PRO Data Collection in Clinical Trials Using Mixed Modes: Report of the ISPOR PRO Mixed Modes Good Research Practices Task Force

AbstractThe objective of this report was to address the use and mixing of data collection modes within and between trials in which patient-reported outcome (PRO) end points are intended to be used to support medical product labeling. The report first addresses the factors that should be considered when selecting a mode or modes of PRO data collection in a clinical trial, which is often when mixing is first considered. Next, a summary of how to "faithfully" migrate instruments is presented followed by a section on qualitative and quantitative study designs used to evaluate measurement equivalence of the new and original modes of data collection. Finally, the report discusses a number of issues that must be taken into account when mixing modes is deemed necessary or unavoidable within or between trials, including considerations of the risk of mixing at different levels within a clinical trial program and mixing between different types of platforms. In the absence of documented evidence of measurement equivalence, it is strongly recommended that a quantitative equivalence study be conducted before mixing modes in a trial to ensure that sufficient equivalence can be demonstrated to have confidence in pooling PRO data collected by the different modes. However, we also strongly discourage the mixing of paper and electronic field-based instruments and suggest that mixing of electronic modes be considered for clinical trials and only after equivalence has been established. If proceeding with mixing modes, it is important to implement data collection carefully in the trial itself in a planned manner at the country level or higher and minimize ad hoc mixing by sites or individual subjects. Finally, when mixing occurs, it must be addressed in the statistical analysis plan for the trial and the ability to pool the data must be evaluated to then evaluate treatment effects with mixed modes data. A successful mixed modes trial requires a "faithful migration," measurement equivalence established between modes, and carefully planned implementation to minimize the risk of increased measurement error impacting the power of the trial to detect a treatment effect

HelioSwarm: A Multipoint, Multiscale Mission to Characterize Turbulence

HelioSwarm (HS) is a NASA Medium-Class Explorer mission of the Heliophysics Division designed to explore the dynamic three-dimensional mechanisms controlling the physics of plasma turbulence, a ubiquitous process occurring in the heliosphere and in plasmas throughout the universe. This will be accomplished by making simultaneous measurements at nine spacecraft with separations spanning magnetohydrodynamic and sub-ion spatial scales in a variety of near-Earth plasmas. In this paper, we describe the scientific background for the HS investigation, the mission goals and objectives, the observatory reference trajectory and instrumentation implementation before the start of Phase B. Through multipoint, multiscale measurements, HS promises to reveal how energy is transferred across scales and boundaries in plasmas throughout the universe

Genome-wide association identifies ATOH7 as a major gene determining human optic disc size

Optic nerve assessment is important for many blinding diseases, with cup-to-disc ratio (CDR) assessments commonly used in both diagnosis and progression monitoring of glaucoma patients. Optic disc, cup, rim area and CDR measurements all show substantial variation between human populations and high heritability estimates within populations. To identify loci underlying these quantitative traits, we performed a genome-wide association study in two Australian twin cohorts and identified rs3858145, P = 6.2 × 10−10, near the ATOH7 gene as associated with the mean disc area. ATOH7 is known from studies in model organisms to play a key role in retinal ganglion cell formation. The association with rs3858145 was replicated in a cohort of UK twins, with a meta-analysis of the combined data yielding P = 3.4 × 10−10. Imputation further increased the evidence for association for several SNPs in and around ATOH7 (P = 1.3 × 10−10 to 4.3 × 10−11, top SNP rs1900004). The meta-analysis also provided suggestive evidence for association for the cup area at rs690037, P = 1.5 × 10−7, in the gene RFTN1. Direct sequencing of ATOH7 in 12 patients with optic nerve hypoplasia, one of the leading causes of blindness in children, revealed two novel non-synonymous mutations (Arg65Gly, Ala47Thr) which were not found in 90 unrelated controls (combined Fisher's exact P = 0.0136). Furthermore, the Arg65Gly variant was found to have very low frequency (0.00066) in an additional set of 672 controls

