Damage to tropical forests caused by cyclones is driven by wind speed but mediated by topographical exposure and tree characteristics.

Each year, an average of 45 tropical cyclones affect coastal areas and potentially impact forests. The proportion of the most intense cyclones has increased over the past four decades and is predicted to continue to do so. Yet, it remains uncertain how topographical exposure and tree characteristics can mediate the damage caused by increasing wind speed. Here, we compiled empirical data on the damage caused by 11 cyclones occurring over the past 40 years, from 74 forest plots representing tropical regions worldwide, encompassing field data for 22,176 trees and 815 species. We reconstructed the wind structure of those tropical cyclones to estimate the maximum sustained wind speed (MSW) and wind direction at the studied plots. Then, we used a causal inference framework combined with Bayesian generalised linear mixed models to understand and quantify the causal effects of MSW, topographical exposure to wind (EXP), tree size (DBH) and species wood density (ρ) on the proportion of damaged trees at the community level, and on the probability of snapping or uprooting at the tree level. The probability of snapping or uprooting at the tree level and, hence, the proportion of damaged trees at the community level, increased with increasing MSW, and with increasing EXP accentuating the damaging effects of cyclones, in particular at higher wind speeds. Higher ρ decreased the probability of snapping and to a lesser extent of uprooting. Larger trees tended to have lower probabilities of snapping but increased probabilities of uprooting. Importantly, the effect of ρ decreasing the probabilities of snapping was more marked for smaller than larger trees and was further accentuated at higher MSW. Our work emphasises how local topography, tree size and species wood density together mediate cyclone damage to tropical forests, facilitating better predictions of the impacts of such disturbances in an increasingly windier world.

Adapting the EQ-5D-3L for adults with mild to moderate learning disabilities.

BACKGROUND: Approximately 1.5 million adults in the UK have a learning disability. The difference between age at death for this group and the general population is 26 years for females and 22 years for males. The NHS Long Term Plan (January 2019) recognises learning disabilities as a clinical priority area. People with a learning disability are often excluded from research by design or lack of reasonable adjustments, and self-reported health status/health-related quality of life questionnaires such as the EQ-5D are often not appropriate for this population. Here, we systematically examine the EQ-5D-3L (its wording, content, and format) using qualitative methods to inform the adaption of the measure for use with adults with mild to moderate learning disabilities. METHODS: Think-aloud interviews with carers/advocates of learning-disabled adults were undertaken to explore the difficulties with completing the EQ-5D-3L. Alternative wording, language, structure, and images were developed using focus groups, stakeholder reference groups, and an expert panel. Data analysis followed a framework method. RESULTS: The dimensions and levels within the EQ-5D-3L were deemed appropriate for adults with mild to moderate learning disabilities. Consensus on wording, structure, and images was reached through an iterative process, and an adapted version of the EQ-5D-3L was finalised. CONCLUSION: The EQ-5D-3L adapted for adults with mild to moderate intellectual/learning disabilities can facilitate measurement of self-reported health status. Research is underway to assess the potential use of the adaptation for economic evaluation.

The Bio-Hermes Study: Biomarker database developed to investigate blood-based and digital biomarkers in community-based, diverse populations clinically screened for Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) trial participants are often screened for eligibility by brain amyloid positron emission tomography/cerebrospinal fluid (PET/CSF), which is inefficient as many are not amyloid positive. Use of blood-based biomarkers may reduce screen failures. METHODS: We recruited 755 non-Hispanic White, 115 Hispanic, 112 non-Hispanic Black, and 19 other minority participants across groups of cognitively normal (n = 417), mild cognitive impairment (n = 312), or mild AD (n = 272) participants. Plasma amyloid beta (Aß)40, Aß42, Aß42/Aß40, total tau, phosphorylated tau (p-tau)181, and p-tau217 were measured; amyloid PET/CSF (n = 956) determined amyloid positivity. Clinical, blood biomarker, and ethnicity/race differences associated with amyloid status were evaluated. RESULTS: Greater impairment, older age, and carrying an apolipoprotein E (apoE) ε4 allele were associated with greater amyloid burden. Areas under the receiver operating characteristic curve for amyloid status of plasma Aß42/Aß40, p-tau181, and p-tau217 with amyloid positivity were ≥ 0.7117 for all ethnoracial groups (p-tau217, ≥0.8128). Age and apoE ε4 adjustments and imputation of biomarker values outside limit of quantitation provided small improvement in predictive power. DISCUSSION: Blood-based biomarkers are highly associated with amyloid PET/CSF results in diverse populations enrolled at clinical trial sites. HIGHLIGHTS: Amyloid beta (Aß)42/Aß40, phosphorylated tau (p-tau)181, and p-tau 217 blood-based biomarkers predicted brain amyloid positivity. P-tau 217 was the strongest predictor of brain amyloid positivity. Biomarkers from diverse ethnic, racial, and clinical cohorts predicted brain amyloid positivity. Community-based populations have similar Alzheimer's disease (AD) biomarker levels as other populations. A prescreen process with blood-based assays may reduce the number of AD trial screen failures.

