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Background: Pain is common in Crohn's disease (CD) even after endoscopic healing is achieved. Depression, sleep disturbances, fatigue, and worry about pain impact the pain experience. There is a bidirectional relationship between sleep and pain, though it has received minimal attention in CD. Herein, we sought to comprehensively assess this relationship in CD using daily diaries., Method: Patients with active symptoms of insomnia and CD were recruited as part of an ongoing clinical trial. Participants completed 14-day diaries on sleep patterns and CD symptoms. Temporal associations between sleep and pain were assessed using cross-lagged path analysis and controlled for age, sex, and menstrual cycle., Results: Overall, 26 participants completed 14-day diaries. All assessed aspects of sleep continuity disturbance were associated with worse next-day abdominal pain (Ps < 0.01). When assessed microlongitudinally, sleep onset latency predicted next-day pain (P = 0.07) and vice versa (P = 0.03). Similarly, nightly awakenings predicted next day pain (P = 0.02) and vice versa (P = 0.04). Sleep efficiency (P = 0.003), sleep quality (P < 0.001), and total sleep time (P = 0.04) predicted next-day pain whereas models with pain as the predictor were not significant., Conclusions: Sleep continuity and abdominal pain are closely related, with sleep efficiency, total sleep time, and sleep quality potentially driving next-day abdominal pain. As interventions for pain in IBD are limited, it may be important to capitalize on the impact of sleep disturbances on pain to optimize overall wellbeing in people with CD., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Poor preoperative sleep quality and impaired sleep continuity may heighten acute postoperative pain intensity and increase analgesic consumption, with negative implications for recovery, mental and physical health. The main objective of the current review was to investigate the relationship between preoperative sleep disturbance and acute postoperative pain control. Four electronic databases were systematically searched from inception to December 2023. Two reviewers screened articles, extracted data, and assessed risk of bias for each included study. The search identified 26 prospective cohort studies and 3 retrospective cohort studies (16104 participants). Of the 29 included studies, 23 focused on preoperative insomnia symptoms, and three studies each focused on preoperative objective sleep continuity or sleep-disordered breathing. Meta-analysis, based on five studies with 1226 participants, showed that clinically significant preoperative insomnia symptoms were associated with moderate to severe pain intensity on the first postoperative day (odds ratio 2.69 (95 % confidence interval 2.03-3.57), p < 0.0001). Qualitative analysis showed relatively robust associations between preoperative insomnia symptoms, impaired sleep continuity and poorer acute, as well as subacute, postoperative pain control. Findings related to obstructive sleep apnea syndrome were mixed. Given that insomnia is a potentially modifiable risk factor, interventions targeting sleep prior to surgery may improve postoperative pain control., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The role of the complement system in pain syndromes has garnered attention on the back of preclinical and clinical evidence supporting its potential as a target for new analgesic pharmacotherapies. Of the components that make up the complement system, component 5a (C5a) and component 3a (C3a) are most strongly and consistently associated with pain. Receptors for C5a are widely found in immune resident cells (microglia, astrocytes, sensory neuron-associated macrophages (sNAMs)) in the central nervous system (CNS) as well as hematogenous immune cells (mast cells, macrophages, T-lymphocytes, etc.). When active, as is often observed in chronic pain conditions, these cells produce various inflammatory mediators including pro-inflammatory cytokines. These events can trigger nervous tissue inflammation (neuroinflammation) which coexists with and potentially maintains peripheral and central sensitization. C5a has a likely critical role in initiating this process highlighting its potential as a promising non-opioid target for treating pain. This review summarises the most up-to-date research on the role of the complement system in pain with emphasis on the C5 pathway in peripheral tissue, dorsal root ganglia (DRG) and the CNS, and explores advances in complement-targeted drug development and sex differences. A perspective on the optimal application of different C5a inhibitors for different types (e.g., neuropathic, post-surgical and chemotherapy-induced pain, osteoarthritis pain) and stages (e.g., acute, subacute, chronic) of pain is also provided to help guide future clinical trials. PERSPECTIVE: This review highlights the role and mechanisms of complement components and their receptors in physiological and pathological pain. The potential of complement-targeted therapeutics for the treatment of chronic pain is also explored with a focus on C5a inhibitors to help guide future clinical trials., (Copyright © 2024. Published by Elsevier Inc.)

Background: Pain management is an essential concept to be integrated throughout undergraduate nursing curricula. Many studies have identified a lack of knowledge in pain assessment and management among nurses. Educators have significant roles in preparing students with pain knowledge and application of alternative nonpharmacological pain management techniques., Aim: The purpose of this research study was to explore the impact of instruction on nonpharmacological pain management techniques in both didactic and simulated laboratory settings on nursing students' application of these techniques in clinical settings., Design: A mixed-method descriptive study, with a survey that included closed and open-ended questions., Participants: The sample included 144 first-semester senior prelicensure baccalaureate nursing students., Method: Investigators developed two research questionnaires. All students were given nonpharmacological pain management instruction didactically and practiced in the simulation lab and a hospital-based obstetrical practicum under faculty supervision. The students completed research questionnaires at the semester's conclusion and again prior to graduation., Results: Students reported that they implemented taught nonpharmacological pain management techniques in the clinical setting under faculty supervision. A review of the follow-up questionnaire indicates that graduating seniors did implement the nonpharmacological pain management techniques in other clinical settings and plan to utilize them in their future nursing practice., Conclusions: Teaching nonpharmacological pain management techniques didactically, in a simulation lab and a supervised clinical setting contributes to students' ability to apply these techniques. The findings of this study have implications for nursing education and students' future clinical practice to foster their utilization of nonpharmacological pain management techniques across all settings., 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 © 2024. Published by Elsevier Inc.)

Background/Objectives : miR-506-3p has been demonstrated to be a strong inducer of neuroblastoma cell differentiation, highlighting the potential of applying miR-506-3p mimics to neuroblastoma differentiation therapy. However, the target genes of miR-506-3p that mediate its differentiation-inducing function have not been fully defined. This study aims to comprehensively investigate the targetome of miR-506-3p regarding its role in regulating neuroblastoma cell differentiation. Methods : We combined gene expression profiling and functional high-content screening (HCS) to identify miR-506-3p target genes that have differentiation-modulating functions. For evaluating the potential clinical relevance of the identified genes, we analyzed the correlations of gene expressions with neuroblastoma patient survival. Results : We identified a group of 19 target genes with their knockdown significantly inducing cell differentiation, suggesting that these genes play a key role in mediating the differentiation-inducing activity of miR-506-3p. We observed significant correlations of higher mRNA levels with lower patient survival with 13 of the 19 genes, suggesting that overexpression of these 13 genes plays important roles in promoting neuroblastoma development by disrupting the cell differentiation pathways. Conclusions : Through this study, we identified novel target genes of miR-506-3p that function as strong modulators of neuroblastoma cell differentiation. Our findings represent a significant advancement in understanding the mechanisms by which miR-506-3p induces neuroblastoma cell differentiation. Future investigations of the identified 13 genes are needed to fully define their functions and mechanisms in controlling neuroblastoma cell differentiation, the understanding of which may reveal additional targets for developing novel differentiation therapeutic agents.

Objective: This study gathered adolescent and caregiver perspectives on sleep hygiene practices and beliefs for Black families living in low-resourced urban communities., Methods: Semistructured interviews were conducted with adolescents (n = 9) and caregivers (n = 9) from January-March 2021, during the COVID-19 pandemic. Interview questions included adolescent's current sleep habits, barriers, and home and neighborhood influences. Trained researchers coded data using inductive analysis and a constant comparative method to derive themes., Results: Two themes focused on sleep hygiene practices, including items used to facilitate sleep (e.g., melatonin, electronics) and COVID-19 consequences on sleep schedules. Two themes focused on sleep hygiene beliefs, including a common value on the importance of sleep and influences on caregiver's bedtime rules., Conclusions: Findings provide important insights on sleep hygiene practices and beliefs in a historically marginalized population of Black adolescents and caregivers in urban communities to inform targeted sleep interventions, policies, and programs for optimal sleep and well-being., Competing Interests: Declaration of conflicts of interest None., (Copyright © 2024. Published by Elsevier Inc.)

