Analysing Deviation-From-Target Data: Applying the Correct Force in Sellick's Maneuver.

The problem of comparing the deviation from a target of two or more treatments or procedures arises now and again in medicine. Practitioners usually carry out a t-test on a loss function such as absolute error. We have adapted and developed statistical methods to give a normative methodology for deviation-from-target problems and exemplify them by evaluating the performance of a tactile feedback device. Parametric and nonparametric analyses are compared and contrasted. We recommend nonparametric methods for inference about loss functions such as absolute error, with a permutation test for testing the hypothesis that the two methods perform identically, and the nonparametric bootstrap for deriving standard errors and confidence intervals on loss function ratios. We develop a new permutation test that can be used when the practitioner is unwilling to decide which loss function should be used. We recommend parametric analysis when more insight into how one method is superior is desired, or there are covariates, and discuss the complications. The results for our example are that the tactile sensing device reduces an upward bias in applied force, and more importantly reduces the spread (variance) of the applied force. It performs significantly better than manual force application.

A cricoid cartilage compression device for the accurate and reproducible application of cricoid pressure.

We describe the development and laboratory assessment of a refined prototype tactile feedback device for the safe and accurate application of cricoid pressure. We recruited 20 operating department practitioners and compared their performance of cricoid pressure on a training simulator using both the device and a manual unaided technique. The device significantly reduced the spread of the applied force: average (SE) root mean squared error decreased from 8.23 (0.48) N to 5.23 (0.32) N (p < 0.001). The average (SE) upwards bias in applied force also decreased, from 2.30 (0.74) N to 0.88 (0.48) N (p < 0.01). Most importantly, the percentage of force applications that deviated from target by more than 10 N decreased from 18% to 7% (p < 0.01). The device requires no prior training, is cheap to manufacture, is single-use and requires no power to operate, whilst ensuring that the correct force is always consistently applied.

Reprint of: Burn wound healing time assessed by laser Doppler imaging. Part 2: Validation of a dedicated colour code for image interpretation.

INTRODUCTION: Laser Doppler imaging (LDI) has been investigated and used since 1993 for the assessment of burn wounds. Here we describe tests that validate use of the dedicated colour palette, derived in Part 1, for a standardised interpretation of LDI images for prediction of healing time (<14 days, 14-21 days or >21 days). We also describe clinical and technical factors to be taken into account during LDI imaging and during image interpretation. METHODS: (1) A cohort of images, selected at random, were assessed, according to strict rules of interpretation, by 6 clinicians against photographs of healing, for accuracy of healing time prediction and clinical usefulness using five-point scales. (2) All images were assessed technically in a similar way for accuracy and the accuracy was further studied by analysing the data by ordinal logistic regression to predict the dependence of burn injury healing time on demographic variables (age, sex, race, %TBSA, burn injury cause and site). (3) Where average LDI blood flow could be determined, regression analysis was used to assess the potential accuracy of the technique. RESULTS: (1) Clinical accuracy was found to be 93% and usefulness was 89%; (2) technical accuracy was found to be 96%; (3) regression analysis found that a potential accuracy of 90.9% could be achieved using LDI results alone, increasing to 92% if gender was also considered; no other parameters had an influence on healing time prediction. CONCLUSION: LDI can be used in a standardised way as a valid tool for improving on clinical assessment of burn wounds. This can enable earlier appropriate management.

Burn wound healing time assessed by laser Doppler imaging (LDI). Part 1: Derivation of a dedicated colour code for image interpretation.

