A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma

Background: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2-deoxyuridine-5- monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of I mM for six or more hours, significantly enhances the efficacy of 5-FU. Patients and methods: 5-FU/FA was given as follows: days 1 and 2 - FA 250 mg/m 2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m 2 by intravenous bolus (ivb) over 15 minutes and subsequently 5-FU 400 mg/m 2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g ivb over 15 minutes followed by 12 g ivi over 12 hours. Results: Thirty patients were entered into the study. Median survival was nine months (range 1-51 + months). There were eight partial responses (28%, 95% CI: 13%-47%). The median duration of response was 6.5 (range 4-9 months). Grade 3-4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another. Conclusion: HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.

Submission to the inquiry into the high level of involvement of Indigenous juveniles and young adults in the criminal justice system

Introduction • The Australian Institute of Criminology (AIC) is Australia's national research and knowledge centre on crime and justice. • The Institute seeks to promote justice and reduce crime by undertaking and communicating evidence-based research to inform policy and practice. • The AIC is governed by the Criminology Research Act and has been in operation since 1973. • The AIC is pleased to have the opportunity to contribute to the Committee's Inquiry into the high level of involvement of Indigenous juveniles and young adults in the criminal justice system. • There is a great deal of evidence to demonstrate that Indigenous young people are significantly over-represented at every stage of the criminal justice system in Australia.

Lesion selection by melanoma high-risk consumers during skin self-examination using mobile teledermoscopy

Mobile teledermatoscopy (MTD) for the early detection of skin cancer uses smartphones with dermatoscope attachments to magnify, capture, and transfer images remotely.1 Using the asymmetry–color variation (AC) rule, consumers achieve dermoscopy sensitivity of 92.9% to 94.0% and specificity of 62.0% to 64.2% for melanoma.2 This pilot randomized trial assessed lesions of concern selected by consumers at high risk of melanoma using MTD plus the AC rule (intervention, n = 10) or the AC rule alone (control, n = 12) during skin self-examination (SSE). Also measured were lesion location patterns, lesions overlooked by participants, provisional clinical diagnoses, likelihood of malignant tumor, and participant pressure to excise lesions.

Evolving progress in oncologic and operative outcomes for esophageal and junctional cancer : lessons from the experience of a high-volume center

Objective: Modern series from high-volume esophageal centers report an approximate 40% 5-year survival in patients treated with curative intent and postoperative mortality rates of less than 4%. An objective analysis of factors that underpin current benchmarks within high-volume centers has not been performed. Methods: Three time periods were studied, 1990 to 1998 (period 1), 1999 to 2003 (period 2), and 2004 to 2008 (period 3), in which 471, 254, and 342 patients, respectively, with esophageal cancer were treated with curative intent. All data were prospectively recorded, and staging, pathology, treatment, operative, and oncologic outcomes were compared. Results: Five-year disease-specific survival was 28%, 35%, and 44%, and in-hospital postoperative mortality was 6.7%, 4.4%, and 1.7% for periods 1 to 3, respectively (P < .001). Period 3, compared with periods 1 and 2, respectively, was associated with significantly (P < .001) more early tumors (17% vs 4% and 6%), higher nodal yields (median 22 vs 11 and 18), and a higher R0 rate in surgically treated patients (81% vs 73% and 75%). The use of multimodal therapy increased (P < .05) across time periods. By multivariate analysis, age, T stage, N stage, vascular invasion, R status, and time period were significantly (P < .0001) associated with outcome. Conclusions: Improved survival with localized esophageal cancer in the modern era may reflect an increase of early tumors and optimized staging. Important surgical and pathologic standards, including a higher R0 resection rate and nodal yields, and lower postoperative mortality, were also observed. Copyright © 2012 by The American Association for Thoracic Surgery.

High-temperature growth of graphene films on copper foils by ethanol chemical vapour deposition

Chemical vapor deposition (CVD) is widely utilized to synthesize graphene with controlled properties for many applications, especially when continuous films over large areas are required. Although hydrocarbons such as methane are quite efficient precursors for CVD at high temperature (∼1000 °C), finding less explosive and safer carbon sources is considered beneficial for the transition to large-scale production. In this work, we investigated the CVD growth of graphene using ethanol, which is a harmless and readily processable carbon feedstock that is expected to provide favorable kinetics. We tested a wide range of synthesis conditions (i.e., temperature, time, gas ratios), and on the basis of systematic analysis by Raman spectroscopy, we identified the optimal parameters for producing highly crystalline graphene with different numbers of layers. Our results demonstrate the importance of high temperature (1070 °C) for ethanol CVD and emphasize the significant effects that hydrogen and water vapor, coming from the thermal decomposition of ethanol, have on the crystal quality of the synthesized graphene.

