Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels.

Eukaryotic cells contain assemblies of RNAs and proteins termed RNA granules. Many proteins within these bodies contain KH or RRM RNA-binding domains as well as low complexity (LC) sequences of unknown function. We discovered that exposure of cell or tissue lysates to a biotinylated isoxazole (b-isox) chemical precipitated hundreds of RNA-binding proteins with significant overlap to the constituents of RNA granules. The LC sequences within these proteins are both necessary and sufficient for b-isox-mediated aggregation, and these domains can undergo a concentration-dependent phase transition to a hydrogel-like state in the absence of the chemical. X-ray diffraction and EM studies revealed the hydrogels to be composed of uniformly polymerized amyloid-like fibers. Unlike pathogenic fibers, the LC sequence-based polymers described here are dynamic and accommodate heterotypic polymerization. These observations offer a framework for understanding the function of LC sequences as well as an organizing principle for cellular structures that are not membrane bound.

Intracellular Ion Control of WNK Signaling.

The with no lysine (K) (WNK) kinases are an evolutionarily ancient group of kinases with atypical placement of the catalytic lysine and diverse physiological roles. Recent studies have shown that WNKs are directly regulated by chloride, potassium, and osmotic pressure. Here, we review the discovery of WNKs as chloride-sensitive kinases and discuss physiological contexts in which chloride regulation of WNKs has been demonstrated. These include the kidney, pancreatic duct, neurons, and inflammatory cells. We discuss the interdependent relationship of osmotic pressure and intracellular chloride in cell volume regulation. We review the recent demonstration of potassium regulation of WNKs and speculate on possible physiological roles. Finally, structural and mechanistic aspects of intracellular ion and osmotic pressure regulation of WNKs are discussed.

WNK1 collaborates with TGF-ß in endothelial cell junction turnover and angiogenesis.

Angiogenesis is essential for growth of new blood vessels, remodeling existing vessels, and repair of damaged vessels, and these require reorganization of endothelial cell-cell junctions through a partial endothelial-mesenchymal transition. Homozygous disruption of the gene encoding the protein kinase WNK1 results in lethality in mice near embryonic day (E) 12 due to impaired angiogenesis. This angiogenesis defect can be rescued by endothelial-specific expression of an activated form of the WNK1 substrate kinase OSR1. We show that inhibition of WNK1 kinase activity not only prevents sprouting of endothelial cells from aortic slices but also vessel extension in inhibitor-treated embryos ex vivo. Mutations affecting TGF-ß signaling also result in abnormal vascular development beginning by E10 and, ultimately, embryonic lethality. Previously, we demonstrated cross-talk of WNK1 with TGF-ß-regulated SMAD signaling, and OSR1 was identified as a component of the TGF-ß interactome. However, molecular events jointly regulated by TGF-ß and WNK1/OSR1 have not been delineated. Here, we show that inhibition of WNK1 promotes TGF-ß-dependent degradation of the tyrosine kinase receptor AXL, which is involved in TGF-ß-mediated cell migration and angiogenesis. We also show that interaction between OSR1 and occludin, a protein associated with endothelial tight junctions, is an essential step to enable tight junction turnover. Furthermore, we show that these phenomena are WNK1 dependent, and sensitive to TGF-ß. These findings demonstrate intimate connections between WNK1/OSR1 and multiple TGF-ß-sensitive molecules controlling angiogenesis and suggest that WNK1 may modulate many TGF-ß-regulated functions.

Nuclear speckle integrity and function require TAO2 kinase.

