A case study approach to high-containment laboratory workflows promoting sustainability, networking and innovation.

Advances in information technologies (ITs) and operational technologies (OTs) offer high-containment laboratories opportunities to evolve scientific and operational approaches, while increasing efficiency. Emerging technologies steadily introduce changes in data generation and management practices. United States (US) government agencies and partners operate high-containment laboratories that rely on ITs/OTs to provide critical scientific functions that support prevention, detection, response and recovery for catastrophic events. These unique operating environments provide an opportunity for implementation of ITs/OTs that can facilitate both efficiency and deeper or parallel study of disease and associated biological phenomena. Operational study by subject matter experts can aid in identification of requirements and challenges pertaining to emerging ITs/OTs, examination of use cases, refinement of technical specifications and optimisation of workflows. The National Bio and Agro-Defense Facility (NBAF) in the United States of America (USA), slated to be fully operational by 2023, will be a state-of-the-art research and diagnostic facility with Biosafety Level 2, 3 and 4 laboratories for the study of high-consequence transboundary animal pathogens and zoonotic diseases impacting public health. The NBAF will support the diagnosis of emerging diseases, development of countermeasures and transboundary animal disease training. Given the rapid emergence of IT/OT solutions, the authors used a case study approach to analyse and assess real-world, high-containment laboratory functions to help maximise efficiency in mission delivery for the NBAF and the broader high-containment laboratory network. The case study approach described here could be widely adapted to diverse situations characterised by a high rate of change to provide accurate, relevant workflow analyses and optimised recommendations.

Les progrès enregistrés dans les domaines des technologies de l'information (IT) et des technologies opérationnelles (OT) offrent aux laboratoires de confinement à haute sécurité la possibilité de faire évoluer leurs approches scientifiques et opérationnelles tout en gagnant en efficacité. Grâce à ces technologies émergentes, les pratiques de production et de gestion des données sont régulièrement affinées. Les organismes gouvernementaux étatsuniens et leurs partenaires exploitent des laboratoires de confinement à haute sécurité qui font appel aux IT/OT pour mettre en oeuvre des fonctionnalités scientifiques cruciales en appui de la prévention, la détection, l'intervention et le rétablissement en cas de catastrophes. Ces environnements opérationnels uniques offrent la possibilité d'introduire des applications IT/OT afin de faciliter aussi bien l'efficacité des opérations que l'étude plus approfondie ou concomitante d'une maladie et des phénomènes biologiques qui lui sont associés. Des études opérationnelles menées par des spécialistes peuvent contribuer à identifier les exigences et les défis liés aux IT/OT émergentes, à vérifier leurs utilisations concrètes, à affiner les spécifications techniques et à optimiser l'ordonnancement des opérations. Le National Bio and Agro-Defense Facility (NBAF) des états-Unis d'Amérique, qui devrait être pleinement opérationnel d'ici 2023, sera une institution de recherche et de diagnostic de pointe dotée de laboratoires de niveaux de biosécurité 2, 3 et 4 pour l'étude des agents pathogènes responsables de maladies animales transfrontalières à haut risque et des agents zoonotiques à fort impact sur la santé publique. Le NBAF contribuera au diagnostic des maladies émergentes et à l'élaboration de mesures de lutte ; il dispensera également des formations sur les maladies animales transfrontalières. Compte tenu du développement rapide des nouvelles solutions IT/OT, les auteurs ont mis au point une méthode d'études de cas pour l'analyse et l'évaluation des fonctionnalités concrètes des laboratoires de confinement à haute sécurité, destinée à maximiser l'efficacité des prestations du NBAF et du réseau plus large de laboratoires de confinement à haute sécurité. La méthode par études de cas décrite ici pourrait être largement adaptée à diverses situations caractérisées par un niveau élevé de changement, afin de fournir des analyses précises et pertinentes de l'ordonnancement des opérations et d'élaborer des recommandations optimisées.

