Mapping the Design Space of Technology-Based Solutions for Better Chronic Pain Care: Introducing the Pain Tech Landscape.

OBJECTIVES: Technology has substantial potential to transform and extend care for persons with chronic pain, a burdensome and costly condition. To catalyze the development of impactful applications of technology in this space, we developed the Pain Tech Landscape (PTL) model, which integrates pain care needs with characteristics of technological solutions. METHODS: Our interdisciplinary group representing experts in pain and human factors research developed PTL through iterative discussions. To demonstrate one potential use of the model, we apply data generated from a narrative review of selected pain and technology journals (2000-2020) in the form of heat map overlays, to reveal where pain tech research attention has focused to date. RESULTS: The PTL comprises three two-dimensional planes, with pain care needs on each x axis (measurement to management) and technology applications on the y axes according to a) user agency (user- to system-driven), b) usage time frame (temporary to lifelong), and c) collaboration (single-user to collaborative). Heat maps show that existing applications reside primarily in the "user-driven/management" quadrant (e.g., self-care apps). Examples of less developed areas include artificial intelligence and Internet of Things (i.e., Internet-linked household objects), and collaborative/social tools for pain management. CONCLUSIONS: Collaborative development between the pain and tech fields in early developmental stages using the PTL as a common language could yield impactful solutions for chronic pain management. The PTL could also be used to track developments in the field over time. We encourage periodic reassessment and refinement of the PTL model, which can also be adapted to other chronic conditions.

Graded chronic pain scale revised: validation in a Veteran sample.

OBJECTIVE: The Graded Chronic Pain Scale (GCPS) is frequently used in pain research and treatment to classify mild, bothersome, and high impact chronic pain. This study's objective was to validate the revised version of the GCPS (GCPS-R) in a US Veterans Affairs (VA) healthcare sample to support its use in this high-risk population. METHODS: Data were collected from Veterans (n = 794) via self-report (GCPS-R and relevant health questionnaires) and electronic health record extraction (demographics and opioid prescriptions). Logistic regression, adjusting for age and gender, was used to test for differences in health indicators by pain grade. Adjusted odds ratio (AOR) with 95% confidence intervals (CIs) were reported with CIs not including an AOR of 1 indicating that the difference exceeded chance. RESULTS: In this population, the prevalence of chronic pain (pain present most or every day, prior 3 months) was 49.3%: 7.1% with mild chronic pain (mild pain intensity and lower interference with activities); 23.3% bothersome chronic pain (moderate to severe pain intensity with lower interference); and 21.1% high impact chronic pain (higher interference). Results of this study mirrored findings in the non-VA validation study; differences between bothersome and high impact were consistent for activity limitations and present but not fully consistent for psychological variables. Those with bothersome chronic pain or high impact chronic pain were more likely to receive long-term opioid therapy compared to those with no/mild chronic pain. CONCLUSIONS: Findings highlight categorical differences captured with the GCPS-R, and convergent validity supports use of the GCPS-R in US Veterans.

Role of the Water-Metal Ion Bridge in Quinolone Interactions with Escherichia coli Gyrase.

Fluoroquinolones are an important class of antibacterials, and rising levels of resistance threaten their clinical efficacy. Gaining a more full understanding of their mechanism of action against their target enzymes-the bacterial type II topoisomerases gyrase and topoisomerase IV-may allow us to rationally design quinolone-based drugs that overcome resistance. As a step toward this goal, we investigated whether the water-metal ion bridge that has been found to mediate the major point of interaction between Escherichia coli topoisomerase IV and Bacillus anthracis topoisomerase IV and gyrase, as well as Mycobacterium tuberculosis gyrase, exists in E. coli gyrase. This is the first investigation of the water-metal ion bridge and its function in a Gram-negative gyrase. Evidence suggests that the water-metal ion bridge does exist in quinolone interactions with this enzyme and, unlike the Gram-positive B. anthracis gyrase, does use both conserved residues (serine and acidic) as bridge anchors. Furthermore, this interaction appears to play a positioning role. These findings raise the possibility that the water-metal ion bridge is a universal point of interaction between quinolones and type II topoisomerases and that it functions primarily as a binding contact in Gram-positive species and primarily as a positioning interaction in Gram-negative species. Future studies will explore this possibility.

