The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

Decentralization in Croatia: problems and possible solutions

El 2001 Croàcia va posar en marxa la iniciativa destinada a afluixar un alt grau de centralització mitjançant l'ampliació dels mandats de les unitats locals i el canvi de les fonts de finançament de les funcions públiques. No obstant això, els passos inicials en el procés de descentralització no ha estat seguida per altres mesures de descentralització fiscal, i en conseqüència, el seu nivell s'ha mantingut pràcticament sense canvis. El treball es proposa elaborar els principals problemes i obstacles en relació amb l'aplicació efectiva del procés de descentralització i donar tres grups de propostes per a la descentralització: (i) la divisió dels poders obligatoris entre les diferents unitats locals, (ii) el canvi en el finançament i (Iii) modificar la divisió territorial del país.

Investment, duration, and exit strategies for corporate and independent venture capital-backed start-ups

We propose a model of investment, duration, and exit strategies for start-ups backed by venture capital (VC) funds that accounts for the high level of uncertainty, the asymmetry of information between insiders and outsiders, and the discount rate. Our analysis predicts that start-ups backed by corporate VC funds remain for a longer period of time before exiting and receive larger investment amounts than those financed by independent VC funds. Although a longer duration leads to a higher likelihood of an exit through an acquisition, a larger investment increases the probability of an IPO exit. These predictions find strong empirical support.

Prevalence and determinants of AK in Euromelanoma screenees

Actinic keratosis (AK) is the most common skin lesion with malignant potential, and one of the main reasons for consulting a dermatologist. Found predominantly on sun-exposed body sites in fairskinned, older and male subjects, AK is among the strongest predictors of skin cancer, and a precursor of SCC. However, estimates of prevalence and study of determinants of AK are relatively scarce and generally based on small, hospital-based series. Clinical suspicion of AK is a reliable predictor of diagnosis. The presence of AK is documented by dermatologists during the Euromelanoma screening examinations so that the Euromelanoma database probably constitutes the largest series of AK cases worldwide. This study aimed at (1) describing the prevalence and risk pattern of AK among Euromelanoma screenees during the 2009-2013 time period, and (2) identifying determinants of AK by means of multivariate analysis. In particular, the contribution of host characteristics, sun exposure and sunrelated behaviour to the risk of AK was explored. Results will be discussed in the light of this large, self-selected, Pan-European series.

Quality of Web-based information on obsessive compulsive disorder.

BACKGROUND: The Internet is increasingly used as a source of information for mental health issues. The burden of obsessive compulsive disorder (OCD) may lead persons with diagnosed or undiagnosed OCD, and their relatives, to search for good quality information on the Web. This study aimed to evaluate the quality of Web-based information on English-language sites dealing with OCD and to compare the quality of websites found through a general and a medically specialized search engine. METHODS: Keywords related to OCD were entered into Google and OmniMedicalSearch. Websites were assessed on the basis of accountability, interactivity, readability, and content quality. The "Health on the Net" (HON) quality label and the Brief DISCERN scale score were used as possible content quality indicators. Of the 235 links identified, 53 websites were analyzed. RESULTS: The content quality of the OCD websites examined was relatively good. The use of a specialized search engine did not offer an advantage in finding websites with better content quality. A score ≥16 on the Brief DISCERN scale is associated with better content quality. CONCLUSION: This study shows the acceptability of the content quality of OCD websites. There is no advantage in searching for information with a specialized search engine rather than a general one. Practical implications: The Internet offers a number of high quality OCD websites. It remains critical, however, to have a provider-patient talk about the information found on the Web.

Modelling short-term ultraviolet exposure as an alternative to individual dosimetry

Background: Excessive exposure to solar Ultra-Violet (UV) light is the main cause of most skin cancers in humans. Factors such as the increase of solar irradiation at ground level (anthropic pollution), the rise in standard of living (vacation in sunny areas), and (mostly) the development of outdoor activities have contributed to increase exposure. Thus, unsurprisingly, incidence of skin cancers has increased over the last decades more than that of any other cancer. Melanoma is the most lethal cutaneous cancer, while cutaneous carcinomas are the most common cancer type worldwide. UV exposure depends on environmental as well as individual factors related to activity. The influence of individual factors on exposure among building workers was investigated in a previous study. Posture and orientation were found to account for at least 38% of the total variance of relative individual exposure. A high variance of short-term exposure was observed between different body locations, indicating the occurrence of intense, subacute exposures. It was also found that effective short-term exposure ranged between 0 and 200% of ambient irradiation, suggesting that ambient irradiation is a poor predictor of effective exposure. Various dosimetric techniques enable to assess individual effective exposure, but dosimetric measurements remain tedious and tend to be situation-specific. As a matter of facts, individual factors (exposure time, body posture and orientation in the sun) often limit the extrapolation of exposure results to similar activities conducted in other conditions. Objective: The research presented in this paper aims at developing and validating a predictive tool of effective individual exposure to solar UV. Methods: Existing computer graphic techniques (3D rendering) were adapted to reflect solar exposure conditions and calculate short-term anatomical doses. A numerical model, represented as a 3D triangular mesh, is used to represent the exposed body. The amount of solar energy received by each "triangle is calculated, taking into account irradiation intensity, incidence angle and possible shadowing from other body parts. The model take into account the three components of the solar irradiation (direct, diffuse and albedo) as well as the orientation and posture of the body. Field measurements were carried out using a forensic mannequin at the Payerne MeteoSwiss station. Short-term dosimetric measurements were performed in 7 anatomical locations for 5 body postures. Field results were compared to the model prediction obtained from the numerical model. Results: The best match between prediction and measurements was obtained for upper body parts such as shoulders (Ratio Modelled/Measured; Mean = 1.21, SD = 0.34) and neck (Mean = 0.81, SD = 0.32). Small curved body parts such as forehead (Mean = 6.48, SD = 9.61) exhibited a lower matching. The prediction is less accurate for complex postures such as kneeling (Mean = 4.13, SD = 8.38) compared to standing up (Mean = 0.85, SD = 0.48). The values obtained from the dosimeters and the ones computed from the model are globally consistent. Conclusion: Although further development and validation are required, these results suggest that effective exposure could be predicted for a given activity (work or leisure) in various ambient irradiation conditions. Using a generic modelling approach is of high interest in terms of implementation costs as well as predictive and retrospective capabilities.

