The impact of fatigue on the non-technical skills performance of critical care air ambulance clinicians.

BACKGROUND: The relationship between fatigue-related risk and impaired clinical performance is not entirely clear. Non-technical factors represent an important component of clinical performance and may be sensitive to the effects of fatigue. The hypothesis was that the sum score of overall non-technical performance is degraded by fatigue. METHODS: Nineteen physicians undertook two different simulated air ambulance missions, once when rested, and once when fatigued (randomised crossover design). Trained assessors blinded to participants' fatigue status performed detailed structured assessments based on expected behaviours in four non-technical skills domains: teamwork, situational awareness, task management, and decision making. Participants also provided self-ratings of their performance. The primary endpoint was the sum score of overall non-technical performance. RESULTS: The main finding, the overall non-technical skills performance rating of the clinicians, was better in rested than fatigued states (mean difference with 95% CI, 2.8 [2.2-3.4]). The findings remained consistent across individual non-technical skills domains; also when controlling for an order effect and examining the impact of a number of possible covariates. There was no difference in self-ratings of clinical performance between rested and fatigued states. CONCLUSION: Non-technical performance of critical care air transfer clinicians is degraded when they are fatigued. Fatigued clinicians may fail to recognise the degree to which their performance is compromised. These findings represent risk to clinical care quality and patient safety in the dynamic and isolated environment of air ambulance transfer.

Prenatal diagnosis of critical congenital heart disease reduces risk of death from cardiovascular compromise prior to planned neonatal cardiac surgery: a meta-analysis.

OBJECTIVE: To determine if prenatal diagnosis improves the chance that a newborn with critical congenital heart disease will survive to undergo planned cardiac surgery. METHODS: A systematic review of the medical literature identified eight studies which met the following criteria: compared outcomes between newborns with prenatal and those with postnatal diagnosis of critical congenital heart disease; compared groups of patients with the same anatomical diagnosis; provided detailed information on cardiac anatomy; included detailed information on preoperative cause of death. A meta-analysis was performed to assess differences in preoperative mortality rates between newborns with prenatal diagnosis and those with postnatal diagnosis. Patients with established risk factors for increased mortality (high risk) and those whose families chose comfort care rather than cardiac surgery were excluded. RESULTS: In patients with comparable anatomy, standard risk, a parental desire to treat and optimal care, newborns with a prenatal diagnosis of critical congenital heart disease were significantly less likely to die prior to planned cardiac surgery than were those with a comparable postnatal diagnosis (pooled odds ratio, 0.26; 95% CI, 0.08-0.84). CONCLUSIONS: For newborns most likely to benefit from treatment for their critical congenital heart disease, because they did not have additional risk factors and their families pursued treatment, prenatal diagnosis reduced the risk of death prior to planned cardiac surgery relative to patients with a comparable postnatal diagnosis. Further study and efforts to improve prenatal diagnosis of congenital heart disease should therefore be considered.

Simulations of the two-dimensional electronic spectroscopy of the photosystem II reaction center.

We report simulations of the two-dimensional electronic spectroscopy of the Q(y) band of the D1-D2-Cyt b559 photosystem II reaction center at 77 K. We base the simulations on an existing Hamiltonian that was derived by simultaneous fitting to a wide range of linear spectroscopic measurements and described within modified Redfield theory. The model obtains reasonable agreement with most aspects of the two-dimensional spectra, including the overall peak shapes and excited state absorption features. It does not reproduce the rapid equilibration from high energy to low energy excitonic states evident by a strong cross-peak below the diagonal. We explore modifications to the model to incorporate new structural data and improve agreement with the two-dimensional spectra. We find that strengthening the system-bath coupling and lowering the degree of disorder significantly improves agreement with the cross-peak feature, while lessening agreement with the relative diagonal/antidiagonal width of the 2D spectra. We conclude that two-dimensional electronic spectroscopy provides a sensitive test of excitonic models of the photosystem II reaction center and discuss avenues for further refinement of such models.

