Phenotypic plasticity may evolve rapidly, enabling a population’s persistence in the face of sudden environmental change. Rapid evolution can occur when there is considerable genetic polymorphism at selected loci. We propose that balancing selection could be one of the mechanisms that sustain such polymorphism for plasticity. We use stochastic Monte Carlo simulations and deterministic analysis to investigate the evolution of a plasticity modifier locus in structured populations inhabiting favorable and adverse environments, i.e. patchy habitats. We survey a wide range of parameters including selective pressures on a target  locus, plasticity effects, population sizes, and migration patterns between demes including periodic or continuous bidirectional and source-sink dynamics. We find that polymorphism in phenotypic plasticity can be maintained under a wide range of environmental scenarios in both favorable and adverse environments due to the balancing effect of population structure in patchy habitats. This effect offers a new plausible explanation for the rapid evolution of plasticity in nature: Phenotypic plasticity may rapidly evolve from genetic variation maintained by balancing selection if the population has experienced immigration from populations under different selection regimes. Plasticity is known to appear in adverse habitats where it buffers the fitness-reducing impacts of selection on maladaptive phenotypes6 and is considered one of the key abilities that allow populations to persist in the face of drastic environmental change or establish in new habitats before constitutive adaptation at a structural locus can occur8. For example, invasive populations that successfully colonize new habitats have been observed to have higher levels of plasticity in fundamental fitness components than non-invaders9. These features of plasticity make it a primary candidate for enabling populations to survive accelerated climate change, range shift of competitors, habitat expansions, or other sudden shifts in the environment. Yet despite its fundamental importance in sustaining biodiversity in the changing world, much is still unclear about how plasticity arises in nature.Phenotypic plasticity is the ability of a single genotype to produce different phenotypes in response to different environmental conditions1. Two genetic mechanisms of plastic response have been widely accepted and supported empirically: environmentally sensitive loci and epistatically interacting loci10. By the former mechanism for example, the environment might induce epigenetic modifications near a directly-selected structural coding sequence which results in plastic phenotypes12. The latter mechanism involves the interaction of loci, such as regulatory loci that affect target expression10, and hence constitutes a kind of epistasis. Theoretical studies have explored this type of epistasis using modifier locus models14. In such models, an allele at the modifier locus, such as a transcription factor or an epigenetic modifier, may affect the expression of a target locus so as to improve the phenotype or fitness in a particular environment. This improvement in turn makes the modifier allele selectively advantageous. The modifier allele remains selectively advantageous until the target locus evolves an optimal phenotype through means independent of environmental cues, such as through beneficial mutation and positive selection, i.e. constitutive adaptation. For example, in constant conditions, there is no longer any advantage to plasticity once constitutive adaptation occurs17. This means that to provide evolutionary rescue, plasticity must evolve more quickly5 than de novo constitutive beneficial mutations.Plasticity may have a genetic basis and, therefore, evolve18. Furthermore, absolute change in allele frequency is greater if the initial allele frequency is already appreciable, due to the multiplicative nature of allele frequency change19. The speed at which both plastic and non-plastic responses can evolve in nature9 could therefore, at least in some conditions, be explained by genetic variation underlying the trait.How phenotypic plasticity could evolve rapidly is unclear. Genetic variation provides one possible explanation because newly adaptive alleles would already be present in a population at the time of environmental change20. In that case plasticity could evolve rapidly due to minute changes at many loci in unison. However, mapping studies indicate that some variation in plasticity comes from a few loci of major effect24. These few loci collectively have a much smaller chance of mutating, while major effect alleles are more likely to be purged or fixed by directional selection. Thus, the mechanisms that maintain diversity at single or a few major effect loci are different from those that maintain diversity across the genome. Molecular evolution studies of single loci offer answers for how variation can be maintained at a gene level27.The necessary genetic variance may exist due to an abundance of mutations at mutation-selection balance if plasticity is a polygenic trait coded by numerous small-effect loci14. Plasticity may further come with fitness costs30. Fitness costs of plasticity may be associated for example with creating or maintaining the systems and structures necessary for osmo- or thermo-regulation31, sensing the environment, or maintaining genes and enzymes involved in modification. Plasticity may be selected against if the cost outweighs the benefit, such as when adverse conditions pass or when less-costly constitutive adaptation takes place at the target locus13. Even in the absence of direct costs, plasticity becomes neutral at best once alleles for constitutive adaptation are available.Plasticity modifiers, however, might evolve differently from single directly-selected loci due to the distinct way in which plasticity affects fitness. Fitness effects of gene regulation by a modifier are indirect and dependent on both the environment and the target locus32 or overdominance33, do not immediately fit the mode of selection on modifiers of phenotypic plasticity. Spatially and temporally varying environments, however, are ubiquitous in nature and have been shown to create opportunities for balancing selection34. Balancing selection for plasticity has been shown in temporally varying environments due to a genomic storage effect13. This genomic storage effect is a consequence of balanced polymorphism at the target locus, which generates heterogeneous genetic backgrounds required for the storage effect to apply to plasticity alleles. Plasticity in spatially varying environments has also been investigated. Classical models found that continuous reaction norms and developmental switches may be favored in metapopulations composed of multiple habitats35 and that some mixture of ancestral and stress-tolerant forms is an evolutionary stable state when stress-tolerant forms are able to invade a new habitat36. Models of the reaction norms themselves have shown that some combination of plastic and constitutive