A pilot study of preemptive morphine analgesia in preterm neonates: effects on head circumference, social behavior, and response latencies in early childhood

Use of preemptive analgesia in Neonatal Intensive Care Units is recommended for severe and/or invasive procedures. However, the potential long-term consequences of such analgesia, which may be prolonged, are only beginning to be studied. In this pilot study, a subset of subjects previously enrolled in the Neurological Outcomes and Preemptive Analgesia in Neonates (NEOPAIN) trial was assessed at early childhood. These ex-preterm infants (born at 23-32 weeks of gestational age) required intubation within 72 h postpartum and were randomized to receive either preemptive morphine analgesia (maximum of 14 days) or placebo within 8 h post-intubation. At 5-7 years of age, neuropsychological outcomes, morphometrics, adaptive behavior, parent-rated behavior, motivation, and short-term memory were measured. Although overall IQ and academic achievement did not differ between the morphine treated (n = 14) and placebo (n = 5) groups, preemptive morphine analgesia was associated with distinct differences in other outcome variables. Head circumference of morphine treated children was approximately 7% smaller (Cohen's d: 2.83, effect size large) and body weight was approximately 4% less (Cohen's d: 0.81, effect size large); however, height did not differ. In the short-term memory task (delayed matching to sample), morphine treated children exhibited significantly longer choice response latencies than placebo children (3.86 ± 0.33 and 2.71 ± 0.24 s, respectively) (p < 0.03) and completed approximately 27% less of the task than placebo children (Cohen's d: 0.96, effect size large). Parents described morphine treated children as having more social problems, an effect specific to creating and maintaining friendships (Cohen's d: − 0.83, effect size large). Despite the small sample size and the preliminary nature of this study, these results are strongly suggestive of long-lasting effects of preemptive morphine analgesia. A larger investigation with more comprehensive assessments of some of these key features will enable a more complete understanding of the relationship between preemptive morphine treatment and long-term neurocognitive, behavioral, and adaptive outcomes.     

The perceived health risks of cannabis use in an Australian household survey

Introduction and Aims. Perceived risks of cannabis use have rarely been researched in Australia. This paper reports on the beliefs about the adverse effects of cannabis use on health, social well-being, driving, mental health and changes in cannabis over time. Design and Methods. Survey of 918 Australian adults was conducted as part of a quarterly omnibus self-report survey of an established panel. Results. Respondents believed that cannabis use can cause health and social problems, can adversely affect a person's ability to drive a car, can be addictive, and can lead to use of other illicit drugs. They were uncertain as to whether cannabis can cause schizophrenia and depression, and whether cannabis had become more potent over time. Implications. Prevention efforts should focus on educating the Australian people about the nature of cannabis-related harms.[Calabria B, Swift W, Slade T, Hall W, Copeland J. The perceived health risks of cannabis use in an Australian household survey. Drug Alcohol Rev 2012;31:809-812].     

Elite athletes' estimates of the prevalence of illicit drug use: evidence for the false consensus effect

Introduction and Aims. The false consensus effect (FCE) is the tendency for people to assume that others share their attitudes and behaviours to a greater extent than they actually do. The FCE has been demonstrated for a range of health behaviours, including substance use. The study aimed to explore the relationship between elite athlete's engagement in recreational drug use and their consensus estimates (the FCE) and to determine whether those who engage in the behaviour overestimate the use of others around them. Design and Method. The FCE was investigated among 974 elite Australian athletes who were classified according to their drug use history. Results. Participants tended to report that there was a higher prevalence of drug use among athletes in general compared with athletes in their sport, and these estimates appeared to be influenced by participants' drug use history. While overestimation of drug use by participants was not common, this overestimation also appeared to be influenced by athletes' drug use history. Discussion and Conclusions. The results suggest that athletes who have a history of illicit drug use overestimate the prevalence of drug use among athletes. These findings may be helpful in the formulation of normative education initiatives.[Dunn M, Thomas JO, Swift W, Burns L. Elite athletes' estimates of the prevalence of illicit drug use: Evidence for the false consensus effect. Drug Alcohol Rev 2012;31:27–32]     

Development of a combination drug-eluting bead: towards enhanced efficacy for locoregional tumour therapies

Drug-eluting beads (DEBs) are becoming a mainstay locoregional therapy for hepatic malignancies but are currently loaded with single drugs alone. Here, we wished to prepare DEB containing different drug combinations, to screen their efficacy using an in-vitro cell culture assay and to include any promising combinations that demonstrate additive efficacy in an in-vivo model of locoregional tumour treatment. A modified in-vitro assay was used based upon the use of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) with either HepG2 liver cancer or PSN1 pancreatic cancer cell lines. The comparative cytotoxicity of DEB combinations prepared containing doxorubicin, irinotecan, topotecan and rapamycin was evaluated. Those combinations that demonstrated an additive cytotoxicity effect were investigated in vivo using a nude mouse xenograft model of pancreatic cancer. Although many of the DEB combinations showed either no effect or a slight antagonistic effect, the combination of doxorubicin and rapamycin DEBs demonstrated synergistic activity. On the basis of these findings, a method was developed to prepare a doxorubicin/rapamycin dual-loaded DEB, which was shown to possess the same drug-loading capacities, drug elution properties and HepG2 cell cytotoxicity synergy as the single drug-loaded DEB combination. Evaluation of this dual-loaded combination DEB versus the respective single drug-loaded DEBs in a mouse xenograft model of pancreatic cancer showed an equivalent tumour volume reduction as the doxorubicin DEB, but with less toxicity than the rapamycin DEB. The doxorubicin/rapamycin combination DEB offers great potential for enhanced efficacy in the locoregional treatment of malignant tumours.     