Los adelantos de las tecnologías de la información (TI) y las tecnologías operativas (TO) ofrecen a los laboratorios de alta contención la posibilidad de transformar sus lógicas y procedimientos de trabajo científico y al mismo tiempo ganar en eficiencia. Progresivamente, a la estela de las nuevas tecnologías, los métodos empleados para generar y gestionar datos van evolucionando. Ciertos organismos públicos estadounidenses administran, junto con entidades colaboradoras, laboratorios de alta contención que dependen de las TI/TO para cumplir una serie de cometidos científicos fundamentales en apoyo de la prevención y detección de sucesos catastróficos, de la respuesta a ellos y de los subsiguientes procesos de recuperación. Estos excepcionales entornos de trabajo ofrecen la posibilidad de implantar TI/TO que a la vez aporten más eficiencia y faciliten un estudio más a fondo o en paralelo de as enfermedades y los fenómenos biológicos asociados a ellas. La realización de estudios operativos a cargo de especialistas en el tema puede ayudar a determinar las necesidades y dificultades que plantean las nuevas TI/TO, a examinar ejemplos de utilización, a afinar las especificaciones técnicas y a optimizar los procesos de trabajo. El órgano nacional de defensa biológica y agrícola (National Bio and Agro-Defense Facility, NBAF) de los Estados Unidos de América, que según las previsiones funcionará a pleno rendimiento en 2023, constituirá un avanzado dispositivo de investigación y diagnóstico al que estarán adscritos laboratorios de nivel 2, 3 y 4 de seguridad biológica para el estudio de agentes patógenos de los animales y enfermedades zoonóticas de carácter transfronterizo y de gran repercusión que afecten a la salud pública. El NBAF secundará el diagnóstico de enfermedades emergentes, la preparación de medidas de lucha y la formación sobre enfermedades animales transfronterizas. Teniendo en cuenta la velocidad a la que surgen soluciones de TI/TO, los autores recurrieron al estudio de ejemplos concretos para analizar y evaluar las funciones que cumplen en el mundo real los laboratorios de alta contención con el objetivo de ayudar al NBAF y a la red general de laboratorios de alta contención a ejercer su cometido con la máxima eficiencia. El método de trabajo aquí descrito, basado en el estudio de casos concretos, podría ser adaptado a diversas situaciones que se caractericen por un alto ritmo de transformaciones para efectuar análisis precisos y pertinentes de los procesos de trabajo y formular recomendaciones optimizadas.

An international study to revise the EORTC questionnaire for assessing quality of life in lung cancer patients.

BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13 was the first module to be used in conjunction with the core questionnaire, the QLQ-C30. Since the publication of the LC13 in 1994, major advances have occurred in the treatment of lung cancer. Given this, an update of the EORTC QLQ-LC13 was undertaken. METHODS: The study followed phases I to III of the EORTC Module Development Guidelines. Phase I generated relevant quality-of-life issues using a mix of sources including the involvement of 108 lung cancer patients. Phase II transformed issues into questionnaire items. In an international multicenter study (phase III), patients completed both the EORTC QLQ-C30 and the 48-item provisional lung cancer module generated in phases I and II. Patients rated each of the items regarding relevance, comprehensibility, and acceptance. Patient ratings were assessed against a set of prespecified statistical criteria. Descriptive statistics and basic psychometric analyses were carried out. RESULTS: The phase III study enrolled 200 patients with histologically confirmed lung cancer from 12 centers in nine countries (Cyprus, Germany, Italy, Israel, Spain, Norway, Poland, Taiwan, and the UK). Mean age was 64 years (39 - 91), 59% of the patients were male, 82% had non-small-cell lung cancer, and 56% were treated with palliative intent. Twenty-nine of the 48 questions met the criteria for inclusion. CONCLUSIONS: The resulting module with 29 questions, thus currently named EORTC QLQ-LC29, retained 12 of the 13 original items, supplemented with 17 items that primarily assess treatment side-effects of traditional and newer therapies.

Impact of place of residence on place of death in Wales: an observational study.

BACKGROUND: Previous research in England showed that deprivation level of a person's place of residence affects the place of death and quality of care received at the end of life. People dying in their preferred place of death has also been shown to act as an indication for high quality of end of life care services and social equality. This study expands on current research to explore the effects of deprivation and place of residence on health related choices and place of death in Wales. METHODS: We used ten years combined mortality statistics from 2005 to 2014 and Welsh Index of Multiple Deprivation rankings for each lower super output area. After accounting for the population's age, the number of deaths in Hospital, Hospice, Home, Care Home, Psychiatric Units, and Elsewhere were compared across deprivation quintiles. RESULTS: Distribution of place of death was found to be concentrated in three places - hospital (60%), home (21%) and care home (13%). Results from this study shows a high number of hospital deaths, especially for more deprived areas, despite being the least preferred place of death. CONCLUSION: This is the first Welsh study investigating place of death in relation to deprivation, which could be of major importance to academics, end of life care providers and policy makers interested in to reduce health care inequality in Wales.

