A thorough understanding of which of the effects assessed in the in vivo Draize eye test are responsible for driving UN GHS/EU CLP classification is critical for an adequate selection of chemicals to ...be used in the development and/or evaluation of alternative methods/strategies and for properly assessing their predictive capacity and limitations. For this reason, Cosmetics Europe has compiled a database of Draize data (Draize eye test Reference Database, DRD) from external lists that were created to support past validation activities. This database contains 681 independent in vivo studies on 634 individual chemicals representing a wide range of chemical classes. A description of all the ocular effects observed in vivo, i.e. degree of severity and persistence of corneal opacity (CO), iritis, and/or conjunctiva effects, was added for each individual study in the database, and the studies were categorised according to their UN GHS/EU CLP classification and the main effect driving the classification. An evaluation of the various in vivo drivers of classification compiled in the database was performed to establish which of these are most important from a regulatory point of view. These analyses established that the most important drivers for Cat 1 Classification are (1) CO mean ≥ 3 (days 1–3) (severity) and (2) CO persistence on day 21 in the absence of severity, and those for Cat 2 classification are (3) CO mean ≥ 1 and (4) conjunctival redness mean ≥ 2. Moreover, it is shown that all classifiable effects (including persistence and CO = 4) should be present in ≥60 % of the animals to drive a classification. As a consequence, our analyses suggest the need for a critical revision of the UN GHS/EU CLP decision criteria for the Cat 1 classification of chemicals. Finally, a number of key criteria are identified that should be taken into consideration when selecting reference chemicals for the development, evaluation and/or validation of alternative methods and/or strategies for serious eye damage/eye irritation testing. Most important, the DRD is an invaluable tool for any future activity involving the selection of reference chemicals.
For more than two decades, scientists have been trying to replace the regulatory in vivo Draize eye test by in vitro methods, but so far only partial replacement has been achieved. In order to better ...understand the reasons for this, historical in vivo rabbit data were analysed in detail and resampled with the purpose of (1) revealing which of the in vivo endpoints are most important in driving United Nations Globally Harmonized System/European Union Regulation on Classification, Labelling and Packaging (UN GHS/EU CLP) classification for serious eye damage/eye irritation and (2) evaluating the method’s within-test variability for proposing acceptable and justifiable target values of sensitivity and specificity for alternative methods and their combinations in testing strategies. Among the Cat 1 chemicals evaluated, 36–65 % (depending on the database) were classified based only on persistence of effects, with the remaining being classified mostly based on severe corneal effects. Iritis was found to rarely drive the classification (<4 % of both Cat 1 and Cat 2 chemicals). The two most important endpoints driving Cat 2 classification are conjunctiva redness (75–81 %) and corneal opacity (54–75 %). The resampling analyses demonstrated an overall probability of at least 11 % that chemicals classified as Cat 1 by the Draize eye test could be equally identified as Cat 2 and of about 12 % for Cat 2 chemicals to be equally identified as No Cat. On the other hand, the over-classification error for No Cat and Cat 2 was negligible (<1 %), which strongly suggests a high over-predictive power of the Draize eye test. Moreover, our analyses of the classification drivers suggest a critical revision of the UN GHS/EU CLP decision criteria for the classification of chemicals based on Draize eye test data, in particular Cat 1 based only on persistence of conjunctiva effects or corneal opacity scores of 4. In order to successfully replace the regulatory in vivo Draize eye test, it will be important to recognise these uncertainties and to have in vitro tools to address the most important in vivo endpoints identified in this paper.