Taking ACTION to Reduce Pain: a Randomized Clinical Trial of a Walking-Focused, Proactive Coaching Intervention for Black Patients with Chronic Musculoskeletal Pain.

BACKGROUND: Black patients in the USA are disproportionately affected by chronic pain, yet there are few interventions that address these disparities. OBJECTIVE: To determine whether a walking-focused, proactive coaching intervention aimed at addressing contributors to racial disparities in pain would improve chronic pain outcomes among Black patients compared to usual care. DESIGN: Randomized controlled trial with masked outcome assessment ( Clinicaltrials.gov : NCT01983228). PARTICIPANTS: Three hundred eighty Black patients at the Atlanta VA Health Care System with moderate to severe chronic back, hip, or knee pain. INTERVENTION: Six telephone coaching sessions over 8-14 weeks, proactively delivered, using action planning and motivational interviewing to increase walking, or usual care. MAIN MEASURES: Primary outcome was a 30% improvement in pain-related physical functioning (Roland Morris Disability Questionnaire [RMDQ]) over 6 months among Black patients, using intention-to-treat. Secondary outcomes were improvements in pain intensity and interference, depression, anxiety, global impression of change in pain, and average daily steps. KEY RESULTS: The intervention did not produce statistically significant effects on the primary outcome (at 6 months, 32.4% of intervention participants had 30% improvement on the RMDQ vs. 24.7% of patients in usual care; aOR=1.61, 95% CI, 0.94 to 2.77), nor on other secondary outcomes assessed at 6 months, with the exception that intervention participants reported more favorable changes in pain relative to usual care (mean difference=-0.54, 95% CI, -0.85 to -0.23). Intervention participants also experienced a significant reduction in pain intensity and pain interference over 3 months (mean difference=-0.55, 95% CI, -0.88 to -0.22). CONCLUSIONS: A novel intervention to improve chronic pain among Black patients did not produce statistically significant improvements on the primary outcome relative to usual care. More intensive efforts are likely required among this population, many of whom were economically disadvantaged and had mental health comorbidities and physical limitations. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01983228.

Longitudinal analysis of the prevalence and correlates of heavy episodic drinking and self-reported opioid use among a national cohort of patients with HIV.

BACKGROUND: Heavy episodic drinking (HED) is a risk factor for opioid-related overdose and negatively impacts HIV disease progression. Among a national cohort of patients with HIV (PWH), we examined sociodemographic and clinical correlates of concomitant HED and self-reported opioid use. METHODS: We used data collected from 2002 through 2018 from the Veterans Aging Cohort Study, a prospective cohort including PWH in care at eight US Veterans Health Administration sites. HED was defined as consuming six or more drinks at least once in the year prior to survey collection. We examined the relationship between HED and self-reported opioid use and created a 4-level composite variable of HED and opioid use. We used multinomial logistic regression to estimate odds of reporting concomitant HED and self-reported opioid use. RESULTS: Among 3702 PWH, 1458 (39.4%) reported HED during the study period and 350 (9.5%) reported opioid use. In the multinomial model, compared to reporting neither HED nor opioid use, lifetime housing instability (adjusted odds ratio [aOR] 1.54, 95% confidence interval [CI] 1.01 to 2.35), Veterans Aging Cohort Study Index 2.0 (a measure of disease severity; aOR 1.14, 95% CI 1.02 to 1.28), depressive symptoms (aOR 2.27, 95% CI 1.42 to 3.62), past-year cigarette smoking (aOR 3.06, 95% CI 1.53 to 6.14), cannabis use (aOR 1.69, 95% CI 1.09 to 2.62), and cocaine/stimulant use (aOR 11.54, 95% CI 7.40 to 17.99) were independently associated with greater odds of concomitant HED and self-reported opioid use. Compared to having attended no college, having some college or more (aOR 0.39, 95% CI 0.26 to 0.59) was associated with lower odds of concomitant HED and self-reported opioid use. CONCLUSIONS: Among PWH, concomitant HED and self-reported opioid use are more common among individuals with depressive symptoms and substance use, structural vulnerabilities, and greater illness severity. Efforts to minimize opioid-related risk should address high-risk drinking as a modifiable risk factor for harm among these groups.

TIDieR-telehealth: precision in reporting of telehealth interventions used in clinical trials - unique considerations for the Template for the Intervention Description and Replication (TIDieR) checklist.

