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According to the free hormone hypothesis, biological activity of a certain hormone is best reflected by free rather than total hormone concentrations. A crucial element in this theory is the presence of binding proteins, which function as gatekeepers for steroid action. For testosterone, tissue exposure is governed by a delicate equilibrium between free and total testosterone which is determined through interaction with the binding proteins sex hormone-binding globulin and albumin. Ageing, genetics and various pathological conditions influence this equilibrium, hereby possibly modulating hormonal exposure to the target tissues. Despite ongoing controversy on the subject, strong evidence from recent in vitro, in vivo and human experiments emphasizes the relevance of free testosterone. Currently, however, clinical possibilities for free hormone diagnostics are limited. Direct immunoassays are inaccurate, while gold standard liquid chromatography with tandem mass spectrometry (LC–MS/MS) coupled equilibrium dialysis is not available for clinical routine. Calculation models for free testosterone, despite intrinsic limitations, provide a suitable alternative, of which the Vermeulen calculator is currently the preferred method. Calculated free testosterone is indeed associated with bone health, frailty and other clinical endpoints. Moreover, the added value of free testosterone in the clinical diagnosis of male hypogonadism is clearly evident. In suspected hypogonadal men in whom borderline low total testosterone and/or altered sex hormone-binding globulin levels are detected, the determination of free testosterone avoids under- and overdiagnosis, facilitating adequate prescription of hormonal replacement therapy. As such, free testosterone should be integrated as a standard biochemical parameter, on top of total testosterone, in the diagnostic workflow of male hypogonadism.

Comfort performance standards often err on the side of caution, leading to higher building costs, excessive material use, and increased embodied carbon, while still adopting a reductionist view of occupant wellbeing. We developed a user centred simulation based co-design strategy to investigate how to incorporate comfort performance with the Self-Determination Theory of well-being through design. We make a thematic analysis of two case studies of office designs where this approach was tested. The initial results demonstrate how performance simulations—such as daylight—can be interpreted from an experiential, rather than purely normative, perspective. Rather than making immediate adjustments to the building’s technical concept, participants explored the qualities of different zones as represented in the simulations and imagined how these spaces could be used in various ways.

Background. Diagnosing polycystic ovary syndrome (PCOS) is based on ovulatory dysfunction, ovarian ultrasound data, and androgen excess. Total testosterone is frequently used to identify androgen excess, but testosterone is mainly bound to sex hormone-binding globulin (SHBG) and albumin. Only 1-2% of nonprotein-bound testosterone (so-called free testosterone) is biologically active and responsible for androgen action. Moreover, automated immunoassays which are frequently used for female testosterone measurements are inaccurate. Objective. To assess the clinical usefulness of liquid chromatography-tandem mass spectrometry measured testosterone and calculated free testosterone in subfertile women attending a fertility clinic with oligomenorrhea and suspected PCOS. Methods. Hormonal and metabolic parameters were evaluated, and ovarian ultrasound was performed. Total testosterone was measured by liquid chromatography-tandem mass spectrometry. Free testosterone was calculated from total testosterone and SHBG. Results. Sixty-six women were included in the study. Total testosterone was associated with ovarian volume and antral follicle count but not with metabolic parameters. However, SHBG and calculated free testosterone were associated with both ovarian ultrasound and metabolic parameters, such as BMI and insulin resistance. Conclusions. Assessing SHBG and free testosterone is important in evaluating androgen excess in subfertile women with ovulatory dysfunction and suspected PCOS, as it reflects both ovarian and metabolic disturbances.

Aims To describe the safety and performance of STENTYS self-expandable bare metal stents (BMS) versus paclitaxel-eluting stents (PES) in saphenous vein grafts (SVGs). Methods and Results A randomised controlled trial was performed in four hospitals in three European countries between December 2011 and December 2013. Patients with de novo lesions (>50% stenosis) in an SVG with a diameter between 2.5–6 mm were included. Primary endpoint was late lumen loss at 6 months. Secondary endpoints included procedural success and the occurrence of major adverse cardiac events (MACE) at 12 months. A total of 57 patients were randomised to STENTYS self-apposing BMS ( n  = 27) or PES ( n  = 30). Procedural success was obtained in 89.5%. No significant differences in late lumen loss were found between BMS and PES at 6 months (0.53 mm vs 0.47; p  = 0.86). MACE rates at 12 months were comparable in both groups (BMS 22.2% vs. PES 26.7%; p  = 0.70). Conclusions Treatment of SVGs with STENTYS self-expandable stents is safe and effective. No significant differences were found in late lumen loss and MACE between BMS and PES.

Cefazolin (CFZ) is highly and saturably bound to human serum albumin (HSA) in adults. We aim to describe CFZ protein binding and its covariates in neonates. In neonates to whom intravenous CFZ (50 mg/kg) was administered prior to a surgical procedure, total and unbound CFZ plasma concentrations (mg/l) were determined at 0.5, 2, 4 and 8 h after CFZ administration. Linear and multiple regression analyses were used to document covariates of unbound CFZ fraction. The Wilcoxon signed-rank test was used for the paired analysis of unbound CFZ fractions. In 40 patients with a median weight of 2,767 (range 830–4,200) g and a postmenstrual age (PMA) of 39 (25–45) weeks, 131 samples were collected. The median unbound CFZ fraction was 0.39 (0.10–0.73). Linear regression of unbound CFZ fraction versus unbound CFZ plasma concentration ( R 2  = 0.39) had a slope significantly different from zero ( p  < 0.001). In a multiple regression analysis, albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA resulted in an R 2 value of 0.496. The median unbound CFZ fraction at the peak concentration (0.46, range 0.28–0.69) was significantly higher compared to the trough level (0.36, range 0.17–0.73) ( p  < 0.001). The between- and within-patient saturability of CFZ plasma protein binding were documented in neonates. The median unbound CFZ fraction in neonates is higher than in adults and depends partly on albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA. Integration of CFZ protein binding in future pharmacokinetic/pharmacodynamic research is warranted in order to optimise neonatal CFZ dosing. We recommend protein binding assessment in the neonatal pharmacokinetic evaluation of highly protein-bound or clinically relevant drugs.

