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BACKGROUND:Sponsors that seek to commercialize new drugs apply to the Food and Drug Administration (FDA) which independently analyzes the raw data and reports the results on its website. OBJECTIVES:This study sought to determine if there are differences between the FDA assessments and journal reports on biologic agents developed for the treatment of rheumatoid arthritis. METHODS:Available data on FDA-approved drugs were extracted from the website, and a systematic literature search was conducted to identify matching studies in peer-reviewed medical journals. Outcome measures were the American College of Rheumatology response criteria ACR20 (efficacy) and withdrawal due to adverse events (safety). As effect size odds ratios were estimated for each active trial arm vs. control arm (i.e. for both sources: FDA and journal report), followed by calculation of the ratios of the FDA and journal report odds ratios. A ratio of odds ratios not equal to 1 was categorized as a discrepancy. RESULTS:FDA reports were available for 8 of 9 FDA-approved biologic agents for rheumatoid arthritis; all identified trials (34) except one were published in peer-reviewed journals. Overall, discrepancies were noted for 20 of the 33 evaluated trials. Differences in the apparent benefit reporting were found in 39% (24/61) pairwise comparisons and in 11 cases these were statistically significant; the FDA report showed greater benefit than the journal publication in 15 comparisons and lesser benefit in 9. Differences in the reported harms were found in 51% (28/55) pairwise comparisons and were statistically significant in 5. The "signal" in FDA reports showed a less harmful effect than the journal publication in 17 comparisons whereas a more harmful effect in 11. The differences were attributed to differences in analytic approach, patient inclusion, rounding effect, and counting discrepancies. However, no differences were categorized as critical. CONCLUSION:There was no empirical evidence to suggest biased estimates between the two sources. Increased and detailed transparency in publications would improve the understanding and credibility of published results. Further, the FDA report was found to be a useful source when data are missing in the published report (i.e. reporting bias).

[This corrects the article DOI: 10.1371/journal.pone.0161148.].

BackgroundThe objectives of the study were to develop web-based Spanish and Catalan versions of the KIDSCREEN, and to compare scores and psychometric properties with the paper version.MethodsInternet and paper Spanish and Catalan versions of the KIDSCREEN-52 were included in a cross-sectional study in school-age children. Web-based and paper Spanish or Catalan versions of the KIDSCREEN-52 were administered to students aged 8 to 18 years from primary and secondary schools in Palafolls (Barcelona, Spain, n = 923). All students completed both web-based and paper versions during school time with an interval of at least 2 hours between administrations. The order of administration was randomized. The KIDSCREEN-52, the Strengths and Difficulties Questionnaire (SDQ), and sociodemographic variables were collected. Missing values, floor and ceiling effects, and internal consistency were compared between both versions, as well as mean score differences, level of agreement, and known groups and construct validity.ResultsParticipation rate was 77% (n = 715). Web-based and paper versions showed low percentage of missing values and similar high ceiling effect (range 0 to 44%). Mean score differences showed an effect size (ES) lower than 0.2 in all dimensions. Internal consistency ranged from 0.7 to 0.88, and degree of agreement was excellent (Intraclass correlation coefficient [ICC] range 0.75 to 0.87). Expected differences were seen by sex, age, socioeconomic status and mental health status.ConclusionsThe web-based KIDSCREEN-52 showed similar scale score and reliability and validity than the paper version. It will incorporate the child population in the assessment of quality of life providing a more attractive format.

BackgroundThe psychometric properties of an online test are not necessarily identical to its paper and pencil original. The aim of this study is to test whether the factor structure of the Community Assessment of Psychic Experiences (CAPE) is measurement invariant with respect to online vs. paper and pencil assessment.MethodThe factor structure of CAPE items assessed by paper and pencil (N = 796) was compared with the factor structure of CAPE items assessed by the Internet (N = 21,590) using formal tests for Measurement Invariance (MI). The effect size was calculated by estimating the Signed Item Difference in the Sample (SIDS) index and the Signed Test Difference in the Sample (STDS) for a hypothetical subject who scores 2 standard deviations above average on the latent dimensions.ResultsThe more restricted Metric Invariance model showed a significantly worse fit compared to the less restricted Configural Invariance model (χ(2)(23) = 152.75, pConclusionsOur findings did not support measurement invariance with respect to assessment method. Because of the small effect sizes, the measurement differences between the online assessed CAPE and its paper and pencil original can be neglected without major consequences for research purposes. However, a person with a high vulnerability for psychotic symptoms would score 4.80 points lower on the total scale if the CAPE is assessed online compared to paper and pencil assessment. Therefore, for clinical purposes, one should be cautious with online assessment of the CAPE.

The paper mulberry is one of the multifunctional tree species in agroforestry systems and is also commonly utilized in traditional medicine in China and other Asian countries. However, little is known about its molecular genetics, which hinders research on and exploitation of this valuable resource. To discern the correlation between gene expression and the essential properties of the paper mulberry, we performed a transcriptomics analysis, assembling a total of 37,725 unigenes from 54,638,676 reads generated by RNA-seq. Among these, 22,692 unigenes showed greater than 60% similarity with genes from other species. The lengths of 13,566 annotated unigenes were longer than 1,000 bp. Functional clustering analysis with COG (Cluster of Orthologous Groups) revealed that 17,184 unigenes are primarily involved in transcription, translation, signal transduction, carbohydrate metabolism, secondary metabolism, and energy metabolism. GO (Gene Ontology) annotation suggests enrichment of genes encoding antioxidant activity, transporter activity, biosynthesis, metabolism and stress response, with a total of 30,659 unigenes falling in these categories. KEGG (Kyoto Encyclopedia of Genes and Genomes) metabolic pathway analysis showed that 7,199 unigenes are associated with 119 metabolic pathways. In addition to the basic metabolism, these genes are enriched for plant pathogen interaction, flavonoid metabolism and other secondary metabolic processes. Furthermore, differences in the transcriptomes of leaf, stem and root tissues were analyzed and 7,233 specifically expressed unigenes were identified. This global expression analysis provided novel insights about the molecular mechanisms of the biosynthesis of flavonoid, lignin and cellulose, as well as on the response to biotic and abiotic stresses including the remediation of contaminated soil by the paper mulberry.

