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Background: Infections caused by multidrug-resistant gram-negative bacteria have caused a resurgence of interest in colistin. To date, information about pharmacokinetics of colistin is very limited in critically ill patients, and no attempts have been made to evaluate its concentration in BAL.Methods: In this prospective, open-label study, 13 adult patients with ventilator-associated pneumonia caused by gram-negative bacteria were treated with colistin methanesulfonate (CMS) IV, 2 million International Units (174 mg) q8h, a usually recommended dose, for at least 2 days. Blood samples were collected from each patient at time intervals after the end of infusion. BAL was performed at 2 h. Colistin was measured by a selective, sensitive high-performance liquid chromatography-based method. Pharmacokinetic parameters were determined by noncompartmental analysis.Results: Patients received 2.19 ± 0.38 mg/kg (range, 1.58-3.16) of CMS per dose. At steady state, mean ± SD plasma colistin maximum (Cmax) and trough (Ctrough) concentrations were 2.21 ± 1.08 and 1.03 ± 0.69 μg/mL, respectively. Mean ± SD area under the plasma concentration-time curve from 0 to 8 h (AUC(0-8)), apparent elimination half-life, and apparent volume of distribution were 11.5 ± 6.2 μg × h/mL, 5.9 ± 2.6 h, and 1.5 ± 1.1 L/kg, respectively. Cmax/minimum inhibitory concentration (MIC) ratio and AUC(0-24)/MIC ratio (MIC = 2 μg/mL) were 1.1 ± 0.5 and 17.3 ± 9.3, respectively. Colistin was undetectable in BAL. Nephrotoxicity was not observed.Conclusions: Although the pharmacodynamic parameters that better predict the efficacy of colistin are not known in humans, in critically ill adult patients the IV administration of CMS 2 million International Units (174 mg) q8h results in apparently suboptimal plasma concentrations of colistin, which is undetectable in BAL. A better understanding of the pharmacokinetic-pharmacodynamic relationship of colistin is urgently needed to determine the optimal dosing regimen. [ABSTRACT FROM AUTHOR]

Background/objectives: This study aimed to analyse the role of the choroid in early age-related macular degeneration (AMD) by analysing choroidal vascularity index (CVI) in pure cohorts of patients with subretinal drusenoid deposits (SDD) or conventional drusen (CD)., Subjects/methods: This was an observational cross-sectional study. Comprehensive ophthalmologic examination and multimodal imaging including fundus photography, autofluorescence, near infrared reflectance, and spectral domain optical coherence tomography (SDOCT) was performed. CVI processing was performed on a foveal horizontal SDOCT scan with binarization using Image J Image software and calculated as the ratio between luminal area (LA) and total area (TA)., Results: Sixty-nine eyes of 69 participants were included; 23 eyes with SDD alone, 22 eyes with CD alone, and 24 control eyes of healthy age-matched subjects. CVI was significantly reduced in the SDD and CD group compared to controls (p = 0.0001). Post-hoc analysis revealed a significant reduction of CVI in the SDD versus the control group (p = 0.0002), in the CD versus the control group (p = 0.001), and in the SDD versus the CD group (p = 0.006). Covariance analysis showed a significant difference of LA (p = 0.033) but no significant difference of TA (p = 0.106) between the three groups. Direct comparison between CD and SDD showed a significant reduction of LA and TA in the SDD group., Conclusions: CVI may have prognostic implications in early AMD. SDD is a biomarker of AMD progression and the mechanism for this could be via reduction of the CVI., (© 2022. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Successful reproduction in avian species requires considerable parental care, and for most species the efforts of both parents are necessary for the survival of offspring. Here we make the case that in these species reproductive interactions are enhanced when neurochemical activity reinforces critical stimuli and behaviors through associative learning. Drawing from research on several different species, we describe evidence for the role of associative learning in the reproductive behaviors of ring neck doves (Streptopelia risoria). A hypothetical mechanism involving a combination of classical and operant conditioning is proposed to explain the formation and maintenance of the pair bond, nest fidelity, and incubation behavior. The role of the opiate system in reinforcing various aspects of reproductive behavior in this and other species is discussed., (© 2022. The Psychonomic Society, Inc.)