loci tend to underly multi-locus traits when both are allowed to evolve37, while other theoretical studies investigate constraints on plasticity39 or conditions under which plasticity is favored40. These studies nonetheless have not explicitly investigated conditions for balanced polymorphism under spatial heterogeneity.Balancing selection is one key mechanism of maintaining elevated genetic variation that would enable rapid evolution. While conditions for balanced polymorphism are well known, the most obvious mechanisms, such as direct negative frequency-dependent selection41 or protists42, or due to anthropogenic disturbance44 such as global transport46 of large groups of invasive individuals in ballast water47. We model the effects of genotype and environment on fitness directly by specifying the fitness of each genotype in each environment, without explicitly modeling the phenotype. By assuming the modeled loci evolve independently of other loci in the genome48, this approach makes relatively weak assumptions about genetic architecture49.Here, we investigate how spatial heterogeneity might induce balancing selection at a plasticity modifier locus in structured populations, and in turn promote rapid evolution of phenotypic plasticity. We develop a haploid, two locus, two allele, two deme population genetic model in which a modifier locus conveys a plastic response at a target  locus underlying a trait under heterogeneous selection between the two habitat patches. This two-habitat model describes many natural situations in which selection might differ due to environmental change in one or another habitat. Such situations arise in naturally patchy habitats or when part of a population finds itself in an adverse habitat patch. Subpopulations that are not yet adapted to a local habitat can occur due to passive dispersal in plantsTo demonstrate balancing selection at the plasticity modifier locus, we use two lines of evidence. First, we derive an analytic solution for a stable polymorphic equilibrium at the plasticity locus in a deterministic model in terms of selection, plasticity effects, and migration rates between demes. Second, we observe whether stable long-term diversity at the modifier locus arises from single-mutant introductions in finite populations in forward-in-time stochastic simulations across a range of selective pressures, costs and benefits to plasticity, rates of periodic and continuous, one- and bi-directional migration between demes, and even and uneven population sizes.13, balanced polymorphism occurs when the target locus is monomorphic. Here, heterogeneous fitness effects at the target locus in different environments play the role of different genetic backgrounds underlying the genomic storage effect13. Balanced polymorphism at modifier loci in turn enables rapid evolution of plasticity by selection on standing variation following a sudden environmental change in a population. These results, therefore, suggest that balancing selection on plasticity modifiers due to migration between patchy habitats may offer a new explanation for many natural cases of rapid plasticity evolution in the face of sudden environmental change.We find balanced polymorphism at the plasticity modifier locus under a wide range of conditions provided that migration is present but limited, selection has opposite direction in each deme, and that neither costs nor benefits to plasticity are overwhelming such that the plasticity allele fixes or is lost. In contrast to previous results on temporally varying selectionWe examine evolution at a plasticity modifier locus under a wide range of evolutionary scenarios in a haploid Wright-Fisher population. We simulate forward-in-time discrete-generation evolution with each generation consisting of migration, selection, recombination, and reproduction. Our main interest is the maintenance of variation in plasticity by selection and migration between demes rather than variation maintained by influx of new mutations. We therefore model what happens following a single-mutant introduction. These results are then easily extrapolated to the case of recurrent mutation. We model one mutation event at each of the plasticity and target loci per simulation run. We allow mutation at both loci at the same rate to account for interference between plastic and constitutive adaptation. Our analysis focuses on polymorphism at the plasticity locus, which determines its potential for rapid adaption.t = 0), a population splits into two demes (subpopulations), or there is a sudden change of environments in one portion of the habitat, such that one deme now inhabits the ancestral favorable habitat while the other deme inhabits a derived adverse habitat patch. We assume that prior to this, a population was at its fitness optimum and therefore that both demes are monomorphic for the non-plastic allele (m) at the plasticity modifier locus and the ancestral allele (a) at the target locus. That is, adaptation to the new environment has not yet occurred. Then, a single novel mutant allele arises at random at one of the two loci in one of the two demes replacing an ancestral (a) allele with a derived allele (d) at a target locus or a non-plasticity allele (m) with a plasticity allele (M) at the modifier locus. The remaining monomorphic locus mutates in a random individual with a probability 34, although we later show results for a case with recurrent mutation as well.At the beginning of each simulation run  in the two demes. The list and description of the main variables used in the study are given in Table In each generation, the frequency of the eight possible haplotypes in the meta-population e1 random individuals to migrate from the ancestral deme (i = 1) to the derived deme (i = 2) and e2 to migrate in the opposite direction, with the migration being either reciprocal when e = e2 = e1 or source-sink dynamics52 when e2 = 0. Migration occurs at each Ith generation with no migration in between. Therefore I = 1 represents continuous migration and I > 1 represents periodic migration. We opted for a wide range of migration settings to accommodate a wide range of scenarios as could arise such as regularly mixing naturally fragmented habitats and irregular mass transports between distinct habitats due to global trade47.Migration allows a and d alleles in the ancestral and derived demes. The haplotype frequencies at the beginning of generation t within each deme i (i = 1 or 2), are modified by selection so that the expected post-selection haplotype frequencies in generation t are We model an adapted-maladapted dynamic with opposite selection on the Wherei, and is initially set to si above with N. When the M allele is paired with the adapted target allele that is already near the fitness optimum, the cost of the plasticity exceeds the benefit resulting in a relative decrease in the fitness of its carriers. These fitness values results in the plasticity modifier allele being disadvantageous  in the ancestral deme when cost is present  population. The cumulative heterozygosity