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Susan F Evans,1 Yuen Kwok,1 Ann Solterbeck,2 Carmen Pyragius,3 Mary Louise Hull,4 Mark R Hutchinson,1,5 Paul Rolan1 1Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; 2Statistical Revelations, Melbourne, Victoria, Australia; 3School of Paediatrics & Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia; 4Robinson Research Institute, School of Pediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia; 5ARC Centre of Excellence for Nanoscale Biophotonics, University of Adelaide, Adelaide, South Australia, AustraliaCorrespondence: Susan F EvansAdelaide Medical School, University of Adelaide, PO Box 4025, Norwood South, Adelaide, 5067, South Australia, AustraliaTel +61 418 840 895Fax +61 8 8363 2911Email susan.evans@adelaide.edu.auPurpose: Women bear a disproportionate burden of persistent pain conditions when compared to men. To determine whether the hormonal environment affects the clinical experience of pain, as measured by the days per month of pelvic pain (DPelvicPM), period pain (DPeriodPM), headache (DHeadachePM) or the in vitro EC50 for Interleukin-1β (IL-1β) release following TLR4 stimulation with Lipopolysaccharide from Peripheral Blood Mononuclear Cells (PBMCs). Findings were stratified according to use or non-use of the oral contraceptive pill.Patients and Methods: Fifty-six women aged 16– 35 years, with minimal or severe dysmenorrhea, and use or non-use of the OC, were enrolled. Blood was collected on two occasions in a single menstrual cycle: Days 1– 2 and Days 7– 10. Hormonal analysis for testosterone, dihydrotestosterone, dehydroepiandrosterone, Androstenedione, 3α-Androstanediol, 3β-androstanediol, estradiol, estrone, 17α-hydroxyprogesterone, progesterone, cortisol and sex-hormone binding globulin was undertaken using ultra-sensitive Liquid Chromatography Mass–Spectrometry (LC-MS). PBMCs were exposed to lipopolysaccharide (LPS) and the resulting Interleukin-1β output was determined.Results: Non-users of the OC showed a strongly inverse correlation between a reducing free androgen index (FAI) and increasing DPelvicPM (p=0.0032), DPeriodPM (p=0.013), DHeadachePM (p=0.041). Non-users of the OC showed a significant increase in DPelvicPM (p=0.049) on Days 7– 10. Modestly significant associations were found between reduced androgens and potentiated LPS-induced IL-1β (lower EC50).Conclusion: This is the first study to investigate the relationship between the hormonal environment and activation of the immune system in young women with dysmenorrhoea-related pain conditions. Low androgen levels were consistently associated with increased pain. Translational implications for the findings are discussed.Keywords: pain, testosterone, oral contraceptive pill, dysmenorrhoea, pelvic pain, IL-1β

Susan F Evans,1 Yuen H Kwok,2 Ann Solterbeck,3 Jiajun Liu,2 Mark R Hutchinson,1,4 M Louise Hull,5 Paul E Rolan6 1Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia; 2Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia; 3Statistical Revelations, Melbourne, Victoria, Australia; 4Australian Research Council Centre of Excellence for Nanoscale BioPhotonics, University of Adelaide, Adelaide, South Australia, Australia; 5Robinson Research Institute, School or Pediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia; 6School of Medicine, University of Adelaide, Adelaide, South Australia, AustraliaCorrespondence: Susan F Evans Tel +61 418 849 895Email susan.evans@adelaide.edu.auPurpose: Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. To determine whether there is evidence of activation of the innate immune system in dysmenorrhea and whether the degree of activation may be used as a biomarker for pain, we compared the responsiveness of peripheral blood mononuclear cells (PBMCs) to toll-like receptor (TLR) 2 or 4 stimulation. We also investigated whether this effect is modulated by the use of the oral contraceptive pill (OC).Patients and Methods: Fifty-six women aged 16– 35 years, with either severe or minimal dysmenorrhea, and use or non-use of the OC, were enrolled. PBMCs were collected on two occasions in a single menstrual cycle: the menstrual phase and the mid-follicular phase. PBMCs were exposed to lipopolysaccharide (LPS), a TLR4 agonist, and PAM3CSK4 (PAM), a TLR2 agonist, and the resulting interleukin-1beta (IL– 1β) output was determined. Statistical analysis compared the EC50 between groups as a measure of TLR responsiveness of PBMCs.Results: The key finding following LPS stimulation was a pain effect of dysmenorrhea (p=0.042) that was independent of use or non-use of OC, and independent of day of testing. Women with dysmenorrhea showed a large 2.15-fold (95% CI − 4.69, − 0.09) increase in IL– 1β release when compared with pain-free participants across both days.Conclusion: This is the first study to demonstrate an ex vivo immune relationship in women with dysmenorrhea-related pelvic pain. It provides evidence for the potential of immune modulation as a novel pharmacological target for future drug development in the management of dysmenorrhea.Keywords: pain, chronic pain, oral contraceptive pill, endometriosis, pelvic pain, IL-1β

