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Shota Oda,1 Masashi Izumi,1,2 Shogo Takaya,1,2 Nobuaki Tadokoro,2 Koji Aso,2 Kristian Kjær Petersen,3 Masahiko Ikeuchi1,2 1Department of Rehabilitation Center, Kochi Medical School Hospital, Nankoku, Kochi, Japan; 2Department of Orthopedic Surgery, Kochi University, Nankoku, Kochi, Japan; 3Center for Neuroplasticity and Pain (CNAP), Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, DenmarkCorrespondence: Masashi IzumiDepartment of Orthopedic Surgery, Kochi University, Oko-Cho Kohasu, Nankoku, Kochi, Japan, 783-8505 Tel +81-88-880-2386Fax +81-88-880-2388Email izumim@kochi-u.ac.jpPurpose: Clinically, arthrogenic muscle inhibition (AMI) has a negative impact on functional recovery in musculoskeletal disorders. One possible technique to relieve AMI is motor imagery, which is widely used in neurological rehabilitation to enhance motor neuron excitability. The purpose of this study was to verify the efficacy of visually-assisted motor imagery against AMI using a human experimental pain model.Methods: Ten healthy volunteers were included. Experimental ankle pain was induced by hypertonic saline infusion into unilateral Kager’s fat pad. Isotonic saline was used as control. Subjects were instructed to imagine while watching a movie in which repetitive motion of their own ankle or fingers was shown. H-reflex normalized by the motor response (H/M ratio) on soleus muscle, maximal voluntary contraction (MVC) force of ankle flexion, and contractile activities of the calf muscles during MVC were recorded at baseline, pre-intervention, post-intervention, and 10 minutes after the pain had subsided.Results: Hypertonic saline produced continuous and constant peri-ankle pain (VAS peak [median]= 6.7 [2.1– 8.4] cm) compared to isotonic saline (0 [0– 0.8] cm). In response to pain, there were significant decreases in the H/M ratio, MVC and contractile activities (P< 0.01), all of which were successfully reversed after the ankle motion imagery. In contrast, no significant changes were observed with the finger motion imagery.Conclusion: Visually-assisted motor imagery improved the pain-induced AMI. Motor imagery of the painful joint itself would efficiently work for relieving AMI. This investigation possibly shows the potential of a novel and versatile approach against AMI for patients with musculoskeletal pain.Keywords: arthrogenic muscle inhibition, experimental ankle pain model, visually-assisted motor imagery

Background: A growing body of evidence suggests that neuroinflammation contributes actively to pathophysiology of Alzheimer's disease (AD) and promotes AD progression. The predictive value of neuroinflammatory biomarkers for disease-staging or estimating disease progression is not well understood. In this study, we investigate the diagnostic and prognostic utility of inflammatory biomarkers in combination with conventional AD biomarkers., Methods: We included 258 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had CSF biomarkers of β-Amyloid (Aβ), tau, and inflammation. The primary outcome of interest was clinically meaningful cognitive decline (CMCD) as defined by an increase of ≥4 on the Alzheimer's Disease Assessment Scale Cognitive Subscore 11 (ADAS-11, scores 0-70, higher scores indicate worse cognition). Predictor variables were categorized as demographics (D; age, sex, and education), genetic (APOE4 status (A)), inflammatory biomarkers (I), and classic (C) cerebrospinal fluid (CSF) biomarkers of Aβ and p-tau181. Simultaneous inclusion of eleven CSF inflammatory biomarkers as covariates in logistic regression models was examined to assess improvements in classifying baseline clinical diagnoses (cognitively normal (CN), mild cognitive impairment (MCI), Dementia) and predicting individuals with and without CMCD over one year of follow-up., Results: At 1-year follow up, 27.1% of participants experienced CMCD. Inclusion of inflammatory biomarkers improved baseline classification of CN vs MCI as well as CN vs Dementia for models including D and A variables (DA; both p <0.001). Similarly, when classic CSF biomarkers of AD were included into the model (DAC model), inclusion of inflammatory markers improved classification of CN vs MCI ( p <0.01) as well as CN vs Dementia ( p <0.001). Addition of inflammatory biomarkers to both DA and DAC models improved predictive performance for CMCD in persons with baseline MCI and Dementia (all p <0.05), but not in the CN group. In addition, the predictive performance of the DAI model was superior to the DAC model in the MCI and Dementia groups (both p <0.05)., Conclusions: Addition of CSF inflammatory biomarkers to CSF biomarkers of AD can improve diagnostic accuracy of clinical disease stage at baseline and add incremental value to AD biomarkers for prediction of cognitive decline., Learning Objective: □ Identify potential diagnostic and prognostic ability of inflammatory biomarkers to assess Alzheimer's disease stage and cognitive decline.

Plasma biomarkers for Alzheimer's disease (AD) are increasingly being used to assist in making an etiological diagnosis for cognitively impaired (CI) individuals or to identify cognitively unimpaired (CU) individuals with AD pathology who may be eligible for prevention trials. However, a better understanding of the timing of plasma biomarker changes is needed to optimize their use in clinical and research settings. The aim of this study was to evaluate the timing of change of key AD plasma biomarkers (Aβ42/Aβ40, p-tau217, p-tau181, GFAP and NfL) from six different companies, along with established AD biomarkers, using AD progression timelines based on amyloid and tau PET. We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 784 individuals with longitudinal 18 F-florbetapir amyloid PET and 359 individuals with longitudinal 18 F-flortaucipir tau PET, to estimate age at amyloid and tau positivity, defined as the age at the first positive PET scan. Of these, longitudinal plasma biomarker measures were available from 190 individuals with an estimated age at amyloid positivity and 70 individuals with an estimated age at tau positivity. Age at tau positivity was a stronger predictor of symptom onset than age at amyloid positivity in 17 individuals who progressed from CU to CI during their participation in the ADNI study (Adj R 2 = 0.86 vs. Adj R 2 = 0.38), and therefore was used to estimate symptom onset age for all individuals with an estimated age at tau positivity. Generalized additive mixed models (GAMMs) were used to model biomarker trajectories across years since amyloid positivity, tau positivity, and symptom onset, and to identify the earliest timepoint of biomarker abnormality when compared to a reference group of amyloid- and tau-negative CU individuals, as well as time periods of significant change in biomarkers. All plasma biomarkers except NfL became abnormal prior to amyloid and tau positivity. Plasma Aβ42/Aβ40 was the first biomarker to reach abnormality consistently across timelines and plasma GFAP became abnormal early in the tau timeline. Plasma Aβ42/Aβ40 levels reached a plateau, while plasma p-tau217, p-tau181, GFAP and NfL increased throughout disease progression. Some differences in the timing of change were observed across biomarker assays. The primary utility of plasma Aβ42/Aβ40 may lie in early identification of individuals at high risk of AD. In contrast, p-tau217, p-tau181, GFAP and NfL increase throughout the estimated timelines, supporting their potential as biomarkers for staging and monitoring disease progression.