Nuclear speckles are non-membrane-bound organelles known as storage sites for messenger RNA (mRNA) processing and splicing factors. More recently, nuclear speckles have also been implicated in splicing and export of a subset of mRNAs, including the influenza virus M mRNA that encodes proteins required for viral entry, trafficking, and budding. However, little is known about how nuclear speckles are assembled or regulated. Here, we uncovered a role for the cellular protein kinase TAO2 as a constituent of nuclear speckles and as a factor required for the integrity of these nuclear bodies and for their functions in pre-mRNA splicing and trafficking. We found that a nuclear pool of TAO2 is localized at nuclear speckles and interacts with nuclear speckle factors involved in RNA splicing and nuclear export, including SRSF1 and Aly/Ref. Depletion of TAO2 or inhibition of its kinase activity disrupts nuclear speckle structure, decreasing the levels of several proteins involved in nuclear speckle assembly and splicing, including SC35 and SON. Consequently, splicing and nuclear export of influenza virus M mRNA were severely compromised and caused a disruption in the virus life cycle. In fact, low levels of TAO2 led to a decrease in viral protein levels and inhibited viral replication. Additionally, depletion or inhibition of TAO2 resulted in abnormal expression of a subset of mRNAs with key roles in viral replication and immunity. Together, these findings uncovered a function of TAO2 in nuclear speckle formation and function and revealed host requirements and vulnerabilities for influenza infection.

Sexual and gender minority content in undergraduate medical education in the United States and Canada: current state and changes since 2011.

PURPOSE: To characterize current lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI +) health-related undergraduate medical education (UME) curricular content and associated changes since a 2011 study and to determine the frequency and extent of institutional instruction in 17 LGBTQI + health-related topics, strategies for increasing LGBTQI + health-related content, and faculty development opportunities. METHOD: Deans of medical education (or equivalent) at 214 allopathic or osteopathic medical schools in Canada and the United States were invited to complete a 36-question, Web-based questionnaire between June 2021 and September 2022. The main outcome measured was reported hours of LGBTQI + health-related curricular content. RESULTS: Of 214 schools, 100 (46.7%) responded, of which 85 (85.0%) fully completed the questionnaire. Compared to 5 median hours dedicated to LGBTQI + health-related in a 2011 study, the 2022 median reported time was 11 h (interquartile range [IQR], 6-16 h, p < 0.0001). Two UME institutions (2.4%; 95% CI, 0.0%-5.8%) reported 0 h during the pre-clerkship phase; 21 institutions (24.7%; CI, 15.5%-33.9%) reported 0 h during the clerkship phase; and 1 institution (1.2%; CI, 0%-3.5%) reported 0 h across the curriculum. Median US allopathic clerkship hours were significantly different from US osteopathic clerkship hours (4 h [IQR, 1-6 h] versus 0 h [IQR, 0-0 h]; p = 0.01). Suggested strategies to increase content included more curricular material focusing on LGBTQI + health and health disparities at 55 schools (64.7%; CI, 54.6%-74.9%), more faculty willing and able to teach LGBTQI + -related content at 49 schools (57.7%; CI, 47.1%-68.2%), and more evidence-based research on LGBTQI + health and health disparities at 24 schools (28.2%; CI, 18.7%-37.8%). CONCLUSION: Compared to a 2011 study, the median reported time dedicated to LGBTQI + health-related topics in 2022 increased across US and Canadian UME institutions, but the breadth, efficacy, or quality of instruction continued to vary substantially. Despite the increased hours, this still falls short of the number of hours based on recommended LGBTQI + health competencies from the Association of American Medical Colleges. While most deans of medical education reported their institutions' coverage of LGBTQI + health as 'fair,' 'good,' or 'very good,' there continues to be a call from UME leadership to increase curricular content. This requires dedicated training for faculty and students.

Opioid-related Mortality in United States Death Certificate Data: A Quantitative Bias Analysis With Expert Elicitation of Bias Parameters.