Mitochondria function and integrity may impact postmortem metabolism and meat quality development. Adaptations in heat tolerant Brahman may persist to limit cellular stress postmortem. Our objective was to evaluate glycolysis, pH decline, and mitochondria function in longissimus lumborum (LL) from Angus and Brahman steers (N = 28) early postmortem (1 to 6 h) and after rigor (24 h). We evaluated metabolites of anaerobic glycolysis, ATP, pH, and temperature, and determined mitochondria oxygen consumption rate (OCR) in permeabilized fibers. The main effects of breed (b) and time (t) and the interaction were tested. Brahman LL contained greater ATP during the first 6 h postmortem; Brahman also tended to exhibit a slower pH decline (b × t, P = 0.07) and more rapid temperature decline (b × t, P < 0.001), but metabolites of anaerobic glycolysis were not different. Mitochondria in Brahman and Angus LL were well-coupled and respired at 1 h postmortem. However, outer membrane integrity became increasingly compromised postmortem (t, P < 0.001). Brahman tended to exhibit greater electron transport system capacity (b, P < 0.1) and had greater capacity for oxidative phosphorylation (complex I and II substrates) at 6 h compared with Angus (P < 0.001). In totality, greater ATP, slower pH decline, and enhanced mitochondria capacity indicate that Brahman possess mitochondrial properties or cellular adaptations that help protect the cell during energy stress postmortem. Slower pH and more rapid temperature decline in LL from Brahman may also help preserve mitochondria function postmortem., Competing Interests: Declaration of competing interest The authors declare that there are no financial or personal relationships with other people or organizations that could inappropriately influence their work., (Copyright © 2023. Published by Elsevier Ltd.)

Knee osteoarthritis (KOA) is linked to an enhanced release of interleukin-6 (IL-6). Increased levels of IL-6 are associated with greater pain and insomnia. While total knee arthroplasty (TKA) typically results in the reduction of pain, for a subgroup of patients, pain does not improve. Understanding patients' propensity to upregulate IL-6 may provide insight into variation in the clinical success of TKA for improving pain, and insomnia may play an important modulatory role. We investigated the association between pre- and post-surgical changes in clinical pain and IL-6 reactivity, and whether change in insomnia moderated this association. Patients (n = 39) with KOA came in-person before and 3-months after TKA. At both visits, patients completed validated measures of clinical pain and insomnia, as well as underwent quantitative sensory testing (QST). Blood samples were collected to analyze IL-expression both before and after QST procedures to assess changes in IL-6 in response to QST (IL-6 reactivity). Patients were categorized into two groups based on change in clinical pain from pre- to post-surgery: 1) pain decreased > 2 points (pain improved) and 2) pain did not decrease > 2 points (pain did not improve). Based on this definition, 49 % of patients had improved pain at 3-months. Among patients with improved pain, IL-6 reactivity significantly decreased from pre- to post-surgery, whereas there was no significant change in IL-6 reactivity among those whose pain did not improve. There was also a significant interaction between pain status and change in insomnia, such that among patients whose insomnia decreased over time, improved pain was significantly associated with a reduction in IL-6 reactivity. However, among patients whose insomnia increased over time, pain status and change in IL-6 reactivity were not significantly associated. Our findings suggest that the resolution of clinical pain after TKA may be associated with discernible alterations in pro-inflammatory responses that can be measured under controlled laboratory conditions, and this association may be moderated by perioperative changes in insomnia. Randomized controlled trials which carefully characterize the phenotypic features of patients are needed to understand how and for whom behavioral interventions may be beneficial in modulating inflammation, pain, and insomnia., 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 © 2024 Elsevier Inc. All rights reserved.)

A subset of individuals exposed to Mycobacterium tuberculosis (Mtb) that we refer to as 'resisters' (RSTR) show evidence of IFN-γ - T cell responses to Mtb-specific antigens despite serially negative results on clinical testing. Here we found that Mtb-specific T cells in RSTR were clonally expanded, confirming the priming of adaptive immune responses following Mtb exposure. RSTR CD4 + T cells showed enrichment of T H 17 and regulatory T cell-like functional programs compared to Mtb-specific T cells from individuals with latent Mtb infection. Using public datasets, we showed that these T H 17 cell-like functional programs were associated with lack of progression to active tuberculosis among South African adolescents with latent Mtb infection and with bacterial control in nonhuman primates. Our findings suggested that RSTR may successfully control Mtb following exposure and immune priming and established a set of T cell biomarkers to facilitate further study of this clinical phenotype., (© 2024. The Author(s).)

Objective: Patients with chronic pain disorders, including Temporomandibular Disorders (TMDs) endorse high levels of sleep disturbances, frequently reporting reduced sleep quality. Despite this, little is known about the effect that daytime pain has on the microstructure and macro-architecture of sleep. Therefore, we aimed to examine the extent to which daytime pain sensitivity, measured using quantitative sensory testing (QST), is associated with objective sleep parameters the following night, including sleep architecture and power spectral density, in women with TMD., Methods: 144 females with myalgia and arthralgia by examination using the Diagnostic criteria for TMD completed a comprehensive QST battery consisting of General Pain Sensitivity, Central Sensitization Index, and Masseter Pressure Pain Threshold assessments. Polysomnography was collected the same night to measure sleep architecture and calculate relative power in delta, theta, alpha, sigma, and beta power bands., Results: Central Sensitization (B = -3.069, P = .009), General Pain Sensitivity Indices (B = -3.069, P = .007), and Masseter Pain Pressure Threshold (B = 0.030, P = .008) were significantly associated with lower REM% both before and after controlling for covariates. Pain sensitivity measures were not significantly associated with relative power in any of the spectral bands nor with any other sleep architectural stages., Conclusions: Our findings demonstrate that higher generalized pain sensitivity, masseter pain pressure threshold, as well as central sensitization were associated with a lower percentage of REM in participants with myofascial pain and arthralgia of the masticatory system. These findings provide an important step toward understanding the mechanistic underpinnings of how chronic pain interacts with sleep physiology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Early adolescence is a critical point for intervention to protect against negative consequences of stress on the developing brain. This study aimed to gather perspectives on stress from adolescents and their caregivers living in under-resourced Baltimore City neighborhoods. Nine African American adolescents and their caregivers (n = 18 total) participated in qualitative interviews exploring neighborhood environments, sources of stress, and coping behaviors. Neighborhood social cohesion was described as a strength of participants' communities, despite concerns about neighborhood safety. Caregivers were highly aware of their child's stressors and coping behaviors. School-related pressure was a prevalent source of stress emphasized by adolescents, along with social stress due to disrupted routines during the COVID-19 pandemic. Adolescents described frequent use of electronics to cope with stress, as well as self-care and relaxation techniques. Themes identified from these data can be used to inform future adolescent stress-reduction interventions and stress-prevention efforts in this priority population., (© 2024. W. Montague Cobb-NMA Health Institute.)

Purpose: Engagement in physical activity (PA) is often associated with better sleep quality and less pain severity among patients diagnosed with breast cancer. However, less research has focused on whether patients' PA prior to breast surgery, including their perceived decrease in PA level, is associated with worse preoperative sleep quality, and subsequently, greater postoperative pain. This longitudinal study investigated whether patients' preoperative PA was associated with their postoperative pain. We also explored whether preoperative sleep disturbance partially mediated the relationship between preoperative PA and postoperative pain., Methods: Prior to breast surgery, patients self-reported both their overall level of PA and whether they perceived a decrease in their PA since the diagnosis/onset of treatment for cancer. Patients also completed a measure of preoperative sleep disturbance. Two weeks after surgery, patients completed a measure of postoperative surgical-area pain severity., Results: Our results showed that preoperatively perceiving a decrease in PA level was significantly associated with greater preoperative sleep disturbance and postoperative pain. A mediation analysis revealed that the association between preoperative decreased PA and postoperative pain was partially mediated by preoperative sleep disturbance. Notably, patients' overall preoperative level of PA was not related to preoperative sleep disturbance or postoperative pain., Conclusion: These findings suggest that maintaining, or even increasing, PA after diagnosis/treatment may be more important than the absolute amount of PA that women engage in during the preoperative period. Potentially, some patients with breast cancer may benefit from a preoperative intervention focused on both maintaining PA and bolstering sleep quality., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: We examined associations of a self-reported history of childhood abuse with pain and physical functioning in patients with knee osteoarthritis (KOA) awaiting total knee arthroplasty (TKA). We also explored the potential moderating effects of positive childhood experiences (PCEs), an index of resilience, on these associations., Methods: Prior to TKA, participants with KOA awaiting surgery ( N = 239) completed self-report measures of adverse childhood experiences (ACEs), PCEs, pain, and physical functioning. We evaluated associations of pain and physical functioning (Brief Pain Inventory [BPI] and Western Ontario and McMaster University of Osteoarthritis Index [WOMAC]) based on the experience of ACEs (childhood abuse), with PCEs (childhood happiness and supportive parental care) as potential moderators., Results: Greater exposure to childhood abuse was positively correlated with BPI pain interference as well as WOMAC pain and functioning scores. Additionally, childhood happiness and supportive parental care moderated the positive associations of childhood abuse with pain and physical functioning; though, surprisingly, the adverse effects of childhood abuse on these outcomes were more pronounced among participants with high levels of childhood happiness and supportive parental care., Conclusion: Overall, results show an association between a self-reported history of childhood abuse and pain and functioning in patients with KOA awaiting TKA. However, PCEs did not protect against the negative consequences of childhood abuse in our cohort. Further research is needed to validate these associations and gain a more comprehensive understanding of the complex interplay between childhood abuse and PCEs and their potential influences on pain experiences in adults with chronic pain conditions, including KOA., (© 2024 the author(s), published by De Gruyter.)

