Ketamine-enhanced prolonged exposure therapy in veterans with PTSD: A randomized controlled trial protocol.

BACKGROUND: The 2023 VA/DoD Clinical Practice Guideline for the Management of PTSD recommends individual, manualized trauma-focused such as Prolonged Exposure (PE) over pharmacologic interventions for the primary treatment of PTSD. Unfortunately, clinical trials of trauma-based therapies in the military and veteran population showed that 30% to 50% of patients did not demonstrate clinically meaningful symptom change. Ketamine, an FDA-approved anesthetic with potent non-competitive glutamatergic N-methyl-d-aspartate antagonistic properties, has demonstrated to enhance the recall of extinction learning and decrease fear renewal without interference of extinction training in preclinical studies. METHODS: We plan to conduct a single site RCT comparing three ketamine treatment vs. active placebo (midazolam) adjunct to PE therapy among Veterans with PTSD. Pharmacological phase will start simultaneously with PE session 1. Infusions will be administered 24 h. prior to PE session for the first 3 weeks. After PE is completed (session 10), patients will be assessed during a 3-month follow-up period at various time points. We estimate that out of 100 veterans, 80 will reach time point for primary outcome measure and will be considered for primary analysis. Secondary outcomes include severity of depression and anxiety scores, safety and tolerability of ketamine-enhanced PE therapy, cognitive performance during treatment and early improvement during PE related to the rate of dropouts during PE therapy. DISCUSSION: Results of the proposed RCT could provide scientific foundation to distinguish the essential components of this approach, enhance the methodology, elucidate the mechanisms involved, and identify sub-PTSD populations that most likely benefit from this intervention.

Early Chronic Fluoxetine Treatment of Ts65Dn Mice Rescues Synaptic Vesicular Deficits and Prevents Aberrant Proteomic Alterations.

Down syndrome (DS) is the most common form of inherited intellectual disability caused by trisomy of chromosome 21, presenting with intellectual impairment, craniofacial abnormalities, cardiac defects, and gastrointestinal disorders. The Ts65Dn mouse model replicates many abnormalities of DS. We hypothesized that investigation of the cerebral cortex of fluoxetine-treated trisomic mice may provide proteomic signatures that identify therapeutic targets for DS. Subcellular fractionation of synaptosomes from cerebral cortices of age- and brain-area-matched samples from fluoxetine-treated vs. water-treated trisomic and euploid male mice were subjected to HPLC-tandem mass spectrometry. Analysis of the data revealed enrichment of trisomic risk genes that participate in regulation of synaptic vesicular traffic, pre-synaptic and post-synaptic development, and mitochondrial energy pathways during early brain development. Proteomic analysis of trisomic synaptic fractions revealed significant downregulation of proteins involved in synaptic vesicular traffic, including vesicular endocytosis (CLTA, CLTB, CLTC), synaptic assembly and maturation (EXOC1, EXOC3, EXOC8), anterograde axonal transport (EXOC1), neurotransmitter transport to PSD (SACM1L), endosomal-lysosomal acidification (ROGDI, DMXL2), and synaptic signaling (NRXN1, HIP1, ITSN1, YWHAG). Additionally, trisomic proteomes revealed upregulation of several trafficking proteins, involved in vesicular exocytosis (Rab5B), synapse elimination (UBE3A), scission of endocytosis (DBN1), transport of ER in dendritic spines (MYO5A), presynaptic activity-dependent bulk endocytosis (FMR1), and NMDA receptor activity (GRIN2A). Chronic fluoxetine treatment of Ts65Dn mice rescued synaptic vesicular abnormalities and prevented abnormal proteomic changes in adult Ts65Dn mice, pointing to therapeutic targets for potential treatment of DS.

Serotonin Transporter (SLC6A4) and FK506-Binding Protein 5 (FKBP5) Genotype and Methylation Relationships with Response to Meditation in Veterans with PTSD.

