Improve disaster response by planning for and logistically supporting acute exacerbations of chronic diseases.

Provide a more effective medical response by emphasizing the management of acute exacerbations of chronic diseases in disasters. Disaster victims need treatment for their acute exacerbations of and ongoing chronic medical conditions, medication refills, mental health resources, and have an expectation that medical facilities will provide resources beyond medical care. Medical response is more efficient, cost effective, and effectual when these considerations are supported.

Adverse Childhood Experiences and Chronic Low Back Pain In Adulthood: The Role of Emotion Regulation.

Chronic low back pain (cLBP) is characterized by biopsychosocial determinants that collectively result in substantial burden at the individual, community, and healthcare system levels. A growing body of literature suggests that childhood adversity is longitudinally associated with the development and maintenance of various chronic pain conditions in adulthood. Little research has investigated the psychological processes that might underlie the association between adverse childhood experiences (ACEs) and cLBP. Emotion regulation comprises a substantive part of the subjective experience of pain and may be a potential mechanism through which ACEs contribute to cLBP etiology and maintenance. Thus, the current study examined the extent to which emotion dysregulation mediated the relationship between ACEs and pain severity (pain at rest and movement-evoked pain) in adults with cLBP. Participants included 183 adults (53.0% female, 62.5% non-Hispanic Black) between the ages of 18 and 85 with cLBP. Participants self-reported on ACEs, pain, difficulties in emotion regulation, depression, and completed brief physical function tasks. In data analytic models, sociodemographic variables were included as covariates. Mediation analyses revealed that emotion regulation mediated the relationship between ACEs and cLBP severity at rest (indirect effect = 0.15 (95% CI [0.06 to 0.25]) and with movement (indirect effect = 1.50 (95% CI [0.69 to 2.57]). Findings suggest ACEs are linked to cLBP severity in adulthood though difficulties in emotion regulation. This aligns with research demonstrating that childhood maltreatment can lead to difficulties in emotion regulation which perpetuate over the lifespan to impact adult health outcomes. TRIAL REGISTRATION: This study utilized baseline data collected as part of a parent trial titled "Examining Racial and SocioEconomic Disparities in Chronic Low Back Pain" (ERASED - ClinicalTrials.gov ID: NCT03338192). PERSPECTIVE: This study presents emotion dysregulation as a psychological pathway through which childhood adversity may contribute to chronic low back pain in adulthood. This work may bolster our understanding of social experiences as risk factors for chronic pain, while identifying targets for clinical intervention.

Elevated pain sensitivity is associated with reduced REM sleep in females with comorbid temporomandibular disorder and insomnia.

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 (PSG) 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 = 0.009), General Pain Sensitivity Indices (B= -3.069, P = 0.007), and Masseter Pain Pressure Threshold (B = 0.030, P = 0.008) 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.

Mutant forms of DDX3X with diminished catalysis form hollow condensates that exhibit sex-specific regulation.

Mutations in the RNA helicase DDX3X, implicated in various cancers and neurodevelopmental disorders, often impair RNA unwinding and translation. However, the mechanisms underlying this impairment and the differential interactions of DDX3X mutants with wild-type (WT) X-linked DDX3X and Y-linked homolog DDX3Y remain elusive. This study reveals that specific DDX3X mutants more frequently found in disease form distinct hollow condensates in cells. Using a combined structural, biochemical, and single-molecule microscopy study, we show that reduced ATPase and RNA release activities contribute to condensate formation and the catalytic deficits result from inhibiting the catalytic cycle at multiple steps. Proteomic investigations further demonstrate that these hollow condensates sequester WT DDX3X/DDX3Y and other proteins crucial for diverse signaling pathways. WT DDX3X enhances the dynamics of heterogeneous mutant/WT hollow condensates more effectively than DDX3Y. These findings offer valuable insights into the catalytic defects of specific DDX3X mutants and their differential interactions with wild-type DDX3X and DDX3Y, potentially explaining sex biases in disease.

DDX3X and DDX3Y constitutively form nano-sized RNA-protein clusters that foster enzymatic activity.

