A Flexible Multi-Metric Bayesian Framework for Decision-Making in Phase II Multi-Arm Multi-Stage Studies

We propose a multi-metric flexible Bayesian framework to support efficient interim decision-making in multi-arm multi-stage phase II clinical trials. Multi-arm multi-stage phase II studies increase the efficiency of drug development, but early decisions regarding the futility or desirability of a given arm carry considerable risk since sample sizes are often low and follow-up periods may be short. Further, since intermediate outcomes based on biomarkers of treatment response are rarely perfect surrogates for the primary outcome and different trial stakeholders may have different levels of risk tolerance, a single hypothesis test is insufficient for comprehensively summarizing the state of the collected evidence. We present a Bayesian framework comprised of multiple metrics based on point estimates, uncertainty, and evidence towards desired thresholds (a Target Product Profile, TPP) for 1) ranking of arms and 2) comparison of each arm against an internal control. Using a large public-private partnership targeting novel TB arms as a motivating example, we find via simulation study that our multi-metric framework provides sufficient confidence for decision-making with sample sizes as low as 30 patients per arm, even when intermediate outcomes have only moderate correlation with the primary outcome. Our reframing of trial design and the decision-making procedure has been well-received by research partners and is a practical approach to more efficient assessment of novel therapeutics.Comment: 16 pages, 6 main text figures, 3 supplemental figure

Analysis of counts for cluster randomized trials: Negative controls and test-negative designs.

In cluster randomized trials (CRTs), the outcome of interest is often a count at the cluster level. This occurs, for example, in evaluating an intervention with the outcome being the number of infections of a disease such as HIV or dengue or the number of hospitalizations in the cluster. Standard practice analyzes these counts through cluster outcome rates using an appropriate denominator (eg, population size). However, such denominators are sometimes unknown, particularly when the counts depend on a passive community surveillance system. We consider direct comparison of the counts without knowledge of denominators, relying on randomization to balance denominators. We also focus on permutation tests to allow for small numbers of randomized clusters. However, such approaches are subject to bias when there is differential ascertainment of counts across arms, a situation that may occur in CRTs that cannot implement blinded interventions. We suggest the use of negative control counts as a method to remove, or reduce, this bias, discussing the key properties necessary for an effective negative control. A current example of such a design is the recent extension of test-negative designs to CRTs testing community-level interventions. Via simulation, we compare the performance of new and standard estimators based on CRTs with negative controls to approaches that only use the original counts. When there is no differential ascertainment by intervention arm, the count-only approaches perform comparably to those using debiasing negative controls. However, under even modest differential ascertainment, the count-only estimators are no longer reliable

Scintillation and charge extraction from the tracks of energetic electrons in superfluid helium-4

An energetic electron passing through liquid helium causes ionization along its track. The ionized electrons quickly recombine with the resulting positive ions, which leads to the production of prompt scintillation light. By applying appropriate electric fields, some of the ionized electrons can be separated from their parent ions. The fraction of the ionized electrons extracted in a given applied field depends on the separation distance between the electrons and the ions. We report the determination of the mean electron-ion separation distance for charge pairs produced along the tracks of beta particles in superfluid helium at 1.5 K by studying the quenching of the scintillation light under applied electric fields. Knowledge of this mean separation parameter will aid in the design of particle detectors that use superfluid helium as a target material.Comment: 10 pages, 8 figure

Spectral Energy Distributions of Local Luminous And Ultraluminous Infrared Galaxies