AimsTo evaluate the relative efficiencies of five Internet-based digital and three paper-based scientific surveys and to estimate the costs for different-sized cohorts.MethodsInvitations to participate in a survey were distributed via e-mail to employees of two university hospitals (E1 and E2) and to members of a medical association (E3), as a link placed in a special text on the municipal homepage regularly read by the administrative employees of two cities (H1 and H2), and paper-based to workers at an automobile enterprise (P1) and college (P2) and senior (P3) students. The main parameters analyzed included the numbers of invited and actual participants, and the time and cost to complete the survey. Statistical analysis was descriptive, except for the Kruskal-Wallis-H-test, which was used to compare the three recruitment methods. Cost efficiencies were compared and extrapolated to different-sized cohorts.ResultsThe ratios of completely answered questionnaires to distributed questionnaires were between 81.5% (E1) and 97.4% (P2). Between 6.4% (P1) and 57.0% (P2) of the invited participants completely answered the questionnaires. The costs per completely answered questionnaire were $0.57-$1.41 (E1-3), $1.70 and $0.80 for H1 and H2, respectively, and $3.36-$4.21 (P1-3). Based on our results, electronic surveys with 10, 20, 30, or 42 questions would be estimated to be most cost (and time) efficient if more than 101.6-225.9 (128.2-391.7), 139.8-229.2 (93.8-193.6), 165.8-230.6 (68.7-115.7), or 188.2-231.5 (44.4-72.7) participants were required, respectively.ConclusionsThe study efficiency depended on the technical modalities of the survey methods and engagement of the participants. Depending on our study design, our results suggest that in similar projects that will certainly have more than two to three hundred required participants, the most efficient way of conducting a questionnaire-based survey is likely via the Internet with a digital questionnaire, specifically via a centralized e-mail.

For several decades, a leading paradigm of how to quantitatively assess scientific research has been the analysis of the aggregated citation information in a set of scientific publications. Although the representation of this information as a citation network has already been coined in the 1960s, it needed the systematic indexing of scientific literature to allow for impact metrics that actually made use of this network as a whole, improving on the then prevailing metrics that were almost exclusively based on the number of direct citations. However, besides focusing on the assignment of credit, the paper citation network can also be studied in terms of the proliferation of scientific ideas. Here we introduce a simple measure based on the shortest-paths in the paper's in-component or, simply speaking, on the shape and size of the wake of a paper within the citation network. Applied to a citation network containing Physical Review publications from more than a century, our approach is able to detect seminal articles which have introduced concepts of obvious importance to the further development of physics. We observe a large fraction of papers co-authored by Nobel Prize laureates in physics among the top-ranked publications.

Loop mediated isothermal amplification (LAMP) provides an opportunity for improved, field-friendly detection of malaria infections in endemic areas. However data on the diagnostic accuracy of LAMP for active case detection, particularly low-density parasitaemias, are lacking. We therefore evaluated the performance of a new LAMP kit compared with PCR using DNA from filter paper blood spots.Samples from 865 fever patients and 465 asymptomatic individuals collected in Zanzibar were analysed for Pan (all species) and Pf (P. falciparum) DNA with the Loopamp MALARIA Pan/Pf kit. Samples were amplified at 65°C for 40 minutes in a real-time turbidimeter and results were compared with nested PCR. Samples with discordant results between LAMP and nested PCR were analysed with real-time PCR. The real-time PCR corrected nested PCR result was defined as gold standard. Among the 117 (13.5%) PCR detected P. falciparum infections from fever patients (mean parasite density 7491/µL, range 6-782,400) 115, 115 and 111 were positive by Pan-LAMP, Pf-LAMP and nested PCR, respectively. The sensitivities were 98.3% (95%CI 94-99.8) for both Pan and Pf-LAMP. Among the 54 (11.6%) PCR positive samples from asymptomatic individuals (mean parasite density 10/µL, range 0-4972) Pf-LAMP had a sensitivity of 92.7% (95%CI 80.1-98.5) for detection of the 41 P. falciparum infections. Pan-LAMP had sensitivities of 97% (95%CI 84.2-99.9) and 76.9% (95%CI 46.2-95) for detection of P. falciparum and P. malariae, respectively. The specificities for both Pan and Pf-LAMP were 100% (95%CI 99.1-100) in both study groups.Both components of the Loopamp MALARIA Pan/Pf detection kit revealed high diagnostic accuracy for parasite detection among fever patients and importantly also among asymptomatic individuals of low parasite densities from minute blood volumes preserved on filter paper. These data support LAMPs potential role for improved detection of low-density malaria infections in pre-elimination settings.

Endocrine disrupting compounds (EDCs) are chemicals that negatively impact endocrine system function, with effluent from paper mills one example of this class of chemicals. In Florida, female Eastern mosquitofish (Gambusia holbrooki) have been observed with male secondary sexual characteristics at three paper mill-impacted sites, indicative of EDC exposure, and are still found at one site on the Fenholloway River. The potential impacts that paper mill effluent exposure has on the G. holbrooki endocrine system and the stream ecosystem are unknown. The objective of this study was to use gene expression analysis to determine if exposure to an androgen receptor agonist was occurring and to couple this analysis with in vitro assays to evaluate the presence of androgen and progesterone receptor active chemicals in the Fenholloway River. Focused gene expression analyses of masculinized G. holbrooki from downstream of the Fenholloway River paper mill were indicative of androgen exposure, while genes related to reproduction indicated potential progesterone exposure. Hepatic microarray analysis revealed an increase in the expression of metabolic genes in Fenholloway River fish, with similarities in genes and biological processes compared to G. holbrooki exposed to androgens. Water samples collected downstream of the paper mill and at a reference site indicated that progesterone and androgen receptor active chemicals were present at both sites, which corroborates previous chemical analyses. Results indicate that G. holbrooki downstream of the Fenholloway River paper mill are impacted by a mixture of both androgens and progesterones. This research provides data on the mechanisms of how paper mill effluents in Florida are acting as endocrine disruptors.

