Reporting bias in drug trials submitted to the Food and Drug Administration: review of publication and presentation.

BackgroundPrevious studies of drug trials submitted to regulatory authorities have documented selective reporting of both entire trials and favorable results. The objective of this study is to determine the publication rate of efficacy trials submitted to the Food and Drug Administration (FDA) in approved New Drug Applications (NDAs) and to compare the trial characteristics as reported by the FDA with those reported in publications.Methods and findingsThis is an observational study of all efficacy trials found in approved NDAs for New Molecular Entities (NMEs) from 2001 to 2002 inclusive and all published clinical trials corresponding to the trials within the NDAs. For each trial included in the NDA, we assessed its publication status, primary outcome(s) reported and their statistical significance, and conclusions. Seventy-eight percent (128/164) of efficacy trials contained in FDA reviews of NDAs were published. In a multivariate model, trials with favorable primary outcomes (OR = 4.7, 95% confidence interval [CI] 1.33-17.1, p = 0.018) and active controls (OR = 3.4, 95% CI 1.02-11.2, p = 0.047) were more likely to be published. Forty-one primary outcomes from the NDAs were omitted from the papers. Papers included 155 outcomes that were in the NDAs, 15 additional outcomes that favored the test drug, and two other neutral or unknown additional outcomes. Excluding outcomes with unknown significance, there were 43 outcomes in the NDAs that did not favor the NDA drug. Of these, 20 (47%) were not included in the papers. The statistical significance of five of the remaining 23 outcomes (22%) changed between the NDA and the paper, with four changing to favor the test drug in the paper (p = 0.38). Excluding unknowns, 99 conclusions were provided in both NDAs and papers, nine conclusions (9%) changed from the FDA review of the NDA to the paper, and all nine did so to favor the test drug (100%, 95% CI 72%-100%, p = 0.0039).ConclusionsMany trials were still not published 5 y after FDA approval. Discrepancies between the trial information reviewed by the FDA and information found in published trials tended to lead to more favorable presentations of the NDA drugs in the publications. Thus, the information that is readily available in the scientific literature to health care professionals is incomplete and potentially biased

Spiders Use Structural Conversion of Globular Amyloidogenic Domains to Make Strong Silk Fibers

Spider silk-an environmentally friendly protein-based material-is widely recognized for its extraordinary mechanical properties. Biomimetic spider silk-like fibers made from recombinant spider silk proteins (spidroins) currently falls short compared to natural silks in terms of mechanical performance. In this study, it is discovered that spiders use structural conversion of molecular enhancers-conserved globular 127-residue spacer domains-to make strong silk fibers. This domain lacks poly-Ala motifs but interestingly contains motifs that are similar to human amyloidogenic motifs, and that it self-assembles into amyloid-like fibrils through a non-nucleation-dependent pathway, likely to avoid the formation of cytotoxic intermediates. Incorporating this spacer domain into a recombinant chimeric spidroin facilitates self-assembly into silk-like fibers, increases fiber molecular homogeneity, and markedly enhances fiber mechanical strength. These findings highlight that spiders employ diverse strategies to produce silk with exceptional mechanical properties. The spacer domain offers a way to enhance the properties of recombinant spider silk-like fibers and other functional materials.Spiders use structural conversion of the conserved globular 127-residue spacer domains to make strong silk fibers. This domain, interestingly containing motifs that are similar to human amyloidogenic motifs, self-assembles into amyloid-like fibrils through a non-nucleation-dependent pathway. Integrating this spacer into a chimeric spidroin enhances silk-like fiber assembly, improves molecular homogeneity and significantly strengthens the fibers. imag

An Investigation of the Mechanism of Emulsion Stabilization by 4-Hydroxy-6-Methyl-1,3,3a,7-Tetraazaindene