Weak evidence of trade-offs modulated by seed mass among a guild of closely related winter annuals.

Plant-plant interactions are integral to the establishment and persistence of diversity in plant communities. For annual plant species that depend on seeds to regenerate, seed characteristics that confer fitness advantages may mediate processes such as plant-plant interactions. Seed mass is known to vary widely and has been shown to associate with species' differences in stress tolerance and competitive effects. However, understanding of how seed mass influences species' responses to competition is less well understood. Using natural assemblages of six closely related annual plant species in Western Australia, we implemented a thinning study to assess how seed mass influences the outcomes of plant-plant interactions. We found relatively weak evidence for competition or facilitation among species. Our strongest results indicated that heavy-seeded species had lower survivorship than light-seeded species when interacting with heterospecifics. Seed mass was also negatively related to overall survival, counter to expectations. These findings indicate some evidence for trade-offs mediated by seed mass in this system. However, we acknowledge that other factors may have influenced our results, such as the use of natural assemblages (rather than using sowing experiments) and the presence of important small-scale environmental variation not captured with our choice of abiotic variables. Further research is required to clarify the role of seed mass in this diverse annual system, ideally including many focal species, and using sowing experiments.

Patterns of frequency and density dependence are highly variable in diverse annual flowering plant communities.

Applications of ecological theory to natural communities often assume that competitive, negative density-dependent processes are the only type of interaction important for diversity maintenance. Recent advances suggest that positive interactions within trophic levels (e.g., plant-plant) may also affect plant coexistence. Though positive plant-plant interactions theoretically might result in positive or nonmonotonic frequency or density dependence (FD/DD), less is known about how commonly these patterns occur or which ecological processes might result in such patterns in natural plant communities. In this study we tested for signals of variable frequency and density dependence in annual flowering plant communities in Western Australia and searched for evidence that interactions among plants during flowering might induce positive or nonmonotonic FD/DD in flowering plants. Using four common annual wildflower species, we ask if plant fecundity exhibited positive or nonmonotonic FD/DD and if pollinator-mediated plant-plant interactions during flowering change patterns of FD/DD relative to pollinator-independent plant interactions. Three species exhibited nonmonotonic (hump-shaped) density dependence, and only one species experienced strictly negative density dependence. Each species exhibited a different pattern of frequency dependence (positive, negative, weakly nonmonotonic, and no detectable frequency dependence). Pollinator-mediated plant-plant interactions during flowering induced both nonmonotonic density dependence and negative frequency dependence in one species. Importantly, the extent of variation in FD/DD observed in our study brings into question the dominance of negative density and frequency dependence in theory, suggesting instead that demographic responses of plants to their communities fall along a continuum of possible density- and frequency-dependent patterns.

Determinants of supplementation among Canadian university students: a theory of planned behavior perspective.

OBJECTIVE: The purpose of this study was to identify the psychosocial determinants of (1) intention to use dietary supplements (DS) and (2) the behavior of engaging in supplementation by testing the fit of the Theory of Planned Behavior (TPB). METHODS: A total of 778 students at a Canadian university in Ontario completed a cross-sectional survey assessing participants' attitude, injunctive norm, descriptive norm, perceived behavioral control and intention toward DS use. Data were analyzed using independent sample t-tests and linear and logistic regressions. RESULTS: Attitude, injunctive norm and perceived behavioral control were significant predictors of intention to use DS. Attitude, injunctive norm and intention were significant predictors of engaging in supplementation. The model explained 75.5% of the variance and correctly classified 89.6% of cases. The odds of using DS doubled with every one-unit increase in intention. CONCLUSIONS: This study confirms the utility of the TPB in predicting university students' supplementation habits.

Changes in trait covariance along an orographic moisture gradient reveal the relative importance of light- and moisture-driven trade-offs in subtropical rainforest communities.