HL measures diversity over time. Under drift or directional selection, alleles are fixed or lost over time and HL approaches a finite expectation with increasing simulation time. Under drift, this expectation is 2 irrespective of population size53 and population structure27. In cases of balanced polymorphism, however, heterozygosity persists for long times, making HL roughly proportional to time even for long simulations, up until the point that alleles go extinct due to long, improbable excursions from equilibrium. This cumulative heterozygosity thus reflects not only the plasticity modifier allele frequencies over time but also the strength of stability of the equilibrium against stochastic fluctuations. Observing HL >  > 2 over a long simulation time, or observing HL continuing to increase over long times therefore proves the presence of long-lived stable polymorphic equilibria. We therefore use HL to confirm the existence of intermediate-frequency stable equilibrium predicted by our stability analysis , therefore, simulations were run for between 40,000 and 2 million generations, way beyond the expected lifetime of a neutral polymorphism, to assure the detection of long-lived stable polymorphism. We conduct many replicates because most single mutant introductions in finite populations are lost to stochastic extinction54. We therefore conduct 1000N replicates for each combination of local directional selection effects , migration rates , the period between migration events , plasticity effects , and recombination rates , with or without environmental perturbations , and a subset of combinations in unequal populations where the ancestral deme is much larger  than the derived deme (N2 = 2000 or 200), with the mutation occurring only once per simulation run at each of the loci with probability = 0.001, 0.1, or 1.0 in each generation.We simulate evolution in populations starting from an initial mutation until either the metapopulation reaches monomorphy through fixation or loss of the mutant alleles or else polymorphism persists for 100In silico, we observe a wide range of naturally plausible scenarios where balanced polymorphism at the plasticity modifier locus arises in both the ancestral and derived deme, as long as there is population structure due to limited migration (gene flow) between the demes Figs. , 2, 3, 4p = pa1 = pd1 = pa2 = pd2. The result is that intermediate equilibria representing balanced polymorphism exist in both ancestral and derived demes and are stable whenever sp and e/IN are strictly greater than zero. That is, the deterministic condition for stable polymorphism requires migration, selection, and some net effect of cost and benefit to plasticity and is fulfilled whenever migration between demes (e/I), selection (s), and the effect of plasticity (p) are all finite and greater than zero. For high migration rates, however, the equilibria collapse onto a line representing homogenization and loss of structure between the two demes. Then, the plasticity modifier either fixes or goes extinct in the limit of very large migration rates depending on its adaptive status. This effect highlights that limited migration is required for the protection of balanced polymorphism. The equilibrium frequencies of the M allele in deme i, sp) and migration (e/IN) in the deterministic model:Mathematical analysis described in Supplementary Information We can represent the relative strength of selection and migration with the parameter mentclass2pt{minimHL) exceeding that expected under neutrality , across a range of rates and types of migration. Balanced polymorphism exists for limited continuous reciprocal rates and periodic reciprocal migration, provided there is some degree of population structure  with higher levels of balanced polymorphism across moderate migration rates, with some increase in diversity for migration rates up to 20% of a deme’s residents per generation  becomes non-neutral if there is a net adaptive or maladaptive effect to plasticity over both environments, in which case the balance is broken and plasticity allele is selected to either fixation or extinction. This highlights, again, that population structure is needed for the protection of polymorphism across patchy habitat.Sufficiently high migration rates erase population structure in the symmetric, deterministic analysis as well  generations of burn-in simulation, which exceeds 10 times neutral expectation in fixation times and therefore demonstrates a long-lived stable polymorphism, we induced an environmental switch after 200 generations by changing the sign of the selective coefficients at 40N + 200 generations, and then observed the simulation for the next 800 generations. Following the switch in demes’ selective environments, plasticity modifier allele frequencies rapidly decrease in the derived deme when it becomes adapted and show the mirror opposite pattern in the ancestral deme when it becomes maladapted , its polymorphism requires protection by limited migration and limited opportunities for one population to genetically swamp the other.Next, we tested how perturbations in the simplifying assumptions, such as symmetric deme sizes, symmetric magnitudes of selection pressure, symmetric migration, the degree and symmetry of plasticity effect, and large census meta-population size affect the maintenance of balanced polymorphism in structured populations. We find that the qualitative effect still occurs under some range of parameters Fig.  online. tes Fig. a, consis52 as well.We postulate that the balanced polymorphism is maintained in each deme by the balance between limited relative immigration (proportion of post-deme membership originating from another deme) and selection on the plasticity locus, and does not depend on reciprocal emigration rate. For example, while selection prefers the plasticity modifier allele in the derived deme, limited immigration from the ancestral deme prevents its fixation without swamping the derived deme even for unidirectional migration. Conversely, the opposite occurs for the ancestral deme if migration occurs in the opposite direction. Therefore, as long as there is limited relative immigration to a deme, even by unidirectional migration, we expect polymorphism in the recipient deme Fig. b. IndeedAn implication of the dynamics above is that, in the case of unidirectional migration, the cost of plasticity is inconsequential if plasticity is adaptive in adverse environments. That is, genetic polymorphism in the adverse environment depends on the balance between positive selection on adaptive plasticity and immigration of non-plastic phenotypes from the favorable environment, irrespective of whether the ancestral deme is non-plastic due to plasticity being maladaptive (costly) or neutral (not costly).N2) still permit high levels of balanced polymorphism. In other words, plasticity is maladaptive for the majority of individuals in the metapopulation who live in the ancestral deme, and so in the absence of structural protection in the smaller deme, the polymorphism