The effect of employment while in high school on educational attainment : a conditional difference-in-differences approach

Using American panel data from the National Education Longitudinal Study of 1988, this article investigates the effect of working during grade 12 on attainment.We employ, for the first time in the related literature, a semiparametric propensity score matching approach combined with difference-in-differences. We address selection on both observables and unobservables associated with part-time work decisions, without the need for instrumental variable. Once such factors are controlled for, little to no effects on reading and math scores are found. Overall, our results therefore suggest a negligible academic cost from part-time working by the end of high school.

High-throughput vectors for efficient gene silencing in plants

A major challenge in the post-genome era of plant biology is to determine the functions of all genes in the plant genome. A straightforward approach to this problem is to reduce or knockout expression of a gene with the hope of seeing a phenotype that is suggestive of its function. Insertional mutagenesis is a useful tool for this type of study but is limited by gene redundancy, lethal knockouts, non-tagged mutants, and the inability to target the inserted element to a specific gene. The efficacy of gene silencing in plants using inverted-repeat transgene constructs that encode a hairpin RNA (hpRNA) has been demonstrated by a number of groups, and has several advantages over insertional mutagenesis. In this paper we describe two improved pHellsgate vectors that facilitate rapid generation of hpRNA-encoding constructs, pHellsgate 4 allows the production of an hpRNA construct in a single step from a single polymerase chain reaction product, while pHellsgate 8 requires a two-step process via an intermediate vector. We show that these vectors are effective at silencing three endogenous genes in Arabidopsis, FLOWERING LOCUS C, PHYTOENE DESATURASE and ETHYLENE INSENSITIVE 2. We also show that a construct of sequences from two genes silences both genes.

Construct design for efficient, effective and high-throughput gene silencing in plants

Post-transcriptional silencing of plant genes using anti-sense or co-suppression constructs usually results in only a modest proportion of silenced individuals. Recent work has demonstrated the potential for constructs encoding self-complementary 'hairpin' RNA (hpRNA) to efficiently silence genes. In this study we examine design rules for efficient gene silencing, in terms of both the proportion of independent transgenic plants showing silencing, and the degree of silencing. Using hpRNA constructs containing sense/anti-sense arms ranging from 98 to 853 nt gave efficient silencing in a wide range of plant species, and inclusion of an intron in these constructs had a consistently enhancing effect. Intron-containing constructs (ihpRNA) generally gave 90-100% of independent transgenic plants showing silencing. The degree of silencing with these constructs was much greater than that obtained using either co-suppression or anti-sense constructs. We have made a generic vector, pHANNIBAL, that allows a simple, single PCR product from a gene of interest to be easily converted into a highly effective ihpRNA silencing construct. We have also created a high-throughput vector, pHELLSGATE, that should facilitate the cloning of gene libraries or large numbers of defined genes, such as those in EST collections, using an in vitro recombinase system. This system may facilitate the large-scale determination and discovery of plant gene functions in the same way as RNAi is being used to examine gene function in Caenorhabditis elegans.

High-efficiency silencing of a β-glucuronidase gene in rice is correlated with repetitive transgene structure but is independent of DNA methylation

Two transgenic callus lines of rice, stably expressing a β-glucuronidase (GUS) gene, were supertransformed with a set of constructs designed to silence the resident GUS gene. An inverted-repeat (i/r) GUS construct, designed to produce mRNA with self-complementarity, was much more effective than simple sense and antisense constructs at inducing silencing. Supertransforming rice calluses with a direct-repeat (d/r) construct, although not as effective as those with the i/r construct, was also substantially more effective in silencing the resident GUS gene than the simple sense and antisense constructs. DNA hybridisation analyses revealed that every callus line supertransformed with either simple sense or antisense constructs, and subsequently showing GUS silencing, had the silence-inducing transgenes integrated into the plant genome in inverted-repeat configurations. The silenced lines containing i/r and d/r constructs did not necessarily have inverted-repeat T-DNA insertions. There was significant methylation of the GUS sequences in most of the silenced lines but not in the unsilenced lines. However, demethylation treatment of silenced lines with 5-azacytidine did not reverse the post-transcriptional gene silencing (PTGS) of GUS. Whereas the levels of RNA specific to the resident GUS gene were uniformly low in the silenced lines, RNA specific to the inducer transgenes accumulated to a substantial level, and the majority of the i/r RNA was unpolyadenylated. Altogether, these results suggest that both sense- and antisense-mediated gene suppression share a similar molecular basis, that unpolyadenylated RNA plays an important role in PTGS, and that methylation is not essential for PTGS.

