The development of the Cystectomy-Pathway Assessment Tool (C-PAT): a concise tool to assess the quality of care in the cystectomy pathway.

OBJECTIVES: To develop and test the psychometric properties of a concise, patient-reported questionnaire, designed to assess key aspects of the radical cystectomy (RC) patient pathway that are important to both patients and clinicians. PATIENTS AND METHODS: Draft items were developed by a consultation with a 13-member expert clinical panel, and the in-depth qualitative analysis of 14 semi-structured interviews with patients who had received RC within the previous 18 months. A further nine cognitive interviews with patients refined the items and ensured they were easy to complete. Pilot testing in 122 patients recruited from five hospitals in England tested the properties of validity and reliability of the resulting 17-item questionnaire. RESULTS: Patients and clinicians identified the following aspects as important for the delivery of quality patient care. These included timely referral and initial test results; an explanation of risk/benefits of treatment; access to a cancer nurse specialist; training and support in stoma management; timely surgery, surgical complications, and timely follow-up. Pilot testing showed missing data was low (≤3% for all items), and between 73% and 89% of the responses to items were the most positive about their care (indicating ceiling effects). Five items were identified using factor analysis as being statistically related (Cronbach's α 0.76, intraclass correlation coefficient test-retest reliability of 0.95) and formed the scored part of the tool 'care and support', scored 0-16. There was insufficient evidence at this stage to show the tool was capable of measuring differences between cancer centres. CONCLUSION: We have developed a questionnaire that captures aspects of quality of care within the RC patient pathway. The results support the validity and reliability of the 17-item Cystectomy-Pathway Assessment Tool (C-PAT). We envisage the tool can be the basis for audit of the patient reported assessment of the quality of care for individual cancer centres.

Carbetocin at elective Cesarean delivery: a sequential allocation trial to determine the minimum effective dose.

PURPOSE: The purpose of this study was to determine the intravenous dose of carbetocin required to produce effective uterine contraction in 90% of females (ED90) undergoing elective Cesarean delivery (CD) under spinal anesthesia. METHODS: We conducted a double-blind dose-finding study of carbetocin. Forty females undergoing elective CD received carbetocin intravenously upon delivery of the fetus. The dose of carbetocin for each patient was determined according to a biased-coin up-and-down sequential allocation scheme designed to cluster doses close to ED90. The initial dose was 10 µg, with increments/decrements of 5 µg. The anesthesiologist, obstetrician, and patient were blinded to the dose. The obstetrician assessed the uterine tone at one-minute intervals for five minutes after carbetocin administration. In case of unsatisfactory tone, additional uterotonics were administered. The primary outcome was requirement for additional intraoperative uterotonics. Secondary outcomes were postoperative requirement for additional uterotonics within 24 hr of delivery, estimated blood loss and side effects. RESULTS: The ED90 of carbetocin was 14.8 µg (95% confidence interval 13.7 to 15.8). Thirty-seven patients (92.5%) had adequate uterine tone with no requirement of additional intraoperative uterotonics. Two patients (5%) required postoperative uterotonics within 24 hr. The overall mean (SD) estimated blood loss was 786 (403) mL and the overall incidence of hypotension (decrease in systolic blood pressure ≥ 20% baseline) was 37.5%. CONCLUSION: Based on our study, the ED90 of carbetocin at elective CD is less than one-fifth the currently recommended dose of 100 µg. This study was registered at clinicaltrials.gov (NCT-01651130).

Low-fidelity simulation improves mastery of the aseptic technique for labour epidurals: an observational study.

PURPOSE: The objective of this study was to determine the impact of a low-fidelity simulation model on mastering the sterile technique during placement of epidural catheters. METHODS: Trainees, including residents and fellows, were given conventional teaching consisting of a lecture and a video demonstration on the appropriate sterile technique to apply during the placement of epidural catheters. The trainees were then provided with a one-on-one demonstration session using a low-fidelity Styrofoam™ epidural model, followed by a series of simulation sessions. After conventional teaching and following each simulation session, the trainees were assessed on their performance until competence was achieved based on a 15-point checklist. The retention of competence was subsequently evaluated bi-weekly in clinical practice for four assessments. RESULTS: Twenty-one trainees participated in the study. The average score for the residents following conventional teaching was 6.0 out of 15 points on the checklist. Following the initial one-on-one hands-on demonstration, the average score increased to 10.8 (difference = 4.8, 95% confidence interval (CI): 3.3 to 6.2; P < 0.001). The average score for the fellows following conventional teaching was 7.9 out of 15 points on the checklist. Following the initial one-on-one hands-on demonstration the average score increased to 11.2 (difference = 3.3, 95% CI: 0.05 to 6.6; P = 0.047). During the retention of competence phase, scores ranged from 13-15 for both residents and fellows. CONCLUSION: This study describes a comprehensive teaching model for mastering the sterile technique during epidural catheter placement. It suggests that low-fidelity simulation improves the learning process when used in addition to conventional teaching.

