Although multisite pain can markedly reduce work ability, the relevance of the bodily pain distribution as a predictor of long-term sick leave is still unknown. This study aimed to investigate the ...association between musculoskeletal pain distributions and long-term sick leave in the general working population of Denmark and included 66,177 currently employed wage earners without long-term sick leave during the prior 52 weeks. Participants reported whether they had pain in the lower extremity (hips/knees), upper extremity (neck/shoulders), or the low back. The analysis controlled for age, sex, year of survey reply, educational level, occupational group, psychosocial work factors, body max index, smoking, leisure-time physical activity, and mental health confounders. The results demonstrated that the risk of long-term sick leave increased with the number of pain sites. Compared with no pain, localized pain in any body region increased the risk/hazard by 25% to 29% (HR 95% CI: 1.29 1.07-1.54 for pain only in the low back), whereas pain in 2 regions increased the risk by 39% to 44% (HR 95% CI: 1.41 1.18-1.69 for pain in the low back + hips/knees). Workers reporting pain in all 3 regions experienced a 72% increased risk (HR 95% CI: 1.72 1.55-1.91). Thus, the number of pain regions seems to matter more than the exact pain location. The spatial extension of musculoskeletal pain in workers functions as a gradient system, where pain spread throughout the body is an independent indicator of the high risk of long-term sick leave.
Postoperative pain is a major clinical problem imposing a significant burden on patients and society. In a survey 2 years after orthopedic surgery, 57% of patients reported persisting postoperative ...pain. However, only limited progress has been made in the development of safe and effective therapies to prevent the onset and chronification of pain after orthopedic surgery. We established a tibial fracture mouse model that recapitulates clinically relevant orthopedic trauma surgery, which causes changes in neuropeptide levels in dorsal root ganglia and sustained neuroinflammation in the spinal cord. Here, we monitored extended pain behavior in this model, observing chronic bilateral hindpaw mechanical allodynia in both male and female C57BL/6J mice that persisted for >3 months after surgery. We also tested the analgesic effects of a novel, minimally invasive, bioelectronic approach to percutaneously stimulate the vagus nerve (termed percutaneous vagus nerve stimulation pVNS). Weekly pVNS treatment for 30 minutes at 10 Hz for 3 weeks after the surgery strongly reduced pain behaviors compared with untreated controls. Percutaneous vagus nerve stimulation also improved locomotor coordination and accelerated bone healing. In the dorsal root ganglia, vagal stimulation inhibited the activation of glial fibrillary acidic protein-positive satellite cells but without affecting microglial activation. Overall, these data provide novel evidence supportive of the use of pVNS to prevent postoperative pain and inform translational studies to test antinociceptive effects of bioelectronic medicine in the clinic.
The pressing need for safer, more efficacious analgesics is felt worldwide. Preclinical tests in animal models of painful conditions represent one of the earliest checkpoints novel therapeutics must ...negotiate before consideration for human use. Traditionally, the pain status of laboratory animals has been inferred from evoked nociceptive assays that measure their responses to noxious stimuli. The disconnect between how pain is tested in laboratory animals and how it is experienced by humans may in part explain the shortcomings of current pain medications and highlights a need for refinement. Here, we survey human patients with chronic pain who assert that everyday aspects of life, such as cleaning and leaving the house, are affected by their ongoing level of pain. Accordingly, we test the impact of painful conditions on an ethological behavior of mice, digging. Stable digging behavior was observed over time in naive mice of both sexes. By contrast, deficits in digging were seen after acute knee inflammation. The analgesia conferred by meloxicam and gabapentin was compared in the monosodium iodoacetate knee osteoarthritis model, with meloxicam more effectively ameliorating digging deficits, in line with human patients finding meloxicam more effective. Finally, in a visceral pain model, the decrease in digging behavior correlated with the extent of disease. Ultimately, we make a case for adopting ethological assays, such as digging, in studies of pain in laboratory animals, which we believe to be more representative of the human experience of pain and thus valuable in assessing clinical potential of novel analgesics in animals.