BACKGROUND: Recent international health events have led to an increased proliferation of remotely delivered health interventions. Even with the pandemic seemingly coming under control, the experiences of the past year have fueled a growth in ideas and technology for increasing the scope of remote care delivery. Unfortunately, clinicians and health systems will have difficulty with the adoption and implementation of these interventions if ongoing and future clinical trials fail to report necessary details about execution, platforms, and infrastructure related to these interventions. The purpose was to develop guidance for reporting of telehealth interventions. METHODS: A working group from the US Pain Management Collaboratory developed guidance for complete reporting of telehealth interventions. The process went through 5-step process from conception to final checklist development with input for many stakeholders, to include all 11 primary investigators with trials in the Collaboratory. RESULTS: An extension focused on unique considerations relevant to telehealth interventions was developed for the Template for the Intervention Description and Replication (TIDieR) checklist. CONCLUSION: The Telehealth Intervention guideline encourages use of the Template for the Intervention Description and Replication (TIDieR) checklist as a valuable tool (TIDieR-Telehealth) to improve the quality of research through a reporting guide of relevant interventions that will help maximize reproducibility and implementation.

Sociodemographic and clinical correlates of gabapentin receipt with and without opioids among a national cohort of patients with HIV.

Gabapentin is commonly prescribed for chronic pain, including to patients with HIV (PWH). There is growing concern regarding gabapentin's potential for harm, particularly in combination with opioids. Among PWH, we examined factors associated with higher doses of gabapentin receipt and determined if receipt varied by opioid use. We examined data from the Veterans Aging Cohort Study, a national prospective cohort including PWH, from 2002 through 2017. Covariates included prescribed opioid dose, self-reported past year opioid use, and other sociodemographic and clinical variables. We used multinomial logistic regression to determine independent predictors of gabapentin receipt. Among 3,702 PWH, 902 (24%) received any gabapentin during the study period at a mean daily dose of 1,469 mg. In the multinomial model, high-dose gabapentin receipt was associated with high-dose benzodiazepine receipt (adjusted odds ratio [aOR], 95% confidence interval [CI]= 1.53, [1.03-2.27]), pain interference (1.65 [1.39-1.95]), and hand or foot pain (1.81, [1.45-2.26]). High-dose gabapentin receipt was associated with prescribed high-dose opioids receipt (2.66 [1.95-3.62]) but not self-reported opioid use (1.03 [0.89-1.21]). PWH prescribed gabapentin at higher doses are more likely to receive high-dose opioids and high-dose benzodiazepines, raising safety concerns.

Risk Factors Associated with Healthcare Utilization for Spine Pain.

OBJECTIVE: This study examined potential risk factors associated with healthcare utilization among patients with spine (i.e., neck and back) pain. METHODS: A two-stage sampling approach examined spine pain episodes of care among veterans with a yearly outpatient visit for six consecutive years. Descriptive and bivariate statistics, followed by logistic regression analyses, examined baseline characteristics of veterans with new episodes of care who either continued or discontinued spine pain care. A multivariable logistic regression model examined correlates associated with seeking continued spine pain care. RESULTS: Among 331,908 veterans without spine pain episodes of care during the 2-year baseline observation period, 16.5% (n = 54,852) had a new episode of care during the following 2-year observation period. Of those 54,852 veterans, 37,025 had an outpatient visit data during the final 2-year follow-up period, with 53.7% (n = 19,865) evidencing continued spine pain care. Those with continued care were more likely to be overweight or obese, non-smokers, Army veterans, have higher education, and had higher rates of diagnoses of all medical and mental health conditions examined at baseline. Among several important findings, women had 13% lower odds of continued care during the final 2-year observation period, OR 0.87 (0.81, 0.95). CONCLUSIONS: A number of important demographics and clinical correlates were associated with increased likelihood of seeking new and continued episodes of care for spine pain; however, further examination of risk factors associated with healthcare utilization for spine pain is indicated.

Long-term Patterns of Self-reported Opioid Use, VACS Index, and Mortality Among People with HIV Engaged in Care.

