Comparison of the Conox (qCON) and Sedline (PSI) depth of anaesthesia indices to predict the hypnotic effect during desflurane general anaesthesia with ketamine

Journal of Clinical Monitoring and Computing - Comparison of two depth of anesthesia indices, qCON (Conox) and PSI (Sedline), during desflurane sedation and their sensitivity to random ketamine...     

Role of lon, an ATP-dependent protease homolog, in resistance of Pseudomonas aeruginosa to ciprofloxacin

With few novel antimicrobials in the pharmaceutical pipeline, resistance to the current selection of antibiotics represents a significant therapeutic challenge. Microbial persistence in subinhibitory antibiotic environments has been proposed to contribute to the development of resistance. Pseudomonas aeruginosa cultures pretreated with subinhibitory concentrations of ciprofloxacin were found to exhibit an adaptive resistance phenotype when cultures were subsequently exposed to suprainhibitory ciprofloxacin concentrations. Microarray experiments revealed candidate genes involved in such adaptive resistance. Screening of 10,000 Tn5-luxCDABE mutants identified several mutants with increased or decreased ciprofloxacin susceptibilities, including mutants in PA1803, a close homolog of the ATP-dependent lon protease, which were found to exhibit > or = 4-fold-increased susceptibilities to ciprofloxacin and other fluoroquinolones, but not to gentamicin or imipenem, as well as a characteristic elongated morphology. Complementation of the lon mutant restored wild-type antibiotic susceptibility and cell morphology. Expression of the lon mutant, as monitored through a luciferase reporter fusion, was found to increase over time in the presence of subinhibitory ciprofloxacin concentrations. The data are consistent with the hypothesis that the induction of Lon by ciprofloxacin is involved in adaptive resistance.     

Involvement of the lon protease in the SOS response triggered by ciprofloxacin in Pseudomonas aeruginosa PAO1

Pseudomonas aeruginosa PAO1 lon mutants have phenotypes of deficiencies in cell division, swarming, twitching, and biofilm formation as well as a phenotype of ciprofloxacin supersusceptibility. In this study, we demonstrated that a lon mutant was also supersensitive to the DNA-damaging agent UV light. To understand the influence of lon in causing these phenotypes, global gene expression was characterized by performing microarrays on the lon mutant and the PAO1 wild type grown in the presence of subinhibitory concentrations of ciprofloxacin. This revealed major differences in the expression of genes involved in the SOS response and DNA repair. Real-time quantitative PCR confirmed that these genes were highly upregulated upon ciprofloxacin exposure in the wild type but were significantly less induced in the lon mutant, indicating that Lon modulates the SOS response and consequentially ciprofloxacin susceptibility. As the known Lon target SulA is a member of the SOS response regulon, the influence of mutating or overexpressing this gene, and the negative regulator of the SOS response, LexA, was examined. Overexpression of lexA had no effect on the Lon-related phenotypes, but sulA overexpression recapitulated certain lon mutant phenotypes, including altered motility and cell division, indicating that Lon regulates these phenotypes through SulA. However, sulA overexpression did not affect ciprofloxacin susceptibility or biofilm formation, indicating that these properties were independently determined. Lon protease was also demonstrated to strongly influence RecA protein accumulation in the presence of ciprofloxacin. A model of DNA repair involving the Lon protease is proposed.     

Associations between digit ratio (2D4D), mood,and autonomic stress response in healthy men