As more HIV-infected people gain access to antiretroviral therapy (ART), monitoring HIV drug resistance (HIVDR) becomes essential to combat both acquired and transmitted HIVDR. Studies have demonstrated dried blood spots (DBS) are a suitable alternative in HIVDR monitoring using DBS collected on Whatman 903 (W-903). In this study, we sought to evaluate two other commercially available filter papers, Ahlstrom 226 (A-226) and Munktell TFN (M-TFN), for HIVDR genotyping following ambient temperature storage. DBS were prepared from remnant blood specimens collected from 334 ART patients and stored at ambient temperature for a median time of 30 days. HIV-1 viral load was determined using NucliSENS EasyQ® HIV-1 v2.0 RUO test kits prior to genotyping of the protease and reverse transcriptase regions of the HIV-1 pol gene using an in-house assay. Among the DBS tested, 26 specimens had a viral load ≥ 1000 copies/mL in all three types of filter paper and were included in the genotyping analysis. Genotyping efficiencies were similar between DBS collected on W-903 (92.3%), A-226 (88.5%), and M-TFN (92.3%) filter papers (P = 1.00). We identified 50 DR-associated mutations in DBS collected on W-903, 33 in DBS collected on A-226, and 48 in DBS collected on M-TFN, resulting in mutation detection sensitivities of 66.0% for A-226 and 88.0% for M-TFN when compared to W-903. Our data indicate that differences among filter papers may exist at this storage condition and warrant further studies evaluating filter paper type for HIVDR monitoring.

Bisphenol A (BPA) is an endocrine disrupting environmental contaminant used in a wide variety of products, and BPA metabolites are found in almost everyone's urine, suggesting widespread exposure from multiple sources. Regulatory agencies estimate that virtually all BPA exposure is from food and beverage packaging. However, free BPA is applied to the outer layer of thermal receipt paper present in very high (∼20 mg BPA/g paper) quantities as a print developer. Not taken into account when considering thermal paper as a source of BPA exposure is that some commonly used hand sanitizers, as well as other skin care products, contain mixtures of dermal penetration enhancing chemicals that can increase by up to 100 fold the dermal absorption of lipophilic compounds such as BPA. We found that when men and women held thermal receipt paper immediately after using a hand sanitizer with penetration enhancing chemicals, significant free BPA was transferred to their hands and then to French fries that were eaten, and the combination of dermal and oral BPA absorption led to a rapid and dramatic average maximum increase (Cmax) in unconjugated (bioactive) BPA of ∼7 ng/mL in serum and ∼20 µg total BPA/g creatinine in urine within 90 min. The default method used by regulatory agencies to test for hazards posed by chemicals is intra-gastric gavage. For BPA this approach results in less than 1% of the administered dose being bioavailable in blood. It also ignores dermal absorption as well as sublingual absorption in the mouth that both bypass first-pass liver metabolism. The elevated levels of BPA that we observed due to holding thermal paper after using a product containing dermal penetration enhancing chemicals have been related to an increased risk for a wide range of developmental abnormalities as well as diseases in adults.

The distinction between worker and reproductive castes of social insects is receiving increased attention from a developmental rather than adaptive perspective. In the wasp genus Polistes, colonies are founded by one or more females, and the female offspring that emerge in that colony are either non-reproducing workers or future reproductives of the following generation (gynes). A growing number of studies now indicate that workers emerge with activated reproductive physiology, whereas the future reproductive gynes do not. Low nourishment levels for larvae during the worker-rearing phase of the colony cycle and higher nourishment levels for larvae when gynes are reared are now strongly suspected of playing a major role in this difference. Here, we present the results of a laboratory rearing experiment in which Polistes metricus single foundresses were held in environmental conditions with a higher level of control than in any previously published study, and the amount of protein nourishment made available to feed larvae was the only input variable. Three experimental feeding treatments were tested: restricted, unrestricted, and hand-supplemented. Analysis of multiple response variables shows that wasps reared on restricted protein nourishment, which would be the case for wasps reared in field conditions that subsequently become workers, tend toward trait values that characterize active reproductive physiology. Wasps reared on unrestricted and hand-supplemented protein, which replicates higher feeding levels for larvae in field conditions that subsequently become gynes, tend toward trait values that characterize inactive reproductive physiology. Although the experiment was not designed to test for worker behavior per se, our results further implicate activated reproductive physiology as a developmental response to low larval nourishment as a fundamental aspect of worker behavior in Polistes.

Sexually selected signals are common in many animals, though little reported in social insects. We investigated the occurrence of male visual signals mediating the dominance relationships among males and female choice of sexual partner in the paper wasp Polistes simillimus. Males have three conspicuous, variable and sexually dimorphic traits: black pigmentation on the head, a pair of yellow abdominal spots and body size differences. By conducting behavioral assays, we found that none of the three visual traits are associated with male-male dominance relationship. However, males with higher proportion of black facial pigmentation and bigger yellow abdominal spots are more likely chosen as sexual partners. Also, after experimentally manipulating the proportion of black pigment on males' face, we found that females may evaluate male facial coloration during the choice of a sexual partner. Thus, the black pigmentation on P. simillimus male's head appears to play a role as a sexually selected visual signal. We suggest that sexual selection is a common force in Polistes and we highlight the importance of this group as a model for the study of visual communication in insects.

