Cortisol response to traumatic stress to predict PTSD symptom development – a systematic review and meta-analysis of experimental studies

Background: Pre-and post-traumatic hypothalamic–pituitary–adrenal (HPA) axis markers have been studied to predict posttraumatic stress disorder (PTSD) risk, but its acute reactivity cannot be measured in real-life settings. Experimental paradigms can depict the cortisol response to stimuli that simulate traumatic events. Objective: To review experimental studies on the cortisol response to traumatic stimuli and the correlation between cortisol and PTSD symptoms. Method: Experimental, (un-)published studies in German or English from any year were eligible if they confronted non-traumatized humans with traumatic stimuli, assessed cortisol before, during or after stimulus presentation and subsequent PTSD symptoms. The literature was searched via PubMed, PubPsych, PsychINFO, PsycArticle, Web of Science, EMBASE, ProQuest and ClinicalTrials.gov up to 16th February 2021. Risk of bias was assessed with the Cortisol Assessment List. Multilevel-meta-analyses were conducted under the random effects model. The standardized mean change (dSMC) indicated the cortisol response. Coefficient r indicated the correlations between cortisol and PTSD symptoms. Results: 14 studies, investigating 1004 individuals, were included. A cortisol response was successfully induced between 21 and 40 min post-presentation onset (kobservations = 25, dSMC = 0.15 [.03; .26]). Cortisol was not associated with overall or cluster-level PTSD symptoms. On a symptom-level, higher pre-presentation onset cortisol was correlated with lower state tension (k = 8, r = −.18 [−.35; −.01]), higher state happiness (k = 8, r = −.34 [−.59; −.03], variable inverted) and lower state anger (k = 9, r = −.14 [−.26; −.01]). Higher post-presentation onset cortisol was correlated with higher state happiness (k = 16, r = −.20 [−.33; −.06]) and lower state sadness (k = 17, r = −.16 [−.25; −.05]), whereas cortisol response was positively correlated with state anxiety (k = 9, r = .16 [0.04; 0.27]). Conclusions: Experimental paradigms effectively induce a cortisol response. Higher basal cortisol, higher cortisol, as measured after traumatic stimulus presentation, and a lower cortisol response were associated with more adaptive emotional reactions. These markers did not predict longer-term PTSD symptoms

Associations between oxytocin and vasopressin concentrations, traumatic event exposure and posttraumatic stress disorder symptoms: group comparisons, correlations, and courses during an internet-based cognitive-behavioural treatment

Background: Posttraumatic stress disorder (PTSD) is characterized by impairments in extinction learning and social behaviour, which are targeted by trauma-focused cognitive behavioural treatment (TF-CBT). The biological underpinnings of TF-CBT can be better understood by adding biomarkers to the clinical evaluation of interventions. Due to their involvement in social functioning and fear processing, oxytocin and arginine vasopressin might be informative biomarkers for TF-CBT, but to date, this has never been tested. Objective: To differentiate the impact of traumatic event exposure and PTSD symptoms on blood oxytocin and vasopressin concentrations. Further, to describe courses of PTSD symptoms, oxytocin and vasopressin during an internet-based TF-CBT and explore interactions between these parameters. Method: We compared oxytocin and vasopressin between three groups of active and former male service members of the German Armed Forces (n = 100): PTSD patients (n = 39), deployed healthy controls who experienced a deployment-related traumatic event (n = 33) and non-deployed healthy controls who never experienced a traumatic event (n = 28). PTSD patients underwent a 5-week internet-based TF-CBT. We correlated PTSD symptoms with oxytocin and vasopressin before treatment onset. Further, we analysed courses of PTSD symptoms, oxytocin and vasopressin from pre- to post-treatment and 3 months follow-up, as well as interactions between the three parameters. Results: Oxytocin and vasopressin did not differ between the groups and were unrelated to PTSD symptoms. PTSD symptoms were highly stable over time, whereas the endocrine parameters were not, and they also did not change in mean. Oxytocin and vasopressin were not associated with PTSD symptoms longitudinally. Conclusions: Mainly due to their insufficient intraindividual stability, single measurements of endogenous oxytocin and vasopressin concentrations are not informative biomarkers for TF-CBT. We discuss how the stability of these biomarkers might be increased and how they could be better related to the specific impairments targeted by TF-CBT

