Twelve tips for implementing a successful peer assessment

Following a multi-institutional research project, the authors formulated 12 tips for the successful implementation of peer assessment in a health-based setting. These tips relate to planning, delivery and feedback. They also offer a wide range of practical guidance and anecdotal evidence relating to peer assessment generally.     

Guidelines for the design, conduct and reporting of human intervention studies to evaluate the health benefits of foods

There is substantial evidence to link what we eat to the reduction of the risk of major chronic diseases and/or the improvement of functions. Thus, it is important for public health agencies and the food industry to facilitate the consumption of foods with particular health benefits by providing consumer products and messages based on scientific evidence. Although fragmentary advice is available from a range of sources, there is a lack of comprehensive scientific guidelines for the design, conduct and reporting of human intervention studies to evaluate the health benefits of foods. Such guidelines are needed both to support nutrition science in general, and to facilitate the substantiation of health claims. In the present study, which presents the consensus view of an International Life Sciences Institute Europe Expert Group that included senior scientists from academia and industry, the term 'foods' refers to foods, dietary supplements and food constituents, but not to whole diets. The present study is based on an initial survey of published papers, which identified the range and strengths and weaknesses of current methodologies, and was finalised following exchanges between representatives from industry, academia and regulatory bodies. The major factors involved in the design, conduct and reporting of studies are identified, summarised in a checklist table that is based on the Consolidated Standards of Reporting Trials guidelines, and elaborated and discussed in the text.     

Lipopolyplex ternary delivery systems incorporating C14 glycerol-based lipids

The structure, biophysical properties and biological behavior of lipopolyplex ternary gene delivery vectors incorporating novel C14 glycerol based lipids of varying alkyl chain geometry (containing cis, trans or alkyne double bonds) have been studied in the presence and absence of a bifunctional targeting peptide designed to both condense DNA and confer integrin-specific targeting. In vitro transfection studies in breast cancer MDA-MB-231 cells revealed that ternary formulations of lipid:peptide:DNA (LPD) complexes prepared using the aforementioned lipids possessed highly synergistic transfection activity up to 2500-fold higher than their respective lipid:DNA (LD) or peptide:DNA (PD) counterparts. Furthermore, the small structural differences in the lipid alkyl chain geometries also resulted in pronounced differences in transfection within each type of formulation, whereby the trans lipids showed best activity when formulated as LD complexes, whereas the cis lipids were superior in LPD formulations. Confocal fluorescence internalization studies using labeled components of the formulations showed both the lipid and the DNA of LD complexes to be trapped in endocytic compartments, whereas in the case of LPD complexes, the DNA was clearly released from the endosomal compartments and, together with the peptide, internalized within the cell nucleus. Physicochemical characterization of the formulations carried out by light and neutron scattering, zeta potential measurement, and negative staining electron microscopy detected major structural differences between LD and LPD complexes. Gel electrophoresis assays additionally showed differences between the individual lipids tested in each type of formulation. In conclusion, the superior transfection of the trans lipids in the LD complexes was thought to be attributed to superior DNA binding caused by a more closely matched charge distribution of the more rigid, trans lipids with the DNA. In the case of the LPD complexes, the DNA was thought to be predominantly condensed by the cationic portion of the peptide forming a central core surrounded by a lipid bilayer from which the targeting sequence partially protrudes. The more fluid, cis lipids were thought to confer better activity in this formulation due to allowing more of the targeting peptide sequence to protrude.     

Substrate specificity and ligand interactions of CYP26A1, the human liver retinoic acid hydroxylase

