SMD=1.13 (0.51-1.75)), functional ability and mobility (SMD=0.61 (0.09-1.14)), and habitual (mean difference (MD)=0.05 m/s (0.02-0.09)) and fast-paced walking speed (MD=0.09 m/s (0.01-0.17)), with very low to moderate certainty of evidence, mainly due to risk of bias and inconsistency. More frequent strength training, traditional strength training programmes and power-focused intensities (ie, emphasis on movement velocity) were positively associated with walking capacity, health-related quality of life and fast-paced walking speed. CONCLUSION: Strength training alone or combined with usual care improves stroke recovery outcomes that are important for decision-making. More frequent strength training, power-focused intensities and traditional programme designs may best support stroke recovery. PROSPERO REGISTRATION NUMBER: CRD42023414077.

Oxytocin Analogues for the Oral Treatment of Abdominal Pain.

Abdominal pain presents an onerous reality for millions of people affected by gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD). The oxytocin receptor (OTR) has emerged as a new analgesic drug target with OTR expression upregulated on colon-innervating nociceptors in chronic visceral hypersensitivity states, accessible via luminal delivery. However, the low gastrointestinal stability of OTR's endogenous peptide ligand oxytocin (OT) is a bottleneck for therapeutic development. Here, we report the development of potent and fully gut-stable OT analogues, laying the foundation for a new area of oral gut-specific peptide therapeutics. Ligand optimisation guided by structure-gut-stability-activity relationships yielded highly stable analogues (t1/2 >24 h, compared to t1/2 <10 min of OT in intestinal fluid) equipotent to OT (~3 nM) and with enhanced OTR selectivity. Intra-colonic administration of the lead ligand significantly reduced colonic mechanical hypersensitivity in a concentration-dependent manner in a mouse model of chronic abdominal pain. Moreover, oral administration of the lead ligand also displayed significant analgesia in this abdominal pain mouse model. The generated ligands and employed strategies could pave the way to a new class of oral gut-specific peptides to study and combat chronic gastrointestinal disorders, an area with substantial unmet medical needs.

Vascular Cytokines and Atherosclerosis: Differential Serum Levels of TRAIL, IL-18, and OPG in Obstructive Coronary Artery Disease.

The risk-factor-based prediction of atherosclerotic coronary artery disease (CAD) remains suboptimal, particularly in the absence of any of the standard modifiable cardiovascular risk factors (SMuRFs), making the discovery of biomarkers that correlate with atherosclerosis burden critically important. We hypothesized that cytokines and receptors associated with inflammation in CAD-tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interleukin-18 (IL-18), and osteoprotegerin (OPG)-would be independently associated with CAD. To determine this, we measured the serum biomarker levels of 993 participants from the BioHEART study who had CT coronary angiograms that were scored for severity of stenosis and plaque composition. We found that the quartiles of TRAIL, OPG, and IL-18 were significantly associated with disease scores, and that the IL-18/TRAIL and OPG/TRAIL ratios demonstrated significant differences between no CAD vs. STEMI whereas only the OPG/TRAIL ratio showed differences between no CAD and obstructive CAD (stenosis > 50%). However, these associations did not persist after adjustment for age, sex, SMuRFs, and a family history of CAD. In conclusion, TRAIL, IL-18, and OPG and the derived ratios of IL-18/TRAIL and OPG/TRAIL demonstrate significant associations with raw disease scores and risk factors, but these markers are not discriminatory biomarkers for the prediction of CAD when incorporated into multi-variable risk models.

Genetic and Epigenetic Factors That Predispose to Musculoskeletal Disorders.

Musculoskeletal soft tissue disorders (MSTDs) are a heterogenous group of maladies that can affect the muscles, bones, nerves, joints, ligaments, tendons, cartilage, and adjoining structures and seriously impact on the quality of life in those affected [...].

Assessing Muscle Protein Synthesis Rates In Vivo in Humans: The Deuterated Water (2H2O) Method.

Skeletal muscle tissue is in a constant state of turnover, with muscle tissue protein synthesis and breakdown rates ranging between 1% and 2% across the day in vivo in humans. Muscle tissue remodeling is largely controlled by the up- and down-regulation of muscle tissue protein synthesis rates. Research studies generally apply stable isotope-labeled amino acids to assess muscle protein synthesis rates in vivo in humans. Following labeled amino acid administration in a laboratory setting, muscle tissue samples are collected over several hours to assess the incorporation rate of these labeled amino acids in muscle tissue protein. To allow quantification of bulk muscle protein synthesis rates over more prolonged periods, the use of deuterated water methodology has regained much interest. Ingestion of daily boluses of deuterium oxide results in 2H enrichment of the body water pool. The available 2H-atoms become incorporated into endogenously synthesized alanine primarily through transamination of pyruvate in the liver. With 2H-alanine widely available to all tissues, it becomes incorporated into de novo synthesized tissue proteins. Assessing the increase in tissue protein-bound 2H-alanine enrichment in muscle biopsy samples over time allows for the calculation of muscle protein synthesis rates over several days or even weeks. As the deuterated water method allows for the assessment of muscle tissue protein synthesis rates under free-living conditions in nonlaboratory settings, there is an increasing interest in its application. This manuscript describes the theoretical background of the deuterated water method and offers a comprehensive tutorial to correctly apply the method to determine bulk muscle protein synthesis rates in vivo in humans.