Positive effects of audit and feedback on antimicrobial use in hospitalized patients limited to audited patients

Objective: Audit and feedback is an antimicrobial stewardship (AMS) strategy, with the potential to also optimize antimicrobial use in non-audited patients. This study aimed to determine whether audit and feedback reduce antimicrobial use in both audited and non-audited patients.Design: Before-after trial with a 1-year intervention period and 2.5-year historical cohort.Setting: 750-bed community hospital in the Netherlands.Patients: All patients admitted to the urology wards during the 3.5-year study period were observed. Patients were classified as using antimicrobials if any antimicrobial was used for therapeutic reasons. Patients using antimicrobials prophylactically were excluded from measurements.Intervention: The AMS team provided audit and feedback on antimicrobial use for patients using antimicrobials for 2 days. Retrospectively, antimicrobial use and length of stay (LOS) were compared with the historical cohort.Results: Audits modified antimicrobial treatment in 52.8% of the cases. De-escalating, stopping, and switching from intravenous to oral treatment accounted for 72% of these modifications. Compared to patients from the cohort, who also used antimicrobials for 2 days, antimicrobial use decreased from 14.21 DDD/patient (95% CI, 13.08–15.34) to 11.45 DDD/patient (95% CI, 8.26–14.64; P = .047) for audited patients. Furthermore, mean LOS decreased from 7.42 days (95% CI, 6.79–8.06) to 6.13 days (95% CI, 5.38–6.89; P = .031). However, looking at all patients admitted to the urology wards, the percentage of patients using antimicrobials and total antimicrobial use remained unchanged.Conclusions: Audit and feedback reduce antimicrobial use and LOS, but only for audited patients. Positive effects are not automatically transferred to patients for whom no audits have been performed

Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3

The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3. Consistent with our findings following self-administration in rats, pretreatment of male C57/BL6 mice with corticosterone (using a dose that reproduced stress-level plasma concentrations) potentiated cocaine-primed reinstatement of extinguished cocaine-induced conditioned place preference. Corticosterone failed to re-establish extinguished preference alone but produced a leftward shift in the dose–response curve for cocaine-primed reinstatement. A similar potentiating effect was observed upon pretreatment of mice with the non-glucocorticoid OCT3 blocker, normetanephrine. To determine the role of OCT3 blockade in these effects, we examined the abilities of corticosterone and normetanephrine to potentiate cocaine-primed reinstatement in OCT3-deficient and wild-type mice. Conditioned place preference, extinction and reinstatement of extinguished preference in response to low-dose cocaine administration did not differ between genotypes. However, corticosterone and normetanephrine failed to potentiate cocaine-primed reinstatement in OCT3-deficient mice. Together, these data provide the first direct evidence that the interaction of corticosterone with OCT3 mediates corticosterone effects on drug-seeking behavior and establish OCT3 function as an important determinant of susceptibility to cocaine use

Early posttraumatic autonomic and endocrine markers to predict posttraumatic stress symptoms after a preventive intervention with oxytocin

Background: Efficient prevention of posttraumatic stress disorder (PTSD) needs to target individuals with an increased risk for adverse outcome after trauma. Prognostic or prescriptive biological markers assessed early posttrauma may inform personalized treatment recommendations. Objective: To test prognostic and prescriptive effects of early (posttraumatic) autonomic and endocrine markers on PTSD symptom development. Method: Autonomic and endocrine markers were assessed within 12 days posttrauma and before treatment initiation within a randomized placebo-controlled trial investigating repeated oxytocin administration as preventive intervention for PTSD. Linear mixed effects models were used to test the effects of heart rate (variability), resting cortisol, morning cortisol and cortisol awakening response (CAR), cortisol suppression by dexamethasone and resting oxytocin on PTSD symptoms 1.5, 3 and 6 months posttrauma in men (n = 54), women using hormonal contraception (n = 27) and cycling women (n = 19). Results: We found significant prognostic effects of resting oxytocin and cortisol suppression. In women using hormonal contraception, higher oxytocin was associated with higher PTSD symptoms across follow-up. Stronger cortisol suppression by dexamethasone, reflecting increased glucocorticoid receptor feedback sensitivity, was associated with lower PTSD symptoms across follow-up in men, but with higher symptoms at 1.5 months in women using hormonal contraception. These effects were independent of treatment condition. No further significant prognostic or prescriptive effects were detected. Conclusion: Our exploratory study indicates that resting oxytocin and glucocorticoid receptor feedback sensitivity early posttrauma are associated with subsequent PTSD symptom severity. Notably, prognostic effects depended on sex and hormonal contraception use, emphasizing the necessity to consider these factors in biomedical PTSD research