Introduction: Hepcidin plays a key role in the regulation of plasma iron levels through inhibition of iron export from enterocytes and macrophages. Hepcidin is considered a promising marker in the investigation of iron status, especially in patients that still pose a diagnostic challenge, such as infants and patients with chronic (kidney) disease. Objective: To critically review the current evidence for the diagnostic utility of hepcidin, including the (pre) analytical aspects in hepcidin determination. Summary: (Pre)analytical aspects - Since it is doubtful that the prohormone prohepcidin is a relevant biomarker, only the mature peptide hepcidin should be measured. Determinations of serum hepcidin are preferable, as the value of urine concentrations is still unclear. Method harmonization is needed since hepcidin values vary widely between methods. Several (pre-) analytical issues remain unanswered. These barriers hamper the investigation into the diagnostic value of hepcidin. Diagnostic utility - Hepcidin is an acute-phase reactant. The diagnostic potential of hepcidin is controversial in the different settings of iron deficiency as evidence is contradictory (anaemia of chronic disease) or limited (infants). In the setting of haemochromatosis, it has been suggested that hepcidin could be useful to stratify molecular testing, or to optimize the frequency of phlebotomies, but this remains to be investigated.

Significant differences in the sensitivity of eight frequently used qualitative urine human chorionic gonadotropin (hCG) tests in Belgium were observed in this study. Although most manufacturers claimed to detect hCG levels as low as 25 mIU/ml, only two out of six tests for home use and one out of two tests for professional use only, achieved the claimed detection limit. According to a survey, we performed among 20 acute care hospitals, 80% of the surveyed hospitals claimed to use these types of hCG analysis in a diagnostic setting. Unsatisfactory performance of these point-of-care testing (POC) assays for urinary hCG could have major consequences in a hospital setting, exposing the early pregnant woman to harmful diagnostic and therapeutic procedures. Although qualitative urine hCG tests are rapid and convenient, determination of hCG in blood remains the gold standard for the diagnosis of pregnancy.

Background and aim Cefazolin (CFZ) is highly and saturably bound to albumin in adults. It is mainly used as prophylactic antibiotic agent. The aim of the present study is to describe CFZ protein binding and its covariates in neonates. Methods Neonates to whom intravenous CFZ (50 mg/kg) was administered as standard care prior to an invasive procedure were included. Total and unbound CFZ plasma concentrations were determined at ½; 2; 4 and 8 hours after CFZ administration. Linear and multiple regression analyses were used to document covariates of unbound CFZ fraction. For paired analysis of unbound CFZ fractions Wilcoxon signed rank test was used. Results Forty patients with median weight 2767 (range 830–4200) grams and median postmenstrual age (PMA) 39 (25–45) weeks were included. Median unbound CFZ fraction was 0.39 (0.10–0.73). Linear regression of unbound CFZ fraction versus unbound CFZ plasma concentration (R²=0.39) had a slope significantly different from zero (p<0.001). In a multiple regression analysis, albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA resulted in an R² value of 0.496. Median unbound CFZ fraction at peak concentration (0.46; range 0.28–0.69) was significantly higher compared to trough level (0.36; range 0.17–0.73) (p<0.001). Conclusions Between patient and within patient saturability of CFZ protein binding were also documented in neonates. We revealed a median plasma unbound CFZ fraction of 0.39 in neonates, which is higher than reported values in adults. The integration of CFZ protein binding aspects in future pharmacokinetic/pharmacodynamic research is warranted to optimize CFZ dosing, especially in neonates.

Background Serum creatinine (Scr) reflects to a certain extent GFR in neonates, but postnatal observations also depends on the technique used (Jaffe colorimetry or enzymatic quantification) as recently quantified in ELBW neonates (1.2). We aimed to assess the impact of enzymatic versus Jaffe quantification and to describe postnatal Scr trends for both techniques in neonates with higher birth weight (3). Methods Scr values quantified by Jaffe in 1140 neonates were compared to values obtained by enzymatic quantification in 1023 neonates in one NICU. All Scr values collected in the first 42 days of postnatal life were included and postnatal trends for cohorts < 1kg, 1–2 kg, 2–3 kg and > 3 kg were compared. Results Postnatal patterns were similar between both techniques, with an initial increase of Scr (highest and last in the smallest neonates) in early postnatal life, and a subsequent decrease, most delayed in the smallest neonates. For all consecutive postnatal observations, Jaffe always resulted in higher Scr compared to the enzymatic technique, but the differences in median values between both techniques (0.1–0.26 mg/dl, equal to 8.8–23 µmol/l), were not a fixed value. Conclusions When using Scr to estimate renal function in neonates, clinicians should in addition to postnatal changes and other covariates of renal function, also consider the technique applied. There is no fixed conversion factor to correct for differences between both techniques. Allegaert, J Matern Fetal Neonatal Med DOI 10.3109/14767058.2012.657277. Kuppens, J Matern Fetal Neonatal Med DOI 10.3109/14767058.2011.602144. Bueva, Pediatr Res 1994.