In vivo / in vitro Correlation of Pharmacokinetics of Gentamicin, Vancomycin, Teicoplanin and Doripenem in a Bovine Blood Hemodialysis Model.

Background: Elimination of a drug during renal replacement therapy is not only dependent on flow rates, molecular size and protein binding, but is often influenced by difficult to predict drug membrane interactions. In vitro models allow for extensive profiling of drug clearance using a wide array of hemofilters and flow rates. We present a bovine blood based in vitro pharmacokinetic model for intermittent renal replacement therapy. Methods: Four different drugs were analyzed: gentamicin, doripenem, vancomicin and teicoplanin. The investigated drug was added to a bovine blood reservoir connected to a hemodialysis circuit. In total seven hemofilter models were analyzed using commonly employed flow rates. Pre-filter, post-filter and dialysate samples were drawn, plasmaseparated and analyzed using turbidimetric assays or HPLC. Protein binding of doripenem and vancomycin was measured in bovine plasma and compared to previously published values for human plasma. Results: Clearance values were heavily impacted by choice of membrane material and surface as well as by dialysis parameters such as blood flow rate. Gentamicin clearance ranged from a minimum of 90.12 ml/min in a Baxter CAHP-170 diacetate hemofilter up to a maximum of 187.90 ml/min in a Fresenius medical company Fx80 polysulfone model (blood flow rate 400 ml/min, dialysate flow rate 800 ml/min). Clearance of Gentamicin vs Vancomicin over the F80s hemofilter model using the same flow rates was 137.62 mL vs 103.25 ml/min. Doripenem clearance with the Fx80 was 141.25 ml/min. Conclusion: Clearance values corresponded very well to previously published data from clinical pharmacokinetic trials. In conjunction with in silico pharmacometric models. This model will allow precise dosing recommendations without the need of large scale clinical trials.

Respiratory specimens and the diagnostic accuracy of Aspergillus lateral flow assays (LFA-IMMY™): real-life data from a multicentre study.

OBJECTIVES: Proper diagnosis of invasive aspergillosis is challenging because conventional methods lack sensitivity and are complicated by time-consuming incubation processes. To meet the requirement for early diagnosis the new Aspergillus-specific point-of-care test LFA-IMMY™ was evaluated with respect to the ability to accurately detect Aspergillus in bronchoalveolar fluids and sputa, and to clarify the potential of cross-reactivity with other fungal pathogens. METHODS: Respiratory specimens (n = 398) from non-selected patients (n = 390) underwent either fungal microscopy, culture or both before Aspergillus lateral flow assay (LFA-IMMY) testing. RESULTS: For Aspergillus culture- and microscopy-positive samples, sensitivity (48/52) and specificity (44/48) were 92% (95% CI 8.0%-9.7%) and 91% (95% CI 7.9%-9.7%), respectively; cross-reactivity was documented with non-Aspergillus pathogens. CONCLUSION: LFA-IMMY is a reliable diagnostic tool for the detection of Aspergillus in respiratory samples.

Elimination of Doripenem during Dialysis and Pharmacokinetic Evaluation of Posthemodialysis Dosing for Patients Undergoing Intermittent Renal Replacement Therapy.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa and Enterobacteriaceae Current dosing regimens recommend the administration of 0.25 to 0.5 g once daily in patients undergoing intermittent renal replacement therapy. As patients are usually dialyzed thrice weekly, we aimed to investigate a 1-g posthemodialysis regimen, thus reducing treatment costs and enhancing patient compliance. A second objective of this trial was to describe the pharmacokinetics of intradialytic doripenem. Ten oliguric or anuric patients in need of intermittent renal replacement therapy were included in this trial. All patients suffered from a septic episode. The mean hemofilter clearance was 123.46 ± 42.03 ml/min, and the total body clearance between hemodialysis sessions was 16.79 ± 6.02 ml/min. The average prehemodialysis trough concentration was 2.4 ± 1.3 mg/liter, while the EUCAST resistance breakpoint for Enterobacteriaceae is set at 2 mg/liter. The interpatient variability was considerably higher than the intrapatient variability. Apart from one patient who suffered an allergic reaction, doripenem was tolerated well by all patients. Our data indicate that posthemodialysis administration of 1 g of doripenem results in sufficient plasma levels in anuric but not oliguric patients during the entire dosing interval. (This trial was registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

Micafungin Plasma Levels Are Not Affected by Continuous Renal Replacement Therapy: Experience in Critically Ill Patients.