A range of functional trait-based approaches have been developed to investigate community assembly processes, but most ignore how traits covary within communities. We combined existing approaches - community-weighted means (CWMs) and functional dispersion (FDis) - with a metric of trait covariance to examine assembly processes in five angiosperm assemblages along a moisture gradient in Australia's subtropics. In addition to testing hypotheses about habitat filtering along the gradient, we hypothesized that trait covariance would be strongest at both ends of the moisture gradient and weakest in the middle, reflecting trade-offs associated with light capture in productive sites and moisture stress in dry sites. CWMs revealed evidence of climatic filtering, but FDis patterns were less clear. As hypothesized, trait covariance was weakest in the middle of the gradient but unexpectedly peaked at the second driest site due to the emergence of a clear drought tolerance-drought avoidance spectrum. At the driest site, the same spectrum was truncated at the 'avoider' end, revealing important information about habitat filtering in this system. Our focus on trait covariance revealed the nature and strength of trade-offs imposed by light and moisture availability, complementing insights gained about community assembly from existing trait-based approaches.

Drivers of Acacia and Eucalyptus growth rate differ in strength and direction in restoration plantings across Australia.

Functional traits are proxies for a species' ecology and physiology and are often correlated with plant vital rates. As such they have the potential to guide species selection for restoration projects. However, predictive trait-based models often only explain a small proportion of plant performance, suggesting that commonly measured traits do not capture all important ecological differences between species. Some residual variation in vital rates may be evolutionarily conserved and captured using taxonomic groupings alongside common functional traits. We tested this hypothesis using growth rate data for 17,299 trees and shrubs from 80 species of Eucalyptus and 43 species of Acacia, two hyper-diverse and co-occurring genera, collected from 497 neighborhood plots in 137 Australian mixed-species revegetation plantings. We modeled relative growth rates of individual plants as a function of environmental conditions, species-mean functional traits, and neighbor density and diversity, across a moisture availability gradient. We then assessed whether the strength and direction of these relationships differed between the two genera. We found that the inclusion of genus-specific relationships offered a significant but modest improvement to model fit (1.6%-1.7% greater R2 than simpler models). More importantly, almost all correlates of growth rate differed between Eucalyptus and Acacia in strength, direction, or how they changed along the moisture gradient. These differences mapped onto physiological differences between the genera that were not captured solely by measured functional traits. Our findings suggest taxonomic groupings can capture or mediate variation in plant performance missed by common functional traits. The inclusion of taxonomy can provide a more nuanced understanding of how functional traits interact with abiotic and biotic conditions to drive plant performance, which may be important for constructing trait-based frameworks to improve restoration outcomes.

The Smarter Safer Homes Solution to Support Older People Living in Their Own Homes Through Enhanced Care Models: Protocol for a Stratified Randomized Controlled Trial.

BACKGROUND: An aging population, accompanied by the prevalence of age-related diseases, presents a significant burden to health systems. This is exacerbated by an increasing shortage of aged care staff due to the existing workforce entering their retirement and fewer young people being attracted to work in aged care. In line with consumer preferences and potential cost-efficiencies, government and aged care providers are increasingly seeking options to move care and support to the community or home as opposed to residential care facilities. However, compared to residential care, home environments may provide limited opportunity for monitoring patients' progression/decline in functioning and therefore limited opportunity to provide timely intervention. To address this, the Smarter Safer Homes (SSH) platform was designed to enable self-monitoring and/or management, and to provide aged care providers with support to deliver their services. The platform uses open Internet of Things communication protocols to easily incorporate commercially available sensors into the system. OBJECTIVE: Our research aims to detail the benefits of utilizing the SSH platform as a service in its own right as well as a complementary service to more traditional/historical service offerings in aged care. This work is anticipated to validate the capacity and benefits of the SSH platform to enable older people to self-manage and aged care service providers to support their clients to live functionally and independently in their own homes for as long as possible. METHODS: This study was designed as a single-blinded, stratified, 12-month randomized controlled trial with participants recruited from three aged care providers in Queensland, Australia. The study aimed to recruit 200 people, including 145 people from metropolitan areas and 55 from regional areas. Participants were randomized to the intervention group (having the SSH platform installed in their homes to assist age care service providers in monitoring and providing timely support) and the control group (receiving their usual aged care services from providers). Data on community care, health and social-related quality of life, health service utilization, caregiver burden, and user experience of both groups were collected at the start, middle (6 months), and end of the trial (12 months). RESULTS: The trial recruited its first participant in April 2019 and data collection of the last participant was completed in November 2020. The trial eventually recruited 195 participants, with 98 participants allocated to the intervention group and 97 participants allocated to the control group. The study also received participants' health service data from government data resources in June 2021. CONCLUSIONS: A crisis is looming to support the aging population. Digital solutions such as the SSH platform have the potential to address this crisis and support aged care in the home and community. The outcomes of this study could improve and support the delivery of aged care services and provide better quality of life to older Australians in various geographical locations. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618000829213; https://tinyurl.com/2n6a75em. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31970.

