Good manufacturing practice-compliant validation and preparation of BM cells for the therapy of acute myocardial infarction

BACKGROUND: Intracoronary application of BM-derived cells for the treatment of acute myocardial infarction (AMI) is currently being studied intensively. Simultaneously, strict legal requirements surround the production of cells for clinical studies. Thus good manufacturing practice (GMP)-compliant collection and preparation of BM for patients with AMI was established by the Cytonet group. METHODS: As well as fulfillment of standard GMP requirements, including a manufacturing license, validation of the preparation process and the final product was performed. Whole blood (n=6) and BM (n=3) validation samples were processed under GMP conditions by gelafundin or hydroxyethylstarch sedimentation in order to reduce erythrocytes/platelets and volume and to achieve specifications defined in advance. Special attention was paid to the free potassium (<6 mmol/L), some rheologically relevant cellular characteristics (hematocrit <0.45, platelets <450 x 10(6)/mL) and the sterility of the final product. RESULTS: The data were reviewed and GMP compliance was confirmed by the German authorities (Paul-Ehrlich Institute). Forty-five BM cell preparations for clinical use were carried out following the validated methodology and standards. Additionally three selections of CD34+ BM cells for infusion were performed. All specification limits were met. Discussion In conclusion, preparation of BM cells for intracoronary application is feasible under GMP conditions. As the results of sterility testing may not be available at the time of intracoronary application, the highest possible standards to avoid bacterial and other contaminations have to be applied. The increased expense of the GMP-compliant process can be justified by higher safety for patients and better control of the final product.

Non-invasive measurement of steroids in fish-holding water: important considerations when applying the procedure to behaviour studies

Fish behaviourists are increasingly turning to non-invasive measurement of steroid hormones in holding water, as opposed to blood plasma. When some of us met at a workshop in Faro, Portugal, in September, 2007, we realised that there were still many issues concerning the application of this procedure that needed resolution, including: Why do we measure release rates rather than just concentrations of steroids in the water? How does one interpret steroid release rates when dealing with fish of different sizes? What are the merits of measuring conjugated as well as free steroids in water? In the ‘static’ sampling procedure, where fish are placed in a separate container for a short period of time, does this affect steroid release—and, if so, how can it be minimised? After exposing a fish to a behavioural stimulus, when is the optimal time to sample? What is the minimum amount of validation when applying the procedure to a new species? The purpose of this review is to attempt to answer these questions and, in doing so, to emphasize that application of the non-invasive procedure requires more planning and validation than conventional plasma sampling. However, we consider that the rewards justify the extra effort.

Validation of the LittlEARS((R)) Auditory Questionnaire in children with normal hearing

OBJECTIVES: With more children receiving cochlear implants during infancy, there is a need for validated assessments of pre-verbal and early verbal auditory skills. The LittlEARS Auditory Questionnaire is presented here as the first module of the LittlEARS test battery. The LittlEARS Auditory Questionnaire was developed and piloted to assess the auditory behaviour of normal hearing children and hearing impaired children who receive a cochlear implant or hearing aid prior to 24 months of age. This paper presents results from two studies: one validating the LittlEARS Auditory Questionnaire on children with normal hearing who are German speaking and a second validating the norm curves found after adaptation and administration of the questionnaire to children with normal hearing in 15 different languages. METHODS: Scores from a group of 218 German and Austrian children with normal hearing between 5 days and 24 months of age were used to create a norm curve. The questionnaire was adapted from the German original into English and then 15 other languages to date. Regression curves were found based on parental responses from 3309 normal hearing infants and toddlers. Curves for each language were compared to the original German validation curve. RESULTS: The results of the first study were a norm curve which reflects the age-dependence of auditory behaviour, reliability and homogeneity as a measure of auditory behaviour, and calculations of expected and critical values as a function of age. Results of the second study show that the regression curves found for all the adapted languages are essentially equal to the German norm curve, as no statistically significant differences were found. CONCLUSIONS: The LittlEARS Auditory Questionnaire is a valid, language-independent tool for assessing the early auditory behaviour of infants and toddlers with normal hearing. The results of this study suggest that the LittlEARS Auditory Questionnaire could also be very useful for documenting children's progress with their current amplification, providing evidence of the need for implantation, or highlighting the need for follow-up in other developmental areas.