The ratio between the length of the second (index) and the fourth (ring) finger (2D4D) is a putative biomarker of prenatal testosterone (T) exposure, with higher exposure leading to a smaller ratio. 2D4D has further been linked to mental and somatic disorders. Healthy male Swiss recruits (N = 245; M_age = 20.30 years) underwent a psychosocial stress test. Mood and salivary alpha‐amylase (sAA) were assessed before and after the stress test, while heart rate (HR) and heart rate variability (HRV) were measured continuously. Additionally, 2D4D (right: R2D4D; left: L2D4D) was determined and divided into quartile groups. Correlation analysis showed no associations between R/L2D4D and outcome measures. Comparing calculated quartiles for R2D4D, subjects in the lowest R2D4D quartile expressed trendwise (p < 0.10) lower positive and higher negative affect, significantly elevated sAA activity (p < 0.05), but no HR and HRV differences at baseline as compared to subjects in the upper three quartiles. With regard to acute stress, subjects in the lowest as compared to subjects in the upper three R2D4D quartiles showed a higher increase of negative affect and a stronger cardiac response (p < 0.05), but no alterations in positive affect and sAA activity. Young healthy men in the lowest R2D4D quartile revealed a more negative affect and increased physiological activity at baseline and in response to acute stress. An exposure to high levels of prenatal T might constitute a risk factor potentially increasing vulnerability to stress‐related disorders in men.     

Human cytomegalovirus activation of ERK and myeloid cell leukemia-1 protein correlates with survival of latently infected cells

The ability of human CMV (HCMV) to enter and establish a latent infection in myeloid cells is crucial for survival and transmission in the human population. Initial pathogen binding and entry triggers a number of antiviral responses, including the activation of proapoptotic cell death pathways, which must be countered during latency establishment. However, mechanisms responsible for a prosurvival state in myeloid cells upon latent HCMV infection remain completely undefined. We hypothesized that the cellular antiapoptotic machinery must be initially activated by HCMV to promote early survival events upon entry. Here we show that HCMV transiently protects nonpermissive myeloid cells from chemical and virus entry induced cell death by up-regulating a key myeloid cell survival gene, myeloid cell leukemia (MCL)-1 protein. The induction of MCL-1 expression was independent of viral gene expression but dependent on activation of the ERK-MAPK pathway by viral glycoprotein B. Inhibition of ERK-MAPK signaling, inhibition of HCMV fusion, antibody-mediated neutralization of glycoprotein B signaling or expression of a shRNA against MCL-1 all correlated with increased cell death in response to virus infection or chemical stimulation. Finally we show that activation of ERK-MAPK signaling impacts on long-term latency and reactivation in hematopoietic cells. Thus, HCMV primes myeloid cells for from the initial virus-cell encounter. Given the importance of ERK and MCL-1 for myeloid cell survival, the successful establishment of HCMV latency in myeloid progenitors begins at the point of virus entry.     

Psychosocial Resources and Quality of Life in Transgender Women following Gender-Affirming Surgery

IntroductionPsychosocial resources like social support or intrapersonal coping skills play an important role in resilience and quality of life (QOL), yet research systematically investigating the availability of different resources and QOL in transgender (trans) women is missing.AimThe present study aimed to systematically investigate the existence of different psychosocial resources and QOL in trans women following gender-affirming surgery (GAS).MethodsUsing a cross-sectional design, 557 trans women who had received GAS at the local urological department were invited to study participation. Criteria for study inclusion were 18 years and older, diagnosis of transsexualism according to the International Classification of Disease, completion of all sessions of GAS, and given written informed consent to study participation.Main Outcome MeasuresPsychosocial resources were assessed using the Essen Resource Inventory (ERI), the Sense of Coherence Scale, and the Social Support Scale. QOL was assessed with the Short Form Health Survey. Data from trans women were compared to normative data of healthy non-trans women as reported in the respective test manuals.ResultsIn total, 158 trans women responded and participated in this study. They had received GAS 4 months to 21 years ago. The total sample was divided into 3 subgroups depending on the time interval since the participants’ last GAS procedure (group 1: GAS 0.3?3 years ago (n = 48); group 2: GAS 3.1?10 years ago (n = 62); and group 3: GAS 10.1?21 years ago (n = 41)). Trans women retrospectively indicated their available resources 3 years ago (ERI 3-years) and in the last 4 weeks (ERI 4-weeks). Trans women who had received GAS within the last 3 years (group 1) showed an increase in resources when comparing ERI 3-year scores (presurgery) with ERI 4-week scores (postsurgery). No differences emerged for group 2 and group 3. Compared to normative data from non-trans women, trans women scored significantly lower on the ERI but not in measures of Social Support Scale or Sense of Coherence Scale. Compared to non-trans women, mental QOL was significantly impaired in trans women, whereas no differences in physical QOL emerged.Clinical ImplicationsAs this study hints towards reduced psychosocial resources in trans women, the offering of specialized counseling can have high beneficial potential to support the development of resources, thereby enhancing QOL.Strength & LimitationsData of a large sample of trans women is provided who were investigated up to 21 years after GAS. The study is limited by its cross-sectional design and the response rate of 42%.ConclusionThis study indicates that psychosocial resources improve around the time of GAS and seem to be improved and sustained in later years following GAS. Still, compared to non-trans women, trans women have a lower availability of resources and a lower mental QOL.Breidenstein A, Hess J, Hadaschik B, et al. Psychosocial Resources and Quality of Life in Transgender Women following Gender-Affirming Surgery. J Sex Med 2019;16:1672–1680.     