Variable seed bed microsite conditions and light influence germination in Australian winter annuals.

Environmentally cued germination may play an important role in promoting coexistence in Mediterranean annual plant systems if it causes niche differentiation across heterogeneous microsite conditions. In this study, we tested how microsite conditions experienced by seeds in the field and light conditions in the laboratory influenced germination in 12 common annual plant species occurring in the understorey of the York gum-jam woodlands in southwest Western Australia. Specifically, we hypothesized that if germination promotes spatial niche differentiation, then we should observe species-specific germination responses to light. In addition, we hypothesized that species' laboratory germination response may depend on the microsite conditions experienced by seeds while buried. We tested the laboratory germination response of seeds under diurnally fluctuating light and complete darkness, which were collected from microsites spanning local-scale environmental gradients known to influence community structure in this system. We found that seeds of 6 out of the 12 focal species exhibited significant positive germination responses to light, but that the magnitude of these responses varied greatly with the relative light requirement for germination ranging from 0.51 to 0.86 for these species. In addition, germination increased significantly across a gradient of canopy cover for two species, but we found little evidence to suggest that species' relative light requirement for germination varied depending on seed bank microsite conditions. Our results suggest that variability in light availability may promote coexistence in this system and that the microsite conditions seeds experience in the intra-growing season period can further nuance species germination behaviour.

Transforming challenges into opportunities: conducting health preference research during the COVID-19 pandemic and beyond.

The disruptions to health research during the COVID-19 pandemic are being recognized globally, and there is a growing need for understanding the pandemic's impact on the health and health preferences of patients, caregivers, and the general public. Ongoing and planned health preference research (HPR) has been affected due to problems associated with recruitment, data collection, and data interpretation. While there are no "one size fits all" solutions, this commentary summarizes the key challenges in HPR within the context of the pandemic and offers pragmatic solutions and directions for future research. We recommend recruitment of a diverse, typically under-represented population in HPR using online, quota-based crowdsourcing platforms, and community partnerships. We foresee emerging evidence on remote, and telephone-based HPR modes of administration, with further studies on the shifts in preferences related to health and healthcare services as a result of the pandemic. We believe that the recalibration of HPR, due to what one would hope is an impermanent change, will permanently change how we conduct HPR in the future.

'Invasion debt' after extensive land-use change: An example from eastern Australia.

Land-use change, and associated land clearing/conversion and fragmentation are major drivers of biodiversity decline across the globe. The spread of invasive species is a well-recognised consequence of land-use change. The extent and intensity of invasion however is often difficult to assess due to a lack of temporal data. Using detailed mapping information for 130, 950 km2 of sub-coastal Queensland, Australia and results from field surveys we investigated changes to land-use, the extent of remnant (intact) vegetation and the spread of prominent invasive plant species over time (1997-2018). In the 50 years prior to 1997 the area underwent significant land development (mostly for livestock grazing and crops), resulting in a reduction of 45% of its remnant vegetation. Despite key policy developments aimed at protecting the remaining vegetation and species, 7392 km2 was cleared/converted between 1997 and 2017, mainly for the expansion of grazing and cropping lands. Vegetation types specifically listed for national protection under these policies were some of the greatest affected, highlighting the need for improved implementation and regulation of these control measures. Within remaining fragments of remnant vegetation, the cover and presence of two invasive perennial grass species indian couch (Bothriochloa pertusa) and buffel grass (Cenchrus ciliaris) increased significantly during this time period. There was also a moderate increase in the cover and presence of the annual herb Parthenium weed (Parthenium hysterophorus). The spread of these species within the landscape likely reflects an 'invasion debt', incurred from an intense history of land-use within the region and we predict this trend will continue to threaten remnant ecosystems.

Education Interventions to Improve Knowledge, Beliefs, Intentions and Practices with Respect to Dietary Supplements and Doping Substances: A Narrative Review.