BACKGROUND: Opioid-related mortality is an important public health problem in the United States. Incidence estimates rely on death certificate data generated by health care providers and medical examiners. Opioid overdoses may be underreported when other causes of death appear plausible. We applied physician-elicited death certificate bias parameters to quantitative bias analyses assessing potential age-related differential misclassification in US opioid-related mortality estimates. METHODS: We obtained cause-of-death data (US, 2017) from the National Center for Health Statistics and calculated crude opioid-related outpatient death counts by age category (25-54, 55-64, 65+). We elicited beliefs from 10 primary care physicians on sensitivity of opioid-related death classification from death certificates. We summarized elicited sensitivity estimates, calculated plausible specificity values, and applied resulting parameters in a probabilistic bias analysis. RESULTS: Physicians estimated wide sensitivity ranges for classification of opioid-related mortality by death certificates, with lower estimated sensitivities among older age groups. Probabilistic bias analyses adjusting for physician-estimated misclassification indicated 3.1 times more (95% uncertainty interval: 1.2-23.5) opioid-related deaths than the observed death count in the 65+ age group. All age groups had substantial increases in bias-adjusted death counts. CONCLUSIONS: We developed and implemented a feasible method of eliciting physician expert opinion on bias parameters for sensitivity of a medical record-based death indicator and applied findings in quantitative bias analyses adjusting for differential misclassification. Our findings are consistent with the hypothesis that opioid-related mortality rates may be substantially underestimated, particularly among older adults, due to misclassification in cause-of-death data from death certificates.

Evaluation of Implementation Strategies for Cognitive Behavioral Therapy (CBT), Acceptance and Commitment Therapy (ACT), and Mindfulness-Based Stress Reduction (MBSR): a Systematic Review.

BACKGROUND: Improving access to evidence-based psychotherapies (EBPs) is a Veterans Health Administration (VHA) priority. Cognitive behavioral therapy (CBT), acceptance and commitment therapy (ACT), and mindfulness-based stress reduction (MBSR) are effective for chronic pain and several mental health conditions. We synthesized evidence on implementation strategies to increase EBP access and use. METHODS: We searched MEDLINE, Embase, PsycINFO, and CINAHL from inception until March 2021 for articles on EBP implementation within integrated health systems to treat chronic pain or chronic mental health conditions. Reviewers independently screened articles, extracted results, coded qualitative findings, and rated quality using modified criteria from Newcastle-Ottawa (quantitative results) or Critical Appraisal Skills Programme (qualitative results). We categorized implementation strategies using the Expert Recommendations for Implementing Change (ERIC) framework and classified outcomes using RE-AIM domains (Reach, Effectiveness, Adoption, Implementation, Maintenance). RESULTS: Twelve articles (reporting results from 10 studies) evaluated CBT (k = 11) and ACT (k = 1) implementation strategies in large integrated healthcare systems. No studies evaluated MBSR implementation. Eight articles evaluated strategies within VHA. Six articles reported on national VHA EBP implementation programs; all involved training/education, facilitation, and audit/feedback. CBT and ACT implementation demonstrated moderate to large improvements in patient symptoms and quality of life. Trainings increased mental health provider self-efficacy in delivering EBPs, improved provider EBP perceptions, and increased provider EBP use during programs, but had unclear impacts on Reach. It was unclear whether external facilitation added benefit. Provider EBP maintenance was modest; barriers included competing professional time demands and patient barriers. DISCUSSION: Multi-faceted CBT and ACT implementation programs increased provider EBP Adoption but had unclear impacts on Reach. Future implementation efforts should further evaluate Reach, Adoption, and Maintenance; assess the added value of external facilitation; and consider strategies targeting patient barriers. Future work should use implementation frameworks to guide evaluations of barriers and facilitators, processes of change, and outcomes. REGISTRATION: PROSPERO registration number CRD42021252038.

Implementation of Evidence-Based Psychotherapies for Posttraumatic Stress Disorder: A Systematic Review.