A System-Wide Approach to Physician Efficiency and Utilization Rates for Non-Operating Room Anesthesia Sites

There has been little in the development or application of operating room (OR) management metrics to non-operating room anesthesia (NORA) sites. This is in contrast to the well-developed management framework for the OR management. We hypothesized that by adopting the concept of physician efficiency, we could determine the applicability of this clinical productivity benchmark for physicians providing services for NORA cases at a tertiary care center. We conducted a retrospective data analysis of NORA sites at an academic, rural hospital, including both adult and pediatric patients. Using the time stamps from WiseOR® (Palo Alto, CA), we calculated site utilization and physician efficiency for each day. We defined scheduling efficiency (SE) as the number of staffed anesthesiologists divided by the number of staffed sites and stratified the data into three categories (SE < 1, SE = 1, and SE >1). The mean physician efficiency was 0.293 (95% CI, [0.281, 0.305]), and the mean site utilization was 0.328 (95% CI, [0.314, 0.343]). When days were stratified by scheduling efficiency (SE < 1, =1, or >1), we found differences between physician efficiency and site utilization. On days where scheduling efficiency was less than 1, that is, there are more sites than physicians, mean physician efficiency (95% CI, [0.326, 0.402]) was higher than mean site utilization (95% CI, [0.250, 0.296]). We demonstrate that scheduling efficiency vis-à-vis physician efficiency as an OR management metric diverge when anesthesiologists travel between NORA sites. When the opportunity to scale operational efficiencies is limited, increasing scheduling efficiency by incorporating different NORA sites into a “block” allocation on any given day may be the only suitable tactical alternative.     

Mutator genes giving rise to decreased antibiotic susceptibility in Pseudomonas aeruginosa

Screening of the PA14 genomic transposon mutant library for resistance to ceftazidime, tobramycin, and ciprofloxacin led to the discovery of several mutants that appeared in more than one screen. Testing of the frequency of mutation to ciprofloxacin resistance revealed previously known mutator genes, including mutS and mutL, as well as mutators that have not yet been described for P. aeruginosa, including PA3958 and RadA (PA4609).     

Complex ciprofloxacin resistome revealed by screening a Pseudomonas aeruginosa mutant library for altered susceptibility

Pseudomonas aeruginosa offers substantial therapeutic challenges due to its high intrinsic resistance to many antibiotics and its propensity to develop mutational and/or adaptive resistance. The PA14 comprehensive mutant library was screened for mutants exhibiting either two- to eightfold increased susceptibilities (revealing genes involved in intrinsic resistance) or decreased susceptibilities (mutational resistance) to the fluoroquinolone ciprofloxacin. Thirty-five and 79 mutants with increased and decreased susceptibilities, respectively, were identified, as confirmed by broth dilution.