Luminous and ultraluminous infrared galaxies ((U)LIRGs) are the most extreme star forming galaxies in the universe. The local (U)LIRGs provide a unique opportunity to study their multi-wavelength properties in detail for comparison to their more numerous counterparts at high redshifts. We present common large aperture photometry at radio through X-ray wavelengths, and spectral energy distributions (SEDs) for a sample of 53 nearby LIRGs and 11 ULIRGs spanning log (LIR/Lsun) = 11.14-12.57 from the flux-limited Great Observatories All-sky LIRG Survey (GOALS). The SEDs for all objects are similar in that they show a broad, thermal stellar peak and a dominant FIR thermal dust peak, where nuLnu(60um) / nuLnu(V) increases from ~2-30 with increasing LIR. When normalized at IRAS-60um, the largest range in the luminosity ratio, R(lambda)=log[nuLnu(lambda)/nuLnu(60um)] observed over the full sample is seen in the Hard X-rays (HX=2-10 keV). A small range is found in the Radio (1.4GHz), where the mean ratio is largest. Total infrared luminosities, LIR(8-1000um), dust temperatures, and dust masses were computed from fitting thermal dust emission modified blackbodies to the mid-infrared (MIR) through submillimeter SEDs. The new results reflect an overall ~0.02 dex lower luminosity than the original IRAS values. Total stellar masses were computed by fitting stellar population synthesis models to the observed near-infrared (NIR) through ultraviolet (UV) SEDs. Mean stellar masses are found to be log(M/Msun) = 10.79+/-0.40. Star formation rates have been determined from the infrared (SFR_IR~45Msun/yr) and from the monochromatic UV luminosities (SFR_UV~1.3Msun/yr), respectively. Multiwavelength AGN indicators have be used to select putative AGN: about 60% of the ULIRGs would have been classified as an AGN by at least one of the selection criteria.Comment: 39 pages, including 12 figures and 11 tables; accepted for publication in ApJ

The Marketization of Religion: Field, Capital, and Consumer Identity

Certain institutions traditionally have had broad socializing influence over their members, providing templates for identity that comprehend all aspects of life from the existential and moral to the mundanely material. Marketization and detraditionalization undermine that socializing role. This study examines the consequences when, for some members, such an institution loses its authority to structure identity. With a hermeneutical method and a perspective grounded in Bourdieu’s theories of fields and capital, this research investigates the experiences of disaffected members of a religious institution and consumption field. Consumers face severe crises of identity and the need to rebuild their self-understandings in an unfamiliar marketplace of identity resources. Unable to remain comfortably in the field of their primary socialization, they are nevertheless bound to it by investments in field-specific capital. In negotiating this dilemma, they demonstrate the inseparability and co-constitutive nature of ideology and consumption.This is the publisher’s final pdf. The published article is copyrighted by the Journal of Consumer Research, Inc. and published by the University of Chicago Press. It can be found at: http://www.jstor.org/page/journal/jconsrese/about.htm

Process evaluation of appreciative inquiry to translate pain management evidence into pediatric nursing practice

Background Appreciative inquiry (AI) is an innovative knowledge translation (KT) intervention that is compatible with the Promoting Action on Research in Health Services (PARiHS) framework. This study explored the innovative use of AI as a theoretically based KT intervention applied to a clinical issue in an inpatient pediatric care setting. The implementation of AI was explored in terms of its acceptability, fidelity, and feasibility as a KT intervention in pain management. Methods A mixed-methods case study design was used. The case was a surgical unit in a pediatric academic-affiliated hospital. The sample consisted of nurses in leadership positions and staff nurses interested in the study. Data on the AI intervention implementation were collected by digitally recording the AI sessions, maintaining logs, and conducting individual semistructured interviews. Data were analysed using qualitative and quantitative content analyses and descriptive statistics. Findings were triangulated in the discussion. Results Three nurse leaders and nine staff members participated in the study. Participants were generally satisfied with the intervention, which consisted of four 3-hour, interactive AI sessions delivered over two weeks to promote change based on positive examples of pain management in the unit and staff implementation of an action plan. The AI sessions were delivered with high fidelity and 11 of 12 participants attended all four sessions, where they developed an action plan to enhance evidence-based pain assessment documentation. Participants labeled AI a 'refreshing approach to change' because it was positive, democratic, and built on existing practices. Several barriers affected their implementation of the action plan, including a context of change overload, logistics, busyness, and a lack of organised follow-up. Conclusions Results of this case study supported the acceptability, fidelity, and feasibility of AI as a KT intervention in pain management. The AI intervention requires minor refinements (e.g., incorporating continued follow-up meetings) to enhance its clinical utility and sustainability. The implementation process and effectiveness of the modified AI intervention require evaluation in a larger multisite study

Update to the AWED (Applying Wolbachia to Eliminate Dengue) trial study protocol: a cluster randomised controlled trial in Yogyakarta, Indonesia.

