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.

Performances of two different panfungal PCRs to detect mould DNA in formalin-fixed paraffin-embedded tissue: what are the limiting factors?

BACKGROUND: Detection of fungal DNA from formalin-fixed, paraffin-embedded (FFPE) tissue is challenging due to degradation of DNA and presence of PCR inhibitors in these samples. We analyzed FFPE samples of 26 patients by panfungal PCR and compared the results to the composite diagnosis according to the European Organization for Research and Treatment of Cancer (EORTC) criteria. Additionally we analyzed the quality of human and fungal DNA and their level of age-dependent degradation, as well as the existence of PCR inhibition in these tissue samples. METHODS: We evaluated two 45-cycle panfungal PCR tests that target the internal transcribed spacer 2 (ITS2) as well as the ITS1-5.8S-ITS2 (ITS1-2) region. The PCRs were applied to 27 FFPE specimens from 26 patients with proven invasive fungal disease (IFD), and one patient with culture and histologically negative but PCR-positive fungal infection collected at our institution from 2003 to 2010. Quality of DNA in FFPE tissue samples was evaluated using fragments of the beta-globin gene for multiplex PCR, inhibition of PCR amplification was evaluated by spiking of C. krusei DNA to each PCR premix. RESULTS: In 27 FFPE samples the ITS2 PCR targeting the shorter fragment showed a higher detection rate with a sensitivity of 53.8% compared to the ITS1-2 fragment (sensitivity 38%). Significant time-dependent degradation of human DNA in FFPE sample extracts was detected based on partial beta-globin gene amplification which was not in correlation to successful panfungal PCR identification of fungal organisms. The analytical sensitivity of both assays compared with culture was 60 CFU/ml of a Candida krusei reference strain. The performance of the two tests in an Aspergillus proficiency panel of an international external quality assessment programme showed considerable sensitivity. CONCLUSION: Panfungal diagnostic PCR assays applied on FFPE specimens provide accurate identification of molds in highly degraded tissue samples and correct identification in samples stored up to 7 years despite sensitivity limitations, mainly caused by partial PCR inhibition and DNA degradation by formalin.

Allometric extension.

Constants of allometric growth are commonly estimated by the first eigenvector of the covariance matrix of log measurements. Hills (1982, in Encyclopedia of Statistical Sciences, 48-54) defines a model of allometric extension for two related species by the conditions that (a) the constants of allometric growth are identical for both species and (b) the vector of mean differences is proportional to the common first eigenvector of both covariance matrices. We give a test for allometric extensionand discuss estimation of the parameters of the allometric extension model, including standard errors.

Retinopathy of prematurity: the influence of gestational age and retinal maturity on the statistical behavior of risk factors.

The clinical and laboratory data on 140 premature infants, 74 cases with retinopathy of prematurity (ROP) and 66 control cases without ROP, were correlated with ROP grades of increasing severity. By using multiple linear regression (MLR), it is shown that for predicting ROP grades the importance of certain variables varies considerably depending on the gestational age. Below 32 weeks of gestation, acidosis, hyperoxemia, gestational age, pathologic paCO2 levels, and multiple birth are strong regressors. Above 31 weeks, the most important regressors are multiple birth and acidosis, while gestational age and duration of FiO2 greater than 0.4 are much less influential. Blood transfusions and artificial ventilation do not seem important in the MLR of either group. When ROP is regressed on the number of paO2 values above 100 torr and gestational age or on the number of paCO2 values above 50 torr and gestational age, the regression coefficients of these variables drop to near zero at a gestational age of about 32 weeks. This loss of weight of the two variables paO2 and paCO2 with increasing gestational age coincides with a comparable drop of the relative incidence of ROP and the relative incidence of immature retinal vessels. It is hypothesized that it is the proportion of infants with an immature retinal vasculature in populations of given gestational ages rather than the gestational age itself which is responsible for the widely varying importance of certain factors during the development of ROP.

Retinopathy of prematurity: a risk factor analysis with univariate and multivariate statistics.

Seventy-three out of 639 ophthalmoscopically examined newborns (11.4%) showed varying degrees of retinopathy of prematurity (ROP). Three infants were blind (0.5%). Sixty-six patients were matched with controls according to gestational age, birth weight, birth date and neonatal unit. Using univariate statistics, the variables representing the extent of O2-exposure, elevated paO2, elevated paCO2, paCO2-fluctuations, acidosis, blood transfusions, and artificial ventilation were found to be significantly associated with ROP. In contrast, the variables representing hypocapnia, Hb-levels, parenteral fluid administration and fluid retention showed no correlation with ROP. When a multivariate statistical method was used, the variables representing gestational age, elevated paO2, elevated paCO2 and paCO2-fluctuations as well as the ones defining blood transfusions lost their association with ROP. Episodes of acidosis, multiple birth, birth weight, total hours with Fio2 greater than 0.4, and total duration of artificial ventilation remained in the regression, and hypocapnia gained a significant negative correlation with ROP. This comparative survey based on univariate and multivariate statistics demonstrates that significance levels of identically defined biological and therapeutic variables obtained from the same population of patients are to be interpreted with caution. This fact may also explain contrasting opinions on risk factors in the literature. Multivariate statistical analyses are useful for a relative comparison of significance within a given set of variables. Conclusions on a possible causal relationship as well as on prophylactic measures are not possible.

Amyloid-containing renal interstitial cell nodules (RICNs) associated with chronic arterial hypertension in older age groups.

A highly significant correlation is demonstrated between the presence in older persons of medullary renal interstitial cell nodules (RICNs) containing amyloid and increased heart weight indicative of chronic arterial hypertension. By contrast, the population with amyloid-free RICNs 1) showed heart weights comparable to those of controls and 2) had a mean age about 11 years less (56.7 +/- 9.6 vs 68 +/- 12 years) than the group with amyloid-containing RICNs. In a series of 55 autopsy cases presenting with RICNs, no individual was younger than 30 years. In two cases, in which fresh material was available, histochemical reactions suggested that the RICNs contained APUD amyloid. It is speculated that fully functional RICNs may evolve on a compensatory base counteracting an increase in mean arterial blood pressure and that the deposition of amyloid within RICNs could be associated with, or be an expression of, a reduced endocrine function of these structures, finally resulting in the development of arterial hypertension.

Prediction of the histological type of glomerulonephritis. Multiple discriminant analysis of clinical and laboratory characteristics at time of diagnosis.

We performed a prospective study on 68 subjects with biopsy-proven clomerulonephritis using a discriminant analysis of 12 clinical and laboratory characteristics. Among these, the selectivity of proteinuria, the presence of hematuria and the plasma level of C3 proved to be the most useful. An equation based on these three variables discriminated without overlap between 17 patients with minimal change glomerulonephritis (MCGN) and 30 patients with either membranoproliferative or rapidly progressive glomerulonephritis. However, some overlap existed between MCGN and focal sclerosis or membranous glomerulonephritis. In addition, the formula seems to identify steroid-resistant patients with MCGN.

[Guttman scales for impairment due to old age in average daily activity (author's transl)]. / Ermittlung von Skalen zur Messung der praktischen Behinderung Betagter.

On the basis of 100 interviews with subjects aged over 65 Guttman scales have been calculated which make it possible to quantitate the degree of competence in two activities, namely house work and mobility.

[House calls in medical practice]. / Hausbesuche in der ärztlichen Praxis

The frequency of daily home visits by practicing physicians has been investigated. A multiple regression analysis indicates that the number of daily home visits is reduced linearly with decreasing age and with increasing specialization of the doctor. With these variables taken into account, urban-rural differences cannot be demonstrated.