Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels.

Caspofungin has a liver-dependent metabolism. Reduction of the dose is recommended based on Child-Pugh (C-P) score. In critically ill patients, drug pharmacokinetics (PK) may be altered. The aim of this study was to investigate the prevalence of abnormal liver function tests, increased C-P scores, their effects on caspofungin PK, and whether pharmacokinetic-pharmacodynamic (PK/PD) targets were attained in patients with suspected candidiasis. Intensive care unit patients receiving caspofungin were prospectively included. PK parameters were determined on days 2, 5, and 10, and their correlations to the individual liver function tests and the C-P score were analyzed. Forty-six patients were included with C-P class A (n = 5), B (n = 40), and C (n = 1). On day 5 (steady state), the median and interquartile range for area under the curve from 0 to 24 h (AUC0-24), clearance (CL), and central volume of distribution (V1) were 57.8 (51.6 to 69.8) mg·h/liter, 0.88 (0.78 to 1.04) liters/h, and 11.9 (9.6 to 13.1) liters, respectively. The C-P score did not correlate with AUC0-24 (r = 0.03; P = 0.84), CL (r = -0.07; P = 0.68), or V1 (r = 0.19; P = 0.26), but there was a bilirubin-driven negative correlation with the elimination rate constant (r = -0.46; P = 0.004). Hypoalbuminemia correlated with low AUC0-24 (r = 0.45; P = 0.005) and was associated with higher clearance (r = -0.31; P = 0.062) and somewhat higher V1 (r = -0.15; P = 0.37), resulting in a negative correlation with the elimination rate constant (r = -0.34; P = 0.042). For Candida strains with minimal inhibitory concentrations of ≥0.064 µg/ml, PK/PD targets were not attained in all patients. The caspofungin dose should not be reduced in critically ill patients in the absence of cirrhosis, and we advise against the use of the C-P score in patients with trauma- or sepsis-induced liver injury.

Valuing and understanding fish populations in the Anthropocene: key questions to address.

Research on the values of fish populations and fisheries has primarily focused on bio-economic aspects; a more nuanced and multidimensional perspective is mostly neglected. Although a range of social aspects is increasingly being considered in fisheries research, there is still no clear understanding as to how to include these additional values within management policies nor is there a cogent appreciation of the major knowledge gaps that should be tackled by future research. This paper results from a workshop held during the 50th anniversary symposium of the Fisheries Society of the British Isles at the University of Exeter, UK, in July 2017. Here, we aim to highlight the current knowledge gaps on the values of fish populations and fisheries thus directing future research. To this end, we present eight questions that are deeply relevant to understanding the values of fish populations and fisheries. These can be applied to all habitats and fisheries, including freshwater, estuarine and marine.

A 10-year retrospective study of infective endocarditis at a university hospital with special regard to the timing of surgical evaluation in S. viridans endocarditis.

A total of 154 episodes of infective endocarditis (IE) in 149 patients were studied retrospectively with special regard to the major aetiological groups and the surgical evaluation. There were 136 episodes of native valve endocarditis (NVE) (88%) and 18 episodes of prosthetic valve endocarditis (PVE) (12%). Three major groups of NVE crystallized: Streptococcus viridans in 37 (27%), Staphylococcus aureus in 39 (29%) and culture negative IE in 28 (21%) episodes. In these groups surgery during the active phase was required in 41, 28 and 18%, respectively. At the operation myocardial abscess was found in as many as 7/15 cases with S. viridans, but in only in 3/11 cases with S. aureus and 1/5 cases with culture negative IE. The mean duration of preoperative antibiotic treatment was 34 d. This long period of unsuccessful pharmacotherapy, preceded by a mean of 47 d from start of symptoms to admission to hospital, has probably resulted in the high frequency of myocardial abscess in S. viridans NVE. Surgical evaluation should be considered when fever persists beyond 10 d of adequate treatment, even in the absence of clinically apparent complications. Among the PVE episodes, 11/18 were managed with pharmacological treatment alone. Uncomplicated PVE may thus often be successfully treated with antibiotics alone.

PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis.

A mouse platelet-derived growth factor A chain (PDGF-A) null allele is shown to be homozygous lethal, with two distinct restriction points, one prenatally before E10 and one postnatally. Postnatally surviving PDGF-A-deficient mice develop lung emphysema secondary to the failure of alveolar septation. This is apparently caused by the loss of alveolar myofibroblasts and associated elastin fiber deposits. PDGF alpha receptor-positive cells in the lung having the location of putative alveolar myofibroblast progenitors were specifically absent in PDGF-A null mutants. We conclude that PDGF-A is crucial for alveolar myofibroblast ontogeny. We have previously shown that PDGF-B is required in the ontogeny of kidney mesangial cells. The PDGFs therefore appear to regulate the generation of specific populations of myofibroblasts during mammalian development. The two PDGF null phenotypes also reveal analogous morphogenetic functions for myofibroblast-type cells in lung and kidney organogenesis.

Replacement of the arytenoid following vertical hemilaryngectomy.

A considerable body of literature advocates and defines treatment of vocal cord cancer with posterior extension by hemilaryngectomy. The present study was carried out to determine the feasibility of using a newly devised pedicle flap, composed of thyroid cartilage and inferior constrictor muscle, to replace the ablated arytenoid cartilage. Animal investigation revealed satisfactory viability of the pedicle flap in canines, and in humans, five patients with T2 glottic carcinoma demonstrated excellent postoperative deglutition and return of voice. The results of the study indicate that this surgical technique merits consideration for its use in minimizing protracted glottic incompetence following hemilaryngectomy. The thyroid cartilage-inferior constrictor muscle pedicle flap may also prove useful as partial cricoid replacement in selected cases of subglottic extension and in cricoid reconstruction following trauma.