Longitudinal analyses of opioid use and overall disease severity among people with HIV (PWH) are lacking. We used joint-trajectory and Cox proportional hazard modeling to examine the relationship between self-reported opioid use and the Veterans Aging Cohort Study (VACS) Index 2.0, a validated measure of disease severity and mortality, among PWH engaged in care. Using data from 2002 and 2018, trajectory modeling classified 20% of 3658 PWH in low (i.e., lower risk of mortality), 40% in moderate, 28% in high, and 12% in extremely high VACS Index trajectories. Compared to those with moderate VACS Index trajectory, PWH with an extremely high trajectory were more likely to have high, then de-escalating opioid use (adjusted odds ratio [AOR], 95% confidence interval [CI] 5·17 [3·19-8·37]) versus stable, infrequent use. PWH who report high frequency opioid use have increased disease severity and mortality risk over time, even when frequency of opioid use de-escalates.

Incorporating walking into cognitive behavioral therapy for chronic pain: safety and effectiveness of a personalized walking intervention.

We examined the effectiveness and safety of a walking program offered as part of cognitive behavioral therapy for chronic pain (CBT-CP). Participants were randomized to 10 weeks of CBT-CP, delivered either in person or by interactive voice response. Participants reported pedometer-measured step counts daily throughout treatment and received a weekly goal to increase their steps by 10% over the prior week's average. Walking-related adverse events (AEs) were assessed weekly. Participants (n = 125) were primarily male (72%), and white (80%) with longstanding pain (median: 11 years). There was no significant difference between treatment groups in rate of change in daily steps, but there was a significant increase in steps from baseline to treatment termination in the combined study sample (1648 steps (95% CI 1063-2225)). Participants classified as active doubled. AEs were mostly minor and temporary. Treatment was effective and safe whether the program was delivered in-person or remotely.Trial registration number: clinicaltrials.gov identifier: NCT01025752.

Correlates of Manual Therapy and Acupuncture Use Among Rural Patients Seeking Conventional Pain Management: A Cross-sectional Study.

OBJECTIVE: In this cross-sectional study, we examined correlates of manual therapy (spinal manipulation, massage therapy) and/or acupuncture use in a population engaging in conventional pain care in West Virginia. METHODS: Participants were patients (aged 18+ years) from 4 Appalachian pain and rheumatology clinics. Of those eligible (N = 343), 88% completed an anonymous survey including questions regarding health history, pain distress (Short Form Global Pain Scale), prescription medications, and current use of complementary health approaches for pain management. We used age-adjusted logistic regression to assess the relation of sociodemographic, lifestyle, and health-related factors to use of manual therapies and/or acupuncture for pain (complete-case N = 253). RESULTS: The majority of participants were white (92%), female (56%), and middle aged (mean age, 54.8 ± 13.4 years). Nearly all reported current chronic pain (94%), and 56% reported ≥5 comorbidities (mean, 5.6 ± 3.1). Manual therapy and/or acupuncture was used by 26% of participants for pain management (n = 66). Current or prior opioid use was reported by 37% of those using manual therapies. Manual therapy and/or acupuncture use was significantly elevated in those using other complementary health approaches (adjusted odds ratio, 3.0; 95% confidence interval, 1.5-5.8). Overall Short Form Global Pain Scale scores were not significantly associated with use of manual therapies and/or acupuncture after adjustment (adjusted odds ratio per 1-point increase, 1.01; 95% confidence interval, 1.00-1.03). CONCLUSION: We found no evidence for an association of pain-related distress and use of manual therapies and/or acupuncture, but identified a strong association with use of dietary supplements and mind-body therapies. Larger studies are needed to further examine these connections in the context of clinical outcomes and cost-effectiveness in rural adults given their high pain burden and unique challenges in access to care.

Identification of an ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate as a catalytic inhibitor of DNA gyrase.