Guidelines strongly recommend trauma-focused therapies to treat posttraumatic stress disorder. Implementation of cognitive processing therapy (CPT) and prolonged exposure (PE) in Veterans Health Administration (VHA) and non-VHA settings began in 2006. We conducted a systematic review of implementation facilitators and challenges and strategies to address barriers. We searched MEDLINE, Embase, PsycINFO, and CINAHL from inception until March 2021 for English-language articles. Two individuals reviewed eligibility and rated quality. Quantitative results were abstracted by one reviewer and verified by a second. Qualitative results were independently coded by two reviewers and finalized through consensus. We used RE-AIM and CFIR frameworks to synthesize findings. 29 eligible studies addressed CPT/PE, mostly conducted in VHA. Training/education with audit/feedback was the primary implementation strategy and was linked to improved provider CPT/PE perceptions and self-efficacy. Use was not widespread. Only six studies tested other implementation strategies with mixed impact. Following VHA implementation, strong support for training, perceived effectiveness for patients and benefits for clinics, and positive patient experiences and relationships with providers were reported. However, barriers persisted including perceived protocol inflexibility, complex referral processes and patient complexity and competing needs. In non-VHA settings, providers perceived fewer barriers, but few were CPT/PE trained. Across both settings, fewer studies targeted patient factors. Training/education with audit/feedback improved perceptions and the availability of CPT/PE, but not consistent use. Studies testing implementation strategies to address post-training challenges, including patient-level factors, are needed. A few studies are underway in VHA to test patient-focused and other implementation strategies. Research assessing actual vs perceived barriers in non-VHA settings is needed to elucidate unique challenges experienced.

Functional divergence caused by mutations in an energetic hotspot in ERK2.

The most frequent extracellular signal-regulated kinase 2 (ERK2) mutation occurring in cancers is E322K (E-K). ERK2 E-K reverses a buried charge in the ERK2 common docking (CD) site, a region that binds activators, inhibitors, and substrates. Little is known about the cellular consequences associated with this mutation, other than apparent increases in tumor resistance to pathway inhibitors. ERK2 E-K, like the mutation of the preceding aspartate (ERK2 D321N [D-N]) known as the sevenmaker mutation, causes increased activity in cells and evades inactivation by dual-specificity phosphatases. As opposed to findings in cancer cells, in developmental assays in Drosophila, only ERK2 D-N displays a significant gain of function, revealing mutation-specific phenotypes. The crystal structure of ERK2 D-N is indistinguishable from that of wild-type protein, yet this mutant displays increased thermal stability. In contrast, the crystal structure of ERK2 E-K reveals profound structural changes, including disorder in the CD site and exposure of the activation loop phosphorylation sites, which likely account for the decreased thermal stability of the protein. These contiguous mutations in the CD site of ERK2 are both required for docking interactions but lead to unpredictably different functional outcomes. Our results suggest that the CD site is in an energetically strained configuration, and this helps drive conformational changes at distal sites on ERK2 during docking interactions.

WNKs are potassium-sensitive kinases.

With no lysine (K) (WNK) kinases regulate epithelial ion transport in the kidney to maintain homeostasis of electrolyte concentrations and blood pressure. Chloride ion directly binds WNK kinases to inhibit autophosphorylation and activation. Changes in extracellular potassium are thought to regulate WNKs through changes in intracellular chloride. Prior studies demonstrate that in some distal nephron epithelial cells, intracellular potassium changes with chronic low- or high-potassium diet. We, therefore, investigated whether potassium regulates WNK activity independent of chloride. We found decreased activity of Drosophila WNK and mammalian WNK3 and WNK4 in fly Malpighian (renal) tubules bathed in high extracellular potassium, even when intracellular chloride was kept constant at either ∼13 mM or 26 mM. High extracellular potassium also inhibited chloride-insensitive mutants of WNK3 and WNK4. High extracellular rubidium was also inhibitory and increased tubule rubidium. The Na+/K+-ATPase inhibitor, ouabain, which is expected to lower intracellular potassium, increased tubule Drosophila WNK activity. In vitro, potassium increased the melting temperature of Drosophila WNK, WNK1, and WNK3 kinase domains, indicating ion binding to the kinase. Potassium inhibited in vitro autophosphorylation of Drosophila WNK and WNK3, and also inhibited WNK3 and WNK4 phosphorylation of their substrate, Ste20-related proline/alanine-rich kinase (SPAK). The greatest sensitivity of WNK4 to potassium occurred in the range of 80-180 mM, encompassing physiological intracellular potassium concentrations. Together, these data indicate chloride-independent potassium inhibition of Drosophila and mammalian WNK kinases through direct effects of potassium ion on the kinase.

A Phosphorylated Intermediate in the Activation of WNK Kinases.