Musculoskeletal (MSK) pain is a common reason for consultation in general practice and frequently reported in children and adolescents. This study examined the prevalence of MSK pain in 13-year-old ...children and assessed associations with physical and psychosocial factors. Data from the Generation R Study, a population-based birth cohort, was used. Prevalence and characteristics of MSK pain were assessed, using a pain mannequin, at 13 years of age (N = 3062). Demographics and data on physical activity, sedentary behaviors, previous reported MSK pain, and behavioral problems were extracted from questionnaires. The body mass index (BMI) SD-score was calculated from objectively measured weight and height. A prevalence of 23.3% was found for MSK pain in children of which 87.2% persisted for more than 3 months (ie, chronic), 45.5% experienced pain daily. More physically active children and children with a higher BMI reported MSK pain more frequently compared with non-MSK pain and no pain. The knee was the most often reported location. Children with MSK pain were more likely to have reported MSK pain at 6 years. Multivariable analyses showed significant associations for male sex (OR 0.74, 95% CI 0.56-0.98), high maternal educational (OR 0.69, 95% CI 0.49-0.96), higher BMI (OR 1.19, 95% CI 1.05-1.35), being physically active (OR 1.41, 95% CI 1.03-1.91), and behavioral problems (OR 1.85, 95% CI 1.33-2.59) with the presence of MSK pain. The chronic nature of MSK pain in combination with the relatively high prevalence of MSK pain in this study shows that MSK pain is already an important problem at a young age.
Abstract Pain anticipation during conditions of uncertainty can unveil intrinsic biases, and understanding these biases can guide pain treatment interventions. This study used machine learning and ...functional magnetic resonance imaging to predict anticipatory responses in a pain anticipation experiment. One hundred forty-seven participants that included healthy controls (n = 57) and individuals with current and/or past mental health diagnosis (n = 90) received cues indicating upcoming pain stimuli: 2 cues predicted high and low temperatures, while a third cue introduced uncertainty. Accurate differentiation of neural patterns associated with specific anticipatory conditions was observed, involving activation in the anterior short gyrus of the insula and the nucleus accumbens. Three distinct response profiles emerged: subjects with a negative bias towards high pain anticipation, those with a positive bias towards low pain anticipation, and individuals whose predictions during uncertainty were unbiased. These profiles remained stable over one year, were consistent across diagnosed psychopathologies, and correlated with cognitive coping styles and underlying insula anatomy. The findings suggest that individualized and stable pain anticipation occurs in uncertain conditions.
Facial expressions of pain play an important role in pain diagnostics and social interactions. Given the prominent impact of sex on various aspects of pain, it is not surprising that sex differences ...have also been explored regarding facial expressions of pain; however, with inconclusive findings. We aim to further investigate sex differences in facial expressions of pain by using a large, combined sample to maximize statistical power. Data from 7 previous studies of our group were merged, combining in total the data of 392 participants (male: 192, female: 200). All participants received phasic heat pain, with intensities being tailored to the individual pain threshold. Pain intensity ratings were assessed, and facial responses were manually analyzed using the Facial Action Coding. To compare facial and subjective responses between sexes, linear mixed-effects models were used, with study ID as a random effect. We found significant sex differences in facial responses, with females showing elevated facial responses to pain, although they received lower physical heat intensities (women had lower pain thresholds). In contrast, pain intensity ratings did not differ between sexes. Additionally, facial and subjective responses to pain were significantly associated across sexes, with females showing slightly stronger associations. Although variations in facial expressions of pain are very large even within each sex, our findings demonstrate that women facially communicate pain more intensively and with a better match to their subjective experience compared with men. This indicates that women might be better in using facial communication of pain in an intensity-discriminative manner.
Parental involvement in neonatal comfort care is a core component of family-centred care. Yet, parents experience a range of positive and negative feelings when providing pain-relieving interventions ...for their infants. Parents of infants who participated in the Parental touch trial (Petal), a multicentre randomised controlled trial investigating the impact of gentle parental touch on neonatal pain, were asked to complete an anonymous survey. This survey aimed to (1) explore parent-reported motivations in deciding to participate in the Petal trial; (2) understand parent-reported experiences related to trial participation; (3) understand parents' willingness to participate in future studies; and (4) evaluate parent-reported feelings while they were delivering a gentle touch intervention either before or after a clinically necessary blood test. One hundred six parents (1 parent per infant) took part in the survey. Primary motivators for participation were altruistic. Parents most frequently reported that they wanted their child to take part in the research because it has a potential benefit to babies in the future and because they wanted to improve scientific understanding. Parents reported that providing gentle touch to their children during painful procedures was associated with positive emotions, such as feeling "useful" (64%) and "reassured" (53%). Furthermore, nearly all parents (98%) were pleased to have participated in the Petal trial and would consider, or maybe consider, participating in further research studies. These results underscore the importance of structuring trials around parental involvement and providing opportunities for parents to be involved in providing comfort to their infants during necessary painful clinical procedures.