In order to reduce the ecotoxicity of paper mill, four different enzymatic pretreatment strategies were investigated in comparison to conventional chemical based processes. In strategy I, xylanase-aided pretreatment of pulp was carried out, and in strategy II, xylanase and laccase-mediator systems were used sequentially. Moreover, to compare the efficiency of Bacillus stearothermophilus xylanase and Ceriporiopsis subvermispora laccase in the reduction of ecotoxicity and pollution, parallel strategies (III and IV) were implemented using commercial enzymes. Conventional C(D)E(OP)D(1)D(2) (C(D), Cl(2) with ClO2; EOP, H2O2 extraction; D1 and D2, ClO2) and X/XLC(D)E(OP)D(1)D(2) (X, xylanase; L, laccase) sequences were employed with non-enzymatic and enzymatic strategies, respectively. Acute toxicity was determined by the extent of inhibition of bioluminescence of Vibrio fischeri with different dilutions of the effluent. Two-fold increase was observed in EC50 values for strategy I compared to the control process. On the other hand, sequential application of commercial enzymes resulted in higher acute toxicity compared to lab enzymes. In comparison to the control process, strategy II was the most efficient and successfully reduced 60.1 and 25.8% of biological oxygen demand (BOD) and color of effluents, respectively. We report for the first time the comparative analysis of the ecotoxicity of industrial effluents.

Here we describe an ultra-low-cost origami-based approach for large-scale manufacturing of microscopes, specifically demonstrating brightfield, darkfield, and fluorescence microscopes. Merging principles of optical design with origami enables high-volume fabrication of microscopes from 2D media. Flexure mechanisms created via folding enable a flat compact design. Structural loops in folded paper provide kinematic constraints as a means for passive self-alignment. This light, rugged instrument can survive harsh field conditions while providing a diversity of imaging capabilities, thus serving wide-ranging applications for cost-effective, portable microscopes in science and education.

The safety of chemicals, drugs, novel foods and genetically modified crops is often tested using repeat-dose sub-acute toxicity tests in rats or mice. It is important to avoid misinterpretations of the results as these tests are used to help determine safe exposure levels in humans. Treated and control groups are compared for a range of haematological, biochemical and other biomarkers which may indicate tissue damage or other adverse effects. However, the statistical analysis and presentation of such data poses problems due to the large number of statistical tests which are involved. Often, it is not clear whether a "statistically significant" effect is real or a false positive (type I error) due to sampling variation. The author's conclusions appear to be reached somewhat subjectively by the pattern of statistical significances, discounting those which they judge to be type I errors and ignoring any biomarker where the p-value is greater than p = 0.05. However, by using standardised effect sizes (SESs) a range of graphical methods and an over-all assessment of the mean absolute response can be made. The approach is an extension, not a replacement of existing methods. It is intended to assist toxicologists and regulators in the interpretation of the results. Here, the SES analysis has been applied to data from nine published sub-acute toxicity tests in order to compare the findings with those of the author's. Line plots, box plots and bar plots show the pattern of response. Dose-response relationships are easily seen. A "bootstrap" test compares the mean absolute differences across dose groups. In four out of seven papers where the no observed adverse effect level (NOAEL) was estimated by the authors, it was set too high according to the bootstrap test, suggesting that possible toxicity is under-estimated.

In an iterated non-cooperative game, if all the players act to maximize their individual accumulated payoff, the system as a whole usually converges to a Nash equilibrium that poorly benefits any player. Here we show that such an undesirable destiny is avoidable in an iterated Rock-Paper-Scissors (RPS) game involving two rational players, X and Y. Player X has the option of proactively adopting a cooperation-trap strategy, which enforces complete cooperation from the rational player Y and leads to a highly beneficial and maximally fair situation to both players. That maximal degree of cooperation is achievable in such a competitive system with cyclic dominance of actions may stimulate further theoretical and empirical studies on how to resolve conflicts and enhance cooperation in human societies.

Citation patterns were examined for Worm et al. 2006 (Science 314:787-790), a high-impact paper that focused on relationships between marine biodiversity and ecosystem services. This paper sparked much controversy through its projection, highlighted in the press release, that all marine fisheries would be collapsed by 2048. Analysis of 664 citing papers revealed that only a small percentage (11%) referred to the 2048 projection, while 39% referred to fisheries collapse in general, and 40% to biodiversity and ecosystem services. The 2048 projection was mentioned more often in papers published soon after the original paper, in low-impact journals, and in journals outside of fields that would be expected to focus on biodiversity. Citing papers also mentioned the 2048 projection more often if they had few authors (28% of single-author papers vs. 2% of papers with 10 or more authors). These factors suggest that the more knowledgeable the authors of citing papers were about the controversy over the 2048 projection, the less likely they were to refer to it. A noteworthy finding was that if the original authors were also involved in the citing papers, they rarely (1 of 55 papers, 2%) mentioned the 2048 projection. Thus the original authors have emphasized the broader concerns about biodiversity loss, rather than the 2048 projection, as the key result of their study.

SettingSouth Africa has the third highest tuberculosis (TB) burden in the world. Intensified case finding, recommended by WHO, is one way to control TB.ObjectiveTo evaluate the effectiveness and acceptability of a paper slip method for TB contact tracing.MethodTB patients were offered paper slips to give to their contacts, inviting them for TB screening. The number of contacts screened and the proportion diagnosed with TB was calculated. Contacts that returned to the clinic after receiving the slips were interviewed. A focus group discussion (FGD) with TB patients was held to determine their acceptability.ResultsFrom 718 paper slips issued, a 26% TB contact tracing rate was found, with a 12% case detection rate. The majority (68%) of contacts were screened within 2 weeks of receiving the slip. Age and gender were not significantly associated with time to screening. 16% of the contacts screened did not reside with the TB patients. 98% of the contacts said the method was acceptable. FGD findings show that this method is acceptable and may prevent stigma associated with TB/HIV.ConclusionThis simple, inexpensive method yields high contact tracing and case detection rates and potentially would yield additional benefits outside households.

