Epidemiology and natural history of central venous access device use and infusion pump function in the NO16966 trial

Background: Central venous access devices in fluoropyrimidine therapy are associated with complications; however, reliable data are lacking regarding their natural history, associated complications and infusion pump performance in patients with metastatic colorectal cancer.<p></p> Methods: We assessed device placement, use during treatment, associated clinical outcomes and infusion pump perfomance in the NO16966 trial.<p></p> Results: Device replacement was more common with FOLFOX-4 (5-fluorouracil (5-FU)+oxaliplatin) than XELOX (capecitabine+oxaliplatin) (14.1% vs 5.1%). Baseline device-associated events and post-baseline removal-/placement-related events occurred more frequently with FOLFOX-4 than XELOX (11.5% vs 2.4% and 8.5% vs 2.1%). Pump malfunctions, primarily infusion accelerations in 16% of patients, occurred within 1.6–4.3% of cycles. Fluoropyrimidine-associated grade 3/4 toxicity was increased in FOLFOX-4-treated patients experiencing a malfunction compared with those who did not (97 out of 155 vs 452 out of 825 patients), predominantly with increased grade 3/4 neutropenia (53.5% vs 39.8%). Febrile neutropenia rates were comparable between patient cohorts±malfunction. Efficacy outcomes were similar in patient cohorts±malfunction.<p></p> Conclusions: Central venous access device removal or replacement was common and more frequent in patients receiving FOLFOX-4. Pump malfunctions were also common and were associated with increased rates of grade 3/4 haematological adverse events. Oral fluoropyrimidine-based regimens may be preferable to infusional 5-FU based on these findings

Multiple populations in globular clusters. Lessons learned from the Milky Way globular clusters

Recent progress in studies of globular clusters has shown that they are not simple stellar populations, being rather made of multiple generations. Evidence stems both from photometry and spectroscopy. A new paradigm is then arising for the formation of massive star clusters, which includes several episodes of star formation. While this provides an explanation for several features of globular clusters, including the second parameter problem, it also opens new perspectives about the relation between globular clusters and the halo of our Galaxy, and by extension of all populations with a high specific frequency of globular clusters, such as, e.g., giant elliptical galaxies. We review progress in this area, focusing on the most recent studies. Several points remain to be properly understood, in particular those concerning the nature of the polluters producing the abundance pattern in the clusters and the typical timescale, the range of cluster masses where this phenomenon is active, and the relation between globular clusters and other satellites of our Galaxy.Comment: In press (The Astronomy and Astrophysics Review

Metformin as an Adjunctive Therapy for Pancreatic Cancer: A Review of the Literature on Its Potential Therapeutic Use

Pancreatic ductal adenocarcinoma has the worst prognosis of any cancer. New adjuvant chemotherapies are urgently required, which are well tolerated by patients with unresectable cancers. This paper reviews the existing proof of concept data, namely laboratory, pharmacoepidemiological, experimental medicine and clinical trial evidence for investigating metformin in patients with pancreatic ductal adenocarcinoma. Laboratory evidence shows metformin inhibits mitochondrial ATP synthesis which directly and indirectly inhibits carcinogenesis. Drug–drug interactions of metformin with proton pump inhibitors and histamine H2-receptor antagonists may be of clinical relevance and pertinent to future research of metformin in pancreatic ductal adenocarcinoma. To date, most cohort studies have demonstrated a positive association with metformin on survival in pancreatic ductal adenocarcinoma, although there are many methodological limitations with such study designs. From experimental medicine studies, there are sparse data in humans. The current trials of metformin have methodological limitations. Two small randomized controlled trials (RCTs) reported null findings, but there were potential inequalities in cancer staging between groups and poor compliance with the intervention. Proof of concept data, predominantly from laboratory work, supports assessing metformin as an adjunct for pancreatic ductal adenocarcinoma in RCTs. Ideally, more experimental medicine studies are needed for proof of concept. However, many feasibility criteria need to be answered before such trials can progress

A comparison between ultraviolet disinfection and copper alginate beads within a vortex bioreactor for the deactivation of bacteria in simulated waste streams with high levels of colour, humic acid and suspended solids.

We show in this study that the combination of a swirl flow reactor and an antimicrobial agent (in this case copper alginate beads) is a promising technique for the remediation of contaminated water in waste streams recalcitrant to UV-C treatment. This is demonstrated by comparing the viability of both common and UV-C resistant organisms in operating conditions where UV-C proves ineffective - notably high levels of solids and compounds which deflect UV-C. The swirl flow reactor is easy to construct from commonly available plumbing parts and may prove a versatile and powerful tool in waste water treatment in developing countries

The role of population PK-PD modelling in paediatric clinical research

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK-PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK-PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK-PD parameters with the highest precision. Once a population PK-PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child

SIVagm Infection in Wild African Green Monkeys from South Africa: Epidemiology, Natural History, and Evolutionary Considerations