Abstract Background Frailty is increasingly present in patients with acute myocardial infarction. The electronic Frailty Index (eFI) is a validated method of identifying vulnerable older patients in ...the community from routine primary care data. Our aim was to assess the relationship between the eFI and outcomes in older patients hospitalised with acute myocardial infarction. Study design and setting Retrospective cohort study using the DataLoch Heart Disease Registry comprising consecutive patients aged 65 years or over hospitalised with a myocardial infarction between October 2013 and March 2021. Methods Patients were classified as fit, mild, moderate, or severely frail based on their eFI score. Cox-regression analysis was used to determine the association between frailty category and all-cause mortality. Results In 4670 patients (median age 77 years 71–84, 43% female), 1865 (40%) were classified as fit, with 1699 (36%), 798 (17%) and 308 (7%) classified as mild, moderate and severely frail, respectively. In total, 1142 patients died within 12 months of which 248 (13%) and 147 (48%) were classified as fit and severely frail, respectively. After adjustment, any degree of frailty was associated with an increased risk of all-cause death with the risk greatest in the severely frail (reference = fit, adjusted hazard ratio 2.87 95% confidence intervals 2.24 to 3.66). Conclusion The eFI identified patients at high risk of death following myocardial infarction. Automatic calculation within administrative data is feasible and could provide a low-cost method of identifying vulnerable older patients on hospital presentation.
Synaptic potentiation has been linked to learning in sensory cortex, but the connection between this potentiation and increased sensory-evoked neural activity is not clear. Here, we used longitudinal ...in vivo Ca 2+ imaging in the barrel cortex of awake mice to test the hypothesis that increased excitatory synaptic strength during the learning of a whisker-dependent sensory-association task would be correlated with enhanced stimulus-evoked firing. To isolate stimulus-evoked responses from dynamic, task-related activity, imaging was performed outside of the training context. Although prior studies indicate that multiwhisker stimuli drive robust subthreshold activity, we observed sparse activation of L2/3 pyramidal (Pyr) neurons in both control and trained mice. Despite evidence for excitatory synaptic strengthening at thalamocortical and intracortical synapses in this brain area at the onset of learning—indeed, under our imaging conditions thalamocortical axons were robustly activated—we observed that L2/3 Pyr neurons in somatosensory (barrel) cortex displayed only modest increases in stimulus-evoked activity that were concentrated at the onset of training. Activity renormalized over longer training periods. In contrast, when stimuli and rewards were uncoupled in a pseudotraining paradigm, stimulus-evoked activity in L2/3 Pyr neurons was significantly suppressed. These findings indicate that sensory-association training but not sensory stimulation without coupled rewards may briefly enhance sensory-evoked activity, a phenomenon that might help link sensory input to behavioral outcomes at the onset of learning.
Abstract Future climatic scenarios forecast increasingly frequent droughts that will pose substantial consequences on tree mortality. In light of this, drought-tolerant eucalypts have been ...propagated; however, the severity of these conditions will invoke adaptive responses, impacting the commercially valuable wood properties. To determine what mechanisms govern the wood anatomical adaptive response, highly controlled drought experiments were conducted in Eucalyptus grandis W. Hill ex Maiden, with the tree physiology and transcriptome closely monitored. In response to water deficit, E. grandis displays an isohydric stomatal response to conserve water and enable stem growth to continue, albeit at a reduced rate. Maintaining gaseous exchange is likely a critical short-term response that drives the formation of hydraulically safer xylem. For instance, the development of significantly smaller fibers and vessels was found to increase cellular density, thereby promoting drought tolerance through improved functional redundancy, as well as implosion and cavitation resistance. The transcriptome was explored to identify the molecular mechanisms responsible for controlling xylem cell size during prolonged water deficit. Downregulation of genes associated with cell wall remodeling and the biosynthesis of cellulose, hemicellulose and pectin appeared to coincide with a reduction in cellular enlargement during drought. Furthermore, transcript levels of NAC and MYB transcription factors, vital for cell wall component biosynthesis, were reduced, while those linked to lignification increased. The upregulation of EgCAD and various peroxidases under water deficit did not correlate with an increased lignin composition. However, with the elevated cellular density, a higher lignin content per xylem cross-sectional area was observed, potentially enhancing hydraulic safety. These results support the requirement for higher density, drought-adapted wood as a long-term adaptive response in E. grandis, which is largely influenced by the isohydric stomatal response coupled with cellular expansion-related molecular processes.
