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Global climate change poses significant threats to the Caribbean islands. Yet, little is known about the long-term disturbance regimes in island ecosystems. This research investigates 2000 yr of natural and anthropogenic fire disturbance through the analysis of a latitudinal transect of sediment records from coastal salt ponds in the British Virgin Islands (BVI). The two research objectives in this study are (1) to determine the fire regime history for the BVI over the last 2000 yr and (2) to explore ecological impacts from anthropogenic landscape modification pre- and post-European settlement. The magnitude of anthropogenic landscape modification, including the introduction of agriculture, was investigated through a multiproxy approach using sedimentary records of fossil pollen and charcoal. Our results suggest fire regimes from Belmont Pond, Thatch Island, and Skeleton Pond have been influenced by human activity, particularly during the postsettlement era, from 500 cal yr BP to modern. Our results suggest that fire regimes during the Medieval Climate Anomaly were responding to changes in climate via dominant atmospheric drivers. The presettlement fire regimes from these islands suggest that fires occurred every 90 to 120 yr. This research represents a significant data contribution to a region with little disturbance and vegetation data available.

QUESTION: As anthropogenic change pushes ecosystems towards historically novel states, understanding how landscape disturbances interact with climate variability becomes increasingly important. We reconstructed the Holocene vegetation and fire history of a small watershed to investigate the linkages among disturbance regimes, biogeochemical cycling and ecosystem structure. Specifically we asked: (i) how do compositional and structural changes in forest ecosystems modify fire regimes; and (ii) how do changes in fuel type and fire regimes impact biogeochemical cycling? LOCATION: Comstock Lake, Wisconsin, USA, a small kettle lake at the modern prairie–forest ecotone in the Great Lakes Region of North America. METHODS: We analysed a lacustrine sediment core from Comstock Lake, Wisconsin, for paleoecological proxies including charcoal quantity and morphotype, pollen composition, magnetic susceptibility, organic matter concentration and stable carbon and nitrogen isotopes. These paleoecological variables were used to reconstruct climate‐mediated shifts in vegetation, fire disturbance and biogeochemical cycling during the last 13 200 calendar years before present (cal yr BP). RESULTS: Forest composition in the landscape surrounding Comstock Lake varied among coniferous forest, deciduous forest and savanna over the Holocene. Independent of the vegetation changes, five distinct fire regimes were identified, ranging from frequent, low‐intensity surface fires to infrequent, high‐intensity crown fires. The main feature of our vegetation reconstruction is a shift from Pinus to Quercus forest that occurred between 10 000 and 11 000 cal yr BP. However, changes in fuel source and forest structure were apparently more important than shifts of species composition in determining fire regimes. We observed an inverse relationship between non‐arboreal fuel sources and biomass burning throughout all five fire regimes. The biogeochemical consequences of fires were apparent during some, but not all regime transitions. Generally, the sediments were composed of relatively small clastic inputs from the catchment and mostly autochthonous organic sources. CONCLUSION: The location of Comstock Lake on the prairie–forest boundary meant that regional climate signals during the Holocene were filtered through vegetation. Both compositional changes in dominant tree taxa and structural changes in canopy openness influenced fire regimes.

Antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor have shown efficacy in the prevention of migraine attacks. We investigated the efficacy and tolerability of fremanezumab, a fully humanised CGRP antibody, in patients with migraine who had previously not responded to two to four classes of migraine preventive medications. The randomised, double-blind, placebo-controlled, parallel-group, phase 3b FOCUS trial was done at 104 sites (including hospitals, medical centres, research institutes, and group practice clinics) across Belgium, the Czech Republic, Denmark, Finland, France, Germany, Italy, the Netherlands, Poland, Spain, Sweden, Switzerland, the UK, and the USA. We enrolled participants aged 18–70 years with episodic or chronic migraine who had documented failure to two to four classes of migraine preventive medications in the past 10 years. Failure was defined as no clinically meaningful improvement after at least 3 months of therapy at a stable dose, as per the treating physician's judgment; discontinuation because of adverse events that made treatment intolerable; or treatment contraindicated or unsuitable for the preventive treatment of migraine for the patient. Participants were randomly assigned (1:1:1) by electronic interactive response technology to subcutaneously administered quarterly fremanezumab (month 1, 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: 225 mg in episodic migraine and 675 mg in chronic migraine; months 2 and 3: 225 mg in both migraine subgroups), or matched monthly placebo for 12 weeks. The primary outcome was mean change from baseline in the monthly average number of migraine days during the 12-week treatment period. This trial is registered with ClinicalTrials.gov, number NCT03308968, and is now completed. Between Nov 10, 2017, and July 6, 2018, 838 participants with episodic (329 [39%]) or chronic (509 [61%]) migraine were randomly assigned to placebo (n=279), quarterly fremanezumab (n=276), or monthly fremanezumab (n=283). Reductions from baseline in monthly average migraine days over 12 weeks were greater versus placebo (least-squares mean [LSM] change −0·6 [SE 0·3]) with quarterly fremanezumab (LSM change −3·7 [0·3]; LSM difference vs placebo −3·1 [95% CI −3·8 to −2·4]; p<0·0001) and with monthly fremanezumab (LSM change −4·1 [0·34]; LSM difference vs placebo −3·5 [−4·2 to −2·8]; p<0·0001). Adverse events were similar for placebo and fremanezumab. Serious adverse events were reported in four (1%) of 277 participants with placebo, two (<1%) of 276 with quarterly fremanezumab, and four (1%) of 285 with monthly fremanezumab. Fremanezumab was effective and well tolerated in patients with difficult-to-treat migraine who had previously not responded to up to four classes of migraine preventive medications. Teva Pharmaceuticals.

Ferns are the closest sister group to all seed plants, yet little is known about their genomes other than that they are generally colossal. Here, we report on the genomes of Azolla filiculoides and Salvinia cucullata (Salviniales) and present evidence for episodic whole-genome duplication in ferns—one at the base of ‘core leptosporangiates’ and one specific to Azolla. One fernspecific gene that we identified, recently shown to confer high insect resistance, seems to have been derived from bacteria through horizontal gene transfer. Azolla coexists in a unique symbiosis with N2-fixing cyanobacteria, and we demonstrate a clear pattern of cospeciation between the two partners. Furthermore, the Azolla genome lacks genes that are common to arbuscular mycorrhizal and root nodule symbioses, and we identify several putative transporter genes specific to Azolla–cyanobacterial symbiosis. These genomic resources will help in exploring the biotechnological potential of Azolla and address fundamental questions in the evolution of plant life.

Our intuitive understanding of adaptation by natural selection is dominated by the power of selection at early ages in large populations. Yet, as the forces of natural selection fall with adult age, we expect adaptation to be attenuated with age. Explicit simulations of age-dependent adaptation suggest that populations adapt to a novel environment quickly at early ages, but only slowly and incompletely at later adult ages. Experimental tests for age-dependent adaptation to a novel diet were performed on populations of Drosophila melanogaster. The results support the prediction that populations should perform better on an ancestral, long-abandoned diet, compared to an evolutionarily recent diet, only at later ages. D. melanogaster populations also perform poorly on a novel diet compared to an evolutionarily recent diet that has been sustained for hundreds of generations, particularly at earlier ages. Additional experiments demonstrate that the timing of the shift to better performance in our populations on the long-abandoned diet is dependent on when the forces of natural selection weaken in the evolutionary history of experimental populations. Taken together, these experimental findings suggest that the forces of natural selection scale the rate of adaptation to novel environments.

Indigenous freshwater mussels (Unionidae) are integral to riverine ecosystems, playing a pivotal role in aquatic food webs and providing ecological services. With populations on the decline worldwide, freshwater mussels are of conservation concern. In this study, we explore the propensity of the invasive Round Goby (Neogobius melanostomus) fish to prey upon indigenous freshwater mussels. First, we conducted lab experiments where Round Gobies were given the opportunity to feed on juvenile unionid mussels and macroinvertebrates, revealing rates and preferences of consumption. Several Round Gobies consumed whole freshwater mussels during these experiments, as confirmed by mussel counts and x-ray images of the fishes. Next, we investigated Round Gobies collected from stream habitats of the French Creek watershed, which is renowned for its unique and rich aquatic biodiversity. We developed a novel DNA metabarcoding method to identify the specific species of mussels consumed by Round Goby and provide a new database of DNA gene sequences for 25 indigenous unionid mussel species. Several of the fishes sampled had consumed indigenous mussels, including the Elktoe (non-endangered), Creeper (non-endangered), Long Solid (state endangered), and Rayed Bean (federally endangered) species. The invasive Round Goby poses a growing threat to unionid mussels, including species of conservation concern. The introduction of the invasive Round Goby to freshwaters of North America is shaping ecosystem transitions within the aquatic critical zone having widespread implications for conservation and management.

