Recommendations on multiple testing adjustment in multi-arm trials with a shared control group

Multi-arm clinical trials assessing multiple experimental treatments against a shared control group can offer efficiency advantages over independent trials through assessing an increased number of hypotheses. Published opinion is divided on the requirement for multiple testing adjustment to control the family-wise type-I error rate (FWER). The probability of a false positive error in multi-arm trials compared to equivalent independent trials is affected by the correlation between comparisons due to sharing control data. We demonstrate that this correlation in fact leads to a reduction in the FWER, therefore FWER adjustment is not recommended solely due to sharing control data. In contrast, the correlation increases the probability of multiple false positive outcomes across the hypotheses, although standard FWER adjustment methods do not control for this. A stringent critical value adjustment is proposed to maintain equivalent evidence of superiority in two correlated comparisons to that obtained within independent trials. FWER adjustment is only required if there is an increased chance of making a single claim of effectiveness by testing multiple hypotheses, not due to sharing control data. For competing experimental therapies, the correlation between comparisons can be advantageous as it eliminates bias due to the experimental therapies being compared to different control populations

Evaluation of Hydrodynamic Drag on Experimental Fouling-release Surfaces, using Rotating Disks

Fouling by biofilms significantly increases frictional drag on ships' hulls. A device, the friction disk machine, designed to measure torque on rotating disks, was used to examine differences among experimental fouling-release coatings in the drag penalty due to accumulated biofilms. Penalties were measured as the percentage change in the frictional resistance coefficient C f . Drag penalties due to microfouling ranged from 9% to 29%, comparable to previously reported values. An antifouling control coating showed a smaller drag penalty than the fouling-release coatings. There were also significant differences among the fouling-release coatings in drag due to biofilm formation. These results indicate that the friction disk machine may serve as a valuable tool for investigating the effects of experimental coatings, both antifouling and fouling-release, on microfouling and associated drag penalties

Can filesharers be triggered by economic incentives? Results of an experiment

Illegal filesharing on the internet leads to considerable financial losses for artists and copyright owners as well as producers and sellers of music. Thus far, measures to contain this phenomenon have been rather restrictive. However, there are still a considerable number of illegal systems, and users are able to decide quite freely between legal and illegal downloads because the latter are still difficult to sanction. Recent economic approaches account for the improved bargaining position of users. They are based on the idea of revenue-splitting between professional sellers and peers. In order to test such an innovative business model, the study reported in this article carried out an experiment with 100 undergraduate students, forming five small peer-to-peer networks.The networks were confronted with different economic conditions.The results indicate that even experienced filesharers hold favourable attitudes towards revenue-splitting.They seem to be willing to adjust their behaviour to different economic conditions

Nogo-A is secreted in extracellular vesicles, occurs in blood and can influence vascular permeability

Nogo-A is a transmembrane protein with multiple functions in the central nervous system (CNS), including restriction of neurite growth and synaptic plasticity. Thus far, Nogo-A has been predominantly considered a cell contact-dependent ligand signaling via cell surface receptors. Here, we show that Nogo-A can be secreted by cultured cells of neuronal and glial origin in association with extracellular vesicles (EVs). Neuron- and oligodendrocyte-derived Nogo-A containing EVs inhibited fibroblast spreading, and this effect was partially reversed by Nogo-A receptor S1PR2 blockage. EVs purified from HEK cells only inhibited fibroblast spreading upon Nogo-A over-expression. Nogo-A-containing EVs were found in vivo in the blood of healthy mice and rats, as well as in human plasma. Blood Nogo-A concentrations were elevated after acute stroke lesions in mice and rats. Nogo-A active peptides decreased barrier integrity in an in vitro blood-brain barrier model. Stroked mice showed increased dye permeability in peripheral organs when tested 2 weeks after injury. In the Miles assay, an in vivo test to assess leakage of the skin vasculature, a Nogo-A active peptide increased dye permeability. These findings suggest that blood borne, possibly EV-associated Nogo-A could exert long-range regulatory actions on vascular permeability