E-readers are fast rivaling print as a dominant method for reading. Because they offer accessibility options that are impossible in print, they are potentially beneficial for those with impairments, such as dyslexia. Yet, little is known about how the use of these devices influences reading in those who struggle. Here, we observe reading comprehension and speed in 103 high school students with dyslexia. Reading on paper was compared with reading on a small handheld e-reader device, formatted to display few words per line. We found that use of the device significantly improved speed and comprehension, when compared with traditional presentations on paper for specific subsets of these individuals: Those who struggled most with phoneme decoding or efficient sight word reading read more rapidly using the device, and those with limited VA Spans gained in comprehension. Prior eye tracking studies demonstrated that short lines facilitate reading in dyslexia, suggesting that it is the use of short lines (and not the device per se) that leads to the observed benefits. We propose that these findings may be understood as a consequence of visual attention deficits, in some with dyslexia, that make it difficult to allocate attention to uncrowded text near fixation, as the gaze advances during reading. Short lines ameliorate this by guiding attention to the uncrowded span.

Informed consent is the cornerstone of human research subject protection. Many subjects sign consent documents without understanding the study purpose, procedures, risks, benefits, and their rights. Proof of comprehension is not required and rarely obtained. Understanding might improve by using an interactive system with multiple options for hearing, viewing and reading about the study and the consent form at the subject's own pace with testing and immediate feedback. This prospective randomized study compared the IRB-approved paper ICF for an actual clinical research study with an interactive presentation of the same study and its associated consent form using an iPad device in two populations: clinical research professionals, and patients drawn from a variety of outpatient practice settings. Of the 90 participants, 69 completed the online test and survey questions the day after the session (maximum 36 hours post-session). Among research professionals (n = 14), there was a trend (p = .07) in the direction of iPad subjects testing better on the online test (mean correct = 77%) compared with paper subjects (mean correct = 57%). Among patients (n = 55), iPad subjects had significantly higher test scores than standard paper consent subjects (mean correct = 75% vs 58%, p < .001). For all subjects, the total time spent reviewing the paper consent was 13.2 minutes, significantly less than the average of 22.7 minutes total on the three components to be reviewed using the iPad (introductory video, consent form, interactive quiz). Overall satisfaction and overall enjoyment slightly favored the interactive iPad presentation. This study demonstrates that combining an introductory video, standard consent language, and an interactive quiz on a tablet-based system improves comprehension of research study procedures and risks.

Adiponectin is an adipocyte-derived hormone that acts as a marker of insulin sensitivity. Bloodspot sampling by fingerstick onto filter paper may increase the feasibility of large-scale studies of the determinants of insulin sensitivity. We first describe the validation of an enzyme-linked immunoassay (ELISA) for quantifying adiponectin from dried blood spots and then demonstrate its application in a large trial (PROBIT).We quantified adiponectin from 3-mm diameter discs (≈3 µL of blood) punched from dried blood spots obtained from: i) whole blood standards (validation); and ii) PROBIT trial samples (application) in which paediatricians collected blood spots from 13,879 children aged 11.5 years from 31 sites across Belarus. We examined the distribution of bloodspot adiponectin by demographic and anthropometric factors, fasting insulin and glucose.In the validation study, mean intra-assay coefficients of variation (n=162) were 15%, 13% and 10% for 'low' (6.78 µg/ml), 'medium' (18.18 µg/ml) and 'high' (33.13 µg/ml) internal quality control (IQC) samples, respectively; the respective inter-assay values (n=40) were 23%, 21% and 14%. The correlation coefficient between 50 paired whole bloodspot versus plasma samples, collected simultaneously, was 0.87 (95% CI: 0.78 to 0.93). Recovery of known quantities of adiponectin (between 4.5 to 36 µg/ml) was 100.3-133%. Bloodspot adiponectin was stable for at least 30 months at -80°C. In PROBIT, we successfully quantified fasting adiponectin from dried blood spots in 13,329 of 13,879 (96%) children. Mean adiponectin (standard deviation) concentrations were 17.34 µg/ml (7.54) in boys and 18.41 µg/ml (7.92) in girls and were inversely associated with body mass index, fat mass, triceps and subscapular skin-fold thickness, waist circumference, height and fasting glucose.Bloodspot ELISA is suitable for measuring adiponectin in very small volumes of blood collected on filter paper and can be applied to large-scale studies.

Monitoring for drug-induced liver injury (DILI) via serial transaminase measurements in patients on potentially hepatotoxic medications (e.g., for HIV and tuberculosis) is routine in resource-rich nations, but often unavailable in resource-limited settings. Towards enabling universal access to affordable point-of-care (POC) screening for DILI, we have performed the first field evaluation of a paper-based, microfluidic fingerstick test for rapid, semi-quantitative, visual measurement of blood alanine aminotransferase (ALT). Our objectives were to assess operational feasibility, inter-operator variability, lot variability, device failure rate, and accuracy, to inform device modification for further field testing. The paper-based ALT test was performed at POC on fingerstick samples from 600 outpatients receiving HIV treatment in Vietnam. Results, read independently by two clinic nurses, were compared with gold-standard automated (Roche Cobas) results from venipuncture samples obtained in parallel. Two device lots were used sequentially. We demonstrated high inter-operator agreement, with 96.3% (95% C.I., 94.3-97.7%) agreement in placing visual results into clinically-defined "bins" (5x upper limit of normal), >90% agreement in validity determination, and intraclass correlation coefficient of 0.89 (95% C.I., 0.87-0.91). Lot variability was observed in % invalids due to hemolysis (21.1% for Lot 1, 1.6% for Lot 2) and correlated with lots of incorporated plasma separation membranes. Invalid rates

We describe a method that uses crowdsourced postcode coordinates and Google maps to estimate average distance and travel time for inhabitants of a municipality to a casualty clinic in Norway. The new method was compared with methods based on population centroids, median distance and town hall location, and we used it to examine how distance affects the utilisation of out-of-hours primary care services. At short distances our method showed good correlation with mean travel time and distance. The utilisation of out-of-hours services correlated with postcode based distances similar to previous research. The results show that our method is a reliable and useful tool for estimating average travel distances and travel times.