Patient characteristics associated with venous thromboembolic events: a cohort study using pooled electronic health record data

Objective

To demonstrate the potential of de-identified clinical data from multiple healthcare systems using different electronic health records (EHR) to be efficiently used for very large retrospective cohort studies.

Materials and methods

Data of 959 030 patients, pooled from multiple different healthcare systems with distinct EHR, were obtained. Data were standardized and normalized using common ontologies, searchable through a HIPAA-compliant, patient de-identified web application (Explore; Explorys Inc). Patients were 26 years or older seen in multiple healthcare systems from 1999 to 2011 with data from EHR.

Results

Comparing obese, tall subjects with normal body mass index, short subjects, the venous thromboembolic events (VTE) OR was 1.83 (95% CI 1.76 to 1.91) for women and 1.21 (1.10 to 1.32) for men. Weight had more effect then height on VTE. Compared with Caucasian, Hispanic/Latino subjects had a much lower risk of VTE (female OR 0.47, 0.41 to 0.55; male OR 0.24, 0.20 to 0.28) and African-Americans a substantially higher risk (female OR 1.83, 1.76 to 1.91; male OR 1.58, 1.50 to 1.66). This 13-year retrospective study of almost one million patients was performed over approximately 125 h in 11 weeks, part time by the five authors.

Discussion

As research informatics tools develop and more clinical data become available in EHR, it is important to study and understand unique opportunities for clinical research informatics to transform the scale and resources needed to perform certain types of clinical research.

Conclusions

With the right clinical research informatics tools and EHR data, some types of very large cohort studies can be completed with minimal resources.     

Real-time in vivo detection of biomaterial-induced reactive oxygen species

The non-specific host response to implanted biomaterials is often a key challenge of medical device design. To evaluate biocompatibility, measuring the release of reactive oxygen species (ROS) produced by inflammatory cells in response to biomaterial surfaces is a well-established method. However, the detection of ROS in response to materials implanted in vivo has not yet been demonstrated. Here, we develop a bioluminescence whole animal imaging approach to observe ROS released in response to subcutaneously-implanted materials in live animals. We compared the real-time generation of ROS in response to two representative materials, polystyrene and alginate, over the course of 28 days. High levels of ROS were observed near polystyrene, but not alginate implants, and persisted throughout the course of 28 days. Histological analysis revealed that high levels of ROS correlated not only with the presence of phagocytic cells at early timepoints, but also fibrosis at later timepoints, suggesting that ROS may be involved in both the acute and chronic phase of the foreign body response. These data are the first in vivo demonstration of ROS generation in response to implanted materials, and describe a novel technique to evaluate the host response.     

Silencing of the imprinted DLK1-MEG3 locus in human clinically nonfunctioning pituitary adenomas

DLK1-MEG3 is an imprinted locus consisting of multiple maternally expressed noncoding RNA genes and paternally expressed protein-coding genes. The expression of maternally expressed gene 3 (MEG3) is selectively lost in clinically nonfunctioning adenomas (NFAs) of gonadotroph origin; however, expression status of other genes at this locus in human pituitary adenomas has not previously been reported. Using quantitative real-time RT-PCR, we evaluated expression of 24 genes from the DLK1-MEG3 locus in 44 human pituitary adenomas (25 NFAs, 7 ACTH-secreting, 7 GH-secreting, and 5 PRL-secreting adenomas) and 10 normal pituitaries. The effects on cell proliferation of five miRNAs whose expression was lost in NFAs were investigated by flow cytometry analysis. We found that 18 genes, including 13 miRNAs at the DLK1-MEG3 locus, were significantly down-regulated in human NFAs. In ACTH-secreting and PRL-secreting adenomas, 12 and 7 genes were significantly down-regulated, respectively; no genes were significantly down-regulated in GH-secreting tumors. One of the five miRNAs tested induced cell cycle arrest at the G2/M phase in PDFS cells derived from a human NFA. Our data indicate that the DLK1-MEG3 locus is silenced in NFAs. The growth suppression by miRNAs in PDFS cells is consistent with the hypothesis that the DLK1-MEG3 locus plays a tumor suppressor role in human NFAs.     

Diversity counts. Visualizing pretumor progression in the gastrointestinal tract

Tumor progression is critically dependent on the selection of genetic alterations. This clonal evolution can be traced to the stage preceding visible tumor formation called pretumor progression, in which genetic change occurs without visible change. Recently, the identification of intestinal stem cell markers in animal models has made visualization of stem cells possible in vivo. Translating this work to the clinical setting by visualizing stem cells in patient material may allow us to understand differences in patients' vulnerability to cancer development and target preventive measures to high-risk groups. In this review article, we examine some of the analytic methods currently used in research settings tracing stem cell dynamics.