Quantitative high-resolution warm season rainfall recorded in varved sediments of Lake Oeschinen, northern Swiss Alps: calibration and validation AD 1901–2008

High-resolution, well-calibrated records of lake sediments are critically important for quantitative climate reconstructions, but they remain a methodological and analytical challenge. While several comprehensive paleotemperature reconstructions have been developed across Europe, only a few quantitative high-resolution studies exist for precipitation. Here we present a calibration and verification study of lithoclastic sediment proxies from proglacial Lake Oeschinen (46°30′N, 7°44′E, 1,580 m a.s.l., north–west Swiss Alps) that are sensitive to rainfall for the period AD 1901–2008. We collected two sediment cores, one in 2007 and another in 2011. The sediments are characterized by two facies: (A) mm-laminated clastic varves and (B) turbidites. The annual character of the laminae couplets was confirmed by radiometric dating (210Pb, 137Cs) and independent flood-layer chronomarkers. Individual varves consist of a dark sand-size spring-summer layer enriched in siliciclastic minerals and a lighter clay-size calcite-rich winter layer. Three subtypes of varves are distinguished: Type I with a 1–1.5 mm fining upward sequence; Type II with a distinct fine-sand base up to 3 mm thick; and Type III containing multiple internal microlaminae caused by individual summer rainstorm deposits. Delta-fan surface samples and sediment trap data fingerprint different sediment source areas and transport processes from the watershed and confirm the instant response of sediment flux to rainfall and erosion. Based on a highly accurate, precise and reproducible chronology, we demonstrate that sediment accumulation (varve thickness) is a quantitative predictor for cumulative boreal alpine spring (May–June) and spring/summer (May–August) rainfall (rMJ = 0.71, rMJJA = 0.60, p < 0.01). Bootstrap-based verification of the calibration model reveals a root mean squared error of prediction (RMSEPMJ = 32.7 mm, RMSEPMJJA = 57.8 mm) which is on the order of 10–13 % of mean MJ and MJJA cumulative precipitation, respectively. These results highlight the potential of the Lake Oeschinen sediments for high-resolution reconstructions of past rainfall conditions in the northern Swiss Alps, central and eastern France and south-west Germany.

An integrated system for 3D hip joint reconstruction from 2D X-rays: a preliminary validation study

The acquisition of conventional X-ray radiographs remains the standard imaging procedure for the diagnosis of hip-related problems. However, recent studies demonstrated the benefit of using three-dimensional (3D) surface models in the clinical routine. 3D surface models of the hip joint are useful for assessing the dynamic range of motion in order to identify possible pathologies such as femoroacetabular impingement. In this paper, we present an integrated system which consists of X-ray radiograph calibration and subsequent 2D/3D hip joint reconstruction for diagnosis and planning of hip-related problems. A mobile phantom with two different sizes of fiducials was developed for X-ray radiograph calibration, which can be robustly detected within the images. On the basis of the calibrated X-ray images, a 3D reconstruction method of the acetabulum was developed and applied together with existing techniques to reconstruct a 3D surface model of the hip joint. X-ray radiographs of dry cadaveric hip bones and one cadaveric specimen with soft tissue were used to prove the robustness of the developed fiducial detection algorithm. Computed tomography scans of the cadaveric bones were used to validate the accuracy of the integrated system. The fiducial detection sensitivity was in the same range for both sizes of fiducials. While the detection sensitivity was 97.96% for the large fiducials, it was 97.62% for the small fiducials. The acetabulum and the proximal femur were reconstructed with a mean surface distance error of 1.06 and 1.01 mm, respectively. The results for fiducial detection sensitivity and 3D surface reconstruction demonstrated the capability of the integrated system for 3D hip joint reconstruction from 2D calibrated X-ray radiographs.

