Role of therapeutic drug monitoring in pulmonary infections : use and potential for expanded use of dried blood spot samples

Respiratory tract infections are among the most common infections in men. We reviewed literature to document their pharmacological treatments, and the extent to which therapeutic drug monitoring (TDM) is needed during treatment. We subsequently examined potential use of dried blood spots as sample procedure for TDM. TDM was found to be an important component of clinical care for many (but not all) pulmonary infections. For gentamicin, linezolid, voriconazole and posaconazole dried blood spot methods and their use in TDM were already evident in literature. For glycopeptides, beta-lactam antibiotics and fluoroquinolones it was determined that development of a dried blood spot (DBS) method could be useful. This review identifies specific antibiotics for which development of DBS methods could support the optimization of treatment of pulmonary infections

Enhanced stability of complex coacervate core micelles following different core-crosslinking strategies

Complex coacervate core micelles (C3Ms) are formed by mixing aqueous solutions of a charged (bio)macromolecule with an oppositely charged-neutral hydrophilic diblock copolymer. The stability of these structures is dependent on the ionic strength of the solution; above a critical ionic strength, the micelles will completely disintegrate. This instability at high ionic strengths is the main drawback for their application in, e.g., drug delivery systems or protein protection. In addition, the stability of C3Ms composed of weak polyelectrolytes is pH-dependent as well. The aim of this study is to assess the effectiveness of covalent crosslinking of the complex coacervate core to improve the stability of C3Ms. We studied the formation of C3Ms using a quaternized and amine-functionalized cationic-neutral diblock copolymer, poly(2-vinylpyridine)-block-poly(ethylene oxide) (QP2VP-b-PEO), and an anionic homopolymer, poly(acrylic acid) (PAA). Two different core-crosslinking strategies were employed that resulted in crosslinks between both types of polyelectrolyte chains in the core (i.e., between QP2VP and PAA) or in crosslinks between polyelectrolyte chains of the same type only (i.e., QP2VP). For these two strategies we used the crosslinkers 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and dimethyl-3,3′-dithiopropionimidate dihydrochloride (DTBP), respectively. EDC provides permanent crosslinks, while DTBP crosslinks can be broken by a reducing agent. Dynamic light scattering showed that both approaches significantly improved the stability of C3Ms against salt and pH changes. Furthermore, reduction of the disulphide bridges in the DTBP core-crosslinked micelles largely restored the original salt-stability profile. Therefore, this feature provides an excellent starting point for the application of C3Ms in controlled release formulations

Cost-effectiveness of CTA, MRA and DSA in patients with non-traumatic subarachnoid haemorrhage

OBJECTIVES: Intra-arterial digital subtraction angiography (DSA), magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) are imaging modalities used for diagnostic work-up of non-traumatic subarachnoid haemorrhage. The aim of our study was to compare the cost-effectiveness of MRA, DSA and CTA in the first year after the bleed. METHODS: A decision model was used to calculate costs and benefits (in quality-adjusted life-years [QALYs]) that accrued to cohorts of 1,000 patients. Costs and characteristics of diagnostic tests, therapy, patients’ quality of life and associated costs were respected. The diagnostic strategy with highest QALYs and lowest costs was considered most cost-effective. RESULTS: DSA was the most effective diagnostic option, yielding on average 0.6039 QALYs (95 % CI, 0.5761–0.6327) per patient, followed by CTA 0.5983 QALYs (95 % CI, 0.5704–0.6278) and MRA 0.5947 QALYs (95 % CI, 0.5674–0.6237). Cost was lowest for DSA (39,808 €; 95 % CI, 37,182–42,663), followed by CTA (40,748 €; 95 % CI, 37,937–43,831) and MRA (41,814 €; 95 % CI, 38,730–45,146). A strategy of CTA followed by DSA if CTA was negative or coiling deemed not feasible, was as effective as DSA alone at average costs of 39,767€ (95 % CI, 36,903–42,402). CONCLUSION: A combined strategy of CTA and DSA was found to be the most cost-effective diagnostic approach. MAIN MESSAGES: • We defined a standard model for cost-effectiveness analysis in diagnostic imaging. • Comparing total 1-year health costs and benefits, CTA is superior to MRA. • A strategy of combining CTA and DSA was found to be the most cost-effective diagnostic approach