INTRODUCTION: Laser Doppler imaging produces a colour-coded image of dermal blood flow, which can be used to quantify the inflammatory response in a burn. The original colour palette had arbitrary boundaries, which inexperienced clinicians found difficult to interpret. The aim of this study was to define clinically useful boundaries that would assist in the prediction of burn healing potential. METHOD: We conducted a prospective, multi-centre study of burns in adults and children. LDI scans were performed between 48 h and 5 days after injury. The burns were assessed clinically and photographed on day of scan, day 14 and day 21 post-injury. Areas healed at day 14, healed between day 14 and 21 and unhealed at day 21 were identified on the LDI scan. The flow values for the pixels in these regions were analysed to calculate boundaries between the three healing categories. RESULTS: We recruited 137 patients (ages 1-88 years, 65% male); 392 LDI scans contained 433 different burn sites; 109 regions of interest were studied. Analysis allowed us to define ranges for the three healing categories: HP14 colour coded red, >600 PU; HP14-21, yellow, 260-440 PU; HP>21, blue, <200 PU; separated by two overlap regions pink, 440-600 PU and green, 200-260 PU. Blue was subdivided to show the very high association between LDI<140 PU and non-healing at day 21. CONCLUSION: We have devised a new colour palette for LDI burn imaging based on healing times of a series of burns. Validation of this palette is described separately, in Part 2.

Burn wound healing time assessed by laser Doppler imaging. Part 2: validation of a dedicated colour code for image interpretation.

INTRODUCTION: Laser Doppler imaging (LDI) has been investigated and used since 1993 for the assessment of burn wounds. Here we describe tests that validate use of the dedicated colour palette, derived in Part 1, for a standardised interpretation of LDI images for prediction of healing time (<14 days, 14-21 days or >21 days). We also describe clinical and technical factors to be taken into account during LDI imaging and during image interpretation. METHODS: (1) A cohort of images, selected at random, were assessed, according to strict rules of interpretation, by 6 clinicians against photographs of healing, for accuracy of healing time prediction and clinical usefulness using five-point scales. (2) All images were assessed technically in a similar way for accuracy and the accuracy was further studied by analysing the data by ordinal logistic regression to predict the dependence of burn healing time on demographic variables (age, sex, race, %TBSA, burn cause and site). (3) Where average LDI blood flow could be determined, regression analysis was used to assess the potential accuracy of the technique. RESULTS: (1) Clinical accuracy was found to be 93% and usefulness was 89%; (2) technical accuracy was found to be 96%; (3) regression analysis found that a potential accuracy of 90.9% could be achieved using LDI results alone, increasing to 92% if gender was also considered; no other parameters had an influence on healing time prediction. CONCLUSION: LDI can be used in a standardised way as a valid tool for improving on clinical assessment of burn wounds. This can enable earlier appropriate management.

Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition.

Gastroesophageal reflux (GER), defined as passage of gastric contents into the esophagus, and GER disease (GERD), defined as symptoms or complications of GER, are common pediatric problems encountered by both primary and specialty medical providers. Clinical manifestations of GERD in children include vomiting, poor weight gain, dysphagia, abdominal or substernal pain, esophagitis and respiratory disorders. The GER Guideline Committee of the North American Society for Pediatric Gastroenterology and Nutrition has formulated a clinical practice guideline for the management of pediatric GER. The GER Guideline Committee, consisting of a primary care pediatrician, two clinical epidemiologists (who also practice primary care pediatrics) and five pediatric gastroenterologists, based its recommendations on an integration of a comprehensive and systematic review of the medical literature combined with expert opinion. Consensus was achieved through Nominal Group Technique, a structured quantitative method. The Committee examined the value of diagnostic tests and treatment modalities commonly used for the management of GERD, and how those interventions can be applied to clinical situations in the infant and older child. The guideline provides recommendations for management by the primary care provider, including evaluation, initial treatment, follow-up management and indications for consultation by a specialist. The guideline also provides recommendations for management by the pediatric gastroenterologist. This document represents the official recommendations of the North American Society for Pediatric Gastroenterology and Nutrition on the evaluation and treatment of gastroesophageal reflux in infants and children. The American Academy of Pediatrics has also endorsed these recommendations. The recommendations are summarized in a synopsis within the article. This review and recommendations are a general guideline and are not intended as a substitute for clinical judgment or as a protocol for the management of all patients with this problem.

Data-based modeling of the failure rate of repairable equipment.