Background: Persistent postsurgical pain (PPSP) following thoracic surgery affects 40%-60% of patients undergoing lung resection due to malignancies. Postoperative pain-related symptoms are common, leading to limitations in activities of daily living (ADL) and deterioration in physical function, which significantly impacts quality of life. Pain-related limitations are of interest, as postsurgical pain may present as a target for intervention to improve postoperative rehabilitation. This study aimed to evaluate the association between PPSP and ADL limitations during the first 12 postoperative months after surgery for lung cancer., Methods: A total of 124 patients undergoing surgery for lung cancer were followed for 12 months. Every 2 months, participants reported ADL limitations attributed to PPSP. Cumulative pain impairment scores were calculated from reported limitations in 14 daily activities, and recovery trajectory patterns were analysed., Results: Daily activities most affected by PPSP were carrying bags, arm elevation, climbing stairs, cleaning floors and coughing, with >50% reporting limitations across all assessment times. Reported pain intensities were generally mild (NRS≤3), but still associated with significant impairment. Some recovery was observed in patients reporting pain at rest, but PPSP was consistently associated with higher cumulative pain impairment scores at all assessments during the 12-month follow-up period., Conclusions: Findings indicate that persistent postsurgical pain, even of mild intensity, is associated with significant limitations in daily activities up to 12 months post-surgery. Some improvement in pain-related impairment was observed, although limitations remained significantly higher in patients reporting persistent postsurgical pain, as compared to pain-free patients., Significance: Surgery remains a cornerstone in the treatment of early-stage lung cancer. Despite advances in minimally invasive techniques and rehabilitation, persisting postsurgical pain and pain-related limitations in daily activities may endure. This study investigated specifically the pain-related limitations in activities of daily living and described recovery trajectories during the first 12 postoperative months. Patients with persistent postsurgical pain experienced multiple limitations compared to pain-free patients. Although partial recovery was observed, impairments remained significant for up to 12 months after surgery., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Introduction: Blood tests have the potential to improve the accuracy of Alzheimer's disease (AD) clinical diagnosis, which will enable greater access to AD-specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD-related outcomes., Methods: Plasma samples from the Alzheimer's Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix. Outcomes measures were amyloid positron emission tomography (PET), tau PET, cortical thickness, and dementia severity. Logistic regression models assessed the classification accuracies of individual or combined plasma biomarkers for binarized outcomes, and Spearman correlations evaluated continuous relationships between individual plasma biomarkers and continuous outcomes., Results: Measures of plasma p-tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with all AD outcomes., Discussion: This study identified the plasma biomarker analytes and assays that most accurately classified amyloid pathology and other AD-related outcomes., Highlights: Plasma p-tau217 measures most accurately classified amyloid and tau status. Plasma Aβ42/Aβ40 had relatively low accuracy in classification of amyloid status. Plasma p-tau217 measures had higher correlations with cortical thickness than NfL. Correlations of plasma biomarkers with dementia symptoms were relatively low., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Understanding the heterogeneity of brain structure in individuals with the Motoric Cognitive Risk Syndrome (MCR) may improve the current risk assessments of dementia., Methods: We used data from 6 cohorts from the MCR consortium (N=1987). A weakly-supervised clustering algorithm called HYDRA was applied to volumetric MRI measures to identify distinct subgroups in the population with gait speeds lower than one standard deviation (1SD) above mean., Results: Three subgroups (Groups A, B & C) were identified through MRI-based clustering with significant differences in regional brain volumes, gait speeds, and performance on Trail Making (Part-B) and Free and Cued Selective Reminding Tests., Discussion: Based on structural MRI, our results reflect heterogeneity in the population with moderate and slow gait, including those with MCR. Such a data-driven approach could help pave new pathways toward dementia at-risk stratification and have implications for precision health for patients., Competing Interests: HMB serves as a consultant for Neural+. RBL is the Edwin S. Lowe Professor of Neurology at the Albert Einstein College of Medicine in New York. He also receives support from the Migraine Research Foundation and the National Headache Foundation and research grants from TEVA, Satsuma and Amgen. He serves on the editorial board of Neurology, senior advisor to Headache, and associate editor to Cephalalgia. He has reviewed for the NIA and NINDS, holds stock and stock options in Axon, Biohaven Holdings, CoolTech and Manistee; serves as consultant, advisory board member, or has received honoraria from: Abbvie (Allergan), American Academy of Neurology, American Headache Society, Amgen, Avanir, Axon, Axsome, Biohaven, Biovision, Boston Scientific, Dr. Reddy’s (Promius), Electrocore, Eli Lilly, eNeura Therapeutics, Equinox, GlaxoSmithKline, Grifols, Lundbeck (Alder), Manistee, Merck, Pernix, Pfizer, Satsuma, Supernus, Teva, Trigemina, Vector, Vedanta. He receives royalties from Wolff’s Headache 7th and 8th Edition, Oxford Press University, 2009, Wiley and Informa. JV serves as an Advisory Committee Member for MedRhythms, and a holds a uncompensated voluntary position at CatchU. Authors BTN, AE, KKP, EA, VGPK, SV, RB, OB, TD, HS, SM, and SA do not have any conflicts of interest to disclose.

Background: Pain profiles (e.g. pro- and anti-nociceptive) can be developed using quantitative sensory testing (QST) but substantial variability exists. This study describes the variability in temporal summation of pain (TSP) and conditioned pain modulation (CPM) in chronic musculoskeletal pain patients, proposes cut-off values, and explores the association with clinical pain intensity., Methods: This is a secondary analysis in which TSP and CPM were assessed using cuff algometry in pain-free subjects (n = 69), and patients with chronic low back pain (cLBP, n = 267), osteoarthritis (n = 134), and fibromyalgia (n = 101). Using TSP and CPM from the pain-free subjects as a reference, four distinct pain profiles TSP (low/high) and CPM (low/high) were created, and differences in clinical pain between pain profiles were explored., Results: Individual data revealed large inter-person variability. High TSP and low CPM were found in fibromyalgia (p < 0.01) and osteoarthritis (p < 0.01) but not cLBP when compared to pain-free subjects. The proportion of patients classified into the distinct pain profiles was significantly different (p < 0.001) with the largest proportion in the high TSP and low CPM group in fibromyalgia (52.5%) and osteoarthritis (41.4%). Clinical pain was not significantly different comparing the pain profiles, and no significant correlations were observed between clinical pain and TSP or CPM., Conclusion: These results demonstrated substantial inter-person variability in TSP and CPM in patients with different chronic pain conditions and pain-free subjects. The proportion of patients with a pro-nociceptive profile appears larger in fibromyalgia and osteoarthritis, but we found no association to clinical pain., Significant Statement: This analysis shows that there is variability when assessing TSP and CPM in both pain-free subjects and patients with chronic pain. A cut-off for determining when a person is pain-sensitive is proposed, and data based on this cut-off approach suggest that significantly more patients with osteoarthritis and fibromyalgia are pain-sensitive (i.e. higher TSP and lower CPM) compared to pain-free subjects. This analysis does not find an association between pain sensitivity and clinical pain., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Abstract: Chronic postoperative pain is present in approximately 20% of patients undergoing total knee arthroplasty. Studies indicate that pain mechanisms are associated with development and maintenance of chronic postoperative pain. The current study assessed pain sensitivity, inflammation, microRNAs, and psychological factors and combined these in a network to describe chronic postoperative pain. This study involved 75 patients with and without chronic postoperative pain after total knee arthroplasty. Clinical pain intensity, Oxford Knee Score, and pain catastrophizing were assessed as clinical parameters. Quantitative sensory testing was assessed to evaluate pain sensitivity and microRNAs, and inflammatory markers were likewise analyzed. Supervised multivariate data analysis with "Data Integration Analysis for Biomarker Discovery" using Latent cOmponents (DIABLO) was used to describe the chronic postoperative pain intensity. Two DIABLO models were constructed by dividing the patients into 3 groups or 2 defined by clinical pain intensities. Data Integration Analysis for Biomarker discovery using Latent cOmponents model explained chronic postoperative pain and identified factors involved in pain mechanistic networks among assessments included in the analysis. Developing models of 3 or 2 patient groups using the assessments and the networks could explain 81% and 69% of the variability in clinical postoperative pain intensity. The reduction of the number of parameters stabilized the models and reduced the explanatory value to 69% and 51%. This is the first study to use the DIABLO model for chronic postoperative pain and to demonstrate how different pain mechanisms form a pain mechanistic network. The complex model explained 81% of the variability of clinical pain intensity, whereas the less complex model explained 51% of the variability of clinical pain intensity., (Copyright © 2024 International Association for the Study of Pain.)