at the plasticity locus is removed quickly to levels below that under drift  locus, making the above results applicable regardless of assumptions about the genetic architecture and specific mechanisms of phenotypic plasticity.In the cases where adaptation at the target locus occurred in the adverse habitat patch, the plasticity modifier allele was selected out if the meta-population evolved towards balanced polymorphism at the target locus, driven by adaptation in each deme and migration between demes. In the absence of recurrent mutation, we do not observe any notable effect of the rate of introducing a new mutant to either locus, on the patterns of molecular evolution at either locus.We also initially assumed symmetric fitness effects of plasticity in order to produce intermediate fitnesses where the adaptive value of plasticity in adverse habitats would not greatly exceed the maladaptive effects in favorable habitats or vice versa. Once the adaptive effects of plasticity and maladaptive effect become asymmetric balance in each deme is perturbed and allele frequencies may approach the boundaries 0 and 1. In finite populations this proximity to the boundaries makes fixation likely. Indeed, in the range of asymmetric fitness effects involving a small cost, including no cost, the balancing effect is limited to stronger population structure. That is, we observe elevated diversity in the limit of lower migration rates . Under symmetric plasticity and selection effects, the observed metapopulation cumulative heterozygosity 58.This study demonstrates a novel mechanism for the rapid evolution of phenotypic plasticity: genetic variation in phenotypic plasticity maintained by balancing selection in patchy habitats. We propose that populations that have previously experienced limited immigration from habitat patches where plasticity had an opposing selective effect may harbor balanced polymorphism for plasticity. These populations are then potentiated to rapidly evolve plasticity when the environment changes suddenly, for example with climate change, range shift of symbionts, sudden environmental shifts in patches within a habitat matrix, or invasion of a subpopulation into a new habitat. This is because once alleles are present at a stable intermediate frequency, allele frequencies quickly approach new equilibria in response to changes in selection or migration between demes. Not only can the proposed mechanism explain the rapid evolution of plastic response in invaders from favorable habitats, but it also suggests that populations in adverse habitats will maintain a sizable proportion of non-plasticity alleles and be able to rapidly evolve non-plastic phenotypes if constitutive adaptation occurs, known as assimilationWe report a mechanism by which plasticity modifier alleles can achieve long-term balanced polymorphism at rates comparable to directionally-selected alleles following single-mutant introduction. The actual prevalence of loci under balanced polymorphism in wild populations due to this mechanism in turn depends on rates of introduction of plasticity modifier alleles, migration rates, and the history of selective conditions across populations. This helps explain how, given the right conditions, genetic diversity that supports rapid evolution of plasticity can accumulate and be maintained in populations over time.The observed effect depends on population structure due to either limited continuous rates of migration or limited frequency of migration events, and on spatially heterogenous indirect selection on the plasticity locus. The effect still occurs in cases of reducing the plasticity effect, introducing uneven selective pressures, uneven or small population sizes, perturbations to the selection coefficient or asymmetry in plasticity effects, and across a wide range of migration rates and periods of complete isolation between demes. Moreover, the results are robust to the recombination rates between the plasticity modifier and the target gene, making them broadly applicable across models of the genetic basis of phenotypic plasticity. That is, the effect appears equally in environmentally sensitive loci and epistatic modifier loci, since the difference between these bases of phenotypic plasticity is in whether there is recombination between the trait and its plasticity.35 (reviewed by Berringan and Scheiner59) or examined only in the settings of multi-locus or phenotypic evolution of plasticity40, it appears to be the key to generating the balancing effect of heterogeneous indirect selection and the consequent rapid evolution at a plasticity modifier locus. Such a population structure is likely to arise as organisms such as plants disperse passively over patchy habitats60, under ecological or evolutionary traps61, or due to anthropogenic disturbance44 such as global transport47, making the mechanisms applicable to natural scenarios where plasticity could rescue populations from extinction62 or aid in their invasive success9. Therefore, this study expands on an important, underexplored, and plausible biological scenario where the rapid molecular evolution of phenotypic plasticity could aid in rapid adaptation, and the findings further highlight the importance of population structure in understanding the evolution of phenotypic plasticity.While population structure is often neglected in deterministic evolutionary models of plasticity63. Costs to plasticity have been difficult to determine64 , although the fact that plasticity may involve complex structures and be evolutionary maladaptive, as evidenced by its disappearance following assimilation, points to nontrivial costs29. Another novel implication of this study is that the cost of plasticity is an important evolutionary factor, not only in whether plasticity can evolve in populations30 but also in whether selection leads to balanced polymorphism for plasticity across structured populations. That is, in the absence of the cost, plasticity would be at worst neutral in ancestral demes while advantageous in adverse environments. This situation would easily lead to its fixation in the metapopulation through immigration from adverse environments, creating a reductio ad absurdum in which plasticity is favored in all traits. Such a cost can therefore maintain genetic differentiation and polymorphism across a structured population and promote rapid adaption through plasticity. Our study, therefore, argues that negative selection due to the cost of plasticity might be an important condition for mechanisms of plasticity that can rapidly evolve when migration is bi-directional. However, cost is not required to maintain the capacity for rapid adaptation when there are unidirectional migration patterns or source-sink dynamics, because migration-selection balance can be maintained in recipient demes without modifiers from the ancestral demes. Therefore, while cost is not required for rapid adaptation, it nonetheless enables plasticity to rapidly evolve in a wider range of conditions.Cost to plasticity is also an important factor