Validation of middle-atmospheric campaign-based water vapour measured by the ground-based microwave radiometer MIAWARA-C

Middle atmospheric water vapour can be used as a tracer for dynamical processes. It is mainly measured by satellite instruments and ground-based microwave radiometers. Ground-based instruments capable of measuring middle-atmospheric water vapour are sparse but valuable as they complement satellite measurements, are relatively easy to maintain and have a long lifetime. MIAWARA-C is a ground-based microwave radiometer for middle-atmospheric water vapour designed for use on measurement campaigns for both atmospheric case studies and instrument intercomparisons. MIAWARA-C's retrieval version 1.1 (v1.1) is set up in a such way as to provide a consistent data set even if the instrument is operated from different locations on a campaign basis. The sensitive altitude range for v1.1 extends from 4 hPa (37 km) to 0.017 hPa (75 km). For v1.1 the estimated systematic error is approximately 10% for all altitudes. At lower altitudes it is dominated by uncertainties in the calibration, with altitude the influence of spectroscopic and temperature uncertainties increases. The estimated random error increases with altitude from 5 to 25%. MIAWARA-C measures two polarisations of the incident radiation in separate receiver channels, and can therefore provide two measurements of the same air mass with independent instrumental noise. The standard deviation of the difference between the profiles obtained from the two polarisations is in excellent agreement with the estimated random measurement error of v1.1. In this paper, the quality of v1.1 data is assessed for measurements obtained at two different locations: (1) a total of 25 months of measurements in the Arctic (Sodankylä, 67.37° N, 26.63° E) and (2) nine months of measurements at mid-latitudes (Zimmerwald, 46.88° N, 7.46° E). For both locations MIAWARA-C's profiles are compared to measurements from the satellite experiments Aura MLS and MIPAS. In addition, comparisons to ACE-FTS and SOFIE are presented for the Arctic and to the ground-based radiometer MIAWARA for the mid-latitude campaigns. In general, all intercomparisons show high correlation coefficients, confirming the ability of MIAWARA-C to monitor temporal variations of the order of days. The biases are generally below 13% and within the estimated systematic uncertainty of MIAWARA-C. No consistent wet or dry bias is identified for MIAWARA-C. In addition, comparisons to the reference instruments indicate the estimated random error of v1.1 to be a realistic measure of the random variation on the retrieved profile between 45 and 70 km.

Development and Validation of a Symptom-Based Activity Index for Adults with Eosinophilic Esophagitis

BACKGROUND & Aims: Standardized instruments are needed to assess the activity of eosinophilic esophagitis (EoE), to provide endpoints for clinical trials and observational studies. We aimed to develop and validate a patient-reported outcome (PRO) instrument and score, based on items that could account for variations in patients' assessments of disease severity. We also evaluated relationships between patients' assessment of disease severity and EoE-associated endoscopic, histologic, and laboratory findings. METHODS We collected information from 186 patients with EoE in Switzerland and the US (69.4% male; median age, 43 years) via surveys (n = 135), focus groups (n = 27), and semi-structured interviews (n = 24). Items were generated for the instruments to assess biologic activity based on physician input. Linear regression was used to quantify the extent to which variations in patient-reported disease characteristics could account for variations in patients' assessment of EoE severity. The PRO instrument was prospectively used in 153 adult patients with EoE (72.5% male; median age, 38 years), and validated in an independent group of 120 patients with EoE (60.8% male; median age, 40.5 years). RESULTS Seven PRO factors that are used to assess characteristics of dysphagia, behavioral adaptations to living with dysphagia, and pain while swallowing accounted for 67% of the variation in patients' assessment of disease severity. Based on statistical consideration and patient input, a 7-day recall period was selected. Highly active EoE, based on endoscopic and histologic findings, was associated with an increase in patient-assessed disease severity. In the validation study, the mean difference between patient assessment of EoE severity and PRO score was 0.13 (on a scale from 0 to 10). CONCLUSIONS We developed and validated an EoE scoring system based on 7 PRO items that assesses symptoms over a 7-day recall period. Clinicaltrials.gov number: NCT00939263.

The Career Engagement Scale: Development and validation of a measure of proactive career behaviors

Careers today increasingly require engagement in proactive career behaviors; however, there is a lack of validated measures assessing the general degree to which somebody is engaged in such career behaviors. We describe the results of six studies with six independent samples of German university students (total N = 2,854), working professionals (total N = 561), and university graduates (N = 141) that report the development and validation of the Career Engagement Scale - a measure of the degree of which somebody is proactively developing her or his career as expressed by diverse career behaviors. The studies provide supprt for measurement invariance across gender and time. In support of convergent and discriminant validity, we find that career engagement is more prevalent among working professionals than among university students and that this scale has incremental validity above several specific career behaviors regarding its relation to vocational identity clarity and career self-efficacy beliefs among students and to job and career satisfaction among employees. In support of incremental predictive validity, beyond the effects of several more specific careeer behaviors, career engagement while at university predicts higher job and career satisfaction several months later after beginning work.