Critically ill patients often experience acute kidney injury and the need for renal replacement therapy in the course of their treatment in an intensive care unit (ICU). These patients are at an increased risk for candidiasis. Although there have been several reports of micafungin disposition during renal replacement therapy, to this date there are no data describing the elimination of micafungin during high-dose continuous venovenous hemodiafiltration with modified AN69 membranes. The aim of this prospective open-label pharmacokinetic study was to assess whether micafungin plasma levels are affected by continuous hemodiafiltration in critical ill patients using the commonly employed AN69 membrane. A total of 10 critically ill patients with micafungin treatment due to suspected or proven candidemia were included in this trial. Prefilter/postfilter micafungin clearance was measured to be 46.0 ml/min (±21.7 ml/min; n = 75 individual time points), while hemofilter clearance calculated by the sieving coefficient was 0.0038 ml/min (±0.002 ml/min; n = 75 individual time points). Total body clearance was measured to be 14.0 ml/min (±7.0 ml/min; n = 12). The population area under the curve from 0 to 24 h (AUC0-24) was calculated as 158.5 mg · h/liter (±79.5 mg · h/liter; n = 13). In spite of high protein binding, no dose modification is necessary in patients receiving continuous venovenous hemodiafiltration with AN69 membranes. A dose elevation may, however, be justified in certain cases. (This study has been registered at ClinicalTrials.gov under identifier NCT02651038.).

Comparison of conventional versus three-dimensional ultrasound in fetal renal pelvis measurement and their potential prediction of neonatal uropathies.

OBJECTIVE: To establish a threshold value for fetal renal pelvis dilatation measured by automatic volume calculation (SonoAVC) in the third trimester of pregnancy to predict neonatal uropathies, and to compare these results with conventional antero-posterior (AP) measurement, fetal kidney 3D volume and renal parenchymal thickness. METHODS: In a prospective cohort study, 125 fetuses with renal pelvis AP diameter of ≥5 mm both at 20 weeks of gestation and in the third trimester, underwent an additional 3D volume measurement of the fetal kidney in the third trimester. Receiver operating characteristic (ROC) curves for establishing threshold values for fetal renal pelvis volume, AP measurement, fetal kidney volume and renal parenchymal thickness to predict neonatal uropathies were analyzed. Also, sensitivity, specificity, area under the curve (AUC) and likelihood ratios were calculated. RESULTS: A cut-off point of 1.58 cm³ was identified in the third trimester of pregnancy (AUC 0.865 (95% CI 0.789-0.940), sensitivity 76.3%, specificity 87.4%, LR+ 6.06, LR- 0.27) for measurements with SonoAVC. A cut-off value of 11.5 mm was established in the third trimester of pregnancy (AUC 0.828 (95% CI 0.737-0.918), sensitivity 71.1%, specificity 85.1%, LR+ 4.77, LR- 0.34) for the conventional AP measurement. A cut-off point for fetal kidney volume was calculated at 13.29 cm³ (AUC 0.769 (95% CI 0.657-0.881), sensitivity 71%, specificity 66%, LR+ 2.09, LR- 0.44). For renal parenchymal thickness, a cut-off point of 8.4 mm was established (AUC 0.216 (95% CI 0.117-0.315), sensitivity 31.6%, specificity 32.6%, LR+ 0.47, LR- 2.10). CONCLUSION: This study demonstrates that 3D fetal renal pelvis volume measurements and AP measurements both have a good and comparable diagnostic performance, fetal renal volume a fair accuracy and renal parenchymal thickness a poor accuracy in predicting postnatal renal outcome.

Losing Items in the Psychogeriatric Nursing Home: The Perspective of Residents and Their Informal Caregivers.

Introduction: Losing items is a time-consuming occurrence in nursing homes that is ill described. An explorative study was conducted to investigate which items got lost by nursing home residents, and how this affects the residents and family caregivers. Method: Semi-structured interviews and card sorting tasks were conducted with 12 residents with early-stage dementia and 12 family caregivers. Thematic analysis was applied to the outcomes of the sessions. Results: The participants stated that numerous personal items and assistive devices get lost in the nursing home environment, which had various emotional, practical, and financial implications. Significant amounts of time are spent on trying to find items, varying from 1 hr up to a couple of weeks. Numerous potential solutions were identified by the interviewees. Discussion: Losing items often goes together with limitations to the participation of residents. Many family caregivers are reluctant to replace lost items, as these items may get lost again.

