One challenge for multisite clinical trials is ensuring that the conditions of an informative trial are incorporated into all aspects of trial planning and execution. The multicenter model can provide the potential for a more informative environment, but it can also place a trial at risk of becoming uninformative due to lack of rigor, quality control, or effective recruitment, resulting in premature discontinuation and/or non-publication. Key factors that support informativeness are having the right team and resources during study planning and implementation and adequate funding to support performance activities. This communication draws on the experience of the National Center for Advancing Translational Science (NCATS) Trial Innovation Network (TIN) to develop approaches for enhancing the informativeness of clinical trials. We distilled this information into three principles: (1) assemble a diverse team, (2) leverage existing processes and systems, and (3) carefully consider budgets and contracts. The TIN, comprised of NCATS, three Trial Innovation Centers, a Recruitment Innovation Center, and 60+ CTSA Program hubs, provides resources to investigators who are proposing multicenter collaborations. In addition to sharing principles that support the informativeness of clinical trials, we highlight TIN-developed resources relevant for multicenter trial initiation and conduct.

Leafy green vegetables are a common source of Shiga toxin-producing Escherichia coli O157:H7 (STEC O157) foodborne illness outbreaks. Ruminant animals, primarily cattle, are the major reservoir of STEC O157. Epidemiological, traceback and field investigations were conducted to identify potential outbreak sources. Product and environmental samples were tested for STEC. A reoccurring strain of STEC O157 caused two multistate outbreaks linked to romaine lettuce in 2018 and 2019, resulting in 234 illnesses in 33 states. Over 80% of patients interviewed consumed romaine lettuce before illness. The romaine lettuce was sourced from two California growing regions: Santa Maria and Salinas Valley in 2018 and Salinas Valley in 2019. The outbreak strain was isolated from environmental samples collected at sites >90 miles apart across growing regions, as well as from romaine-containing products in 2019. Although the definitive route of romaine contamination was undetermined, use of a contaminated agricultural water reservoir in 2018 and contamination from cattle grazing on adjacent land in 2019 were suspected as possible factors. Preventing lettuce contamination from growth to consumption is imperative to preventing illness. These outbreaks highlight the need to further understand mechanisms of romaine contamination, including the role of environmental or animal reservoirs for STEC O157.

Microscopic examination of blood smears remains the gold standard for laboratory inspection and diagnosis of malaria. Smear inspection is, however, time-consuming and dependent on trained microscopists with results varying in accuracy. We sought to develop an automated image analysis method to improve accuracy and standardization of smear inspection that retains capacity for expert confirmation and image archiving. Here, we present a machine learning method that achieves red blood cell (RBC) detection, differentiation between infected/uninfected cells, and parasite life stage categorization from unprocessed, heterogeneous smear images. Based on a pretrained Faster Region-Based Convolutional Neural Networks (R-CNN) model for RBC detection, our model performs accurately, with an average precision of 0.99 at an intersection-over-union threshold of 0.5. Application of a residual neural network-50 model to infected cells also performs accurately, with an area under the receiver operating characteristic curve of 0.98. Finally, combining our method with a regression model successfully recapitulates intraerythrocytic developmental cycle with accurate lifecycle stage categorization. Combined with a mobile-friendly web-based interface, called PlasmoCount, our method permits rapid navigation through and review of results for quality assurance. By standardizing assessment of Giemsa smears, our method markedly improves inspection reproducibility and presents a realistic route to both routine lab and future field-based automated malaria diagnosis.

Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.

The Neotropics house two guilds of large arboreal vertebrate seed predators: parrots and the pitheciin primates. Both have diets dominated by immature fruits. The possibility of members of the Pitheciinae (genera Cacajao, Chiropotes and Pithecia) acting as occasional seed dispersers has been mooted, but not experimentally shown. We combined primate behavioural data and seed germination data from three separate field studies in the Brazilian states of Amazonas and Pará to analyse patterns of post-consumption seed survivorship for seeds discarded by three pitheciin species (Cacajao melanocephalus ouakary, Chiropotes chiropotes and Chiropotes albinasus). We then calculated the frequency of dispersal events for four species eaten by C. m. ouakary. All three primate species dropped intact seeds while feeding, and 30.7% of 674 dropped seeds germinated ex situ. Undamaged seeds from unripe and ripe samples germinated (29.3% and 42.7%, respectively), and all three primate species carried some fruits up to 20 m from the parent tree before consuming them. Potential seed-dispersal events varied from 1 (Macrolobium acaciifolium) per fruiting cycle to more than 6500 (Duroia velutina), suggesting that there are differences in dispersal potential. In summary, although they are highly specialized seed predators, these primates may also act as important dispersers for some plant species, and effective dispersal is not restricted to ripe fruits, as immature fruits removed from a tree may continue to mature and the seeds later germinate, a much-neglected aspect of dispersal ecology. The possibility that similar events occur in parrots should be experimentally investigated.