The Medication Quantification Scale III (MQS) is a tool to represent the negative impact of medication. A reduction in medication can serve as an indicator to evaluate treatment success. However, no ...cut-off value has yet been determined to evaluate whether a decrease in medication is clinically relevant. Therefore, the objective is to estimate the thresholds for the MQS and morphine milligram equivalents (MMEs) that best identify a clinically relevant important improvement for patients. Data from the Discover registry, in which patients with failed back surgery syndrome were treated with high-dose spinal cord stimulation, were used. Patient satisfaction was utilized to evaluate a clinically important outcome 12 months after stimulation. Anchor-based and distribution-based methods were applied to determine the minimal clinical important difference (MCID). Distribution-based methods revealed a value of 4.28 for the MQS and 33.61 for the MME as MCID. Anchor-based methods indicated a percentage change score of 41.2% for the MQS and 28.2% for the MME or an absolute change score of 4.72 for the MQS and 22.65 for the MME. For assessing a treatment outcome, we recommend using the percentage change score, which better reflects a clinically important outcome and is not severely influenced by high medication intake at baseline.
Patients recovered from a COVID-19 infection often report vague symptoms of fatigue or dyspnoea, comparable to the manifestations in patients with central sensitisation. The hypothesis was that ...central sensitisation could be the underlying common aetiology in both patient populations. This study explored the presence of symptoms of central sensitisation, and the association with functional status and health-related quality of life, in patients post COVID-19 infection. Patients who were previously infected with COVID-19 filled out the Central Sensitisation Inventory (CSI), the Post-COVID-19 Functional Status (PCFS) Scale and the EuroQol with five dimensions, through an online survey. Eventually, 567 persons completed the survey. In total, 29.73% of the persons had a score of <40/100 on the CSI and 70.26% had a score of ≥40/100. Regarding functional status, 7.34% had no functional limitations, 9.13% had negligible functional limitations, 37.30% reported slight functional limitations, 42.86% indicated moderate functional limitations and 3.37% reported severe functional limitations. Based on a one-way ANOVA test, there was a significant effect of PCFS Scale group level on the total CSI score (F(4,486) = 46.17, p < 0.001). This survey indicated the presence of symptoms of central sensitisation in more than 70% of patients post COVID-19 infection, suggesting towards the need for patient education and multimodal rehabilitation, to target nociplastic pain.
Virtual reality (VR) is a computer technology that immerses a user in a completely different reality. The application of VR in acute pain settings is well established. However, in chronic pain, the ...applications and outcome parameters influenced by VR are less clear.
This review aimed to systematically identify all outcome parameters that are reported in relation to VR in patients with chronic pain.
A total of 4 electronic databases (PubMed, Scopus, Web of Science, and Embase) were searched for relevant studies. Multilevel random-effect meta-analyses were performed, whereby the standardized mean difference was chosen as the effect size to denote the difference between measurements before and after a VR intervention.
The initial database search identified 1430 studies, of which 41 (2.87%) were eventually included in the systematic review. Evidence has been found for the effects of VR on pain, functioning, mobility, functional capacity, psychological outcomes, quality of life, neuropsychological outcomes, and physical sensations. The overall effect size (a total of 194 effect sizes from 25 studies) based on a three level meta-analysis was estimated at 1.22 (95% CI 0.55-1.89; z=3.56; P<.001), in favor of improvements after a VR intervention. When categorizing effect sizes, the overall effect sizes were reported as follows: 1.60 (95% CI 0.83-2.36; z=4.09; P<.001) for the effect of VR on pain (n=31), 1.40 (95% CI 0.13-2.67; z=2.17; P=.03) for functioning (n=60), 0.49 (95% CI -0.71 to 1.68; z=0.80; P=.42) for mobility (n=24), and 0.34 (95% CI -1.52 to 2.20; z=0.36; P=.72) for functional capacity (n=21).
This systematic review revealed a broad range of outcome variables influenced by an intervention of VR technology, with statistically significant pain relief and improvements in functioning. These findings indicate that VR not only has applications in acute pain management but also in chronic pain settings, whereby VR might be able to become a promising first-line intervention as complementary therapy for patients with chronic pain.
PROSPERO International Prospective Register of Systematic Reviews CRD42021227016; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=227016.
