A Harm Reduction Framework for Integrated Treatment of Co-Occurring Opioid Use Disorder and Trauma-Related Disorders.

The opioid epidemic has exposed a gulf in mental health research, treatment, and policy: Most patients with comorbid trauma-related disorder (TRD) and opioid use disorder (OUD) (TRD + OUD) remain undiagnosed or unsuccessfully treated for the combination of TRD symptoms and opioid use. TRD treatments tend to be psychotherapies that are not accessible or practical for many individuals with TRD + OUD, due to TRD treatment models not systematically incorporating principles of harm reduction (HR). HR practices prioritize flexibility and unequivocally improve outcomes and save lives in the treatment of OUD. Considering the urgent need to improve TRD + OUD treatment and outcomes, we propose that the OUD and TRD fields can be meaningfully reconciled by integrating HR principles with classic phasic treatment for TRD. Adding a "prestabilization" phase of treatment for TRD - largely analogous to the precontemplation Stage of Change - creates opportunities to advance research, clinical practice, and policies and potentially improve patient outcomes.

Practical Considerations for Treating Comorbid Posttraumatic Stress Disorder in the Addictions Clinic: Approaches to Clinical Care, Leadership, and Alleviating Shame.

A practical, common-sense framework for recognizing and addressing comorbid posttraumatic stress disorder (PTSD) in the substance use disorder (SUD) clinic is outlined. The article focuses on strategies that can help establish trauma-informed care or augment an existing approach. Interventions are organized around the task of ameliorating shame (or shame sensitivity), which represents a transdiagnostic mediator of psychopathology and, potentially, capacity for change. Countershaming strategies can guide a trauma-responsive leadership approach. Considering the striking rate of underdiagnosis of PTSD among patients with SUD, implementing routine systematic PTSD screening likely represents the single most consequential trauma-informed intervention that SUD clinics can adopt.

Going through the barrier: coupled disulfide exchange reactions promote efficient catalysis in quiescin sulfhydryl oxidase.

The quiescin sulfhydryl oxidase (QSOX) family of enzymes generates disulfide bonds in peptides and proteins with the reduction of oxygen to hydrogen peroxide. Determination of the potentials of the redox centers in Trypanosoma brucei QSOX provides a context for understanding catalysis by this facile oxidant of protein thiols. The CXXC motif of the thioredoxin domain is comparatively oxidizing (E'0 of -144 mV), consistent with an ability to transfer disulfide bonds to a broad range of thiol substrates. In contrast, the proximal CXXC disulfide in the ERV (essential for respiration and vegetative growth) domain of TbQSOX is strongly reducing (E'0 of -273 mV), representing a major apparent thermodynamic barrier to overall catalysis. Reduction of the oxidizing FAD cofactor (E'0 of -153 mV) is followed by the strongly favorable reduction of molecular oxygen. The role of a mixed disulfide intermediate between thioredoxin and ERV domains was highlighted by rapid reaction studies in which the wild-type CGAC motif in the thioredoxin domain of TbQSOX was replaced by the more oxidizing CPHC or more reducing CGPC sequence. Mixed disulfide bond formation is accompanied by the generation of a charge transfer complex with the flavin cofactor. This provides thermodynamic coupling among the three redox centers of QSOX and avoids the strongly uphill mismatch between the formal potentials of the thioredoxin and ERV disulfides. This work identifies intriguing mechanistic parallels between the eukaryotic QSOX enzymes and the DsbA/B system catalyzing disulfide bond generation in the bacterial periplasm and suggests that the strategy of linked disulfide exchanges may be exploited in other catalysts of oxidative protein folding.

Disulfide bond generation in mammalian blood serum: detection and purification of quiescin-sulfhydryl oxidase.