Validation of the IMPACT-III quality of life questionnaire in Swiss children with inflammatory bowel disease

BACKGROUND AND AIMS Inflammatory bowel disease (IBD) frequently manifests during childhood and adolescence. For providing and understanding a comprehensive picture of a patients' health status, health-related quality of life (HRQoL) instruments are an essential complement to clinical symptoms and functional limitations. Currently, the IMPACT-III questionnaire is one of the most frequently used disease-specific HRQoL instrument among patients with IBD. However, there is a lack of studies examining the validation and reliability of this instrument. METHODS 146 paediatric IBD patients from the multicenter Swiss IBD paediatric cohort study database were included in the study. Medical and laboratory data were extracted from the hospital records. HRQoL data were assessed by means of standardized questionnaires filled out by the patients in a face-to-face interview. RESULTS The original six IMPACT-III domain scales could not be replicated in the current sample. A principal component analysis with the extraction of four factor scores revealed the most robust solution. The four factors indicated good internal reliability (Cronbach's alpha=.64-.86), good concurrent validity measured by correlations with the generic KIDSCREEN-27 scales and excellent discriminant validity for the dimension of physical functioning measured by HRQoL differences for active and inactive severity groups (p<.001, d=1.04). CONCLUSIONS This study with Swiss children with IBD indicates good validity and reliability for the IMPACT-III questionnaire. However, our findings suggest a slightly different factor structure than originally proposed. The IMPACT-III questionnaire can be recommended for its use in clinical practice. The factor structure should be further examined in other samples.

Taking personalized medicine seriously: Biomarker approaches in phase IIb/III studies in major depression and schizophrenia

The success rate in the development of psychopharmacological compounds is insufficient. Two main reasons for failure have been frequently identified: 1) treating the wrong patients and 2) using the wrong dose. This is potentially based on the known heterogeneity among patients, both on a syndromal and a biological level. A focus on personalized medicine through better characterization with biomarkers has been successful in other therapeutic areas. Nevertheless, obstacles toward this goal that exist are 1) the perception of a lack of validation, 2) the perception of an expensive and complicated enterprise, and 3) the perception of regulatory hurdles. The authors tackle these concerns and focus on the utilization of biomarkers as predictive markers for treatment outcome. The authors primarily cover examples from the areas of major depression and schizophrenia. Methodologies covered include salivary and plasma collection of neuroendocrine, metabolic, and inflammatory markers, which identified subgroups of patients in the Netherlands Study of Depression and Anxiety. A battery of vegetative markers, including sleep-electroencephalography parameters, heart rate variability, and bedside functional tests, can be utilized to characterize the activity of a functional system that is related to treatment refractoriness in depression (e.g., the renin-angiotensin-aldosterone system). Actigraphy and skin conductance can be utilized to classify patients with schizophrenia and provide objective readouts for vegetative activation as a functional marker of target engagement. Genetic markers, related to folate metabolism, or folate itself, has prognostic value for the treatment response in patients with schizophrenia. Already, several biomarkers are routinely collected in standard clinical trials (e.g., blood pressure and plasma electrolytes), and appear to be differentiating factors for treatment outcome. Given the availability of a wide variety of markers, the further development and integration of such markers into clinical research is both required and feasible in order to meet the benefit of personalized medicine. This article is based on proceedings from the "Taking Personalized Medicine Seriously-Biomarker Approaches in Phase IIb/III Studies in Major Depression and Schizophrenia" session, which was held during the 10th Annual Scientific Meeting of the International Society for Clinical Trials Meeting (ISCTM) in Washington, DC, February 18 to 20, 2014.