A database of failures of many types of medical equipment was analysed, to study the dependence of failure rate on equipment age and on time since repair. The intention was to use this large dataset to assess the validity of some widely-used models of failure rate, such as the power-law and loglinear Poisson processes, and so to recommend simple and adequate models to those practitioners having little data to discriminate between rival models. The aim is also to illustrate a methodology for computing policy costs from failure databases. The power-law process model was found to fit slightly better overall than did the loglinear and linear processes. Some related models were created to fit an observed peaking of failure rate. The data showed a decreasing hazard of (first) failure after repair for some equipment types. This can be due to imperfect or hazardous repair, and also to differing failure rates among a population of machines. Two simple models of imperfect repair were used to fit the data, and an Empirical Bayes method was used to fit a model of variable failure rate between machines. Neglect of such variation can lead to an over-estimate of the hazardousness of repair.

Quantitative assessment of a circulating depolarizing factor in shock.

Sustained depolarization of cell membranes and cellular edema are known to accompany various forms of circulatory shock and probably contribute to hypovolemia and cellular dysfunction. It has been proposed that a circulating protein is responsible for these effects. In the present study we have confirmed the existence of a circulating depolarizing factor (CDF) in hemorrhagic shock, burn shock, sepsis, and cardiopulmonary bypass. Plasma samples from pigs or sheep in shock were quantitatively assayed for depolarizing activity using a microelectrode method on rat diaphragm in vitro. The depolarizing effect of CDF in vitro was similar in magnitude to that of shock in situ. We conclude that CDF can entirely account for membrane depolarization during shock. The depolarizing effect of CDF was dose-dependent and saturable; it could be reversed by rinsing the diaphragm with Ringer's or control plasma. CDF activity was detectable in plasma within 5 min after a severe scald and gradually increased over the next 25 min. Resuscitation of hemorrhaged pigs, but not burned sheep, eliminated plasma CDF activity.

Randomized, double-blind, placebo-controlled pilot trial of megestrol acetate in malnourished children with cystic fibrosis.

BACKGROUND: Undernutrition is common in patients with cystic fibrosis (CF). Nutritional rehabilitation has been shown to improve linear growth, pulmonary function, well-being, and resistance to infection in this population. The purpose of this study was to determine whether the administration of megestrol acetate (MA) induces weight gain in malnourished patients with CF, and to assess the composition of weight gain. METHODS: In a randomized, placebo-controlled, double-blind, crossover study, 12 children with CF received MA (10 mg/kg/d) or placebo for 12 weeks, followed by a 12-week washout period, then the alternative treatment. Anthropometrics, caloric intake, and clinical assessment were obtained every 6 weeks; pulmonary function tests, biochemistry, hematology, cortisol, growth hormone, insulin, C-peptide, insulin-like growth factor-1, insulin-like growth factor binding protein-3, and dual-energy x-ray absorptiometry scans were obtained every 12 weeks. RESULTS: Six children did not complete the study, three for reasons unrelated to the study, two because they developed diabetes while receiving MA, and one who had glucose intolerance while receiving the placebo. Average weight gain was 3.05 kg in the MA group and 0.3 kg in the placebo group. The change in weight z score was +0.76 in the MA group and -0.05 in the placebo group. The change in height z score was -0.06 in the MA group and +0.06 in the placebo group. Lean body mass and body fat increased by 1507 g and 1192 g respectively in the MA group. Pulmonary function tests improved in the MA group; serum cortisol levels decreased. Side effects included glucosuria, insomnia, hyperactivity, and irritability. CONCLUSIONS: Weight, body fat, and lean body mass increased and pulmonary function improved in the children with CF given MA. Adrenal suppression, glucose intolerance, and diabetes are side effects.

Glutathione oxidation and PTPase inhibition by hydrogen peroxide in Caco-2 cell monolayer.