WNK kinases autoactivate by autophosphorylation. Crystallography of the kinase domain of WNK1 phosphorylated on the primary activating site (pWNK1) in the presence of AMP-PNP reveals a well-ordered but inactive configuration. This new pWNK1 structure features specific and unique interactions of the phosphoserine, less hydration, and smaller cavities compared with those of unphosphorylated WNK1 (uWNK1). Because WNKs are activated by osmotic stress in cells, we addressed whether the structure was influenced directly by osmotic pressure. pWNK1 crystals formed in PEG3350 were soaked in the osmolyte sucrose. Suc-WNK1 crystals maintained X-ray diffraction, but the lattice constants and pWNK1 structure changed. Differences were found in the activation loop and helix C, common switch loci in kinase activation. On the basis of these structural changes, we tested for effects on in vitro activity of two WNKs, pWNK1 and pWNK3. The osmolyte PEG400 enhanced ATPase activity. Our data suggest multistage activation of WNKs.

Complementary, Integrative, and Nondrug Therapy Use for Pain Among US Military Veterans on Long-term Opioids.

BACKGROUND: Long-term opioid therapy for chronic pain arose amid limited availability and awareness of other pain therapies. Although many complementary and integrative health (CIH) and nondrug therapies are effective for chronic pain, little is known about CIH/nondrug therapy use patterns among people prescribed opioid analgesics. OBJECTIVE: The objective of this study was to estimate patterns and predictors of self-reported CIH/nondrug therapy use for chronic pain within a representative national sample of US military veterans prescribed long-term opioids for chronic pain. RESEARCH DESIGN: National two-stage stratified random sample survey combined with electronic medical record data. Data were analyzed using logistic regressions and latent class analysis. SUBJECTS: US military veterans in Veterans Affairs (VA) primary care who received ≥6 months of opioid analgesics. MEASURES: Self-reported use of each of 10 CIH/nondrug therapies to treat or cope with chronic pain in the past year: meditation/mindfulness, relaxation, psychotherapy, yoga, t'ai chi, aerobic exercise, stretching/strengthening, acupuncture, chiropractic, massage; Brief Pain Inventory-Interference (BPI-I) scale as a measure of pain-related function. RESULTS: In total, 8891 (65%) of 13,660 invitees completed the questionnaire. Eighty percent of veterans reported past-year use of at least 1 nondrug therapy for pain. Younger age and female sex were associated with the use of most nondrug therapies. Higher pain interference was associated with lower use of exercise/movement therapies. Nondrug therapy use patterns reflected functional categories (psychological/behavioral, exercise/movement, manual). CONCLUSIONS: Use of CIH/nondrug therapies for pain was common among patients receiving long-term opioids. Future analyses will examine nondrug therapy use in relation to pain and quality of life outcomes over time.

Sleep Disturbance Predicts Less Improvement in Pain Outcomes: Secondary Analysis of the SPACE Randomized Clinical Trial.

OBJECTIVE: Sleep disturbance may limit improvement in pain outcomes if not directly addressed in treatment. Moreover, sleep problems may be exacerbated by opioid therapy. This study examined the effects of baseline sleep disturbance on improvement in pain outcomes using data from the Strategies for Prescribing Analgesics Comparative Effectiveness (SPACE) trial, a pragmatic 12-month randomized trial of opioid vs nonopioid medication therapy. DESIGN: Participants with chronic back pain or hip or knee osteoarthritis pain were randomized to either opioid therapy (N = 120) or nonopioid medication therapy (N = 120). METHODS: We used mixed models for repeated measures to 1) test whether baseline sleep disturbance scores modified the effect of opioid vs nonopioid treatment on pain outcomes and 2) test baseline sleep disturbance scores as a predictor of less improvement in pain outcomes across both treatment groups. RESULTS: The tests for interaction of sleep disturbance by treatment group were not significant. Higher sleep disturbance scores at baseline predicted less improvement in Brief Pain Inventory (BPI) interference (ß = 0.058, P = 0.0002) and BPI severity (ß = 0.026, P = 0.0164). CONCLUSIONS: Baseline sleep disturbance adversely affects pain response to treatment regardless of analgesic regimen. Recognition and treatment of sleep impairments that frequently co-occur with pain may optimize outcomes.