We evaluated the reproducibility of landmarks used for accurate anatomic placement of the tibial tunnel in anterior cruciate ligament reconstruction. Landmarks evaluated were the medial tibial eminence, the posterior cruciate ligament, the 'over-the-back' position, the true posterior border of the tibia, and the posterior border of the lateral meniscus. Forty-two pairs of cadaveric knees were dissected, and anatomic measurements were made regarding the anterior cruciate ligament insertion and these various landmarks. Statistical analysis was used to confirm reproducibility and significance. Measurements based on the medial tibial eminence and posterior border of the meniscus were particularly erratic. The most reproducible anatomic landmark was the posterior cruciate ligament. The anterior border of the posterior cruciate ligament was consistently 6.7 mm posterior to the posterior border of the anterior cruciate ligament and 10.9 mm posterior to the central sagittal insertion point of the anterior cruciate ligament. The over-the-back position was consistently in contact with the anterior border of the posterior cruciate ligament if the knee was flexed with a posterior-directed force applied. In this position, the over-the-back position was equally reproducible as compared with the posterior cruciate ligament. Measurements gauged from the true posterior border of the tibia gave a second rigid bony landmark but with a wider standard deviation than the posterior cruciate ligament-based landmarks. The relative anterior-posterior dimension of the tibia did not correlate with the relationship between the anterior cruciate ligament and other anatomic landmarks. [ABSTRACT FROM AUTHOR]

Chronic pain in the calf, tibia, fibula, or muscle compartments of the leg must be carefully evaluated to make the proper diagnosis and define the most appropriate course of treatment. The most common overuse leg injuries are stress fractures, chronic exertional compartment syndrome, medial tibial stress syndrome, and strains and sprains. The history is the key component of the evaluation. Targeted questions can suggest which ancillary tests can confirm the working diagnosis. Infection, tumors, radiculopathy, and vascular compromise other than compartment syndrome are rare but must be considered in the differential. [ABSTRACT FROM AUTHOR]