Sleep disturbances exacerbate chronic pain, increase psychological load, and increase inflammation. Delayed onset muscle soreness (DOMS) mimics aspects of chronic pain, predominantly affecting peripheral pain mechanisms, while experimental sleep provocations have been shown to impact central pain mechanisms. This study aimed to combine a DOMS model with total sleep deprivation (TSD) to create a novel model affecting both peripheral and central pain mechanisms. A total of 30 healthy participants attended two sessions (baseline and follow-up) separated by 24 h of TSD and a home rating after 48 h. Assessments of interleukin 6 (IL-6) levels, sleep quality, pain catastrophising, affect, and symptoms of depression and anxiety were included in the baseline and follow-up sessions. Additionally, pressure pain and tolerance thresholds, temporal summation, and conditioned pain modulation (CPM) were assessed using cuff-pressure algometry in the baseline and follow-up sessions. DOMS was induced with eccentric calf raises during the baseline session followed by 24 h of TSD. At follow-up pain tolerance (p = 0.012) was significantly reduced, and CPM (p = 0.036) was significantly impaired compared to baseline. Psychological changes included decreases in pain catastrophising (p = 0.027), positive affect (p < 0.001), negative affect (p = 0.003), and anxiety (p = 0.012). Explorative regression models predicted 58% and 68% of DOMS pain intensity after 24 and 48 h, respectively, based on baseline body mass index, pain thresholds, psychological measures, and IL-6 (p < 0.01). Combining DOMS with 1 night of TSD induced pain hypersensitivity, impaired CPM, and altered psychological states. A combination of baseline inflammation, psychological measures, and pain sensitivity significantly predicted DOMS pain intensity after 24 and 48 h., (© 2024 The Author(s). Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Temporal summation of pain (TSP) is a human proxy for wind-up of dorsal horn neurons as assessed in animals. The common paradigm for eliciting TSP is evoked by repetitive nociceptive stimuli of equal intensity. Various stimulation and assessment protocols have been used. This scoping review aims to provide insight into key elements of TSP stimulation and assessment: modality, instruments, test location, familiarization, train characteristics, and calculations. PubMed, Embase, and Ebsco/CINAHL were searched for studies that measured TSP in adults with musculoskeletal conditions and healthy people. Four hundred six studies were included. Mechanical stimuli were the most commonly used modality (250 studies), followed by thermal stimuli (125 studies). Forty-six different instruments were used. Disregarding studies on widespread musculoskeletal pain and healthy participants, 40 studies evaluated TSP at painful sites, 77 in remote areas, and 66 in both locations. Of the 13 tested locations in patients, the hand (74 studies), lower leg (64 studies), and forearm (59 studies) were most commonly tested. A single practice round was the most common familiarization method (46 studies). Repeated stimuli were applied using 31 different frequencies (0.03-200 Hz) and sustained stimulations ranging from 5 to 1080 seconds were used. Twenty-two different train lengths, 63 different calculations (37 absolute, 19 relative, and 7 alternatives using data directly), and 14 different outcome measures (eg, self-reported pain rating scales and reflex thresholds) were used. Temporal summation of pain protocols vary excessively, hindering the comparison and pooling of results. None of the studies provided substantiation for their protocol choice., Competing Interests: The authors have no conflicts of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Background: Persistent postsurgical pain (PPSP) after lung cancer surgery is common and current definitions are based on evaluations at a single time point after surgery. Pain intensity and symptoms may however fluctuate and change over time, and be impacted by multiple and shifting factors. Studies of postoperative recovery patterns and transition from acute to chronic pain are needed for further investigation of preventive measures and treatments to modify unfavourable recovery paths., Methods: In this explorative study, 85 patients undergoing surgery due to either presumptive or confirmed lung cancer reported pain intensities bi-monthly for 12 months. Pain trajectories during recovery were investigated, using group-based trajectory modelling. Associations with possible risk factors for PPSP, including clinical variables and anxiety and depression score (HADS), were also explored., Results: A trajectory model containing three 12-month pain recovery groups was computed. One group without PPSP fully recovered (50%) within two to three months. Another group with mild-intensity PPSP followed a protracted recovery trajectory (37%), while incomplete recovery was observed in the last group (13%). Acute postoperative pain and younger age were associated with a less favourable recovery trajectory. More neuropathic pain symptoms were observed in patients with incomplete recovery., Conclusions: Three clinically relevant recovery trajectories were identified, based on comprehensive pain tracking. Higher acute postoperative pain intensity was associated with an unfavourable pain recovery trajectory., Significance Statement: Understanding the transition from acute to chronic postoperative pain and identifying preoperative risk factors is essential for the development of targeted treatments and the implementation of preventive measures. This study (1) identified distinct recovery trajectories based on frequent pain assessment follow-ups for 12 months after surgery and (2) evaluated risk factors for unfavourable postoperative pain recovery paths. Findings suggest that early higher postoperative pain intensity is associated with an unfavourable long-term recovery path., (© 2024 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Background: Total knee replacement (TKR) is the gold standard treatment for end-stage chronic osteoarthritis pain, yet many patients report chronic postoperative pain after TKR. The search for preoperative predictors for chronic postoperative pain following TKR has been studied with inconsistent findings., Methods: This study investigates the predictive value of quantitative sensory testing (QST) and PainDETECT for postoperative pain 3, 6 and 12 months post-TKR. We assessed preoperative and postoperative (3 and 6 months) QST measures in 77 patients with knee OA (KOA) and 41 healthy controls, along with neuropathic pain scores in patients (PainDETECT). QST parameters included pressure pain pressure threshold (PPT), pain tolerance threshold (PTT), conditioned pain modulation (CPM) and temporal summation (TS) using cuff algometry, alongside mechanical hyperalgesia and temporal summation to repeated pinprick stimulation., Results: Compared to healthy controls, KOA patients at baseline demonstrated hyperalgesia to pinprick stimulation at the medial knee undergoing TKR, and cuff pressure at the calf. Lower cuff algometry PTT and mechanical pinprick hyperalgesia were associated with preoperative KOA pain intensity. Moreover, preoperative pinprick pain hyperalgesia explained 25% of variance in pain intensity 12 months post-TKR and preoperative neuropathic pain scores also captured 30% and 20% of the variance in postoperative pain at 6 and 12 months respectively. A decrease in mechanical pinprick hyperalgesia from before surgery to 3 months after TKR was associated with lower postoperative pain at the 12 months post-TKR follow-up., Conclusion: Our findings suggest that preoperative pinprick hyperalgesia and neuropathic-like pain symptoms show predictive value for the development of chronic post-TKR pain., Significance Statement: This study's findings hold significant implications for chronic pain management in knee osteoarthritis patients, particularly those undergoing total knee replacement surgery (TKR). Mechanical hyperalgesia and neuropathic pain-like characteristics predict postoperative pain 1 year after TKR, emphasizing the importance of understanding pain phenotypes in OA for selecting appropriate pain management strategies. The normalization of hyperalgesia after surgery correlates with better long-term outcomes, further highlighting the therapeutic potential of addressing abnormal pain processing mechanisms pre- and post-TKR., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Abstract: Substantial interindividual variability characterizes osteoarthritis (OA) pain. Previous findings identify quantitative sensory testing (QST), psychological factors, and health-related quality of life as contributors to OA pain and predictors of treatment outcomes. This exploratory study aimed to explain baseline OA pain intensity and predict OA pain after administration of a nonsteroidal anti-inflammatory drug in combination with paracetamol for 3 weeks. The Knee Injury and Osteoarthritis Outcome Score (KOOS) pain score was used to estimate OA pain presentation. One hundred one patients were assessed at baseline and follow-up using QST (pressure pain thresholds and temporal summation of pain [TSP]), symptoms of depression and anxiety, pain catastrophizing scales (PCSs), and health-related quality of life. Linear regression with backward selection identified that PCS significantly explained 34.2% of the variability in baseline KOOS pain, with nonsignificant contributions from TSP. Pain catastrophizing score and TSP predicted 29.3% of follow-up KOOS pain, with nonsignificant contributions from symptoms of anxiety. When assessed separately, PCS was the strongest predictor (32.2% of baseline and 24.1% of follow-up pain), but QST, symptoms of anxiety and depression, PCS, and quality of life also explained some variability in baseline and follow-up knee OA pain. Further analyses revealed that only TSP and PCS were not mediated by any other included variables, highlighting their role as unique contributors to OA pain presentation. This study emphasizes the importance of embracing a multimodal approach to OA pain and highlights PCS and TSP as major contributors to the baseline OA pain experience and the OA pain experience after OA treatment., (Copyright © 2024 International Association for the Study of Pain.)