Recurrent loss-of-function deletions cause frequent inactivation of tumour suppressor genes but often also involve the collateral deletion of essential genes in chromosomal proximity, engendering dependence on paralogues that maintain similar function. Although these paralogues are attractive anticancer targets, no methodology exists to uncover such collateral lethal genes. Here we report a framework for collateral lethal gene identification via metabolic fluxes, CLIM, and use it to reveal MTHFD2 as a collateral lethal gene in UQCR11-deleted ovarian tumours. We show that MTHFD2 has a non-canonical oxidative function to provide mitochondrial NAD + , and demonstrate the regulation of systemic metabolic activity by the paralogue metabolic pathway maintaining metabolic flux compensation. This UQCR11-MTHFD2 collateral lethality is confirmed in vivo, with MTHFD2 inhibition leading to complete remission of UQCR11-deleted ovarian tumours. Using CLIM's machine learning and genome-scale metabolic flux analysis, we elucidate the broad efficacy of targeting MTHFD2 despite distinct cancer genetic profiles co-occurring with UQCR11 deletion and irrespective of stromal compositions of tumours., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

In avian brood parasitism, parasites lay their eggs in the nests of hosts, and many hosts in the wild respond by eliminating or abandoning foreign eggs in their clutch. However, a limitation upon the study of proximate, especially physiological and experience-dependent cognitive mechanisms of egg rejection, has been the lack of a suitable model system in captivity. Here, we tested whether laboratory-kept ringneck doves (Streptopelia risoria) respond to visually distinct egg types (through applying an ink treatment upon the doves' own eggs) by rejecting them. We found that in two of two experiments, brown eggs were more often rejected, through predominantly egg burial, relative to control eggs but were done so only by a subset of dove pairs. These results are supportive of ringneck doves to become a suitable captive model for the study of foreign-egg rejection, and open the way for future research on the integrative (e.g., genetic, endocrine, ontogenetic, and cognitive) study of egg-rejection responses in a tractable research system. However, the ecological validity and applicability of this model system for the analysis of host-parasite interactions in the wild remain narrowly limited. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Incubation of eggs is a critical component of parental care in avian species. However, we do not fully understand the neuroendocrine mechanisms underlying this vital behavior. While prolactin is clearly involved, it alone cannot explain the fine-tuning of incubation behavior. The present experiments explored the possibility that incubation is reinforced through a hedonic system in which contact with eggs elicited an opiate-mediated reinforcing state. Blockade of opiate receptors with naloxone reduced time ring neck doves (Streptopelia risoria) spent on the nest, possibly by uncoupling the opiate-receptor mediated hedonic experience of contact with eggs from nest-sitting behavior. Likewise, activation of opiate receptors with morphine also reduced time spent on the nest, possibly by activating an opiate-receptor mediated hedonic experience, hence rendering the eliciting behavior (contact with eggs) unnecessary. Taken together, the results suggest that the opiate system may play a previously unrecognized role in facilitating incubation through reinforcement., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background . Intraperitoneal nebulization of ropivacaine reduces postoperative pain and morphine consumption after laparoscopic surgery. The aim of this multicenter double-blind randomized controlled trial was to assess the efficacy of different doses and dose-related absorption of ropivacaine when nebulized in the peritoneal cavity during laparoscopic cholecystectomy. Methods . Patients were randomized to receive 50, 100, or 150 mg of ropivacaine 1% by peritoneal nebulization through a nebulizer. Morphine consumption, pain intensity in the abdomen, wound and shoulder, time to unassisted ambulation, discharge time, and adverse effects were collected during the first 48 hours after surgery. The pharmacokinetics of ropivacaine was evaluated using high performance liquid chromatography. Results . Nebulization of 50 mg of ropivacaine had the same effect of 100 or 150 mg in terms of postoperative morphine consumption, shoulder pain, postoperative nausea and vomiting, activity resumption, and hospital discharge timing (>0.05). Plasma concentrations did not reach toxic levels in any patient, and no significant differences were observed between groups ( P > 0.05). Conclusions . There is no enhancement in analgesic efficacy with higher doses of nebulized ropivacaine during laparoscopic cholecystectomy. When administered with a microvibration-based aerosol humidification system, the pharmacokinetics of ropivacaine is constant and maintains an adequate safety profile for each dosage tested., Competing Interests: The authors declare that they have no competing interests.