Arterial stiffness as underlying mechanism of disagreement between an oscillometric blood pressure monitor and a sphygmomanometer

Oscillometric blood pressure devices tend to overestimate systolic blood pressure and underestimate diastolic blood pressure compared with sphygmomanometers. Recent studies indicate that discrepancies in performance between these devices may differ between healthy and diabetic subjects. Arterial stiffness in diabetics could be the underlying factor explaining these differences. We studied differences between a Dinamap oscillometric blood pressure monitor and a random-zero sphygmomanometer in relation to arterial stiffness in 1808 healthy elderly subjects. The study was conducted within the Rotterdam Study, a population-based cohort study of subjects aged 55 years and older. Systolic and diastolic blood pressure differences between a Dinamap and a random-zero sphygmomanometer were related to arterial stiffness, as measured by carotid-femoral pulse wave velocity. Increased arterial stiffness was associated with higher systolic and diastolic blood pressure readings by the Dinamap compared with the random-zero sphygmomanometer, independent of age, gender, and average mean blood pressure level of both devices. The beta-coefficient (95% CI) was 0.25 (0.00 to 0.50) mm Hg/(m/s) for the systolic blood pressure difference and 0.35 (0.20 to 0.50) mm Hg/(m/s) for the diastolic blood pressure difference. The results indicate that a Dinamap oscillometric blood pressure device, in comparison to a random-zero sphygmomanometer, overestimates systolic and diastolic blood pressure readings in subjects with stiff arteries

Low serum vitamin D is associated with axial length and risk of myopia in young children

The aim of the study was to investigate the relationship between serum 25(OH)D levels and axial length (AL) and myopia in 6-year-old children. A total of 2666 children aged 6 years participating in the birth-cohort study Generation R underwent a stepwise eye examination. First, presenting visual acuity (VA) and AL were performed. Second, automated cycloplegic refraction was measured if LogMAR VA > 0.1. Serum 25-hydroxyvitamin D [25(OH)D] was determined from blood using liquid chromatography/tandem mass spectrometry. Vitamin D related SNPs were determined with a SNP array; outdoor exposure was assessed by questionnaire. The relationships between 25(OH)D and AL or myopia were investigated using linear and logistic regression analysis. Average 25(OH)D concentration was 68.8 nmol/L (SD ± 27.5; range 4–211); average AL 22.35 mm (SD ± 0.7; range 19.2–25.3); and prevalence of myopia 2.3 % (n = 62). After adjustment for covariates, 25(OH)D concentration (per 25 nmol/L) was inversely associated with AL (β −0.043; P < 0.01), and after additional adjusting for time spent outdoors (β −0.038; P < 0.01). Associations were not different between European and non-European children (β −0.037 and β −0.039 respectively). Risk of myopia (per 25 nmol/L) was OR 0.65 (95 % CI 0.46–0.92). None of the 25(OH)D related SNPs showed an association with AL or myopia. Lower 25(OH)D concentration in serum was associated with longer AL and a higher risk of myopia in these young children. This effect appeared independent of outdoor exposure and may suggest a more direct role for 25(OH)D in myopia pathogenesis

LOng-term follow-up after liVE kidney donation (LOVE) study: A longitudinal comparison study protocol

