Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study.

OBJECTIVES: Toxic serum cefepime trough concentrations are not well defined in the current literature. We aimed to define a more precise plasma trough concentration threshold for this antibiotic's neurological toxicity and to identify individuals at risk for developing neurotoxic side effects. METHODS: Retrospective study including all individuals who underwent cefepime therapeutic drug monitoring (TDM) between 2013 and 2017. Individuals with cefepime concentrations other than trough were excluded. The primary outcome was to assess the incidence of neurotoxicity and its relationship with cefepime plasma trough concentrations. Secondary outcomes were the relationship of renal function, cefepime daily dose, age, and cerebral and general co-morbidities with the occurrence of neurotoxicity. We also compared the mortality rate during hospitalization in individuals with and without neurotoxicity, and the possible impact of neuroprotective co-medications on outcomes. RESULTS: Cefepime concentrations were determined in 584 individuals. Among 319 individuals with available trough concentrations included, the overall incidence of neurotoxicity was 23.2% (74 of 319 individuals). Higher cefepime plasma trough concentrations were significantly associated with risk of neurotoxicity (no neurotoxicity 6.3 mg/L (interquartile range (IQR) 4.1-8.6) versus with neurotoxicity 21.6 mg/L (IQR 17.0-28.6), p <0.001). Individuals with presumed cefepime neurotoxicity had a significantly lower renal function (estimated glomerular filtration rate 82.0 mL/min/1.73 m2 (IQR 45.0-105.0) versus 35.0 mL/min/1.73 m2 (IQR 23.3-53.3], p <0.001), and significantly higher in-hospital mortality (19 (7.8%) versus 26 (35.1%) individuals, p <0.001). No neurotoxic side effects were seen below a trough concentration of 7.7 mg/L. Levels ≥38.1 mg/L always led to neurological side effects. CONCLUSION: In individuals with risk factors for cefepime neurotoxicity, such as renal insufficiency, TDM should be systematically performed, aiming at trough concentrations <7.5 mg/L.

NADH-linked mitochondrial respiration in the developing mouse brain is sex-, age- and tissue-dependent.

Mitochondria play a major role in the brain. Apart from energy production, mitochondria regulate key factors in the activation of cell signaling pathways such as survival, proliferation, and differentiation. While all these processes occur during the physiological development of the brain, it is surprising that the mitochondrial functions and functioning in the brain during the postnatal development remain poorly explored. In this work, we collected samples of brainstem and cortex of mice at postnatal ages 3 (P3), 21 (P21), and at adulthood (3 months old) and evaluated the mitochondrial oxygen consumption after complex I activation. To do so, we used our oxygraph-2 K system (OROBOROS) that measures the mitochondrial bioenergetics in saponin-permeabilized tissue punches of 2  mg weight. Furthermore, as sex dimorphism in the brain occurs since very early stages of development, we performed experiments in brain samples of male and female mice. Accordingly, the mitochondrial oxygen consumption rate (OCR) was evaluated under activation of complex I (NADH-linked respiration - mitochondrial state 3), and during the inhibition of the complex V (ATP synthase) with oligomycin (mitochondrial state 4). In following, the respiratory control ratio (RCR - state 3/state4) was calculated as an index of mitochondrial oxidative-phosphorylation coupling. Our results show that the activity of the mitochondrial complex I in the brain increases along with the postnatal development in a sex- and tissue-dependent manner, with males showing higher activity than females, and with brainstem tissue showing higher activity than cortex. Our data may contribute to a better understanding of the sex-dependent maturation of the cortex and the cardiorespiratory network located in the brainstem.

Remission of diabetes mellitus in cats cannot be predicted by the arginine stimulation test.

BACKGROUND: Cats with diabetes mellitus frequently achieve clinical remission, suggesting residual ß-cell function. Responsiveness of ß-cells to arginine persists the longest during diabetes progression, making the intravenous arginine stimulation test (IVAST) a useful tool to assess residual insulin and glucagon secretion. HYPOTHESIS: Diabetic cats with and without remission will have different arginine-induced insulin or glucagon response. ANIMALS: Seventeen cats with diabetes, 7 healthy cats. METHODS: Blood samples collected on admission and during subsequent IVAST. Glucose, insulin, and glucagon were measured. Response to IVAST was assessed by calculating the insulin and glucagon area under the curve (AUC) and the AUC glucagon-to-insulin ratio. Diabetic cats were treated with insulin and were followed for 18 weeks. Remission was defined as normoglycemia and disappearance of clinical signs of diabetes for ≥4 weeks, without requiring insulin. RESULTS: Seven diabetic cats (41%) achieved remission. On admission, blood glucose concentration was significantly lower in cats with remission (median, 389 mg/dL; range, 342-536 mg/dL) than in those without remission (median, 506 mg/dL; range, 266-738 mg/dL). After IVAST, diabetic cats with remission had higher AUC glucagon-to-insulin ratios (median, 61; range, 34-852) than did cats without remission (median, 26; range, 20-498); glucose, insulin, and glucagon AUCs were not different. Diabetic cats had lower insulin AUC than did healthy cats but comparable glucagon AUC. CONCLUSIONS AND CLINICAL IMPORTANCE: Diabetic cats with and without remission have similar arginine-stimulated insulin secretion on admission. Although cats with remission had lower blood glucose concentrations and higher AUC glucagon-to-insulin ratios, large overlap between groups prevents use of these parameters in clinical practice.

Dynamics of Rn transport from the cellar to the living area in an unheated house.

Environmental parameters such as temperature and wind, occupant activities, and house-specific parameters such as subsoil geology, leakiness of the substructure to soil gas, and air exchange rate are the main factors influencing Rn entry into a building and its subsequent indoor behavior. Experiments performed in an unheated, uninhabited house showed a reproducible diurnal fluctuation of the indoor concentration of Rn decay products. Strong, long-term correlations between temperature differences indoor-outdoor (indoor temperature minus outdoor temperature) and pressure differences outdoor-indoor (outdoor pressure minus indoor pressure) were found. At positive temperature differences inside-outside, an average airflow velocity of about 0.05 m s-1 between ground floor and first floor was detected. This air movement was able to vertically transport Rn at a rate of approximately 11 kBq h-1 in a volume of air of about 5.5 m3 through a cross-sectional area of only 0.03 m2. For this specific house, stack effects were identified as the main driving force for Rn migration from the cellular to higher floors. The diurnal fluctuation of Rn progeny concentrations in the living area can be explained by temporal variations in the amount of Rn-rich air transported vertically from the cellar into the building as a consequence of stack effects.

[Test for the determination of endurance fitness and training style in young ice hockey players]. / Test zur Bestimmung der Ausdauerleistungsfähigkeit und Trainingsgestaltung beim jugendlichen Eishockeyspieler.

A test similar to the Conconi test was developed by the authors, to be used specifically with ice hockey players. The aim was to measure the aerobic performance capacity of these athletes. The results give us on one hand informations on the actual performance potential of these sportsmen. On the other hand, they enable us to design an optimal training schedule. With such data in hand, it becomes possible to determine which intensity of endurance training is optimally adapted to an individual's progress of performance. It is thus easier to develop the sought after basic fitness in youth players. 120 ice hockey players of several leagues had to go through either a Conconi test, or our modified, more sports specific Probst test. 54 of these were junior players (age 15-16). Our purpose in this paper is to discuss the aim of such endurance tests for youth players.