DEAD-box helicases, which are crucial for many aspects of RNA metabolism, often contain intrinsically disordered regions (IDRs), whose functions remain unclear. Using multiparameter confocal microscopy, we reveal that sex chromosome-encoded homologous RNA helicases, DDX3X and DDX3Y, form nano-sized RNA-protein clusters (RPCs) that foster their catalytic activities in vitro and in cells. The IDRs are critical for the formation of these RPCs. A thorough analysis of the catalytic cycle of DDX3X and DDX3Y by ensemble biochemistry and single molecule photon bursts in the confocal microscope showed that RNA release is a major step that differentiates the unwinding activities of DDX3X and DDX3Y. Our findings provide new insights that the nano-sized helicase RPCs may be the normal state of these helicases under non-stressed conditions that promote their RNA unwinding and act as nucleation points for liquid-liquid phase separation under stress. This mechanism may apply broadly among other members of the DEAD-box helicase family.

Mitochondrial reactivity following acute exposure to experimental pain testing in people with HIV and chronic pain.

Background: Physical stressors can cause a physiological response that can contribute to an increase in mitochondrial dysfunction and Mitochondrial DNA damage (mtDNA damage). People living with HIV (PWH) are more likely to suffer from chronic pain and may be more susceptible to mitochondrial dysfunction following exposure to a stressor. We used Quantitative Sensory Testing (QST) as an acute painful stressor in order to investigate whether PWH with/without chronic pain show differential mitochondrial physiological responses. Methods: The current study included PWH with (n = 26), and without (n = 29), chronic pain. Participants completed a single session that lasted approximately 180 min, including QST. Blood was taken prior to and following the QST battery for assays measuring mtDNA damage, mtDNA copy number, and mtDNA damage-associated molecular pattern (DAMP) levels (i.e., ND1 and ND6). Results: We examined differences between those with and without pain on various indicators of mitochondrial reactivity following exposure to QST. However, only ND6 and mtDNA damage were shown to be statistically significant between pain groups. Conclusion: PWH with chronic pain showed greater mitochondrial reactivity to laboratory stressors. Consequently, PWH and chronic pain may be more susceptible to conditions in which mitochondrial damage/dysfunction play a central role, such as cognitive decline.

Presurgical sleep and pain behaviors predict insomnia symptoms and pain after total knee arthroplasty: a 12-month longitudinal, observational study.

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 (ß = 2.828), 3 (ß = 2.140), 6 (ß = 2.962), and 12 months (ß = 1.835) and pain at 6 weeks (ß = 6.722), 3 (ß = 5.536), and 6 months (ß = 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.

Perioperative insomnia trajectories and functional outcomes after total knee arthroplasty.

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.

Digital Inclusion as a Lens for Equitable Parent Engagement.

Digital inclusion (DI) represents a framework for educational leaders to address ongoing digital access and participation divides for adult caretakers (e.g., parents) of school-aged children, as schools continue adopting new education technology tools. This preliminary research investigates teacher perceptions of different DI needs for parents during the pandemic. This research examines teacher perceptions of parents' knowledge and use of online tools in providing supervision to support home-based learning for their student children. A sample of K-12 teachers in the United States responded to open-ended survey questions relating to their observation and evaluation of student learning, parent involvement, and DI needs in their classes. The researchers used a framework drawn from Maslow's Hierarchy of Needs to categorize key DI components teachers identified, finding both digital access and digital participation needs existed in their students' homes. Ultimately, the framework of DI recognizes that household digital access alone does not create equitable opportunities for online instruction without holistic consideration of digital literacy training, technical support, and relevant online tools for parents and caretakers.

Coordination of RNA modifications in the brain and beyond.

Gene expression regulation is a critical process throughout the body, especially in the nervous system. One mechanism by which biological systems regulate gene expression is via enzyme-mediated RNA modifications, also known as epitranscriptomic regulation. RNA modifications, which have been found on nearly all RNA species across all domains of life, are chemically diverse covalent modifications of RNA nucleotides and represent a robust and rapid mechanism for the regulation of gene expression. Although numerous studies have been conducted regarding the impact that single modifications in single RNA molecules have on gene expression, emerging evidence highlights potential crosstalk between and coordination of modifications across RNA species. These potential coordination axes of RNA modifications have emerged as a new direction in the field of epitranscriptomic research. In this review, we will highlight several examples of gene regulation via RNA modification in the nervous system, followed by a summary of the current state of the field of RNA modification coordination axes. In doing so, we aim to inspire the field to gain a deeper understanding of the roles of RNA modifications and coordination of these modifications in the nervous system.