Doripenem Treatment during Continuous Renal Replacement Therapy.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa. While the initial dosing recommendation for renally competent patients and patients undergoing continuous renal replacement therapy (cRRT) was 500 mg every 8 h (q8h), the dose for renally competent patients was updated to 1 g q8h in June 2012. There are no updated data for the dosing of patients on continuous renal replacement therapy. The original dosing regimen for cRRT patients was based on nonseptic patients, while newer publications chose comparatively low target concentrations for a carbapenem. Thus, there is an urgent need for updated recommendations for dosing during cRRT. In the trial presented here, we included 13 oliguric septic patients undergoing cRRT in an intensive care setting. Five patients each were treated with hemodiafiltration or hemodialysis, while three patients received hemofiltration treatment. All patients received 1 g doripenem every 8 h. Doripenem concentrations in the plasma and ultrafiltrate were measured over 48 h. The mean hemofilter clearance was 36.53 ml/min, and the mean volume of distribution was 59.26 liters. The steady-state trough levels were found at 8.5 mg/liter, with no considerable accumulation. Based on pharmacokinetic and pharmacodynamic considerations, we propose a regimen of 1 g q8h, which may be combined with a loading dose of 1.5 to 2 g for critically ill patients. (This study has been registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.).

Reproducibility of fetal renal pelvis volume assessed by three-dimensional ultrasonography with two different measurement techniques.

PURPOSE: To evaluate reproducibility of fetal renal pelvis volume as assessed by the Virtual Organ Computer Aided AnaLysis (VOCAL) imaging program and by Automatic Volume Calculation (SonoAVC). In addition, the intra- and interobserver reliability of fetal renal pelvis volume measurements with SonoAVC were established. METHODS: In this study, the fetal renal pelvis volume was measured using 3D ultrasonography in 76 kidneys of 66 fetuses with renal pelvis dilatation in the second or third trimester of pregnancy. After volume acquisition by one observer, the reproducibility of volume calculation was assessed using VOCAL imaging program and SonoAVC by two observers. Intra- and interobserver reproducibility was evaluated by calculating intraclass correlation coefficients (ICC), coefficient of variation (CV) and repeatability coefficient (r). Bland-Altman plots were generated to explore agreement. RESULTS: A high degree of reproducibility was observed between VOCAL and SonoAVC, ICC of 0.989; 95% CI 0.983-0.993, respectively. Intraobserver reproducibility of volume measurements performed by SonoAVC demonstrated a high degree of reliability with ICC of 0.995 (95% CI 0.993-0.997), CV 6.05% and r of 0.75. The interobserver reproducibility with ICC of 0.995 (95% CI 0.992-0.997), CV 10.14% and r 1.21 was also indicative of good reliability. CONCLUSION: Volume measurements of fetal renal pelvis performed by SonoAVC renders reproducible measurements in comparison with the VOCAL imaging program. There is no significant difference between VOCAL imaging program and SonoAVC. The intra- and interobserver reliability of the fetal renal pelvis measurements made by SonoAVC were considered to be very good. SonoAVC, however, needs post processing in the majority of cases but is less time consuming than VOCAL.

Why do individuals not lose more weight from an exercise intervention at a defined dose? An energy balance analysis.

Weight loss resulting from an exercise intervention tends to be lower than predicted. Modest weight loss can arise from an increase in energy intake, physiological reductions in resting energy expenditure, an increase in lean tissue or a decrease in non-exercise activity. Lower than expected, weight loss could also arise from weak and invalidated assumptions within predictive models. To investigate these causes, we systematically reviewed studies that monitored compliance to exercise prescriptions and measured exercise-induced change in body composition. Changed body energy stores were calculated to determine the deficit between total daily energy intake and energy expenditures. This information combined with available measurements was used to critically evaluate explanations for low exercise-induced weight loss. We conclude that the small magnitude of weight loss observed from the majority of evaluated exercise interventions is primarily due to low doses of prescribed exercise energy expenditures compounded by a concomitant increase in caloric intake.