Compared with other sports, cheerleading carries a relatively low risk of injury, but the injuries that do occur tend to be relatively severe in terms of time lost. The most common injury site is the ankle, with head and neck injuries less common but more severe. Two case reports illustrate overuse and acute injuries typical of the sport. Cheerleading injuries have been attributed to lack of experience, inadequate conditioning, insufficient supervision, difficult stunts, and inappropriate surfaces and equipment. Prevention recommendations are included. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stromal cell (MSC) therapy commonly involves systemic infusion of MSCs, which undergo apoptosis in the lung and induce immunoregulatory macrophages that reduce disease. The relevance of this mode of action, however, is yet to be determined for MSCs administered via other routes. Here, we administered MSCs via subcutaneous (SC) injection into inflamed tissue and investigated the immunomodulatory effects on the local lymph node (LN), which is a major site for the initiation and regulation of immune responses., Methods: A mouse model of localised skin inflammation was established with low-dose lipopolysaccharide (LPS) to in vivo prime adipose-derived MSCs delivered via SC injection. We then analysed the immunomodulatory changes in the LN draining the inflamed tissue, as well as the neutrophil TNF response to LPS re-exposure., Results: When administered directly into the inflamed skin tissue, SC MSC injection induced an expansion of IL-10-producing MerTK + subcapsular sinus macrophages and T cell zone macrophages, as well as activated CD44 + regulatory T cells (Tregs), in the draining LN, which was not observed in the non-draining LN. SC injection of viable, but not apoptotic, MSCs dampened TNF production by inflammatory cells in the draining LN when re-exposed to the inflammatory stimulus. SC injection of MSCs remote to the site of inflammation also did not attenuate the LN response to subsequent inflammatory challenge., Conclusions: MSCs delivered directly into inflamed skin activated immunoregulatory cells in the local LN and inhibited LN responsiveness to subsequent inflammatory challenge. The immunoregulatory effects of SC-injected MSCs in the LN require priming by inflammatory cytokines in the local milieu. Furthermore, SC-injected MSCs exert anti-inflammatory effects in the draining LN prior to their apoptosis, in contrast to intravenously delivered MSCs, where anti-inflammatory effects are linked to their apoptosis., Competing Interests: Declarations Ethics approval and consent to participate All animal experiments received approval from Monash University Animal Ethics Committee (Project title: Mesenchymal stromal cells and the innate immune system; Approval number: 23407; Date of approval: 01/04/2020) and were performed in accordance with the guidelines of the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes. Human MSCs were isolated from healthy donor lipoaspirate, performed with informed patient consent in accordance with Monash University Human Research Ethics Committee (Project title: Immunomodulatory properties of different stem cell types; Approval number: 2007/1798; Date of approval: 10/10/2007). Consent for publication Not applicable. Competing interests TSPH had received funding from Regeneus Ltd. MRH had also undertaken other related funded research for Regeneus Ltd. FM, CM and GV were employees of Regeneus Ltd. The funders were not involved in the study design, collection, analysis or interpretation of data, the writing of this article or the decision to submit it for publication. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Rheumatoid Arthritis (RA) is a chronic inflammatory disease resulting in joint swelling and pain. Treatment options can be reliant on disease activity scores (DAS) incorporating patient global assessments, which are quantified via visual analogue scales (VAS). VAS can be subjective and not necessarily align with clinical symptoms, such as inflammation, resulting in a disconnect between the patient's and practitioners' experience. The development of more objective assessments of pain would enable a more targeted and personalised management of pain within individuals with RA and have the potential to improve the reliability of assessments in research. Using emerging light-based hyperspectral autofluorescence imaging (HAI) technology, we aimed to objectively differentiate disease and pain states based on the analysis of synovial tissue (ST) samples from RA patients. In total, 22 individuals with RA were dichotomised using the DAS in 28-joint counts (DAS-28) into an inactive (IA) or active disease (active-RA) group and then three sub-levels of pain (low, mid, high) based on VAS. HAI was performed on ST sections to identify and quantify the most prominent fluorophores. HAI fluorophore analysis revealed a distinct separation between the IA-RA and active-RA mid-VAS cohort, successfully determining disease state. Additionally, the separation between active-RA Mid-VAS and active RA High-VAS cohort suggests that HAI could be used to objectively separate individuals based on pain severity.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abstract: Preclinical research supports a critical role for nervous system glia in pain pathophysiology. This systematic review of human trials of potential glia-modulating drugs for the prevention or treatment of pain followed a predefined search strategy and protocol registration. We searched for English language, randomized, double-blind trials comparing putative glia-modulating drugs to placebo or other comparators. The primary outcomes included validated participant-reported measures of pain intensity or relief and, in studies of opioid administration, measures of opioid consumption and/or opioid-related adverse effects. Twenty-six trials (2132 participants) of glial modulators (12 minocycline, 11 pentoxifylline, and 3 ibudilast) were included. Because of clinical heterogeneity related to study drug, participant population, outcome measures, and trial design, no meta-analysis was possible. Only 6 trials reported a positive effect of the treatment (pentoxifylline-4 trials; minocycline-2 trials), whereas 11 trials reported mixed results and 9 trials reported no effect. This review does not provide convincing evidence of efficacy of current pharmacological targets of nervous system glial function for pain treatment or prevention. However, in light of ample preclinical evidence of the importance of neuroimmune signalling and glial functions in pain pathophysiology, continued strategic human research is anticipated to identify (1) drugs with maximal activity as selectively targeted glial modulators, (2) the necessary timing and duration of pharmacological glial modulation needed for pain prevention or treatment for specific injuries or pain conditions, and (3) the best design of future clinical trials of glial-targeted drugs for pain treatment and/or prevention., (Copyright © 2024 International Association for the Study of Pain.)

This commentary provides an update and clarification on the legislative landscape surrounding mulesing in Australia since the publication of the 2023 study, "How Well Does Australian Animal Welfare Policy Reflect Scientific Evidence: A Case Study Approach Based on Lamb Marking". The article explores legislative changes mandating the use of pain relief for mulesing in various states, emphasising Victoria's original role, and highlighting the fragmented state-based legislative approach to animal welfare. It discusses the impact of these legislative changes on industry practices and animal welfare outcomes. The commentary highlights the complexities of policy development in this area, due in part to the diverse and often conflicting interests of stakeholders and the public. It underscores the importance of transparency, stakeholder collaboration, and scientifically informed policymaking to effectively enhance animal welfare standards.

