A proteomic perspective on the resistance response of Klebsiella pneumoniae to antimicrobial peptide PaDBS1R1.

BACKGROUND: The synthetic antimicrobial peptide, PaDBS1R1, has been reported as a powerful anti-Klebsiella pneumoniae antimicrobial. However, there is only scarce knowledge about whether K. pneumoniae could develop resistance against PaDBS1R1 and which resistance mechanisms could be involved. OBJECTIVES: Identify via label-free shotgun proteomics the K. pneumoniae resistance mechanisms developed against PaDBS1R1. METHODS: An adaptive laboratory evolution experiment was performed to obtain a PaDBS1R1-resistant K. pneumoniae lineage. Antimicrobial susceptibility was determined through microdilution assay. Modifications in protein abundances between the resistant and sensitive lineages were measured via label-free quantitative shotgun proteomics. Enriched Gene Ontology terms and KEGG pathways were identified through over-representation analysis. Data are available via ProteomeXchange with identifier PXD033020. RESULTS: K. pneumoniae ATCC 13883 parental strain challenged with increased subinhibitory PaDBS1R1 concentrations allowed the PaDBS1R1-resistant K. pneumoniae lineage to emerge. Proteome comparisons between PaDBS1R1-resistant K. pneumoniae and PaDBS1R1-sensitive K. pneumoniae under PaDBS1R1-induced stress conditions enabled the identification and quantification of 1702 proteins, out of which 201 were differentially abundant proteins (DAPs). The profiled DAPs comprised 103 up-regulated proteins (adjusted P value < 0.05, fold change ≥ 2) and 98 down-regulated proteins (adjusted P value < 0.05, fold change ≤ 0.5). The enrichment analysis suggests that PhoPQ-guided LPS modifications and CpxRA-dependent folding machinery could be relevant resistance mechanisms against PaDBS1R1. CONCLUSIONS: Based on experimental evolution and a label-free quantitative shotgun proteomic approach, we showed that K. pneumoniae developed resistance against PaDBS1R1, whereas PhoPQ-guided LPS modifications and CpxRA-dependent folding machinery appear to be relevant resistance mechanisms against PaDBS1R1.

Efficacy and safety of sugammadex in the reversal of deep neuromuscular blockade induced by rocuronium in patients with end-stage renal disease: A comparative prospective clinical trial.

BACKGROUND: Renal failure affects the pharmacology of nondepolarizing neuromuscular blockers making recovery of neuromuscular function unpredictable. Sugammadex antagonises rocuronium-induced neuromuscular blockade by encapsulating rocuronium, creating a stable complex molecule that is mainly excreted by the kidneys. Previous studies suggest that sugammadex is effective in reversing moderate neuromuscular block in the presence of renal failure, but no data are available regarding reversal of profound neuromuscular block in patients with renal failure. OBJECTIVE: The objective of this study is to compare the efficacy and safety of sugammadex in reversing profound neuromuscular block induced by rocuronium in patients with end-stage renal disease and those with normal renal function. DESIGN: A prospective clinical trial. SETTING: Two university hospitals, from 1 October 2011 to 31 January 2012. PATIENTS: Forty patients undergoing kidney transplant: 20 with renal failure [creatinine clearance (ClCr) <30 ml min] and 20 control patients (ClCr >90 ml min). INTERVENTION: Neuromuscular monitoring was performed by acceleromyography and train-of-four (TOF) stimulation. Profound neuromuscular block (posttetanic count, one to three responses) was maintained during surgery. Sugammadex 4 mg kg was administered on completion of skin closure. Recovery of the TOF ratio to 0.9 was recorded. Monitoring of neuromuscular function continued in the postanesthesia care unit for a further 2 h. MAIN OUTCOME MEASURES: The efficacy of sugammadex was evaluated by the time taken for the TOF ratio to recover to 0.9. The safety of sugammadex was assessed by monitoring for recurrence of neuromuscular block every 15 min for 2 h. Secondary variables were time to recovery of TOF ratio to 0.7 and 0.8. RESULTS: After sugammadex administration, the mean time for recovery of the TOF ratio to 0.9 was prolonged in the renal failure group (5.6 ±â€Š3.6 min) compared with the control group (2.7 ±â€Š1.3 min, P = 0.003). No adverse events or evidence of recurrence of neuromuscular block were observed. CONCLUSION: In patients with renal failure, sugammadex (4 mg kg) effectively and safely reversed profound rocuronium induced neuromuscular block, but the recovery was slower than healthy patients. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01785758.

Skin picking treatment with the Rothbaum cognitive behavioral therapy protocol: a randomized clinical trial.