Validation of the EORTC QLQ-BIL21 questionnaire for measuring quality of life in patients with cholangiocarcinoma and cancer of the gallbladder.

BACKGROUND: There is no specific quality of life (QoL) measurement tool to quantify QoL in patients with biliary tract cancer. Quality of life measurement is an increasingly crucial trial end point and is now being incorporated into clinical practice. METHODS: This International Multicentre Phase IV Validation Study assessed the QLQ-BIL21 module in 172 patients with cholangiocarcinoma and 91 patients with cancer of the gallbladder. Patients completed the questionnaire at baseline pretherapy and subsequently at 2 months. Following this, the psychometric properties of reliability, validity, scale structure and responsiveness to change were analysed. RESULTS: Analysis of the QLQ-BIL21 scales showed appropriate reliability with Cronbach's α-coefficients >0.70 for all scales overall. Intraclass correlations exceeded 0.80 for all scales. Convergent validity >0.40 was demonstrated for all items within scales, and discriminant validity was confirmed with values <0.70 for all scales compared with each other. Scale scores changed in accordance with Karnofsky performance status and in response to clinical change. CONCLUSIONS: The QLQ-BIL21 is a valid tool for the assessment of QoL in patients with cholangiocarcinoma and cancer of the gallbladder.

Blood: tests used to assess the physiological and immunological properties of blood.

The properties of blood and the relative ease of access to which it can be retrieved make it an ideal source to gauge different aspects of homeostasis within an individual, form an accurate diagnosis, and formulate an appropriate treatment regime. Tests used to determine blood parameters such as the erythrocyte sedimentation rate, hemoglobin concentration, hematocrit, bleeding and clotting times, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean cell volume, and determination of blood groups are routinely used clinically, and deviations outside the normal range can indicate a range of conditions such as anemia, pregnancy, dehydration, overhydration, infectious disease, cancer, thyroid disease, and autoimmune conditions, to mention a few. As these tests can be performed relatively inexpensively and do not require high levels of technical expertise, they are ideally suited for use in the teaching laboratory, enabling undergraduate students to link theory to practice. The practicals described here permit students to examine their own blood and that of their peers and compare these with clinically accepted normal ranges. At the end of the practicals, students are required to answer a number of questions about their findings and to link abnormal values to possible pathological conditions by answering a series of questions based on their findings.

Classifying the severity of acute pancreatitis: towards a way forward.

BACKGROUND: The recent development of two different severity classifications for acute pancreatitis has appropriately raised questions about which should be used. The aim of this paper is to review the two new severity classifications, outline their differences, review validation studies, and identify gaps in knowledge to suggest a way forward. METHODS: A literature review was performed to identify the purposes and differences between the classifications. Validation studies and those comparing the two different classifications were also reviewed. RESULTS: The Revised Atlanta Classification (RAC) and the Determinants Based Classification (DBC) both rely on assessment of local and systemic factors. The differences between the classifications provides opportunities for further research to improve the accuracy and utility of severity classification. This includes understanding how best to tailor severity classification to setting (e.g. secondary or tertiary hospital) and purpose (e.g. clinical management or research). A key difference is that the RAC does not consider infected pancreatic necrosis an indicator of severe disease. There is also the need to develop methods for the accurate non-invasive diagnosis of infected necrosis and evaluation of the characteristics of organ dysfunction in relation to severity and outcome. CONCLUSION: Further improvement in severity classification is possible and research priorities have been identified. For now, the decision as to which classification to use should be on the basis of setting, validity, accuracy, and ease of use.

Skeletal muscle-specific overexpression of SIRT1 does not enhance whole-body energy expenditure or insulin sensitivity in young mice.

