Augmented Renal Clearance Implies a Need for Increased Amoxicillin-Clavulanic Acid Dosing in Critically Ill Children

There is little data available to guide amoxicillin-clavulanic acid dosing in critically ill children. The primary objective of this study was to investigate the pharmacokinetics of both compounds in this pediatric subpopulation. Patients admitted to the pediatric intensive care unit (ICU) in whom intravenous amoxicillin-clavulanic acid was indicated (25 to 35 mg/kg of body weight every 6 h) were enrolled. Population pharmacokinetic analysis was conducted, and the clinical outcome was documented. A total of 325 and 151 blood samples were collected from 50 patients (median age, 2.58 years; age range, 1 month to 15 years) treated with amoxicillin and clavulanic acid, respectively. A three-compartment model for amoxicillin and a two-compartment model for clavulanic acid best described the data, in which allometric weight scaling and maturation functions were added a priori to scale for size and age. In addition, plasma cystatin C and concomitant treatment with vasopressors were identified to have a significant influence on amoxicillin clearance. The typical population values of clearance for amoxicillin and clavulanic acid were 17.97 liters/h/70 kg and 12.20 liters/h/70 kg, respectively. In 32% of the treated patients, amoxicillin-clavulanic acid therapy was stopped prematurely due to clinical failure, and the patient was switched to broader-spectrum antibiotic treatment. Monte Carlo simulations demonstrated that four-hourly dosing of 25 mg/kg was required to achieve the therapeutic target for both amoxicillin and clavulanic acid. For patients with augmented renal function, a 1-h infusion was preferable to bolus dosing. Current published dosing regimens result in subtherapeutic concentrations in the early period of sepsis due to augmented renal clearance, which risks clinical failure in critically ill children, and therefore need to be updated. (This study has been registered at Clinicaltrials.gov as an observational study [{"type":"clinical-trial","attrs":{"text":"NCT02456974","term_id":"NCT02456974"}}NCT02456974].)     

Cognitive bias in action: Evidence for a reciprocal relation between confirmation bias and fear in children

Background and objectives

Some cognitive models propose that information processing biases and fear are reciprocally related. This idea has never been formally tested. Therefore, this study investigated the existence of a vicious circle by which confirmation bias and fear exacerbate each other.

Methods

One-hundred-and-seventy-one school children (8–13 years) were first provided with threatening, ambiguous, or positive information about an unknown animal. Then they completed a computerized information search task during which they could collect additional (negative, positive, or neutral) information about the novel animal. Because fear levels were repeatedly assessed during the task, it was possible to examine the reciprocal relationship between confirmation bias and fear.

Results

A reciprocal relation of mutual reinforcement was found between confirmation bias and fear over the course of the experiment: increases in fear predicted subsequent increases in the search for negative information, and increases in the search for negative information further enhanced fear on a later point-in-time. In addition, the initial information given about the animals successfully induced diverging fear levels in the children, and determined their first inclination to search for additional information.

Limitations

As this study employed a community sample of primary school children, future research should test whether these results can be generalized to clinically anxious youth.

Conclusions

These findings provide first support for the notion that fearful individuals may become trapped in a vicious circle in which fear and a fear-related confirmation bias mutually strengthen each other, thereby maintaining the anxiety pathology.     

Env-less endogenous retroviruses are genomic superspreaders

Endogenous retroviruses (ERVs) differ from typical retroviruses in being inherited through the host germline and therefore are a unique combination of pathogen and selfish genetic element. Some ERV lineages proliferate by infecting germline cells, as do typical retroviruses, whereas others lack the env gene required for virions to enter cells and thus behave like retrotransposons. We wished to know what factors determined the relative abundance of different ERV lineages, so we analyzed ERV loci recovered from 38 mammal genomes by in silico screening. By modeling the relationship between proliferation and replication mechanism in detail within one group, the intracisternal A-type particles (IAPs), and performing simple correlations across all ERV lineages, we show that when ERVs lose the env gene their proliferation within that genome is boosted by a factor of ～30. We also show that ERV abundance follows the Pareto principle or 20/80 rule, with ～20% of lineages containing 80% of the loci. This rule is observed in many biological systems, including infectious disease epidemics, where commonly ～20% of the infected individuals are responsible for 80% of onward infection. We thus borrow simple epidemiological and ecological models and show that retrotransposition and loss of env is the trait that leads endogenous retroviruses to becoming genomic superspreaders that take over a significant proportion of their host's genome.     