Oral Microbiota Composition Predicts Early Childhood Caries Onset.

As the most common chronic disease in preschool children in the United States, early childhood caries (ECC) has a profound impact on a child's quality of life, represents a tremendous human and economic burden to society, and disproportionately affects those living in poverty. Caries risk assessment (CRA) is a critical component of ECC management, yet the accuracy, consistency, reproducibility, and longitudinal validation of the available risk assessment techniques are lacking. Molecular and microbial biomarkers represent a potential source for accurate and reliable dental caries risk and onset. Next-generation nucleotide-sequencing technology has made it feasible to profile the composition of the oral microbiota. In the present study, 16S ribosomal RNA (rRNA) gene sequencing was applied to saliva samples that were collected at 6-mo intervals for 24 mo from a subset of 56 initially caries-free children from an ongoing cohort of 189 children, aged 1 to 3 y, over the 2-y study period; 36 children developed ECC and 20 remained caries free. Analyses from machine learning models of microbiota composition, across the study period, distinguished between affected and nonaffected groups at the time of their initial study visits with an area under the receiver operating characteristic curve (AUC) of 0.71 and discriminated ECC-converted from healthy controls at the visit immediately preceding ECC diagnosis with an AUC of 0.89, as assessed by nested cross-validation. Rothia mucilaginosa, Streptococcus sp., and Veillonella parvula were selected as important discriminatory features in all models and represent biomarkers of risk for ECC onset. These findings indicate that oral microbiota as profiled by high-throughput 16S rRNA gene sequencing is predictive of ECC onset.

The role of neutropenia on outcomes of cancer patients with community-acquired pneumonia.

Although the presence of neutropenia may predispose cancer patients to develop community-acquired pneumonia, the role of neutropenia on their outcomes has not been investigated. The purpose of the present study was to compare clinical outcomes of cancer community-acquired pneumonia patients with and without neutropenia. Patients with cancer, identified in the Community-Acquired Pneumonia Organization database, were divided into two groups according to the type of cancer and the presence of neutropenia: patients with solid cancer without neutropenia versus those with functional or absolute neutropenia. Among the 3,106 community-acquired pneumonia patients enrolled, 135 had cancer without neutropenia and 75 had cancer with neutropenia. No significant difference was found between patients with and without neutropenia regarding mean time to clinical stability (5.4+/-2.7 versus 4.9+/-2.7 days, respectively), mean length of hospital stay (9.2+/-7.7 versus 9.9+/-9.6 days) and in-hospital mortality (18 versus 15%, respectively). Using a multiple logistic regression model, neutropenia was not associated with mortality in cancer patients when adjusting for significant covariates (odds ratio 1.30). Lack of neutropenia, during the initial evaluation of a cancer community-acquired pneumonia patient, should not be considered an indicator of better clinical outcome.

Laparoscopic ultrasound as the primary method for bile duct imaging during cholecystectomy.

BACKGROUND: Intraoperative fluorocholangiography (IOC) has been the standard method for bile duct imaging during cholecystectomy. Laparoscopic ultrasound (LUS) has been evaluated as a possible alternative, but has been used less frequently. The authors examined the evolving use of these two methods to assess the relative utility of LUS as the primary method for routine bile duct imaging during laparoscopic cholecystectomy (LC). METHODS: This study analyzed a prospective database containing 423 consecutive cholecystectomies performed by one attending surgeon in an academic medical center between 1995 and 2005. RESULTS: Intraoperative bile duct imaging was performed in 371 (94%) of 396 LCs performed for cholelithiasis. As recorded, IOC was performed in 239 cases, LUS in 236 cases, and both in 104 cases. Choledocholithiasis was present in 50 patients (13%). Common bile duct stones (CBDS) were identified by LUS in 3% of the patients without preoperative indicators of CBDS, and in 10% of the patients with one or more indicators. As shown by the findings, LUS had a positive predictive value of 100%, a negative predictive value of 99.6%, a sensitivity of 92.3%, and a specificity of 100% for detecting CBDS. Also, LUS identified clinically significant bile duct anatomy in 6% of the patients. In 1995, LUS was used for 20% of cases, whereas by 2005, it was used for 97% of cases. Conversely, the use of IOC decreased from 93% to 23%. CONCLUSIONS: With moderate experience, LUS can become the primary routine imaging method for evaluating the bile duct during LC. It is as reliable as IOC for detecting choledocholithiasis. In addition, LUS can locate the common bile duct during difficult dissections. On the basis of this experience, LUS is used currently in nearly all LCs and is the sole method for bile duct imaging in 75% of these cases. IOC is used as an adjunct to LUS when LUS imaging is inadequate, when stronger clinical indicators of choledocholithiasis are present, or when biliary anatomy remains uncertain.