Sex-differential PTSD symptom trajectories across one year following suspected serious injury

Background Recent years have shown an increased application of prospective trajectory-oriented approaches to posttraumatic stress disorder (PTSD). Although women are generally considered at increased PTSD risk, sex and gender differences in PTSD symptom trajectories have not yet been extensively studied. Objective To perform an in-depth investigation of differences in PTSD symptom trajectories across one-year post-trauma between men and women, by interpreting the general trends of trajectories observed in sex-disaggregated samples, and comparing within-trajectory symptom course and prevalence rates. Method We included N = 554 participants (62.5% men, 37.5% women) from a multi-centre prospective cohort of emergency department patients with suspected severe injury. PTSD symptom severity was assessed at 1, 3, 6, and 12 months post-trauma, using the Clinician-Administered PTSD Scale for DSM-IV. Latent growth mixture modelling on longitudinal PTSD symptoms was performed within the sex-disaggregated and whole samples. Bayesian modelling with informative priors was applied for reliable model estimation, considering the imbalanced prevalence of the expected latent trajectories. Results In terms of general trends, the same trajectories were observed for men and women, i.e. resilient, recovery, chronic symptoms and delayed onset. Within-trajectory symptom courses were largely comparable, but resilient women had higher symptoms than resilient men. Sex differences in prevalence rates were observed for the recovery (higher in women) and delayed onset (higher in men) trajectories. Model fit for the sex-disaggregated samples was better than for the whole sample, indicating preferred application of sex-disaggregation. Analyses within the whole sample led to biased estimates of overall and sex-specific trajectory prevalence rates. Conclusions Sex-disaggregated trajectory analyses revealed limited sex differences in PTSD symptom trajectories within one-year post-trauma in terms of general trends, courses and prevalence rates. The observed biased trajectory prevalence rates in the whole sample emphasize the necessity to apply appropriate statistical techniques when conducting sex-sensitive research

Neurobiological Mechanisms That Contribute to Stress-related Cocaine Use

The ability of stressful life events to trigger drug use is particularly problematic for the management of cocaine addiction due to the unpredictable and often uncontrollable nature of stress. For this reason, understanding the neurobiological processes that contribute to stress-related drug use is important for the development of new and more effective treatment strategies aimed at minimizing the role of stress in the addiction cycle. In this review we discuss the neurocircuitry that has been implicated in stress-induced drug use with an emphasis on corticotropin releasing factor actions in the ventral tegmental area (VTA) and an important pathway from the bed nucleus of the stria terminalis to the VTA that is regulated by norepinephrine via actions at beta adrenergic receptors. In addition to the neurobiological mechanisms that underlie stress-induced cocaine seeking, we review findings suggesting that the ability of stressful stimuli to trigger cocaine use emerges and intensifies in an intake-dependent manner with repeated cocaine self-administration. Further, we discuss evidence that the drug-induced neuroadaptations that are necessary for heightened susceptibility to stress-induced drug use are reliant on elevated levels of glucocorticoid hormones at the time of cocaine use. Finally, the potential ability of stress to function as a “stage setter” for drug use – increasing sensitivity to cocaine and drug-associated cues – under conditions where it does not directly trigger cocaine seeking is discussed. As our understanding of the mechanisms through which stress promotes drug use advances, the hope is that so too will the available tools for effectively managing addiction, particularly in cocaine addicts whose drug use is stress-driven