The misuse of dietary supplements and doping substances is commonly associated with toxicity, nutritional imbalances, and health and psychological consequences. This is alarming especially in light of the increasing prevalence of the use of dietary supplements and doping, particularly among young adults including athletes. There is evidence that education interventions can lead to improved knowledge, intentions, and practices. However, no review has summarized and evaluated the effectiveness of such interventions. The aim of this article is to review the characteristics, contents and effects of education interventions that were designed and implemented to improve knowledge, attitudes, beliefs and intentions with respect to the use of dietary supplements and doping agents in different populations. PubMed, Scopus, CINAHL, PsycInfo and Google Scholar were searched for English-language education interventions targeting dietary supplements and doping substances. A total of 20 articles were identified and have generally provided consistent findings. Most interventions reported a significant improvement in knowledge on dietary supplements and doping agents. Unfortunately, the heavy reliance on self-reported assessment tools limits the validity of these interventions, with almost all articles targeting athletes and adolescents.

Genetically-encoded discovery of proteolytically stable bicyclic inhibitors for morphogen NODAL.

In this manuscript, we developed a two-fold symmetric linchpin (TSL) that converts readily available phage-displayed peptides libraries made of 20 common amino acids to genetically-encoded libraries of bicyclic peptides displayed on phage. TSL combines an aldehyde-reactive group and two thiol-reactive groups; it bridges two side chains of cysteine [C] with an N-terminal aldehyde group derived from the N-terminal serine [S], yielding a novel bicyclic topology that lacks a free N-terminus. Phage display libraries of SX1CX2X3X4X5X6X7C sequences, where X is any amino acid but Cys, were converted to a library of bicyclic TSL-[S]X1[C]X2X3X4X5X6X7[C] peptides in 45 ± 15% yield. Using this library and protein morphogen NODAL as a target, we discovered bicyclic macrocycles that specifically antagonize NODAL-induced signaling in cancer cells. At a 10 µM concentration, two discovered bicyclic peptides completely suppressed NODAL-induced phosphorylation of SMAD2 in P19 embryonic carcinoma cells. The TSL-[S]Y[C]KRAHKN[C] bicycle inhibited NODAL-induced proliferation of NODAL-TYK-nu ovarian carcinoma cells with apparent IC50 of 1 µM. The same bicycle at 10 µM concentration did not affect the growth of the control TYK-nu cells. TSL-bicycles remained stable over the course of the 72 hour-long assays in a serum-rich cell-culture medium. We further observed general stability in mouse serum and in a mixture of proteases (Pronase™) for 21 diverse bicyclic macrocycles of different ring sizes, amino acid sequences, and cross-linker geometries. TSL-constrained peptides to expand the previously reported repertoire of phage-displayed bicyclic architectures formed by cross-linking Cys side chains. We anticipate that it will aid the discovery of proteolytically stable bicyclic inhibitors for a variety of protein targets.

Phenotypic plasticity masks range-wide genetic differentiation for vegetative but not reproductive traits in a short-lived plant.

Genetic differentiation and phenotypic plasticity jointly shape intraspecific trait variation, but their roles differ among traits. In short-lived plants, reproductive traits may be more genetically determined due to their impact on fitness, whereas vegetative traits may show higher plasticity to buffer short-term perturbations. Combining a multi-treatment greenhouse experiment with observational field data throughout the range of a widespread short-lived herb, Plantago lanceolata, we (1) disentangled genetic and plastic responses of functional traits to a set of environmental drivers and (2) assessed how genetic differentiation and plasticity shape observational trait-environment relationships. Reproductive traits showed distinct genetic differentiation that largely determined observational patterns, but only when correcting traits for differences in biomass. Vegetative traits showed higher plasticity and opposite genetic and plastic responses, masking the genetic component underlying field-observed trait variation. Our study suggests that genetic differentiation may be inferred from observational data only for the traits most closely related to fitness.

Negative effects of nitrogen override positive effects of phosphorus on grassland legumes worldwide.

Anthropogenic nutrient enrichment is driving global biodiversity decline and modifying ecosystem functions. Theory suggests that plant functional types that fix atmospheric nitrogen have a competitive advantage in nitrogen-poor soils, but lose this advantage with increasing nitrogen supply. By contrast, the addition of phosphorus, potassium, and other nutrients may benefit such species in low-nutrient environments by enhancing their nitrogen-fixing capacity. We present a global-scale experiment confirming these predictions for nitrogen-fixing legumes (Fabaceae) across 45 grasslands on six continents. Nitrogen addition reduced legume cover, richness, and biomass, particularly in nitrogen-poor soils, while cover of non-nitrogen-fixing plants increased. The addition of phosphorous, potassium, and other nutrients enhanced legume abundance, but did not mitigate the negative effects of nitrogen addition. Increasing nitrogen supply thus has the potential to decrease the diversity and abundance of grassland legumes worldwide regardless of the availability of other nutrients, with consequences for biodiversity, food webs, ecosystem resilience, and genetic improvement of protein-rich agricultural plant species.