Preeclampsia inactivates glucose-6-phosphate dehydrogenase and impairs the redox status of erythrocytes and fetal endothelial cells.

Inactivation of glucose-6-phosphate dehydrogenase (G6PD) may contribute to vascular dysfunction in preeclampsia, and oxidative stress has been implicated in the pathogenesis of this disease. We have compared the susceptibility of erythrocytes and human umbilical vein endothelial cells (HUVEC) to oxidative stress in women with normotensive or preeclamptic pregnancies. The redox status of erythrocytes was also correlated with neutrophil-mediated superoxide (O(2)(.-)) production in women recruited to the "Vitamins in Preeclampsia" (VIP) trial. Erythrocytes and HUVEC from women with preeclampsia demonstrated impaired redox regulation and diminished response to glucose, detectable at 14-20 weeks gestation prior to onset of the clinical disease. Hexokinase and G6PD activities were decreased in erythrocytes and G6PD activity was decreased in HUVEC from preeclamptic pregnancies. Phorbol-ester-stimulated O(2)(.-) was enhanced in preeclamptic neutrophils. Impaired redox regulation in erythrocytes and HUVEC in preeclampsia may be due to diminished hexokinase and G6PD activities resulting from increased release of reactive oxygen species from activated neutrophils. Our findings provide the first evidence that decreased G6PD activity in preeclampsia is associated with impaired redox regulation in erythrocytes and fetal endothelial cells. The deficiency in G6PD in preeclampsia potentially accounts for the lack of protection against oxidative stress afforded by antioxidant vitamin C/E supplementation in the VIP trial.

Development of disulfiram-loaded poly(lactic-co-glycolic acid) wafers for the localised treatment of glioblastoma multiforme: a comparison of manufacturing techniques.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumour in adults with a very poor prognosis. This paper describes the development of disulfiram (DSF)-loaded biodegradable wafers manufactured using three standard techniques: compression, solvent casting and heat compression moulding. The paper demonstrates that neither technique has an adverse effect on the stability of the DSF within the wafers. However, the solvent casting technique results in an interaction between the poly(lactic-co-glycolic acid) (PLGA) and the DSF. The physical state of the DSF within the wafers was dependent on the manufacturing technique, with the DSF in the wafers manufactured by compression or solvent casting retaining between 40% and 98% crystallinity, whereas the DSF in the wafers manufactured using heat compression moulding was completely amorphous. Release of DSF from the wafers is dependent on the degradation of the PLGA, the manufacturing technique used, and the DSF loading. DSF in the compressed and heat compression moulded wafers had a similar cytotoxicity against a GBM cell line compared with the unprocessed DSF control. However, the cytotoxicity of the DSF in the solvent-casted wafers was significantly lower than the unprocessed DSF.

Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport.

1 Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. 2 The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (P<0.01). Less potent nootropics, D-levetiracetam and D-pyroglutamate, have higher antagonist Ki's against pentobarbital inhibition of glucose transport than more potent L-stereoisomers (P<0.001). 3 Piracetam and TRH have no direct effects on net glucose transport, but competitively antagonise hypnotic drug inhibition of glucose transport. Other nootropics, like aniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. 4 There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABAA (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. 5 Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis.

Docking studies show that D-glucose and quercetin slide through the transporter GLUT1.

On a three-dimensional templated model of GLUT1 (Protein Data Bank code 1SUK), a molecular recognition program, AUTODOCK 3, reveals nine hexose-binding clusters spanning the entire "hydrophilic" channel. Five of these cluster sites are within 3-5 A of 10 glucose transporter deficiency syndrome missense mutations. Another three sites are within 8 A of two other missense mutations. D-glucose binds to five sites in the external channel opening, with increasing affinity toward the pore center and then passes via a narrow channel into an internal vestibule containing four lower affinity sites. An external site, not adjacent to any mutation, also binding phloretin but recognizing neither D-fructose nor L-glucose, may be the main threading site for glucose uptake. Glucose exit from human erythrocytes is inhibited by quercetin (K(i) = 2.4 mum) but not anionic quercetin-semiquinone. Quercetin influx is retarded by extracellular D-glucose (50 mm) but not by phloretin and accelerated by intracellular D-glucose. Quercetin docking sites are absent from the external opening but fill the entire pore center. In the inner vestibule, Glu(254) and Lys(256) hydrogen-bond quercetin (K(i) approximately 10 microm) but not quercetin-semiquinone. Consistent with the kinetics, this site also binds D-glucose, so quercetin displacement by glucose could accelerate quercetin influx, whereas quercetin binding here will competitively inhibit glucose efflux. Beta-D-hexoses dock twice as frequently as their alpha-anomers to the 23 aromatic residues in the transport pathway, suggesting that endocyclic hexose hydrogens, as with maltosaccharides in maltoporins, form pi-bonds with aromatic rings and slide between sites instead of being translocated via a single alternating site.