In Part 1 of this work, we derived general asymptotic results for the three-dimensional flow field and energy fluxes for flow within a tube whose walls perform prescribed small-amplitude periodic oscillations of high frequency and large axial wavelength. In the current paper, we illustrate how these results can be applied to the case of flow through a finite-length axially non-uniform tube of elliptical cross-section – a model of flow in a Starling resistor. The results of numerical simulations for three model problems (an axially uniform tube under pressure–flux and pressure–pressure boundary conditions and an axially non-uniform tube with prescribed flux) with prescribed wall motion are compared with the theoretical predictions made in Part 1, each showing excellent agreement. When upstream and downstream pressures are prescribed, we show how the mean flux adjusts slowly under the action of Reynolds stresses using a multiple-scale analysis. We test the asymptotic expressions obtained for the mean energy transfer E from the flow to the wall over a period of the motion. In particular, the critical point at which E = 0 is predicted accurately: this point corresponds to energetically neutral oscillations, the condition which is relevant to the onset of global instability in the Starling resistor.

We examine the effect of prescribed wall-driven oscillations of a flexible tube of arbitrary cross-section, through which a flow is driven by prescribing either a steady flux at the downstream end or a steady pressure difference between the ends. A large-Womersley-number large-Strouhal-number regime is considered, in which the oscillations of the wall are small in amplitude, but sufficiently rapid to ensure viscous effects are confined to a thin boundary layer. We derive asymptotic expressions for the flow fields and evaluate the energy budget. A general result for the conditions under which there is zero net energy transfer from the flow to the wall is provided. This is presented as a critical inverse Strouhal number (a dimensionless measure of the background flow rate) which is expressed only in terms of the tube geometry, the fluid properties and the profile of the prescribed wall oscillations. Our results identify an essential component of a fundamental mechanism for self-excited oscillations in three-dimensional collapsible tube flows, and enable us to assess how geometric and flow properties affect the stability of the system.

The introduction of mammal predators to islands often results in rapid declines in the number and range of seabirds. On Ascension Island the introduction of cats in 1815 resulted in extirpation of large seabird colonies from the main island, with relict populations of most species persisting only in cat-inaccessible locations. We describe the eradication of feral cats from this large and populated island. The campaign had to minimize risk to humans and maintain domestic animals in a state that prevented them re-establishing a feral population. Feral cat numbers declined rapidly in response to the strategic deployment of poisoning and live trapping, and cats were eradicated from the island within 2 years. During the project 38% of domestic cats were killed accidentally, which caused public consternation; we make recommendations for reducing such problems in future eradications. Since the completion of the eradication campaign cat predation of adult seabirds has ceased and five seabird species have recolonized the mainland in small but increasing numbers. Breeding success of seabirds at Ascension was low compared to that of conspecifics elsewhere, and the roles of food availability, inexperience of parent birds and black rat predation in causing this warrant further investigation. It is likely that the low breeding success will result in the rate of increase in seabird populations being slow.

The membrane vertical phase separation hypothesis predicts that a decrease in plasma membrane acyl chain order will increase major histocompatibility complex (MHC) class I surface expression. The hypothesis is based on modification of plasma membrane acyl chain order in cell culture and has not been tested in vivo. In the present study, we isolated splenic B cells from C57/BL6 mice fed either a normal diet or high-fat diets enriched in SFA or MUFA and assayed for changes in plasma membrane acyl chain order and MHC class I surface expression. Plasma membranes of B cells from MUFA-fed mice had significantly decreased acyl chain order and increased headgroup order. The decrease in acyl chain order correlated with a significant increase in the acyl chain unsaturation of B cells from the MUFA-fed mice. MHC class I surface levels on B cells were not affected by the MUFA-rich diet. This study suggests that the membrane vertical phase separation hypothesis may have limited application in a physiologically relevant setting.