Background: Chronic postoperative pain after total knee replacement (TKR) is a major clinical problem. It is still unclear if specific inflammatory mediators are associated with long-term postoperative pain complications. The current exploratory study aimed to (1) evaluate a multiplex of inflammatory mediators 5 years after TKR surgery in patients with different degrees of postoperative pain intensities and (2) study any association of the markers with clinical pain intensity, cognitive and functional outcomes., Methods: Plasma samples were collected 5 years after TKR surgery from 76 knee patients (43 females; 33 males) and analysed for 44 inflammatory markers. Pain (using visual analogue scale, VAS), the pain catastrophizing scale (PCS) and the Oxford knee score (OKS) were evaluated. Patients were categorized as high or low groups based on VAS, PCS and OKS scores. Associations between inflammatory markers, VAS, PCS and OKS were analysed and the marker expressions were compared between groups., Results: Pearson's correlations found 12 biomarkers associated with VAS (p < 0.05), 4 biomarkers with PCS and 3 biomarkers with OKS (p < 0.05). Four markers were altered in patients suffering from high compared to low chronic postoperative pain, three markers were altered in high compared to low catastrophizers and three markers were altered in patients with poor functional scores (p < 0.05)., Conclusions: The present exploratory study suggests that low-grade inflammation might be present in a subset of patients with high pain, high catastrophizing and low function 5 years after TKR. These exploratory results provide insights into some of the long-term postoperative complications after TKR surgery., Significance Statement: This exploratory study evaluated a subset of inflammatory markers and the association to clinical pain intensity, knee function and pain catastrophizing in patients 5 years after total knee replacement surgery. Our results provide insights into the understanding of the underlying mechanisms that may drive the long experience of pain after TKR surgery., (© 2024 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Background: Recently, in an open pilot study, we found up to two years, a potential pain-relieving effect of intra-articular gold micro-particles using the patient's synovial fluid for patients with knee osteoarthritis (KOA). During the study the excluded group of patients, due to multisite pain, co-morbidities, and other exclusion criteria., received intra-articular gold micro-particles using hyaluronic acid,. We aimed to identify if pre-treatment characteristics influence the global outcome two years after intra-articular treatment for painful KOA with gold microparticles using hyaluronic acid., Methods: Using hyaluronic acid as the carrier, 136 patients with KOA received intraarticular injections with 20 mg gold microparticles (72.000 particles, 20-40 μm in diameter). In the analysis, we included the Global Rating of Change Scale, Pain Detect Questionnaire (PDQ), Body Mass Index (BMI), and Kellgren & Lawrence score at the inclusion, Western Ontario, and McMaster Universities Osteoarthritis Index (WOMAC) sub-scores for pain, stiffness, and function at inclusion and two years., Results: On the Global Rating Change Scale, 69.1% of patients reported a positive effect, 28.7% no effect, and 2.2% worse. PDQ and the three WOMAC subscores all improved at two years of follow-up. PDQ ≥ 13 (P = 0.028), BMI (P = 0.022) and Kellgren & Lawrence grade 4 (P = 0.028) at inclusion reduced the effect with a minor odds ratio compared to the baseline effect of treatment (P = 0.025). WOMAC subscores at inclusion did not influence the outcome (P > 0.5)., Conclusions: Severe osteoarthritis, obesity, and neuropathic pain, reduced the effect of intra-articular gold microparticles for knee OA., Trial Registration: The study followed the principles of the Declaration of Helsinki and was approved by the local ethics committee of the North Denmark Region by 27/07/2016 (N-20,160,045). The regional data protection agency approved the project by 06/07/2016 (2008-58-0028, ID 2016 - 116) and registered in ClinicalTrial.Gov by 04/01/2018 (NCT03389906)., (© 2024. The Author(s).)

Background: Chronic pain is the hallmark symptom of joint diseases. This study examined the differences in quantitative sensory testing between patients with psoriatic arthritis (PsA), hand osteoarthritis (hand-OA) and a pain-free control group and differences between patients with and without concomitant fibromyalgia (cFM)., Methods: All patients and pain-free controls were assessed using pressure pain thresholds (PPT), temporal summation of pain (TSP), conditioned pain modulation (CPM) and clinical pain intensities. Psychological distress was assessed with the Hospital Anxiety and Depression Scale, Pain Catastrophizing Scale, and Pittsburgh Sleep Quality Index. Disability was assessed with the Health Assessment Questionnaire and pain quality with the painDETECT questionnaire. cFM was identified using the revised 2016 American College of Rheumatology diagnostic criteria., Results: Patients with hand-OA (n = 75) or PsA (n = 58) had statistically significant lower PPTs and CPM, greater TSP, and higher scores of psychological distress (p < 0.05) than controls (n = 20). Patients with cFM (58%) had higher scores of depression (p = 0.001), anxiety (p = 0.004), catastrophizing (p = 0.012), disability (p < 0.001), higher painDETECT score (p = 0.001), TSP (p = 0.027), and reduced sleep quality (p = 0.021) when compared to patients without cFM., Conclusion: Patients with hand-OA and PsA exhibited signs of pain sensitization and a higher degree of psychological distress and disability than pain-free individuals. Patients with cFM had greater TSP, painDETECT score, disability, catastrophizing, and reduced sleep quality, than patients without, indicating greater degree of pain sensitization, psychological burden, and disability., Statement of Significance: This paper shows that a significant proportion of patients with hand osteoarthritis and psoriatic arthritis with moderate pain intensity have significantly increased signs of pain sensitization and markers of psychological distress. A large proportion of these patients fulfil the criteria for concomitant fibromyalgia and these patients show even greater propensity towards pain sensitization and psychological distress., (© 2023 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Abstract: Total knee arthroplasty (TKA) is the end-stage treatment of knee osteoarthritis (OA), and approximately 20% of patients experience chronic postoperative pain. Studies indicate that inflammatory biomarkers might be associated with pain in OA and potentially linked to the development of chronic postoperative pain after TKA. This study aimed to (1) evaluate preoperative serum levels of inflammatory biomarkers in patients with OA and healthy control subjects, (2) investigate preoperative differences of inflammatory biomarker profiles in subgroups of patients, and (3) compare subgroups of patients with and without postoperative pain 12 months after surgery. Serum samples from patients with OA scheduled for TKA (n = 127) and healthy participants (n = 39) were analyzed. Patients completed the Knee-injury-and-Osteoarthritis-Outcome-Score (KOOS) questionnaire and rated their clinical pain intensity using a visual analog scale (VAS) before and 12 months after TKA. Hierarchical cluster analysis and Orthogonal Partial Least Squares Discriminant Analysis were used to compare groups (patients vs control subjects) and to identify subgroups of patients in relation to postoperative outcomes. Difference in preoperative and postoperative VAS and KOOS scores were compared across subgroups. Twelve inflammatory markers were differentially expressed in patients when compared with control subjects. Cluster analysis identified 2 subgroups of patients with 23 proteins being significantly different ( P < 0.01). The 12-months postoperative VAS and KOOS scores were significantly different between subgroups of patients ( P < 0.05). This study identified differences in specific inflammatory biomarker profiles when comparing patients with OA and control subjects. Cluster analysis identified 2 subgroups of patients with OA, with one subgroup demonstrating comparatively worse 12-month postoperative pain intensity and function scores., (Copyright © 2023 International Association for the Study of Pain.)

Background: Blood-based biomarkers (BBMs) are of growing interest in the field of Alzheimer's disease (AD) and related dementias., Objective: This study aimed to assess the ability of plasma biomarkers to 1) predict disease progression from mild cognitive impairment (MCI) to dementia and 2) improve the predictive ability of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) measures when combined., Methods: We used data from the Alzheimer's Disease Neuroimaging Initiative. Machine learning models were trained using the data from participants who remained cognitively stable (CN-s) and with Dementia diagnosis at 2-year follow-up visit. The models were used to predict progression to dementia in MCI individuals. We assessed the performance of models with plasma biomarkers against those with CSF and MRI measures, and also in combination with them., Results: Our models with plasma biomarkers classified CN-s individuals from AD with an AUC of 0.75±0.03 and could predict conversion to dementia in MCI individuals with an AUC of 0.64±0.03 (17.1% BP, base prevalence). Models with plasma biomarkers performed better when combined with CSF and MRI measures (CN versus AD: AUC of 0.89±0.02; MCI-to-AD: AUC of 0.76±0.03, 21.5% BP)., Conclusions: Our results highlight the potential of plasma biomarkers in predicting conversion to dementia in MCI individuals. While plasma biomarkers could improve the predictive ability of CSF and MRI measures when combined, they also show the potential to predict non-progression to AD when considered alone. The predictive ability of plasma biomarkers is crucially linked to reducing the costly and effortful collection of CSF and MRI measures.