Radio Astronomy

Contains reports on five research projects.National Science Foundation (Grant AST82-14296)National Aeronautics and Space Administration (Grant NAG W-373)National Aeronautics and Space Administration (Grant NAG5-537)U.S. Navy - Office of Naval Research (Contract N00014-84-C-2082)SM Systems and Research, Inc.Defense Advanced Research Project Agency (Contract MDA903-82-K-0521

Radio Astronomy

Contains summary of research and reports on seven research projects.National Science Foundation (Grant AST82-14296)National Aeronautics and Space Administration (Grant NAGW-373)National Aeronautics and Space Administration (Contract NAS5-28410)U.S. Navy - Office of Naval Research (Contract N00014-84-C-2082)M.I.T. Sloan Fund for Basic ResearchNational Oceanic and Atmospheric Administration (Grant 04-8-M01-1)National Aeronautics and Space Administration (Grant NAG5-10)Defense Advanced Research Project Agency (Contract MDA 903-84-K-0297

Comparison of F(ab') versus Fab antivenom for pit viper envenomation: A prospective, blinded, multicenter, randomized clinical trial

BACKGROUND: Crotalidae Polyvalent Immune Fab (Ovine) has been the only antivenom commercially available in the US since 2007 for treatment of Crotalinae envenomation. Late coagulopathy can occur or recur after clearance of Fab antivenom, often after hospital discharge, lasting in some cases more than 2 weeks. There have been serious, even fatal, bleeding complications associated with recurrence phenomena. Frequent follow-up is required, and additional intervention or hospitalization is often necessary. F(ab')2 immunoglobulin derivatives have longer plasma half life than do Fab. We hypothesized that F(ab')2 antivenom would be superior to Fab in the prevention of late coagulopathy following treatment of patients with Crotalinae envenomation. METHODS: We conducted a prospective, double-blind, randomized clinical trial, comparing late coagulopathy in snakebitten patients treated with F(ab')2 with maintenance doses [F(ab')2/F(ab')2], or F(ab')2 with placebo maintenance doses [F(ab')2/placebo], versus Fab with maintenance doses [Fab/Fab]. The primary efficacy endpoint was coagulopathy (platelet count < 150 K/mm(3), fibrinogen level < 150 mg/dL) between end of maintenance dosing and day 8. RESULTS: 121 patients were randomized at 18 clinical sites and received at least one dose of study drug. 114 completed the study. Of these, 11/37 (29.7%) in the Fab/Fab cohort experienced late coagulopathy versus 4/39 (10.3%, p < 0.05) in the F(ab')2/F(ab')2 cohort and 2/38 (5.3%, p < 0.05) in the F(ab')2/placebo cohort. The lowest heterologous protein exposure was with F(ab')2/placebo. No serious adverse events were related to study drug. In each study arm, one patient experienced an acute serum reaction and one experienced serum sickness. CONCLUSIONS: In this study, management of coagulopathic Crotalinae envenomation with longer-half-life F(ab')2 antivenom, with or without maintenance dosing, reduced the risk of subacute coagulopathy and bleeding following treatment of envenomation

Characterizing phytoplankton biomass seasonal cycles in two NE Atlantic coastal bays

