Inflated Clinical Evaluations: a Comparison of Faculty-Selected and Mathematically Calculated Overall Evaluations Based on Behaviorally Anchored Assessment Data.

OBJECTIVE: This retrospective study compared faculty-selected evaluation scores with those mathematically calculated from behaviorally anchored assessments. METHODS: Data from 1036 psychiatry clerkship clinical evaluations (2012-2015) was reviewed. These clinical evaluations required faculty to assess clinical performance using 14 behaviorally anchored questions followed by a faculty-selected overall evaluation. An explicit rubric was included in the overall evaluation to assist the faculty in interpreting their 14 assessment responses. Using the same rubric, mathematically calculated evaluations of the same assessment responses were generated and compared to the faculty-selected evaluations. RESULTS: Comparison of faculty-selected to mathematically calculated evaluations revealed that while the two methods were reliably correlated (Cohen's kappa = 0.314, Pearson's coefficient = 0.658, p < 0.001), there was a notable difference in the results (t = 24.5, p < 0.0001). The average faculty-selected evaluation was 1.58 (SD = 0.61) with a mode of "1" or "outstanding," while the mathematically calculated evaluation had an average of 2.10 (SD = 0.90) with a mode of "3" or "satisfactory." 51.0% of the faculty-selected evaluations matched the mathematically calculated results: 46.1% were higher and 2.9% were lower. CONCLUSIONS: Clerkship clinical evaluation forms that require faculty to make an overall evaluation generate results that are significantly higher than what would have been assigned solely using behavioral anchored assessment questions. Focusing faculty attention on assessing specific behaviors rather than overall evaluations may reduce this inflation and improve validity. Clerkships may want to consider removing overall evaluation questions from their clinical evaluation tools.

UK Role 4 military infectious diseases and tropical medicine cases in 2005-2013.

INTRODUCTION: Infectious diseases are a frequent cause of morbidity among British troops. The aim of this paper is to describe the spectrum of infectious diseases seen when UK service personnel are evacuated for definitive care to the Role 4 Medical Treatment Facility based at Birmingham Heartlands Hospital. METHOD: A retrospective analysis of all military patients presenting with infectious diseases and treated at Birmingham Heartlands Hospital between 14 April 2005 and 31 December 2013 was undertaken. RESULTS: During this period, 502 patients were identified. Infections originated in 49 countries, most commonly Afghanistan (46% cases), the UK (10% cases) and Belize (9% of cases). The most common presentations were dermatological conditions, gastroenterological illnesses and undifferentiated fevers. CONCLUSION: UK service personnel in significant numbers continue to suffer a wide range of infectious diseases, acquired throughout the globe, which often require specialist tertiary infection services to diagnose and manage. Future prospective data collection is recommended to identify trends, which in turn will inform military training needs and future research priorities in the Defence Medical Services (DMS) and allows development of appropriate policies and clinical guidelines for management of DMS personnel with infectious diseases.

COVID-19: responding to a pandemic on Operation TORAL.

Operation TORAL was the UK's contribution to NATO's Operation RESOLUTE SUPPORT in Kabul, Afghanistan. Approximately 1000 British troops were deployed in Kabul when the arrival of the COVID-19 pandemic in Afghanistan was declared. This article will describe the challenges faced due to COVID-19 in Kabul.Medical planning considerations, occupational health issues, implementation of behaviour change and operating as part of a multinational organisation are all discussed, with challenges encountered detailed and potential solutions offered. The use of a suggested framework for ensuring the medical estimate process covered all areas relevant to an emerging viral pandemic -the 4Ds and 4Cs approach-proved particularly useful in the early stages of the pandemic in Afghanistan.

Control of three gastrointestinal illness outbreaks in a British Role 1 facility in Afghanistan: a primary care perspective.