Discovery and analysis of genetic variants underlying agriculturally important traits are key to molecular breeding of crops. Reduced representation approaches have provided cost-efficient genotyping using next-generation sequencing. However, accurate genotype calling from next-generation sequencing data is challenging, particularly in polyploid species due to their genome complexity. Recently developed Bayesian statistical methods implemented in available software packages, polyRAD, EBG, and updog, incorporate error rates and population parameters to accurately estimate allelic dosage across any ploidy. We used empirical and simulated data to evaluate the three Bayesian algorithms and demonstrated their impact on the power of genome-wide association study (GWAS) analysis and the accuracy of genomic prediction. We further incorporated uncertainty in allelic dosage estimation by testing continuous genotype calls and comparing their performance to discrete genotypes in GWAS and genomic prediction. We tested the genotype-calling methods using data from two autotetraploid species, Miscanthus sacchariflorus and Vaccinium corymbosum, and performed GWAS and genomic prediction. In the empirical study, the tested Bayesian genotype-calling algorithms differed in their downstream effects on GWAS and genomic prediction, with some showing advantages over others. Through subsequent simulation studies, we observed that at low read depth, polyRAD was advantageous in its effect on GWAS power and limit of false positives. Additionally, we found that continuous genotypes increased the accuracy of genomic prediction, by reducing genotyping error, particularly at low sequencing depth. Our results indicate that by using the Bayesian algorithm implemented in polyRAD and continuous genotypes, we can accurately and cost-efficiently implement GWAS and genomic prediction in polyploid crops., (© 2023 The Authors. The Plant Genome published by Wiley Periodicals LLC on behalf of Crop Science Society of America.)

Competing Interests: Kristian K-S Petersen chairs the Special Interest Group for Musculoskeletal Pain under the International Association for the study of Pain (IASP). Lars Arendt-Nielsen was the president for the IASP and initiated the IASP Presidential Task Force on Cannabis and Cannabinoid Analgesia and Andrew SC Rice chaired the Task Force.

Objectives: Studies suggest that a range of pain mechanisms, such as poor quality of sleep, perceived stress, pain catastrophizing or pain sensitivity, are likely to enhance clinical pain. Animal studies suggest that these pain mechanisms can be modulated by increasing physical activity, but human data are needed to support this hypothesis. This exploratory study aimed to investigate the changes in pain mechanisms after a simple self-directed walking program of 8-weeks. Additionally, this exploratory study investigated the interaction between changes over time in assessments of poor quality of sleep, perceived stress, pain catastrophizing or pain sensitivity and how these changes interacted with each other., Methods: This prospective cohort study included 30 healthy subjects who were assessed at baseline and 4- and 8-weeks after initiating the walking program (30 min walking/day for 8 weeks). Self-report outcomes included: Pain Catastrophizing Scale (PCS), the Perceived Stress Scale (PSS) and Pittsburgh Sleep Quality Index. Pressure pain thresholds, temporal summation of pain and conditioned pain modulation (CPM) were assessed using cuff algometry., Results: Twenty-four subjects completed all the visits (age: 42.2, SD: 14.9, 16 females). PCS and PSS significantly decreased at the 8-week's visit compared to baseline (p<0.05). No significant differences were seen for an improvement in quality of sleep (p=0.071) and pain sensitivity (p>0.075) when comparing the 8-week's visit to the baseline visit. Changes in pain mechanisms comparing baseline and 8-weeks data were calculated and regression analyses found that an improvement in PCS was associated with an improvement in CPM (R 2 =0.197, p=0.017) and that a higher adherence to the walking program was associated with a larger improvement in PCS (R 2 =0.216, p=0.013)., Conclusions: The current exploratory study indicates that a simple self-directed walking program of 8-weeks can improve pain catastrophizing thoughts, perceived stress. Higher adherence to the walking program were associated with an improvement in pain catastrophizing and an improvement in pain catastrophizing was associated with an increase in conditioned pain modulation., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Osseointegrated implants is a surgical treatment permitting a direct skeletal attachment of an external prosthesis. It is a treatment for healthy transfemoral amputated patients who cannot tolerate or use a socket prosthesis, thereby alleviating related issues with poor fit, skin problems or discomfort. This review provides a summary of the indications and contraindications for surgery, the most common implants and reported outcomes.

