Methylation of FKBP5 and SLC6A4 in Relation to Treatment Response to Mindfulness Based Stress Reduction for Posttraumatic Stress Disorder

Mindfulness Based Stress Reduction (MBSR) is an effective non-pharmacologic treatment for veterans with PTSD. Extensive work has identified epigenetic factors related to PTSD disease risk and pathophysiology, but how these factors influence treatment response is unclear. Serotonin signaling and hypothalamic-pituitary-adrenal (HPA) axis functioning may be perturbed in PTSD and are molecular pathways targeted by PTSD treatments. To identify potential biomarkers for treatment response, we utilized genomic DNA isolated from peripheral blood samples from veterans with PTSD who were responders (n = 11) or non-responders (n = 11) to MBSR as part of a clinical trial. We assessed methylation levels at CpG sites in regions of the serotonin transporter (SLC6A4) previously associated with expression and depression outcomes, as well as the Intron 7 region of the FK506 binding protein 5 (FKBP5) containing known glucocorticoid response elements suggested to regulate this gene. Selected subjects were matched across MBSR responder status by baseline symptoms, age, sex, current smoking status, and current antidepressant use. Percent methylation was compared between responders and non-responders at baseline (pre-MBSR treatment). Additionally, percent change in methylation from baseline to post-treatment was compared between responders and non-responders. There was a significant time x responder group interaction for methylation in FKBP5 intron 7 bin 2 [F(1, 19) = 7.492, p = 0.013] whereby responders had a decrease in methylation and non-responders had an increase in methylation from before to after treatment in this region. Analyses of the three CpG sites within bin 2 revealed a significant time x responder group interaction for CpG_35558513 [F(1, 19) = 5.551, p = 0.029] which resides in a known glucocorticoid response element (GRE). Decreases in FKBP5 methylation after treatment in responders as compared to increases in non-responders suggest that effective meditation intervention may be associated with stress-related pathways at the molecular level. These preliminary findings suggest that DNA methylation signatures within FKBP5 are potential indicators of response to meditation treatment in PTSD and require validation in larger cohorts

D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.2018-05-0

Prevalence of resistance to ceftolozane/tazobactam and comparator agents in relation to resistance category and <i>H</i>30 subclone status among 595 <i>E</i>. <i>coli</i> clinical isolates from veterans.

<p>Prevalence of resistance to ceftolozane/tazobactam and comparator agents in relation to resistance category and <i>H</i>30 subclone status among 595 <i>E</i>. <i>coli</i> clinical isolates from veterans.</p

Prevalence of resistance to ceftolozane/tazobactam among <i>Escherichia coli</i> clinical isolates susceptible or resistant to alternative agents.

<p>Prevalence of resistance to ceftolozane/tazobactam among <i>Escherichia coli</i> clinical isolates susceptible or resistant to alternative agents.</p

MICs for ceftolozane/tazobactam and comparator agents in relation resistance category among 595 <i>Escherichia coli</i> clinical isolates from veterans.

<p>MICs for ceftolozane/tazobactam and comparator agents in relation resistance category among 595 <i>Escherichia coli</i> clinical isolates from veterans.</p

MICs for ceftolozane/tazobactam and comparator agents in relation to <i>H</i>30 subclone status among 594 <i>Escherichia coli</i> clinical isolates from veterans.

<p>MICs for ceftolozane/tazobactam and comparator agents in relation to <i>H</i>30 subclone status among 594 <i>Escherichia coli</i> clinical isolates from veterans.</p

Using consumer-wearable technology for remote assessment of physiological response to stress in the naturalistic environment.

Psychosocial stress is a major risk factor for morbidity and mortality related to a wide range of health conditions and has a significant negative impact on public health. Quantifying exposure to stress in the naturalistic environment can help to better understand its health effects and identify strategies for timely intervention. The objective of the current project was to develop and test the infrastructure and methods necessary for using wearable technology to quantify individual response to stressful situations and to determine if popular and accessible fitness trackers such as Fitbit® equipped with an optical heart rate (HR) monitor could be used to detect physiological response to psychosocial stress in everyday life. The participants in this study were University of Minnesota students (n = 18) that owned a Fitbit® tracker and had at least one upcoming examination. Continuous HR and activity measurements were obtained during a 7-day observation period containing examinations self-reported by the participants. Participants responded to six ecological momentary assessment surveys per day (~ 2 hour intervals) to indicate occurrence of stressful events. We compared HR during stressful events (e.g., exams) to baseline HR during periods indicated as non-stressful using mixed effects modeling. Our results show that HR was elevated by 8.9 beats per minute during exams and by 3.2 beats per minute during non-exam stressors. These results are consistent with prior laboratory findings and indicate that consumer wearable fitness trackers could serve as a valuable source of information on exposure to psychosocial stressors encountered in the naturalistic environment