The seasonal and interannual variability of chlorophyll a was studied between 2008 and 2016 in two coastal bays located in the northeastern limit of the Iberia/Canary upwelling ecosystem. The work aims (i) to understand if small latitudinal distances and/or coastline orientation can promote different chlorophyll a seasonal cycles; and (ii) to investigate if different meteorological and oceanographic variables can explain the differences observed on seasonal cycles. Results indicate three main biological seasons with different patterns in the two studied bays. A uni-modal pattern with a short early summer maximum and relatively low chlorophyll a concentration characterized the westernmost sector of the South coast, while a uni-modal pattern characterized by high biomass over a long period, slightly higher in spring than in summer, and high chlorophyll a concentration characterized the central West coast. Comparisons made between satellite estimates of chlorophyll a and in situ data in one of the bays revealed some important differences, namely the overestimation of concentrations and the anticipation of the beginning and end time of the productive period by satellite. Cross-correlation analyses were performed for phytoplankton biomass and different meteorological and oceanographic variables (SST, PAR, UI, MLD and precipitation) using different time lags to identify the drivers that promote the growth and the high levels of phytoplankton biomass. PAR contributed to the increase of phytoplankton biomass observed during winter/midspring, while upwelling and SST were the main explanatory drivers to the high Chl-a concentrations observed in late-spring/summer. Zonal transport was the variable that contributed most to the phytoplankton biomass during late-spring/summer in Lisbon Bay, while the meridional transport combined with SST was more important in Lagos Bay.FCT: SFRH/BD/52560/2014/ IPMA-BCC-2016-35/ UIDB/04292/2020/ UID/Multi/04326/2020/ UID/MAT/04561/2020 LISBOA-01-0145FEDER-031265 IPMA: MAR2020PO2M01-1490 Pinfo:eu-repo/semantics/publishedVersio

No changes in parieto-occipital alpha during neural phase locking to visual quasi-periodic theta-, alpha-, and beta-band stimulation

Recent studies have probed the role of the parieto‐occipital alpha rhythm (8 – 12 Hz) in human visual perception through attempts to drive its neural generators. To that end, paradigms have used high‐intensity strictly‐periodic visual stimulation that created strong predictions about future stimulus occurrences and repeatedly demonstrated perceptual consequences in line with an entrainment of parieto‐occipital alpha. Our study, in turn, examined the case of alpha entrainment by non‐predictive low‐intensity quasi‐periodic visual stimulation within theta‐ (4 – 7 Hz), alpha‐ (8 – 13 Hz) and beta (14 – 20 Hz) frequency bands, i.e. a class of stimuli that resemble the temporal characteristics of naturally occurring visual input more closely. We have previously reported substantial neural phase‐locking in EEG recording during all three stimulation conditions. Here, we studied to what extent this phase‐locking reflected an entrainment of intrinsic alpha rhythms in the same dataset. Specifically, we tested whether quasi‐periodic visual stimulation affected several properties of parieto‐occipital alpha generators. Speaking against an entrainment of intrinsic alpha rhythms by non‐predictive low‐intensity quasi‐periodic visual stimulation, we found none of these properties to show differences between stimulation frequency bands. In particular, alpha band generators did not show increased sensitivity to alpha band stimulation and Bayesian inference corroborated evidence against an influence of stimulation frequency. Our results set boundary conditions for when and how to expect effects of entrainment of alpha generators and suggest that the parieto‐occipital alpha rhythm may be more inert to external influences than previously thought

Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes ($\textit{ITGA4 }$ and $\textit{ITGB8}$) and at previously implicated loci ($\textit{ITGAL }$and $\textit{ICAM1}$). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, $\textit{PLCG2}$, and a negative regulator of inflammation, $\textit{SLAMF8}$. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.This work was co-funded by the Wellcome Trust [098051] and the Medical Research Council, UK [MR/J00314X/1]. Case collections were supported by Crohn’s and Colitis UK. KMdL, LM, CAL, YL, DR, JG-A, NJP, CAA and JCB are supported by the Wellcome Trust [098051; 093885/Z/10/Z; 094491/Z/10/Z]. KMdL is supported by a Woolf Fisher Trust scholarship. CAL is a clinical lecturer funded by the NIHR. We thank Anna Stanton for co-ordinating the Guy’s and St Thomas’ patient recruitment. We acknowledge support from the Department of Health via the NIHR comprehensive Biomedical Research Centre awards to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and to Addenbrooke’s Hospital, Cambridge in partnership with the University of Cambridge. This research was also supported by the NIHR Newcastle Biomedical Research Centre. The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council