Meeting the four-hour deadline in an A&E department

This is the print version of the Article. The official published version can be obtained from the link below - Copyright @ 2011 EmeraldPurpose – Accident and emergency (A&E) departments experience a secondary peak in patient length of stay (LoS) at around four hours, caused by the coping strategies used to meet the operational standards imposed by government. The aim of this paper is to build a discrete-event simulation model that captures the coping strategies and more accurately reflects the processes that occur within an A&E department. Design/methodology/approach – A discrete-event simulation (DES) model was used to capture the A&E process at a UK hospital and record the LoS for each patient. Input data on 4,150 arrivals over three one-week periods and staffing levels was obtained from hospital records, while output data were compared with the corresponding records. Expert opinion was used to generate the pathways and model the decision-making processes. Findings – The authors were able to replicate accurately the LoS distribution for the hospital. The model was then applied to a second configuration that had been trialled there; again, the results also reflected the experiences of the hospital. Practical implications – This demonstrates that the coping strategies, such as re-prioritising patients based on current length of time in the department, employed in A&E departments have an impact on LoS of patients and therefore need to be considered when building predictive models if confidence in the results is to be justified. Originality/value – As far as the authors are aware this is the first time that these coping strategies have been included within a simulation model, and therefore the first time that the peak around the four hours has been analysed so accurately using a model

A phase II study of capecitabine and oxalplatin combination chemotherapy in patients with inoperable adenocarcinoma of the gall bladder or biliary tract

Background: Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer. Methods: This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Com mittee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecit abine (1000 mg/m2 po, twice daily, days 1–14) and oxaliplatin (130 mg/m2 i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival. Results: Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8 % (95 % CI 12.05–39.5 %). Stable disease was observed in a further 13 patients (31 %) and progressive disease observed in 12 (28.6 %) of patients. The median progression-free survival was 4.6 months (95 % CI 2.8–6.4 months; Fig. 1) and the median overall survival 7.9 months (95 % CI 5.3–10.4 months; Fig. 2). Conclusion: Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease. How ever, capecitabine in combination with oxaliplatin does have modest activity in this disease, and can be considered as an alternative treatment option for patients in whom cisplatin and/or gemcitabine are contra-indicated

Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma

Background: AZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 + chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC). Methods: AZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin + capecitabine) for eight 21-day cycles, continuously or with intermittent schedule (4 days on/3 off every week; 14 days on/7 off, per cycle) in a rolling-six design. Subsequently, patients with OGC were randomised 2:1 to AZD8931 + Xelox at RP2D or Xelox only for two cycles, followed by radical oesophagogastric surgery. Secondary outcomes were safety, complete resection (R0) rate, six-month progression-free survival (PFS) and overall survival. Results: During escalation, four dose-limiting toxicities were observed among 24 patients: skin rash (1) and failure to deliver 100% of Xelox because of treatment-associated grade III-IV adverse events (AEs) (3: diarrhoea and vomiting; vomiting; fatigue). Serious adverse events (SAE) occurred in 15 of 24 (63%) patients. RP2D was 20-mg bd with the 4/3 schedule. In the expansion phase, 2 of 20 (10%) patients in the Xelox + AZD8931 group and 5/10 (50%) patients in the Xelox group had grade III–IV AEs. Six-month PFS was 85% (90% CI: 66%–94%) in Xelox + AZD8931 and 100% in Xelox alone. Seven deaths (35%) occurred with Xelox + AZD8931 and one (10%) with Xelox. R0 rate was 45% (9/20) with Xelox + AZD8931 and 90% (9/10) with Xelox-alone (P = 0.024). Conclusion: Xelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC. (Trial registration: EudraCT 2011-003169-13, ISRCTN-68093791)

Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma

A two-stage Simon design was used to evaluate the response rate of OSI-7904L, a liposome encapsulated thymidylate synthase inhibitor, in advanced gastric and/or gastroesophageal adenocarcinoma (A-G/GEJA), administered intravenously at 12 mg m−2 over 30 min every 21 days. Fifty patients were treated. Median age was 64 years (range 35–82), 62% were male and 89% had ECOG PS of 0/1. A total of 252 cycles were administered; median of 4 per patient (range 1–21). Twelve patients required dose reductions, mainly for skin toxicity. Investigator assessed response rate was 17.4% (95% CI 7.8–31.4) with one complete and seven partial responses in 46 evaluable patients. Twenty-one patients (42%) had stable disease. Median time to progression and survival were 12.4 and 36.9 weeks, respectively. NCI CTCAE Grade 3/4 neutropenia (14%) and thrombocytopenia (4%) were uncommon. The main G3/4 nonhaematological toxicities were skin-related 22%, stomatitis 14%, fatigue/lethargy 10%, and diarrhea 8%. Pharmacokinetic data showed high interpatient variability. Patients with higher AUC were more likely to experience G3/4 toxicity during cycle 1 while baseline homocysteine did not predict toxicity. Response did not correlate with AUC. Elevations in 2′-dU were observed indicating target inhibition. Analysis of TS genotype, TS protein and expression did not reveal any correlation with outcome. OSI-7904L has activity in A-G/GEJA similar to other active agents and an acceptable safety profile

Self-tuning to the Hopf bifurcation in fluctuating systems

The problem of self-tuning a system to the Hopf bifurcation in the presence of noise and periodic external forcing is discussed. We find that the response of the system has a non-monotonic dependence on the noise-strength, and displays an amplified response which is more pronounced for weaker signals. The observed effect is to be distinguished from stochastic resonance. For the feedback we have studied, the unforced self-tuned Hopf oscillator in the presence of fluctuations exhibits sharp peaks in its spectrum. The implications of our general results are briefly discussed in the context of sound detection by the inner ear.Comment: 37 pages, 7 figures (8 figure files

Linear Wave Interaction with a Vertical Cylinder of Arbitrary Cross Section: An Asymptotic Approach

An asymptotic approach to the linear problem of regular water waves interacting with a vertical cylinder of an arbitrary cross section is presented. The incident regular wave was one-dimensional, water was of finite depth, and the rigid cylinder extended from the bottom to the water surface. The nondimensional maximum deviation of the cylinder cross section from a circular one plays the role of a small parameter of the problem. A fifth-order asymptotic solution of the problem was obtained. The problems at each order were solved by the Fourier method. It is shown that the first-order velocity potential is a linear function of the Fourier coefficients of the shape function of the cylinder, the second-order velocity potential is a quadratic function of these coefficients, and so on. The hydrodynamic forces acting on the cylinder and the water surface elevations on the cylinder are presented. The present asymptotic results show good agreement with numerical and experimental results of previous investigations. Long-wave approximation of the hydrodynamic forces was derived and used for validation of the asymptotic solutions. The obtained values of the forces are exact in the limit of zero wave numbers within the linear wave theory. An advantage of the present approach compared with the numerical solution of the problem by an integral equation method is that it provides the forces and the diffracted wave field in terms of the coefficients of the Fourier series of the deviation of the cylinder shape from the circular one. The resulting asymptotic formula can be used for optimization of the cylinder shape in terms of the wave loads and diffracted wave fields

Retinoic acid degradation shapes zonal development of vestibular organs and sensitivity to transient linear accelerations

Each vestibular sensory epithelium in the inner ear is divided morphologically and physio- logically into two zones, called the striola and extrastriola in otolith organ maculae, and the central and peripheral zones in semicircular canal cristae. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)- mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, formation of striolar/central zones is compromised, such that they resemble extrastriolar/peripheral zones in multiple features. Mutants have deficient vestibular evoked potential (VsEP) responses to jerk stimuli, head tremor and deficits in balance beam tests that are consistent with abnormal vestibular input, but normal vestibulo-ocular reflexes and apparently normal motor performance during swimming. Thus, degradation of RA during embryogenesis is required for formation of highly specialized regions of the vestibular sensory epithelia with specific functions in detecting head motions

Communications Biophysics

Contains research objectives and reports on eight research projects split into three sections.National Institutes of Health (Grant 2 PO1 NS13126)National Institutes of Health (Grant 5 RO1 NS18682)National Institutes of Health (Grant 5 RO1 NS20322)National Institutes of Health (Grant 1 RO1 NS 20269)National Institutes of Health (Grant 5 T32 NS 07047)Symbion, Inc.National Institutes of Health (Grant 5 R01 NS10916)National Institutes of Health (Grant 1 RO NS 16917)National Science Foundation (Grant BNS83-19874)National Science Foundation (Grant BNS83-19887)National Institutes of Health (Grant 5 RO1 NS12846)National Institutes of Health (Grant 1 RO1 NS21322-01)National Institutes of Health (Grant 5 T32-NS07099-07)National Institutes of Health (Grant 1 RO1 NS14092-06)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 5 RO1 NS11080