Pilot study to determine the feasibility of radiation therapy for dogs with right atrial masses and hemorrhagic pericardial effusion.

OBJECTIVES: To determine the short-term safety and biologic activity of radiation therapy (RT) for presumptive cardiac hemangiosarcoma in pet dogs. ANIMALS: Six dogs with echocardiographic evidence of a right atrial/auricular mass, and hemorrhagic pericardial effusion, were enrolled in a prospective, single-arm clinical trial. METHODS: A single fraction of 12 Gy was delivered using conformal external beam irradiation. Serum cardiac troponin I and plasma concentrations of vascular endothelial growth factor were quantified before, 4 and 24 h after RT. The frequency of required pericardiocenteses (quantified as the number of pericardiocenteses per week) before RT was compared to that after treatment. Overall survival time was determined. RESULTS: No treatment-related complications were observed. Pericardiocentesis was performed an average of 0.91 times per week before RT, and an average of 0.21 times per week after RT; this difference was statistically significant (p=0.03, as compared using a Wilcoxon signed-rank test of paired data). Pre- and post-treatment plasma vascular endothelial growth factor concentrations were not significantly different at any time point; there was a statistically significant (p=0.04; Friedman's test for non-parametric repeated measures) increase in cardiac troponin concentrations 4 h after irradiation. Median overall survival time was 79 days. CONCLUSIONS: In this population of dogs, RT was delivered without complication, and appears to have reduced the frequency of periacardial tamponade that necessitated pericardiocentesis. Serum cardiac troponin levels are altered after RT. RT alone, or in combination with chemotherapy, may provide clinical benefit to dogs with presumptive diagnoses of cardiac hemangiosarcoma.

Common side closure type, but not stapler brand or oversewing, influences side-to-side anastomotic leak rates.

BACKGROUND: Anastomotic leak (AL) increases costs and cancer recurrence. Studies show decreased AL with side-to-side stapled anastomosis (SSA), but none identify risk factors within SSAs. We hypothesized that stapler characteristics and closure technique of the common enterotomy affect AL rates. METHODS: Retrospective review of bowel SSAs was performed. Data included stapler brand, staple line oversewing, and closure method (handsewn, HC; linear stapler [Barcelona technique], BT; transverse stapler, TX). Primary endpoint was AL. Statistical analysis included Fisher's test and logistic regression. RESULTS: 463 patients were identified, 58.5% BT, 21.2% HC, and 20.3% TX. Covidien staplers comprised 74.9%, Ethicon 18.1%. There were no differences between stapler types (Covidien 5.8%, Ethicon 6.0%). However, AL rates varied by common side closure (BT 3.7% vs. TX 10.6%, p = 0.017), remaining significant on multivariate analysis. CONCLUSION: Closure method of the common side impacts AL rates. Barcelona technique has fewer leaks than transverse stapled closure. Further prospective evaluation is recommended.

In-vivo secondary structure analysis of the small nuclear RNA U1 using psoralen cross-linking.