Glycomics of cervicovaginal fluid from women at risk of preterm birth reveals immuno-regulatory epitopes that are hallmarks of cancer and viral glycosylation.

During pregnancy the immune system needs to maintain immune tolerance of the foetus while also responding to infection, which can cause premature activation of the inflammatory pathways leading to the onset of labour and preterm birth. The vaginal microbiome is an important modifier of preterm birth risk, with Lactobacillus dominance during pregnancy associated with term delivery while high microbial diversity is associated with an increased risk of preterm birth. Glycans on glycoproteins along the lower female reproductive tract are fundamental to microbiota-host interactions and the mediation of inflammatory responses. However, the specific glycan epitopes involved in these processes are not well understood. To address this, we conducted glycomic analyses of cervicovaginal fluid (CVF) from 36 pregnant women at high risk of preterm birth and 4 non-pregnant women. Our analysis of N- and O-glycans revealed a rich CVF glycome. While O-glycans were shown to be the main carriers of ABO blood group epitopes, the main features of N-glycans were the presence of abundant paucimannose and high mannose glycans, and a remarkable diversity of complex bi-, tri-, and tetra-antennary glycans decorated with fucose and sialic acid. We identified immuno-regulatory epitopes, such as Lewis antigens, and found that fucosylation was negatively correlated to pro-inflammatory factors, such as IL-1ß, MMP-8, C3a and C5a, while glycans with only sialylated antennae were mainly positively correlated to those. Similarly, paucimannose glycans showed a positive correlation to pro-inflammatory factors. We revealed a high abundance of glycans which have previously been identified as hallmarks of cancer and viral glycosylation, such as Man8 and Man9 high mannose glycans. Although each pregnant woman had a unique glycomic profile, longitudinal studies showed that the main glycosylation features were consistent throughout pregnancy in women who delivered at term, whereas women who experienced extreme preterm birth exhibited sharp changes in the CVF glycome shortly before delivery. These findings shed light on the processes underlying the role of glycosylation in maintaining a healthy vaginal microbiome and associated host immune responses. In addition, these discoveries facilitate our understanding of the lower female reproductive tract which has broad implications for women's health.

Mitigating disuse-induced skeletal muscle atrophy in ageing: Resistance exercise as a critical countermeasure.

The gradual deterioration of physiological systems with ageing makes it difficult to maintain skeletal muscle mass (sarcopenia), at least partly due to the presence of 'anabolic resistance', resulting in muscle loss. Sarcopenia can be transiently but markedly accelerated through periods of muscle disuse-induced (i.e., unloading) atrophy due to reduced physical activity, sickness, immobilisation or hospitalisation. Periods of disuse are detrimental to older adults' overall quality of life and substantially increase their risk of falls, physical and social dependence, and early mortality. Disuse events induce skeletal muscle atrophy through various mechanisms, including anabolic resistance, inflammation, disturbed proteostasis and mitochondrial dysfunction, all of which tip the scales in favour of a negative net protein balance and subsequent muscle loss. Concerningly, recovery from disuse atrophy is more difficult for older adults than their younger counterparts. Resistance training (RT) is a potent anabolic stimulus that can robustly stimulate muscle protein synthesis and mitigate muscle losses in older adults when implemented before, during and following unloading. RT may take the form of traditional weightlifting-focused RT, bodyweight training and lower- and higher-load RT. When combined with sufficient dietary protein, RT can accelerate older adults' recovery from a disuse event, mitigate frailty and improve mobility; however, few older adults regularly participate in RT. A feasible and practical approach to improving the accessibility and acceptability of RT is through the use of resistance bands. Moving forward, RT must be prescribed to older adults to mitigate the negative consequences of disuse atrophy.

Cellular heterogeneity of pluripotent stem cell-derived cardiomyocyte grafts is mechanistically linked to treatable arrhythmias.

Preclinical data have confirmed that human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) can remuscularize the injured or diseased heart, with several clinical trials now in planning or recruitment stages. However, because ventricular arrhythmias represent a complication following engraftment of intramyocardially injected PSC-CMs, it is necessary to provide treatment strategies to control or prevent engraftment arrhythmias (EAs). Here, we show in a porcine model of myocardial infarction and PSC-CM transplantation that EAs are mechanistically linked to cellular heterogeneity in the input PSC-CM and resultant graft. Specifically, we identify atrial and pacemaker-like cardiomyocytes as culprit arrhythmogenic subpopulations. Two unique surface marker signatures, signal regulatory protein α (SIRPA)+CD90-CD200+ and SIRPA+CD90-CD200-, identify arrhythmogenic and non-arrhythmogenic cardiomyocytes, respectively. Our data suggest that modifications to current PSC-CM-production and/or PSC-CM-selection protocols could potentially prevent EAs. We further show that pharmacologic and interventional anti-arrhythmic strategies can control and potentially abolish these arrhythmias.