A Brief Overview: Sex Differences in Prevalent Chronic Musculoskeletal Conditions.

Musculoskeletal (MSK) pain disorders are some of the most prevalent and disabling chronic pain conditions worldwide. These chronic conditions have a considerable impact on the quality of life of individuals, families, communities, and healthcare systems. Unfortunately, the burden of MSK pain disorders does not fall equally across the sexes. Females consistently demonstrate more prevalent and severe clinical presentations of MSK disorders, and this disparity increases in magnitude with age. The aim of the present article is to review recent studies that have examined sex differences between males and females in four of the most common MSK pain disorders: neck pain, low back pain, osteoarthritis, and rheumatoid arthritis.

TRIBE-STAMP reveals new insights into the functions of RNA binding proteins.

RNA binding proteins (RBPs) are important players in RNA metabolism and gene regulation. In this issue of Genes & Development, Flamand and colleagues (pp. 1002-1015) developed a new method (TRIBE-STAMP) that detects binding events by two distinct RBPs on single mRNA molecules, which they first applied to the YTHDF family of N 6-methyladenosine (m6A) reader proteins. The investigators show that these RBPs largely share a common pool of bound transcripts and that an individual mRNA may be bound by multiple YTHDF proteins throughout its lifetime. This single-molecule technique is an exciting new method to study potential synergy and/or antagonism between different RBPs.

Sleep after burn injuries: A systematic review and meta-analysis.

Burn injuries are a complex medical condition associated with negative physical and emotional consequences including disturbances in sleep. The goals of this systematic review were to examine the prevalence of sleep disturbances in adult burn survivors and evaluate the effects of intervention to improve sleep. Eight electronic databases were systematically searched and yielded 49 studies (13 interventional and 36 non-interventional). Results from the systematic review demonstrate that a variety of sleep disturbances are common in burn survivors, persisting years after the injury and are associated with pain, itch, emotional distress and reduction in quality of life. Sleep assessment was primarily based on subjective measures and the available data did not allow for assessing the prevalence of sleep disorders in burn survivors. Results of the meta-analysis of four studies demonstrated that a variety of interventions improved sleep quality. These findings provide further evidence that sleep is compromised in burn survivors and highlight the need for ongoing assessment using a combination of validated self-reports and objective measures of sleep. More research is needed to determine the most effective treatments for sleep disorders in burn survivors and if early intervention will serve to improve long term outcomes.

Treatment planning system commissioning of the first clinical biology-guided radiotherapy machine.

PURPOSE: The RefleXion X1 is a novel radiotherapy machine designed for image-guided radiotherapy (IGRT) and biology-guided radiotherapy (BgRT). Its treatment planning system (TPS) generates IMRT and SBRT plans for a 6MV-FFF beam delivered axially via 50 firing positions with the couch advancing every 2.1 mm. The purpose of this work is to report the TPS commissioning results for the first clinical installation of RefleXion™ X1. METHODS: CT images of multiple phantoms were imported into the RefleXion TPS to evaluate the accuracy of data transfer, anatomical modeling, plan evaluation, and dose calculation. Comparisons were made between the X1, Eclipse™, and MIM™. Dosimetric parameters for open static fields were evaluated in water and heterogeneous slab phantoms. Representative clinical IMRT and SBRT cases were planned and verified with ion chamber, film, and ArcCHECK@ measurements. The agreement between TPS and measurements for various clinical plans was evaluated using Gamma analysis with a criterion of 3%/2 mm for ArcCHECK@ and film. End-to-end (E2E) testing was performed using anthropomorphic head and lung phantoms. RESULTS: The average difference between the TPS-reported and known HU values was -1.4 ± 6.0 HU. For static fields, the agreements between the TPS-calculated and measured PDD10 , crossline profiles, and inline profiles (FWHM) were within 1.5%, 1.3%, and 0.5 mm, respectively. Measured output factors agreed with the TPS within 1.3%. Measured and calculated dose for static fields in heterogeneous phantoms agreed within 2.5%. The ArcCHECK@ mean absolute Gamma passing rate was 96.4% ± 3.4% for TG 119 and TG 244 plans and 97.8% ± 3.6% for the 21 clinical plans. E2E film analysis showed 0.8 mm total targeting error for isocentric and 1.1 mm for off-axis treatments. CONCLUSIONS: The TPS commissioning results of the RefleXion X1 TPS were within the tolerances specified by AAPM TG 53, MPPG 5.a, TG 119, and TG 148. A subset of the commissioning tests has been identified as baseline data for an ongoing QA program.