A Model Course to Enhance Veterinary Student Exposure to Research.

Despite many career opportunities available to veterinarians in research related fields and requirements for training in research methodologies by the American Veterinary Medical Association Council on Education (AVMA COE), formal approaches to development of veterinary curriculum related to research topics have not been widely reported. Colorado State University (CSU) offers a one-credit course that introduces first-year veterinary students to skills and career opportunities in research. Here we provide information about the course structure and content, and report outcomes of survey data that assesses the impact of the course on student appreciation and understanding of the research process. We found that most United States (US) veterinary colleges do not offer a didactic course on the research process. Student opinions of veterinary researchers were generally high, though a proportion of students (30%-40%) would have preferred a practice management class to a course on research principles. Nearly 25% of students reported that they were significantly influenced to consider research careers after taking the course. We document that this one-credit seminar course improved veterinary student perceptions of their understanding of the research process and resulted in self-reported influence of career choice.

Intracellular Chloride and Scaffold Protein Mo25 Cooperatively Regulate Transepithelial Ion Transport through WNK Signaling in the Malpighian Tubule.

Background With No Lysine kinase (WNK) signaling regulates mammalian renal epithelial ion transport to maintain electrolyte and BP homeostasis. Our previous studies showed a conserved role for WNK in the regulation of transepithelial ion transport in the Drosophila Malpighian tubule.Methods Using in vitro assays and transgenic Drosophila lines, we examined two potential WNK regulators, chloride ion and the scaffold protein mouse protein 25 (Mo25), in the stimulation of transepithelial ion flux.ResultsIn vitro, autophosphorylation of purified Drosophila WNK decreased as chloride concentration increased. In conditions in which tubule intracellular chloride concentration decreased from 30 to 15 mM as measured using a transgenic sensor, Drosophila WNK activity acutely increased. Drosophila WNK activity in tubules also increased or decreased when bath potassium concentration decreased or increased, respectively. However, a mutation that reduces chloride sensitivity of Drosophila WNK failed to alter transepithelial ion transport in 30 mM chloride. We, therefore, examined a role for Mo25. In in vitro kinase assays, Drosophila Mo25 enhanced the activity of the Drosophila WNK downstream kinase Fray, the fly homolog of mammalian Ste20-related proline/alanine-rich kinase (SPAK), and oxidative stress-responsive 1 protein (OSR1). Knockdown of Drosophila Mo25 in the Malpighian tubule decreased transepithelial ion flux under stimulated but not basal conditions. Finally, whereas overexpression of wild-type Drosophila WNK, with or without Drosophila Mo25, did not affect transepithelial ion transport, Drosophila Mo25 overexpressed with chloride-insensitive Drosophila WNK increased ion flux.Conclusions Cooperative interactions between chloride and Mo25 regulate WNK signaling in a transporting renal epithelium.

How activating mutations affect MEK1 regulation and function.

The MEK1 kinase directly phosphorylates ERK2, after the activation loop of MEK1 is itself phosphorylated by Raf. Studies over the past decade have revealed a large number of disease-related mutations in the MEK1 gene that lead to tumorigenesis and abnormal development. Several of these mutations result in MEK1 constitutive activity, but how they affect MEK1 regulation and function remains largely unknown. Here, we address these questions focusing on two pathogenic variants of the Phe-53 residue, which maps to the well-characterized negative regulatory region of MEK1. We found that these variants are phosphorylated by Raf faster than the wild-type enzyme, and this phosphorylation further increases their enzymatic activity. However, the maximal activities of fully phosphorylated wild-type and mutant enzymes are indistinguishable. On the basis of available structural information, we propose that the activating substitutions destabilize the inactive conformation of MEK1, resulting in its constitutive activity and making it more prone to Raf-mediated phosphorylation. Experiments in zebrafish revealed that the effects of activating variants on embryonic development reflect the joint control of the negative regulatory region and activating phosphorylation. Our results underscore the complexity of the effects of activating mutations on signaling systems, even at the level of a single protein.