Pathogenesis studies of SIV infection have not been performed to date in wild monkeys due to difficulty in collecting and storing samples on site and the lack of analytical reagents covering the extensive SIV diversity. We performed a large scale study of molecular epidemiology and natural history of SIVagm infection in 225 free-ranging AGMs from multiple locations in South Africa. SIV prevalence (established by sequencing pol, env, and gag) varied dramatically between infant/juvenile (7%) and adult animals (68%) (p<0.0001), and between adult females (78%) and males (57%). Phylogenetic analyses revealed an extensive genetic diversity, including frequent recombination events. Some AGMs harbored epidemiologically linked viruses. Viruses infecting AGMs in the Free State, which are separated from those on the coastal side by the Drakensberg Mountains, formed a separate cluster in the phylogenetic trees; this observation supports a long standing presence of SIV in AGMs, at least from the time of their speciation to their Plio-Pleistocene migration. Specific primers/probes were synthesized based on the pol sequence data and viral loads (VLs) were quantified. VLs were of 104-106 RNA copies/ml, in the range of those observed in experimentally-infected monkeys, validating the experimental approaches in natural hosts. VLs were significantly higher (107-108 RNA copies/ml) in 10 AGMs diagnosed as acutely infected based on SIV seronegativity (Fiebig II), which suggests a very active transmission of SIVagm in the wild. Neither cytokine levels (as biomarkers of immune activation) nor sCD14 levels (a biomarker of microbial translocation) were different between SIV-infected and SIV-uninfected monkeys. This complex algorithm combining sequencing and phylogeny, VL quantification, serology, and testing of surrogate markers of microbial translocation and immune activation permits a systematic investigation of the epidemiology, viral diversity and natural history of SIV infection in wild African natural hosts. © 2013 Ma et al

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Self-reported smoking cessation activities among Swiss primary care physicians

ABSTRACT: BACKGROUND: Individual counselling, pharmacotherapy, and group therapy are evidence-based interventions that help patients stop smoking. Acupuncture, hypnosis, and relaxation have no demonstrated efficacy on smoking cessation, whereas self-help material may only have a small benefit. The purpose of this study is to assess physicians' current clinical practice regarding smokers motivated to stop smoking. METHODS: The survey included 3385 Swiss primary care physicians. Self-reported use of nine smoking cessation interventions was scored. One point was given for each positive answer about practicing interventions with demonstrated efficacy, i.e. nicotine replacement therapy, bupropion, counselling, group therapy, and smoking cessation specialist. No points were given for the recommendation of acupuncture, hypnosis, relaxation, and self-help material. Multivariable logistic analysis was performed to identify factors associated with a good practice score, defined as &gt;1. RESULTS: The response rate was 55%. Respondents were predominately over the age of 40 years (88%), male (79%), and resided in urban areas (74%). Seventeen percent reported being smokers. Most of the physicians prescribed nicotine replacement therapy (84%), bupropion (65%), or provided counselling (70%). A minority of physicians recommended acupuncture (26%), hypnosis (8%), relaxation (7%), or self-help material (24%). A good practice score was obtained by 85% of respondents. Having attended a smoking cessation training program was the only significant predictor of a good practice score (odds ratio: 6.24 , 95% CI 1.95-20.04). CONCLUSION: The majority of respondents practice recommended smoking cessation interventions. However, there is room for improvement and implementing an evidence-based smoking cessation-training program could provide additional benefit

Implementing the European guidelines for cardiovascular disease prevention in the primary care setting in Cyprus: Lessons learned from a health care services study

<p>Abstract</p> <p>Background</p> <p>Recent guidelines recommend assessment and treatment of the overall risk for cardiovascular disease (CVD) through management of multiple risk factors in patients at high absolute risk. The aim of our study was to assess the level of cardiovascular risk in patients with known risk factors for CVD by applying the SCORE risk function and to study the implications of European guidelines on the use of treatment and goal attainment for blood pressure (BP) and lipids in the primary care of Cyprus.</p> <p>Methods</p> <p>Retrospective chart review of 1101 randomly selected patients with type 2 diabetes mellitus (DM2), or hypertension or hyperlipidemia in four primary care health centres. The SCORE risk function for high-risk regions was used to calculate 10-year risk of cardiovascular fatal event. Most recent values of BP and lipids were used to assess goal attainment to international standards. Most updated medications lists were used to compare proportions of current with recommended antihypertensive and lipid-lowering drug (LLD) users according to European guidelines.</p> <p>Results</p> <p>Implementation of the SCORE risk model labelled overall 39.7% (53.6% of men, 31.3% of women) of the study population as high risk individuals (CVD, DM2 or SCORE ≥5%). The SCORE risk chart was not applicable in 563 patients (51.1%) due to missing data in the patient records, mostly on smoking habits. The LDL-C goal was achieved in 28.6%, 19.5% and 20.9% of patients with established CVD, DM2 (no CVD) and SCORE ≥5%, respectively. BP targets were achieved in 55.4%, 5.6% and 41.9% respectively for the above groups. There was under prescription of antihypertensive drugs, LLD and aspirin for all three high risk groups.</p> <p>Conclusion</p> <p>This study demonstrated suboptimal control and under-treatment of patients with cardiovascular risk factors in the primary care in Cyprus. Improvement of documentation of clinical information in the medical records as well as GPs training for implementation and adherence to clinical practice guidelines are potential areas for further discussion and research.</p