to rapid adaptation. Under bi-directional migration, the strength of the proposed mechanism depends on the cost to plasticity58, the basis for the rapid plastic response is a qualitatively distinct phenomenon that requires further theoretical investigation. Given that the main role of plastic response is to protect populations from the negative effects of selection when conditions change, its ability to rapidly arise seems to be key to its benefit. However, so far, models recovering rapid plastic response assumed evolution across multiple loci or depend on high mutation rates65. These same mechanisms could just as well drive fast adaption at the directly selected structural loci, quickly rendering plasticity obsolete. Balanced polymorphism represents another venue for the rapid evolution of plastic or non-plastic response, via protected balanced polymorphisms at the plasticity modifier locus. Gulisija et al.14 offered a plausible scenario for balanced polymorphism and rapid molecular evolution of phenotypic plasticity that requires predictably changing temporally varying environments. However, by the nature of temporal change this scenario is limited predominantly to evolution in seasonally evolving organisms67 and makes specific assumptions about genetic architecture and recombination. As biodiversity faces increasing rates and magnitudes of environmental change68 due to global climate change, habitat conversion, invasive species transport, range shift, and many other natural and anthropogenic stressors, the rapid evolution of phenotypic plasticity needs to be better understood in order to predict future patterns of biodiversity. Mechanisms akin to the one uncovered in this study could greatly advance modeling and understanding of the effects of global climate change on persistence in perturbed habitats or forced dispersal to novel habitats.Phenotypic plasticity is an important biological phenomenon that promotes population persistence in the face of environmental change. While many theoretical studies have greatly advanced our understanding of the evolution of plasticity64. However, in reality, plasticity may be controlled by more than two loci64, and the presence of many loci may result in interactions that affect evolution at a modifier-target pair. In addition, the evolution of plasticity depends on the trait’s constitutive loci, and might further be affected by the number of such non-plasticity loci as well69. Therefore, extending the proof-of-concept results reported here to multi-locus case remains open for future study.Our study, however, introduces two caveats. The population genetics approach applied here allowed us to achieve an elegant and explicit examination of molecular evolution at a plasticity locus in a structured population in patchy habitats, unlike typically examined in optimality and quantitative genetics modelsFurthermore, the findings in this study apply to evolution in patchy habitats when recurrent mutation rates are low, and argue that rapid evolution of plasticity can occur as conditions change because of pervasive balanced polymorphism at plasticity modifier loci. Another caveat of our findings is the assumption that mutation rates are low, or by extension that constitutive adaptation is unlikely or not possible, and hence plasticity will aid in population persistence. This assumption excludes cases characterized by high beneficial mutation rates at loci under direct selection. In fact, balanced polymorphism can occur either at the plasticity locus or at the target locus, but not both. Indeed, following adaptation in all demes under our model, the polymorphism in phenotypic plasticity is removed from populations. Therefore, this model does not apply to the rapid evolution of phenotypic plasticity in populations adapted to local conditions. Such cases are subject to future studies of the evolution of plasticity needed to fully elucidate this important biological phenomenon.Supplementary Information 1.Supplementary Information 2.


New-onset refractory status epilepticus (NORSE) is a clinical presentation where an individual develops refractory status epilepticus without active epilepsy, or related neurological conditions. A subset of these individuals has a preceding fever and would be diagnosed with febrile infection-related epilepsy syndrome (FIRES). The underlying etiology of this condition varies and includes autoimmune and viral encephalitides. These conditions require multiple specialized health care teams working collaboratively and specific resources for investigation of the underlying etiology and management to provide optimal patient care. In this paper, we provide: (1) recommendations upon early recognition of NORSE and FIRES, (2) guidance on the resources needed to optimally provide care, and (3) guidance on considerations to initiate transfer of patients to a more specialized medical center. Additional recommendations for resource-austere centers without the ability to transfer such patients are also discussed. These recommendations are only for adult patients with NORSE as pediatric patients may require additional special considerations. New-onset refractory status epilepticus (NORSE) can be defined as a clinical presentation in a patient without active epilepsy or other existing relevant neurological disorder, with new onset of refractory status epilepticus in the absence of a clear acute or active structural, metabolic, or toxic cause. Refractory status epilepticus (RSE) is a condition where continuous or recurrent seizures do not stop with standard anti-epileptic medications . The durAlthough the prevalence of NORSE has not been studied and identified, the annual incidence of refractory status epilepticus is estimated to be 3.0–7.2 per 100,000 adults per year . One stuA prodromal period can precede the onset NORSE by a couple of weeks and often includes non-specific symptoms such as confusion, fever, fatigue, headache, gastrointestinal, or respiratory symptoms. It is estimated that this prodromal period is present in ~60% of cases . IndividNORSE should be a diagnostic consideration in individuals presenting with new onset recurrent seizures evolving into status epilepticus with no known history of epilepsy and no clear identifiable etiology after initial blood work, CSF studies, and brain imaging has been completed.There are several identified predictors of prolonged refractory status epilepticus. These include the presence of acute brain lesions, increased severity of status epilepticus (measured using the status epilepticus severity score [STESS] ), non-coWhile it is of prime importance to provide airway and cardiovascular/blood pressure support and to halt seizures as soon as possible to prevent further neurologic injury, further consideration must be given to other aspects, including monitoring for breakthrough or nonconvulsive seizures and searching for an underlying etiology; especially one that can be treated. Once the patient is reasonably stabilized, consideration should be given to transferring the patient to a tertiary