The role of H(2)O(2) and protein thiol oxidation in oxidative stress-induced epithelial paracellular permeability was investigated in Caco-2 cell monolayers. Treatment with a H(2)O(2) generating system (xanthine oxidase + xanthine) or H(2)O(2) (20 microM) increased the paracellular permeability. Xanthine oxidase-induced permeability was potentiated by superoxide dismutase and prevented by catalase. H(2)O(2)-induced permeability was prevented by ferrous sulfate and potentiated by deferoxamine and 1,10-phenanthroline. GSH, N-acetyl-L-cysteine, dithiothreitol, mercaptosuccinate, and diethylmaleate inhibited H(2)O(2)-induced permeability, but it was potentiated by 1,3-bis(2-chloroethyl)-1-nitrosourea. H(2)O(2) reduced cellular GSH and protein thiols and increased GSSG. H(2)O(2)-mediated reduction of GSH-to-GSSG ratio was prevented by ferrous sulfate, GSH, N-acetyl-L-cysteine, diethylmaleate, and mercaptosuccinate and potentiated by 1,10-phenanthroline and 1, 3-bis(2-chloroethyl)-1-nitrosourea. Incubation of soluble fraction of cells with GSSG reduced protein tyrosine phosphatase (PTPase) activity, which was prevented by coincubation with GSH. PTPase activity was also lower in H(2)O(2)-treated cells. This study indicates that H(2)O(2), but not O(2)(-). or.OH, increases paracellular permeability of Caco-2 cell monolayer by a mechanism that involves oxidation of GSH and inhibition of PTPases.

Effective time to satisfactory intubation conditions after administration of rocuronium in adults. Comparison of propofol and thiopentone for rapid sequence induction of anaesthesia.

We determined the effective time to satisfactory intubation conditions after the administration of rocuronium 0.6 mg.kg-1 to 120 unpremedicated adult patients anaesthetised with propofol 2.5 mg.kg-1 or thiopentone 5 mg.kg-1. Intubation conditions were assessed in 10 subgroups of 12 patients at 30, 40, 50, 60 and 70 s. The effective times to satisfactory intubation conditions in 50 and 90% of patients were obtained by the method of maximum likelihood after log time-probit response transformations. Intubation conditions after induction of anaesthesia with propofol were satisfactory in 5/12 patients at 30 s, 7/12 at 40 s, 10/12 at 50 s, 11/12 at 60 s and 11/12 at 70 s compared with 1/12 patients at 30 s, 2/12 at 40 s, 5/12 at 50 s, 7/12 at 60 s and 8/12 at 70 s after induction with thiopentone. The effective times to satisfactory intubation conditions in 50% and 90% (95% confidence intervals) of patients after rocuronium 0.6 mg.kg-1 were 34 (26-40) s and 61 (50-81) s in patients given propofol compared with 57 (48-69) s and 101 (79-167) s in patients given thiopentone. We conclude that rocuronium 0.6 mg.kg-1 may be a suitable alternative to suxamethonium during rapid sequence induction of anaesthesia with propofol in situations where suxamethonium is contraindicated.

Inhibition of oxidant-induced barrier disruption and protein tyrosine phosphorylation in Caco-2 cell monolayers by epidermal growth factor.

The effect of epidermal growth factor (EGF) on the H202-induced increase in paracellular permeability in Caco-2 and T-84 cell monolayers was evaluated to examine the role of EGF in intestinal mucosal protection from oxidative stress. Oxidative stress was induced by exposing cell monolayers to H2O2 or a mixture of xanthine oxidase + xanthine (XO + X). Paracellular permeability was assessed by measuring transepithelial electrical resistance (TER), sodium chloride dilution potential, and unidirectional flux of [3H]mannitol. H2O2 (0.1 to 5.0 mM) reduced TER and dilution potential and increased mannitol flux. Administration of EGF delayed H2O2 and XO + X-induced changes in TER, dilution potential, and [3H]mannitol flux. This protective effect of apically or basally administered EGF was concentration-related, with A50 (95% confidence limits) values of 2.1 (1.17 to 4.34) and 6.0 (4.37 to 8.34) nM, respectively. The EGF-mediated protection was prevented by treatment of cell monolayers with genistein (10 microM), a tyrosine kinase inhibitor. H2O2 and XO + X also induced tyrosine phosphorylation of a number of proteins in Caco-2 and T-84 cell monolayers. EGF treatment inhibited the oxidant-induced tyrosine phosphorylation of proteins, particularly those with a molecular mass of 110-220 kDa. Treatment of Caco-2 cells with anti-transforming growth factor-alpha antibodies potentiated the H2O2-induced changes in TER, dilution potential, and mannitol flux. These studies demonstrated that an EGF receptor-mediated mechanism delays oxidant-induced disruption of the epithelial barrier function, possibly by suppressing the oxidant-induced tyrosine phosphorylation of proteins.