Intramolecular base-pairing interactions have been probed in the small nuclear RNA U1 in vivo. HeLa cells were treated with the psoralen derivative aminomethyltrioxsalen, and cross-linking was carried out by irradiating the intact cells with light of 365 nm wavelength. Cross-linking resulted in a discrete shift in electrophoretic mobility of approximately 65 to 70% of the U1. This intramolecularly cross-linked U1 RNA, termed XU1, was purified and shown to co-migrate with uncross-linked U1 upon photo-reversal of psoralen cross-links with light of 254 nm wavelength. XU1 was also generated by the in-vitro cross-linking of deproteinized U1, suggesting that the secondary structure of U1 RNA in solution is similar to that of U1 ribonucleoprotein in the cell. A sequencing analysis was developed, based on partial enzymatic and alkaline cleavage of psoralen-treated RNA, to identify the position of psoralen cross-links and to distinguish between psoralen monoadducts and diadducts (cross-links). Sequencing of 3' and 5' end-labeled XU1 provided direct evidence for the presence of a unique intramolecular cross-link in XU1, located on uridine 116 (U116). This result is consistent with several secondary-structure models for U1 in which U116 is located in a base-paired stem. The proximity of uridine 96 (U96) to U116 on the opposite side of the base-paired stem suggested that U116 was cross-linked to U96. An additional U1 species having an electrophoretic mobility between those of U1 and XU1 was also generated by psoralen treatment. Analysis of this U1 species, termed U1M, revealed a psoralen monoadduct on U96. Further longwave (365 nm) irradiation of purified U1M resulted in its conversion to XU1 by completion of the U96-U116 cross-link. This suggested that cross-linking at the U96-U116 site occurred as a two-step process in which the psoralen first reacted with U96 and then with U116. Sequencing analysis also identified a psoralen monoadduct on uridine 45 (U45) of XU1. Efficient psoralen-adduct formation, which resulted in cross-linking at the U96-U116 site and monoaddition on U45, suggests that these regions are relatively accessible in the native U1 small nuclear ribonucleoprotein particle in vivo.

Bupivacaine protein binding in the term parturient: effects of lactic acidosis.

The effects of lactic acidosis on bupivacaine serum protein binding was studied in a group of term parturients and a group of nonpregnant female control subjects. Groups were matched in age and health. Distribution characteristics of bupivacaine in pregnancy were determined. Bupivacaine protein binding was best characterized by the model for two classes of binding sites in all studies. The parturients exhibited a lower capacity for the high-affinity, low-capacity (alpha 1-acid glycoprotein) site and higher affinity for the low-affinity, high-capacity (albumin) site. Lactic acidosis decreased the affinity constant for the high-affinity, low-capacity site in the control group but did not change binding characteristics in the parturients. Free concentration of bupivacaine (Cu) was elevated at low total bupivacaine concentrations (Ct) (less than 10 micrograms/ml). No differences in Cu were detected at concentrations in the cardiotoxic range (greater than 20 micrograms/ml). The Cu values predicted by the estimated binding parameters from in vitro experiments were compared with actual Cu measured in nine parturients at delivery; they correlated significantly (r = 0.94). Distribution changes for bupivacaine in the parturients were consistent with known physiologic changes in body composition associated with pregnancy. Alterations that occur in serum protein binding during pregnancy should not result in increased risk of central nervous system or cardiovascular system toxicity since these alterations do not increase free tissue concentration.

Catalytic properties of the ATPase on submitochondrial particles after exchange of tightly bound nucleotides under different steady state conditions.

Energized submitochondrial particles were subjected to high or low [3H]ATP/[3H]ADP ratios, maintained during steady state by a pyruvate kinase or hexokinase regenerating system, respectively. Under both steady state conditions, about 1.4 mol [3H]nucleotide/mol ATPase was retained but considerably more [3H]ATP was retained with the high [3H]ATP/[3H]ADP ratio. The ATPase activity and the oxygen exchange of these differentially labeled SMP were the same, suggesting a lack of control function of non-catalytic tightly bound nucleotides.

Generalized seizures and cocaine abuse.