Activity of meropenem/vaborbactam against international carbapenem-resistant Escherichia coli isolates in relation to clonal background, resistance genes, resistance to comparators and region

Objectives: Carbapenem resistance has emerged inEscherichia coli, including sequence type 131 (ST131) and its fluoroquinolone-resistant H30R subclone, the leading cause of extraintestinal E. coli infections globally. Meropenem/vaborbactam (MVB) is a recently approved carbapenem/β-lactamase inhibitor combination with broad-spectrum inhibition of β-lactamases, including serine carbapenemases. The activity of MVB against carbapenem-resistant (CR) E. coli infections in relation to phylogenetic background, resistance genotype and geographical region is unknown. Methods: We characterised 140 contemporary CR clinicalE. coli isolates from 17 non-US countries (2003–2017) for phylogroup, clonal group (including ST131, H30R and the CTX-M-15-associated H30Rx subset), relevant β-lactamase genes, and broth microdilution MICs for MVB and 11 comparators. Results: Overall, MVB was moderately active (66% susceptible), more so than all comparators except tigecycline and amikacin (100% and 74% susceptible, respectively). Most MVB-non-susceptible isolates carried metallo-β-lactamase or OXA-48 resistance genes. MVB’s activity varied significantly in relation to phylogroup, clonal background, resistance genotype and global region: it was greatest among phylogroup F, ST131-H30R, H30Rx, Klebsiella pneumoniae carbapenemase (KPC)-positive and Latin American isolates, and lowest among phylogroup B1, metallo-β-lactamase gene-containing and Asia-West Pacific region isolates. Enhancement of meropenem’s activity by vaborbactam was most evident for isolates from phylogroups B2, C and D, and those containing KPC. MVB retained appreciable (albeit somewhat reduced) activity against isolates resistant to comparator agents. Conclusion: MVB should be useful for treating international CRE. coli infections, largely independent of other resistance phenotypes, although this likely will vary with the local prevalence of specific E. coli lineages and carbapenem resistance mechanisms

Colonization with <i>Escherichia coli</i> ST131-<i>H</i>30R (<i>H</i>30R) Corresponds with Increased Serum Anti-O25 IgG Levels and Decreased TNFα and IL-10 Responsiveness to <i>H</i>30R

An exceptional gut-colonizing ability may underlie the dramatic epidemiological success of the multidrug-resistant H30R subclone of Escherichia coli sequence type 131 (O25b:K+:H4). In order to inform the development of colonization-preventing measures, we studied systemic immune correlates of H30R intestinal colonization. Human volunteers’ fecal samples were screened for H30R by selective culture and PCR. Subjects were assessed by enzyme immunoassay for serum levels of anti-O25 IgG (representing H30R) and anti-O6 IgG (representing non-H30 E. coli generally), initially and for up to 14 months. Whole blood was tested for the antigen-stimulated release of IFNγ, TNFα, IL-4, IL-10, and IL-17 after incubation with E. coli strains JJ1886 (H30R; O25b:K+:H4) or CFT073 (non-H30; O6:K2:H1). Three main findings were obtained. First, H30R-colonized subjects had significantly higher anti-O25 IgG levels than controls, but similar anti-O6 IgG levels, suggesting an IgG response to H30R colonization. Second, anti-O25 and anti-O6 IgG levels were stable over time. Third, H30R-colonized subjects exhibited a lower TNFα and IL-10 release than controls in response to strain JJ1886 (H30R) relative to strain CFT073 (non-H30R), consistent with TNFα hypo-responsiveness to H30R possibly predisposing to H30R colonization. Thus, H30R-colonized hosts exhibit a sustained serum anti-O25 IgG response and an underlying deficit in TNFα responsiveness to H30R that could potentially be addressed for colonization prevention