Meditation-based interventions are novel and effective non-pharmacologic treatments for veterans with PTSD. We examined relationships between treatment response, early life trauma exposure, DNA polymorphisms, and methylation in the serotonin transporter (SLC6A4) and FK506-binding protein 5 (FKBP5) genes. DNA samples and clinical outcomes were examined in 72 veterans with PTSD who received meditation-based therapy in two separate studies of mindfulness-based stress reduction (MBSR) and Transcendental Meditation (TM). The PTSD Checklist was administered to assess symptoms at baseline and after 9 weeks of meditation intervention. We examined the SLC6A4 promoter (5HTTLPR_L/S insertion/deletion + rs25531_A/G) polymorphisms according to previously defined gene expression groups, and the FKBP5 variant rs1360780 previously associated with PTSD disease risk. Methylation for CpG sites of SLC6A4 (28 sites) and FKBP5 (45 sites) genes was quantified in DNA samples collected before and after treatment. The 5HTTLPR LALA high expression genotype was associated with greater symptom improvement in participants exposed to early life trauma (p = 0.015). Separately, pre to post-treatment change of DNA methylation in a group of nine FKBP5 CpG sites was associated with greater symptom improvement (OR = 2.8, 95% CI 1.1-7.1, p = 0.027). These findings build on a wealth of existing knowledge regarding epigenetic and genetic relationships with PTSD disease risk to highlight the potential importance of SLC6A4 and FKBP5 for treatment mechanisms and as biomarkers of symptom improvement.

Antidepressant Strategies for Treatment of Acute Depressive Episodes Among Veterans.

OBJECTIVE: The 2016 VA/DoD Clinical Practice Guideline for Management of Major Depressive Disorder offers consensus-based recommendations when response to the initial antidepressant medication is suboptimal; however, little is known about "real-world" pharmacological strategies used by providers treating depression in the Veterans Affairs Health Care System (VAHCS). METHODS: We extracted pharmacy and administrative records of patients diagnosed with a depressive disorder and treated at the Minneapolis VAHCS between January 1, 2010 and May 11, 2021. Patients with bipolar disorder, psychosis-spectrum, or dementia diagnoses were excluded. An algorithm was developed to identify antidepressant strategies: monotherapy (MONO); optimization (OPM); switching (SWT); combination (COM); and augmentation (AUG). Additional data extracted included demographics, service utilization, other psychiatric diagnoses, and clinical risk for hospitalization and mortality. RESULTS: The sample consisted of 1298 patients, 11.3% of whom were female. The mean age of the sample was 51 years. Half of the patients received MONO, with 40% of those patients receiving inadequate doses. OPM was the most common next-step strategy. SWT and COM/AUG were used for 15.9% and 2.6% of patients, respectively. Overall, patients who received COM/AUG were younger. OPM, SWT, and COM/AUG occurred more frequently in psychiatric services settings and required a greater number of outpatient visits. The association between antidepressant strategies and risk of mortality became nonsignificant after accounting for age. CONCLUSIONS: Most of the veterans with acute depression were treated with a single antidepressant, while COM and AUG were rarely used. The age of the patient, and not necessarily greater medical risks, appeared to be a major factor in decisions about antidepressant strategies. Future studies should evaluate whether implementation of underutilized COM and AUG strategies early in the course of depression treatment are feasible.

Colonization with Escherichia coli ST131-H30R (H30R) Corresponds with Increased Serum Anti-O25 IgG Levels and Decreased TNFα and IL-10 Responsiveness to H30R.

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.

Evidence for an alcohol-related "harm paradox" in individuals with internalizing disorders: Test and replication in two independent community samples.