care center where more specialized investigations and care can be implemented.An important aspect of a higher-level of care includes the multidisciplinary team, and ability to case conference about such patients with actionable diagnostic and treatment strategies. Centers with neurocritical care expertise are also uniquely qualified to monitor and treat these complex patients. Consultant teams are essential for the co-management of these cases. These services include Neurology with expertise in epilepsy and Internal Medicine and its subspecialties, who may be needed to help manage the multi-system effects of prolonged seizure activity and complications of antiseizure treatments including anesthetics . IndividFurthermore, specialized neuro-focused centers play an important role in the recovery phase where multidisciplinary team members such as physiotherapy, occupational therapy, speech language pathology, and rehabilitation medicine can collaboratively address the ongoing needs of patients who survive the acute phase of this illness. The burden of critical illness on NORSE patients is an important consideration with individuals exhibiting prolonged hospital stays, with a median ICU stay of 26 days , 14, oftFrom an investigation standpoint, readily available access to continuous scalp EEG monitoring with video and MR imaging are important aspects of care. Having access to specialized diagnostic tests including autoimmune, paraneoplastic antibody testing, viral PCR testing may aid in early diagnosis (or lack thereof) of underlying etiology. In a significant proportion of cases, no etiology is identified, rendering their classification as cryptogenic , althougIn resource-austere settings where transfer to a comprehensive center is not possible, substitution of modalities of investigation and/or virtual care may be considered. Critical care settings without subspecialized expertise, CT imaging instead of MRI to rule out gross structural lesions, and serial routine EEGs instead of continuous monitoring can be considered .When a patient is identified as having ongoing seizure activity, beyond the timepoints required for meeting criteria of status epilepticus , and aftWhen transferring a patient with NORSE to a specialized critical care facility, special considerations with attention to airway patency, adequate circulatory support, and provision of seizure-stabilizing medications and equipment for transport are necessary. A trained medical team with expertise in critical care and neurology should oversee the transfer, with appropriate monitoring and interventions in place to manage any potential complications that may arise during transport.Early transfer should be facilitated, when possible, especially in cases where a transfer would enable access to essential tests , and neuromodulatory treatment options . Early transfer is especially important when nonconvulsive status epilepticus is suspected or there is lack of access to routine and serial EEG given the morbidity and mortality associated with prolonged status epilepticus . See FigOverall, early identification of NORSE and associated conditions such as FIRES is essential to initiate appropriate investigations and management. Optimal patient care involves a multidisciplinary approach and numerous investigations and treatments. We advocate for early transfer to a specialized center with these resources with the aim of mitigating the known risks and downstream complications of NORSE. These recommendations pertain to adult patients as pediatric patients may require additional special considerations.The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.HK conceived this manuscript and oversaw direction and planning. SV wrote the first draft of this manuscript in consultation with HK and GY. All authors contributed to the content of this manuscript and were involved in editing this work.This work was supported by the University of Toronto.The authors declare that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


A misunderstanding of the mechanism of action and bacterial targets of antibiotics by consumers may drive inappropriate antibiotic use and antimicrobial resistance (AMR). Tackling AMR requires an in-depth understanding of consumer beliefs and misconceptions. We explored consumer conversations on a number of social media platforms on antibiotic use and AMR in the context of sore throat and how coronavirus disease 2019 (COVID-19) affected online conversations between 1 January 2018 and 25 November 2021 across eight countries. Five distinct consumer groups were identified  with a wide spectrum of beliefs around antibiotics in sore throat. Many opinions were based upon misconceptions, the most prominent of which was that antibiotics are strong medications that can treat all types of sore throat. COVID-19 had a multifaceted effect on the sore throat and AMR conversation. Sore throat triggered anxiety as consumers feared it may be a COVID-19 symptom while engagement in conversations around antibiotics for COVID-19 increased. Finally, consumers sought multiple routes to access antibiotics, such as directly from the pharmacy or by attempting to persuade physicians to prescribe. Knowledge obtained from this study could be used to develop focused approaches to dispel consumer misconceptions and mitigate AMR. Antimicrobial resistance (AMR) is one of the most urgent global health challenges of the 21st century . In 2019Overuse and misuse of antimicrobials significantly contribute to AMR ,5. DespiInappropriate antibiotic use, whether obtained on prescription or over the counter (OTC), is likely to be influenced by consumer misunderstanding. Studies conducted prior to coronavirus disease 2019 (COVID-19) revealed that up to 71% of patients believed that viruses can be treated with antibiotics ,12,13,14It has also been shown that consumers have a poor understanding of AMR. A study using qualitative semi-structured interviews with patients or parents of children presenting with an acute respiratory infection to general practices in Australia, revealed a lack of understanding of what becomes resistant (the person or the bacteria), how patients contribute to AMR, and that resistance can spread between people in close proximity . FurtherAddressing the challenge of AMR as we move past the height of the COVID-19 pandemic requires an in-depth understanding of consumer perceptions and misconceptions around antibiotic use and AMR, so that targeted educational materials/messages and strategies  can be developed and delivered. Social media provides unprecedented communication opportunities between individuals, companies and organizations. In 2021, around one-half of the global population (approximately 4.26 billion people) used social media worldwide . In addiThe extensive use of social media provides an opportunity to further explore consumer beliefs and conversations regarding antibiotics and AMR and offers opportunities to share appropriate messages through such platforms. The aim of this study was to explore consumer conversations on