Introduction: Current wearables that collect heart rate and acceleration were not designed for children and/or do not allow access to raw signals, making them fundamentally unverifiable. This study describes the creation and calibration of an open-source multichannel platform (PATCH) designed to measure heart rate and acceleration in children ages 3-8 yr., Methods: Children (N = 63; mean age, 6.3 yr) participated in a 45-min protocol ranging in intensities from sedentary to vigorous activity. Actiheart-5 was used as a comparison measure. We calculated mean bias, mean absolute error (MAE) mean absolute percent error (MA%E), Pearson correlations, and Lin's concordance correlation coefficient (CCC)., Results: Mean bias between PATCH and Actiheart heart rate was 2.26 bpm, MAE was 6.67 bpm, and M%E was 5.99%. The correlation between PATCH and Actiheart heart rate was 0.89, and CCC was 0.88. For acceleration, mean bias was 1.16 mg and MAE was 12.24 mg. The correlation between PATCH and Actiheart was 0.96, and CCC was 0.95., Conclusions: The PATCH demonstrated clinically acceptable accuracies to measure heart rate and acceleration compared with a research-grade device., (Copyright © 2024 by the American College of Sports Medicine.)

During the eradication program undertaken against Anoplophora glabripennis (Motschulsky) in the Greater Toronto Area, information was collected on the numerous signs of injury found on wounded trees. Herein, we used a portion of this information to assess the characteristics of logs with signs of oviposition (i.e., pits). Specifically, we related the basal diameter, type (log bole vs. log branch), height above ground, and branch hierarchy level of logs with pits to tree size (i.e., height and diameter at breast height) and level of infestation intensity. In general, pits were concentrated on logs from the bole and branches that were 8-14 cm in diameter in the lower 8 m of the bole and in the first 2 levels of the branching hierarchy. Oviposition pit location was strongly influenced by tree size-both height and diameter at breast height, with more pits on the lower bole in small trees and then higher on the bole and into the branches as tree size increased. As tree-level infestation intensity increased, pits were found on both larger and smaller diameter portions of the trees, presumably as preferred oviposition sites became saturated. These findings can improve the efficacy of surveillance activities for A. glabripennis., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

T cells are required for protective immunity against Mycobacterium tuberculosis. We recently described a cohort of Ugandan household contacts of tuberculosis cases who appear to "resist" M. tuberculosis infection (resisters; RSTRs) and showed that these individuals harbor IFN-γ-independent T cell responses to M. tuberculosis-specific peptide antigens. However, T cells also recognize nonprotein antigens via antigen-presenting systems that are independent of genetic background, known as donor-unrestricted T cells (DURTs). We used tetramer staining and flow cytometry to characterize the association between DURTs and "resistance" to M. tuberculosis infection. Peripheral blood frequencies of most DURT subsets were comparable between RSTRs and latently infected controls (LTBIs). However, we observed a 1.65-fold increase in frequency of MR1-restricted T (MR1T) cells among RSTRs in comparison with LTBIs. Single-cell RNA sequencing of 18,251 MR1T cells sorted from 8 donors revealed 5,150 clonotypes that expressed a common transcriptional program, the majority of which were private. Sequencing of the T cell receptor α/T cell receptor δ (TCRα/δ) repertoire revealed several DURT clonotypes were expanded among RSTRs, including 2 MR1T clonotypes that recognized mycobacteria-infected cells in a TCR-dependent manner. Overall, our data reveal unexpected donor-specific diversity in the TCR repertoire of human MR1T cells as well as associations between mycobacteria-reactive MR1T clonotypes and resistance to M. tuberculosis infection.

Study Objectives: Opioid withdrawal is an aversive experience that often exacerbates depressive symptoms and poor sleep. The aims of the present study were to examine the effects of suvorexant on oscillatory sleep-electroencephalography (EEG) band power during medically managed opioid withdrawal, and to examine their association with withdrawal severity and depressive symptoms., Methods: Participants with opioid use disorder (N = 38: age-range:21-63, 87% male, 45% white) underwent an 11-day buprenorphine taper, in which they were randomly assigned to suvorexant (20 mg [n = 14] or 40 mg [n = 12]), or placebo [n = 12], while ambulatory sleep-EEG data was collected. Linear mixed-effect models were used to explore: (1) main and interactive effects of drug group, and time on sleep-EEG band power, and (2) associations between sleep-EEG band power change, depressive symptoms, and withdrawal severity., Results: Oscillatory spectral power tended to be greater in the suvorexant groups. Over the course of the study, decreases in delta power were observed in all study groups (β = -189.082, d = -0.522, p = <0.005), increases in beta power (20 mg: β = 2.579, d = 0.413, p = 0.009 | 40 mg β = 5.265, d = 0.847, p < 0.001) alpha power (20 mg: β = 158.304, d = 0.397, p = 0.009 | 40 mg: β = 250.212, d = 0.601, p = 0.001) and sigma power (20 mg: β = 48.97, d = 0.410, p < 0.001 | 40 mg: β = 71.54, d = 0.568, p < 0.001) were observed in the two suvorexant groups. During the four-night taper, decreases in delta power were associated with decreases in depressive symptoms (20 mg: β = 190.90, d = 0.308, p = 0.99 | 40 mg: β = 433.33, d = 0.889 p = <0.001), and withdrawal severity (20 mg: β = 215.55, d = 0.034, p = 0.006 | 40 mg: β = 192.64, d = -0.854, p = <0.001), in both suvorexant groups and increases in sigma power were associated with decreases in withdrawal severity (20 mg: β = -357.84, d = -0.659, p = 0.004 | 40 mg: β = -906.35, d = -1.053, p = <0.001). Post-taper decreases in delta (20 mg: β = 740.58, d = 0.964 p = <0.001 | 40 mg: β = 662.23, d = 0.882, p = <0.001) and sigma power (20 mg only: β = 335.54, d = 0.560, p = 0.023) were associated with reduced depressive symptoms in the placebo group., Conclusions: Results highlight a complex and nuanced relationship between sleep-EEG power and symptoms of depression and withdrawal. Changes in delta power may represent a mechanism influencing depressive symptoms and withdrawal., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Only a few diurnal animals, such as bumblebees, extend their activity into the time around sunrise and sunset when illumination levels are low. Low light impairs viewing conditions and increases sensory costs, but whether diurnal insects use low light as a cue to make behavioural decisions is uncertain. To investigate how they decide to initiate foraging at these times of day, we observed bumblebee nest-departure behaviours inside a flight net, under naturally changing light conditions. In brighter light bees did not attempt to return to the nest and departed with minimal delay, as expected. In low light the probability of non-departures increased, as a small number of bees attempted to return after spending time on the departure platform. Additionally, in lower illumination bees spent more time on the platform before flying away, up to 68 s. Our results suggest that bees may assess light conditions once outside the colony to inform the decision to depart. These findings give novel insights into how behavioural decisions are made at the start and the end of a foraging day in diurnal animals when the limits of their vision impose additional costs on foraging efficiency.

Background: Systemic inflammation, particularly the elevation of interleukin-6 (IL-6), plays an important role in the maintenance and progression of knee osteoarthritis. Insomnia, being highly prevalent in knee osteoarthritis, is understood to be a risk factor for systemic inflammation. The present study examined if cognitive behavioral therapy for insomnia (CBT-I) would reduce circulating IL-6 levels to a larger extent than the active control condition via greater improvement in sleep maintenance disturbance at mid-treatment, among individuals with knee osteoarthritis and insomnia disorder., Methods: This is an ancillary study (N = 64) from a larger double-blind, randomized, active controlled clinical trial. Serum IL-6 was measured at baseline, post-treatment, and 3- and 6-month follow-ups. Sleep was measured by daily sleep diaries., Results: Overall, there was no significant IL-6 trajectory differences between CBT-I and the active control (p = .64). Compared to the active control, CBT-I demonstrated greater improvement in sleep maintenance disturbance at mid-treatment (p = .01), which, in turn, was significantly associated with lower levels of IL-6 at 3-month follow-up (p < .05). Sleep maintenance disturbance at mid-treatment did not significantly predict changes in IL-6 levels at post-treatment (p = .43) and 6-month follow-up (p = .90)., Conclusions: Our study demonstrates that CBT-I can be efficacious in improving sleep maintenance disturbance among individuals with knee osteoarthritis and insomnia disorder. However, no convincing evidence was found that CBT-I can substantially reduce IL-6 levels via improvement in sleep. CBT-I alone may not be effective in reducing systematic inflammation in this clinical population., Trial Registration: NCT00592449., (© 2023. International Society of Behavioral Medicine.)

