Quantifying individual noxious-evoked baseline sensitivity to optimise analgesic trials in neonates
- University of Oxford, United Kingdom
Abstract
Despite the high burden of pain experienced by hospitalised neonates there are few analgesics with proven efficacy. Testing analgesics in neonates is experimentally and ethically challenging and minimising the number of neonates required to demonstrate efficacy is essential. EEG-derived measures of noxious-evoked brain activity can be used to assess analgesic efficacy, however, as variability exists in neonate's responses to painful procedures, large sample sizes are often required. Here we present a novel experimental paradigm to account for individual differences in noxious-evoked baseline sensitivity which can be used to improve the design of analgesic trials in neonates. The paradigm is developed and tested across four observational studies using clinical, experimental and simulated data (92 neonates). We provide evidence of the efficacy of gentle brushing and paracetamol, substantiating the need for randomised controlled trials of these interventions. This work provides an important step towards safe, cost-effective clinical trials of analgesics in neonates.
Data availability
Source data to produce figures 2-5 are provided with the paper. The data that support the findings of this study are available upon reasonable request from the corresponding author. Due to ethical restrictions, we consider appropriate to monitor the access and usage of the data as it includes highly sensitive information. Data sharing requests should be directed to rebeccah.slater@paediatrics.ox.ac.uk.Code availability: The magnitude of noxious-evoked brain activity in response to the experimental noxious stimuli and clinically-required procedures was calculated using the template of noxious evoked brain activity previously validated for experimental and clinical stimuli and available from (Hartley et al., 2017). The code to perform simulations to compare the sample size needed to assess an intervention effect with and without taking into account individual nociceptive sensitivity presented in study 2 are available from https://gitlab.com/paediatric_neuroimaging/simulating_power_nociceptive_sensitivity.git
Article and author information
Author details
Funding
Wellcome Trust (Senior Fellowship Award,207457/Z/17/Z)
- Rebeccah Slater
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Markus Ploner, Technische Universität München, Germany
Ethics
Human subjects: Studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Ethical approval was obtained from the National Research Ethics Service (reference 12/SC/0447) and informed written parental consent was obtained prior to each study.
Version history
- Received: November 27, 2020
- Accepted: March 17, 2021
- Accepted Manuscript published: April 13, 2021 (version 1)
- Version of Record published: April 30, 2021 (version 2)
Copyright
© 2021, Cobo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Quantifying individual noxious-evoked baseline sensitivity to optimise analgesic trials in neonates
eLife 10:e65266.
https://doi.org/10.7554/eLife.65266
Further reading
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- Medicine
Background:
Diffuse large B-cell lymphoma (DLBCL) is the predominant type of malignant B-cell lymphoma. Although various treatments have been developed, the limited efficacy calls for more and further exploration of its characteristics.
Methods:
Datasets from the Gene Expression Omnibus (GEO) database were used for identifying the tumor purity of DLBCL. Survival analysis was employed for analyzing the prognosis of DLBCL patients. Immunohistochemistry was conducted to detect the important factors that influenced the prognosis. Drug-sensitive prediction was performed to evaluate the value of the model.
Results:
VCAN, CD3G, and C1QB were identified as three key genes that impacted the outcome of DLBCL patients both in GEO datasets and samples from our center. Among them, VCAN and CD3G+ T cells were correlated with favorable prognosis, and C1QB was correlated with worse prognosis. The ratio of CD68 + macrophages and CD8 + T cells was associated with better prognosis. In addition, CD3G+T cells ratio was significantly correlated with CD68 + macrophages, CD4 + T cells, and CD8 +T cells ratio, indicating it could play an important role in the anti-tumor immunity in DLBCL. The riskScore model constructed based on the RNASeq data of VCAN, C1QB, and CD3G work well in predicting the prognosis and drug sensitivity.
Conclusions:
VCAN, CD3G, and C1QB were three key genes that influenced the tumor purity of DLBCL, and could also exert certain impact on drug sensitivity and prognosis of DLBCL patients.
Funding:
This work is supported by the Shenzhen High-level Hospital Construction Fund and CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-C&T-B-062).
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- Medicine
There is clear evidence that the sympathetic nervous system (SNS) mediates bone metabolism. Histological studies show abundant SNS innervation of the periosteum and bone marrow-these nerves consist of noradrenergic fibers that immunostain for tyrosine hydroxylase, dopamine beta hydroxylase, or neuropeptide Y. Nonetheless, the brain sites that send efferent SNS outflow to bone have not yet been characterized. Using pseudorabies (PRV) viral transneuronal tracing, we report, for the first time, the identification of central SNS outflow sites that innervate bone. We find that the central SNS outflow to bone originates from 87 brain nuclei, sub-nuclei and regions of six brain divisions, namely the midbrain and pons, hypothalamus, hindbrain medulla, forebrain, cerebral cortex, and thalamus. We also find that certain sites, such as the raphe magnus (RMg) of the medulla and periaqueductal gray (PAG) of the midbrain, display greater degrees of PRV152 infection, suggesting that there is considerable site-specific variation in the levels of central SNS outflow to bone. This comprehensive compendium illustrating the central coding and control of SNS efferent signals to bone should allow for a greater understanding of the neural regulation of bone metabolism, and importantly and of clinical relevance, mechanisms for central bone pain.