Sexually dimorphic RNA helicases DDX3X and DDX3Y differentially regulate RNA metabolism through phase separation.

Sex differences are pervasive in human health and disease. One major key to sex-biased differences lies in the sex chromosomes. Although the functions of the X chromosome proteins are well appreciated, how they compare with their Y chromosome homologs remains elusive. Herein, using ensemble and single-molecule techniques, we report that the sex chromosome-encoded RNA helicases DDX3X and DDX3Y are distinct in their propensities for liquid-liquid phase separation (LLPS), dissolution, and translation repression. We demonstrate that the N-terminal intrinsically disordered region of DDX3Y more strongly promotes LLPS than the corresponding region of DDX3X and that the weaker ATPase activity of DDX3Y, compared with DDX3X, contributes to the slower disassembly dynamics of DDX3Y-positive condensates. Interestingly, DDX3Y-dependent LLPS represses mRNA translation and enhances aggregation of FUS more strongly than DDX3X-dependent LLPS. Our study provides a platform for future comparisons of sex chromosome-encoded protein homologs, providing insights into sex differences in RNA metabolism and human disease.

Sleep, Positive Affect, and Circulating Interleukin-6 in Women With Temporomandibular Joint Disorder.

OBJECTIVE: Systemic inflammation is commonly observed in idiopathic chronic pain conditions, including temporomandibular joint disorder (TMD). Trait positive affect (PA) is associated with lower inflammation in healthy controls, but those effects may be threatened by poor sleep. The associations between PA with proinflammatory cytokine activity and potential moderation by sleep in chronic pain are not known. We thus investigated the association between PA and circulating interleukin-6 (IL-6) and moderation of that association by sleep in a sample of women with TMD and sleep difficulties. METHODS: Participants (n = 110) completed the insomnia severity index and provided blood samples at five intervals throughout an evoked pain testing session. They then completed a 14-day diary assessing sleep and affect, along with wrist actigraphy. RESULTS: There was not a significant main effect of PA on resting or pain-evoked IL-6 (b = 0.04, p = .33). Diary total sleep time (b = -0.002, p = .008), sleep efficiency (b = -0.01, p = .005), sleep onset latency (b = 0.006, p = .010), and wake after sleep onset (b = 0.003, p = .033) interacted with PA to predict IL-6, such that PA inversely predicted IL-6 at higher levels of total sleep time and sleep efficiency and at lower levels of sleep onset latency and wake after sleep onset. Surprisingly, when sleep was poor, PA predicted greater IL-6. CONCLUSIONS: The potential salutary effects of PA on resting IL-6 erode when sleep is poor, underscoring the importance of considering sleep in conceptual and intervention models of TMD.

Locus Coeruleus Noradrenergic Modulation of Diurnal Corticosterone, Stress Reactivity, and Cardiovascular Homeostasis in Male Rats.