BACKGROUND: Internalizing (anxiety and mood) disorders (INTD) commonly co-occur (are "comorbid") with alcohol use disorder (AUD). The literature suggests that excessive alcohol use aimed at coping with INTD symptoms is, at best, a partial explanation for the high comorbidity rates observed. We hypothesized that individuals with INTD experience greater susceptibility to developing AUD symptoms due to the partially shared neurobiological dysfunctions underlying both conditions. We probe this hypothesis by testing the prediction that, after accounting for the volume of alcohol intake, individuals with INTD experience higher levels of alcohol-related symptoms. METHODS: Data from the National Epidemiological Survey on Alcohol-Related Conditions (NESARC) Wave 3 were used for the primary analyses, and NESARC Wave 1 data were used for independent replication analyses. Individuals who reported any alcohol use in the prior year were categorized as: (1) never having had an INTD diagnosis ("INTD-Never"); (2) having a remitted INTD diagnosis only ("INTD-Remitted"); or (3) having current INTD diagnosis ("INTD-Current"). Between-group contrasts of alcohol-related symptoms controlled for total alcohol intake (past year), drinking pattern (e.g., binging) and variables previously shown to mark exaggerated AUD symptoms relative to drinking amount (e.g., SES, gender, and family history). RESULTS: With all covariates in the model, individuals in the INTD-Current group and the INTD-Remitted group reported significantly greater alcohol-related symptoms than those in the INTD-Never group but did not themselves differ in level of alcohol-related symptoms. These results were replicated in the NESARC 1 dataset. CONCLUSIONS: Individuals with INTD experience more alcohol-related symptoms than those who drink at the same level. While considering other explanations, we argue that this "harm paradox" is best explained by the view that INTD confers a neurobiologically mediated susceptibility to the development of AUD symptoms.

Feasibility of Using an Armband Optical Heart Rate Sensor in Naturalistic Environment.

Consumer-grade heart rate (HR) sensors including chest straps, wrist-worn watches and rings have become very popular in recent years for tracking individual physiological state, training for sports and even measuring stress levels and emotional changes. While the majority of these consumer sensors are not medical devices, they can still offer insights for consumers and researchers if used correctly taking into account their limitations. Multiple previous studies have been done using a large variety of consumer sensors including Polar® devices, Apple® watches, and Fitbit® wrist bands. The vast majority of prior studies have been done in laboratory settings where collecting data is relatively straightforward. However, using consumer sensors in naturalistic settings that present significant challenges, including noise artefacts and missing data, has not been as extensively investigated. Additionally, the majority of prior studies focused on wrist-worn optical HR sensors. Arm-worn sensors have not been extensively investigated either. In the present study, we validate HR measurements obtained with an arm-worn optical sensor (Polar OH1) against those obtained with a chest-strap electrical sensor (Polar H10) from 16 participants over a 2-week study period in naturalistic settings. We also investigated the impact of physical activity measured with 3-D accelerometers embedded in the H10 chest strap and OH1 armband sensors on the agreement between the two sensors. Overall, we find that the arm-worn optical Polar OH1 sensor provides a good estimate of HR (Pearson r = 0.90, p <0.01). Filtering the signal that corresponds to physical activity further improves the HR estimates but only slightly (Pearson r = 0.91, p <0.01). Based on these preliminary findings, we conclude that the arm-worn Polar OH1 sensor provides usable HR measurements in daily living conditions, with some caveats discussed in the paper.

World Health Organization (WHO) risk level reductions in inpatients with alcohol use disorder and comorbid anxiety disorders.

OBJECTIVE: Studies have demonstrated that reduced drinking without total abstinence is associated with improved outcomes in outpatients with alcohol use disorder (AUD). We sought to examine this question in AUD inpatients who have comorbid anxiety disorders, a common presentation in AUD. METHOD: This is a secondary analysis of data from a randomized controlled trial for N = 241 inpatients with AUD and comorbid anxiety disorders. Change from baseline drinking level was measured at 1-, 4-, and 12-months postdischarge, and psychological and functional outcomes were measured at 4- and 12-months postdischarge. Three groups were compared: abstinent, reduced (reduced drinking by 1-3 World Health Organization drinking risk levels without abstinence), or nonreduced (maintained or increased drinking risk level). RESULTS: At 1-, 4-, and 12-months posttreatment, most patients reported abstinence (83, 63, and 60%), and 11, 25, and 26% reported drinking at a reduced level. Drinking reductions achieved at 1-month posttreatment were maintained at 12-month posttreatment by 74% of participants. Overall, the abstinent group reported the best psychological and functional outcomes at follow-ups, followed by the reduced group. Few differences were observed between reducers and nonreducers, but reducers reported significantly better alcohol dependence severity and alcohol-related problems than nonreducers. CONCLUSIONS: Though abstinence was associated with the best outcomes in this abstinence-based treatment sample, we conclude that reduced drinking is also associated with significant improvements in alcohol-related outcomes in inpatients with AUD and comorbid anxiety disorders.At 1-, 4-, and 12-months posttreatment, most patients reported abstinence (83, 63, and 60%), and 11, 25, and 26% reported drinking at a reduced level. Drinking reductions achieved at 1-month posttreatment were maintained at 12-month posttreatment by 74% of participants. Overall, the abstinent group reported the best psychological and functional outcomes at follow-ups, followed by the reduced group. Few differences were observed between reducers and nonreducers, but reducers reported significantly (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A Retrospective Pilot Study of Imagery Rehearsal Therapy Enhanced with Narrative Therapy Principles for the Treatment of Nightmares in US Military Veterans.