Substrate metabolism, nutrient balance and obesity development in children and adolescents: a target for intervention?

Obesity results from the organism's inability to maintain energy balance over a long term. Childhood obesity and its related factors and pathological consequences tend to persist into adulthood. A cluster of factors, including high energy density in the diet (high fat intake), low energy expenditure, and disturbed substrate oxidation, favour the increase in fat mass. Oxidation of three major macronutrients and their roles in the regulation of energy balance, particularly in children and adolescents, are discussed. Total glucose oxidation is not different between obese and lean children; exogenous glucose utilization is higher whereas endogenous glucose utilization is lower in obese compared with lean children. Carbohydrate composition of the diet determines carbohydrate oxidation regardless of fat content of the diet. Both exogenous and endogenous fat oxidation are higher in obese than in lean subjects. The influence of high fat intake on accumulation of fat mass is operative rather over a long term. Several future directions are addressed, such that a combination of increased physical activity and modification in diet composition, in terms of energy density and glycemic index, is recommended for children and adolescents.

MPI-DING reference glasses for in situ microanalysis: New reference values for element concentrations and isotope ratios

[1] We present new analytical data of major and trace elements for the geological MPI-DING glasses KL2-G, ML3B-G, StHs6/80-G, GOR128-G, GOR132-G, BM90/21-G, T1-G, and ATHO-G. Different analytical methods were used to obtain a large spectrum of major and trace element data, in particular, EPMA, SIMS, LA-ICPMS, and isotope dilution by TIMS and ICPMS. Altogether, more than 60 qualified geochemical laboratories worldwide contributed to the analyses, allowing us to present new reference and information values and their uncertainties ( at 95% confidence level) for up to 74 elements. We complied with the recommendations for the certification of geological reference materials by the International Association of Geoanalysts (IAG). The reference values were derived from the results of 16 independent techniques, including definitive ( isotope dilution) and comparative bulk ( e. g., INAA, ICPMS, SSMS) and microanalytical ( e. g., LA-ICPMS, SIMS, EPMA) methods. Agreement between two or more independent methods and the use of definitive methods provided traceability to the fullest extent possible. We also present new and recently published data for the isotopic compositions of H, B, Li, O, Ca, Sr, Nd, Hf, and Pb. The results were mainly obtained by high-precision bulk techniques, such as TIMS and MC-ICPMS. In addition, LA-ICPMS and SIMS isotope data of B, Li, and Pb are presented.

Guidelines for the use and interpretation of assays for monitoring autophagy.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Prospective analysis of KRAS, BRAF, and PIK3CA mutations and EGFR copy number in patients (pts) with locally advanced rectal cancer: A translational substudy of a clinical trial (SAKK 41/07) evaluating the effect of neoadjuvant chemoradiation (CRT) with or without panitumumab

