Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Clinical benefit in Phase-I trials of novel molecularly targeted agents: does dose matter?

Phase-I trials traditionally involve dose-escalation to determine the maximal tolerated dose (MTD). With conventional chemotherapy, efficacy is generally deemed to be dose-dependent, but the same may not be applicable to molecularly targeted agents (MTAs). We analysed consecutive patients included in Phase-I trials at the Royal Marsden Hospital from 5 January 2005 to 6 June 2006. We considered only trials of monotherapy MTAs in which the MTD was defined. Three patient cohorts (A, B, and C) were identified according to the dose received as a percentage of the final trial MTD (0–33%, 34–65%, >66%). Potential efficacy was assessed using the non-progression rate (NPR), that is, complete/partial response or stable disease for at least 3 months by RECIST. A total of 135 patients having progressive disease before enrolment were analysed from 15 eligible trials. Median age was 57 years (20–86); male : female ratio was 1.8 : 1. Cohort A, B, and C included 28 (21%), 22 (16%), and 85 (63%) patients; NPR at 3 and 6 months was 21% and 11% (A), 50% and 27% (B), 31% and 14% (C), respectively, P=0.9. Median duration of non-progression (17 weeks; 95% CI=13–22) was not correlated with the MTD level, P=0.9. Our analysis suggests that the potential for clinical benefit is not confined to patients treated at doses close to the MTD in Phase-I trials of MTAs

Pharmaceutical electrochemistry: the electrochemical detection of aspirin utilising screen printed graphene electrodes as sensors platforms.

A sensitive electrochemical sensor was designed for acetyl salicylic acid detection using graphene modified Screen Printed Electrodes. The electrochemical response of the sensor with graphene was improved compared to Screen Printed Electrodes without graphene and displayed an excellent analytical performance for the detection of acetyl salicylic acid. The high acetyl salicylic acid loading capacity on the electrode surface and the outstanding electric conductivity of graphene were also discussed in this manuscript. When a range of different concentrations of acetyl salicylic acid from 0.1 to 100 μM into a pH 4 buffer solution (N defined as the sample size N = 9) were plotted against the oxidation peak a linear response was observed. The detection limit was found to be 0.09 μM based on (3-σ/slope). Screen Printed Graphene electrodes sensors methodology is shown to be useful for quantifying low levels of acetyl salicylic acid in a buffer solution as well as in biological matrixes such as human oral fluid. A linear response was obtained over a range of concentrations from 10 to 150 μM into a human oral fluid solution (N = 10) giving a detection limit of 8.7 μM

An Exploratory Study of Primary Care Physician Decision Making Regarding Total Joint Arthroplasty

BACKGROUND: For patients to experience the benefits of total joint arthroplasty (TJA), primary care physicians (PCPs) ought to know when to refer a patient for TJA and/or optimize nonsurgical treatment options for osteoarthritis (OA). OBJECTIVE: To evaluate the ability of physicians to make clinical treatment decisions. DESIGN AND PARTICIPANTS: A survey, using ten clinical vignettes, of PCPs in Indiana. MEASUREMENTS: A test score (range 0 to 10) was computed based on the number of correct answers consistent with published explicit appropriateness criteria for TJA. We also collected demographic characteristics and physicians’ perceived success rate of TJA in terms of pain relief and functional improvement. RESULTS: There were 149 PCPs (response rate = 61%) who participated. The mean test score was 6.5 ± 1.5. Only 17% correctly identified the published success rate of TJA (i.e., ≥90%). In multivariate analysis, the only physician-related variables associated with test score were ethnicity, board status, and perceived success rate of TJA. Physicians who were white (P = .001), board-certified (P = .04), and perceived a higher success rate of TJA (P = .004) had higher test scores. CONCLUSIONS: PCP knowledge with respect to guideline-concordant care for OA could be improved, specifically in deciding when to consider TJA versus optimizing nonsurgical options. Moreover, the perception of the success rate of TJA may influence a clinician’s decision making

Boron microlocalization in oral mucosal tissue: implications for boron neutron capture therapy

Clinical studies of the treatment of glioma and cutaneous melanoma using boron neutron capture therapy (BNCT) are currently taking place in the USA, Europe and Japan. New BNCT clinical facilities are under construction in Finland, Sweden, England and California. The observation of transient acute effects in the oral mucosa of a number of glioma patients involved in the American clinical trials, suggests that radiation damage of the oral mucosa could be a potential complication in future BNCT clinical protocols, involving higher doses and larger irradiation field sizes. The present investigation is the first to use a high resolution surface analytical technique to relate the microdistribution of boron-10 (10B) in the oral mucosa to the biological effectiveness of the 10B(n,α)7Li neutron capture reaction in this tissue. The two boron delivery agents used clinically in Europe/Japan and the USA, borocaptate sodium (BSH) and p-boronophenylalanine (BPA), respectively, were evaluated using a rat ventral tongue model. 10B concentrations in various regions of the tongue mucosa were estimated using ion microscopy. In the epithelium, levels of 10B were appreciably lower after the administration of BSH than was the case after BPA. The epithelium:blood 10B partition ratios were 0.2:1 and 1:1 for BSH and BPA respectively. The 10B content of the lamina propria was higher than that measured in the epithelium for both BSH and BPA. The difference was most marked for BSH, where 10B levels were a factor of six higher in the lamina propria than in the epithelium. The concentration of 10B was also measured in blood vessel walls where relatively low levels of accumulation of BSH, as compared with BPA, was demonstrated in blood vessel endothelial cells and muscle. Vessel wall:blood 10B partition ratios were 0.3:1 and 0.9:1 for BSH and BPA respectively. Evaluation of tongue mucosal response (ulceration) to BNC irradiation indicated a considerably reduced radiation sensitivity using BSH as the boron delivery agent relative to BPA. The compound biological effectiveness (CBE) factor for BSH was estimated at 0.29 ± 0.02. This compares with a previously published CBE factor for BPA of 4.87 ± 0.16. It was concluded that variations in the microdistribution profile of 10B, using the two boron delivery agents, had a significant effect on the response of oral mucosa to BNC irradiation. From a clinical perspective, based on the findings of the present study, it is probable that potential radiation-induced oral mucositis will be restricted to BNCT protocols involving BPA. However, a thorough high resolution analysis of 10B microdistribution in human oral mucosal tissue, using a technique such as ion microscopy, is a prerequisite for the use of experimentally derived CBE factors in clinical BNCT. © 2000 Cancer Research Campaig