Background and Objective: Temporal summation of pain (TSP) and conditioned pain modulation (CPM) are the two most commonly used clinical measures of central sensitization (CS). However, the effectiveness of exercise on TSP and CPM has yet to be evaluated. This review aims to investigate the effect of exercise alone on CS outcomes in individuals with chronic musculoskeletal pain., Databases and Data Treatment: This is a systematic review and meta-analysis. MEDLINE, EMBASE, CINAHL, PEDro and Cochrane databases were searched. Data were extracted based on the exercise modality and grouped into aerobic, resistance, isometric, or motor control modalities. Risk of bias was assessed using RoB2, RoB2 for crossover trials and ROBINS-I tools. Quality of evidence was assessed using GRADE. Random-effects meta-analyses were conducted, with subgroup analysis conducted for each exercise modality., Results: The meta-analyses included thirteen studies, consisting of eight non-randomized studies, three randomized controlled trials and three randomized crossover trials. Data were categorized into four subgroups for analyses based on exercise modality. No statistically significant effect existed for both TSP and conditioned pain modulation. However, motor control exercise was found to have a significant enhancing effect on conditioned pain modulation. No significant differences were found between the exercise subgroup for both TSP and conditioned pain modulation., Conclusions: We did not find an overall effect of physical exercise on TSP and CPM. However, subgroup analysis shows favourable effects of motor control exercise in individuals with chronic neck pain. Future research should focus on exercise modality and dosage and their role in the mechanism involved in TSP and CPM in predefined populations., Significance Statement: Results from this study found that motor control exercise has a significant enhancing effect on conditioned pain modulation, with subgroup analysis showing favourable effects of motor control exercise in individuals with chronic neck pain. This indicates that physical exercise may have a positive effect on central sensitisation in individual with chronic neck pain. However, differential effects may exist between different types of exercise. These findings will inform understanding of neurobiological effects underlying chronic neck pain and may guide the development of more effective, personalised treatments., (© 2024 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Neuroimmune interactions are essential for the development of neuropathic pain, yet the contributions of distinct immune cell populations have not been fully unraveled. Here, we demonstrate the critical role of B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury in male and female mice. Depletion of B cells with a single injection of anti-CD20 monoclonal antibody at the time of injury prevented the development of allodynia. B cell-deficient (muMT) mice were similarly spared from allodynia. Nerve injury was associated with increased immunoglobulin G (IgG) accumulation in ipsilateral lumbar dorsal root ganglia (DRGs) and dorsal spinal cords. IgG was colocalized with sensory neurons and macrophages in DRGs and microglia in spinal cords. IgG also accumulated in DRG samples from human donors with chronic pain, colocalizing with a marker for macrophages and satellite glia. RNA sequencing revealed a B cell population in naive mouse and human DRGs. A B cell transcriptional signature was enriched in DRGs from human donors with neuropathic pain. Passive transfer of IgG from injured mice induced allodynia in injured muMT recipient mice. The pronociceptive effects of IgG are likely mediated through immune complexes interacting with Fc gamma receptors (FcγRs) expressed by sensory neurons, microglia, and macrophages, given that both mechanical allodynia and hyperexcitability of dissociated DRG neurons were abolished in nerve-injured FcγR-deficient mice. Consistently, the pronociceptive effects of IgG passive transfer were lost in FcγR-deficient mice. These data reveal that a B cell-IgG-FcγR axis is required for the development of neuropathic pain in mice.

Competing Interests: The authors report no conflicts of interest.