Per- and poly-fluoroalkyl substances (PFASs) are persistent, toxic chemicals that pose significant hazards to human health and the environment. Screening large numbers of chemicals for their ability to act as endocrine disruptors by modulating the activity of nuclear receptors (NRs) is challenging because of the time and cost of in vitro and in vivo experiments. For this reason, we need computational approaches to screen these chemicals and quickly prioritize them for further testing. Here, we utilized molecular modeling and machine-learning predictions to identify potential interactions between 4545 PFASs with ten different NRs. The results show that some PFASs can bind strongly to several receptors. Further, PFASs that bind to different receptors can have very different structures spread throughout the chemical space. Biological validation of these in silico findings should be a high priority.

Annual surveys of Irish soil samples identified three isolates, CBS 16921 (UCD88), CBS 18246 (UCD443), and CBS 18247 (UCD483), of an apiculate yeast species within the Hanseniaspora genus. The internal transcribed spacer (ITS) and D1/D2 region of the large subunit (LSU) rRNA sequences showed that these are isolates of the recently described species Hanseniaspora menglaensis , first isolated from Southwest China. No genome sequence for H. menglaensis is currently available. The genome sequences of the three Irish isolates were determined using short-read (Illumina) sequencing, and the sequence of one isolate (CBS 16921) was assembled to chromosome level using long-read sequencing (Oxford Nanopore Technologies). Phylogenomic analysis shows that H. menglaensis belongs to the fast-evolving lineage (FEL) of Hanseniaspora . Only one MAT idiomorph (encoding MAT α1) was identified in all three sequenced H. menglaensis isolates, consistent with one mating type of a heterothallic species. Genome comparisons showed that there has been a rearrangement near MAT α of FEL species compared to isolates from the slowly evolving lineage (SEL).

There is a large unmet need for novel pain-killers to improve relief of painful diabetic neuropathy (PDN). Herein, we assessed the efficacy of the somatostatin type 4 (SST 4 ) receptor agonist, J-2156, for relief of PDN in rats. Diabetes was induced with streptozotocin (STZ; 70 mg/kg) and bilateral hindpaw hypersensitivity was fully developed by 8-week post-STZ. In the intervals, 8-12-weeks (morphine-sensitive phase; Phase 1) and 16-18-weeks (morphine-hyposensitive phase; Phase 2) post-STZ, rats received a single dose of intraperitoneal (i.p.) J-2156 (10, 20, 30 mg/kg), gabapentin (100 mg/kg i.p.), subcutaneous morphine (1 mg/kg) or vehicle. Hindpaw withdrawal thresholds (PWTs) were assessed using von Frey filaments pre-dose and at regular intervals over 3-h post-dose. In Phase 1, J-2156 at 30 mg/kg evoked significant anti-allodynia in the hindpaws with maximal effect at 1.5 h compared with 1 h for gabapentin and morphine. The durations of action for all three compounds were greater than 3 h. The corresponding mean (±SEM) extent and duration of anti-allodynia (ΔPWT AUC) for gabapentin did not differ significantly from that for J-2156 (30 mg/kg) or morphine. However, in Phase 2, the ΔPWT AUC for morphine was reduced to approximately 25% of that in Phase 1, mirroring our previous work. Similarly, the mean (±SEM) ΔPWT AUC for J-2156 (30 mg/kg) in Phase 2 was approximately 45% of that for Phase 1 whereas for gabapentin the mean (±SEM) ΔPWT AUCs did not differ significantly ( p > 0.05) between the two phases. Our findings further describe the preclinical pain relief profile of J-2156 and complement previous work in rat models of inflammatory pain, neuropathic pain and low back pain. SST 4 receptor agonists hold promise as novel therapeutics for the relief of PDN, a type of peripheral neuropathic pain that is often intractable to relief with clinically used drug treatment options., Competing Interests: AK and this project were supported financially by an Australian Research Council Large Linkage grant in collaboration with Boehringer Ingelheim Pharma GmbH & Co. KG (#LP120200623) with both the Australian Research Council and Boehringer Ingelheim providing funding in an approximately 50:50 ratio. JRN and LC (paid employees of Boehringer Ingelheim) were involved in the study design but had no role in data collection, analysis or interpretation of data or the writing of the first draft of this article. Both JRN and LC provided comments on manuscript drafts and approved the final version of the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kuo, Imam, Li, Lin, Raboczyj, Bohmer, Nicholson, Corradini and Smith.)

The unusual and sterically constrained amino acid, seco -1-azacubane-2-carboxylic acid, was incorporated into a range of bioactive chemical templates, including enalaprilat, perindoprilat, endomorphin-2 and isoniazid, and subjected to biological testing. The endomorphin-2 derivative displayed increased activity at the δ opioid receptor, but a loss in activity was observed in the other cases, although human normal cell line evaluation suggests limited cytotoxic effects.

Background: Sleep disturbance is commonly reported among individuals meeting criteria for cannabis use disorder (CUD), and people who use cannabis frequently report sleep disturbance as a contributor to failed quit attempts. The purpose of this study was to measure sleep in individuals enrolled in treatment for CUD, and to determine whether use of hypnotic medication during treatment increased abstinence rates., Method: The study enrolled 127 adults seeking treatment for CUD in a 12-week clinical trial and randomized to receive extended-release zolpidem (zolpidem-XR) or placebo. All participants received computerized behavioral therapy and abstinence-based contingency management. The study conducted in-home ambulatory polysomnography (PSG) assessments at baseline and during treatment to objectively measure sleep. Self-report measures of recent sleep, Insomnia Severity Index (ISI), and drug use (Timeline Follow-Back) were collected at each study visit, and the study confirmed self-reported abstinence via quantitative urine drug testing., Result: Participants randomized to placebo, but not zolpidem-XR exhibited significant sleep disturbance during week 1 of treatment. Sleep disturbance emerged in the zolpidem-XR group after study medication was stopped at the end of treatment. Though participants assigned to the zolpidem-XR condition had qualitatively greater rates of abstinence compared with placebo (27 % versus 15 % negative at end of treatment), the difference was not statistically significant. Treatment retention was poor (about 50 % drop out in both groups) and medication adherence was a challenge without the use of contingent incentives., Conclusion: Results from this randomized controlled trial suggest that zolpidem-XR can attenuate abstinence-induced sleep disturbance early in treatment for CUD, but that sleep problems are likely to emerge after the medication is stopped. Further research should identify alternative pharmacotherapies and behavioral treatments for CUD and elucidate the role of sleep disturbance in the development and maintenance of CUD., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Poor sleep is common in inflammatory bowel disease (IBD) and may be associated with overall worse disease outcomes. While the sleep/IBD literature is growing, the data are often self-reported. Further, much of the research using objective measures of sleep architecture, or the overall pattern of sleep depth, rely on single-night assessments, which can be of questionable validity., Design: Participants with IBD and healthy controls were recruited from Dartmouth-Hitchcock Medical Center as part of a two-phase clinical trial. Sleep architecture was assessed using three nights of in-home electroencephalographic monitoring and scored according to the American Academy of Sleep Medicine guidelines., Results: Our sample included 15 participants with IBD and 8 healthy controls. Participants with IBD were more psychiatrically complex, with more self-reported insomnia, anxiety and depression. Participants with IBD evidenced greater microarousals than healthy controls. In participants with IBD, microarousals were associated with lower insomnia and greater depression scores. Within IBD, participants with clinically significant insomnia evidenced trend towards lower sleep efficiency, while self-reported disease activity did not significantly impact findings., Conclusions: The methodology of past research may have impacted findings, including the reliance on single-night assessments and limited generalisability. Future research that uses robust, multinight assessments of sleep architecture in large, diverse samples is clearly warranted, as is research exploring the impact of cognitive and behavioural factors on sleep architecture and arousal., Trial Registration Number: NCT04132024., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: Longitudinal total knee arthroplasty (TKA) studies indicate that a substantial percentage of patients continue to experience clinically significant pain and functional impairment after surgery. Insomnia has been associated with poorer surgical outcomes; however, previous work has largely focused on long-term postsurgical insomnia. This study builds on previous work by examining sleep and pain outcomes about perioperative insomnia trajectories. Insomnia symptoms (using the Insomnia Severity Index) during the acute perioperative period (2 weeks pre-TKA to 6 weeks post-TKA) were used to classify participants into perioperative insomnia trajectories: (1) No Insomnia (ISI < 8), (2) New Insomnia (baseline < 8; postoperative ≥ 8 or ≥6-point increase), (3) Improved Insomnia (baseline ≥ 8, postoperative < 8 or ≥6-point decrease), and (4) Persistent Insomnia (ISI ≥ 8). Insomnia, pain, and physical functioning were assessed in participants with knee osteoarthritis (n = 173; M age = 65 ± 8.3, 57.8% female) at 5 time points: 2 weeks pre-TKA, post-TKA: 6 weeks, 3 months, 6 months, and 12 months. Significant main effects were seen for insomnia trajectory and time, and trajectory-by-time interactions for postoperative insomnia, pain severity, and physical functioning ( P' s < 0.05). The Persistent Insomnia trajectory had the worst postoperative pain at all follow-ups and marked insomnia and physical functioning impairment post-TKA ( P' s < 0.05). The New Insomnia trajectory had notable long-term insomnia (6 weeks to 6 months) and acute (6 weeks) postoperative pain and physical functioning ( P' s < 0.05). Findings indicated a significant relationship between perioperative insomnia trajectory and postoperative outcomes. Results of this study suggest that targeting presurgical insomnia and preventing the development of acute postoperative insomnia may improve long-term postoperative outcomes, with an emphasis on persistent perioperative insomnia due to poorer associated outcomes., (Copyright © 2023 International Association for the Study of Pain.)