Ability to recognize and differentiate between predators and non-predators is a crucial component of successful anti-predator behavior. While there is evidence that both genetic and experiential mechanisms mediate anti-predator behaviors in various animal species, it is unknown to what extent each of these two mechanisms are utilized by the green monkey (Chlorocebus sabaeus). Green monkeys on the West Indies island of Barbados offer a unique opportunity to investigate the underpinnings of anti-predator behaviors in a species that has been isolated from ancestral predators for over 350 years. In the first experiment, monkeys in two free-ranging troops were presented with photographs of an ancestral predator (leopard, Panthera pardus) and a non-predator (African Buffalo, Syncerus caffer). Relative to non-predator stimuli, images of a leopard elicited less approach, more alarm calls, and more escape responses. Subsequent experiments were conducted to determine whether the monkeys were responding to a leopard-specific feature (spotted fur) or a general predator feature (forward facing eyes). The monkeys showed similar approach to images of an unfamiliar non-predator regardless of whether the image had forward facing predator eyes or side facing non-predator eyes. However, once near the images, the monkeys were less likely to reach for peanuts near the predator eyes than the non-predator eyes. The monkeys avoided an image of spotted leopard fur but approached the same image of fur when the dark spots had been removed. Taken together, the results suggest that green monkey anti-predator behavior is at least partially mediated by genetic factors., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Epidural infusion of levobupivacaine and ropivacaine provides adequate postoperative pain management by minimizing side effects related to IV opioids and improving patient outcome. The safety profile of different drugs can be better estimated by comparing their pharmacokinetic profiles than by considering their objective side effects. Because levobupivacaine and ropivacaine have different pharmacokinetic properties, our aim was to investigate whether there is a difference in the pharmacokinetic variability of the 2 drugs in a homogeneous population undergoing continuous epidural infusion. This double-blind, multicenter, randomized, controlled trial study was designed to compare the pharmacokinetics of continuous thoracic epidural infusion of levobupivacaine 0.125% or ropivacaine 0.2% for postoperative pain management in adult patients who had undergone major abdominal, urological, or gynecological surgery. This study is focused on the evaluation of the coefficient of variation (CV) to assess the equivalence in the systemic exposure and interindividual variability between levobupivacaine and ropivacaine and, therefore, the possible differences in the predictability of the plasmatic concentrations of the 2 drugs during thoracic epidural infusion., Methods: One hundred eighty-one adults undergoing major abdominal surgery were enrolled in the study. Patients were randomized to receive an epidural infusion of levobupivacaine 0.125% + sufentanil 0.75 μg/mL or of ropivacaine 0.2% + sufentanil 0.75 μg/mL at 5 mL/h for 48 hours. The primary end point of this study was to analyze the variability of plasma concentration of levobupivacaine and ropivacaine via an area under the curve within a range of 15% of the CV during 48 hours of continuous epidural infusion. The CV shows how the concentration values of local anesthetics are scattered around the median concentration value, thus indicating the extent to which plasma concentration is predictable during infusion. Secondary end points were to assess the pharmacologic profile of the local anesthetics used in the study, including an analysis of mean peak plasma concentrations, and also to assess plasma clearance, side effects, pain intensity (measured with a verbal numeric ranging score, i.e., static Numeric Rating Scale [NRS] and dynamic NRS]), and the need for rescue doses., Results: The comparison between the 2 CVs showed no statistical difference: the difference between area under the curve was within the range of 15%. The CV was 0.54 for levobupivacaine and 0.51 for ropivacaine (P = 0.725). The plasma concentrations of ropivacaine approached the Cmax significantly faster than those of levobupivacaine. Clearance of ropivacaine decreases with increasing patient age. There were no significant differences in NRS, dynamic NRS scores, the number of rescue doses, or in side effects between groups., Conclusions: Considering the CV, the interindividual variability of plasma concentration for levobupivacaine and ropivacaine is equivalent after thoracic epidural infusion in adults. We found a reduction in clearance of ropivacaine depending on patient age, but this finding could be the result of some limitations of our study. The steady-state concentration was not reached during the 48-hour infusion and the behavior of plasma concentrations of ropivacaine and levobupivacaine during continuous infusions lasting more than 48 hours remains to be investigated, because they could reach toxic levels. Finally, no differences in the clinical efficacy or in the incidence of adverse effects between groups were found for either local anesthetic.