social media on antibiotic use and AMR in the context of sore throat using Brandwatch, a social listening platform that allows one to monitor and analyze online conversations , to deteThere were ~760,000 social media posts related to AMR and ~3,500,000 social media posts related to sore throat across the eight countries between 1 January 2018 and 25 November 2021. The social media listening exercise revealed three critical findings: (1) distinct consumer groups were involved in conversations on antibiotic use in sore throat with a substantial number of opinions based upon misconceptions; (2) COVID-19 impacted conversations on sore throat and AMR; and (3) COVID-19 impacted how the patient responded to early sore throat symptoms.Five distinct consumer profiles were identified with diverse opinions and beliefs on antibiotic use in sore throat .The first two consumer profiles had the greatest understanding of antibiotics and AMR. Antibiotic-preserving peer educators shared knowledge of the difference between viral and bacterial infections manifesting in sore throat and had a strong opinion on if and when antibiotics should be taken. Consumers in this group tended to share advice only when asked, and while their posts were largely neutral and educational, they appeared to be strongly against antibiotic misuse. Antibiotic-cautious consumers were more hesitant to take antibiotics for a sore throat for different reasons. On one hand, reluctance was due to an awareness of AMR or the knowledge that antibiotics are not indicated for self-limiting sore throat of viral etiology. On the other hand, reluctance stemmed from the perception that antibiotics are ‘too strong’ a medication to take for something as trivial as sore throat; the tone of the conversation by these consumers made it seem that they had a moral reluctance to take antibiotics for sore throat . These consumers often preferred home remedies and symptom relief; however, this was not driven by a belief that ‘natural’ solutions are superior, but rather by the knowledge that sore throat is self-limiting and will resolve over time with symptomatic management.The third group were categorized as medication-resistant antibiotic opponents, who appeared to prefer home remedies and were reluctant to take antibiotics due to a misunderstanding of AMR. Consumers in this group believed that AMR could be ‘caught through antibiotics’ and believed that antibiotics make bacteria in their body stronger, which was partially reinforced by a concern about missing antibiotic doses and forgetting to finish the full course of treatment. This group also included pregnant women and parents who were hesitant to give/take antibiotics because of a perception that they could cause side effects or weaken the immune system of their child.The final two consumer profiles appeared to be supporters of antibiotics with a lesser understanding of the mechanism of action of antibiotics. Consumers that were believers in the strength of antibiotics were typically keen to use antibiotics as they believed they are ‘strong medications’ that provide quick relief of symptoms. Consumers in this group were unable to make the distinction between viral and bacterial infections and often felt frustrated when their sore throat did not clear up with antibiotic treatment. Determined pro-antibiotic consumers were part of a smaller group. They often shared their beliefs that antibiotics are ‘strong medications’ and proactively attempted to source antibiotics by trying to persuade their physician. Some consumers even went directly to a pharmacy to obtain antibiotics OTC.A number of consumer misconceptions were identified, with the most prevalent often being misinterpretations of the science behind AMR rather than outright fallacies. The most common consumer misconception was that antibiotics are strong medications that can treat all types of sore throat .COVID-19 had a multifaceted effect on sore throat and AMR conversations. Firstly, sore throat triggered anxiety in consumers as they feared it may be a symptom of COVID-19, which prompted consumers to test for COVID-19. Secondly, the pandemic led to consumers engaging in conversations around antibiotics and the distinction between viral and bacterial infections in the context of COVID-19, and antibiotics not being effective against viral infections. Furthermore, early in the pandemic, commentary by consumers and HCPs was directed towards people being prescribed antibiotics for COVID-19. A minority of consumers suggested that antibiotic prescriptions for COVID-19 may play a role in the prevention of opportunistic bacterial infections. Finally, public interest in natural remedies for sore throat remained prominent, and possibly even increased during the pandemic, driven by a reluctance to visit healthcare centers for fear of contracting COVID-19 or overburdening the health system, as well as a desire to lead a healthy lifestyle focused on wellness.In addition to consumers, the study found that other stakeholders played a larger part in conversations that included sore throat, AMR and COVID-19. For example, activities carried out during World Antibiotic Awareness Week (WAAW) by government agencies, health authorities, local branches of the WHO and regional healthcare bodies focused on raising awareness of AMR and the dangers it poses in general, and garnered significant coverage through online platforms. A small proportion of individual campaigners and consumers  joined the conversations. Supportive campaigns and conversations around AMR became less prominent during the height of the COVID-19 pandemic, as health authorities focused on tackling COVID-19. Furthermore, many stakeholders outside of government influenced the AMR conversation, including peer educators  and non-healthcare figures in the public domain .Consumers sought advice for sore throat relief through multiple routes. Consumers seeking advice from people in an individual’s social network was common in online sore throat conversation. Some consumers frequently visited the pharmacy for OTC symptom relief if they did not already have this at home. Meanwhile, other consumers visited their physician or pharmacist immediately, especially when they were unsure if their symptoms were COVID-19-related. In some markets , consumers with sore throat were more likely to demand specific antibiotics from their physician. In other markets , consumers attempted to persuade their physician to prescribe antibiotics by stating that they were necessary or exaggerating their symptoms. Antibiotics or antibiotic-containing products frequently mentioned by people experiencing sore throat included amoxicillin (Thailand), amoxicillin combined with clavulanic acid (Thailand), penicillin V (Germany), Benzetacil (benzyl penicillin) (Brazil), Grammidin (gramicidin) (Russian Federation), and Bioparox (fusafungine) spray (Romania). A trigger for visiting primary care/family physicians was when symptoms worsened or lingered for some time and depended on factors related to COVID-19, such as the desire to test