Fluoroquinolones are a class of antibacterial agents used clinically to treat a wide array of bacterial infections and target bacterial type-II topoisomerases (DNA gyrase and topoisomerase IV). Fluoroquinolones, however potent, are susceptible to bacterial resistance with prolonged use, which limits their use in the clinic. Quinazoline-2,4-diones also target bacterial type-II topoisomerases and are not susceptible to bacterial resistance similar to fluoroquinolones, however, their potency pales in comparison to fluoroquinolones. To meet the increasing demand for antibacterial development, nine modified quinazoline-2,4-diones were developed to probe quinazoline-2,4-dione structure modification for possible new binding contacts with the bacterial type-II topoisomerase, DNA gyrase. Evaluation of compounds for inhibition of the supercoiling activity of DNA gyrase revealed a novel ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate derivative as a modest inhibitor of DNA gyrase, having an IC50 of 3.5 µM. However, this ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate does not trap the catalytic intermediate like fluoroquinolones or typical quinazoline-2,4-diones do. Thus, the ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate derivative discovered in this work acts as a catalytic inhibitor of DNA gyrase and therefore represents a new structural type of catalytic inhibitor of DNA gyrase.

Designing Trials with Purpose: Pragmatic Clinical Trials of Nonpharmacological Approaches for Pain Management.

OBJECTIVE: Pain is one of the most significant causes of morbidity and disability worldwide. The efficacy of several nonpharmacological approaches for pain management has been established, but significant gaps exist between this evidence and their limited availability and use in routine clinical practice. Questions remain about their effectiveness and how best to integrate them in usual care to optimize patient-centered outcomes. Pragmatic clinical trials (PCTs) may help address this gap. Informed by the Pragmatic Explanatory Continuum Indicator Summary (PRECIS-2), we sought to describe the key features of optimized PCTs of nonpharmacological approaches for the management of pain and common co-occurring conditions. METHODS: To accomplish this objective, we searched the published literature on PCTs of nonpharmacological pain management approaches from 2010-2019 and applied the PRECIS-2 criteria. We discuss key PRECIS-2 domains of interest for designing and performing PCTs and cite specific examples from the published literature as potential models for future PCTs. RESULTS: We found 13 nonpharmacological PCTs. They were heterogeneous in size, recruitment, follow-up time, and location. The lessons learned from these studies led us to explicate key features of trials on the explanatory-pragmatic continuum across the PRECIS-2 domains that can be used by future investigators when designing their clinical trials of nonpharmacological approaches to pain management. CONCLUSIONS: We encourage the increased application of PCTs to produce timely and valuable results and products that will inform the development of safe and effective integrated pain care plans that optimize important patient-centered outcomes.

Identifying Multisite Chronic Pain with Electronic Health Records Data.

BACKGROUND: Multisite chronic pain (MSCP) is associated with increased chronic pain impact, but methods for identifying MSCP for epidemiological research have not been evaluated. OBJECTIVE: We assessed the validity of identifying MSCP using electronic health care data compared with survey questionnaires. METHODS: Stratified random samples of adults served by Kaiser Permanente Northwest and Washington (N = 2,059) were drawn for a survey, oversampling persons with frequent use of health care for pain. MSCP and single-site chronic pain were identified by two methods, with electronic health care data and with self-report of common chronic pain conditions by survey questionnaire. Analyses were weighted to adjust for stratified sampling. RESULTS: MSCP was somewhat less common when ascertained by electronic health records (14.7% weighted prevalence) than by survey questionnaire (25.9% weighted prevalence). Agreement of the two MSCP classifications was low (kappa agreement statistic of 0.21). Ascertainment of MSCP with electronic health records was 30.9% sensitive, 91.0% specific, and had a positive predictive value of 54.5% relative to MSCP identified by self-report as the standard. After adjusting for age and gender, patients with MSCP identified by either electronic health records or self-report showed higher levels of pain-related disability, pain severity, depressive symptoms, and long-term opioid use than persons with single-site chronic pain identified by the same method. CONCLUSIONS: Identification of MSCP with electronic health care data was insufficiently accurate to be used as a surrogate or screener for MSCP identified by self-report, but both methods identified persons with heightened chronic pain impact.

"Asking Is Never Bad, I Would Venture on That": Patients' Perspectives on Routine Pain Screening in VA Primary Care.

OBJECTIVE: Screening for pain in routine care is one of the efforts that the Veterans Health Administration has adopted in its national pain management strategy. We aimed to understand patients' perspectives and preferences about the experience of being screened for pain in primary care. DESIGN: Semistructured interviews captured patient perceptions and preferences of pain screening, assessment, and management. SUBJECTS: We completed interviews with 36 patients: 29 males and seven females ranging in age from 28 to 94 years from three geographically distinct VA health care systems. METHODS: We evaluated transcripts using constant comparison and identified emergent themes. RESULTS: Theme 1: Pain screening can "determine the tone of the examination"; Theme 2: Screening can initiate communication about pain; Theme 3: Screening can facilitate patient recall and reflection; Theme 4: Screening for pain may help identify under-reported psychological pain, mental distress, and suicidality; Theme 5: Patient recommendations about how to improve screening for pain. CONCLUSION: Our results indicate that patients perceive meaningful, positive impacts of routine pain screening that as yet have not been considered in the literature. Specifically, screening for pain may help capture mental health concerns that may otherwise not emerge.