AIMS/HYPOTHESIS: The NAD(+)-dependent protein deacetylase sirtuin (SIRT)1 is thought to be a key regulator of skeletal muscle metabolism. However, its precise role in the regulation of insulin sensitivity is unclear. Accordingly, we sought to determine the effect of skeletal muscle-specific overexpression of SIRT1 on skeletal muscle insulin sensitivity and whole-body energy metabolism. METHODS: At 10 weeks of age, mice with muscle-specific overexpression of SIRT1 and their wild-type littermates were fed a standard diet with free access to chow or an energy-restricted (60% of standard) diet for 20 days. Energy expenditure and body composition were measured by indirect calorimetry and magnetic resonance imaging, respectively. Skeletal muscle insulin-stimulated glucose uptake was measured ex vivo in soleus and extensor digitorum longus muscles using a 2-deoxyglucose uptake technique with a physiological insulin concentration of 360 pmol/l (60 µU/ml). RESULTS: Sirt1 mRNA and SIRT1 protein levels were increased by approximately 100- and 150-fold, respectively, in skeletal muscle of mice with SIRT1 overexpression compared with wild-type mice. Despite this large-scale overexpression of SIRT1, body composition, whole-body energy expenditure, substrate oxidation and voluntary activity were comparable between genotypes. Similarly, skeletal muscle basal and insulin-stimulated glucose uptake were unaltered with SIRT1 overexpression. Finally, while 20 days of energy restriction enhanced insulin-stimulated glucose uptake in skeletal muscles of wild-type mice, no additional effect of SIRT1 overexpression was observed. CONCLUSIONS/INTERPRETATION: These results demonstrate that upregulation of SIRT1 activity in skeletal muscle does not affect whole-body energy expenditure or enhance skeletal muscle insulin sensitivity in young mice on a standard diet with free access to chow or in young mice on energy-restricted diets.

The role of neural tension in hamstring flexibility.

Resistance to stretch, electromyographic (EMG) response to stretch, stretch discomfort and maximum range of motion (ROM) were measured during passive hamstring stretches performed in the slump test position (neural tension stretch) and in the upright position (neutral stretch) in eight healthy subjects. Stretches were performed on an isokinetic dynamometer at 5°/s with the test thigh flexed 40° above the horizontal, and the seat back at 90° to the horizontal. Surface EMG signals were recorded from the medial and lateral hamstrings during stretches. Knees were passively extended to maximum stretch tolerance with test order (neural tension vs neutral) alternated between legs. For neural tension stretches, the cervical and thoracic spine were manually flexed. Maximum ROM was 8° less for the neural tension stretch vs the neutral stretch (P<0.01). Resistance to stretch was 14-15% higher for the neural tension stretch vs the neutral stretch (P<0.001) at common joint angles in the final third of ROM. Stretch discomfort and EMG response were unaffected by neural tension. In conclusion, an increased passive resistance to stretch with the addition of neural tension during passive hamstring stretch despite no change in the EMG response indicates that passive extensibility of neural tissues can limit hamstring flexibility.

Development of a questionnaire (EORTC module) to measure quality of life in patients with cholangiocarcinoma and gallbladder cancer, the EORTC QLQ-BIL21.

BACKGROUND: Quality of life measurement in cholangiocarcinoma and gallbladder cancer involves the assessment of patient-reported issues related to the symptoms, disease and treatment of these tumours. This study describes the development of the disease-specific quality of life (QoL) questionnaire for patients with cholangiocarcinoma and gallbladder cancer to supplement the European Organization for Research and Treatment of Cancer (EORTC)-QLQ C30 core cancer questionnaire. METHODS: Phases 1-3 of the guidelines for module development published by the EORTC were followed, with adaptations for incorporation of questions from existing modules. RESULTS: A total of 47 QoL issues (questions) were identified; 44 questions from the two related validated questionnaires, the EORTC QLQ-PAN26 (pancreatic module) and the EORTC QLQ-LMC21 (liver metastases module), two from the Functional Assessment of Cancer Therapy hepatobiliary module questionnaire in the literature search and one from healthcare professional interviews. Following phase 1 and 2 interviews with patients (n=101) and health care professionals (n=6), a 23-question provisional questionnaire was formulated. There were five questions from PAN26, 15 from LMC21 and three extra questions. In phase 3, the provisional item list was pre-tested in 52 patients in four languages and this resulted in a 21-item module. CONCLUSION: This is the only disease-specific QoL questionnaire for patients with cholangiocarcinoma and gallbladder cancer, and initial assessments show it to be accurate and acceptable to patients in reflecting QoL in these diseases.