Background: The benefits of live donor kidney transplantation must be balanced against the potential harm to the donor. Well-designed prospective studies are needed to study the long-term consequences of kidney donation. Methods: The "LOng-term follow-up after liVE kidney donation" (LOVE) study is a single center longitudinal cohort study on long-term consequences after living kidney donation. We will study individuals who have donated a kidney from 1981 through 2010 in the Erasmus University Medical Center in Rotterdam, The Netherlands. In this time period, 1092 individuals donated a kidney and contact information is available for all individuals. Each participating donor will be matched (1:4) to non-donors derived from the population-based cohort studies of the Rotterdam Study and the Study of Health in Pomerania. Matching will be based on baseline age, gender, BMI, ethnicity, kidney function, blood pressure, pre-existing co-morbidity, smoking, the use of alcohol and highest education degree. Follow-up data is collected on kidney function, kidney-related comorbidity, mortality, quality of life and psychological outcomes in all participants. Discussion: This study will provide evidence on the long-term consequences of live kidney donation for the donor compared to matched non-donors and evaluate the current donor eligibility criteria. Trial registration: Dutch Trial Register NTR3795

Long-term prognosis after kidney donation: a propensity score matched comparison of living donors and non-donors from two population cohorts

Background: Live donor nephrectomy is a safe procedure. However, long-term donor prognosis is debated, necessitating high-quality studies. Methods: A follow-up study of 761 living kidney donors was conducted, who visited the outpatient clinic and were propensity score matched and compared to 1522 non-donors from population-based cohort studies. Primary outcome was kidney function. Secondary outcomes were BMI (kg/m2), incidences of hypertension, diabetes, cardiovascular events, cardiovascular and overall mortality, and quality of life. Results: Median follow-up after donation was 8.0 years. Donors had an increase in serum creatinine of 26 μmol/l (95% CI 24–28), a decrease in eGFR of 27 ml/min/1.73 m2 (95% CI − 29 to − 26), and an eGFR decline of 32% (95% CI 30–33) as compared to non-donors. There was no difference in outcomes between the groups for ESRD, microalbuminuria, BMI, incidence of diabetes or cardiovascular events, and mortality. A lower risk of new-onset hypertension (OR 0.45, 95% CI 0.33–0.62) was found among donors. The EQ-5D health-related scores were higher among donors, whereas the SF-12 physical and mental component scores were lower. Conclusion: Loss of kidney mass after live donation does not translate into negative long-term outcomes in terms of morbidity and mortality compared to non-donors. Trial registration: Dutch Trial Register NTR3795

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Photocytotoxicity of mTHPC (Temoporfin) Loaded Polymeric Micelles Mediated by Lipase Catalyzed Degradation

Purpose. To study the in vitro photocytotoxicity and cellular uptake of biodegradable polymeric micelles loaded with the photosensitizer mTHPC, including the effect of lipase-catalyzed micelle degradation. Methods. Micelles of mPEG750-b-oligo(ɛ-caprolactone)5 (mPEG750-b-OCL5) with a hydroxyl (OH), benzoyl (Bz) or naphthoyl (Np) end group were formed and loaded with mTHPC by the film hydration method. The cellular uptake of the loaded micelles, and their photocytotoxicity on human neck squamous carcinoma cells in the absence and presence of lipase were compared with free and liposomal mTHPC (Fospeg ®). Results. Micelles composed of mPEG750-b-OCL5 with benzoyl and naphtoyl end groups had the highest loading capacity up to 30 % (w/w), likely due to π–π interactions between the aromatic end group and the photosensitizer. MTHPC-loaded benzoylated micelles (0.5 mg/mL polymer) did not display photocytotoxicity or any mTHPC-uptake by the cells, in contrast to free and liposomal mTHPC. After dilution of the micelles below the critical aggregation concentration (CAC), or after micelle degradation by lipase, photocytotoxicity and cellular uptake of mTHPC were restored. Conclusion. The high loading capacity of the micelles, the high stability of mTHPC-loaded micelles above the CAC, and the lipase-induced release of the photosensitizer makes these micelles very promising carriers for photodynamic therapy in vivo. KEY WORDS: drug release; enzymatic degradation; meta-tetra(hydroxyphenyl)chlorin (mTHPC); photodynamic therapy (PDT); polymeric micelles