INTRODUCTION: Although behavioral therapies can effectively treat skin picking disorder (SPD), there is no standardized treatment for improving SPD and its comorbidities and there is no group intervention option. This trial aimed to adapt the Rothbaum trichotillomania protocol to SPD (Study 1) and test its efficacy for treating SPD and comorbidities in individual and group formats (Study 2). METHODS: The adapted protocol was applied to 16 SPD patients, who were allocated to group or individual treatment (Study 1). Afterwards, 54 patients were randomly allocated to treatment in an individual (n=27) or group format (n=27) (Study 2). In both studies, assessments of SPD severity, anxiety, depression, clinical status and skin lesion severity were performed at baseline and the endpoint. RESULTS: The adapted protocol was feasible in both treatment modalities (Study 1) and led to high SPD remission rates (individual 63%; group 52%), with no significant difference between intervention types (p = 0.4) (Study 2). SPD, anxiety, and depression symptoms and objective patient lesion measures improved after treatment. There was large effect size for SPD symptom improvement in both treatment types (Cohen's d: group = 0.88; individual = 1.15) (Study 2). CONCLUSION: The adapted Rothbaum protocol was effective for SPD remission, comorbidities, and skin lesions, both in individual and group formats. CLINICAL TRIAL REGISTRATION: NCT03182478.

The Mood Rhythm Instrument: development and preliminary report.

OBJECTIVE: To describe the initial steps in the development and validation of a new self-reported instrument designed to assess daily rhythms of mood symptoms, namely, the Mood Rhythm Instrument. METHODS: A multidisciplinary group of experts took part in systematic meetings to plan the construction of the instrument. Clarity of items, their relevance to evaluation of mood states, and the consistency of findings in relation to the available evidence on the biological basis of mood disorders were investigated. The internal consistency of the questionnaire was evaluated through Cronbach's alpha. RESULTS: All of the items proposed in a first version were well rated in terms of clarity. The items more frequently rated as "rhythmic" were related to the somatic symptoms of mood. Their peaks in 24 hours were more frequent in the morning. The items associated with affective symptoms of mood were rated as less rhythmic, and their peak in 24 hours occurred more frequently in the afternoon and evening. Males and females behaved more similarly with respect to somatic than behavioral-affective items. The second version of the Mood Rhythm Instrument had a Cronbach's alpha of 0.73. CONCLUSION: The proposed Mood Rhythm Instrument may be able to detect individual rhythms of cognitive and behavioral measures associated with mood states. Validation in larger samples and against objective measures of rhythms, such as actigraphy, is warranted.

Skin picking treatment with the Rothbaum cognitive behavioral therapy protocol: a randomized clinical trial

Introduction: Although behavioral therapies can effectively treat skin picking disorder (SPD), there is no standardized treatment for improving SPD and its comorbidities and there is no group intervention option. This trial aimed to adapt the Rothbaum trichotillomania protocol to SPD (Study 1) and test its efficacy for treating SPD and comorbidities in individual and group formats (Study 2). Methods: The adapted protocol was applied to 16 SPD patients, who were allocated to group or individual treatment (Study 1). Afterwards, 54 patients were randomly allocated to treatment in an individual (n=27) or group format (n=27) (Study 2). In both studies, assessments of SPD severity, anxiety, depression, clinical status and skin lesion severity were performed at baseline and the endpoint. Results: The adapted protocol was feasible in both treatment modalities (Study 1) and led to high SPD remission rates (individual 63%; group 52%), with no significant difference between intervention types (p = 0.4) (Study 2). SPD, anxiety, and depression symptoms and objective patient lesion measures improved after treatment. There was large effect size for SPD symptom improvement in both treatment types (Cohen's d: group = 0.88; individual = 1.15) (Study 2). Conclusion: The adapted Rothbaum protocol was effective for SPD remission, comorbidities, and skin lesions, both in individual and group formats. Clinical trial registration: NCT03182478

The Mood Rhythm Instrument: development and preliminary report

Objective: To describe the initial steps in the development and validation of a new self-reported instrument designed to assess daily rhythms of mood symptoms, namely, the Mood Rhythm Instrument. Methods: A multidisciplinary group of experts took part in systematic meetings to plan the construction of the instrument. Clarity of items, their relevance to evaluation of mood states, and the consistency of findings in relation to the available evidence on the biological basis of mood disorders were investigated. The internal consistency of the questionnaire was evaluated through Cronbach’s alpha. Results: All of the items proposed in a first version were well rated in terms of clarity. The items more frequently rated as “rhythmic” were related to the somatic symptoms of mood. Their peaks in 24 hours were more frequent in the morning. The items associated with affective symptoms of mood were rated as less rhythmic, and their peak in 24 hours occurred more frequently in the afternoon and evening. Males and females behaved more similarly with respect to somatic than behavioral-affective items. The second version of the Mood Rhythm Instrument had a Cronbach’s alpha of 0.73. Conclusion: The proposed Mood Rhythm Instrument may be able to detect individual rhythms of cognitive and behavioral measures associated with mood states. Validation in larger samples and against objective measures of rhythms, such as actigraphy, is warranted.