Cocaine is a commonly abused drug. We report three patients who had generalized seizures immediately following intravenous injection of cocaine. Previous experimental and clinical literature have documented a relationship between cocaine and convulsions. The rising incidence of cocaine use may be associated with a rising incidence of cocaine-associated seizures.

Cyanide-induced parkinsonism: clinical, MRI, and 6-fluorodopa PET studies.

A 46-year-old man ingested 1,500 mg of potassium cyanide in a suicide attempt. He survived, but later developed a severe parkinsonian syndrome. MRI revealed multiple areas of low-signal intensity in the globus pallidus and posterior putamen. A 6-fluorodopa PET study revealed bilateral decreased uptake in the basal ganglia. This evidence of functional impairment of dopaminergic nigrostriatal neurons is related either to direct toxicity of cyanide or to the effects of cerebral hypoxia secondary to cyanide intoxication.

In vitro and in vivo antitumor activity of a novel immunomodulatory drug, leflunomide: mechanisms of action.

Leflunomide, a novel immunomodulatory drug, has two biochemical activities: inhibition of tyrosine phosphorylation and inhibition of pyrimidine nucleotide synthesis. In the present study, we first showed that A77 1726 [N-(4-trifluoromethylphenyl-2-cyano-3-hydroxycrotoamide)], the active metabolite of leflunomide, was more effective at inhibiting the tyrosine kinase activity of platelet-derived growth factor (PDGF) receptor than that of epidermal growth factor (EGF) receptor, and had no effect on the tyrosine kinase activity of the fibroblast growth factor receptor. In the presence of exogenous uridine, A77 1726 was more effective at inhibiting the PDGF-stimulated proliferation of PDGF receptor-overexpressing C6 glioma than the EGF-stimulated proliferation of EGF receptor-overexpressing A431 cells. In vivo studies demonstrated that leflunomide treatment strongly inhibited the growth of the C6 glioma but had only a modest effect on the growth of the A431 tumor. Uridine co-administered with leflunomide did not reverse the antitumor activity of leflunomide on C6 and A431 tumors significantly. Quantitation of nucleotide levels in the tumor tissue revealed that leflunomide treatment significantly reduced pyrimidine nucleotide levels in the fast-growing C6 glioma but had no effect on the relatively slow-growing A431 tumor. Whereas uridine co-administration normalized pyrimidine nucleotide levels, it had minimal effects on the antitumor activity of leflunomide in both tumor models. Immunohistochemical analysis revealed that leflunomide treatment significantly reduced the number of proliferating cell nuclear antigen-positive cells in C6 glioma, and that uridine only partially reversed this inhibition. These results collectively suggest that the in vivo antitumor effect of leflunomide is largely independent of its inhibitory effect on pyrimidine nucleotide synthesis. The possibility that leflunomide exerts its antitumor activity by inhibition of tyrosine phosphorylation or by a yet unidentified mode of action is discussed.

Radiosensitization by derivatives of isoindole-4,7-dione.

New derivatives of isoindole -4,7-dione have been synthesized and their radiation sensitization and chemical behavior have been studied. One-electron reduction potentials have been determined by pulse radiolysis and found to be in the range of -0.45 to -0.36 V vs NHE . Radiosensitization effects were tested in vivo using soft tissue sarcoma transplanted in mice. All the isoindole -4,7-diones tested were found to exert considerable radiosensitization, approaching that of misonidazole tested under comparable conditions. The derivatives which contain a carbethoxy group on the pyrrolic ring were found to have more positive reduction potentials and to act as more efficient sensitizers. Further development of this class of radiosensitizers is underway.

Pupil diameter and the principal ray.