Hormones, Hypertrophy, and Hype: An Evidence-Guided Primer on Endogenous Endocrine Influences on Exercise-Induced Muscle Hypertrophy.

We review the evidence indicating that endogenous changes in these hormones, including testosterone, growth hormone, insulin growth factor-1, and estrogen, and their proposed anabolic effects contribute to and augment resistance exercise training (RET)-induced hypertrophy. Additionally, we provide recommendations for gold-standard methodological rigor to establish best practices for verifying menstrual phases as part of their research, ultimately enhancing our understanding of the impact of ovarian hormones on RET-induced adaptations.

Generative Pre-trained Transformer for Pediatric Stroke Research: A Pilot Study.

BACKGROUND: Pediatric stroke is an important cause of morbidity in children. Although research can be challenging, large amounts of data have been captured through collaborative efforts in the International Pediatric Stroke Study (IPSS). This study explores the use of an advanced artificial intelligence program, the Generative Pre-trained Transformer (GPT), to enter pediatric stroke data into the IPSS. METHODS: The most recent 50 clinical notes of patients with ischemic stroke or cerebral venous sinus thrombosis at the UTHealth Pediatric Stroke Clinic were deidentified. Domain-specific prompts were engineered for an offline artificial intelligence program (GPT) to answer IPSS questions. Responses from GPT were compared with the human rater. Percent agreement was assessed across 50 patients for each of the 114 queries developed from the IPSS database outcome questionnaire. RESULTS: GPT demonstrated strong performance on several questions but showed variability overall. In its early iterations it was able to match human judgment occasionally with an accuracy score of 1.00 (n = 20, 17.5%), but it scored as low as 0.26 in some patients. Prompts were adjusted in four subsequent iterations to increase accuracy. In its fourth iteration, agreement was 93.6%, with a maximum agreement of 100% and minimum of 62%. Of 2400 individual items assessed, our model entered 2247 (93.6%) correctly and 153 (6.4%) incorrectly. CONCLUSIONS: Although our tailored generative model with domain-specific prompt engineering and ontological guidance shows promise for research applications, further refinement is needed to enhance its accuracy. It cannot enter data entirely independently, but it can be employed in tandem with human oversight contributing to a collaborative approach that reduces overall effort.

How Better Health Strategies Could Reduce Juvenile Crime.

This JAMA Forum discusses health strategies that could be used to reduce juvenile crime, including identifying and treating trauma with behavioral health, rethinking the punishment approach, and incorporating other methods to overcome current challenges.

Smartphone-based hyperspectral imaging for ice sheet and proglacial applications in South-West Greenland.

Hyperspectral imaging is a valuable analytical technique with significant benefits for environmental monitoring. However, the application of these technologies remains limited, largely by the cost and bulk associated with available instrumentation. This results in a lack of high-resolution data from more challenging and extreme environmental settings, limiting our knowledge and understanding of the effects of climate change in these regions. In this article we challenge these limitations through the application of a low-cost, smartphone-based hyperspectral imaging instrument to measurement and monitoring activities at the Greenland Ice Sheet. Datasets are captured across a variety of supraglacial and proglacial locations covering visible and near infrared wavelengths. Our results are comparable to the existing literature, despite being captured with instrumentation costing over an order of magnitude less than currently available commercial technologies. Practicalities for field deployment are also explored, demonstrating our approach to be a valuable addition to the research field with the potential to improve the availability of datasets from across the cryosphere, unlocking a wealth of data collection opportunities that were hitherto infeasible.

Exercise-specific adaptations in human skeletal muscle: Molecular mechanisms of making muscles fit and mighty.

The mechanisms leading to a predominantly hypertrophied phenotype versus a predominantly oxidative phenotype, the hallmarks of resistance training (RT) or aerobic training (AT), respectively, are being unraveled. In humans, exposure of naïve persons to either AT or RT results in their skeletal muscle exhibiting generic 'exercise stress-related' signaling, transcription, and translation responses. However, with increasing engagement in AT or RT, the responses become refined, and the phenotype typically associated with each form of exercise emerges. Here, we review some of the mechanisms underpinning the adaptations of how muscles become, through AT, 'fit' and RT, 'mighty.' Much of our understanding of molecular exercise physiology has arisen from targeted analysis of post-translational modifications and measures of protein synthesis. Phosphorylation of specific residue sites has been a dominant focus, with canonical signaling pathways (AMPK and mTOR) studied extensively in the context of AT and RT, respectively. These alone, along with protein synthesis, have only begun to elucidate key differences in AT and RT signaling. Still, key yet uncharacterized differences exist in signaling and regulation of protein synthesis that drive unique adaptation to AT and RT. Omic studies are required to better understand the divergent relationship between exercise and phenotypic outcomes of training.