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

A Cdc48 “Retrochaperone” Function Is Required for the Solubility of Retrotranslocated, Integral Membrane Endoplasmic Reticulum-associated Degradation (ERAD-M) Substrates* * This work was supported by National Institutes of Health Grant 5R37DK051996-18 (to R. H.), National Institutes of Health Postdoctoral Fellowship 1F32GM111024-01 (to S. N.), and Burroughs Wellcome Fund 1013987 (to S. N.) and DP2GM119132 (to E. J. B). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

A surprising feature of endoplasmic reticulum (ER)-associated degradation (ERAD) is the movement, or retrotranslocation, of ubiquitinated substrates from the ER lumen or membrane to the cytosol where they are degraded by the 26S proteasome. Multispanning ER membrane proteins, called ERAD-M substrates, are retrotranslocated to the cytosol as full-length intermediates during ERAD, and we have investigated how they maintain substrate solubility. Using an in vivo assay, we show that retrotranslocated ERAD-M substrates are moved to the cytoplasm as part of the normal ERAD pathway, where they are part of a solely proteinaceous complex. Using proteomics and direct biochemical confirmation, we found that Cdc48 serves as a critical "retrochaperone" for these ERAD-M substrates. Cdc48 binding to retrotranslocated, ubiquitinated ERAD-M substrates is required for their solubility; removal of the polyubiquitin chains or competition for binding by addition of free polyubiquitin liberated Cdc48 from retrotranslocated proteins and rendered them insoluble. All components of the canonical Cdc48 complex Cdc48-Npl4-Ufd1 were present in solubilized ERAD-M substrates. This function of the complex was observed for both HRD and DOA pathway substrates. Thus, in addition to the long known ATP-dependent extraction of ERAD substrates during retrotranslocation, the Cdc48 complex is generally and critically needed for the solubility of retrotranslocated ERAD-M intermediates

Malaria in the Australian Defence Force: the Bougainville experience

During a 5-year period, almost 4000 Australian personnel served in the Papua New Guinean province of\ud Bougainville.\ud \ud 1.The first randomised, double-blind trial comparing Malarone (a combination of atovaquone and proguanil) with doxycycline was conducted during the deployment. Malarone was as effective as doxycycline and better tolerated.\ud \ud 2.Another trial compared a 3-day course of tafenoquine with the course of primaquine that was standard at that\ud time for post-exposure prophylaxis. There was no statistical difference in rates of malaria following either regimen.\ud \ud 3. There were 64 episodes of malaria affecting 50 individuals. This gave an attack rate of 41.6 malarious\ud episodes per 1000 man years. Most attacks occurred after the person had returned to Australia.\ud 4.The dosage of primaquine was increased partway through the deployment, from 22.5mg to 30mg per day.\ud \ud The attack rate fell from 67.1 to 13.2 per 1000 man years. The attack rate following tafenoquine post-exposure\ud ADF Health 2004; 5: 69-72 prophylaxis was 63.5 per 1000 man years

Unseen Labor

Interview portion of Lost in the Stacks, episode 526. Features interview with Ann Kardos, metadata librarian at the University of Massachusetts Amherst, and creator of the Unseen Labor project. Unseen Labor is a collaboration of creative embroidered, cross-stitched, and sewn pieces that represent the often unrecognized work of metadata librarians

The Library Between the Lines

Interview portion of Lost in the Stacks, episode 428. Features interview with Dr Jacqueline Royster, Dean of the Ivan Allen College of Liberal Arts at Georgia Tech, about her experiences in libraries in her academic career, and how marginalized groups can be discovered in a research setting

Uncatalogung Neutrality

Interview portion of Lost in the Stacks Episode 392, broadcast July 20, 2018. Features guest producers Sonya Slutskaya and Marlee Givens interviewing Amber Billey of Bard College about the impossibility of being neutral in the cataloging of library resources