Background: There is no consensus on darunavir (DRV) target levels in plasma for clinical use, and information about variability in plasma concentrations is limited., Aim: : To investigate the variability in DRV plasma trough concentrations in the clinical setting, evaluating interindividual and intraindividual variabilities of plasma drug levels among HIV-infected patients receiving ritonavir (RTV)-boosted DRV (DRV/r) within salvage regimens, and evaluate the potential correlation between variability and virological response., Methods: Sixty-two patients taking DRV/r (600/100 mg twice a day) were evaluated for trough plasma concentrations and immunovirological parameters after 6 months from the start of the regimen. A subgroup of patients (n = 21) was also evaluated for intraindividual variability (expressed as coefficient of variation) on 2 samples taken at different time points. Drug concentrations were assayed by high-performance liquid chromatography with ultraviolet detection, and the values were expressed as medians with interquartile range (IQR). Genotypic sensitivity score and genotypic inhibitory quotient were calculated., Results: DRV/r was used with a median of 3 other antiretroviral drugs (raltegravir use 88.7%). Median plasma concentrations were 3.22 mcg/mL (IQR, 2.04-5.69) for DRV and 0.44 mcg/mL (IQR, 0.21-0.70) for RTV. Both drugs showed a high interindividual variability in plasma concentrations (61% and 99.3%, respectively). Only 3 patients (4.8%) had undetectable DRV plasma levels. DRV plasma concentrations showed a significant positive correlation with age (r = 0.298, P = 0.019), but no significant correlation between DRV genotypic inhibitory quotient and HIV-RNA plasma levels (P = 0.614) was found. Intraindividual coefficients of variation were 58.4% for DRV and 47.1% for RTV. Patients with undetectable HIV-RNA showed a trend for lower intraindividual coefficients of variation compared with patients with detectable HIV-RNA (55.9% versus 83.8%, P = 0.156). No major interaction effects with other antiretroviral drugs were found., Conclusions: In a context of salvage therapy, both DRV and RTV plasma levels showed high interindividual and intraindividual variabilities. Lower intraindividual variability could be beneficial in maintaining viral suppression.

Vervet monkeys (Chlorocebus pygerythrus) produce alarm calls and anti-predator behaviors that are specific to a threatening predator's mode of attack. Upon hearing a leopard alarm, the monkeys will run up trees where they are relatively safe. In contrast, eagle alarms prompt the monkeys to run under bushes and snake alarms stimulate bipedal standing. Early researchers proposed that the meaning of each alarm call is conveyed by observational learning. If this true then absence of the predator that elicits the alarm call may lead to alteration or decay of the alarm's meaning since there is no longer opportunity for observational learning to occur. The present study tested this hypothesis by presenting alarm calls to a closely related species of monkeys (Chlorocebus sabaeus) that have been isolated from their ancestral predators for more than 350 years. The monkeys ran up trees in response to a leopard alarm, but not when the same alarm was played backwards and not in response to a snake alarm. Snake alarms failed to reliably elicit bipedal standing. These results suggest that the leopard alarm call conveys the same information to Barbados green monkeys as West African green monkeys despite generations of isolation from leopards., (Copyright © 2013 Elsevier B.V. All rights reserved.)