A high number of online support groups have been created on social media platforms to reinforce personal empowerment and social support. The goal of this study was to perform natural language ...processing by constructing a bag-of-words model and conducting topic modelling based on posts extracted from a chronic pain community. The subreddit called 'r/sChronicPain' was used to investigate communication on social media platforms for chronic pain patients. After data cleaning and lemmatisation, a word cloud was constructed, and the most frequent words and most frequent body regions were counted. Latent Dirichlet allocation was used to perform topic modelling. In the final analysis set, 937 unique posts were included. The most frequent word was 'pain', followed by 'doctor', 'day', 'feel', 'back', 'year', and 'time'. Concerning the body regions, 'back' was most often mentioned, followed by 'neck' and 'leg'. Based on coherence scores, one topic was extracted with 'pain' as the keyword with the highest weight. In line with the allocation of chronic low-back pain as a major health problem and increasing prevalence, back pain was most often mentioned. It seems that the primarily treatment trajectories that are proposed by medical physicians are discussed on social media, compared to interventions by other healthcare providers.
Despite the well-known clinical effects of spinal cord stimulation (SCS), the mechanisms of action have not yet been fully unraveled. The primary aim of this study was to measure whether ...electrochemical skin conductance, as a measure of peripheral sympathetic autonomic function, is altered by SCS. A second aim was to compare skin conductance levels of patients with failed back surgery syndrome (FBSS) with age- and sex-matched healthy controls. Twenty-three patients with FBSS treated with SCS participated in this study. Sudomotor function was measured with the Sudoscan
instrument on the hands and feet during SCS on and off states. Difference scores in skin conductance between patients and age- and sex-matched healthy controls were calculated. Normal sudomotor function at the painful lower limb was revealed for 61% of the patients when SCS was activated. Skin conductance levels were not altered between on and off states of SCS. Differences in scores between patients and healthy controls were significantly different from zero. This study showed that SCS does not influencing the sympathetic nervous system in patients with FBSS, as measured by skin conductance levels. Moreover, it suggested that there is no normalization of the functioning of the sympathetic nervous system, despite the effectiveness of SCS to reduce pain intensity.
Background
Autonomic nervous system dysfunction is common after acute stroke and is associated with elevated risk of cardiac arrhythmia and mortality. Heart rate variability and baroreceptor ...sensitivity have been investigated as parameters of autonomic nervous system dysfunction for the prediction of stroke outcome.
Summary
We performed a systematic literature review on heart rate variability and baroreceptor sensitivity as parameters for autonomic nervous function in acute stroke. Twenty-two studies were included. Associations between heart rate variability or baroreceptor sensitivity and stroke severity, early and late complications, dependency and mortality were reported. However, interpretability of most studies and extrapolation to general stroke population are limited due to many confounding factors such as varying methodology, small sample sizes, survival selection, and exclusion of patients with frequently occurring comorbidities in stroke. Key issues, such as the effect of thrombolytic therapy on autonomic function, autonomic nervous system dysfunction in the hyperacute phase of stroke, and correlation with the risk of recurrent stroke have not been investigated. Also, nonlinear techniques have remained largely unexplored in this domain, in spite of their advantage to provide more solid evaluation in the occurrence of arrhythmia.
Key messages
Cardiac autonomic dysfunction, represented by reduced heart rate variability or impaired baroreceptor sensitivity, is associated with stroke severity, early and late complications, dependency, and mortality. Large-scale prospective studies applying internationally accepted standards of measures for analysis of heart rate variability and baroreceptor sensitivity are needed in patients with acute stroke.
This paper deals with the analysis of data from a HET-CAM(VT) experiment. From a statistical perspective, such data yield many challenges. First of all, the data are typically time-to-event like ...data, which are at the same time interval censored and right truncated. In addition, one has to cope with overdispersion as well as clustering. Traditional analysis approaches ignore overdispersion and clustering and summarize the data into a continuous score that can be analysed using simple linear models. In this paper, a novel combined frailty model is developed that simultaneously captures all of the aforementioned statistical challenges posed by the data.
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