The aim of this paper is to introduce and assess three algorithms for the identification of overlapping thematic structures in networks of papers. We implemented three recently proposed approaches to the identification of overlapping and hierarchical substructures in graphs and applied the corresponding algorithms to a network of 492 information-science papers coupled via their cited sources. The thematic substructures obtained and overlaps produced by the three hierarchical cluster algorithms were compared to a content-based categorisation, which we based on the interpretation of titles, abstracts, and keywords. We defined sets of papers dealing with three topics located on different levels of aggregation: h-index, webometrics, and bibliometrics. We identified these topics with branches in the dendrograms produced by the three cluster algorithms and compared the overlapping topics they detected with one another and with the three predefined paper sets. We discuss the advantages and drawbacks of applying the three approaches to paper networks in research fields.

BACKGROUND: The CONSORT Statement is a reporting guideline for authors when reporting randomized controlled trials (RCTs). It offers a standard way for authors to prepare RCT reports. It has been endorsed by many high-impact medical journals and by international editorial groups. This study was conducted to assess the endorsement of the CONSORT Statement by high-impact medical journals in China by reviewing their instructions for authors. METHODOLOGY/PRINCIPAL FINDINGS: A total of 200 medical journals were selected according to the Chinese Science and Technology Journal Citation Reports, 195 of which publish clinical research papers. Their instructions for authors were reviewed and all texts mentioning the CONSORT Statement or CONSORT extension papers were extracted. Any mention of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals (URM) developed by the International Committee of Medical Journal Editors (ICMJE) or 'clinical trial registration' was also extracted. For journals endorsing the CONSORT Statement, their most recently published RCT reports were retrieved and evaluated to assess whether the journals have followed what the CONSORT Statement required. Out of the 195 medical journals publishing clinical research papers, only six (6/195, 3.08%) mentioned 'CONSORT' in their instructions for authors; out of the 200 medical journals surveyed, only 14 (14/200, 7.00%) mentioned 'ICMJE' or 'URM' in their instructions for authors, and another five journals stated in their instructions for authors that clinical trials should have trial registration numbers and that priority would be given to clinical trials which had been registered. Among the 62 RCT reports published in the six journals endorsing the CONSORT Statement, 20 (20/62, 32.26%) contained flow diagrams and only three (3/62, 4.84%) provided trial registration information. CONCLUSIONS/SIGNIFICANCE: Medical journals in China endorsing either the CONSORT Statement or the ICMJE's URM constituted a small percentage of the total; all of these journals used ambiguous language regarding what was expected of authors.

A Kuhnian approach to research assessment requires us to consider that the important scientific breakthroughs that drive scientific progress are infrequent and that the progress of science does not depend on normal research. Consequently, indicators of research performance based on the total number of papers do not accurately measure scientific progress. Similarly, those universities with the best reputations in terms of scientific progress differ widely from other universities in terms of the scale of investments made in research and in the higher concentrations of outstanding scientists present, but less so in terms of the total number of papers or citations. This study argues that indicators for the 1% high-citation tail of the citation distribution reveal the contribution of universities to the progress of science and provide quantifiable justification for the large investments in research made by elite research universities. In this tail, which follows a power low, the number of the less frequent and highly cited important breakthroughs can be predicted from the frequencies of papers in the upper part of the tail. This study quantifies the false impression of excellence produced by multinational papers, and by other types of papers that do not contribute to the progress of science. Many of these papers are concentrated in and dominate lists of highly cited papers, especially in lower-ranked universities. The h-index obscures the differences between higher- and lower-ranked universities because the proportion of h-core papers in the 1% high-citation tail is not proportional to the value of the h-index.

In large-scale epidemiology, bloodspot sampling by fingerstick onto filter paper has many advantages, including ease and low costs of collection, processing and transport. We describe the development of an enzyme-linked immunoassay (ELISA) for quantifying insulin from dried blood spots and demonstrate its application in a large trial.We adapted an existing commercial kit (Mercodia Human Insulin ELISA, 10-1113-01) to quantify insulin from two 3-mm diameter discs (≈6 µL of blood) punched from whole blood standards and from trial samples. Paediatricians collected dried blood spots in a follow-up of 13,879 fasted children aged 11.5 years (interquartile range 11.3-11.8 years) from 31 trial sites across Belarus. We quantified bloodspot insulin levels and examined their distribution by demography and anthropometry.Mean intra-assay (n = 157) coefficients of variation were 15% and 6% for 'low' (6.7 mU/L) and 'high' (23.1 mU/L) values, respectively; the respective inter-assay values (n = 33) were 23% and 11%. The intraclass correlation coefficient between 50 paired whole bloodspot versus serum samples, collected simultaneously, was 0.90 (95% confidence interval 0.85 to 0.95). Bloodspot insulin was stable for at least 31 months at -80°C, for one week at +30°C and following four freeze-thaw cycles. Paediatricians collected a median of 8 blood spots from 13,487 (97%) children. The geometric mean insulin (log standard deviation) concentrations amongst 12,812 children were 3.0 mU/L (1.1) in boys and 4.0 mU/L (1.0) in girls and were positively associated with pubertal stage, measures of central and peripheral adiposity, height and fasting glucose.Our simple and convenient bloodspot assay is suitable for the measurement of insulin in very small volumes of blood collected on filter paper cards and can be applied to large-scale epidemiology studies of the early-life determinants of circulating insulin.