Objectives: High intensity and longer duration of acute postoperative pain are generally associated with a higher risk of developing chronic postoperative pain. Therefore, it is important to identify the preoperative predictors for acute postoperative pain. Preoperative evaluation of offset analgesia (OA) and the Pain Catastrophising Scale (PCS) may be potential predictors for acute postoperative pain. This study aimed to investigate the relationship between preoperative OA, PCS, and acute postoperative pain following orthognathic surgery., Methods: Thirty patients (19 females) scheduled to undergo orthognathic surgery were included in this study. OA and PCS were evaluated preoperatively, and the patients reported their postoperative pain intensity using the visual analogue scale [0-100 mm] until it reached zero (number of days with pain). OA was induced on the dominant forearm via three consecutive painful heat pulses delivered for 5 s (T1=46 °C), 5 s (T2=47 °C), and 20 s (T3=46 °C). Subsequently, the associations between OA, PCS, and the number of days with pain were analysed., Results: The median duration of postoperative pain was 10.3 days. Multiple linear regression analysis showed a significant (p=0.0019) predictive value of OA (p=0.008) for the number of days with pain. The PCS-magnification component was positively correlated with the number of days with pain (R=0.369, p=0.045), with no predictive values of PCS-total and PCS-subscale scores observed., Conclusions: Preoperative evaluation of OA may be a new individualised, predictive tool for the number of days with acute postoperative pain following orthognathic surgery; hence, a possible biomarker for the patient's vulnerability to developing chronic postoperative pain., Ethical Committee Number: The study was approved by the Ethics Committee of Meikai University (A1624, A2113)., Trial Registry Number: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) Clinical Trial (Unique ID: UMIN000026719, UMIN000046957)., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Background: Poor quality sleep is a common complaint among people with chronic pain. The co-occurrence of poor sleep quality and chronic pain often comes with increased pain intensity, more disability and a higher cost of healthcare. Poor sleep has been suggested to affect measures of peripheral and central pain mechanisms. To date, sleep provocations are the only models proven to affect measures of central pain mechanisms in healthy subjects. However, there are limited studies investigating the effect of several nights of sleep disruption on measures of central pain mechanisms., Methods: The current study implemented three nights of sleep disruption with three planned awakenings per night in 30 healthy subjects sleeping at home. Pain testing was conducted at the same time of day at baseline and follow-up for each subject. Pressure pain thresholds were assessed bilaterally on the infraspinatus and gastrocnemius muscles. Using handheld pressure algometry, suprathreshold pressure pain sensitivity and area were also investigated on the dominant infraspinatus muscle. Cuff-pressure pain detection and tolerance thresholds, temporal summation of pain and conditioned pain modulation were investigated using cuff-pressure algometry., Results: Temporal summation of pain was significantly facilitated (p = 0.022), suprathreshold pain areas (p = 0.005) and intensities (p < 0.05) were significantly increased, and all pressure pain thresholds were decreased (p < 0.005) after sleep disruption compared to baseline., Conclusions: The current study found that three consecutive nights of sleep disruption at home induced pressure hyperalgesia and increased measures of pain facilitation in healthy subjects, which is consistent with previous findings., Significance: Poor quality of sleep is often experienced by patients with chronic pain, with the most common complaint being nightly awakenings. This exploratory study is the first to investigate changes in measures of central and peripheral pain sensitivity in healthy subjects after sleep disruptions for three consecutive nights without any restrictions on total sleep time. The findings suggest that disruptions to sleep continuity in healthy individuals can induce increased sensitivity to measures of central and peripheral pain sensitization., (© 2023 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Emerging evidence suggest that quantitative sensory testing (QST) may predict the treatment response to pain-relieving therapies. This systematic review and meta-analysis focus on the predictive value of QST for pain management of knee osteoarthritis (OA). MEDLINE and EMBASE were systematically searched for all studies from year 2000 to 2023 on pretreatment QST and treatment of OA including surgical, pharmaceutical, and nonsurgical and nonpharmaceutical therapies. Preclinical studies and reviews were excluded. The systematic review followed the PRISMA guidelines and was pre-registered on the Open Science Framework website (link: https://osf.io/4FETK/, Identifier: DOI 10.17605/OSF.IO/4FETK). Meta-analysis were conducted to demonstrate the strength of the pre-treatment QST predictions on pain outcomes after OA treatments. Sixteen surgical (all on total knee arthroplasty [TKA], N = 1967), 5 pharmaceutical (4 on non-steroidal anti-inflammatory drugs [NSAIDs], N = 271), and 4 exercise-based therapy studies (N = 232) were identified. Pretreatment QST parameters predicted pain-relieving treatment outcomes in 81% of surgical, 100% of pharmaceutical, and 50% of exercise-based therapy studies. Meta-analyses found pretreatment QST profiles to predicted pain outcomes after TKA (random effects: 0.309, 95% confidence interval [CI]: 0.206-0.405, P < 0.001), NSAIDs (random effects: 0.323, 95% CI: 0.194-0.441, P < 0.001), and exercise-based therapies (random effects: 0.417, 95% CI: 0.138-0.635, P = 0.004). The overall risk of bias for the included studies was low to moderate. This systematic review and meta-analysis demonstrate weak-to-moderate associations between pretreatment QST and pain outcomes after standard OA pain treatments. Based on this work, it is hypothesized that a subset of specific pain sensitive patients with OA exist and that these patients do not respond adequately to standard OA pain treatments., Competing Interests: The authors have no conflict of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Introduction: At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias., Methods: The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry., Results: During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα])., Discussion: This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: Increasing evidence indicates that a subset of cognitively normal individuals has subtle cognitive impairment at baseline. We sought to identify them using the Stages of Objective Memory Impairment (SOMI) system. Symptomatic cognitive impairment was operationalized by a Clinical Dementia Rating (CDR) ≥0.5. We hypothesized that incident impairment would be higher for participants with subtle retrieval impairment (SOMI-1), higher still for those with moderate retrieval impairment (SOMI-2), and highest for those with storage impairment (SOMI-3/4) after adjusting for demographics and APOE ε4 status. A secondary objective was to determine whether including biomarkers of β-amyloid, tau pathology, and neurodegeneration in the models affect prediction. We hypothesized that even after adjusting for in vivo biomarkers, SOMI would remain a significant predictor of time to incident symptomatic cognitive impairment., Methods: Among 969 cognitively normal participants, defined by a CDR = 0, from the Knight Alzheimer Disease Research Center, SOMI stage was determined from their baseline Free and Cued Selective Reminding Test scores, 555 had CSF and structural MRI measures and comprised the biomarker subgroup, and 144 of them were amyloid positive. Cox proportional hazards models tested associations of SOMI stages at baseline and biomarkers with time to incident cognitive impairment defined as the transition to CDR ≥0.5., Results: Among all participants, the mean age was 69.35 years, 59.6% were female, and mean follow-up was 6.36 years. Participants in SOMI-1-4 had elevated hazard ratios for the transition from normal to impaired cognition in comparison with those who were SOMI-0 (no memory impairment). Individuals in SOMI-1 (mildly impaired retrieval) and SOMI-2 (moderately impaired retrieval) were at nearly double the risk of clinical progression compared with persons with no memory problems. When memory storage impairment emerges (SOMI-3/4), the hazard ratio for clinical progression increased approximately 3 times. SOMI stage remained an independent predictor of incident cognitive impairment after adjusting for all biomarkers., Discussion: SOMI predicts the transition from normal cognition to incident symptomatic cognitive impairment (CDR ≥0.5). The results support the use of SOMI to identify those cognitively normal participants most likely to develop incident cognitive impairment who can then be referred for biomarker screening., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: MicroRNAs (miRNAs) can modulate several biological systems, including the pain system. This study aimed to evaluate the temporal expression of circulating miRNAs in the plasma of healthy volunteers as a marker for epigenetic changes before and after an acute, experimental, pain provocation by intramuscular hypertonic saline injection., Methods: Twenty volunteers were randomly allocated into two groups and received either hypertonic (pain) or isotonic (control) saline injection in the first dorsal interosseous muscle of their dominant hand. Pain intensity was continuously recorded for 20 minutes after injection on a VAS scale from 0 to 100 (0 indicates no pain and 100 the worst imaginable pain). Blood samples were taken at baseline, 30 minutes, 3 hours, and 24 hours post-injection, and plasma was separated. MiRNA extracts were used for RNA sequencing with the Illumina NextSeq platform. MiRNA transcripts were compared between the pain and the no-pain, control group at every time point. Significant differences were considered when folds were >2 and the False Discovery Rate was p < 0.05., Results: After 30 minutes, 4 miRNAs were significantly altered in the pain group compared to controls, which increased to 24 after 3 hours and to 42 after 24 hours from baseline (p < 0.0001). Two miRNAs were consistently upregulated throughout the experiment. Enrichment analysis showed significant miRNAs involved in brain perception of pain, brain signalling and response to stimuli., Conclusions: This exploratory study is the first to report on the temporal expression of circulating miRNAs after an acute, human experimental muscle pain model., Significance: This exploratory study evaluated the temporal profile of circulating miRNAs in the plasma of healthy subjects after acute experimental pain. Several miRNAs were altered in subjects at the times of follow-up after the acute pain model when compared to controls. MiRNAs previously associated with pain processes were altered in the pain group. Our results, by showing the fast and prolonged modifications of miRNA elicited by the acute experimental pain model, add new perspectives to the topic of epigenetics and pain., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Objective: To investigate cerebrospinal fluid (CSF) and neuroimaging correlates of Stages of Objective Memory Impairment (SOMI) based on Free and Cued Selective Reminding Test (FCSRT) performance, and to evaluate the effect of APOE ε4 status on this relationship., Methods: Data from 586 cognitively unimpaired individuals who had FCSRT, CSF, and volumetric magnetic resonance imaging (MRI) measures available was used. We compared CSF measures of β-amyloid (Aβ42/Aβ40 ratio), phosphorylated tau (p-Tau181), total tau (t-Tau), hippocampal volume, and PIB-PET mean cortical binding potential with partial volume correction (MCBP) among SOMI groups in the whole sample and in subsamples stratified by APOE ε4 status., Results: Participants had a mean age of 67.4 (SD=9.1) years, had 16.1 (SD=2.6) years of education, 57.0% were female, and 33.8% were APOE ε4 positive. In the entire sample, there was no significant difference between SOMI stages in Aβ42/Aβ40 ratio, p-Tau181, t-Tau, or PIB-PET MCBP when adjusted for age, sex, and education. However, higher SOMI stages had smaller hippocampal volume (F=3.29, p=0.020). In the stratified sample based on APOE ε4 status, in APOE ε4 positive individuals, higher SOMI stages had higher p-Tau181 (F=2.94, p=0.034) higher t-Tau (F=3.41, p=0.019), and smaller hippocampal volume (F=5.78, p<0.001). There were no significant differences in CSF or imaging biomarkers between SOMI groups in the APOE ε4 negative subsample., Conclusion: Cognitively normal older individuals with higher SOMI stages have higher in-vivo tau and neurodegenerative pathology only in APOE ε4 carriers. These original results indicate the potential usefulness of the SOMI staging system in assessing of tau and neurodegenerative pathology., Competing Interests: K.K.P. has no disclosures. A.E. serves as consultant, advisory board member, or has received honoraria from: Eisai, PCORI Health Care Horizon Scanning System, BioDelivery Sciences International, Inc, and is the owner of Neurodiction, LLC. R.B.L. receives research support from the following sources unrelated to this manuscript: 5U10 NS077308 (PI), R21 AG056920 (Investigator), 1RF1 AG057531 (Site PI), RF1 AG054548 (Investigator), 1RO1 AG048642 (Investigator), R56 AG057548 (Investigator), U01062370 (Investigator), RO1 AG060933 (Investigator), RO1 AG062622 (Investigator), 1UG3FD006795 (mPI), 1U24NS113847 (Investigator). He holds stock options in eNeura Therapeutics and Biohaven Holdings; serves as consultant, advisory board member, or has received honoraria from: Abbvie (Allergan), American Academy of Neurology, American Headache Society, Amgen, Avanir, Biohaven, Biovision, Boston Scientific, Dr. Reddy’s (Promius), Electrocore, Eli Lilly, eNeura Therapeutics, Equinox, GlaxoSmithKline, Grifols, Lundbeck (Alder), Merck, Pernix, Pfizer, Supernus, Teva, Trigemina, Vector, Vedanta. He receives royalties from Wolff’s Headache 7th and 8th Edition, Oxford Press University, 2009, Wiley and Informa. B.A.G has no disclosures. J.H. has no disclosures. J.C.M. and his family do not own stock or have equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. E.G. receives a small royalty for commercial use of the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT+IR). The test is available at no cost to researchers and clinicians. The Albert Einstein College of Medicines holds the copyright for the test. Inquiries should be addressed to Dr. Benjamin Neymotin (Benjamin.Neymotin@einsteinmed.org) in the Office of Biotechnology and Business Development.