A sensitive new plate-reader assay has been developed showing that adult mammalian blood serum contains circulating soluble sulfhydryl oxidase activity that can introduce disulfide bonds into reduced proteins with the reduction of oxygen to hydrogen peroxide. The activity was purified 5000-fold to >90% homogeneity from bovine serum and found by mass spectrometry to be consistent with the short isoform of quiescin-sulfhydryl oxidase 1 (QSOX1). This FAD-dependent enzyme is present at comparable activity levels in fetal and adult commercial bovine sera. Thus cell culture media that are routinely supplemented with either fetal or adult bovine sera will contain this facile catalyst of protein thiol oxidation. QSOX1 is present at approximately 25 nM in pooled normal adult human serum. Examination of the unusual kinetics of QSOX1 toward cysteine and glutathione at low micromolar concentrations suggests that circulating QSOX1 is unlikely to significantly contribute to the oxidation of these monothiols in plasma. However, the ability of QSOX1 to rapidly oxidize conformationally mobile protein thiols suggests a possible contribution to the redox status of exofacial and soluble proteins in blood plasma. Recent proteomic studies showing that plasma QSOX1 can be utilized in the diagnosis of pancreatic cancer and acute decompensated heart failure, together with the overexpression of this secreted enzyme in a number of solid tumors, suggest that the robust QSOX assay developed here may be useful in the quantitation of enzyme levels in a wide range of biological fluids.

Short-term stability of sleep and heart rate variability in good sleepers and patients with insomnia: for some measures, one night is enough.

STUDY OBJECTIVES: Quantify the short-term stability of multiple indices of sleep and nocturnal physiology in good sleeper controls and primary insomnia patients. DESIGN: Intra-class correlation coefficients (ICC) were used to quantify the short-term stability of study outcomes. SETTING: Sleep laboratory. PARTICIPANTS: Fifty-four adults with primary insomnia (PI) and 22 good sleeper controls (GSC). MEASUREMENTS: Visually scored sleep outcomes included indices of sleep duration, continuity, and architecture. Quantitative EEG outcomes included power in the delta, theta, alpha, sigma, and beta bands during NREM sleep. Power spectral analysis was used to estimate high-frequency heart rate variability (HRV) and the ratio of low- to high-frequency HRV power during NREM and REM sleep. RESULTS: With the exception of percent stage 3+4 sleep; visually scored sleep outcomes did not exhibit short-term stability across study nights. Most QEEG outcomes demonstrated short-term stability in both groups. Although power in the beta band was stable in the PI group (ICC = 0.75), it tended to be less stable in GSCs (ICC = 0.55). Both measures of cardiac autonomic tone exhibited short-term stability in GSCs and PIs during NREM and REM sleep. CONCLUSIONS: Most QEEG bandwidths and HRV during sleep show high short-term stability in good sleepers and patients with insomnia alike. One night of data is, thus, sufficient to derive reliable estimates of these outcomes in studies focused on group differences or correlates of QEEG and/or HRV. In contrast, one night of data is unlikely to generate reliable estimates of PSG-assessed sleep duration, continuity or architecture, with the exception of slow wave sleep.

Protein substrate discrimination in the quiescin sulfhydryl oxidase (QSOX) family.

This work explores the substrate specificity of the quiescin sulfhydryl oxidase (QSOX) family of disulfide-generating flavoenzymes to provide enzymological context for investigation of the physiological roles of these facile catalysts of oxidative protein folding. QSOX enzymes are generally unable to form disulfide bonds within well-structured proteins. Use of a temperature-sensitive mutant of ubiquitin-conjugating enzyme 4 (Ubc4') as a model substrate shows that QSOX activity correlates with the unfolding of Ubc4' monitored by circular dichroism. Fusion of Ubc4' with the more stable glutathione-S-transferase domain demonstrates that QSOX can selectively introduce disulfides into the less stable domain of the fusion protein. In terms of intermolecular disulfide bond generation, QSOX is unable to cross-link well-folded globular proteins via their surface thiols. However, the construction of a septuple mutant of RNase A, retaining a single cysteine residue, demonstrates that flexible protein monomers can be directly coupled by the oxidase. Steady- and pre-steady-state kinetic experiments, combined with static fluorescence approaches, indicate that while QSOX is an efficient catalyst for disulfide bond formation between mobile elements of structure, it does not appear to have a significant binding site for unfolded proteins. These aspects of protein substrate discrimination by QSOX family members are rationalized in terms of the stringent steric requirements for disulfide exchange reactions.