Selenium deficiency in tissue culture: implications for oxidative metabolism.

BACKGROUND: Selenium is located at the catalytic site of the enzyme glutathione peroxidase, and with selenium deficiency the activity of glutathione peroxidase is decreased. Cell culture is an important tool for studying oxidative processes-that is generation and metabolism of oxygen-derived metabolites in the gastrointestinal system. Cell culture is also used to understand the mechanisms of cell injury by oxygen-derived metabolites. METHODS: To assess the importance of the selenium content of cell culture media, Caco-2 cells and the hepatoma-derived cell lines, Hep3B and HepG2, were grown to confluence and placed in media with various concentrations of selenium. After 7 to 14 days, cells were harvested and assayed for glutathione peroxidase, lactate dehydrogenase, and protein content. RESULTS: Cells maintained in media unsupplemented with selenium demonstrated a progressive decrease in glutathione peroxidase activity. Cells maintained in media supplemented with various concentrations of selenium demonstrated a dose-dependent increase in glutathione peroxidase until a plateau was reached. The plateau was reached at approximately 400 times the selenium concentration routinely used in cell culture. In the Caco-2 and hepatoma cells, no toxicity was observed at selenium supplementation five times the lowest concentration needed to reach a plateau. CONCLUSIONS: Cell culture media are routinely deficient in selenium, and cells that are cultured in this medium are deficient in glutathione peroxidase activity. Studies of oxidative metabolism based on cultures deficient in selenium may yield results that could be falsely interpreted. The addition of 1 nM selenium is sufficient for these cell lines to reach a plateau for intracellular glutathione peroxidase activity. These observations may have important ramifications for the study of reactive oxygen metabolite injury in cell culture.

Enteral nutrition in the pediatric population.

Enteral feeding, the provision of liquid nutrients into the gastrointestinal tract, is an important component of pediatric care. For the infant or child with a functioning or even a partially-functioning GI tract, the use of the enteral route provides a safe and efficient means of delivering nutrition at a time of life when requirements are extremely high. In addition to high nutrient requirements in the early years of life, there are a number of specific pediatric conditions, such as failure to thrive, short bowel syndrome, and congenital heart disease, which place further demands on the growing child. These demands can be met through the careful use of enteral feeds. This article reviews the physiology and practical application of enteral feeding to the pediatric age group.

Bovine milk inhibits proteolytic degradation of epidermal growth factor in human gastric and duodenal lumen.

Degradation of epidermal growth factor (EGF) in human gastric and duodenal lumen was analyzed by incubating 125I-labeled or unlabeled human recombinant EGF with human gastric or duodenal luminal fluids in vitro. Degradation of EGF was assessed by measuring the generation of acid soluble radioactivity or by reversed-phase high-performance liquid chromatography (HPLC). Incubation with gastric luminal fluids resulted in a time- and dose-dependent degradation of labeled and unlabeled EGF at pH 2.5 but not at pH 7.5. Duodenal luminal fluids, on the other hand, degraded EGF at pH 7.5 but not at pH 2.5. The rate of degradation of unlabeled EGF in gastric luminal fluids was nearly 12-fold higher than the rate of degradation of labeled EGF, whereas only a slight difference in rates of degradation of labeled and unlabeled EGF was observed in duodenal luminal fluids. High-performance liquid chromatography analysis detected three major degradation products that eluted with retention time of 17.5 min, 20.0 min, and 22.5 min that was associated with a reduction of intact EGF (retention time 23.5 min). Defatted and decaseinated supernatant of bovine milk effectively inhibited the degradation of EGF in both gastric and duodenal luminal fluids. Dietary derived protease inhibitors, such as soya bean trypsin inhibitor, lima bean trypsin inhibitor, egg white protease inhibitor, and Bowman-Birk protease inhibitor prevented EGF degradation in duodenal luminal fluids but failed to inhibit EGF degradation in gastric luminal fluids. These results suggest that bovine milk may contain specific inhibitors that protect EGF from proteolytic degradation in human gastric lumen.

Use of a mathematical model to evaluate breast cancer screening policy.