EORTC workshop on clinical trial methodology in older individuals with a diagnosis of solid tumors.

BACKGROUND: Due to the aging of the population, the number of older patients diagnosed with a malignant disease is increasing. A multidisciplinary approach to the senior adult cancer patient is mandatory, to assure optimal diagnosis and therapeutic management. DESIGN: European Organisation for Research and Treatment of Cancer (EORTC) has currently defined senior adult oncology as one of its priorities and has established an active Elderly Task Force (ETF). Under the auspices of the EORTC, the ETF organized a workshop on clinical trial methodology in older cancer patients and in this article, we present the conclusions of this workshop. RESULTS: Besides the 'classical' efficacy end points, quality of life, functional status and independence of the patient should be assessed in clinical trials in older patients. The participants of the workshop agreed on the use of a minimum dataset for the assessment of global health and functional status in older cancer patients. The panel also recommended that optimization of collaboration with pharmaceutical industry requires reporting of age-related data (subgroup analyses of clinical trials, age-related pooled analyses and obligatory post-marketing studies in vulnerable and frail older patients). CONCLUSION: The identification of proper clinical outcomes and the validation of geriatric screening tools are needed for conducting sound and comparable clinical trials.

Clinical, emotional and social factors associated with quality of life in chronic pancreatitis.

BACKGROUND: In chronic pancreatitis (CP), a debilitating, progressive and incurable disease, patients' wellbeing is considerably impaired, but the different factors affecting quality of life (QoL), have not been identified yet. METHODS: 69 patients with CP were evaluated (M/F 55/14; mean age 46.6 +/- 10.05 years). Different degrees of pancreatic damage were defined using the Cambridge classification; pain intensity and frequency were assessed using pain index. QoL was measured using EORTC QLQ-C30 and the PAN26 questionnaire. Although developed for pancreatic cancer, the C30/PAN26 has been validated for chronic pancreatitis. RESULTS: Digestive symptoms, financial difficulties, fear of future health and general pain scales showed considerable effects of CP on QoL. We observed significant negative correlation between mean QoL scores and pain index in almost all domains (p < 0.001, p < 0.05). Pain intensity affects QoL scales more often than pain frequency. BMI correlated positively with QoL in global health status, altered bowel habits, body image and satisfaction with health care domains (p < 0.01, p < 0.05). CONCLUSION: Pain index, BMI, Cambridge classification and disease duration are the most important factors adversely affecting QoL in CP. Measurement of QoL is essential in the disease management and improves the knowledge of psychosocial functioning of these patients. and IAP.

Building Patient-Physician Trust: A Medical Student Perspective.

Public trust in physicians has declined over the last 50 years. Future physicians will need to mend the patient-physician trust relationship. In conjunction with the American Medical Association's Accelerating Change in Medical Education initiative, the Mayo Clinic Alix School of Medicine implemented the Science of Health Care Delivery (SHCD) curriculum-a 4-year curriculum that emphasizes interdisciplinary training across population-centered care; person-centered care; team-based care; high-value care; leadership; and health policy, economics, and technology-in 2015. In this medical student perspective, the authors highlight how the SHCD curriculum has the potential to address issues that have eroded patient-physician trust. The curriculum reaches this aim through didactic and/or experiential teachings in health equity, cultural humility and competence, shared decision making, patient advocacy, and safety and quality of care. It is the authors' hope that novel medical education programs such as the SHCD curriculum will allow the nation's future physicians to own their role in rebuilding and fostering public trust in physicians and the health care system.

CT enterography and fistulizing Crohn's disease: clinical benefit and radiographic findings.