Background: Prognostic and predictive markers are of great importance for future study designs and essential for the interpretation of clinical trials incorporating an EGFR-inhibitor. The current study prospectively assessed and validated KRAS, BRAF and PIK3CA mutations in rectal cancer patients screened for the trial SAKK41/07 of concomitant preoperative radio-chemotherapy with or without panitumumab.Methods: Macrodissection was performed on pretreatment formalin fixed paraffin embedded biopsy tissue sections to arrive at a minimum of 50% of tumor cells. DNA was extracted with the Maxwell 16 FFPE Tissue LEV DNA purification kit. After PCR amplification, mutations were identified by pyrosequencing. We prospectively analysed pretreatment biopsy material from 149 rectal cancer pts biopsies for KRAS (exon 2 codon 12 [2-12] and 13 [2-13], exon 3 codon 59 [3-59]) and 61 [3-61], exon 4 codon 117 [4-117] and 146 [4-146]). Sixty-eight pts (KRASwt exon 2, 3 only) were further analysed for BRAF (exon 15 codon 600) and PIK3CA (exon 9 codon 542, 545 and 546, exon 20 codon 1043 [20-1043] and 1047 [20-1047]) mutations, and EGFR copy number by qPCR. For the calculation of the EGFR copy number, we used KRAS copy number as internal reference standard. The calculation was done on the basis of the two standard curves relative quantification method.Results: In 149 screened pts with rectal cancer, the prevalence of KRAS mutations was 36%. Among the 68 pts enrolled in SAKK 41/07 based on initially presumed KRASwt status (exon 2/codons 12+13), 18 pts (26%) had a total of 23 mutations in the RAS/PIK3CA-pathways upon validation analysis. Twelve pts had a KRAS mutation, 7 pts had a PIK3CA mutation, 3 pts had a NRAS mutation, 1 patient a BRAF mutation. Surprisingly, five of these pts had double- mutations, including 4 pts with KRAS plus PIK3CA mutations, and 1 pt with NRAS plus PIK3CA mutations. The median normalized EGFR copy number was 1. Neither mutations of KRAS, BRAF, and PIK3CA, nor EGFR copy number were statistically associated with the primary study endpoint pCR (pathological complete regression).Conclusions: The prevalence of KRAS mutations in rectal and in colon cancer appears to be similar. BRAF mutations are rare; PIK3CA mutations are more common (10%). EGFR copy number is not increased in rectal cancer. A considerable number or KRAS exon 2 wt tumors harbored KRAS exon 3+4 mutations. Further study is needed to determine if KRAS testing should include exons 2-4.

Acute life-threatening presentation of vitamin d deficiency rickets.

Context: Clinical manifestations of vitamin D deficiency rickets are widely described; however cardiorespiratory arrest is an extremely rare presentation. Objective: The aim of this paper is to present the symptoms of severe vitamin D deficiency rickets and to highlight the importance of vitamin D prophylaxis in infants. Results: We report a case of a 16-month-old infant who presented to emergency room with a stridor that evolved into a full cardiorespiratory arrest secondary to hypocalcemia. Medical history revealed that the infant was exclusively breastfed without vitamin D supplementation until the age of 10 months. Due to cultural habits, his diet was also grossly deficient in dairy products. Physical exam revealed clinical signs of rickets. Laboratory test showed severe hypocalcemia, elevated alkaline phosphatase, normal serum phosphorous, decreased 25(OH) cholecalciferol, increased intact parathyroid hormone level, and normal urine calcium excretion. The radiography of the wrist showed evidence of cupping, fraying, metaphyseal widening, and demineralization of the distal radial and ulnar metaphyses. The bone mineral density of the lumbar spine measured by dual x-ray absorptiometry showed a Z-score below -2 SD. His cardiorespiratory arrest secondary to hypocalcemia was therefore attributed to severe nutritional rickets. Conclusion: Vitamin D deficiency rickets can be life threatening. Vitamin D supplementation is therefore crucial, especially in breastfed infants and some ethnic minorities (dark-skinned people, poor sun exposure), more at risk for developing severe rickets if not supplemented.

Avaruusinstrumentin mekaniikkasuunnittelu

Tämän insinöörityön tarkoituksena on kehittää avaruusinstrumentti, joka on osa Euroopan avaruusjärjestön ESA:n ja Japanin avaruusjärjestön JAXA:n BepiColombo-yhteistyöhanketta. Satelliitti lähetetään Merkurius-planeetan kiertoradalle vuonna 2013. Avaruusaluksen matka Merkuriukseen kestää yhteensä kuusi vuotta ja on perillä vuonna 2019. Yksi BepiColombo-satelliitin tieteellisistä instrumenteista on Oxford Instruments Analytical Oy:n kehittämä SIXS-instrumentti (Solar Intensity X-ray and particle Spectrometer). Instrumentin tarkoituksena on mitata auringosta tulevaa röntgen- ja partikkelisäteilyä. Se toimii yhteistyössä Merkuriuksen pintaa mittaavan MIXS-instrumentin (Mercury Imaging X-ray Spectrometer) kanssa. Tuloksista pystytään analysoimaan ne alkuaineet, joista Merkuriuksen pinta koostuu. Työn alussa esitellään teoriataustaa alkuaineiden mittauksesta niiltä osin, kuin se tämän työn kannalta on tarpeellista. Työssä syvennytään tarkemmin auringosta tulevan säteilyn mittauksesta vastaavan instrumentin tekniikkaan ja mekaniikkasuunnitteluun. Instrumentin lämpöteknisestä suunnittelusta, värähtelymittauksista ja lujuusanalyysista on työhön sisällytetty pääasiat. Työn tuloksena on kehitetty instrumenttiin tulevan partikkelidetektorin prototyyppi sekä instrumenttikotelon malli. Lopullisen koon instrumenttikotelolle määrittää vaadittavan elektroniikan viemä tila. Mittalaitteen kehitystyö jatkuu Oxford Instruments Analytical Oy:ssä vuoteen 2011 saakka.

Is it Time to Change Your Hat?, 2003

A one page informational sheet about skin cancer and the hat you wear. Sun Safety