A radiofrequency coil configuration for imaging the human vertebral column at 7 T.

We describe the design and testing of a quadrature transmit, eight-channel receive array RF coil configuration for the acquisition of images of the entire human spinal column at 7 T. Imaging parameters were selected to enable data acquisition in a clinically relevant scan time. Large field-of-view (FOV) scanning enabled sagittal imaging of the spine in two or three-stations, depending upon the height of the volunteer, with a total scan time of between 10 and 15 min. A total of 10 volunteers have been scanned, with results presented for the three subjects spanning the range of heights and weights, namely one female (1.6 m, 50 kg), one average male (1.8 m, 70 kg), and one large male (1.9 m, 100 kg).

Reproducibility of fetal renal pelvis volume measurement using three-dimensional ultrasound.

OBJECTIVE: To assess the reproducibility of fetal renal pelvis volume measurement in hydronephrotic kidneys using transabdominal three-dimensional (3D) ultrasound. METHODS: The fetal renal pelvis volume was measured using 3D ultrasound in one kidney in each of 15 fetuses with hydronephrosis in the second or third trimester of pregnancy. Hydronephrosis was diagnosed when the fetus had an anteroposterior renal pelvis diameter > or = 5 mm. After volume acquisition by one of the observers, the repeatability of volume calculation with manual delineation of the fetal renal pelvis was assessed by six different observers using the Virtual Organ Computer-aided AnaLysis (VOCAL(trade mark)) imaging program. The intraclass correlation coefficients (ICC), coefficient of variation (CV) and within- and between-observer repeatability coefficient (r) were calculated and Bland-Altman plots were constructed. RESULTS: Both intra- and interobserver reliability of the fetal renal pelvis volume measurements were considered to be very good. For intraobserver reliability, the ICC was 0.996 and the CV was 10.8%. For the overall interobserver reliability, the ICC was 0.998 and the CV was 15.7%; the interobserver reliability between pairs of observers had ICCs between 0.994 and 0.999, and CVs between 19.5% and 7.6% for inexperienced and experienced observers, respectively. CONCLUSION: With 3D ultrasound using the VOCAL imaging program, it is technically feasible to reproduce fetal renal pelvis volume measurements. Further research to establish the clinical applications of this technology is warranted.

Hyperechogenic fetal bowel: counseling difficulties.

The detection of echodense fetal bowel on ultrasound examination in the second trimester of pregnancy justifies invasive procedures such as amniocentesis to detect an underlying cause. We present a case in which initial tests identified only one mutation in the cystic fibrosis transmembrane regulator (CFTR)-gene of the fetus, the family history being negative for CF. Strongly reduced intestinal enzyme activities suggested intestinal obstruction and further increased the estimated risk for CF. After the 24th gestational week, a second mutation was found, confirming cystic fibrosis in this child. Problems in counseling in this particular case are discussed.

Formulation of trichloroacetic acid peeling solution: a bibliometric analysis.

Since the beginning of this century, trichloroacetic acid solutions of various concentrations have been used for chemical exfoliation. These solutions have been prepared by using four different formulas. To prepare a 50% solution, for instance, water may be added to 50 g of trichloroacetic acid crystals until 100 ml of solution is obtained (weight-to-volume solution). Alternatively, 50 g of water may be added to 50 g of trichloroacetic acid crystals (weight-to-weight solution), or 50 g of trichloroacetic acid crystals may be solved in 100 ml of water (weight-plus-volume solution). Finally, a saturated trichloroacetic acid solution (or "100% solution") may be diluted by an equal volume of water (dilution). Depending on the method used, these so-called 50% solutions contain 40 to 71 weight-to-volume percentages of trichloroacetic acid. From a review of 120 publications on trichloroacetic acid peeling that have appeared since 1926, it was concluded that the authors of 87 of these publications (73 percent) did not report their formula for the trichloroacetic acid solution. Any one of the four methods was reported to have been used by the 33 authors who did report their formula. Eight of 10 internationally reputed pharmacopeias were found not to include the formula of a trichloroacetic acid solution. Proper evaluation of results and prevention of complications of trichloroacetic acid chemexfoliation is only feasible if both the concentration and the formula of trichloroacetic acid solution are reported by the author. Practitioners who use a trichloroacetic acid solution need to establish that the concentration of the solution they apply corresponds with that of the solution reported in the literature.