•We introduce a case replacement framework for sensitivity analysis of clinical trials.•The framework supports statements such as “The inference would change if xx of the treatment patients who experienced positive outcomes were replaced by hypothetical patients who did not receive a treatment.”•The framework complements the Fragility Index by accounting for the rarity of negative outcomes. For example, large case replacement is required when the Fragility Index is small but negative outcomes are rare.•The framework can be used for any threshold, including minimally important differences and statistical significance.•The framework applies to a broad set of models and research designs. We apply a general case replacement framework for quantifying the robustness of causal inferences to characterize the uncertainty of findings from clinical trials. We express the robustness of inferences as the amount of data that must be replaced to change the conclusion and relate this to the fragility of trial results used for dichotomous outcomes. We illustrate our approach in the context of an RCT of hydroxychloroquine on pneumonia in COVID-19 patients and a cumulative meta-analysis of the effect of antihypertensive treatments on stroke. We developed the Robustness of an Inference to Replacement (RIR), which quantifies how many treatment cases with positive outcomes would have to be replaced with hypothetical patients who did not receive a treatment to change an inference. The RIR addresses known limitations of the Fragility Index by accounting for the observed rates of outcomes. It can be used for varying thresholds for inference, including clinical importance. Because the RIR expresses uncertainty in terms of patient experiences, it is more relatable to stakeholders than P-values alone. It helps identify when results are statistically significant, but conclusions are not robust, while considering the rareness of events in the underlying data.

Background Fetal alcohol spectrum disorder (FASD) is a lifelong condition. Early interventions targeting core neurocognitive deficits have the potential to confer long-term neurodevelopmental benefits. Time-targeted choline supplementation is one such intervention that has been shown to provide neurodevelopmental benefits that emerge with age during childhood. We present a long-term follow-up study evaluating the neurodevelopmental effects of early choline supplementation in children with FASD approximately 7 years on average after an initial efficacy trial. Methods The initial study was a randomized, double-blind, placebo-controlled trial of choline vs. placebo in 2.5 to 5 year olds with FASD. Participants in this long-term follow-up study include 18 children (9 placebo; 9 choline) seen 7 years on average following initial trial completion. The mean age at follow-up was 11.0 years old. Diagnoses were 28% fetal alcohol syndrome (FAS), 28% partial FAS, and 44% alcohol-related neurodevelopmental disorder. The follow-up included measures of executive functioning and an MRI scan. Results Children who received choline had better performance on several tasks of lower-order executive function (e.g., processing speed) and showed higher white matter microstructure organization (i.e., greater axon coherence) in the splenium of the corpus callosum compared to the placebo group. Conclusions These preliminary findings, although exploratory at this stage, highlight potential long-term benefits of choline as a neurodevelopmental intervention for FASD and suggest that choline may affect white matter development, representing a potential target of choline in this population. Trial registration Prior to enrollment, this trial was registered with clinicaltrials.gov ( NCT01149538 ) on June 23, 2010.

Global impact models represent process-level understanding of how natural and human systems may be affected by climate change. Their projections are used in integrated assessments of climate change. Here we test, for the first time, systematically across many important systems, how well such impact models capture the impacts of extreme climate conditions. Using the 2003 European heat wave and drought as a historical analogue for comparable events in the future, we find that a majority of models underestimate the extremeness of impacts in important sectors such as agriculture, terrestrial ecosystems, and heat-related human mortality, while impacts on water resources and hydropower are overestimated in some river basins; and the spread across models is often large. This has important implications for economic assessments of climate change impacts that rely on these models. It also means that societal risks from future extreme events may be greater than previously thought. Impact models projections are used in integrated assessments of climate change. Here the authors test systematically across many important systems, how well such impact models capture the impacts of extreme climate conditions.