A Rational Reconstruction and Extension of Recursion Analysis

The focus of this paper is the technique of recur8\on analysis. Recursion analysis is used by the Boyer-Moore Theorem Prover to choose an appropriate induction schema and variable to prove theorems by mathematical induction. A rational reconstruction of recursion analysis is outlined, using the technique of proof plans. This rational reconstruction suggests an extension of recursion analysis which frees the induction suggestion from the forms of recursion found in the conjecture. Preliminary results are reported of the automation of this rational reconstruction and extension using the CLAM-Oyster system

Joint synthesis of conditionally related multiple outcomes makes better use of data than separate meta-analyses

Background: When there are structural relationships between outcomes reported in different trials, separate analyses of each outcome do not provide a single coherent analysis, which is required for decision-making. For example, trials of intrapartum anti-bacterial prophylaxis (IAP) to prevent early onset group B streptococcal (EOGBS) disease can report three treatment effects: the effect on bacterial colonisation of the newborn, the effect on EOGBS, and the effect on EOGBS conditional on newborn colonisation. These outcomes are conditionally related, or nested, in a multi-state model. This paper shows how to exploit these structural relationships, providing a single coherent synthesis of all the available data, while checking to ensure that different sources of evidence are consistent. Results: Overall, the use of IAP reduces the risk of EOGBS (RR: 0.03; 95% Credible Interval (CrI): 0.002-0.13). Most of the treatment effect is due to the prevention of colonisation in newborns of colonised mothers (RR: 0.08, 95% CrI: 0.04-0.14). Node-splitting demonstrated that the treatment effect calculated using only direct evidence was consistent with that predicted from the remaining evidence (p=0.15). The findings accorded with previously published separate meta-analyses of the different outcomes, once these are re-analysed correctly accounting for zero cells. Conclusion: Multiple outcomes should be synthesised together where possible, taking account of their structural relationships. This generates an internally coherent analysis, suitable for decision making, in which estimates of each of the treatment effects are based on all available evidence (direct and indirect). Separate meta-analyses of each outcome have none of these properties

Assessment of funnel plot asymmetry and publication bias in reproductive health meta-analyses: an analytic survey

BACKGROUND: Despite efforts to assure high methodological standards, systematic reviews may be affected by publication bias. The objective of this study was to evaluate the occurrence of publication bias in a collection of high quality systematic reviews on reproductive health. METHODS: Systematic reviews included in the Reproductive Health Library (RHL), issue No 9, were assessed. Funnel plot was used to assess meta-analyses containing 10 or more trials reporting a binary outcome. A funnel plot, the estimated number of missing studies and the adjusted combined effect size were obtained using the "trim and fill method". Meta-analyses results that were not considered to be robust due to a possible publication bias were submitted to a more detailed assessment. RESULTS: A total of 21 systematic reviews were assessed. The number of trials comprising each one ranged from 10 to 83 (median = 13), totaling 379 trials, whose results have been summarized. None of the reviews had reported any evaluation of publication bias or funnel plot asymmetry. Some degree of asymmetry in funnel plots was observed in 18 of the 21 meta-analyses evaluated (85.7%), with the estimated number of missing studies ranging from 1 to 18 (median = 3). Only for three meta-analyses, the conclusion could not be considered robust due to a possible publication bias. CONCLUSION: Asymmetry is a frequent finding in funnel plots of meta-analyses in reproductive health, but according to the present evaluation, less than 15% of meta-analyses report conclusions that would not be considered robust. Publication bias and other sources of asymmetry in funnel plots should be systematically addressed by reproductive health meta-analysts. Next amendments in Cochrane systematic reviews should include this type of evaluation. Further studies regarding the evolution of effect size and publication bias over time in systematic reviews in reproductive health are needed

Economics methods in Cochrane systematic reviews of health promotion and public health related interventions.

Peer reviewedPublisher PD

Restoring tumour selectivity of the bioreductive prodrug pr-104 by developing an analogue resistant to aerobic metabolism by human aldo-keto reductase 1c3