Placement of the surgical zone is critical in refractive procedures that alter a portion of the corneal curve. An improperly centered optical zone may produce glare, decrease best corrected visual acuity, and decrease contrast sensitivity. For proper placement, the new surface should be centered around the line of sight, which is the principal ray from the object of regard that passes through the image of the patient's pupil as projected on the cornea. This point is not necessarily at the geometric center of the cornea and is found by locating the center of the pupil while the patient is maintaining fixation coaxially with the surgeon. However, the pupil does not dilate concentrically and its geometric center moves as the pupil diameter changes. We have found a shift up to 0.7 mm in the geometric center of the pupil as it dilates. Therefore, centration of an ablated or a radial keratotomy zone is most efficiently done when the diameter of the modified corneal optical zone is centered around the line of sight and is superimposed upon the entrance pupil. This will minimize extension of the edge of the large pupil beyond the ablated zone and reduce unwanted secondary optical effects from degrading vision.

An optical fiber transducer for single myofibril force measurement.

A force transducer has been developed for use in force measurement of skeletal muscle myofibrils. The transducer is suitable for measurement of passive and contractile forces in a range up to 200 micrograms, with 1 microgram resolution. It is based upon the operating principle of the deflection of an optical fiber of known compliance, sensed by the differential illumination of two phototransistors. Attractive features include ease of operation and specimen mounting, high bandwidth, adaptability for different force ranges, and simple and inexpensive construction.

A low-cost fiber-optic instrument to colorimetrically detect patients with Barrett's esophagus for early detection of esophageal adenocarcinoma.

In Barrett's esophagus, the precursor to esophageal adenocarcinoma, the squamocolumnar junction (SCJ) between the normal esophagus and the stomach like mucosa is proximally displaced. Currently it can be detected only by an expensive upper GI endoscopic procedure. We have developed a minimally invasive and easy to operate colorimetric instrument for the low-cost detection of Barrett's esophagus. The instrument is based on a flexible, narrow diameter, fiber-optic probe that performs a colorimetric scan of the esophageal lumen. The instrument was clinically evaluated in 50 subjects. The instrument could identify both symmetric and asymmetric SCJ's. The SCJ locations determined by the colorimetric instrument correlated strongly (R2 = 0.89) with those determined by endoscopy. The instrument identified the SCJ locations accurately (Mean of difference +/- SEM: 0.97 +/- 1.72 cm) and reproducibly (Mean of absolute difference +/- SEM: 1.33 +/- 1.40 cm). The instrument has a 90% sensitivity of identifying patients with Barrett's esophagus, based on the clinical algorithm that if the SCJ is located at a distance less than 37 cm from the teeth, then the subject has Barrett's esophagus, otherwise the subject does not have Barrett's esophagus. In conclusion, the colorimetric instrument has the potential of being a cost-effective way of determining patients likely to have Barrett's esophagus in the population.

Do angiogenesis and growth factor expression predict prognosis of esophageal cancer?

A retrospective study of surgically resectable esophageal cancers was undertaken to determine the relationship between angiogenesis score and growth factor expression with tumor size, histology, degree of differentiation, depth of invasion, nodal disease, and the presence of Barrett's esophagus. The office and hospital charts of 27 patients who had esophageal resection for carcinoma between 1990 and 1995 at Rush-Presbyterian-St. Luke's Medical Center were reviewed. Data collection included patient demographics, survival, tumor size, histology, differentiation, depth of invasion, nodal metastases, and the presence of Barrett's esophagus. The pathology specimens were immunostained for von Willebrand factor (factor VIII-related antigen). Immunostaining was also performed for vascular endothelial growth factor and transforming growth factor alpha. Twenty normal esophageal specimens served as controls. Angiogenesis score was determined by counting vessels under conventional light microscopy at x200 magnification, and growth factor expression was graded on a scale of 1 to 4. Cancers had higher angiogenesis and growth factor expression than controls (P = 0.01). Patient age, tumor size, histology, differentiation, depth of invasion, and Barrett's esophagus did not correlate with angiogenesis score or tumor growth factor expression. Lymph node status did correlate with both angiogenesis score and growth factor expression (P < or = 0.02). We conclude that high angiogenesis score and growth factor expression correlate with the presence of lymph node metastases. This may help select patients for preoperative radiation and chemotherapy or determine the extent of surgery performed for esophageal carcinoma.