Introduction Chronic nightmares are a common and disabling feature of posttraumatic stress disorder (PTSD) for which broadly effective treatments are still lacking. While imagery rehearsal therapy (IRT) demonstrates benefits for patients with idiopathic nightmares and some patients with PTSD-related nightmares, research indicates it may be less beneficial for veterans. Narrative therapy (NT) is a form of psychotherapy which is client-centered and value-focused and has demonstrated benefits for PTSD patients. The application of NT principles to IRT may provide a valuable therapeutic approach for treatment in veterans. Objective To perform a retrospective chart review of veteran clients participating in a novel, brief intervention developed by the first author consisting of IRT enhanced with NT principles (N-IRT) for the treatment of nightmares. The primary outcomes were nightmare frequency and intensity, and the secondary outcome was the impact of the intervention on nightmare distress and coping, subjective sleep quality, and overall PTSD symptoms. Materials and Methods We conducted retrospective chart reviews for eight veterans referred to the first author for the treatment of nightmares, who completed N-IRT, including baseline and end-of-treatment measures. The protocol involved a single 60-minute NT-enhanced rescripting session and assigned homework to rehearse the revised dream script, and a follow-up evaluation 4 weeks later. The subjects completed a sleep and nightmare interview developed by the first author and the PTSD Checklist at baseline and after the intervention at the follow-up evaluation. Paired t -tests were conducted to test for pre-to-post differences. Results In the statistical analysis, we observed a statistically significant and clinically meaningful reduction in the frequency ( p = 0.04) and intensity of nightmares ( p = 0.001) from pretreatment to the 1-month follow-up. Measures of nightmare-associated emotional distress, the ability to cope with nightmares, sleep duration and sleep efficiency, as well as overall PTSD symptoms also demonstrated significant improvements. Conclusion These pilot data provide compelling preliminary evidence that a single-session IRT intervention modified with NT (N-IRT) is effective in reducing nightmare frequency and intensity, reducing nightmare distress, improving the act of coping with nightmares, and improving sleep quality and overall PTSD symptoms in veterans. Further investigation of this method with gold-standard clinical trial designs and larger sample sizes is indicated to confirm effectiveness and to better understand the possible mechanisms of treatment effect.

Neurocognitive effects of repeated ketamine infusions in comorbid posttraumatic stress disorder and major depressive disorder.