Experimental Study of the Course of Threshold Current,Voltage and Electrode Impedance During Stepwise Stimulation From the Skin Surface to the Human Cortex

BackgroundTranscranial electric stimulation as used during intraoperative neurostimulation is dependent on electrode and skull impedances.ObjectiveThreshold currents, voltages and electrode impedances were evaluated with electrical stimulation at 8 successive layers between the skin and the cerebral cortex.Patients and MethodsData of 10 patients (6f, 53 ± 11 years) were analyzed. Motor evoked potentials were elicited by constant current stimulation with corkscrew type electrodes (CS) at C3 and C4 in line with standard transcranial electric stimulation. A monopolar anodal ball tip shaped probe was used for all other measurements being performed at the level of the skin, dura and cortex, as well as within the skull by stepwise performed burr holes close to C3 resp. C4.ResultsAverage stimulation intensity, corresponding voltage and impedance for muscle MEPs at current motor threshold (CMT) were recorded: CS 54 ± 23 mA (mean ± SD), 38 ± 21 V, 686 ± 146 Ω; with the monopolar probe on skin 55 ± 28 mA, 100 ± 44 V, 1911 ± 683 Ω and scalp 59 ± 32 mA, 56 ± 28 V, 1010 ± 402 Ω; within the skull bone: outer compact layer 33 ± 23 mA, 91 ± 53 V, 3734 ± 2793 Ω; spongiform layer 33 ± 23 mA, 70 ± 44 V, 2347 ± 1327 Ω; inner compact layer (ICL) 28 ± 19 mA, 48 ± 23 V, 2103 ± 1498 Ω; on dura 25 ± 12 mA, 17 ± 12 V, 643 ± 244 Ω and cortex 14 ± 6 mA, 11 ± 5 V, 859 ± 300 Ω. CMTs were only significantly different for CS (P = 0.02) and for the monopolar probe between the cortex and ICL (P = 0.03), scalp (P = 0.01) or skin (P = 0.01) and between ICL and CS (P ≤ 0.01) or skin (P ≤ 0.01).ConclusionThe mean stimulation current of the CMT along the extracranial to intracranial anodal trajectory followed a stepwise reduction. VMT was strongly dependent on electrode impedance. CMT within the skull layers was noted to have relative strong shunting currents in scalp layers.     

Strictureplasty in Crohn’s Disease: Short and Long-Term Follow-Up

Strictureplasty for obstructive Crohn’s disease is still controversial because lesions are left in place and the suture is performed on a diseased bowel. Many surgeons prefer to perform bowel resection, hoping for fewer complications and a lower recurrence rate. In this paper, the authors report their strictureplasty experience. They performed a systematic retrospective review of the patients suffering from Crohn’s disease who underwent strictureplasties during a 10-year period in the abdominal surgery department of the University Hospital of Liège Sart Tilman, and studied the short-and long-term clinical results of 68 strictureplasties performed in 18 patients. Median follow-up was 63 months (range 12 to 144). Mortality was 0% and septic morbidity was 11% (one wound abscess and one leakage). Among the 16 patients available for the latest follow-up, symptomatic stenotic recurrence had to be medically treated in hospital for 4 patients (25%) with a recurrence delay range of 19 to 49 months. Stenosis recurrence needed re-intervention in one patient 48 months after surgery: stenosis occurred at a distance from the corrected site. These results confirmed that strictureplasty is a safe and efficient procedure in selected patients undergoing surgery for obstructive Crohn’s disease.