Translating promising preclinical pain relief data for novel molecules from drug discovery to positive clinical trial outcomes is challenging. The angiotensin II type 2 (AT 2 ) receptor is a clinically-validated target based upon positive proof-of-concept clinical trial data in patients with post-herpetic neuralgia. This trial was conducted because AT 2 receptor antagonists evoked pain relief in rodent models of neuropathic pain. EMA401 was selected as the drug candidate based upon its suitable preclinical toxicity and safety profile and good pharmacokinetics. Herein, we provide an overview of the discovery, preclinical and clinical development of EMA401, for the alleviation of peripheral neuropathic pain., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MTS is named as inventor on two granted University of Queensland (UQ) patents (Smith MT, Wyse B. Methods of treatment or prophylaxis PCT/AU2005/001975. Published Jun 29, 2006. Smith MT. Methods of treatment or prophylaxis PCT/AU2007/00339. Published Sep 27, 2007). The AT(2) receptor antagonist technology was commercialized by the UQ spin-out company, Spinifex Pharmaceuticals Pty Ltd that was formed in 2005. In 2015, Spinifex was acquired by Novartis. In 2019, clinical development was terminated due to unexpected hepatotoxicity in a long-term (39-weeks) monkey toxicity study. MTS is undertaking contract research in collaboration with Boehringer Ingelheim Pharma GmbH & Co. KG, Argenica Pharmaceuticals and Cassowary Pharmaceuticals (on which MTS is a co-founder). AJS is named as an inventor on University of Southern California patent application (‘AT2 antagonists for non-addictive pain relief,’ PCT/IB2023/057041) and declares consultancy income from Eli Lilly & Co. for advisory work in relation to AT(2) receptor antagonists. ASCR declares funding to his laboratory at Imperial College London from Spinifex to conduct pre-clinical evaluation of EMA401. He held share options in Spinifex which resulted in personal gain on the acquisition of Spinifex by Novartis. Consultancy income via Imperial Consultants for advisory work in relation to the analgesic effects of AT(2) receptor antagonists from Spinifex, Novartis and Confo. He is a member of the Medicines and Healthcare products Regulatory Agency (MHRA), Commission on Human Medicines - Neurology, Pain & Psychiatry Expert Advisory Group., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Up to 40% of individuals who undergo total knee arthroplasty (TKA) experience some degree of pain following surgery. Presurgical insomnia has been identified as a predictor of postsurgical pain; however, modifiable presurgical behaviors related to insomnia have received minimal attention. The objective of the present study was to develop a 2-item sleep and pain behavior scale (SP2) to investigate a maladaptive sleep and pain behavior and is a secondary analysis of a larger, parent study., Methods: Patients (N = 109) completed SP2 at baseline and 12 months and questionnaires assessing sleep and pain at baseline (pre-TKA), 6 weeks, 3, 6, and 12 months post-TKA. SP2 demonstrated adequate preliminary psychometric properties., Results: As hypothesized, even after controlling for baseline insomnia, pain, anxiety and other covariates, baseline SP2 predicted insomnia symptom severity at 6 weeks (β = 2.828), 3 (β = 2.140), 6 (β = 2.962), and 12 months (β = 1.835) and pain at 6 weeks (β = 6.722), 3 (β = 5.536), and 6 months (β = 7.677) post-TKA (P < .05). Insomnia symptoms at 6-weeks post-TKA mediated the effect of presurgical SP2 on pain at 3 (95% CI: 0.024-7.054), 6 (95%CI: 0.495-5.243), and 12 months (95% CI: 0.077-2.684)., Conclusions: This provides preliminary evidence that patients who cope with pain by retiring to their bed and bedroom have higher rates of post-surgical insomnia and pain and supports efforts to target this maladaptive sleep and pain behavior to reduce postsurgical pain., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Allergen immunotherapy (AIT) is a well-established disease-modifying therapy for allergic rhinitis, yet the fundamental mechanisms underlying its clinical effect remain inadequately understood. Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy was a randomized, double-blind, placebo-controlled trial of individuals allergic to timothy grass who received 2 years of placebo (n = 30), subcutaneous immunotherapy (SCIT) (n = 27), or sublingual immunotherapy (SLIT) (n = 27) and were then followed for 1 additional year., Objective: We used yearly biospecimens from the Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy study to identify molecular mechanisms of response., Methods: We used longitudinal transcriptomic profiling of nasal brush and PBMC samples after allergen provocation to uncover airway and systemic expression pathways mediating responsiveness to AIT., Trial Registration: ClinicalTrials.gov Identifier: NCT01335139, EudraCT Number: 2010-023536-16., Results: SCIT and SLIT demonstrated similar changes in gene module expression over time. In nasal samples, alterations included downregulation of pathways of mucus hypersecretion, leukocyte migration/activation, and endoplasmic reticulum stress (log2 fold changes -0.133 to -0.640, false discovery rates [FDRs] <0.05). We observed upregulation of modules related to epithelial development, junction formation, and lipid metabolism (log2 fold changes 0.104 to 0.393, FDRs <0.05). In PBMCs, modules related to cellular stress response and type 2 cytokine signaling were reduced by immunotherapy (log2 fold changes -0.611 to -0.828, FDRs <0.05). Expression of these modules was also significantly associated with both Total Nasal Symptom Score and peak nasal inspiratory flow, indicating important links between treatment, module expression, and allergen response., Conclusions: Our results identify specific molecular responses of the nasal airway impacting barrier function, leukocyte migration activation, and mucus secretion that are affected by both SCIT and SLIT, offering potential targets to guide novel strategies for AIT., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

We previously described five trajectories of insomnia (each defined by a distinct pattern of insomnia severity over 12 months following traumatic brain injury [TBI]). Our objective in the present study was to estimate the association between insomnia trajectory status and trajectories of mental health and neurocognitive outcomes during the 12 months after TBI. In this study, participants included N  = 2022 adults from the Federal Inter-agency Traumatic Brain Injury Repository database and Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. The following outcome measures were assessed serially at 2 weeks, and 3, 6, and 12 months post-injury: Insomnia Severity Index, Patient Health Questionnaire, Post-Traumatic Stress Disorder (PTSD) Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), Patient Reported Outcomes Measurement Information System-Pain, and Quality of Life After Brain Injury-Overall Scale. Neurocognitive performance was assessed at 2 weeks, and 6 and 12 months using the Wechsler Adult Intelligence Scales Processing Speed Index and the Trails Making Test Parts A and B. Results indicated that g reater insomnia severity was associated with greater abnormality in mental health, quality of life, and neuropsychological testing outcomes. The pattern of insomnia over time tracked the temporal pattern of all these outcomes for all but a very small number of participants. Notably, severe insomnia at 3 or 6 months post-TBI was a risk factor for poor recovery at 12 months post-injury. In conclusion, in this well-characterized sample of individuals with TBI, insomnia severity generally tracked severity of depression, pain, PTSD, quality of life, and neurocognitive outcomes over 12 months post-injury. More intensive sleep assessment is needed to elucidate the nature of these relationships and to help inform best strategies for intervention.