Queensland’s high risk foot database : tracking the length and width of Queensland’s foot ulcers

Background Foot ulcers are a leading cause of avoidable hospital admissions and lower extremity amputations. However, large clinical studies describing foot ulcer presentations in the ambulatory setting are limited. The aim of this descriptive observational paper is to report the characteristics of ambulatory foot ulcer patients managed across 13 of 17 Queensland Health & Hospital Services. Methods Data on all foot ulcer patients registered with a Queensland High Risk Foot Form (QHRFF) was collected at their first consult in 2012. Data is automatically extracted from each QHRFF into a Queensland high risk foot database. Descriptive statistics display age, sex, ulcer types and co-morbidities. Statewide clinical indicators of foot ulcer management are also reported. Results Overall, 2,034 people presented with a foot ulcer in 2012. Mean age was 63(±14) years and 67.8% were male. Co-morbidities included 85% had diabetes, 49.7% hypertension, 39.2% dyslipidaemia, 25.6% cardiovascular disease, 13.7% kidney disease and 12.2% smoking. Foot ulcer types included 51.6% neuropathic, 17.8% neuro-ischaemic, 7.2% ischaemic, 6.6% post-surgical and 16.8% other; whilst 31% were infected. Clinical indicator results revealed 98% had their wound categorised, 51% received non-removable offloading, median ulcer healing time was 6-weeks and 37% had ulcer recurrence. Conclusion This paper details the largest foot ulcer database reported in Australia. People presenting with foot ulcers appear predominantly older, male with several co-morbidities. Encouragingly it appears most patients are receiving best practice care. These results may be a factor in the significant reduction of Queensland diabetes foot-related hospitalisations and amputations recently reported.

Is the clinical Queensland High Risk Foot Form valid or reliable for research?

Background High-risk foot complications such as neuropathy, ischaemia, deformity, infections, ulcers and amputations consume considerable health care resources and typically result from chronic diseases. This study aimed to develop and test the validity and reliability of a Queensland High Risk Foot Form (QHRFF) tool. Methods Phase one involved developing a QHRFF using an existing diabetes high-risk foot tool, literature search, expert panel and several state-wide stakeholder groups. Phase two tested the criterion-related validity along with inter- and intra-rater reliability of the final QHRFF. Three cohorts of patients (n = 94) and four clinicians, representing different levels of expertise, were recruited. Validity was determined by calculating sensitivity, specificity and positive predictive values (PPV). Kappa and intra-class correlation (ICC) statistics were used to establish reliability. Results A QHRFF tool containing 46-items across seven domains was developed and endorsed. The majority of QHRFF items achieved moderate-to-perfect validity (PPV = 0.71 – 1) and reliability (Kappa/ICC = 0.41 – 1). Items with weak validity and/or reliability included those identifying health professionals previously attending the patient, other (non-listed) co-morbidity, previous foot ulcer, foot deformity, optimum offloading and optimum footwear. Conclusions The QHRFF had moderate-to-perfect validity and reliability across the majority of items, particularly identifying individual co-morbidities and foot complications. Items with weak validity or reliability need to be re-defined or removed. Overall, the QHRFF appears to be a valid and reliable tool to assess, collect and measure clinical data pertaining to high-risk foot complications for clinical or research purposes.

High risk feet in subacute rehabilitation facilities : how many are there?