Introduction to the Maïdo Lidar Calibration Campaign dedicated to the validation of upper air meteorological parameters

The first operations at the new High-altitude Maïdo Observatory at La Réunion began in 2013. The Maïdo Lidar Calibration Campaign (MALICCA) was organized there in April 2013 and has focused on the validation of the thermodynamic parameters (temperature, water vapor, and wind) measured with many instruments including the new very large lidar for water vapor and temperature profiles. The aim of this publication consists of providing an overview of the different instruments deployed during this campaign and their status, some of the targeted scientific questions and associated instrumental issues. Some specific detailed studies for some individual techniques were addressed elsewhere. This study shows that temperature profiles were obtained from the ground to the mesopause (80 km) thanks to the lidar and regular meteorological balloon-borne sondes with an overlap range showing good agreement. Water vapor is also monitored from the ground to the mesopause by using the Raman lidar and microwave techniques. Both techniques need to be pushed to their limit to reduce the missing range in the lower stratosphere. Total columns obtained from global positioning system or spectrometers are valuable for checking the calibration and ensuring vertical continuity. The lidar can also provide the vertical cloud structure that is a valuable complementary piece of information when investigating the water vapor cycle. Finally, wind vertical profiles, which were obtained from sondes, are now also retrieved at Maïdo from the newly implemented microwave technique and the lidar. Stable calibrations as well as a small-scale dynamical structure are required to monitor the thermodynamic state of the middle atmosphere, ensure validation of satellite sensors, study the transport of water vapor in the vicinity of the tropical tropopause and study their link with cirrus clouds and cyclones and the impact of small-scale dynamics (gravity waves) and their link with the mean state of the mesosphere.

Development and preliminary validation of the cancer family impact scale for colorectal cancer

This study aimed to develop and validate The Cancer Family Impact Scale (CFIS), an instrument for use in studies investigating relationships among family factors and colorectal cancer (CRC) screening when family history is a risk factor. We used existing data to develop the measure from 1,285 participants (637 families) across the United States who were in the Johns Hopkins Colon Cancer Genetic Testing study. Participants were 94% white with an average age of 50.1 years, and 60% were women. None had a personal CRC history, and eighty percent had 1 FDR with CRC and 20% had more than one FDR with CRC. The study had three aims: (1) to identify the latent factors underlying the CFIS via exploratory factor analysis (EFA); (2) to confirm the findings of the EFA via confirmatory factor analysis (CFA); and (3) to assess the reliability of the scale via Cronbach's alpha. Exploratory analyses were performed on a split half of the sample, and the final model was confirmed on the other half. The EFA suggested the CFIS was an 18-item measure with 5 latent constructs: (1) NEGATIVE: negative effects of cancer on the family; (2) POSITIVE: positive effects of cancer on the family; (3) COMMUNICATE: how families communicate about cancer; (4) FLOW: how information about cancer is conveyed in families; and (5) NORM: how individuals react to family norms about cancer. CFA on the holdout sample showed the CFIS to have a reasonably good fit (Chi-square = 389.977, df = 122, RMSEA= 0.058 (.052-.065), CFI=.902, TLI=.877, GF1=.939). The overall reliability of the scale was α=0.65. The reliability of the subscales was: (1) NEGATIVE α = 0.682; (2) POSITIVE α = 0.686; (3) COMMUNICATE α = 0.723; (4) FLOW α = 0.467; and (5) NORM α = 0.732. ^ We concluded the CFIS to be a good measure with most fit levels over 0.90. The CFIS could be used to compare theoretically driven hypotheses about the pathways through which family factors could influence health behavior among unaffected individuals at risk due to family history, and also aid in the development and evaluation of cancer prevention interventions including a family component. ^