Glyphosate was classified as a probable human carcinogen (Group 2A) by the International Agency for Research on Cancer (IARC) partially due to strong mechanistic evidence in 2015. Since then, numerous studies of glyphosate and its formulations (GBF) have emerged. These studies can be evaluated for cancer hazard identification with the newly described ten key characteristics (KC) of carcinogens approach. Our objective was to assess all in vivo, ex vivo, and in vitro mechanistic studies of human and experimental animals (mammals) that compared exposure to glyphosate/GBF with low/no exposure counterparts for evidence of the ten KCs. A protocol with our methods adhering to PRISMA guidelines was registered a priori (INPLASY202180045). Two blinded reviewers screened all in vivo, ex vivo, and in vitro studies of glyphosate/GBF exposure in humans/mammals reporting any KC-related outcome available in PubMed before August 2021. Studies that met inclusion criteria underwent data extraction conducted in duplicate for each KC outcome reported along with key aspects of internal/external validity, results, and reference information. These data were used to construct a matrix that was subsequently analyzed in the program R to conduct strength of evidence and quality assessments. Of the 2537 articles screened, 175 articles met inclusion criteria, from which we extracted >50,000 data points related to KC outcomes. Data analysis revealed strong evidence for KC2, KC4, KC5, KC6, KC8, limited evidence for KC1 and KC3, and inadequate evidence for KC7, KC9, and KC10. Notably, our in-depth quality analyses of genotoxicity (KC2) and endocrine disruption (KC8) revealed strong and consistent positive findings. For KC2, we found: 1) studies conducted in humans and human cells provided stronger positive evidence than counterpart animal models; 2) GBF elicited a stronger effect in both human and animal systems when compared to glyphosate alone; and 3) the highest quality studies in humans and human cells consistently revealed strong evidence of genotoxicity. Our analysis of KC8 indicated that glyphosate's ability to modulate hormone levels and estrogen receptor activity is sensitive to both exposure concentration and formulation. The modulations observed provide clear evidence that glyphosate interacts with receptors, alters receptor activation, and modulates the levels and effects of endogenous ligands (including hormones). Our findings strengthen the mechanistic evidence that glyphosate is a probable human carcinogen and provide biological plausibility for previously reported cancer associations in humans, such as non-Hodgkin lymphoma. We identified potential molecular interactions and subsequent key events that were used to generate a probable pathway to lymphomagenesis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martyn Smith reports a relationship with Andrus Wagstaff Law Firm, Maurice Blackburn Lawyers, and Thornton Law Firm that includes: consulting or advisory and paid expert testimony. Luoping Zhang reports a relationship with Thornton Law Firm and Kirkendall Dwyer LLP that includes: consulting or advisory., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sleep has a homeostatic role in the regulation of the immune system and serves to constrain activation of inflammatory signalling and expression of cellular inflammation. In patients with rheumatoid arthritis (RA), a misaligned inflammatory profile induces a dysregulation of sleep-wake activity, which leads to excessive inflammation and the induction of increased sensitivity to pain. Given that multiple biological mechanisms contribute to sleep disturbances (such as insomnia), and that the central nervous system communicates with the innate immune system via neuroendocrine and neural effector pathways, potential exists to develop prevention opportunities to mitigate the risk of insomnia in RA. Furthermore, understanding these risk mechanisms might inform additional insomnia treatment strategies directed towards steering and reducing the magnitude of the inflammatory response, which together could influence outcomes of pain and disease activity in RA., (© 2023. Springer Nature Limited.)

microRNA mimics are synthetic RNA molecules that imitate the mature miRNA duplexes and their functions. These mimics have shown promise in treating cancers. Nucleotide chemical modifications of microRNA mimics have been investigated and have improved the stability of miRNA mimics. However, the potential therapeutic benefit of mimic analogs based on sequence modifications has not been explored. miR-506-3p was identified as a differentiation-inducing microRNA in neuroblastoma cells, suggesting the potential of applying the miR-506-3p mimic in neuroblastoma differentiation therapy. In this study, we explored the possibility of developing shortened miR-506-3p analogs that can maintain differentiation-inducing activities comparable to the wild-type miR-506-3p mimic. We found that deleting up to two nucleotides at either the 3' end or within the middle region of the miR-506-3p sequence fully maintained the differentiation-inducing activity when compared to the wild-type mimic. Deleting up to four nucleotides from the 3' end or deleting three nucleotides in the middle positions diminished the differentiation-inducing activity, but the analogs still maintained differentiation-inducing activities that were significantly higher than the negative control oligo. The shortened analog designs potentially benefit patients from two perspectives: (1) the reduced cost of manufacturing shortened analogs, and (2) the reduced non-specific toxicity due to their smaller molecular sizes.

Chronic pain is not only one of the most common health problems, it is often challenging to treat adequately. Chronic pain has a high prevalence globally, affecting approximately 20% of the adult population. Chronic inflammatory pain and neuropathic (nerve) pain conditions are areas of large unmet medical need because analgesic/adjuvant agents recommended for alleviation of these types of chronic pain often lack efficacy and/or they produce dose-limiting side effects. Recent work has implicated the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome in the pathobiology of chronic pain, especially neuropathic and inflammatory pain conditions. NLRP3 is activated by damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). This in turn leads to recruitment and activation of caspase-1 an enzyme that cleaves the inactive IL-1β and IL-18 precursors to their respective mature pro-inflammatory cytokines (IL-1β and IL-18) for release into the cellular milieu. Caspase-1 also cleaves the pyroptosis-inducing factor, gasdermin D, that leads to oligomerization of its N-terminal fragment to form pores in the host cell membrane. This then results in cellular swelling, lysis and release of cytoplasmic contents in an inflammatory form of cell death, termed pyroptosis. The ultimate outcome may lead to the development of neuropathic pain and/or chronic inflammatory pain. In this review, we address a role for NLRP3 inflammasome activation in the pathogenesis of various chronic pain conditions., (© 2023. The Author(s).)

Background and Objectives: Knee osteoarthritis is one of the primary causes of chronic pain among older adults and because of the aging population, the number of total knee arthroplasties (TKAs) performed is exponentially increasing. While pain reduction is a goal of TKA, movement-evoked pain is rarely assessed pre- and post-TKA. We characterized the distributions of change in pain, function, and situational catastrophizing in patients from presurgery to 3 months postsurgery and explored associations among these pre-post changes., Research Design and Methods: This prospective study longitudinally assessed movement-evoked pain, function, and situational catastrophizing in patients with knee osteoarthritis ( N = 92) using in-person performance-based tests (6-min walk test [6MWT], stair-climb test [SCT]) prior to and 3 months after TKA. Patients also completed the Western Ontario McMaster Universities Scales (WOMAC) pain and function subscales, and Pain Catastrophizing Scale, presurgery and 3- and 6-months postsurgery., Results: Movement-evoked pain and function on performance tests significantly improved from pre- to post-TKA. Improved SCT function was associated with reduced SCT pain and catastrophizing. Similarly, reduced pain during the SCT was associated with reduced catastrophizing during the SCT. However, 6MWT function was not associated with 6MWT pain or catastrophizing; yet reduced pain during the 6MWT was associated with reduced catastrophizing during the 6MWT. Reduced movement-evoked pain during both performance tests was consistently associated with improved WOMAC function and pain, whereas improved function on performance tests was inconsistently associated with WOMAC function and pain. Notably, greater movement-evoked pain on both performance tests at 3-month post-TKA was associated with worse WOMAC function and pain at 6 months, whereas better function on performance tests at 3 months was associated with better WOMAC function, but not related to WOMAC pain at 6 months., Discussion and Implications: Findings highlight the importance of situation-specific and in vivo assessments of pain and catastrophizing during physical activity., Competing Interests: None., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Impairment of the hematopoietic system is one of the primary adverse health effects from exposure to benzene. We previously have shown that exposure to benzene at low levels (<1 ppm) affects the blood forming system and that these effects were proportionally stronger at lower versus higher levels of benzene exposure. This observation is potentially explained by saturation of enzymatic systems., Methods: Here we extend these analyses by detailed modeling of the exposure response association of benzene and its major metabolites (i.e. catechol, muconic acid, phenol, and hydroquinone) on peripheral white blood cell (WBC) counts and its major cell-subtypes (i.e. granulocytes, lymphocytes, and monocytes) using two previously published cross-sectional studies among occupationally exposed Chinese workers., Results: Supra-linear exposure response associations were observed between air benzene concentrations (range ∼ 0.1 - 100 ppm) and WBC counts and its cell-subtypes, with a larger than proportional decrease in cell counts at lower than at higher levels of benzene exposure. The hematotoxicity associations were largely similar in shape when the analyses were repeated with benzene urinary metabolites suggesting that enzymatic saturation is not a full explanation of the observed non-linearity with WBC endpoints., Discussion: We hypothesize that the flattening of the exposure response curve especially at higher benzene exposure levels may reflect a response by the bone marrow to maintain hematopoietic homeostasis. Toxicity to the bone marrow and an induced hyper-proliferative response could both contribute to risk of subsequently developing a hematopoietic malignancy. Additional work is needed to explore this hypothesis., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The prevalence of tuberculosis among men who work in the gold mines of South Africa is among the highest in the world, but a fraction of miners demonstrate consistently negative results upon tuberculin skin test (TST) and IFN-γ release assay (IGRA). We hypothesized that these "resisters" (RSTRs) may display unconventional immune signatures of exposure to M. tuberculosis (M.tb)., Methods: In a cohort of RSTRs and matched controls with latent TB infection (LTBI), we profiled the functional breadth of M.tb antigen-specific T cell and antibody responses using multi-parameter flow cytometry and systems serology, respectively., Findings: RSTRs and LTBI controls both exhibited IFN-γ independent T-cell and IgG antibody responses to M.tb-specific antigens ESAT-6 and CFP-10. Antigen-specific antibody Fc galactosylation and sialylation were higher among RSTRs. In a combined T-cell and antibody analysis, M.tb lysate-stimulated TNF secretion by T cells correlated positively with levels of purified protein derivative-specific IgG. A multivariate model of the combined data was able to differentiate RSTR and LTBI subjects., Interpretation: IFN-γ independent immune signatures of exposure to M.tb, which are not detected by approved clinical diagnostics, are readily detectable in an occupational cohort uniquely characterized by intense and long-term infection pressure. Further, TNF may mediate a coordinated response between M.tb-specific T-cells and B-cells., Funding: This work was supported by the US National Institutes of Health (R01-AI124348 to Boom, Stein, and Hawn; R01-AI125189 and R01-AI146072 to Seshadri; and 75N93019C00071 to Fortune, Alter, Seshadri, and Boom), the Doris Duke Charitable Foundation (Davies), the Bill & Melinda Gates Foundation (OPP1151836 and OPP1109001 to Hawn; and OPP1151840 to Alter), Mass Life Science Foundation (Fortune), and Good Ventures Fund (Fortune)., Competing Interests: Declaration of interests Galit Alter became an employee of Moderna Therapeutics after completion of the work described here and holds equity in Leyden Labs and Systems Seromyx., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Studies in thoracic surgery have long raised concerns that intraoperative administration of intravenous fluids exacerbates or causes postoperative complications and hence advocate fluid restriction. Methods: This retrospective 3-year study investigated the role of intraoperative crystalloid administration rates on the duration of postoperative hospital length of stay (phLOS) and on the incidences of previously reported adverse events (AEs) in 222 consecutive patients following thoracic surgery. Results: Higher rates of intraoperative crystalloid administration were significantly associated with shorter phLOS ( P =0.0006) and with less variance in phLOS. Dose-response curves showed progressive decreases in the postoperative incidences of surgical, cardiovascular, pulmonary, renal, other, and long-term AEs with higher intraoperative crystalloid administration rates. Conclusion: The rate of intravenous crystalloid administration during thoracic surgery was significantly associated with duration of and variance in phLOS, and dose-response curves showed progressive decreases in the incidences of AEs associated with this surgery. We cannot confirm that restrictive intraoperative crystalloid administration benefits patients undergoing thoracic surgery., (©2023 by the author(s); Creative Commons Attribution License (CC BY).)

