Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients

The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter. Secondarily, the AUC/MIC targets of 450, 865, and 1,185 were used to calculate PTAs for Candida glabrata, C. albicans, and C. parapsilosis, respectively. The final 2-compartment model included weight as a covariate on volume of distribution (V). The mean V of the central compartment was 7.71 (standard deviation [SD], 2.70) liters/kg of body weight, the mean elimination constant (Ke) was 0.09 (SD, 0.04) h-1, the rate constant for the caspofungin distribution from the central to the peripheral compartment was 0.44 (SD, 0.39) h-1, and the rate constant for the caspofungin distribution from the peripheral to the central compartment was 0.46 (SD, 0.35) h-1. A loading dose of 2 mg/kg on the first day, followed by 1.25 mg/kg as a maintenance dose, was chosen. With this dose, 98% of the patients were expected to reach the AUC target on the first day and 100% of the patients on the third day. The registered caspofungin dose might not be suitable for critically ill patients who were all overweight (≥120 kg), over 80% of median weight (78 kg), and around 25% of lower weight (≤50 kg). A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in intensive care unit patients

Clusters with random size: maximum likelihood versus weighted estimation

Abstract: There are many contemporary designs that do not use a random sample of a fixed, a priori determined size. In case of informative cluster sizes, the cluster size is influenced by the the cluster's data, but here we cope with some issues that even occur when the cluster size and the data are unrelated. First, fitting models to clusters of varying sizes is often more complicated than when all cluster have the same size. Secondly, in such cases, there usually is no so-called complete sufficient statistic

Public/community engagement in health research with men who have sex with men in sub-Saharan Africa: challenges and opportunities

Abstract Background Community engagement, incorporating elements of the broader concepts of public and stakeholder engagement, is increasingly promoted globally, including for health research conducted in developing countries. In sub-Saharan Africa, community engagement needs and challenges are arguably intensified for studies involving gay, bisexual and other men who have sex with men, where male same-sex sexual interactions are often highly stigmatised and even illegal. This paper contextualises, describes and interprets the discussions and outcomes of an international meeting held at the Kenya Medical Research Institute-Wellcome Trust in Kilifi, Kenya, in November 2013, to critically examine the experiences with community engagement for studies involving men who have sex with men. Discussion We discuss the ethically charged nature of the language used for men who have sex with men, and of working with ‘representatives’ of these communities, as well as the complementarity and tensions between a broadly public health approach to community engagement, and a more rights based approach. We highlight the importance of researchers carefully considering which communities to engage with, and the goals, activities, and indicators of success and potential challenges for each. We suggest that, given the unintended harms that can emerge from community engagement (including through labelling, breaches in confidentiality, increased visibility and stigma, and threats to safety), representatives of same-sex populations should be consulted from the earliest possible stage, and that engagement activities should be continuously revised in response to unfolding realities. Engagement should also include less vocal and visible men who have sex with men, and members of other communities with influence on the research, and on research participants and their families and friends. Broader ethics support, advice and research into studies involving men who have sex with men is needed to ensure that ethical challenges – including but not limited to those related to community engagement – are identified and addressed. Summary Underlying challenges and dilemmas linked to stigma and discrimination of men who have sex with men in Africa raise special responsibilities for researchers. Community engagement is an important way of identifying responses to these challenges and responsibilities but itself presents important ethical challenges

Evidence Based Selection of Housekeeping Genes

For accurate and reliable gene expression analysis, normalization of gene expression data against housekeeping genes (reference or internal control genes) is required. It is known that commonly used housekeeping genes (e.g. ACTB, GAPDH, HPRT1, and B2M) vary considerably under different experimental conditions and therefore their use for normalization is limited. We performed a meta-analysis of 13,629 human gene array samples in order to identify the most stable expressed genes. Here we show novel candidate housekeeping genes (e.g. RPS13, RPL27, RPS20 and OAZ1) with enhanced stability among a multitude of different cell types and varying experimental conditions. None of the commonly used housekeeping genes were present in the top 50 of the most stable expressed genes. In addition, using 2,543 diverse mouse gene array samples we were able to confirm the enhanced stability of the candidate novel housekeeping genes in another mammalian species. Therefore, the identified novel candidate housekeeping genes seem to be the most appropriate choice for normalizing gene expression data

The individual-cell-based cryo-chip for the cryopreservation, manipulation and observation of spatially identifiable cells. I: Methodology

<p>Abstract</p> <p>Background</p> <p>Cryopreservation is the only widely applicable method of storing vital cells for nearly unlimited periods of time. Successful cryopreservation is essential for reproductive medicine, stem cell research, cord blood storage and related biomedical areas. The methods currently used to retrieve a specific cell or a group of individual cells with specific biological properties after cryopreservation are quite complicated and inefficient.</p> <p>Results</p> <p>The present study suggests a new approach in cryopreservation, utilizing the Individual Cell-based Cryo-Chip (i3C). The i3C is made of materials having appropriate durability for cryopreservation conditions. The core of this approach is an array of picowells, each picowell designed to maintain an individual cell during the severe conditions of the freezing - thawing cycle and accompanying treatments. More than 97% of cells were found to retain their position in the picowells throughout the entire freezing - thawing cycle and medium exchange. Thus the comparison between pre-freezing and post-thawing data can be achieved at an individual cell resolution. The intactness of cells undergoing slow freezing and thawing, while residing in the i3C, was found to be similar to that obtained with micro-vials. However, in a fast freezing protocol, the i3C was found to be far superior.</p> <p>Conclusions</p> <p>The results of the present study offer new opportunities for cryopreservation. Using the present methodology, the cryopreservation of individual identifiable cells, and their observation and retrieval, at an individual cell resolution become possible for the first time. This approach facilitates the correlation between cell characteristics before and after the freezing - thawing cycle. Thus, it is expected to significantly enhance current cryopreservation procedures for successful regenerative and reproductive medicine.</p