Focused Evidence Review: Psychometric Properties of Patient-Reported Outcome Measures for Chronic Musculoskeletal Pain.

BACKGROUND: Developing successful interventions for chronic musculoskeletal pain requires valid, responsive, and reliable outcome measures. The Minneapolis VA Evidence-based Synthesis Program completed a focused evidence review on key psychometric properties of 17 self-report measures of pain severity and pain-related functional impairment suitable for clinical research on chronic musculoskeletal pain. METHODS: Pain experts of the VA Pain Measurement Outcomes Workgroup identified 17 pain measures to undergo systematic review. In addition to a MEDLINE search on these 17 measures (1/2000-1/2017), we hand-searched (without publication date limits) the reference lists of all included studies, prior systematic reviews, and-when available-Web sites dedicated to each measure (PROSPERO registration CRD42017056610). Our primary outcome was the measure's minimal important difference (MID). Secondary outcomes included responsiveness, validity, and test-retest reliability. Outcomes were synthesized through evidence mapping and qualitative comparison. RESULTS: Of 1635 abstracts identified, 331 articles underwent full-text review, and 43 met inclusion criteria. Five measures (Oswestry Disability Index (ODI), Roland-Morris Disability Questionnaire (RMDQ), SF-36 Bodily Pain Scale (SF-36 BPS), Numeric Rating Scale (NRS), and Visual Analog Scale (VAS)) had data reported on MID, responsiveness, validity, and test-retest reliability. Seven measures had data reported on three of the four psychometric outcomes. Eight measures had reported MIDs, though estimation methods differed substantially and often were not clinically anchored. CONCLUSIONS: In this focused evidence review, the most evidence on key psychometric properties in chronic musculoskeletal pain populations was found for the ODI, RMDQ, SF-36 BPS, NRS, and VAS. Key limitations in the field include substantial variation in methods of estimating psychometric properties, defining chronic musculoskeletal pain, and reporting patient demographics. TRIAL REGISTRATION: Registered in the PROSPERO database: CRD42017056610.

Patterns of conventional and complementary non-pharmacological health practice use by US military veterans: a cross-sectional latent class analysis.

BACKGROUND: Non-pharmacological therapies and practices are commonly used for both health maintenance and management of chronic disease. Patterns and reasons for use of health practices may identify clinically meaningful subgroups of users. The objectives of this study were to identify classes of self-reported use of conventional and complementary non-pharmacological health practices using latent class analysis and estimate associations of participant characteristics with class membership. METHODS: A mailed survey (October 2015 to September 2016) of Minnesota National Guard Veterans from a longitudinal cohort (n = 1850) assessed current pain, self-reported overall health, mental health, substance use, personality traits, and health practice use. We developed the Health Practices Inventory, a self-report instrument assessing use of 19 common conventional and complementary non-pharmacological health-related practices. Latent class analysis was used to identify subgroups of health practice users, based on responses to the HPI. Participants were assigned to their maximum-likelihood class, which was used as the outcome in multinomial logistic regression to examine associations of participant characteristics with latent class membership. RESULTS: Half of the sample used non-pharmacological health practices. Six classes of users were identified. "Low use" (50%) had low rates of health practice use. "Exercise" (23%) had high exercise use. "Psychotherapy" (6%) had high use of psychotherapy and support groups. "Manual therapies" (12%) had high use of chiropractic, physical therapy, and massage. "Mindfulness" (5%) had high use of mindfulness and relaxation practice. "Multimodal" (4%) had high use of most practices. Use of manual therapies (chiropractic, acupuncture, physical therapy, massage) was associated with chronic pain and female sex. Characteristics that predict use patterns varied by class. Use of self-directed practices (e.g., aerobic exercise, yoga) was associated with the personality trait of absorption (openness to experience). Use of psychotherapy was associated with higher rates of psychological distress. CONCLUSIONS: These observed patterns of use of non-pharmacological health practices show that functionally similar practices are being used together and suggest a meaningful classification of health practices based on self-directed/active and practitioner-delivered. Notably, there is considerable overlap in users of complementary and conventional practices.