An Exploration of Blood Marker×Environment Interaction Effects on Pain Severity and Interference Scores in People With Acute Musculoskeletal Trauma.

OBJECTIVES: Explore the moderating effects of psychological or social variables on associations between biomarkers of inflammation/stress and clinical reports of pain. METHODS: This is a cross-sectional exploratory study. Data were drawn from the Systematic Merging of Biology, Mental Health and Environment (SYMBIOME) longitudinal study (clinicaltrials.gov ID no. NCT02711085). Eligible participants were adults who presented to an Urgent Care Centre in Ontario, Canada within 3 weeks of a noncatastrophic musculoskeletal trauma (no surgery or hospitalization). A questionnaire package was given that included the Brief Pain Inventory (capturing pain severity and pain interference) and relevant person-level variables. Blood samples were also drawn for serum analysis of 8 target biomarkers (brain-derived neurotrophic factor, transforming growth factor beta 1 [TGF-ß1], c-reactive protein, tumor necrosis factor-α, interleukin [IL]-1ß, IL-6, IL-10, and cortisol). RESULTS: Employment before trauma (employed for pay/not employed for pay) fully moderated the association between tumor necrosis factor-α and pain severity (∆R2=4.4%). Pre-existing psychopathology (yes/no) fully moderated the association between TGF-ß1 and pain severity (∆R2=8.0%). Sex (male/female) fully moderated the association between c-reactive protein and pain severity (∆R2=6.3%). A pre-existing pain condition (yes/no) was significantly associated with worse pain interference (R2=7.2%), and partially moderated the effect of IL-1ß on pain interference (∆R2=6.9%). Higher peritraumatic life stress significantly explained 8.9% of variance in pain interference alone, and partially moderated the effect of TGF-ß1 on interference (∆R2=4.4%). DISCUSSION: Simple bivariate associations between blood-based markers and clinical symptoms are unlikely to reveal meaningful relationships. However, when stratified by existing person-level or "metadata" variables, an association may exist for at least 1 clinically relevant subgroup.

Identification of clinically-useful cut scores of the Traumatic Injuries Distress Scale (TIDS) for predicting rate of recovery following musculoskeletal trauma.

OBJECTIVE: The Traumatic Injuries Distress Scale (TIDS) is a 12-item self-report tool intended for prognostic risk phenotyping in people with acute musculoskeletal (MSK) trauma. The initial validation study showed good associations with outcomes 12 weeks later in a cohort of 72 acutely injured patients from one region in Canada. This study aims to provide further clinical utility through identification of meaningful cut scores in a larger, mixed geography sample, and expands the prediction window from 12 to 52 weeks. METHODS: Data were drawn from databanks in London, Canada and Chicago, United States. Participants were recruited within 3 weeks of non-catastrophic MSK trauma and followed for 12 months. Using outcomes trajectories, the TIDS underwent linear regression-based analysis to predict 52-week outcomes, and area under the receiver operating characteristic curves to identify discriminative accuracy and meaningful cut scores. RESULTS: N = 224 participants with acute trauma were followed and both %Interference and Pain Severity were captured at intake and 3 follow-ups to establish curvilinear recovery trajectories. The TIDS explained significant variance in both the interference and severity outcomes after controlling for sex, region of injury, and baseline scores. ROC analysis revealed significant discriminative accuracy for predicting both the trajectories and the distal outcomes over 52 weeks. The TIDS was more accurate for identifying the low-risk than high-risk patients. CONCLUSION: The TIDS is a useful tool for 'ruling out' high risk of poor outcome in a mixed sample of participants from two different countries. IMPACT STATEMENT: The TIDS will be a useful tool for clinicians to predict the rate of recovery by displaying meaningful cut-scores for their patients after an acute musculoskeletal injury. This could lead to reduced burden of care for low risk patients and more informed treatment options for higher risk patients.

Xenopus pitx3 target genes lhx1 and xnr5 are identified using a novel three-fluor flow cytometry-based analysis of promoter activation and repression.

BACKGROUND: Pitx3 plays a well understood role in directing development of lens, muscle fiber, and dopaminergic neurons; however, in Xenopus laevis, it may also play a role in early gastrulation and somitogenesis. Potential downstream targets of pitx3 possess multiple binding motifs that would not be readily accessible by conventional promoter analysis. RESULTS: We isolated and characterized pitx3 target genes lhx1 and xnr5 using a novel three-fluor flow cytometry tool that was designed to dissect promoters with multiple binding sites for the same transcription factor. This approach was calibrated using a known pitx3 target gene, Tyrosine hydroxylase. CONCLUSIONS: We demonstrate how flow cytometry can be used to detect gene regulatory changes with exquisite precision on a cell-by-cell basis, and establish that in HEK293 cells, pitx3 directly activates lhx1 and represses xnr5. Developmental Dynamics 246:657-669, 2017. © 2017 Wiley Periodicals, Inc.