Despite the emergence of novel diagnostic, pharmacological, interventional, and prevention strategies, atherosclerotic cardiovascular disease remains a significant cause of morbidity and mortality. Nanoparticle (NP)-based platforms encompass diverse imaging, delivery, and pharmacological properties that provide novel opportunities for refining diagnostic and therapeutic interventions for atherosclerosis at the cellular and molecular levels. Macrophages play a critical role in atherosclerosis and therefore represent an important disease-related diagnostic and therapeutic target, especially given their inherent ability for passive and active NP uptake. In this review, we discuss an array of inorganic, carbon-based, and lipid-based NPs that provide magnetic, radiographic, and fluorescent imaging capabilities for a range of highly promising research and clinical applications in atherosclerosis. We discuss the design of NPs that target a range of macrophage-related functions such as lipoprotein oxidation, cholesterol efflux, vascular inflammation, and defective efferocytosis. We also provide examples of NP systems that were developed for other pathologies such as cancer and highlight their potential for repurposing in cardiovascular disease. Finally, we discuss the current state of play and the future of theranostic NPs. Whilst this is not without its challenges, the array of multifunctional capabilities that are possible in NP design ensures they will be part of the next frontier of exciting new therapies that simultaneously improve the accuracy of plaque diagnosis and more effectively reduce atherosclerosis with limited side effects., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Paediatric sport participation continues to increase in the United States, with a corresponding increase in sports-related concussions or traumatic brain injuries (TBIs). It is important to recognize which sports are at elevated risk and identify risk factors for hospital admission and length of stay (LOS). Paediatric patients (ages 5-18) from 2008 to 2014 were identified from the Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample (NIS). Eight hundred and ninety-four patients included those who were hospitalized with a TBI resulting from participation in an individual (451 patients) or team (443 patients) sport. We evaluated the differences in LOS and total charges between individual and team sports and found that compared to team sports, TBI patients in individual sports had significantly longer hospital stays compared to team sports (1.75 days versus 1.34 days, p  < 0.001) and costlier ($27,333 versus $19,069, p  < 0.001) hospital stays. This may be due to reduced awareness and reduced compliance with return-to-play protocols in individual sports. Safety education information at a young age, increased awareness of TBIs, and additional medical support for individual sports as well as team sports may help mitigate these findings.

Affective state encompasses emotional responses to our physiology and influences how we perceive and respond within our environment. In affective disorders such as depression, cognitive adaptability is challenged, and structural and functional brain changes have been identified. However, an incomplete understanding persists of the molecular and cellular mechanisms at play in affective state. An exciting area of newly appreciated importance is perineuronal nets (PNNs); a specialised component of extracellular matrix playing a critical role in neuroprotection and synaptic plasticity. A scoping review found 24 studies demonstrating that PNNs are still a developing field of research with a promising general trend for stress in adulthood to increase the intensity of PNNs, whereas stress in adolescence reduced (potentially developmentally delayed) PNN numbers and intensity, while antidepressants correlated with reduced PNN numbers. Despite promising trends, limited research underscores the need for further exploration, emphasizing behavioral outcomes for validating affective states. Understanding PNNs' role may offer therapeutic insights for depression and inform biomarker development, advancing precision medicine and enhancing well-being., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Electric-field stimulation of neuronal activity can be used to improve the speed of regeneration for severed and damaged nerves. Most techniques, however, require invasive electronic circuitry which can be uncomfortable for the patient and can damage surrounding tissue. A recently suggested technique uses a graft-antenna-a metal ring wrapped around the damaged nerve-powered by an external magnetic stimulation device. This technique requires no electrodes and internal circuitry with leads across the skin boundary or internal power, since all power is provided wirelessly. This paper examines the microscopic basic mechanisms that allow the magnetic stimulation device to cause neural activation via the graft-antenna. A computational model of the system was created and used to find that under magnetic stimulation, diverging electric fields appear at the metal ring's edges. If the magnetic stimulation is sufficient, the gradients of these fields can trigger neural activation in the nerve. In-vivo measurements were also performed on rat sciatic nerves to support the modeling finding that direct contact between the antenna and the nerve ensures neural activation given sufficient magnetic stimulation. Simulations also showed that the presence of a thin gap between the graft-antenna and the nerve does not preclude neural activation but does reduce its efficacy., (© 2023 The Authors. Bioelectromagnetics published by Wiley Periodicals LLC on behalf of Bioelectromagnetics Society.)

The Allen Institute Mouse Brain Atlas, with visualisation using the Brain Explorer software, offers a 3-dimensional view of region-specific RNA expression of thousands of mouse genes. In this Viewpoint, we focused on the region-specific expression of genes related to cellular glycosylation, and discuss their relevance towards psychoneuroimmunology. Using specific examples, we show that the Atlas validates existing observations reported by others, identifies previously unknown potential region-specific glycan features, and highlights the need to promote collaborations between glycobiology and psychoneuroimmunology researchers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)