Background: Alcohol use disorders have been categorized as a 'strongly modifiable' risk factor for dementia., Objective: To investigate the cross-sectional association between alcohol consumption and cognition in older adults and if it is different across sexes or depends on amyloid-β (Aβ) accumulation in the brain., Methods: Cognitively unimpaired older adults (N = 4387) with objective and subjective cognitive assessments and amyloid positron emission tomography (PET) imaging were classified into four categories based on their average daily alcohol use. Multivariable linear regression was then used to test the main effects and interactions with sex and Aβ levels., Results: Individuals who reported no alcohol consumption had lower scores on the Preclinical Alzheimer Cognitive Composite (PACC) compared to those consuming one or two drinks/day. In sex-stratified analysis, the association between alcohol consumption and cognition was more prominent in females. Female participants who consumed two drinks/day had better performance on PACC and Cognitive Function Index (CFI) than those who reported no alcohol consumption. In an Aβ-stratified sample, the association between alcohol consumption and cognition was present only in the Aβ- subgroup. The interaction between Aβ status and alcohol consumption on cognition was not significant., Conclusion: Low or moderate consumption of alcohol was associated with better objective cognitive performance and better subjective report of daily functioning in cognitively unimpaired individuals. The association was present only in Aβ- individuals, suggesting that the pathophysiologic mechanism underlying the effect of alcohol on cognition is independent of Aβ pathology. Further investigation is required with larger samples consuming three or more drinks/day.

Fracture-related infections (FRI) is a challenging complication with a high risk of devastation outcomes for the patients. Diagnosing FRI is often difficult, and treatment frequently requires the effort of a multidisciplinary team. Recently, an international consensus group of experts from various scientific and medical organisations has published standardised guidelines of diagnosis and treatment. This review provides a summary of the latest studies and the general principles with respect to diagnosis, treatment and aftercare of patients with FRI.

Background: A subset of osteoarthritis patients will experience chronic postoperative pain after total knee arthroplasty (TKA), but the source of pain is unclear. The aim of this exploratory study was to assess patients with and without postoperative pain after TKA using magnetic resonance imaging (MRI), quantitative sensory testing (QST), clinical assessment of pain and assessments of catastrophizing thoughts., Methods: Forty-six patients completed the 6-month postoperative assessment. MRI findings were scored according to the MRI Osteoarthritis Knee Score recommendation for Hoffa synovitis, effusion size and bone marrow lesions. QST included assessment of pressure pain thresholds (PPTs), temporal summation of pain (TSP) and conditioned pain modulation (CPM). Pain catastrophizing was assessed using the Pain Catastrophizing Scale (PCS). Clinical pain assessment was conducted using a visual analogue scale (VAS, 0-10 cm), and groups of moderate-to-severe (VAS > 3) and none-to-mild postoperative pain (VAS ≤ 3) were identified., Results: Patients with moderate-to-severe postoperative pain (N = 15) demonstrated higher grades of Hoffa synovitis (p < 0.001) and effusion size (p < 0.001), lower PPTs (p = 0.039), higher TSP (p = 0.001) and lower CPM (p = 0.014) when compared with patients with none-to-mild postoperative pain (N = 31). No significant difference was found in PCS scores between the two groups. Multiple linear regression models found synovitis (p = 0.036), effusion size (p = 0.003), TSP (p = 0.013) and PCS (p < 0.001) as independent parameters contributing to the postoperative pain intensity., Conclusion: These exploratory findings could indicate that chronic postoperative pain after TKA is a combination of joint-related synovitis and effusion, sensitization of central pain mechanisms and potentially pain catastrophizing thoughts, but larger studies are needed to confirm this., Significance: The end-stage treatment of knee osteoarthritis is total knee arthroplasty. Some patients experience chronic postoperative pain after total knee arthroplasty, but the mechanism for chronic postoperative pain is widely unknown. The current study indicates that higher levels postoperative of synovitis and effusion, higher temporal summation of pain and higher pain catastrophizing scores could be associated with higher chronic postoperative pain., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Background: Few studies have investigated the underlying mechanisms for unilateral subacromial pain syndrome (SAPS). Therefore, this study examined (1) if 8-weeks of exercise could modulate clinical pain or temporal summation of pain (TSP), conditioned pain modulation (CPM), and exercise-induced hypoalgesia (EIH) and (2) if any of these parameters could predict the effect of 8-weeks of exercise in patients with unilateral SAPS., Methods: Thirty-seven patients completed a progressive abduction exercise program every other day for 8-weeks. Worst shoulder pain in full abduction was rated on a numeric rating scale (NRS). Pain pressure thresholds (PPTs), TSP, CPM, EIH, Shoulder Pain and Disability Index (SPADI), Pain Catastrophizing Scale (PCS), PainDETECT questionnaire (PD-Q), Pain Self-Efficacy Questionnaire (PSE-Q) and Pittsburgh Sleep Quality Index (PSQI) were assessed before and after intervention., Results: The intervention improved worst pain intensity (p < 0.001), increased the CPM (p < 0.001), improved the sleep scores (p < 0.005) and reduced the PainDETECT ratings (p < 0.001). No changes were observed in PPT, TSP, EIH, SPADI, PCS and PSE-Q (all p > 0.05). In a linear regression, the combination of all baseline parameters predicted 23.2% variance in absolute change in pain after 8 weeks. Applying backwards elimination to the linear regression yielded that baseline pain intensity combined with TSP predicted 33.8% variance., Conclusion: This explorative study suggested reduction in pain, improved sleep quality and increased CPM after 8-weeks of exercise. Furthermore, the results suggests that low pain intensity and high TSP scores (indicative for pain sensitisation) may predict a lack of pain improvement after exercise., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Necrotizing soft tissue infections (NSTI) is a serious infection with a mortality of up to 25% at three months. This review gives an overview of the diagnosis and treatment of NSTI. The prognosis is dependent on rapid surgical treatment, aggressive, prompt removal of infected tissue, broad spectrum antibiotic treatment and supportive care. In cases with suspected or verified infection with Streptococcus pyogenes, adjuvant therapy with immunoglobulins can be considered.

Background: Duloxetine is indicated in the management of pain in osteoarthritis. Evidence suggests that duloxetine modulates central pain mechanisms and cognitive factors, and these factors are assumed contributing to the analgesic effect. This proof-of-mechanism, randomized, placebo-controlled, crossover, double-blinded trial evaluated the effect of duloxetine on quantitative sensory testing (QST), cognitive factors and clinical pain in patients with osteoarthritis and to predict the analgesic effect., Methods: Twenty-five patients completed this cross-over study with either 18-week duloxetine (maximum 60 mg/daily) followed by placebo or vice-versa. Pressure pain thresholds, temporal summation of pain and conditioned pain modulation were assessed using cuff algometry. The Hospital Anxiety and Depression Scale and the Pain Catastrophizing Scale evaluated cognitive factors. Clinical pain was assessed using Brief Pain Inventory and Western Ontario and McMaster Universities Osteoarthritis Index. Linear regression models were used to predict the analgesic effect of duloxetine., Results: Depending on the clinical pain outcome, 40%-68% of patients were classified as responders to duloxetine. Linear regression models predicted the analgesic effect (predictive value of 45%-75% depending on clinical pain outcome parameter) using a combination of pretreatment QST parameters, cognitive factors and clinical pain. No significant changes were found for QST, cognitive factors or clinical pain on a group level when comparing duloxetine to placebo., Conclusion: A combination of pretreatment QST, cognitive factors and clinical pain was able to predict the analgesic response of duloxetine. However, in this relatively small study, duloxetine did not selectively modulate QST, cognitive factors or clinical pain intensity when compared with placebo., Significance: Duloxetine is proposed as a treatment for chronic pain. Pre-clinical trials suggest that duloxetine provides analgesia through modulation of descending pain inhibitory pathways or through improvements in cognitive factors. The current study demonstrates that pretreatment mechanistic pain profiling, cognitive factors and clinical pain can predict the analgesic effect of duloxetine and that only a subset of patients might benefit from duloxetine treatment., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.)