INTRODUCTION: Activation of the locus coeruleus-noradrenergic (LC-NA) system during awakening is associated with an increase in plasma corticosterone and cardiovascular tone. These studies evaluate the role of the LC in this corticosterone and cardiovascular response. METHODS: Male rats, on day 0, were treated intraperitoneally with either DSP4 (50 mg/kg body weight) (DSP), an LC-NA specific neurotoxin, or normal saline (SAL). On day 10, animals were surgically prepared with jugular vein (hypothalamic-pituitary-adrenal [HPA] axis) or carotid artery (hemodynamics) catheters and experiments performed on day 14. HPA axis activity, diurnally (circadian) and after stress (transient hemorrhage [14 mL/kg body weight] or air puff-startle), and basal and post-hemorrhage hemodynamics were evaluated. On day 16, brain regions from a subset of rats were dissected for norepinephrine and corticotropin-releasing factor (CRF) assay. RESULTS: In DSP rats compared to SAL rats, (1) regional brain norepinephrine was decreased, but there was no change in median eminence or olfactory bulb CRF content; (2) during HPA axis acrophase, the plasma corticosterone response was blunted; (3) after hemorrhage and air puff-startle, the plasma adrenocorticotropic hormone response was attenuated, whereas the corticosterone response was dependent on stressor category; (4) under basal conditions, hemodynamic measures exhibited altered blood flow dynamics and systemic vasodilation; and (5) after hemorrhage, hemodynamics exhibited asynchronous responses. CONCLUSION: LC-NA modulation of diurnal and stress-induced HPA axis reactivity occurs via distinct neurocircuits. The integrity of the LC-NA system is important to maintain blood flow dynamics. The importance of increases in plasma corticosterone at acrophase to maintain short- and long-term cardiovascular homeostasis is discussed.

Pain Expectancy and Positive Affect Mediate the day-to-day Association Between Objectively Measured Sleep and Pain Severity Among Women With Temporomandibular Disorder.

The majority of individuals with temporomandibular disorders (TMD) experience sleep disturbance, which can maintain and exacerbate chronic pain. However, the factors underlying the sleep-pain link have not been fully elucidated, especially beyond the laboratory. Sleep deprivation can induce threat interpretation bias, as well as impairment in positive affective functioning. Using both actigraphy and daily diaries, we examined whether morning pain expectancy and positive affect mediate the association between previous night's sleep disturbance and next-day overall pain severity. Total sleep time (TST) was selected as the primary measure of sleep. The sample included 144 women (mean age = 36 [SD = 11.1]) with TMD who displayed at least subclinical insomnia. Sleep was assessed for 14 days using actigraphy which was validated by concurrent sleep diaries. Daily diary assessments of pain-related experiences and affective states were conducted twice per day (ie, once upon participants' waking and the other prior to going to sleep) for the same 14-day period. Multilevel structural equation modeling revealed that both morning pain expectancy (95% CI: -.0004, -.00003) and positive affect (95% CI: -.0005, -.000001) mediated the association between previous night's TST and next-day's overall pain severity, such that shorter previous night TST was associated with higher next-morning pain expectancy and lower positive affect, which in turn were associated with a greater level of next-day's overall pain severity while controlling for morning pain severity. Reducing exaggerated daily pain expectancy and up-regulating positive affect may be important intervention targets for disengaging the sleep-pain link among individuals with co-occurring TMD and sleep disturbance. PERSPECTIVE: The daily link between previous night sleep duration and next day pain severity is mediated by morning pain expectancy and positive affect among women with temporomandibular disorder and sleep disturbance. Reducing pain expectancy and increasing positive affect may serve an important role in improving self-management of chronic pain.

Recent technical advances in the study of nucleic acid modifications.

Enzyme-mediated chemical modifications of nucleic acids are indispensable regulators of gene expression. Our understanding of the biochemistry and biological significance of these modifications has largely been driven by an ever-evolving landscape of technologies that enable accurate detection, mapping, and manipulation of these marks. Here we provide a summary of recent technical advances in the study of nucleic acid modifications with a focus on techniques that allow accurate detection and mapping of these modifications. For each modification discussed (N6-methyladenosine, 5-methylcytidine, inosine, pseudouridine, and N4-acetylcytidine), we begin by introducing the "gold standard" technique for its mapping and detection, followed by a discussion of techniques developed to address any shortcomings of the gold standard. By highlighting the commonalities and differences of these techniques, we hope to provide a perspective on the current state of the field and to lay out a guideline for development of future technologies.