Sex-differential PTSD symptom trajectories across one year following suspected serious injury

Background: Recent years have shown an increased application of prospective trajectory-oriented approaches to posttraumatic stress disorder (PTSD). Although women are generally considered at increased PTSD risk, sex and gender differences in PTSD symptom trajectories have not yet been extensively studied. Objective: To perform an in-depth investigation of differences in PTSD symptom trajectories across one-year post-trauma between men and women, by interpreting the general trends of trajectories observed in sex-disaggregated samples, and comparing within-trajectory symptom course and prevalence rates. Method: We included N = 554 participants (62.5% men, 37.5% women) from a multi-centre prospective cohort of emergency department patients with suspected severe injury. PTSD symptom severity was assessed at 1, 3, 6, and 12 months post-trauma, using the Clinician-Administered PTSD Scale for DSM-IV. Latent growth mixture modelling on longitudinal PTSD symptoms was performed within the sex-disaggregated whole samples. Bayesian modelling with informative priors was applied for reliable model estimation, considering the imbalanced prevalence of the expected latent trajectories. Results: In terms of general trends, the same trajectories were observed for men and women, i.e. resilient, recovery, chronic symptoms and delayed onset. Within-trajectory symptom courses were largely comparable, but resilient women had higher symptoms than resilient men. Sex differences in prevalence rates were observed for the recovery (higher in women) and delayed onset (higher in men) trajectories. Model fit for the sex-disaggregated samples was better than for the whole sample, indicating preferred application of sex-disaggregation. Analyses within the whole sample led to biased estimates of overall and sex-specific trajectory prevalence rates. Conclusions: Sex-disaggregated trajectory analyses revealed limited sex differences in PTSD symptom trajectories within one-year post-trauma in terms of general trends, courses and prevalence rates. The observed biased trajectory prevalence rates in the whole sample emphasize the necessity to apply appropriate statistical techniques when conducting sex-sensitive research

Structural asymmetry and discrete nucleic acid subdomains in the Trypanosoma brucei kinetoplast

The mitochondrial genome of Trypanosoma brucei is contained in a specialized structure termed the kinetoplast. Kinetoplast DNA (kDNA) is organized into a concatenated network of mini and maxicircles, positioned at the base of the flagellum, to which it is physically attached. Here we have used electron microscope cytochemistry to determine structural and functional domains involved in replication and segregation of the kinetoplast. We identified two distinct subdomains within the kinetoflagellar zone (KFZ) and show that the unilateral filaments are composed of distinct inner and outer filaments. Ethanolic phosphotungstic acid (E-PTA) and EDTA regressive staining indicate that basic proteins and DNA are major constituents of the inner unilateral filaments adjoining the kDNA disc. This evidence for an intimate connection of the unilateral filaments in the KFZ with DNA provides support for models of minicircle replication involving vectorial export of free minicircles into the KFZ. Unexpectedly however, detection of DNA in the KFZ throughout the cell cycle suggests that other processes involving kDNA occur in this domain. We also describe a hitherto unrecognized, intramitochondrial, filamentous structure rich in basic proteins that links the kDNA discs during their segregation and is maintained between them for an extended period of the cell cycle

Thermal Dileptons at LHC

We predict dilepton invariant-mass spectra for central 5.5 ATeV Pb-Pb collisions at LHC. Hadronic emission in the low-mass region is calculated using in-medium spectral functions of light vector mesons within hadronic many-body theory. In the intermediate-mass region thermal radiation from the Quark-Gluon Plasma, evaluated perturbatively with hard-thermal loop corrections, takes over. An important source over the entire mass range are decays of correlated open-charm hadrons, rendering the nuclear modification of charm and bottom spectra a critical ingredient.Comment: 2 pages, 2 figures, contributed to Workshop on Heavy Ion Collisions at the LHC: Last Call for Predictions, Geneva, Switzerland, 14 May - 8 Jun 2007 v2: acknowledgment include