Genome-Wide Analysis Reveals a Major Role in Cell Fate Maintenance and an Unexpected Role in Endoreduplication for the Drosophila FoxA Gene Fork Head

Transcription factors drive organogenesis, from the initiation of cell fate decisions to the maintenance and implementation of these decisions. The Drosophila embryonic salivary gland provides an excellent platform for unraveling the underlying transcriptional networks of organ development because Drosophila is relatively unencumbered by significant genetic redundancy. The highly conserved FoxA family transcription factors are essential for various aspects of organogenesis in all animals that have been studied. Here, we explore the role of the single Drosophila FoxA protein Fork head (Fkh) in salivary gland organogenesis using two genome-wide strategies. A large-scale in situ hybridization analysis reveals a major role for Fkh in maintaining the salivary gland fate decision and controlling salivary gland physiological activity, in addition to its previously known roles in morphogenesis and survival. The majority of salivary gland genes (59%) are affected by fkh loss, mainly at later stages of salivary gland development. We show that global expression of Fkh cannot drive ectopic salivary gland formation. Thus, unlike the worm FoxA protein PHA-4, Fkh does not function to specify cell fate. In addition, Fkh only indirectly regulates many salivary gland genes, which is also distinct from the role of PHA-4 in organogenesis. Our microarray analyses reveal unexpected roles for Fkh in blocking terminal differentiation and in endoreduplication in the salivary gland and in other Fkh-expressing embryonic tissues. Overall, this study demonstrates an important role for Fkh in determining how an organ preserves its identity throughout development and provides an alternative paradigm for how FoxA proteins function in organogenesis

How Noisy Does a Noisy Miner Have to Be? Amplitude Adjustments of Alarm Calls in an Avian Urban ‘Adapter’

Background: Urban environments generate constant loud noise, which creates a formidable challenge for many animals relying on acoustic communication. Some birds make vocal adjustments that reduce auditory masking by altering, for example, the frequency (kHz) or timing of vocalizations. Another adjustment, well documented for birds under laboratory and natural field conditions, is a noise level-dependent change in sound signal amplitude (the ‘Lombard effect’). To date, however, field research on amplitude adjustments in urban environments has focused exclusively on bird song. Methods: We investigated amplitude regulation of alarm calls using, as our model, a successful urban ‘adapter ’ species, the Noisy miner, Manorina melanocephala. We compared several different alarm calls under contrasting noise conditions. Results: Individuals at noisier locations (arterial roads) alarm called significantly more loudly than those at quieter locations (residential streets). Other mechanisms known to improve sound signal transmission in ‘noise’, namely use of higher perches and in-flight calling, did not differ between site types. Intriguingly, the observed preferential use of different alarm calls by Noisy miners inhabiting arterial roads and residential streets was unlikely to have constituted a vocal modification made in response to sound-masking in the urban environment because the calls involved fell within the main frequency range of background anthropogenic noise. Conclusions: The results of our study suggest that a species, which has the ability to adjust the amplitude of its signals

The phosphatase and tensin homologue deleted on chromosome 10 mediates radiosensitivity in head and neck cancer

BACKGROUND: For locally advanced squamous cell carcinoma of the head and neck (HNSCC), the recurrence rate after surgery and postoperative radiotherapy is between 20 and 40%, and the 5- year overall survival rate is similar to 50%. Presently, no markers exist to accurately predict treatment outcome. Expression of proteins in the human epidermal growth factor receptor (EGFR) pathway has been reported as a prognostic marker in several types of cancer. METHODS: The aim of this study was to investigate the prognostic value of proteins in the EGFR pathway in HNSCC. For this purpose, we collected surgically resected tissue of 140 locally advanced head and neck cancer patients, all treated with surgery and postoperative radiotherapy. RESULTS: In a multivariate analysis, expression of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was significantly related to worse locoregional control (LRC; HR: 2.2, 95% CI: 1.1-4.6; P = 0.03), independent of lymph node metastases (HR: 5.6, 95% CI: 1.2-27.4; P = 0.03) and extranodal spread (HR: 2.7; 95% CI: 1.2- 6.5; P = 0.02). In vitro clonogenic radiosensitivity assays confirmed that overexpression of PTEN resulted in increased radioresistance. CONCLUSION: Our study is the first report showing that expression of PTEN mediates radiosensitivity in vitro and that increased expression in advanced HNSCC predicts worse LRC. British Journal of Cancer (2010) 102, 1778-1785. doi: 10.1038/sj.bjc.6605707 www.bjcancer.com Published online 25 May 2010 (C) 2010 Cancer Research U