There is considerable speculation in literature as to the mechanism of photographic emulsion stabilization by 4-hydroxy-6-methyl-1,3,3a,7-tetraazaindene, (Aza). Aza is important as a stabilizer because, unlike the heterocyclic mercaptans, it causes no desensitization when the emulsion is processed in the commonly used MQ developing agents. The mercaptans are strongly adsorbed, whereas Aza is weakly adsorbed on silver halide. Therefore, there has been speculation that the stabilization mechanism of Aza is distinctly different from that of the mercaptans. For this work, Aza was tested as an antifogging agent and development restrainer along with KBr, as a reference, in two developers which function at emulsion pH, (6 to 7): (1) Amidol at pH 6, 7, and 8, and (2) the ferrous ethylenediaminetetraacetate (EDTA) complex ion at pH 4.5, 7.0, 8.5, and 10.0. KODAK Fine Grain Positive Film, 5302, was used with both developers, and KODAK PANATOMIC-X Fine Grain Film, 5060, was used only with Fe-EDTA. Aza and KBr were compared sensitometrically for effects on fog, contrast index, and exposure index. This sensitometric evaluation comprises Section 1 of this work. The evaluation yielded evidence that at the pH of photographic emulsions, (near 7), and in concentrations of Aza normally used in the emulsions, (1 to 2 grams/mol Ag X), Aza, like KBr, was both a restrainer and an antifoggant during the development of the 5302 Film by both Amidol and Fe-EDTA. PANATOMIC-X Film, 5060, processed in Fe-EDTA gave similar results. The restraint of development by Aza decreased at pH values above 8.5. This evidence and the fact that Aza is adsorbed on the grains of the emulsion to the same extent as the mercaptans, when present in amounts normally used, remove the necessity for assuming two distinctly different mechanisms of emulsion stabilization. The fact that Aza caused no desensitization or restraining action during development at the high pH of the commonly used MQ developers is explained by its desorption from the development centers. Section 2 of this work consists of a study in determining if there was an increase in the adsorption of Aza on silver bromide as a result of any effective increase in the concentration of Aza after drying the emulsion. An adsorption equilibrium exists between 1, 1\u27-diethyl-2, 2\u27-cyanine iodide dye and Aza on silver bromide in the emulsion. Because the displacement, or deaggregation, of dye by Aza was evidenced by a decrease in the J-band strength of the dye, this decrease in J-band absorption at 575 nm was a convenient measure of the equilibrium. Aza not only decreased the J-band strength of the dye but also caused the appearance of two bands, identified as unaggregated dye in gelatin, one with maximum at 495 nm and the other near 530 nm. This is evidence that Aza not only deaggregated the dye but also displaced it from the AgBr. The analysis was made with a Beckman DK-2A Spectrophotometer which measured total reflectance and transmittance by means of an integrating sphere over the wavelength range 380 to 730 nm. From these data, absorption was calculated for the dye in the presence and the absence of Aza both wet and dry. The results of Section 2 of this work are evidence that the adsorption equilibrium between Aza and dye on silver bromide did not significantly change on drying the emulsion in spite of the change in the concentration of Aza from the wet to the dry emulsion

Decision-making and integrated assessment models of the water-energy-food nexus

Studying trade-offs in the long-term development of water-energy-food systems requires a new family of hydroeconomic optimization models. This article reviews the central con- siderations behind these models, highlighting the importance of water infrastructure, the foundations of a theory of decision-making, and the handling of uncertainty. Integrated as- sessment models (IAMs), used in climate change policy research, provide insights that can support this development. In particular, IAM approaches to intertemporal decision-making and economic valuation can improve existing models. At the same time, IAMs have weak- nesses identified elsewhere and can benefit from the development of hydroeconomic models, which have complementary strengths

Canadian American Relations and World Peace: an Address

An address made at the Annual Conference of the 193rd District, Rotary International at Quebec, May 25-27, 1939

Advances in the Theory of Determinantal Point Processes

The theory of determinantal point processes has its roots in work in mathematical physics in the 1960s, but it is only in recent years that it has been developed beyond several specific examples. While there is a rich probabilistic theory, there are still many open questions in this area, and its applications to statistics and machine learning are still largely unexplored. Our contributions are threefold. First, we develop the theory of determinantal point processes on a finite set. While there is a small body of literature on this topic, we offer a new perspective that allows us to unify and extend previous results. Second, we investigate several new kernels. We describe these processes explicitly, and investigate the new discrete distribution which arises from our computations. Finally, we show how the parameters of a determinantal point process over a finite ground set with a symmetric kernel may be computed if infinite samples are available. This algorithm is a vital step towards the use of determinantal point processes as a general statistical model