Background: Strong opioid analgesics such as morphine alleviate moderate to severe acute nociceptive pain (e.g. post-surgical or post-trauma pain) as well as chronic cancer pain. However, they evoke many adverse effects and so there is an unmet need for opioid analgesics with improved tolerability. Recently, a prominent hypothesis has been that opioid-related adverse effects are mediated by β-arrestin2 recruitment at the µ-opioid (MOP) receptor and this stimulated research on discovery of G-protein biassed opioid analgesics. In other efforts, opioids with MOP agonist and δ-opioid (DOP) receptor antagonist profiles are promising for reducing side effects c.f. morphine. Herein, we report on the in vivo pharmacology of a novel opioid peptide (CYX-5) that is a G-protein biassed MOP receptor agonist, DOP receptor antagonist and kappa opioid (KOP) receptor agonist., Methods: Male Sprague-Dawley received intracerebroventricular bolus doses of CYX-5 (3, 10, 20 nmol), morphine (100 nmol) or vehicle, and antinociception (tail flick) was assessed relative to constipation (charcoal meal and castor oil-induced diarrhoea tests) and respiratory depression (whole body plethysmography)., Results: CYX-5 evoked naloxone-sensitive, moderate antinociception, at the highest dose tested. Although CYX-5 did not inhibit gastrointestinal motility, it reduced stool output markedly in the castor oil-induced diarrhoea test. In contrast to morphine that evoked respiratory depression, CYX-5 increased tidal volume, thereby stimulating respiration., Conclusion: Despite its lack of recruitment of β-arrestin2 at MOP, DOP and KOP receptors, CYX-5 evoked constipation, implicating a mechanism other than β-arrestin2 recruitment at MOP, DOP and KOP receptors, mediating constipation evoked by CYX-5 and potentially other opioid ligands., (© 2023. The Author(s).)

Objective: To assess whether brief mindfulness-based cognitive behavioral therapy (MBCBT) could enhance the benefits of total knee arthroplasty (TKA) in improving pain and pain-related disability. Specifically, to determine 1) whether patients who received MBCBT differed from matched controls who received treatment-as-usual with regard to postsurgical pain outcomes and 2) whether changes in pain catastrophizing, depression, or anxiety explained the potential effects of MBCBT on pain outcomes., Design: Pilot clinical trial., Setting: An academic teaching hospital serving a large urban and suburban catchment area surrounding the Boston, Massachusetts metropolitan region., Subjects: Sample of 44 patients undergoing TKA. Patients who completed a brief MBCBT intervention (n = 22) were compared with age-, race-, and sex-matched controls who received treatment-as-usual (n = 22)., Methods: The MBCBT intervention included four 60-minute sessions delivered by a pain psychologist in person and via telephone during the perioperative period. Participants were assessed at baseline and at 6 weeks, 3 months, and 6 months after surgery., Results: Compared with matched controls, patients who received MBCBT had lower pain severity and pain interference at 6 weeks after surgery. Group differences in outcomes were mediated by changes in pain catastrophizing but not by changes in depression or anxiety. The MBCBT group had similar reductions in pain severity and interference as the control group did at 3 and 6 months after surgery., Conclusions: This work offers evidence for a safe and flexibly delivered nonpharmacological treatment (MBCBT) to promote faster recovery from TKA and identifies change in pain catastrophizing as a mechanism by which this intervention could lead to enhanced pain-related outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Post-ERCP pancreatitis (PEP) is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). Limited existing data suggest that prophylactic pancreatic duct (PD) stenting in pediatric patients may increase the risk of PEP. The aim of this study is to identify factors associated with PEP in pediatric patients., Methods: Patients at a single institution who underwent ERCP between 2012 and 2020 were retrospectively reviewed. Patient and procedure-related factors were collected. Data were analyzed using Chi-square or Fisher exact tests as appropriate and Mann-Whitney-Wilcoxon tests., Results: Seven hundred thirty-six ERCPs were performed for 402 unique patients. Ninety-four cases were complicated by PEP (12.8%), of which 91 were mild and 3 were moderately severe. Pancreatic indication, native major papilla, PD cannulation and injection, and higher American Society for Gastrointestinal Endoscopy (ASGE) complexity were associated with PEP. A higher proportion of patients who received rectal indomethacin (65% vs 47%, P = 0.002), or who had placement of a prophylactic (31% vs 20%, P = 0.01) or therapeutic PD stent (37% vs 27%, P = 0.04) developed PEP; however, in a subgroup analysis of high-risk patients, this association was not persistent. A smaller proportion of PEP patients had PRSS1 mutation compared to non-PEP patients (22% vs 40%, P = 0.04)., Conclusions: This study evaluates factors associated with developing PEP in a large pediatric cohort. A high rate of PEP was observed, likely secondary to higher rates of pancreatic indication and higher ASGE complexity scores compared to previously reported literature. Randomized prospective trials are needed to better define the utility of various interventions., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background and Aims: Poor sleep may be prospectively associated with worse disease course in inflammatory bowel disease (IBD). Chronic insomnia is the most common cause of poor sleep complaints in IBD and is theorized to be maintained by dysfunctional thoughts and behavioral patterns. However, data characterizing patterns specific to insomnia in IBD are lacking. Understanding the nuances of insomnia and patients' preferences for treatment is critical for addressing this significant comorbidity in IBD., Methods: We conducted an anonymous, mixed-method online survey of people with IBD and asked questions about sleep patterns, thoughts, and behaviors related to sleep, treatment preferences, and barriers to treatment., Results: 312 participants (60.9% Crohn's, 66.3% women, mean age of 48.62 years) were included in this study. Participants with insomnia were significantly more concerned about the consequences of sleep loss, felt more helpless about their sleep, and were more likely to engage in behaviors known to perpetuate insomnia (e.g., spending time in bed in pain; ps ≤ 0.001) than those without insomnia. 70.3% of participants were interested in discussing sleep as part of IBD care, 63.5% were interested in receiving sleep recommendations from their gastroenterologist, and 84.6% of those with insomnia were interested in participating in sleep treatments., Conclusion: Participants with IBD and insomnia are interested in treatment and reported patterns that can be targeted in Cognitive Behavioral Therapy for Insomnia, as opposed to traditional sleep hygiene guidelines. Additionally, people with insomnia engaged in several sleep-interfering behaviors related to pain. Clinical trials that target insomnia in people with IBD should include pain management in the intervention., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chronic pain is prevalent in older adults. Treatment, especially with opioids, is often ineffective and poses considerable negative consequences in this population. To improve treatment, it is important to understand why older adults are at a heightened risk for developing chronic pain. Insomnia is a major modifiable risk factor for chronic pain that is ubiquitous among older adults. Insomnia can also lead to heightened systemic inflammation and affective disturbance, both of which may further exacerbate pain conditions in older adults. Endotoxin exposure can be used as an experimental model of systemic inflammation and affective disturbance. The current study aims to understand how insomnia status and endotoxin-induced changes in inflammation and affect (increased negative affect and decreased positive affect) may interact to impact pain facilitatory and inhibitory processes in older adults. Longitudinal data will also assess how pain processing, affective, and inflammatory responses to endotoxin may predict the development of pain and/or depressive symptoms. The current study is a randomized, double-blinded, placebo-controlled, mechanistic clinical trial in men and women, with and without insomnia, aged 50 years and older. Participants were randomized to either 0.8ng/kg endotoxin injection or saline placebo injection. Daily diaries were used to collect variables related to sleep, mood, and pain at two-week intervals during baseline and 3-, 6-, 9-, and 12-months post-injection. Primary outcomes during the experimental phase include conditioned pain modulation, temporal summation, and affective pain modulation ∼5.5 hours after injection. Primary outcomes for longitudinal assessments are self-reported pain intensity and depressive symptoms. The current study uses endotoxin as an experimental model for pain. In doing so, it aims to extend the current literature by: (1) including older adults, (2) investigating insomnia as a potential risk factor for chronic pain, (3) evaluating the role of endotoxin-induced affective disturbances on pain sensitivity, and (4) assessing sex differences in endotoxin-induced hyperalgesia., Clinicaltrialsgov: NCT03256760., Trial Sponsor: NIH R01AG057750-01., Competing Interests: 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., (© 2023 The Author(s).)