PR-104 is a phosphate ester pre-prodrug that is converted in vivo to its cognate alcohol, PR-104A, a latent alkylator which forms potent cytotoxins upon bioreduction. Hypoxia selectivity results from one-electron nitro reduction of PR-104A, in which cytochrome P450 oxidoreductase (POR) plays an important role. However, PR-104A also undergoes ‘off-target’ two-electron reduction by human aldo-keto reductase 1C3 (AKR1C3), resulting in activation in oxygenated tissues. AKR1C3 expression in human myeloid progenitor cells probably accounts for the dose-limiting myelotoxicity of PR-104 documented in clinical trials, resulting in human PR-104A plasma exposure levels 3.4- to 9.6-fold lower than can be achieved in murine models. Structure-based design to eliminate AKR1C3 activation thus represents a strategy for restoring the therapeutic window of this class of agent in humans. Here, we identified SN29176, a PR-104A analogue resistant to human AKR1C3 activation. SN29176 retains hypoxia selectivity in vitro with aerobic/hypoxic IC(50) ratios of 9 to 145, remains a substrate for POR and triggers γH2AX induction and cell cycle arrest in a comparable manner to PR-104A. SN35141, the soluble phosphate pre-prodrug of SN29176, exhibited superior hypoxic tumour log cell kill (>4.0) to PR-104 (2.5–3.7) in vivo at doses predicted to be achievable in humans. Orthologues of human AKR1C3 from mouse, rat and dog were incapable of reducing PR-104A, thus identifying an underlying cause for the discrepancy in PR-104 tolerance in pre-clinical models versus humans. In contrast, the macaque AKR1C3 gene orthologue was able to metabolise PR-104A, indicating that this species may be suitable for evaluating the toxicokinetics of PR-104 analogues for clinical development. We confirmed that SN29176 was not a substrate for AKR1C3 orthologues across all four pre-clinical species, demonstrating that this prodrug analogue class is suitable for further development. Based on these findings, a prodrug candidate was subsequently identified for clinical trials

Sustained antiproliferative mechanisms by RB24, a targeted precursor of multiple inhibitors of epidermal growth factor receptor and a DNA alkylating agent in the A431 epidermal carcinoma of the vulva cell line

Recently, with the purpose of enhancing the potency of epidermal growth factor receptor (EGFR)-based therapies, we designed a novel strategy termed ‘Cascade-release targeting’ that seeks to develop molecules capable of degrading to multiple tyrosine kinase (TK) inhibitors and highly reactive electrophiles, in a stepwise fashion. Here we report on the first prototype of this model, RB24, a masked methyltriazene, that in addition to being an inhibitor on its own was designed to degrade to RB14, ZR08, RB10+a DNA alkylating methyldiazonium species. The cascade degradation of RB24 requires the generation of two reactive electrophiles: (a) an iminium ion and (b) a methyldiazonium ion. Thus, we surmise that these species could alkylate the active site of EGFR, thereby irreversibly blocking its action and that DNA damage could be induced by the methyldiazonium. Using the EGFR-overexpressing human epidermoid carcinoma of the vulva cell line, A431, we demonstrate herein that (a) RB24 and its derived species (e.g. RB14, ZR08) irreversibly inhibit EGFR autophosphorylation, (b) RB24 induced significant levels of DNA strand breaks, (c) sustained inhibition of EGFR by RB24 was associated with blockade of MAPK activation and c-fos gene expression, (d) RB24 induced irreversible cell growth inhibition with a 100-fold greater potency than Temodal™, a clinical methyltriazene. The pronounced growth inhibitory potency of RB24 was attributed to its ability to simultaneously damage DNA and irreversibly block EGFR TK activity

Ampicillin/Sulbactam versus Cefuroxime as antimicrobial prophylaxis for cesarean delivery: a randomized study

<p>Abstract</p> <p>Background</p> <p>The efficacy and safety of a single dose of ampicillin/sulbactam compared to a single dose of cefuroxime at cord clamp for prevention of post-cesarean infectious morbidity has not been assessed.</p> <p>Methods</p> <p>Women scheduled for cesarean delivery were randomized to receive a single dose of either 3 g of ampicillin-sulbactam or 1.5 g of cefuroxime intravenously, after umbilical cord clamping. An evaluation for development of postoperative infections and risk factor analysis was performed.</p> <p>Results</p> <p>One hundred and seventy-six patients (median age 28 yrs, IQR: 24-32) were enrolled in the study during the period July 2004 - July 2005. Eighty-five (48.3%) received cefuroxime prophylaxis and 91 (51.7%) ampicillin/sulbactam. Postoperative infection developed in 5 of 86 (5.9%) patients that received cefuroxime compared to 8 of 91 (8.8%) patients that received ampicillin/sulbactam (p = 0.6). In univariate analyses 6 or more vaginal examinations prior to the operation (p = 0.004), membrane rupture for more than 6 hours (p = 0.08) and blood loss greater than 500 ml (p = 0.018) were associated with developing a postoperative surgical site infection (SSI). In logistic regression having 6 or more vaginal examinations was the most significant risk factor for a postoperative SSI (OR 6.8, 95% CI: 1.4-33.4, p = 0.019). Regular prenatal follow-up was associated with a protective effect (OR 0.04, 95% CI: 0.005-0.36, p = 0.004).</p> <p>Conclusions</p> <p>Ampicillin/sulbactam was as safe and effective as cefuroxime when administered for the prevention of infections following cesarean delivery.</p> <p>Trial registration</p> <p>Clinicaltrials.gov identifier: NCT01138852</p