INTRODUCTION: In 2019, Camp Qargha (QAA), a British-led multinational military camp in Kabul, had three of the largest outbreaks of gastrointestinal illness (GI) experienced by the British Military since 2003. This paper discusses the incidence, the response of the British-led Role 1 (R1) medical treatment facility, identifies potential causative and exacerbating factors, and explains the control measures initiated. METHOD: GI in QAA results in local and UK military-wide data collection including in the form of local GI questionnaires, FMed85 forms and EpiNATO returns. The data from these was used to identify trends during and after outbreaks and produce environmental health (EH) and local outbreak reports. RESULTS: Overall, among the outbreaks 56% of stool samples tested positive for norovirus. In each outbreak incidence peaked within the first 3 days, and hardened multiperson rooms were worst affected. 206 patient presentations occurred during the three outbreaks, 706 working days were lost in isolation, with QAA shut down while in quarantine for 27 days. DISCUSSION: Significant strain was placed on QAA and the R1. Causative factors may include close interaction with the local national (LN) population, a high population density and accommodation being limited by specific national infrastructure protocols in an operational environment. CONCLUSION: Early recognition of GI, positive standard operating procedures and good hygiene habits are essential to prevent the spread of GI such as norovirus. An early awareness of LN population illness patterns will allow the R1 and command to be better prepared for outbreaks in the future.

Rapid calibration of near-infrared spectroscopic measurements of mammalian cell cultivations.

Near-infrared (NIR) spectroscopy is a flexible method that can be employed to noninvasively monitor the concentrations of multiple nutrients and wastes in mammalian cell bioreactors. Development of suitable calibrations can be a labor- and time-intensive process that must be repeated when process conditions are altered significantly. To address this difficulty, we have produced a new approach for generating NIR spectroscopic calibrations that requires significantly less time compared with standard calibration schemes. This method reduces development time from the present level of several weeks to several hours. A small number of experimentally collected spectra serve as inputs to a computational procedure that yields a large number of simulated spectra, each containing both analyte-specific and analyte-independent information. Such simulated spectra may be employed as a calibration set for quantifying analytes in experimentally collected spectra. Spectroscopic measurements of the concentrations of five components (ammonia, glucose, glutamate, glutamine, and lactate) can be accomplished with levels of error similar to those obtained with full experimental calibrations. A key to this process is the utilization of random numbers, which randomizes the influence of natural variations, present in each experimentally collected spectrum, on the resultant composite spectrum. This approach may increase the feasibility of employing NIR spectroscopy to monitor bioreactors and other biological processes subjected to varying operating conditions.

Effect of oxygen limitations on monoclonal antibody production by immobilized hybridoma cells.

The productivity of an immobilized cell biocatalyst is often limited by the amount of oxygen that reaches cells located at interior regions of the biocatalyst. These diffusive limitations depend on a multitude of factors including the oxygen supply, the cellular uptake kinetics, and the cell density of the material. Large cell densities, which are desired for high productivity, are also likely to reduce the percentage of cells that receive an adequate supply of oxygen. To develop a better understanding of how different conditions affect biocatalyst behavior, a computational model of immobilized hybridoma cells was developed. The model accounts for oxygen diffusion and consumption, cell proliferation and death, and monoclonal antibody production. This model assumes that cellular productivity is limited only by the supply of oxygen and that the growth media is continually replenished so that nutrient levels remain high and wastes are eliminated. Biocatalyst performance is evaluated by monitoring the amount of monoclonal antibody produced by the cells. Model predictions agree with experimental measurements reported in the literature and indicate that for long operation time the supply of oxygen, biocatalyst size, and cell kinetics have a significant effect on biocatalyst performance, whereas the initial cell loading has only a relatively small effect. Under typical culture conditions, we find that oxygen penetrates to a maximum depth of about 0.4 mm. Accordingly, cells immobilized farther than this threshold distance receive an insufficient supply of oxygen.

Adaptive calibration scheme for quantification of nutrients and byproducts in insect cell bioreactors by near-infrared spectroscopy.

Spectroscopic methods are gaining in popularity in biotechnology because of their ability to deliver rapid, noninvasive measurements of the concentrations of multiple chemical species. Such measurements are particularly necessary for the implementation of control schemes for cell culture bioreactors. One of the major challenges to the development of spectroscopic methods for bioreactor monitoring is the generation of accurate and robust calibration models, particularly because of the inherent variability of biological processes. We have evaluated several methods of building calibration models, including synthetic calibrations and medium spiking methods. The approach that consistently produced reliable models incorporated samples removed from a bioreactor that were subsequently altered so as to increase the sample variation. Several large volume samples were removed from a bioreactor at varying time points and divided into multiple aliquots to which were added random, known amounts of the analytes of interest. Near-infrared spectra of these samples were collected and used to build calibration models. Such models were used to quantify analyte concentrations from independent samples removed from a second bioreactor. Prediction errors for alanine, glucose, glutamine, and leucine were 1.4, 1.0, 1.1, and 0.31 mM, respectively. This adaptive calibration method produces models with less error and less bias than observed with other calibration methods. Somewhat more accurate measurements could be attained with calibrations consisting of a combination of synthetic samples and spiked medium samples, but with an increase in calibration development time.