BACKGROUND: The glutamate N-methyl-d-aspartate (NMDA) receptor antagonist ketamine rapidly ameliorates posttraumatic stress disorder (PTSD) and depression symptoms in individuals with comorbid PTSD and major depressive disorder (MDD). However, concerns over ketamine's potential neurocognitive side effects have yet to be assessed in this population. The current study investigated 1) changes in neurocognitive performance after a repeated ketamine dosing regimen and 2) baseline neurocognitive performance as a predictor of ketamine treatment effect. METHOD: Veterans with comorbid PTSD and MDD (N = 15) received six infusions of 0.5 mg/kg ketamine over a 12-day period. Neurocognitive and clinical outcomes assessments occurred at baseline and within 7 days of infusion-series completion using the CogState battery. RESULTS: Repeated ketamine infusions did not significantly worsen any measures of cognition. Rather, significant improvement was observed in working memory following completion of the infusion series. In addition, greater improvements in PTSD and MDD symptoms were associated with lower working memory, slower processing speed and faster set shifting at baseline. Lower verbal learning was also predictive of improvement in depression. LIMITATIONS: This study applied an open-label design without a placebo control. As such, it is not known to what extent the correlations or improvement in neurocognitive performance may have occurred under placebo conditions. CONCLUSION: This is the first study to examine the neurocognitive effects of repeated ketamine in participants with comorbid PTSD and MDD. Our findings suggest potential baseline neurocognitive predictors of ketamine response for comorbid PTSD and MDD symptoms.

Intestinal Persistence of Colonizing Escherichia coli Strains, Especially ST131-H30, in Relation to Bacterial and Host Factors.

BACKGROUND: Superior gut colonization may underlie the pandemic emergence of the resistance-associated H30 subclone of Escherichia coli sequence type 131 (ST131-H30). Little is known about the associated host and bacterial characteristics, or the comparative persistence of non-ST131 intestinal E. coli. METHODS: Generic and fluoroquinolone-resistant E. coli isolates from volunteers' serial fecal samples underwent clonal analysis and extensive polymerase chain reaction (PCR)-based characterization (phylogroup, selected sequence types, virulence genes). Kaplan-Meier survival analysis and Cox proportional hazards survival analysis using penalized regression (a machine-learning method) were used to identify correlates of strain persistence. RESULTS: Screening of 2005 subjects at the Minneapolis VA Medical Center identified 222 subjects (117 veterans, 105 human and animal household members) for longitudinal fecal surveillance. Analysis of their 585 unique-by-subject fecal E. coli strains identified multiple epidemiological, ecological, and bacterial correlates of strain persistence. ST131-H30, a strong univariable correlate of persistence, was superseded in multivariable analysis by outpatient status, fluoroquinolone resistance, and diverse (predominantly iron uptake-related) virulence genes. CONCLUSIONS: ST131-H30 exhibits exceptional intestinal persistence, possibly due to a combination of fluoroquinolone resistance and virulence factors, which may be primarily colonization factors. This identifies both likely contributors to the ST131-H30 pandemic and potential targets for interventions against it.

The Proposal Preparation Program: A Group Mentoring, Faculty Development Model to Facilitate the Submission and Funding of NIH Grant Applications.

This article describes the University of Minnesota Medical School Proposal Preparation Program (P3). P3 is designed to develop grant-writing skills for assistant professors preparing their first K- or R-series application to the National Institutes of Health (NIH). Three 4-month P3 cycles are conducted annually. For each cycle, a cohort of around 10 assistant professor participants and 5 regular faculty mentors meet for ten ~2-hour group sessions. Participants receive iterative oral and written feedback on their proposals in development within a small, interdisciplinary, group mentoring setting providing structure, accountability, guidance, and support. Between sessions, 1 peer and 1 mentor are assigned (on a rotating basis) to critique each participant's developing application. The sessions include a brief mentor-led presentation on a particular grant section followed by discussion of each participant's application conducted by the assigned reviewers. The cycle concludes with a mock NIH review session, in which each participant is matched with a University of Minnesota faculty content expert who critiques their completed application using NIH guidelines. In a survey sent to all past P3 participants as of 2018 (n = 194), 88% of respondents reported having submitted their P3-developed NIH grant, and 35% of these submitters reported funding success. A separate analysis of institutional data for all past P3 participants as of 2016 (n = 165) showed that 73% submitted at least 1 NIH proposal since completing P3 and that 43% of these had acquired NIH funding, for a combined total of $193 million in funding awarded. The estimated rate at which participants obtained funding for their P3-developed grant application (~35%) exceeds the national annual NIH grant funding rates (~20%) by approximately 50%. This article provides the practical information needed for other institutions to implement a P3-like program and presents a cost-benefit analysis showing the advantages of doing so.