Background Australian subacute rehabilitation facilities face significant challenges from the ageing population with increased burden of chronic disease. High risk foot complications are a negative consequence of many chronic diseases. With the rapid expansion of subacute services, it seems imperative to investigate the prevalence of foot complications in this population. The primary aim of this study was to quantify the high risk foot complication prevalence in a subacute rehabilitation population. Methods Eligible participants were all adults admitted overnight, over two 4 week periods, into a large Australian subacute rehabilitation facility. Consenting participants underwent a short non-invasive foot examination by a podiatrist. The standard Queensland Health High Risk Foot Form collected data on age, sex, co-morbidities and foot complications. Descriptive statistics, logistic regression and odds ratios were used to determine the prevalence of foot complications and associations with explanatory variables. Results Overall, 85 of 97 eligible participants consented; mean age 80(9) and 71% were female. At least one foot complication was present in 56.5% participants; including 21.2% defined as high risk and 11.8% current foot ulcer. A previous diagnosis of neuropathy increased the risk of presenting with a high risk foot by 13-fold (OR 13.504, p = 0.001). Conclusion This study highlights the significance of foot complications in the subacute population. It appears that one in every two patients present with a foot complication and one in eight with a foot ulcer. It is suggested all patients admitted to subacute rehabilitation services should be screened for foot complications.

Evaluating the impact of high risk foot training on undergraduate podiatry students

Background Diabetes is the leading cause of high risk foot (HRF) complications, admissions and lower limb amputation. Best practice training of podiatrists is known to have a beneficial impact on such outcomes; however, there has been a paucity of studies into undergraduate diabetes podiatry training. The primary aim of this paper was to investigate the changes in final year podiatry students’ confidence, knowledge and clinical practice in the management of HRF complications. Methods This was a prospective longitudinal study of final year podiatry students (n=25) at the Queensland University of Technology. All participants throughout 2011 undertook an intervention of a series of “hands on” HRF workshops, on-campus clinics and external clinical rotations. Outcome measures included customised confidence and knowledge surveys in HRF management across four time points. A timed simulated case scenario was used to evaluate changes in clinical practice at two time points. Friedman and Wilcoxon Signed Rank Tests were used to calculate differences between time points Results Overall improvements between the first and last time points were demonstrated in 20/21 confidence items (p<0.001), 12/27 clinical practice items (p<0.05) and 3/12 knowledge items (p<0.001). Although 8/12 knowledge items recorded high baseline scores of over 80%. Conclusions Overall, it appears student confidence and clinical practice improved with the introduction of designated HRF activities, whilst knowledge remained high. This suggests “hands on” practice and not didactic lectures improve students’ clinical confidence and practice. Results from the 2012 student cohort will also be presented at this conference.

Prevalence of risk factors for undiagnosed obstructive sleep apnoea is high in truck drivers on UK roads

Objectives To determine the prevalence of symptoms and risk factors of obstructive sleep apnoea (OSA) in truck drivers at a UK large truck stop. Methods Over a 5 day period, truck drivers completed a short questionnaire at a major UK ‘truck stop’. The questionnaire asked about OSA rist factors and symptoms, and included the Epworth Sleepiness Scale (ESS). Additionally, measurements of height, weight and collar size were taken. 148 truck drivers participated and within this random group the risk factors of OSA that were looked for were:men age over 40 y, obesity, parge neck circumference, smoking, high ESS and bed partner reporting snoring with witnessed apnoeas. Results Our sample were all men, with 82% aged over 40 y. 47% were obese (compared with 23% for UK men in general) and average neck circumference was 42 cm (compared with 38 cm for UK men in general – Martin et al 1997). 31% smoked (vs 21% for general population), and ESS averaged 2.1 points higher than expected for a healthy population (Johns et al 1997). Snoring was quite evident at 57% (compared wth 40% for men in general) and witnessed apnoeas were almost double (7%) compared with 3.8% given by Ohayon et al (1997) generally for men. Conclusion 8 key symptoms and risk factors of OSA have been found to be prevalent in a sample of truck drivers on UK roads, and to greater extent that for estimates in the general male population. Bed partners of truck drivers reporting witnessed apnoeas strongly suggests this group has a high potential for undiagnosed OSA. OSA sufferers are known to be at high risk of causing road traffi c accidents. This, together with the large size of trucks, then the potential for serious road crashes is great. Truck drivers, especially those who are obese, ought to be a high priority population for OSA screening.

Impact of high PV penetration on distribution transformer insulation life

The reliable operation of distribution systems is critically dependent on detailed understanding of load impacts on distribution transformer insulation systems. This paper estimates the impact of rooftop photovoltaic (PV) generation on a typical 200-kVA, 22/0.415-kV distribution transformer life under different operating conditions. This transformer supplies a suburban area with a high penetration of roof top photovoltaic systems. The transformer loads and the phase distribution of the PV systems are significantly unbalanced. Oil and hot-spot temperature and remnant life of distribution transformer under different PV and balance scenarios are calculated. It is shown that PV can significantly extend the transformer life.