Simultaneous measurement of 19 components in serum-containing animal cell culture media by fourier transform near-infrared spectroscopy.

Animal cell cultures generate maximal amounts of desired products when maintained in a controlled environment with low and constant concentrations of nutrients and wastes. Traditionally this has involved slow addition of glucose and glutamine; however, recent studies have indicated that a number of low concentration amino acids are required to prevent initiation of apoptosis. Therefore, optimal control of animal cell cultures will likely require measurement of a large number of chemical components. We present here the evaluation of a near-infrared spectroscopic (NIRS) monitoring scheme to quantify 19 cellular nutrients and wastes in culture medium with and without serum. The components include glucose, lactate, ammonia, pyruvate, glutamine, and 14 other amino acids. Spectroscopic calibrations were generated for a synthetic version of a standard culture medium (DMEM) in which the concentrations of 17 DMEM components and ammonia and lactate were varied in a random fashion. This randomization provides a stringent evaluation of the measurement scheme. Reasonably accurate measurements of these 19 components could be accomplished in the absence or presence of 10% horse serum by volume with percent errors ranging from 3% to 37%. Analytes with concentrations as low as 0.3 mM could be reliably quantified. The presence of serum, when properly included in the calibration, has little effect on measurement error. These results provide an important step toward application of NIRS for monitoring the large number of varying components of animal cell cultivations.

Prescribing of nebulized bronchodilators--can we change bad habits?

The accuracy of prescriptions for bronchodilator drugs was monitored before and after an educational circular to the medical staff of five medical wards. The circular contained model prescriptions for beta-agonists alone and combined with ipratropium bromide. There was a significant improvement overall in the accuracy of prescribing.

In vitro alveolar cytotoxicity of soluble components of airborne particulate matter: effects of serum on toxicity of transition metals.

Respiration of fossil fuel-derived airborne particulate matter (PM) has been linked to various pulmonary disorders. Transition metals contained in such PM, such as zinc, iron and vanadium, have been suggested as the primary culprits in PM-induced pulmonary distress by rat instillation studies. In this study, the cytotoxicity of zinc, iron, and vanadium on confluent monolayers of rat alveolar epithelial cells was evaluated as the inhibition of cellular succinate dehydrogenase metabolic activity as quantified via the MTT assay. In addition, the effect of culture medium serum concentration on the toxicities of these three metals was investigated. Of the three metals tested, zinc was the most toxic, with an EC50 of 0.6 mM in culture medium with 10% serum; vanadium and iron had EC50's of 3 and 4 mM, respectively. Serum in culture medium was found to substantially reduce the apparent toxicity of zinc: EC50's for zinc ranged from 0.6 mM in 10% serum to 0.1 mM in serum-free medium. Zinc toxicity analyses in various culture medium conditions demonstrated that the toxicity-reducing effect of serum was due largely and perhaps entirely, to serum albumin. Some, but not all of the effect of serum and albumin on zinc toxicity is apparently due to zinc-albumin binding.

Alterations of A549 lung cell gene expression in response to biochemical toxins.

Health risks associated with the inhalation of potentially toxic materials have been a topic of great public concern. In vitro cellular analyses can provide mechanistic information on the molecular-level responses of lung-derived cell lines to a variety of these hazards. This understanding may be used to develop methods to reduce the damage from such toxins or to detect early stages of their effects. Here we describe an evaluation of the alterations in gene expression of an immortalized lung cell line (A549, human type II epithelia) to a variety of inhalation health hazards including etoposide, gliotoxin, streptolysin O, methyl methansesulfonate (MMS), and Triton X-100. The A549 cells display a dose-response relationship to each toxin with initial responses including alterations in metabolic activity, increases in membrane permeability, and initiation of response genes. In general, membrane-damaging agents (streptolysin O and Triton X-100) induce production of new ion channel proteins, structural proteins, and metabolic enzymes. Gliotoxin impacted the metabolic machinery, but also altered ion channels. Etoposide and MMS caused alterations in the cell cycle, induced DNA repair enzymes, and initiated apoptotic pathways, but MMS also induced immune response cascades. The mechanism of cell response to each toxin is supported by physiological analyses that indicated a fairly slow initiation of cell response to all compounds tested, except for Triton, which caused rapid decline in cell function due to solubilization of the cell membrane. However, Triton does induce production of a number of cell membrane-associated proteins and so its effects at low concentrations are likely translated throughout the cell. Together these results indicate a broader array of cellular responses to each of the test toxins than have previously been reported.