The Relationship Between Body Mass Index and Pain Intensity Among Veterans with Musculoskeletal Disorders: Findings from the MSD Cohort Study.

OBJECTIVE: To examine the relationship between body mass index (BMI) and pain intensity among veterans with musculoskeletal disorder diagnoses (MSDs; nontraumatic joint disorder; osteoarthritis; low back, back, and neck pain). SETTING: Administrative and electronic health record data from the Veterans Health Administration (VHA). SUBJECTS: A national cohort of US military veterans with MSDs in VHA care during 2001-2012 (N = 1,759,338). METHODS: These cross-sectional data were analyzed using hurdle negative binomial models of pain intensity as a function of BMI, adjusted for comorbidities and demographics. RESULTS: The sample had a mean age of 59.4, 95% were male, 77% were white/Non-Hispanic, 79% were overweight or obese, and 42% reported no pain at index MSD diagnosis. Overall, there was a J-shaped relationship between BMI and pain (nadir = 27 kg/m2), with the severely obese (BMI ≥ 40 kg/m2) being most likely to report any pain (OR vs normal weight = 1.23, 95% confidence interval = 1.21-1.26). The association between BMI and pain varied by MSD, with a stronger relationship in the osteoarthritis group and a less pronounced relationship in the back and low back pain groups. CONCLUSIONS: There was a high prevalence of overweight/obesity among veterans with MSD. High levels of BMI (>27 kg/m2) were associated with increased odds of pain, most markedly among veterans with osteoarthritis.

Stakeholder Engagement in Pragmatic Clinical Trials: Emphasizing Relationships to Improve Pain Management Delivery and Outcomes.

BACKGROUND: The NIH-DOD-VA Pain Management Collaboratory (PMC) supports 11 pragmatic clinical trials (PCTs) on nonpharmacological approaches to management of pain and co-occurring conditions in U.S. military and veteran health organizations. The Stakeholder Engagement Work Group is supported by a separately funded Coordinating Center and was formed with the goal of developing respectful and productive partnerships that will maximize the ability to generate trustworthy, internally valid findings directly relevant to veterans and military service members with pain, front-line primary care clinicians and health care teams, and health system leaders. The Stakeholder Engagement Work Group provides a forum to promote success of the PCTs in which principal investigators and/or their designees discuss various stakeholder engagement strategies, address challenges, and share experiences. Herein, we communicate features of meaningful stakeholder engagement in the design and implementation of pain management pragmatic trials, across the PMC. DESIGN: Our collective experiences suggest that an optimal stakeholder-engaged research project involves understanding the following: i) Who are research stakeholders in PMC trials? ii) How do investigators ensure that stakeholders represent the interests of a study's target treatment population, including individuals from underrepresented groups?, and iii) How can sustained stakeholder relationships help overcome implementation challenges over the course of a PCT? SUMMARY: Our experiences outline the role of stakeholders in pain research and may inform future pragmatic trial researchers regarding methods to engage stakeholders effectively.

Internet-Based Pain Self-Management for Veterans: Feasibility and Preliminary Efficacy of the Pain EASE Program.