Psychosocial measures reported by parents in studies of skin cancer prevention

Background. Because it is important to minimize children's sun exposure to reduce skin cancer risk, much of the extensive skin cancer prevention literature consists of studies of children's sun protection, sun avoidance and ultraviolet radiation (UVR) exposure. Little attention has been focused on the measurement of psychosocial constructs in these studies. Identification of the psychosocial correlates or determinants of children's skin cancer risk or risk-reduction behavior is critical to more fully understand and predict behavior. Furthermore, psychosocial variables may be influenced by interventions to reduce risk. Thus, it is important to examine the psychosocial measures used in studies of children's skin cancer prevention. Information on the validity and reliability of psychosocial measures may increase confidence in study findings based on these measures. In particular, self-efficacy and barriers are key constructs in several major theoretical frameworks and parental measures have been associated with children's sun protection. However, there is conceptual overlap of self-efficacy and barriers measures and little is known about the psychometric properties of these measures.^ Study Aims and Methods. The overall goal of this dissertation was to examine the measurement of psychosocial constructs relevant to children's skin cancer prevention. Because children depend primarily on their parents for skin cancer prevention, measures of parents' psychosocial constructs are the focus. Study 1 was a systematic review of parental psychosocial measures used in studies of children's sun protection, sun avoidance and UVR exposure. The specific aims of Study 1 were to (1) describe psychosocial measures reported by parents, including available information on the psychometric properties of these measures and their use in analyses and (2) provide recommendations for the development, refinement and standardized reporting of measures. ^ Study 2 examined the psychometric properties of measures of parental self-efficacy and barriers regarding children's sun protection. Melanoma patients (N=205) who were parents of children ≤ 12 years of age completed a telephone interview that included self-efficacy and barriers measures specific to sunscreen, clothing, shade and limiting time outdoors. The specific aims of Study 2 were to (1) use a confirmatory factor analytic approach to examine the factorial validity of parental self-efficacy and barriers measures, (2) examine the convergent and discriminant validity of behavior-specific measures of self-efficacy and barriers and (3) assess the reliability of item and scale measures.^ Results. In Study 1, a search of standard databases yielded 48 eligible studies. Most studies assessed only one or two psychosocial constructs. Knowledge was measured most frequently. There was little discussion of measure source, development, theoretical background or psychometric properties, besides internal consistency reliability. There was conceptual overlap of some measures. In Study 2, confirmatory factor analytic findings supported the factorial validity of the self-efficacy and barriers measures. When all eight self-efficacy and barriers measures were included in the same model, a modified eight-factor model adequately fit the data, providing preliminary evidence that the measures are distinct. Measure associations supported the convergent validity of all measures and the discriminant validity of most measures. The self-efficacy and barriers measures were reliable.^ Conclusions. Recommendations based on the literature review include developing and refining psychosocial measures based on theory. Describing a measure's theoretical basis and psychometric properties would facilitate critical evaluation. Standardized reporting of source, development, theory, construct, items and analytic role would facilitate comparison of findings, continual refinement and future applications of measures. In the validation study, self-efficacy and barriers measures were examined in a sample of parents with a personal history of melanoma. Findings suggested that these measures are valid and reliable for use in studies of children's sun protection. There was preliminary evidence that these measures are distinct but additional study is needed. ^

Mistreatment and self-neglect in community dwelling older adults: Studies of construct validity, measurement invariance and latent classes

Mistreatment and self-neglect significantly increase the risk of dying in older adults. It is estimated that 1 to 2 million older adults experience elder mistreatment and self-neglect every year in the United States. Currently, there are no elder mistreatment and self-neglect assessment tools with construct validity and measurement invariance testing and no studies have sought to identify underlying latent classes of elder self-neglect that may have differential mortality rates. Using data from 11,280 adults with Texas APS substantiated elder mistreatment and self-neglect 3 studies were conducted to: (1) test the construct validity and (2) the measurement invariance across gender and ethnicity of the Texas Adult Protective Services (APS) Client Assessment and Risk Evaluation (CARE) tool and (3) identify latent classes associated with elder self-neglect. Study 1 confirmed the construct validity of the CARE tool following adjustments to the initial hypothesized CARE tool. This resulted in the deletion of 14 assessment items and a final assessment with 5 original factors and 43 items. Cross-validation for this model was achieved. Study 2 provided empirical evidence for factor loading and item-threshold invariance of the CARE tool across gender and between African-Americans and Caucasians. The financial status domain of the CARE tool did not function properly for Hispanics and thus, had to be deleted. Subsequent analyses showed factor loading and item-threshold invariance across all 3 ethnic groups with the exception of some residual errors. Study 3 identified 4-latent classes associated with elder self-neglect behaviors which included individuals with evidence of problems in the areas of (1) their environment, (2) physical and medical status, (3) multiple domains and (4) finances. Overall, these studies provide evidence supporting the use of APS CARE tool for providing unbiased and valid investigations of mistreatment and neglect in older adults with different demographic characteristics. Furthermore, the findings support the underlying notion that elder self-neglect may not only occur along a continuum, but that differential types may exist. All of which, have very important potential implications for social and health services distributed to vulnerable mistreated and neglected older adults.^