The effect of analyte concentration range on measurement errors obtained by NIR spectroscopy.

Near infrared spectroscopy (NIRS) was employed to quantify five compounds, ammonium, glucose, glutamate, glutamine, and lactate, in conditions similar to those obtained in animal cell cultivations over varying ranges of analyte concentrations. These components represent the primary nutrients and wastes of animal cells for which such noninvasive monitoring schemes are required for development of accurate control schemes. Ideal cultivation conditions involve maintaining concentrations of these components as low as 1 mM each, however, it is not known if measurements of these compounds can be accurately accomplished at such a low level. We have found that NIRS measurements of these analytes over narrow and low (0-1 mM) concentration ranges yield measurement errors of roughly 11% of the concentration range. By contrast, wide concentration ranges (0-30 mM) yield measurement errors of roughly 1.6% of the concentration range. Decreasing the concentration range over which an analyte is quantified in four out of five cases decreases the optimal spectral range by 100 cm(-1) for measurement by partial least squares regression analysis. There appears a similarity in the ratio of (standard error of prediction (SEP)/concentration range) which may provide an estimation of the anticipated SEP to be obtained for measurement over a new concentration range. It was found that for the five analytes evaluated here, the ratio of SEP to concentration range divided by that obtained for a second concentration range is equal to a fairly constant value of 6.6. This relationship was found to be followed reasonably well by an extensive number of measurement results reported in the literature for similar conditions.

Effects of ammonia and lactate on hybridoma growth, metabolism, and antibody production.

The influence of ammonia and lactate on cell growth, metabolic, and antibody production rates was investigated for murine hybridoma cell line 163.4G5.3 during batch culture. The specific growth rate was reduced by one-half in the presence of an initial ammonia concentration of 4 mM. Increasing ammonia levels accelerated glucose and glutamine consumption, decreased ammonia yield from glutamine, and increased alanine yield from glutamine. Although the amount of antibody produced decreased with increasing ammonia concentration, the specific antibody productivity remained relatively constant around a value of 0.22 pg/cell-h. The specific growth rate was reduced by one-half at an initial lactate concentration of 55 mM. Although specific glucose and glutamine uptake rates were increased at high lacatate concentration, they showed a decrease after making corrections for medium osmolarity. The yield coefficient of lactate from glucose decreased at high lactate concentrations. A similar decrease was observed for the ammonia yield coefficient from glutamine. At elevated lactate concentrations, specific antibody productivities increased, possibly due to the increase in medium osmolarity. The specific oxygen uptake rate was insensitive to ammonia and lactate concentrations. Addition of ammonia and lactate increased the calculated metabolic energy production of the cells. At high ammonia and lactate, the contribution of glycolysis to total energy production increased. Decreasing external pH and increasing ammonia concentrations caused cytoplasmic acidification. Effect of lactate on intracellular pH was insignificant, whereas increasing osmolarity caused cytoplasmic alkalinization.

Noninvasive measurement of effective diffusivities in cell immobilization gels through use of near-infrared spectroscopy.

Encapsulated cell systems provide some advantages over typical suspension cell cultivations as higher cell densities may be obtained; however, the supply of nutrients to the cells often is a limiting factor in productivity. In this study, we describe the development of a new approach to characterize the effective diffusivity of nutrients in immobilized cell materials. Near-infrared spectroscopy is employed to measure nutrient concentrations within a specially designed diffusion chamber that permits noninvasive sampling at ten spatial positions and multiple timepoints. To demonstrate this technique, we measured the effective diffusivity of glutamine in a cell-free 3% (w/w) agarose gel and determined the effective diffusivity (D(eff)) = 6.46 x 10(-10) m(2)/s, which is in good agreement with theoretical values.

A simple correlation for predicting effective diffusivities in immobilized cell systems.