Objectives: The prevalence of osteoarthritis (OA) is rising, and pain is the hallmark symptom of OA. Pain in OA is complicated and can be influenced by multiple joint-related factors and factors related to, e.g., physiological, epigenetic, and pain sensory profiles. Increasing evidence suggests that a subset of patients with OA are pain sensitive. This can be assessed using quantitative sensory testing (QST). Common treatments of OA are total knee arthroplasty (TKA) and administration of 3-weeks of non-steroidal anti-inflammatory drugs (NSAIDs), which provide pain relief to many patients with OA. However, approx. 20% of patients experience chronic postoperative pain after TKA, whereas NSAIDs provide an average pain relief of approx. 25%. The current topical review focuses on the emerging evidence linking pretreatment QST to the treatment response of TKA and NSAID treatments., Content: MEDLINE was systematically searched for all studies from 2000 to 2022 on pretreatment QST, TKA, and NSAIDs. Pre-clinical studies, reviews, and meta-analyses were excluded., Summary: Currently, 14 studies on TKA and four studies on NSAIDs have been published with the aim to attempt prediction of the treatment response. The QST methodologies in the studies are inconsistent, but 11/14 (79%) studies on TKA and 4/4 (100%) studies on NSAIDs report statistically significant associations between pretreatment QST and chronic postoperative pain after TKA or analgesic effect after NSAID treatment. The strength of the associations remains low-to-moderate. The most consistent pretreatment QST predictors are pressure pain thresholds, temporal summation of pain, and conditioned pain modulation., Outlook: The use of QST as predictors of standard OA treatment is interesting, but the predictive strength remains low-to-moderate. A transition of QST from a research-based setting and into the clinic is not advised until the predictive strength has been improved and the methodology has been standardized., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Existing equipment for quantitative sensory testing is generally expensive and not easily applicable in a clinical setting thus simple bed-side devices are warranted. Pressure hyperalgesia is a common finding in patients with musculoskeletal pain and an experimental model is delayed-onset muscle soreness (DOMS). DOMS is characterised by muscle hyperalgesia and some studies report facilitation of temporal summation of pain. This study aimed to detect DOMS induced muscle hyperalgesia and temporal summation of pain using a newly developed bed-side quantitative sensory testing device to deliver standardised pressure., Methods: Twenty-two healthy participants participated in two sessions with the second session approximately 48 h after baseline. Pressure pain intensities were assessed from the gastrocnemius muscle with four probes calibrated to apply 2, 4, 6 and 8 kg, respectively. Temporal summation of pain (10 stimuli delivered at 0.5 Hz using the 6 kg probe) intensities were assessed from the same location. DOMS was evoked in the gastrocnemius muscle by an eccentric exercise. Sleepiness and physical activity were measured with the Epworth Sleepiness Scale and the Global Physical Activity Questionnaire to investigate if they were associated with the quantitative sensory testing measures., Results: Pressure pain intensity was significantly increased 48 h after induction of DOMS when compared to baseline for all four probes (p<0.05). Temporal summation of pain was not statistically significant affected by DOMS and sleep quality and physical activity did not associate with any of the measures., Conclusions: This study introduces a simple, bed-side assessment tool for the assessment of pressure pain intensity and hence hyperalgesia and temporal summation of pain., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Background and Objectives: To develop and test the performance of the Positive Aβ Risk Score (PARS) for prediction of β-amyloid (Aβ) positivity in cognitively unimpaired individuals for use in clinical research. Detecting Aβ positivity is essential for identifying at-risk individuals who are candidates for early intervention with amyloid targeted treatments., Methods: We used data from 4,134 cognitively normal individuals from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study. The sample was divided into training and test sets. A modified version of AutoScore, a machine learning-based software tool, was used to develop a scoring system using the training set. Three risk scores were developed using candidate predictors in various combinations from the following categories: demographics (age, sex, education, race, family history, body mass index, marital status, and ethnicity), subjective measures (Alzheimer's Disease Cooperative Study Activities of Daily Living-Prevention Instrument, Geriatric Depression Scale, and Memory Complaint Questionnaire), objective measures (free recall, Mini-Mental State Examination, immediate recall, digit symbol substitution, and delayed logical memory scores), and APOE4 status. Performance of the risk scores was evaluated in the independent test set., Results: PARS model 1 included age, body mass index (BMI), and family history and had an area under the curve (AUC) of 0.60 (95% CI 0.57-0.64). PARS model 2 included free recall in addition to the PARS model 1 variables and had an AUC of 0.61 (0.58-0.64). PARS model 3, which consisted of age, BMI, and APOE4 information, had an AUC of 0.73 (0.70-0.76). PARS model 3 showed the highest, but still moderate, performance metrics in comparison with other models with sensitivity of 72.0% (67.6%-76.4%), specificity of 62.1% (58.8%-65.4%), accuracy of 65.3% (62.7%-68.0%), and positive predictive value of 48.1% (44.1%-52.1%)., Discussion: PARS models are a set of simple and practical risk scores that may improve our ability to identify individuals more likely to be amyloid positive. The models can potentially be used to enrich trials and serve as a screening step in research settings. This approach can be followed by the use of additional variables for the development of improved risk scores., Classification of Evidence: This study provides Class II evidence that in cognitively unimpaired individuals PARS models predict Aβ positivity with moderate accuracy., (© 2022 American Academy of Neurology.)

Abstract: Cannabidiol (CBD) is increasingly used as analgesic medication although the recent International Association for the Study of Pain Presidential Task Force on cannabis and cannabinoid analgesia found a lack of trials examining CBD for pain management. This trial examines CBD as add-on analgesic therapy in patients with hand osteoarthritis or psoriatic arthritis experiencing moderate pain intensity despite therapy. Using a randomized, double-blind, placebo-controlled design, patients received synthetic CBD 20 to 30 mg or placebo daily for 12 weeks. The primary outcome was pain intensity during the past 24 hours (0-100 mm); safety outcomes were percentage of patients experiencing adverse events and a characterization of serious adverse events. Explorative outcomes included change in Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, Pain Catastrophizing Scale (PCS), and Health Assessment Questionnaire Disability Index. One hundred thirty-six patients were randomized, of which 129 were included in the primary analysis. Between-group difference in pain intensity at 12 weeks was 0.23 mm (95% confidence interval -9.41 to 9.90; P = 0.96). Twenty-two percent patients receiving CBD and 21% receiving placebo experienced a reduction in pain intensity of more than 30 mm. We found neither clinically nor statistically significant effects of CBD for pain intensity in patients with hand osteoarthritis and psoriatic arthritis when compared with placebo. In addition, no statistically significant effects were found on sleep quality, depression, anxiety, or pain catastrophizing scores., (Copyright © 2021 International Association for the Study of Pain.)

Objectives: Treatment for childhood Complex Regional Pain Syndrome (CRPS) is associated with long-term recovery. The present study aimed to investigate the long-term biopsychosocial status and quality of life in young adolescents and adults after the treatment of childhood CRPS., Methods: A 4 year follow-up of individuals with childhood-CRPS, type 1 (n=22; age:12 years (years) [median] at treatment and 17 years at follow-up) was completed. Biopsychosocial status and quality of life were assessed with structured interviews, using the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), the Strengths and Difficulties Questionnaire (SDQ), the Pediatric Pain Coping Inventory (PPCI), and the Pediatric Quality of Life Inventory (PedsQL). Comparisons were made with normative samples of age-matched controls., Results: CRPS at follow-up was still present in seven out of 22, and non-CRPS pain symptoms were found in 12 out of 22 individuals. Signs of mental health pain-related problems, including phobias and obsessive-compulsive disorder, were observed in ten out of 19 individuals. Mental well-being, social functioning, and quality of life (SDQ and PedsQL) were independent of pain status (p>0.05). Adaptive pain coping strategies were utilized regardless of pain status (PPCI). Social functioning (p<0.01) and the quality of life (p=0.01) were attenuated and statistically significantly poorer than healthy age-matched young adults but better than for fibromyalgia subjects., Conclusions: A subset of individuals treated for childhood-CRPS, type 1 experiences long-term consequences of persistent pain, a decrease in quality of life indicators, and demonstrates significant psychosocial issues. Childhood-CRPS is suggested to be associated with long-term psychosocial consequences and poorer quality of life than found in age-related healthy peers. Subjects treated for childhood CRPS may need a longer clinical follow-up attempting to preclude relapse of CRPS and non-CRPS pain., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

We thank Dr. Jensen for his interest [...].