BACKGROUND: The AWED (Applying Wolbachia to Eliminate Dengue) trial is a parallel, two-arm, non-blinded cluster randomised controlled trial that is under way in Yogyakarta, Indonesia, with the aim of measuring the efficacy of Wolbachia-infected Aedes aegypti deployments in reducing dengue incidence in an endemic setting. Enrolment began in January 2018 and is ongoing. The original study protocol was published in April 2018. Here, we describe amendments that have been made to the study protocol since commencement of the trial. METHODS: The key protocol amendments are (1) a revised study duration with planned end of participant enrolment in August 2020, (2) the addition of new secondary objectives (i) to estimate serotype-specific efficacy of the Wolbachia intervention and (ii) to compare Ae. aegypti abundance in intervention versus untreated clusters, (3) an additional exposure classification for the per-protocol analysis where the Wolbachia exposure index is calculated using only the cluster-level Wolbachia prevalence in the participant's cluster of residence, (4) power re-estimation using a multinomial sampling method that better accounts for randomness in sampling, and (5) the addition of two trial stopping rules to address the potential for persistently low rates of virologically confirmed dengue case enrolment and Wolbachia contamination into untreated clusters. Additional minor changes to the protocol are also described. DISCUSSION: The findings from this study will provide the first experimental evidence for the efficacy of Wolbachia in reducing dengue incidence. Enrolment in the trial will conclude this year (2020) and results will be reported shortly thereafter. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT03055585. Registered on 14 February 2017. Last updated 22 March 2020

Site fidelity and movement patterns of short-finned pilot whales within the Canary Islands : evidence for resident and transient populations

Funding: co-funded by the Canary Government (Consejería de Política Territorial, Sostenibilidad y Seguridad), the Spanish Government (Fundación Biodiversidad and Ministerio de Medio Ambiente, Medio Rural y Marino), Fundación La Caixa, and by a number of international projects funded by EU programmes MACETUS (FEDER/INTERREG III-B MAC/4.2/M10), EMECETUS (FEDER/INTERREG III-B56105/MAC/4.2/M10), LIFE (LIFE03NAT0062), INDEMARES LIFE+ (LIFE07/NAT/E/00732).1. The geographic location and oceanographic, physical, and chemical water properties make the Canary Islands one of the planet's biodiversity hotspots. The short‐finned pilot whale (Globicephala macrorhynchus) is one of the archipelago's most commonly encountered species and is potentially vulnerable to a range of anthropogenic pressures, including habitat degradation, acoustic pollution, fishing, whale‐watching operations, and shipping. Assessment of impact has not been possible because of a lack of even basic information about occurrence and distribution. 2. Spatial and temporal distributions, ranging behaviour, and residence patterns of short‐finned pilot whales were explored for the first time using survey and photo‐identification data collected in the Canary Islands between 1999 and 2012. In total, 1,081 pilot whale sightings were recorded during 70,620 km of search effort over 1,782 survey days. 3. Pilot whales were detected year round and distributed non‐uniformly within the archipelago, with greater densities concentrated in patchy areas mainly on the leeward side of the main islands. In total, 1,320 well‐marked individuals were identified, which exhibited a large degree of variability in site fidelity. 4. Different but not isolated subpopulations of pilot whales that share ranges and maintain social interactions were apparently present in the Canary Islands. Strong evidence of an island‐associated subpopulation was found, with a group of 50 ‘core resident’ individuals associated particularly with Tenerife. There were also ‘transient’ individuals or temporary migrants, which, probably driven by inter‐ and intra‐specific competition, may travel long distances whilst using the archipelago as part of a larger range. 5. These findings fill a major gap in the knowledge of this species’ occurrence, distribution, movements, and site fidelity in the archipelago and provide much needed data to allow the initiation of informed conservation assessments and management actions.PostprintPeer reviewe

Mercury from chlor-alkali plants: measured concentrations in food product sugar

Mercury cell chlor-alkali products are used to produce thousands of other products including food ingredients such as citric acid, sodium benzoate, and high fructose corn syrup. High fructose corn syrup is used in food products to enhance shelf life. A pilot study was conducted to determine if high fructose corn syrup contains mercury, a toxic metal historically used as an anti-microbial. High fructose corn syrup samples were collected from three different manufacturers and analyzed for total mercury. The samples were found to contain levels of mercury ranging from below a detection limit of 0.005 to 0.570 micrograms mercury per gram of high fructose corn syrup. Average daily consumption of high fructose corn syrup is about 50 grams per person in the United States. With respect to total mercury exposure, it may be necessary to account for this source of mercury in the diet of children and sensitive populations