Characterization of Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder Using Ketamine as an Experimental Medicine Probe †.

Comorbid posttraumatic stress disorder and major depressive disorder (PTSD + MDD) is the most common pathological response to trauma, yet despite their synergistic detriment to health, knowledge regarding the neurobiological mechanism underlying PTSD + MDD is extremely limited. This study proposes a novel model of PTSD + MDD that is built on biological systems shown to underlay PTSD + MDD and takes advantage of ketamine's unique suitability to probe PTSD + MDD due to its rescue of stress-related neuroplasticity deficits. The central hypothesis is that changes in PTSD + MDD clinical symptoms are associated with functional connectivity changes and cognitive dysfunction and that ketamine infusions improve clinical symptoms by correction of functional connectivity changes and improvement in cognition. Participants with PTSD + MDD (n = 42) will be randomized to receive a series of six ketamine infusions or saline-placebo over three weeks. Pre/post-measures will include: (1) neuroimaging; (2) cognitive functioning task performance; and (3) PTSD, MDD, and rumination self-report measures. These measures will also be collected once in a trauma-exposed group including PTSD-only (n = 10), trauma-exposed-MDD (TE-MDD; n = 10), and healthy controls (HC, n = 21). Successful completion of the study will strongly support the concept of a biologically-based model of PTSD + MDD. The results will (1) identify functional imaging signatures of the mechanisms underpinning pathological responses to trauma, (2) shift focus from mono-diagnostic silos to unified biological and behavioral disease processes and, thus, (3) inform interventions to correct dysregulation of PTSD + MDD symptom clusters thereby supporting more precise treatments and better outcomes.

Reduced alcohol use in patients prescribed pioglitazone.

BACKGROUND AND OBJECTIVES: Alcohol use disorder (AUD) is common and causes significant morbidity and mortality. Currently approved medications are moderately effective. Novel medications are needed to address AUD. Preliminary data suggests pioglitazone may reduce alcohol use. METHODS: Veterans seen at the Minneapolis VA Health Care System, who were prescribed pioglitazone for diabetes between October 1, 2015 and September 30, 2016, were identified using a national VA database (N = 49). Further chart review was performed to identify all Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores prior to starting pioglitazone. Hierarchical Linear models were used to compare all AUDIT-C scores on and off pioglitazone and compare the change in AUDIT-C scores over time before and during pioglitazone was prescribed. AUDIT-C scores were nested within subject with fixed effects for pioglitazone and random intercept and slope for time. RESULTS: Forty-nine patients were prescribed pioglitazone and had AUDIT-C scores of 3 or more. The estimated mean AUDIT-C score prior to receiving pioglitazone was 3.98 (95% confidence interval [CI]: 3.51-4.44) and this was reduced to 2.89 (95% CI: 2.46-3.32), reflecting a significant change F(1, 323) = 43.3, p < .001 in the score. The primary reduction occurred within the first year of the pioglitazone prescription. This effect remained significant after controlling for age. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: This is the first study of pioglitazone used in a clinical sample focused on alcohol use outcome. The data show that pioglitazone may reduce alcohol use in patients with heavy drinking. Clinical trials of pioglitazone are warranted in patients with AUD.

Global molecular epidemiology of carbapenem-resistant Escherichia coli (2002-2017).

The emergence of carbapenem-resistant (CR) Escherichia coli obliges an assessment of such strains' molecular epidemiology. Accordingly, we characterized in detail a globally distributed collection of CR E. coli isolates, then explored for associations between geographical origin and bacterial traits, and between different bacterial traits. We used established PCR-based assays and broth microdilution MIC determinations to characterize 343 global CR (i.e., non-susceptible to ≥ 1 carbapenem) extraintestinal E. coli isolates (2002-2017) for diverse molecular traits-including phylogroups, sequence types (STs), beta-lactamase genes, and 51 virulence genes-and susceptibility to 12 relevant antimicrobial agents. The study population was tremendously diverse according to all assessed variables. Nonetheless, certain geographically aligned, unifying themes emerged. These included an association of an Asia/West Pacific origin with non-B2/D/F phylogroups and STs, lower molecularly inferred virulence, more extensive resistance, and specific resistance genes (notably, metallo-beta-lactamases). Likewise, U.S. isolates from the central region, vs. other regions, were more virulent-appearing and more often from phylogroup B2 and ST131, but less extensively resistant and more often carbapenemase-gene negative. The global CR E. coli population is highly diverse according to multiple characteristics and varies significantly by geographical region. This predictably will pose challenges for prevention and management, and obliges ongoing surveillance.