Background: Complex systems models of breast cancer have previously focused on prediction of prognosis and clinical events for individual women. There is a need for understanding breast cancer at the population level for public health decision-making, for identifying gaps in epidemiologic knowledge and for the education of the public as to the complexity of this most common of cancers., Methods and Findings: We developed an agent-based model of breast cancer for the women of the state of California using data from the U.S. Census, the California Health Interview Survey, the California Cancer Registry, the National Health and Nutrition Examination Survey and the literature. The model was implemented in the Julia programming language and R computing environment. The Paradigm II model development followed a transdisciplinary process with expertise from multiple relevant disciplinary experts from genetics to epidemiology and sociology with the goal of exploring both upstream determinants at the population level and pathophysiologic etiologic factors at the biologic level. The resulting model reproduces in a reasonable manner the overall age-specific incidence curve for the years 2008-2012 and incidence and relative risks due to specific risk factors such as BRCA1, polygenic risk, alcohol consumption, hormone therapy, breastfeeding, oral contraceptive use and scenarios for environmental toxin exposures., Conclusions: The Paradigm II model illustrates the role of multiple etiologic factors in breast cancer from domains of biology, behavior and the environment. The value of the model is in providing a virtual laboratory to evaluate a wide range of potential interventions into the social, environmental and behavioral determinants of breast cancer at the population level., Competing Interests: No authors have competing interests., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Abstract: Sleep loss heightens pain sensitivity, but the pathways underlying this association are not known. Given that experimental sleep disruption induces increases in cellular inflammation as well as selective loss of slow wave, N3 sleep, this study examined whether these mechanisms contribute to pain sensitivity following sleep loss in healthy adults. This assessor-blinded, cross-over sleep condition, single-site, randomized clinical trial enrolled 95 healthy adults (mean [SD] age, 27.8 [6.4]; female, 44 [53.7%]). The 2 sleep conditions were 2 nights of undisturbed sleep (US) and 2 nights of sleep disruption or forced awakening (FA, 8 pseudorandomly distributed awakenings and 200 minutes wake time during the 8-hour sleep opportunity), administered in a cross-over design after 2 weeks of washout and in a random order (FA-US; US-FA). Primary outcome was heat pain threshold (hPTH). Sleep architecture was assessed by polysomnography, and morning levels of cellular inflammation were evaluated by Toll-like receptor-4 stimulated monocyte intracellular proinflammatory cytokine production. As compared with US, FA was associated with decreases in the amount of slow wave or N3 sleep ( P < 0.001), increases in Toll-like receptor-4 stimulated production of interleukin-6 and tumor necrosis factor-α ( P = 0.03), and decreases in hPTH ( P = 0.02). A comprehensive causal mediation analysis found that FA had an indirect effect on hPTH by decreases in N3 sleep and subsequent increases in inflammation (estimate=-0.15; 95% confidence interval, -0.30 to -0.03; P < 0.05) with the proportion mediated 34.9%. Differential loss of slow wave, N3 sleep, and increases in cellular inflammation are important drivers of pain sensitivity after sleep disruption.Clinical Trials Registration: NCT01794689., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Background: Chronic pancreatitis is a debilitating, life-altering disease; however, the long-term outcomes after operative intervention have not been established., Study Design: Patients who underwent operative intervention at a single institution between 2000 and 2020 for chronic pancreatitis were included, and survival was assessed using the National Death Index., Results: A total of 493 patients who underwent 555 operative interventions for chronic pancreatitis during 2 decades were included. Of these patients, 48.5% underwent total pancreatectomy ± islet autotransplantation, 21.7% underwent a duodenal preserving pancreatic head resection and/or drainage procedure, 16.2% underwent a pancreaticoduodenectomy, and 12.8% underwent a distal pancreatectomy. The most common etiology of chronic pancreatitis was idiopathic (41.8%), followed by alcohol (28.0%) and known genetic polymorphisms (9.9%). With a median follow-up of 83.9 months, median overall survival was 202.7 months, with a 5- and 10-year overall survival of 81.3% and 63.5%. One hundred sixty-five patients were deceased, and the most common causes of death included infections (16.4%, n=27), cardiovascular disease (12.7%, n=21), and diabetes-related causes (10.9%, n=18). On long-term follow-up, 73.1% (n=331) of patients remained opioid free, but 58.7% (n=266) had insulin-dependent diabetes. On multivariate Cox proportional hazards modeling, only persistent opioid use (hazard ratio 3.91 [95% CI 2.45 to 6.24], p < 0.01) was associated with worse overall survival., Conclusions: Our results represent the largest series to date evaluating long-term survival outcomes in patients with chronic pancreatitis after operative intervention. Our data give insight into the cause of death and allow for the development of mitigation strategies and long-term monitoring of comorbid conditions., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Racism-based discrimination in healthcare settings has been associated with clinical pain in adults living with sickle cell disease; however, no studies have examined depressive and insomnia symptoms as mechanisms that may drive this relationship. This secondary data analysis examined associations between depressive and insomnia symptoms, racism-based discrimination, and clinical pain. Seventy-one adults with sickle cell disease (70% female, M age  = 38.79) provided baseline reports of racism-based discrimination, depressive symptoms, insomnia symptoms, and pain (severity, interference, catastrophizing), and they completed daily diaries of pain severity and interference over 3 months. In a sequential mediation model, baseline depressive (1st) and insomnia symptoms (2nd) significantly mediated the association between racism-based discrimination and baseline pain interference, average daily diary pain severity, and average daily diary pain interference. Although the mediation model with baseline pain severity as the outcome was significant, the total and direct effects were not. Results indicate that discrimination in healthcare settings contributes to depression, which may act on pain through sleep disturbance. Findings support the need for systemic and structural changes to eliminate discrimination in healthcare settings and behavioral mood and sleep interventions to reduce the impact of discrimination on clinical pain. PERSPECTIVE: The relationship between discrimination in healthcare settings and pain in adults with sickle cell disease may be driven by depression and sleep disturbance, modifiable risk factors and potential treatment targets. Results suggest that systemic, structural, and institutional changes must be implemented to promote better patient care and health outcomes., (Copyright © 2022 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)