Analysis of human papillomavirus type 16 E6 variants in relation to p53 codon 72 polymorphism genotypes in cervical carcinogenesis.

This study aimed to assess the role of specific human papillomavirus type 16 (HPV-16) variants, in combination with p53 codon 72 polymorphism genotypes, in cervical carcinogenesis. An initial sequence analysis of HPV-16 long control, E6 and E7 regions of 53 well-defined cervical samples containing HPV-16 revealed that a T to G transition at nucleotide position 350 within the E6 open reading frame was the most common variation, the frequency of which seemed to decrease with increasing severity of the lesion. Therefore, a total of 246 cervical samples of residents of The Netherlands was specifically analysed for HPV-16 350G/T variants and/or p53 codon 72 genotypes. These comprised HPV-negative normal cervical scrapes (n=40), normal cervical scrapes containing HPV-16 (n=46), scrapes containing HPV-16 from women with abnormal cervical cytology participating in a non-intervention follow-up study without (n=38) and with (n=51) a histologically proven cervical intraepithelial neoplasia (CIN) III lesion at the end of the study, and cervical squamous cell carcinomas (n=71). Neither specific HPV-16 350G/T variants nor specific p53 genotypes were associated with a higher risk of developing CIN III or cervical cancer. However, HPV-16 350T variants were significantly over-represented in p53 Arg homozygous women with cervical cancer. This suggests that, in p53 Arg/Arg women, infection with HPV-16 350T variants confers a higher risk of cervical cancer.

Rhinoplasty as part of gender-confirming surgery in male transsexuals: basic considerations and clinical experience.

Because psychotherapy will not change the profound incongruence between the objective biological sex and subjective gender identity experienced by transsexuals, hormonal and surgical treatment to change the body toward the experienced gender is the only way out of this dilemma. To allow the male-to-female transsexual to pass as a member of this gender in public, rhinoplasty may be as important as genital reassignment surgery. In this paper the surgical considerations on gender-confirming rhinoplasty are presented and discussed. From December 1985 to January 1996, 22 male-to-female transsexuals underwent rhinoplasty at the Department of Plastic and Reconstructive Surgery of the Academisch Ziekenhuis Vrije Universiteit to obtain a less masculine appearance. Although revisional surgery was performed in four patients, all were satisfied with the final result in that they were convinced that their faces had become more feminine. We conclude that in selected patients rhinoplasty may help to create a feminine countenance for male-to-female transsexuals.

Local delivery of antibiotics via an implantable pump in the treatment of osteomyelitis.

Twenty-one patients with osteomyelitis were treated with surgical debridement and local antibiotic therapy. Amikacin (19 patients) or netilmicin (2 patients) was delivered locally via a pump implanted subcutaneously. The outflow catheters were led from the pump subcutaneously to the infected area and placed in the defect created by the surgical debridement. The pump was refilled at intervals, on an outpatient basis. The pump was surgically removed at the conclusion of therapy. Follow-up evaluation was for 12-27 months. The duration of hospitalization was five to 52 days (mean, 23 days). The infusions were sustained for 32-140 days (mean, 63 days). Systemic levels of antibiotics were always below acceptable trough levels. Levels in the wound drainage of the 11 patients who drained after operation were always greater than the upper limit of the assay. Nephrotoxicity and ototoxicity were determined using pre- and posttherapy creatinine clearances and audiograms. Two patients exhibited minimal nephrotoxicity (creatinine clearance of 66 ml/minute and 55 ml/minute; normal, 70 ml/minute). There were no other adverse effects of the antibiotics. Sixteen patients have not drained since removal of the pumps.

Antibiotic stability in an implantable pump.

We measured the stability of vancomycin, amikacin, netilmicin, tobramycin, gentamicin, clindamycin, and aztreonam in an implantable drug pump. Two pumps were filled with the antibiotic being tested and were incubated at 37 degrees for 3 weeks. Samples were taken daily. At 3 weeks the pumps were disassembled and examined microscopically for signs of deterioration. If the pumps were intact, bioassays were used to quantitate the biologic activity of each daily antibiotic sample. Vancomycin degraded the pump. Amikacin, netilmicin, tobramycin, gentamicin, clindamycin, and aztreonam had no effect on the pump and maintained their biologic activity over the 3-week period.