An International Comparison of EQ-5D-5L and EQ-5D-3L for Use in Cost-Effectiveness Analysis.

OBJECTIVES: To estimate the impact of using EQ5D-5L (5L) compared with EQ5D-3L (3L) in cost-effectiveness analyses in 6 countries with 3L and 5L values: Germany, Japan, Korea, The Netherlands, China, and Spain. METHODS: Eight cost-effectiveness analyses based on clinical studies with 3L provided 11 pairwise comparisons. We estimated cost-effectiveness by applying the appropriate country values for 3L to observed responses. We re-estimated cost-effectiveness for each country by predicting the 5L tariff score for each respondent, for each country, using a previously published mapping method. We compared results in terms of impact on estimated incremental quality-adjusted life-year (QALY) gain and cost-effectiveness ratios. RESULTS: For most countries the impact of moving from 3L to 5L is to lower the incremental QALY gain in the majority of comparisons. The only exception to this was Japan, where 4 out of 11 cases (37%) saw lower QALYs gained when using 5L. The mean and median reductions in health gain, in those case studies where 5L does lead to lower health gain, are largest in The Netherlands (84% mean reduction, 41% median reduction), Germany (68% and 27%), and Spain (30% and 31%). For most countries, those studies where 5L leads to lower health gain see larger reductions than the gains in studies showing the opposite tendency. CONCLUSIONS: Overall, 3L and 5L are not interchangeable in these countries. Differences between results are large, but the direction of change can be unpredictable. These findings should prompt further investigation into the reasons for differences.

Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial.

BACKGROUND: Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission. METHODS: In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent controlled trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive hydroxychloroquine (HCQ) (400 mg BID x1day, followed by 200 mg BID x9days) with or without azithromycin (AZ) (500 mg, then 250 mg daily x4days) or placebo-equivalent (ascorbic acid (HCQ) and folic acid (AZ)), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs were collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility. FINDINGS: Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Among 129 high-risk participants, incident LRTI occurred in six (4.7%) participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in seven (5.4%) (four control, one HCQ, two HCQ/AZ); no LRTI and two (2%) hospitalizations occurred in the 102 low-risk participants (one HCQ, one HCQ/AZ). There were no deaths. Among 152 participants with viral shedding at enrollment, median time to clearance was 5 days (95% CI=4-6) in HCQ, 6 days (95% CI=4-8) in HCQ/AZ, and 8 days (95% CI=6-10) in control. Viral clearance was faster in HCQ (HR=1.62, 95% CI=1.01-2.60, p = 0.047) but not HCQ/AZ (HR=1.25, p = 0.39) compared to control. Among 197 participants who met the COVID-19 definition at enrollment, time to symptom resolution did not differ by group (HCQ: HR=1.02, 95% CI-0.63-1.64, p = 0.95, HCQ/AZ: HR=0.91, 95% CI=0.57-1.45, p = 0.70). INTERPRETATION: Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection. FUNDING: The COVID-19 Early Treatment Study was funded by the Bill & Melinda Gates Foundation (INV-017062) through the COVID-19 Therapeutics Accelerator. University of Washington Institute of Translational Health Science (ITHS) grant support (UL1 TR002319), KL2 TR002317, and TL1 TR002318 from NCATS/NIH funded REDCap. The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. PAN and MJA were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.Trial registration ClinicalTrials.gov number NCT04354428.

Climatic and evolutionary contexts are required to infer plant life history strategies from functional traits at a global scale.

Life history strategies are fundamental to the ecology and evolution of organisms and are important for understanding extinction risk and responses to global change. Using global datasets and a multiple response modelling framework we show that trait-climate interactions are associated with life history strategies for a diverse range of plant species at the global scale. Our modelling framework informs our understanding of trade-offs and positive correlations between elements of life history after accounting for environmental context and evolutionary and trait-based constraints. Interactions between plant traits and climatic context were needed to explain variation in age at maturity, distribution of mortality across the lifespan and generation times of species. Mean age at maturity and the distribution of mortality across plants' lifespan were under evolutionary constraints. These findings provide empirical support for the theoretical expectation that climatic context is key to understanding trait to life history relationships globally.