Background: Prior studies have suggested that misconceptions (i.e., unhelpful thoughts or cognitive errors resulting from cognitive bias) and distress (symptoms of anxiety or depression) are key factors associated with variation in health, as quantified with use of patient-reported outcome measures. The primary purpose of the present study was to identify mental-health phenotypes (i.e., combinations of various types of misconceptions and distress) that might help direct care and to test for differences in magnitude of activity tolerance, pain intensity, and self-efficacy in response to pain between phenotypes. We also studied demographic factors and diagnostic categories associated with mental-health phenotypes.Methods: In a cross-sectional study, 137 patients seeking upper-extremity musculoskeletal specialty care completed a survey including demographics, mental-health questionnaires, and measures of upper-extremity-specific activity tolerance, pain intensity, and pain self-efficacy. We used cluster analysis to identify groups of patients with similar phenotypes. We used analysis of variance testing to assess differences in activity tolerance, pain intensity, and pain self-efficacy among phenotypes. Results:The cluster analysis yielded 4 unique mental-health phenotypes, which fit the theoretical conceptualizations of "low misconception and low distress," "notable misconception," "notable depression and notable misconception," and "notable anxiety, depression, and misconception." Patients with low bias and low distress had significantly greater activity tolerance and greater pain self-efficacy than the other phenotypes, as well as a significantly lower pain intensity than phenotypes with notable distress.Conclusions: Cluster analysis of mental-health questionnaire data can identify mental-health phenotypes that are associated with greater activity tolerance and pain intensity. This approach might help clinicians to strategize and prioritize approaches that correct unhelpful thoughts and ameliorate symptoms of distress among patients seeking musculoskeletal specialty care. Such strategies have the potential to achieve more comprehensive, whole-person care, more selective operative treatment, and improved outcomes.Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. Extensive research regarding musculoskeletal illness has established that variations in the intensity of pain and magnitude of activity intolerance cannot be explained through a purely biomedical paradigm. In other words, there is limited correspondence between objective pathology and the state of being unwell (i.e., illness). Prior studies indicate that this variation in illness may be the result of psychological factors, such as common misconceptions about symptoms (i.e., cognitive biases) and the symptoms of anxiety or depression (i.e., distress) 1-7 .These cognitive biases are common and arise from the normal functioning of the human mind. The Nobel Prize-winning research of Kahneman ...

Patient-reported experience measures have notable ceiling effects which can hinder efforts to learn and improve. This study tested whether an iterative (Guttman-style) satisfaction questionnaire combined with instructions intended to give people agency to critique us primes responses on an ordinal scale and reduces ceiling effects. Among the 161 subjects randomly assigned to complete an iterative satisfaction questionnaire before or after an ordinal scale, there was no difference in mean satisfaction (no priming). The Guttman scale was more normally distributed and had slightly less ceiling effect when compared to the ordinal scale. Iterative satisfaction scales partially mitigate ceiling effects. The absence of priming suggests that attempts to encourage agency and reflection have limited ability to reduce ceiling effects, and alternative approaches should be tested.

Mitochondria modulate inflammatory processes in various model organisms, but it is unclear how much mitochondria regulate immune responses in human blood leukocytes. Here, we examine the effect of i) experimental perturbations of mitochondrial respiratory chain function, and ii) baseline inter-individual variation in leukocyte mitochondrial energy production capacity on stimulated cytokine release and glucocorticoid (GC) sensitivity. In a first cohort, whole blood from 20 healthy women and men was stimulated with increasing concentrations of the immune agonist lipopolysaccharide (LPS). Four inhibitors of mitochondrial respiratory chain Complexes I, III, IV, and V were used (LPS + Mito-Inhibitors) to acutely perturb mitochondrial function, GC sensitivity was quantified using the GC-mimetic dexamethasone (DEX) (LPS + DEX), and the resultant cytokine signatures mapped with a 20-cytokine array. Inhibiting mitochondrial respiration caused large inter-individual differences in LPS-stimulated IL-6 reactivity (Cohen’s d = 0.72) and TNF-α ( d = 1.55) but only minor alteration in EC 50 -based LPS sensitivity ( d = 0.21). Specifically, inhibiting mitochondrial Complex IV potentiated LPS-induced IL-6 levels by 13%, but inhibited TNF-α induction by 72%, indicating mitochondrial regulation of the IL-6/TNF-α ratio. As expected, DEX treatment suppressed multiple LPS-induced pro-inflammatory cytokines (IFN-γ, IL-6, IL-8, IL-1β, .TNF-α) by >85% and increased the anti-inflammatory cytokine IL-10 by 80%. Inhibiting Complex I potentiated DEX suppression of IL-6 by a further 12% ( d = 0.73), indicating partial mitochondrial modulation of glucocorticoid sensitivity. Finally, to examine if intrinsic mitochondrial respiratory capacity may explain a portion of immune reactivity differences across individuals, we measured biochemical respiratory chain enzyme activities and mitochondrial DNA copy number in isolated peripheral blood mononuclear cells (PBMCs) from a second cohort of 44 healthy individuals in parallel with LPS-stimulated IL-6 and TNF-α response. Respiratory chain .function, particularly Complex IV activity, was positively correlated with LPS-stimulated IL-6 levels (r = 0.45, p = 0.002). Overall, these data provide preliminary evidence that mitochondrial behavior modulates LPS-induced inflammatory cytokine signatures in human blood.

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