In vitro 3D culture is an important model for tissues in vivo. Cells in different locations of 3D tissues are physiologically different, because they are exposed to different concentrations of oxygen, nutrients, and signaling molecules, and to other environmental factors (temperature, mechanical stress, etc). The majority of high-throughput assays based on 3D cultures, however, can only detect the average behavior of cells in the whole 3D construct. Isolation of cells from specific regions of 3D cultures is possible, but relies on low-throughput techniques such as tissue sectioning and micromanipulation. Based on a procedure reported previously ("cells-in-gels-in-paper" or CiGiP), this paper describes a simple method for culture of arrays of thin planar sections of tissues, either alone or stacked to create more complex 3D tissue structures. This procedure starts with sheets of paper patterned with hydrophobic regions that form 96 hydrophilic zones. Serial spotting of cells suspended in extracellular matrix (ECM) gel onto the patterned paper creates an array of 200 micron-thick slabs of ECM gel (supported mechanically by cellulose fibers) containing cells. Stacking the sheets with zones aligned on top of one another assembles 96 3D multilayer constructs. De-stacking the layers of the 3D culture, by peeling apart the sheets of paper, "sections" all 96 cultures at once. It is, thus, simple to isolate 200-micron-thick cell-containing slabs from each 3D culture in the 96-zone array. Because the 3D cultures are assembled from multiple layers, the number of cells plated initially in each layer determines the spatial distribution of cells in the stacked 3D cultures. This capability made it possible to compare the growth of 3D tumor models of different spatial composition, and to examine the migration of cells in these structures.

Recently, there has been a growing emphasis on basic number processing competencies (such as the ability to judge which of two numbers is larger) and their role in predicting individual differences in school-relevant math achievement. Children's ability to compare both symbolic (e.g. Arabic numerals) and nonsymbolic (e.g. dot arrays) magnitudes has been found to correlate with their math achievement. The available evidence, however, has focused on computerized paradigms, which may not always be suitable for universal, quick application in the classroom. Furthermore, it is currently unclear whether both symbolic and nonsymbolic magnitude comparison are related to children's performance on tests of arithmetic competence and whether either of these factors relate to arithmetic achievement over and above other factors such as working memory and reading ability. In order to address these outstanding issues, we designed a quick (2 minute) paper-and-pencil tool to assess children's ability to compare symbolic and nonsymbolic numerical magnitudes and assessed the degree to which performance on this measure explains individual differences in achievement. Children were required to cross out the larger of two, single-digit numerical magnitudes under time constraints. Results from a group of 160 children from grades 1-3 revealed that both symbolic and nonsymbolic number comparison accuracy were related to individual differences in arithmetic achievement. However, only symbolic number comparison performance accounted for unique variance in arithmetic achievement. The theoretical and practical implications of these findings are discussed which include the use of this measure as a possible tool for identifying students at risk for future difficulties in mathematics.

The action required to stem the environmental and social implications of climate change depends crucially on how humankind shapes technology, economy, lifestyle and policy. With transport CO2 emissions accounting for about a quarter of the total, we examine the contribution of CO2 output by scientific travel. Thankfully for the reputation of the scientific community, CO2 emissions associated with the trips required to present a paper at a scientific conference account for just 0.003% of the yearly total. However, with CO2 emissions for a single conference trip amounting to 7% of an average individual's total CO2 emissions, scientists should lead by example by demonstrating leadership in addressing the issue.

Background: Adiponectin is an adipocyte-derived hormone that acts as a marker of insulin sensitivity. Bloodspot sampling by fingerstick onto filter paper may increase the feasibility of large-scale studies of the determinants of insulin sensitivity. We first describe the validation of an enzyme-linked immunoassay (ELISA) for quantifying adiponectin from dried blood spots and then demonstrate its application in a large trial (PROBIT). Methods: We quantified adiponectin from 3-mm diameter discs (≈3 µL of blood) punched from dried blood spots obtained from: i) whole blood standards (validation); and ii) PROBIT trial samples (application) in which paediatricians collected blood spots from 13,879 children aged 11.5 years from 31 sites across Belarus. We examined the distribution of bloodspot adiponectin by demographic and anthropometric factors, fasting insulin and glucose. Results: In the validation study, mean intra-assay coefficients of variation (n = 162) were 15%, 13% and 10% for ‘low’ (6.78 µg/ml), ‘medium’ (18.18 µg/ml) and 'high’ (33.13 µg/ml) internal quality control (IQC) samples, respectively; the respective inter-assay values (n = 40) were 23%, 21% and 14%. The correlation coefficient between 50 paired whole bloodspot versus plasma samples, collected simultaneously, was 0.87 (95% CI: 0.78 to 0.93). Recovery of known quantities of adiponectin (between 4.5 to 36 µg/ml) was 100.3–133%. Bloodspot adiponectin was stable for at least 30 months at −80°C. In PROBIT, we successfully quantified fasting adiponectin from dried blood spots in 13,329 of 13,879 (96%) children. Mean adiponectin (standard deviation) concentrations were 17.34 µg/ml (7.54) in boys and 18.41 µg/ml (7.92) in girls and were inversely associated with body mass index, fat mass, triceps and subscapular skin-fold thickness, waist circumference, height and fasting glucose. Conclusions: Bloodspot ELISA is suitable for measuring adiponectin in very small volumes of blood collected on filter paper and can be applied to large-scale studies. [ABSTRACT FROM AUTHOR]

Highly porous polypyrrole (PPy)-nanocellulose paper sheets have been evaluated as inexpensive and disposable electrochemically controlled three-dimensional solid phase extraction materials. The composites, which had a total anion exchange capacity of about 1.1 mol kg(-1), were used for extraction and subsequent release of negatively charged fluorophore tagged DNA oligomers via galvanostatic oxidation and reduction of a 30-50 nm conformal PPy layer on the cellulose substrate. The ion exchange capacity, which was, at least, two orders of magnitude higher than those previously reached in electrochemically controlled extraction, originated from the high surface area (i.e. 80 m(2) g(-1)) of the porous composites and the thin PPy layer which ensured excellent access to the ion exchange material. This enabled the extractions to be carried out faster and with better control of the PPy charge than with previously employed approaches. Experiments in equimolar mixtures of (dT)(6), (dT)(20), and (dT)(40) DNA oligomers showed that all oligomers could be extracted, and that the smallest oligomer was preferentially released with an efficiency of up to 40% during the reduction of the PPy layer. These results indicate that the present material is very promising for the development of inexpensive and efficient electrochemically controlled ion-exchange membranes for batch-wise extraction of biomolecules.