Activity of plazomicin against carbapenem-intermediate or -resistant Escherichia coli isolates from the United States and international sites in relation to clonal background, resistance genes, co-resistance, and region.

BACKGROUND: Emerging carbapenem resistance in Escherichia coli, including sequence type 131 (ST131), threatens therapeutic efficacy. Plazomicin (PLZ), a semisynthetic aminoglycoside approved by the FDA in 2018, overcomes the most common aminoglycoside resistance mechanisms and maintains activity against many carbapenem-intermediate or -resistant (CIR) E. coli strains. OBJECTIVES: To assess plazomicin susceptibility among CIR E. coli in relation to region and multiple bacterial characteristics. METHODS: We determined broth microdilution MICs for plazomicin and 11 comparators against 343 CIR clinical E. coli isolates, then compared susceptibility results by bacterial characteristics and region. The collection comprised 203 US isolates (2002-17) and 141 isolates from 17 countries in Europe, Latin America, and the Asia-West Pacific region (2003-17). Isolates were characterized for phylogenetic group, resistance-associated sequence types (STs) and subsets thereof, and relevant ß-lactamase-encoding genes. RESULTS: Plazomicin exhibited the highest percentage susceptible (89%) after tigecycline (99%). The percentage susceptible to plazomicin varied significantly by phylogroup (63%, group B1; versus >93%, others) and ST131 subclone (92%, H30Rx; versus 87%-89%, H30R1 and non-H30), but not ST. It also varied by resistance genotype [higher with Klebsiella pneumoniae carbapenemase (KPC), lower with metallo-ß-lactamases], global region [highest for Latin America (94%), lowest for Asia-West Pacific (69%)], and US region (80%, South, versus 96%-100%, others). Although reduced susceptibility to comparators often predicted reduced susceptibility to plazomicin, even among comparator-intermediate or -resistant isolates the plazomicin-susceptible fraction was ≥77%, except for amikacin (53%). CONCLUSIONS: The likely utility of plazomicin against CIR E. coli is high overall, but varies with region and multiple bacterial characteristics.

Comparative activity of plazomicin against extended-spectrum cephalosporin-resistant Escherichia coli clinical isolates (2012-2017) in relation to phylogenetic background, sequence type 131 subclones, blaCTX-M genotype, and resistance to comparator agents.

Extended-spectrum cephalosporin-resistant Escherichia coli (ESCREC) are a growing threat. Leading ESCREC lineages include sequence type ST131, especially its (blaCTX-M-15-associated) H30Rx subclone and (blaCTX-M-27-associated) C1-M27 subset within the H30R1 subclone. The comparative activity against such strains of alternative antimicrobial agents, including the recently developed aminoglycoside plazomicin, is undefined, so was investigated here. We assessed plazomicin and 11 comparators for activity against 216 well-characterized ESCREC isolates (Minnesota, 2012-2017) and then compared broth microdilution MICs with phylogenetic and clonal background, beta-lactamase genotype (blaCTX-M; group 1 and 9 variants), and co-resistance. Percent susceptible was > 99% for plazomicin, meropenem, imipenem, and tigecycline; 96-98% for amikacin and ertapenem; and ≤ 75% for the remaining comparators. For most comparators, MICs varied significantly in relation to multiple bacterial characteristics, in agent-specific patterns. By contrast, for plazomicin, the only bacterial characteristic significantly associated with MICs was ST131 subclone: plazomicin MICs were lowest among O16 ST131 isolates and highest among ST131-H30R1 C1-M27 subclone isolates. Additionally, plazomicin MICs varied significantly in relation to resistance vs. susceptibility to comparator agents only for amikacin and levofloxacin. For most study agents, antimicrobial activity against ESCREC varied extensively in relation to multiple bacterial characteristics, including clonal background, whereas for plazomicin, it varied only by ST131 subclone (C1-M27 isolates least susceptible, O16 isolates most susceptible). These findings support plazomicin as a reliable alternative for treating ESCREC infections and urge continued attention to the C1-M27 ST131 subclone.