OBJECTIVE: To develop and test the feasibility and preliminary efficacy of a cognitive behavioral therapy-based, internet-delivered self-management program for chronic low back pain (cLBP) in veterans. METHODS: Phase I included program development, involving expert panel and participant feedback. Phase II was a single-arm feasibility and preliminary efficacy study of the Pain e-health for Activity, Skills, and Education (Pain EASE) program. Feasibility (ie, website use, treatment credibility, satisfaction) was measured using descriptive methods. Mixed models were used to assess mean within-subject changes from baseline to 10 weeks post-baseline in pain interference (primary outcome, West Haven-Yale Multidimensional Pain Inventory, scale of 0 to 6), pain intensity, mood, fatigue, sleep, and depression. RESULTS: Phase I participants (n = 15) suggested modifications including style changes, content reduction, additional "Test Your Knowledge" quizzes, and cognitive behavioral therapy skill practice monitoring form revisions for enhanced usability. In Phase II, participants (n = 58) were mostly male (93%) and White (60%), and had an average age of 55 years (standard deviation [SD] = 12) and moderate pain (mean score 5.9/10); 41 (71%) completed the post-baseline assessment. Participants (N = 58) logged on 6.1 (SD = 8.6) times over 10 weeks, and 85% reported being very or moderately satisfied with Pain EASE. Pain interference improved from a mean of 3.8 at baseline to 3.3 at 10 weeks (difference 0.5 [95% confidence interval 0.1 to 0.9], P = 0.008). Within-subject improvement also occurred for some secondary outcomes, including mood and depression symptoms. DISCUSSION: Veterans with cLBP may benefit from technology-delivered interventions, which may also reduce pain interference. Overall, veterans found that Pain EASE, an internet-based self-management program, is feasible and satisfactory for cLBP.

Novel N-1 substituted fluoroquinolones inhibit human topoisomerase I activity and exhibit anti-proliferative activity.

Fluoroquinolone-class agents selectively target the bacterial type IIA topoisomerases DNA gyrase and topoisomerase IV, with a few exceptions that target eukaryotic type IIA topoisomerases. Fluoroquinolones bind and stabilize type IIA topoisomerase-DNA covalent complexes that contain a double-strand break. This unique mode of action is referred to as 'topoisomerase poisoning'. We discovered that two novel fluoroquinolones having aryl functionality at the N-1 position, UITT-3-217 (217) and UITT-3-227 (227), could inhibit the catalytic activity of human topoisomerase II without stabilizing topoisomerase-DNA complexes, i.e., without poisoning it. Surprisingly, these compounds are more effective in inhibiting the catalytic activities of human and bacterial topoisomerase I. The National Cancer Institute's 60 human tumor cell lines screen revealed significant anti-proliferative activities with 217 and 227 against the majority of 60 cancer cell lines. A proof of concept in vivo efficacy study using an HT-29 xenograft model of human colorectal cancer showed that 217 could inhibit the proliferation of human colorectal cancer cells to a degree comparable to fluorouracil in mice. Although 227 also exhibited anti-proliferative activity, it was not as effective as 217 in this xenograft model. These novel fluoroquinolones may serve as promising lead compounds for the development of new anticancer drugs.

Evaluation of Complementary and Integrative Health Approaches Among US Veterans with Musculoskeletal Pain Using Propensity Score Methods.

Objectives: To examine the treatment effectiveness of complementary and integrative health approaches (CIH) on chronic pain using Propensity Score (PS) methods. Design, Settings, and Participants: A retrospective cohort of 309,277 veterans with chronic musculoskeletal pain assessed over three years after initial diagnosis. Methods: CIH exposure was defined as one or more clinical visits for massage, acupuncture, or chiropractic care. The treatment effect of CIH on self-rated pain intensity was examined using a longitudinal model. PS-matching and inverse probability of treatment weighting (IPTW) were used to account for potential selection and confounding biases. Results: At baseline, veterans with (7,621) and without (301,656) CIH exposure differed significantly in 21 out of 35 covariates. During the follow-up period, on average CIH recipients had 0.83 (95% confidence interval [CI] = 0.77 to 0.89) points higher pain intensity ratings (range = 0-10) than nonrecipients. This apparent unfavorable effect size was reduced to 0.37 (95% CI = 0.28 to 0.45) after PS matching, 0.36 (95% CI = 0.29 to 0.44) with IPTW on the treated (IPTW-T) weighting, and diminished to null when integrating IPTW-T with PS matching (0.004, 95% CI = -0.09 to 0.10). An alternative IPTW model and conventional covariate adjustment appeared least powerful in terms of potential bias reduction. Sensitivity analyses restricting the follow-up period to one year after CIH initiation derived consistent results. Conclusions: PS-based causal methods successfully eliminated baseline difference between exposure groups in all measured covariates, yet they did not detect a significant difference in the self-rated pain intensity outcome between veterans who received CIHs and those who did not during the follow-up period.