All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. atRA is also used as a drug, and synthetic atRA analogs and inhibitors of retinoic acid (RA) metabolism have been developed. The hepatic clearance of atRA is mediated primarily by CYP26A1, but design of CYP26A1 inhibitors is hindered by lack of information on CYP26A1 structure and structure-activity relationships of its ligands. The aim of this study was to identify the primary metabolites of atRA formed by CYP26A1 and to characterize the ligand selectivity and ligand interactions of CYP26A1. On the basis of high-resolution tandem mass spectrometry data, four metabolites formed from atRA by CYP26A1 were identified as 4-OH-RA, 4-oxo-RA, 16-OH-RA and 18-OH-RA. 9-cis-RA and 13-cis-RA were also substrates of CYP26A1. Forty-two compounds with diverse structural properties were tested for CYP26A1 inhibition using 9-cis-RA as a probe, and IC(50) values for 10 inhibitors were determined. The imidazole- and triazole-containing inhibitors [S-(R*,R*)]-N-[4-[2-(dimethylamino)-1-(1H-imidazole-1-yl)propyl]-phenyl]2-benzothiazolamine (R116010) and (R)-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzothiazolamine (R115866) were the most potent inhibitors of CYP26A1 with IC(50) values of 4.3 and 5.1 nM, respectively. Liarozole and ketoconazole were significantly less potent with IC(50) values of 2100 and 550 nM, respectively. The retinoic acid receptor (RAR) γ agonist CD1530 was as potent an inhibitor of CYP26A1 as ketoconazole with an IC(50) of 530 nM, whereas the RARα and RARβ agonists tested did not significantly inhibit CYP26A1. The pan-RAR agonist 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid and the peroxisome proliferator-activated receptor ligands rosiglitazone and pioglitazone inhibited CYP26A1 with IC(50) values of 3.7, 4.2, and 8.6 μM, respectively. These data demonstrate that CYP26A1 has high ligand selectivity but accepts structurally related nuclear receptor agonists as inhibitors.     

Should experienced open prostatic surgeons convert to robotic surgery? The real learning curve for one surgeon over 3 years

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To critically analyse the learning curve for one experienced open surgeon converting to robotic surgery for radical prostatectomy (RP).

PATIENTS AND METHODS

From February 2006 to December 2008, 502 patients had retropubic RP (RRP) while concurrently 212 had robot‐assisted laparoscopic RP (RALP) by one urologist. We prospectively compared the baseline patient and tumour characteristics, variables during and after RP, histopathological features and early urinary functional outcomes in the two groups.

RESULTS

The patients in both groups were similar in age, preoperative prostate‐specific antigen level, and prostatic volume. However, there were more high‐stage (T2b and T3, P= 0.02) and ‐grade (Gleason 9, P= 0.01) tumours in the RRP group. The mean (range) operative duration was 147 (75–330) min for RRP and 192 (119–525) min for RALP (P < 0.001); 110 cases were required to achieve ‘3‐h proficiency’. Major complication rates were 1.8% and 0.8% for RALP and RRP, respectively. The overall positive surgical margin (PSM) rate was 21.2% in the RALP and 16.7% in the RRP group (P= 0.18). PSM rates for pT2 were comparable (11.6% vs 10.1%, P= 0.74). pT3 PSM rates were higher for RALP than RRP (40.5% vs 28.8%, P= 0.004). The learning curve started to plateau in the overall PSM rate after 150 cases. For the pT2 and pT3 PSM rates, the learning curve tended to flatten after 140 and 170 cases, respectively. The early continence rates were comparable (P= 0.07) but showed a statistically significant improvement after 200 cases.

CONCLUSIONS

Our analysis of the learning curve has shown that certain components of the curve for an experienced open surgeon transferring skills to the robotic platform take different times. We suggest that patient selection is guided by these milestones, to maximize oncological outcomes.     

Integration of new biological and physical retrospective dosimetry methods into EU emergency response plans – joint RENEB and EURADOS inter-laboratory comparisons

Abstract

Purpose: RENEB, ‘Realising the European Network of Biodosimetry and Physical Retrospective Dosimetry,’ is a network for research and emergency response mutual assistance in biodosimetry within the EU. Within this extremely active network, a number of new dosimetry methods have recently been proposed or developed. There is a requirement to test and/or validate these candidate techniques and inter-comparison exercises are a well-established method for such validation.

Materials and methods: The authors present details of inter-comparisons of four such new methods: dicentric chromosome analysis including telomere and centromere staining; the gene expression assay carried out in whole blood; Raman spectroscopy on blood lymphocytes, and detection of radiation-induced thermoluminescent signals in glass screens taken from mobile phones.

Results: In general the results show good agreement between the laboratories and methods within the expected levels of uncertainty, and thus demonstrate that there is a lot of potential for each of the candidate techniques.

Conclusions: Further work is required before the new methods can be included within the suite of reliable dosimetry methods for use by RENEB partners and others in routine and emergency response scenarios.