Pre-deployment personality traits predict prescription opioid receipt over 2-year post-deployment period in a longitudinal cohort of deployed National Guard soldiers.

BACKGROUND: While military service members are at risk forpain conditions, receipt of prescribed opioids is associated with a range of serious adverse outcomes. The goal of this study is to examine the association between pre-deployment personality traits and receipt of prescription opioids after return from deployment. METHOD: Data were drawn from the Readiness and Resilience in National Guard Soldiers (RINGS) cohort study, an ongoing study of post-deployment health. Participants (N = 522) completed baseline assessments one month prior to deploying to Iraq (2006-2007). At baseline, we assessed personality traits using abbreviated versions of the Personality Psychopathology Five scales from the Minnesota Multiphasic Personality Inventory-2. Follow-up assessments were conducted three months, one year, and two years post-deployment. The primary outcome was total amount of prescribed opioids dispensed from Department of Veterans Affairs outpatient pharmacies in the two-year period following soldiers' return from deployment. Unadjusted and adjusted negative binomial regression models examined the relationships of pre-deployment personality traits, demographics (age, gender, and rank), baseline trauma symptoms, deployment related risk factors (difficult living/working environment, deployment injury, combat exposure), and post-deployment trauma symptoms with post-deployment opioid prescribing. RESULTS: Disconstraint, negative emotionality, and introversion/low positive emotionality were associated with receipt of more prescribed opioids over the two years after return from deployment. Personality traits measured at baseline remained statistically significantly after adjusting for all eight baseline and deployment risk factors of interest. CONCLUSIONS: Understanding how pre-deployment personality traits contribute to post-deployment prescription opioid use could inform efforts to improve veterans' health.

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

[This corrects the article DOI: 10.3389/fpsyt.2018.00418.].

Activity of cefiderocol, ceftazidime-avibactam, and eravacycline against extended-spectrum cephalosporin-resistant Escherichia coli clinical isolates (2012-20017) in relation to phylogenetic background, sequence type 131 subclones, blaCTX-M genotype, and coresistance.

Extended-spectrum cephalosporin-resistant Escherichia coli (ESCREC) are a growing threat. Leading ESCREC lineages include sequence type ST131, especially its (blaCTX-M-15-associated) H30Rx subclone and (blaCTX-M-27-associated) C1-M27 subset within the H30R1 subclone. We assessed cefiderocol, ceftazidime-avibactam, eravacycline, and 11 comparators for activity against 216 well-characterized ESCREC isolates (Minnesota, 2012-2017), then compared broth microdilution MICs with phylogenetic and clonal background, beta-lactamase genotype (blaCTX-M; group 1 and 9 variants), and coresistance. Percent susceptible was >95% (cefiderocol, ceftazidime-avibactam, eravacycline, carbapenems, amikacin, piperacillin-tazobactam, tigecycline), 64% to 75% (gentamicin, minocycline), or <40% (ceftazidime, levofloxacin, colistin). MICs varied significantly by multiple bacterial characteristics, in agent-specific patterns. The least-susceptible ST131 subset was the non-C1-M27 fraction within H30R1. Cefiderocol, ceftazidime-avibactam, and eravacycline MICs tended to be higher among isolates resistant (vs. susceptible) to diverse comparators. Thus, cefiderocol, ceftazidime-avibactam, and eravacycline are promising carbapenem-sparing alternatives for treating ESCREC infections, and their strength of activity varies in relation to diverse bacterial characteristics.