A model of breast cancer screening was developed, in which the processes of tumour origination and growth, detection of tumours at screening, presentation of women with cancers to their GP, and of survival after diagnosis were modelled parametrically. The model was fitted to data from the North-West of the UK, for 413 women who screened positive, and for 761 women who developed interval cancers. Model validation comprised verification that the final model fitted the data adequately, together with the comparison of model predictions with findings by other workers. The mathematical model was used to assess different screening policies, and to ask "what if" questions. Taking the cost of breast cancer to be the sum of the cost of screening and the cost of PYLL (person years of life lost due to cancer), the optimal screening policy was calculated. The costs of the current policy and of other possible screening policies were found, together with their effects on life lost and on mortality. The tentative conclusion was that if monies can be found to extend the screening programme, for example to carry out one more screen per woman, most benefit would be obtained by reducing the start age of screening by 3 years.

Oxidant-induced disruption of intestinal epithelial barrier function: role of protein tyrosine phosphorylation.

The effect of hydrogen peroxide (H2O2) on intestinal epithelial barrier function was examined in Caco-2 and T84 cell monolayers. H2O2 reduced transepithelial electrical resistance (TER) of Caco-2 and T84 cell monolayers. This decrease in TER was associated with a decrease in dilution potential and an increase in [3H]mannitol permeability, suggesting an H2O2-induced disruption of the paracellular junctional complexes. H2O2 administration also induced tyrosine phosphorylation of several proteins (at the molecular mass ranges of 50-90, 100-130, and 150-180 kDa) in Caco-2 cell monolayers. Phenylarsine oxide and sodium orthovanadate, inhibitors of protein tyrosine phosphatase, decreased TER and increased mannitol permeability and protein tyrosine phosphorylation (PTP). A low concentration of sodium orthovanadate also potentiated the effect of H2O2 on TER, dilution potential, mannitol permeability, and PTP. Pretreatment with genistein (30-300 microM) and tyrphostin (100 microM) inhibited the effect of H2O2 on TER, dilution potential, mannitol permeability, and PTP. These studies show that H2O2 increases the epithelial permeability by disrupting paracellular junctional complexes, most likely by a PTP-dependent mechanism.

Dose-response relationship and effective time to satisfactory intubation conditions after rocuronium in children.

We assessed the neuromuscular blocking effects of, and intubation conditions following, rocuronium in 81 children aged 2-12 years. The study was conducted in three parts. Parts 1 and 2 were undertaken during anaesthesia with thiopentone, alfentanil and nitrous oxide. Neuromuscular blockade was evaluated by recording the force of contraction of the adductor pollicis in response to train-of-four stimulation at 2 Hz repeated every 10s. In Part 1 the potency of rocuronium was determined in 15 children using a single dose-response technique; in Part 2 onset and recovery times were determined in six children following rocuronium 0.6 mg.kg-1. In Part 3 of the study, intubation conditions were assessed in five groups of 12 children whose tracheas were intubated 30, 40, 50, 60 and 70s after rocuronium 0.6 mg.kg-1 during anaesthesia with thiopentone. The times to satisfactory intubation conditions in 50% and 90% of children were determined by probit analysis. The effective doses of rocuronium to produce 50% and 95% twitch depression were 151 micrograms.kg-1 (95% confidence intervals: 129-173 micrograms.kg-1) and 331 micrograms.kg-1 (95% confidence intervals: 249-543 micrograms.kg-1), respectively. The mean times (SD) to 90% and 100% depression of control twitch following rocuronium 0.6 mg.kg-1 were 42 (11.8) s and 60.3 (19.3) s, respectively. The times to 5%, 25%, 75% and 90% recovery were 20.5 (3.1) min, 26.1 (4.1) min, 35.1 (5.4) min, and 39.5 (6.4) min, respectively. Intubation conditions were satisfactory in 4/12 children at 30 s, 6/12 at 40 s, 8/12 at 50 s, 11/12 at 60 s and 12/12 at 70 s. The times to satisfactory intubation conditions in 50% and 90% of children after rocuronium 0.6 mg.kg-1 were 38 s (95% confidence intervals: 30-44 s) and 61 s (95% confidence intervals: 55-70 s), respectively.