Understanding intraspecific geographic variation in animal signals poses a challenging evolutionary problem. Studies addressing geographic variation typically focus on signals used in mate-choice, however, geographic variation in intrasexual signals involved in competition is also known to occur. In Polistes dominulus paper wasps, females have black facial spots that signal dominance: individuals wasps with more complex 'broken' facial patterns are better fighters and are avoided by rivals. Recent work suggests there is dramatic geographic variation in these visual signals of quality, though this variation has not been explicitly described or quantified. Here, we analyze variation in P. dominulus signals across six populations and explore how environmental conditions may account for this variation. Overall, we found substantial variation in facial pattern brokenness across populations and castes. Workers have less broken facial patterns than gynes and queens, which have similar facial patterns. Strepsipteran parasitism, body size and temperature are all correlated with the facial pattern variation, suggesting that developmental plasticity likely plays a key role in this variation. First, the extent of parasitism varies across populations and parasitized individuals have lower facial pattern brokenness than unparasitized individuals. Second, there is substantial variation in body size across populations and a weak but significant relationship between facial pattern brokenness and body size. Wasps from populations with smaller body size (e.g. Italy) tend to have less broken facial patterns than wasps from populations with larger body size (e.g. New York, USA). Third, there is an apparent association between facial patterns and climate, with wasp from cooler locations tending to have higher facial pattern brokenness than wasps from warmer locations. Additional experimental work testing the causes and consequences of facial pattern variation will be important, as geographic variation in signals has important consequences for the evolution of communication systems and social behavior.

Ecological studies of orangutans have almost exclusively focused on populations living in primary or selectively logged rainforest. The response of orangutans to severe habitat degradation remains therefore poorly understood. Most experts assume that viable populations cannot survive outside undisturbed or slightly disturbed forests. This is a concern because nearly 75% of all orangutans live outside protected areas, where degradation of natural forests is likely to occur, or where these are replaced by planted forests. To improve our understanding of orangutan survival in highly altered forest habitats, we conducted population density surveys in two pulp and paper plantation concessions in East Kalimantan, Indonesia. These plantations consist of areas planted with fast-growing exotics intermixed with stands of highly degraded forests and scrublands. Our rapid surveys indicate unexpectedly high orangutan densities in plantation landscapes dominated by Acacia spp., although it remains unclear whether such landscapes can maintain long-term viable populations. These findings indicate the need to better understand how plantation-dominated landscapes can potentially be incorporated into orangutan conservation planning. Although we emphasize that plantations have less value for overall biodiversity conservation than natural forests, they could potentially boost the chances of orangutan survival. Our findings are based on a relatively short study and various methodological issues need to be addressed, but they suggest that orangutans may be more ecologically flexible than previously thought.

In the context of a randomized controlled trial (RCT) on HIV testing in the emergency department (ED) setting, we evaluated preferences for survey modality and data quality arising from each modality.Enrolled participants were offered the choice of answering a survey via audio computer assisted self-interview (ACASI) or pen and paper self-administered questionnaire (SAQ). We evaluated factors influencing choice of survey modality. We defined unusable data for a particular survey domain as answering fewer than 75% of the questions in the domain. We then compared ACASI and SAQ with respect to unusable data for domains that address sensitive topics.Of 758 enrolled ED patients, 218 (29%) chose ACASI, 343 chose SAQ (45%) and 197 (26%) opted not to complete either. Results of the log-binomial regression indicated that older (RR = 1.08 per decade) and less educated participants (RR = 1.25) were more likely to choose SAQ over ACASI. ACASI yielded substantially less unusable data than SAQ.In the ED setting there may be a tradeoff between increased participation with SAQ versus better data quality with ACASI. Future studies of novel approaches to maximize the use of ACASI in the ED setting are needed.

Amongst the numerous problems associated with the use of impact factors as a measure of quality are the systematic differences in impact factors that exist among scientific fields. While in theory this can be circumvented by limiting comparisons to journals within the same field, for a diverse and multidisciplinary field like evolutionary biology, in which the majority of papers are published in journals that publish both evolutionary and non-evolutionary papers, this is impossible. However, a journal's overall impact factor may well be a poor predictor for the impact of its evolutionary papers. The extremely high impact factors of some multidisciplinary journals, for example, are by many believed to be driven mostly by publications from other fields. Despite plenty of speculation, however, we know as yet very little about the true impact of evolutionary papers in journals not specifically classified as evolutionary. Here I present, for a wide range of journals, an analysis of the number of evolutionary papers they publish and their average impact. I show that there are large differences in impact among evolutionary and non-evolutionary papers within journals; while the impact of evolutionary papers published in multidisciplinary journals is substantially overestimated by their overall impact factor, the impact of evolutionary papers in many of the more specialized, non-evolutionary journals is significantly underestimated. This suggests that, for evolutionary biologists, publishing in high-impact multidisciplinary journals should not receive as much weight as it does now, while evolutionary papers in more narrowly defined journals are currently undervalued. Importantly, however, their ranking remains largely unaffected. While journal impact factors may thus indeed provide a meaningful qualitative measure of impact, a fair quantitative comparison requires a more sophisticated journal classification system, together with multiple field-specific impact statistics per journal.