BACKGROUND: To estimate the clinical benefit of CT enterography (CTE) in patients with fistulizing Crohn's disease and describe the appearance of fistulas at CTE. METHODS: Crohn's patients who had undergone CTE, which diagnosed an abscess or fistula, were identified. A gastroenterologist reviewed clinical notes prior to and following CTE to assess the pre-CTE clinical suspicion for fistula/abscess, and post-CTE alteration in patient management. A radiologist reassessed all fistula-positive cases, which were confirmed by a non-CT reference standard, to describe their radiologic appearance. RESULTS: Fifty-six patients had CT exams identifying 19 abscesses and 56 fistulas. There was no or remote suspicion of fistula or abscess at pre-imaging clinical assessment in 50% of patients. Thirty-four patients (61%) required a change in or initiation of medical therapy and another 10 (18%) underwent an interventional procedure based on CT enterography findings. Among 37 fistulas with reference standard confirmation, 30 (81%) were extraenteric tracts, and 32 (86%) were hyperenhancing compared to adjacent bowel loops. Most fistulas (68%) contained no internal air or fluid. CONCLUSION: CTE detects clinically occult fistulas and abscesses, resulting in changes in medical management and radiologic or surgical intervention. Most fistulas appear as hyperenhancing, extraenteric tracts, usually without internal air or fluid.

Evaluation of colitis: usefulness of CT enterography technique.

Computed tomographic enterography (CTE) is a useful technique for evaluating the small bowel and has the capability to include the colon for evaluation of patients with inflammatory bowel disease (IBD). The aims of this study are (1) to determine if CTE is a sensitive method for detecting Crohn colitis and ulcerative colitis and (2) to assess the accuracy of determining the extent and activity of colonic disease in patients with proven IBD. Seventy patients (35 patients with proven colitis at colonoscopy and 35 negative patients with a proven normal colon) having both a CTE examination and recent colonoscopy formed the retrospective study group. A radiologist evaluated the examinations in a blinded fashion for disease presence, activity, and extent. Sensitivity was 93% for the detection of moderate and severe disease in well-distended colons. Specificity was 91%. In good to excellent distended colons, mild, moderate, and severe disease was detected with a sensitivity of 67%, 90%, and 100%, respectively. Severe disease activity was commonly underestimated, and mild disease when detected was usually overestimated. The full extent of colonic disease at CTE was usually underestimated. CTE is a valid technique for detecting colitis in the colon in patients with IBD. Better methods for assessing disease activity and extent are needed.

Establishing the European Norm for the health-related quality of life domains of the computer-adaptive test EORTC CAT Core.

OBJECTIVE: The computer-adaptive test (CAT) of the European Organisation for Research and Treatment of Cancer (EORTC), the EORTC CAT Core, assesses the same 15 domains as the EORTC QLQ-C30 health-related quality of life questionnaire but with increased precision, efficiency, measurement range and flexibility. CAT parameters for estimating scores have been established based on clinical data from cancer patients. This study aimed at establishing the European Norm for each CAT domain based on general population data. METHODS: We collected representative general population data across 11 European Union (EU) countries, Russia, Turkey, Canada and the United States (n ≥ 1000/country; stratified by sex and age). We selected item subsets from each CAT domain for data collection (totalling 86 items). Differential item functioning (DIF) analyses were conducted to investigate cross-cultural measurement invariance. For each domain, means and standard deviations from the EU countries (weighted by country population, sex and age) were used to establish a T-metric with a European general population mean = 50 (standard deviation = 10). RESULTS: A total of 15,386 respondents completed the online survey (n = 11,343 from EU countries). EORTC CAT Core norm scores for all 15 countries were calculated. DIF had negligible impact on scoring. Domain-specific T-scores differed significantly across countries with small to medium effect sizes. CONCLUSION: This study establishes the official European Norm for the EORTC CAT Core. The European CAT Norm can be used globally and allows for meaningful interpretation of scores. Furthermore, CAT scores can be compared with sex- and age-adjusted norm scores at a national level within each of the 15 countries.

General population normative data for the EORTC QLQ-C30 health-related quality of life questionnaire based on 15,386 persons across 13 European countries, Canada and the Unites States.