A simple correlation method has been developed to predict effective diffusivities of small molecules in heterogeneous materials such as immobilized cell systems. This correlation uses a single diffusivity measurement at one cell volume fraction to predict diffusivities for any other volume fraction of cell. The method has been applied to 20 sets of published diffusivity measurements in immobilized cell systems and accurately predicts affective diffusivities of molecules for the full range of cell fractions. It may also be used to predict effective diffusivities in heterogeneous materials in which the diffusivity of a molecule in each phase and the volume fraction of each phase are known. (c) 1996 John Wiley & Sons, Inc.

Comparative topical anaesthesia of EMLA and liposome-encapsulated tetracaine.

BACKGROUND: The eutectic mixture of local anaesthetics (EMLA) provides effective topical anaesthesia after a minimum of 60 to 90 min application. Since liposome-encapsulated tetracaine (LET) can provide rapid dermal penetration, the goal of this study was to compare the local anaesthetic effects of EMLA and LET in human volunteers after 60 min application. METHODS: After obtaining institutional approval and informed consent, healthy volunteers were recruited in a double blind, crossover, randomized trial. The study creams (0.5 ml EMLA and 0.5 ml LET 5%) were applied randomly to opposite arms for 60 min. The discomfort of i.v. catheterization was assessed using a visual analogue pain score (VAS). Cutaneous side effects of the creams were recorded. RESULTS: Sixty-one subjects were studied. Twenty-one were excluded because of technical difficulties. Forty subjects completed the study and were included in the data analysis. The mean ( +/- SD) VAS was lower for LET than for EMLA (10.9 +/- 9.0 mm vs 22.7 +/- 17.1 mm, P < 0.001). Erythema secondary to vasodilatation occurred more frequent in the LET group than in the EMLA group (33 vs 3, P < 0.001). One subject with a history of atopy developed a rash at the LET application site. CONCLUSION: Liposome-encapsulated tetracaine can provide a more effective topical anaesthesia than EMLA for intravenous catheterization after 60 min application. Clinical evaluations are necessary to determine the efficacy and safety of LET in providing topical anaesthesia for various invasive percutaneous procedures in other patient populations.

Monte Carlo simulation of diffusion and reaction in two-dimensional cell structures.

Diffusion and reaction processes control the dynamics of many different biological systems. For example, tissue respiration can be limited by the delivery of oxygen to the cells and to the mitochondria. In this case, oxygen is small and travels quickly compared with the mitochondria, which can be considered as immobile reactive traps in the cell cytoplasm. A Monte Carlo theoretical investigation quantifying the interplay of diffusion, reaction, and structure on the reaction rate constant is reported here for diffusible particles in two-dimensional, reactive traps. The placement of traps in overlapping, nonoverlapping, and clustered spatial arrangements can have a large effect on the rate constant when the process is diffusion limited. However, under reaction-limited conditions the structure has little effect on the rate constant. For the same trap fractions and reactivities, nonoverlapping traps have the highest rate constants, overlapping traps yield intermediate rate constants, and clustered traps have the lowest rate constants. An increase in the particle diffusivity in the traps can increase the rate constant by reducing the time required by the particles to reach reactive sites. Various diffusive, reactive, and structural conditions are evaluated here, exemplifying the versatility of the Monte Carlo technique.

Simultaneous measurement of glucose and glutamine in insect cell culture media by near infrared spectroscopy.

The purpose of this study was to develop non-invasive techniques to monitor the composition of cell culture media in insect cell bioreactors. Such a monitor could be used in conjunction with a fed-batch feeding scheme to ensure that cells are maintained in an optimal environment for growth and protein production. Glucose and glutamine concentrations in an insect cell culture bioreactor were determined off-line with near-infrared (NIR) absorption spectroscopy. Spectra were collected from 5000 to 4000 cm(-1) with a 1.5-mm optical path length. Partial least squares (PLS) regression was applied to correlate the collected spectra with the concentration of the desired analytes. Under the culture conditions evaluated here, glucose and glutamine concentrations ranged from 38 to 55 mM and from 3 to 13 mM, respectively. Accurate measurements of glucose and glutamine in insect cell culture samples were possible over these entire ranges. The standard error of prediction (SEP) and mean percent error (MPE) for glutamine were 0.52 mM and 5.3%, respectively. Glucose could be measured with an SEP of 1.30 mM and an MPE of 2.3%. These levels of error are quite low considering the changing complexity of the growth media due to the shifting levels of amino acids, carbohydrates, yeastolate, proteins, and cell debris. This study represents an important step in the development of noninvasive on-line monitoring devices for cell culture bioreactors.