OBJECTIVE: The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 health-related quality of life questionnaire is one of the most widely used cancer-specific health-related quality of life questionnaires worldwide. General population norm data can facilitate the interpretation of QLQ-C30 data obtained from cancer patients. This study aimed at systematically collecting norm data from the general population to develop European QLQ-C30 norm scores and to generate comparable norm data for individual countries in Europe and North America. METHODS: We collected QLQ-C30 data from the general population across 11 European Union (EU) countries, Russia, Turkey, Canada and United States (n ≥ 1000/country). Representative samples were stratified by sex and age groups (18-39, 40-49, 50-59, 60-69 and ≥ 70 years). After applying weights based on the United Nations population distribution statistics, we calculated QLQ-C30 domain scores to generate a 'European QLQ-C30 Norm' based on the EU countries. Further, we calculated QLQ-C30 norm scores for all 15 individual countries. RESULTS: A total of 15,386 respondents completed the online survey. For the EU sample, most QLQ-C30 domains showed differences by sex/age, with men scoring somewhat better health than women, while age effects varied across domains. Substantially larger differences were seen in inter-country comparisons, with Austrian and Dutch respondents reporting consistently better health compared with British and Polish respondents. CONCLUSIONS: This study is the first to systematically collect EORTC QLQ-C30 general population norm data across Europe and North America applying a consistent data collection method across 15 countries. These new norm data facilitate valid intra-country as well as inter-country comparisons and QLQ-C30 score interpretation.

The acetylcholinesterase genes of C. elegans: identification of a third gene (ace-3) and mosaic mapping of a synthetic lethal phenotype.

In C. elegans, the newly identified ace-3 is the third gene affecting acetylcholinesterase (AChE) activity. ace-3 II specifically affects class C AChE and is unlinked to ace-1 X or ace-2 I, which affect the other two AChE classes (A and B, respectively). Strains homozygous for an ace-3 mutation have no apparent behavioral or developmental defect; ace-1 ace-3 and ace-2 ace-3 double mutants are also nearly wild type. In contrast, ace-1 ace-2 ace-3 triple mutant animals are paralyzed and developmentally arrested; their embryonic development is relatively unimpaired, but they are unable to grow beyond the hatching stage. Based on the analysis of genetic mosaics, we conclude that in the absence of ace-2 and ace-3 function, the expression of ace-1(+) in muscle cells, but not in neurons, is essential for postembryonic viability.

Large Draining Focal Fibrous Hyperplasia Secondary to Periapical Granuloma.

Periapical granuloma is a pathological diagnosis associated clinically and radiographically with a nonvital tooth and a periapical radiolucency, respectively. It is frequently seen as a sequela of long-standing pulpal necrosis. Often times, a draining fistula is observed near the nonvital tooth. We report an unusual case of a large draining focal fibrous hyperplasia in association with a large periapical granuloma treated at our clinic. The diagnosis was made by the clinical presentation, radiologic and histopathologic findings.

Specific Nanoporous Geometries on Anodized Alumina Surfaces Influence Astrocyte Adhesion and Glial Fibrillary Acidic Protein Immunoreactivity Levels.

Electrodes implanted in the brain or spinal cord trigger the activation of resident astrocytes. In their reactive state, astrocytes surrounding the electrode form a glial scar, compromising the ability of the electrode to interface with the surrounding neural tissue. One approach to reduce the inhibiting scar tissue is to incorporate nanoarchitecture on the surface of the implanted materials to modify the astrocytic response. The incorporated nanoarchitecture changes both the surface characteristics and the material properties of the implant interface. We investigated the response of rat cortical astrocytes to nanoporous anodic aluminum oxide (AAO) surfaces. Astrocytes were seeded onto nonporous aluminum control surfaces and AAO surfaces with average nanopore diameters of 20 and 90 nm. The surfaces were characterized by assessing their nanomorphology, hydrophobicity, surface chemistry, mechanical properties, and surface roughness. For cell response characterization, calcein-based viability and adhesion studies were performed. Plasmid-assisted vinculin live cell imaging was done to characterize focal adhesion number and distribution. Immunocytochemistry was used to assess glial fibrillary acidic protein (GFAP) expression. We found that astrocyte adhesion was significantly higher on small pore surfaces compared to large pore surfaces. Astrocytes produced more focal adhesions (FA) and distributed these FA peripherally when cultured on small pore samples compared to the other groups. Astrocyte GFAP expression was lower when astrocytes were cultured on surfaces with small nanopores compared to the control and large pore surfaces. These results indicate that unique surface nanoporosities influence astrocyte adhesion and subsequent cellular response. The reduction in GFAP immunoreactivity exhibited by the smaller pore surfaces can improve the long-term performance of the implanted neurodevices, thus making them credible candidates as a coating material for neural implants.