and fear of infection, as well as factors related to the health systems . In addition, in countries where antibiotics were more commonly available without a prescription directly from the pharmacy , some consumers went directly to the pharmacy to access treatment.To our knowledge this is the first study to examine consumer beliefs and conversations on sore throat, antibiotics and AMR, and the impact that the COVID-19 pandemic has had on such conversations, using posts from multiple social platforms and forums. Our study assessed a large number of social media posts, which allowed us to unpack the diverse consumer beliefs related to antibiotic use. We found that consumer conservations were clustered, which allowed us to define five distinct groups, with many groups’ opinions based upon misconceptions. In addition, COVID-19 impacted conversations around sore throat and AMR and how patients respond to early sore throat symptoms.Beliefs and misconceptions observed among the five groups aligned with previous studies. At one end of the scale were antibiotic-preserving peer educators and antibiotic-cautious consumers who had the greatest understanding of antibiotics and AMR. Other survey-based studies also found that there were a proportion of patients (between 36.5% and ~50%) who clearly understand that antibiotics are only effective against bacterial infections ,13. PrevAsk questions to establish the understanding of AMR by the consumer and identify misconceptions; Customize messages according to the consumer profile; Empower consumers with the knowledge to understand the cause of their illness and why symptomatic relief can be effective.For HCPs to help address consumer misconceptions, we recommend a multifaceted approach. Firstly, we would suggest that HCPs become knowledgeable on the identified consumer profiles and the desired messages that should be conveyed to bring a shift in belief/behavior. Secondly, as it may be difficult to determine the beliefs of a consumer on first contact, we would suggest utilizing open-ended statements and questions to explore what consumers are looking for and identify any misconceptions. Once this information has been gathered, messages can be customized and relevant decision aids and knowledge bites on appropriate antibiotic use and symptomatic management can be provided, to address misconceptions and empower the consumer to make appropriate health decisions . A simplThe large number of social media posts analyzed in our study indicated that social media platforms are regularly used by various stakeholders to share opinions and perspectives and engage in discussions. Other studies have also found that social media is widely used by patients to source information and connect with their peers, healthcare organizations and HCPs ,24,25,26Along with the development of social media content to provide education and convey messages, consumers and HCPs that are less familiar with social media should not be overlooked. We recommend that targeted educational materials  remain available within the healthcare setting to ensure all consumers continue to receive relevant education. Notably, future HCPs (including community pharmacists and pharmacy counter assistants) are likely to be digitally native in their forms of communication and digital social engagement, meaning that they may not need as much training and education in this area. However, it is essential that future HCPs receive appropriate training on the different consumer profiles that have been identified in this study, along with AMR and antimicrobial stewardship , so thatSocial media can be a useful tool for health promotion, providing communication opportunities between several stakeholders and audiences . HoweverCOVID-19 had a multifaceted effect on sore throat and AMR conversations. For example, sore throat triggered anxiety in consumers as they feared it may be a symptom of COVID-19, which prompted them to carry out diagnostic testing. Interestingly, supportive campaigns and conversations around AMR became less prominent during the height of the COVID-19 pandemic, as health authorities focused on tackling COVID-19. Given that AMR remains a major health issue, we recommend that communications should be refocused on how inappropriate antibiotic use can contribute to AMR and the threat that it poses and should leverage our learnings from the COVID-19 pandemic.Streptococcus pyogenes (S. pyogenes) [S. pyogenes; therefore, it is considered the antibiotic of choice for the treatment of group A streptococcal pharyngitis [In addition to targeted materials, messages and approaches to address consumer misconceptions on sore throat and antibiotic use, additional strategies could be employed to further help in the fight against AMR. Most cases of sore throat (up to 80%) are of viral etiology, meaning that antibiotics will not work . Furtheryogenes) . Penicilryngitis . Howeverryngitis ,37,38. Bryngitis . It is iThis was a multinational, observational, consumer content analysis study initiated and commissioned by Reckitt, the maker of Strepsils. The study was conducted across eight countries: Germany, Italy, Spain, Mexico, Brazil, Thailand, Romania and the Russian Federation. Social media searches were conducted between 1 January 2018 and 25 November 2021 to explore conversations around AMR and sore throat and the effect of COVID-19 on online conversations by contrasting the conversation before and after 1 January 2020. The master search terms in English are provided in During Step 1, Brandwatch, a social listening platform that allows one to monitor and analyze what is being said online about brands, people and products , was utiStep 3 consisted of a preliminary analysis, which was conducted in local languages. During this step, social media conversations were reviewed by analysts to identify and summarize the most prevalent themes (‘conversation drivers’) of the conversations around antibiotics in the context of sore throat. Data were then distilled into an initial update by cross-referencing and validating the preliminary observations (Step 4).The first qualitative analysis was conducted (Step 5) by a team of social media analysts who were proficient in the local language of each country. The analysis explored how antibiotics were being perceived and used by consumers within the context of sore throat. Data collection via Brandwatch was supplemented with extensive human-led manual identification and exploration of additional forums and data-limited channels. These additional country-specific sources were identified by analysts with local country knowledge, and through internet searches using the terms that had featured most prominently within the conversations identified via Brandwatch. The full qualitative analysis included the review of ~2500 posts per country and focused on the following topics: sore throat diagnosis; sore throat tests; sore throat self-treatment; sore throat hospital treatment; sore throat treatment with antibiotics; health literacy; AMR in the context of sore throat; consumer perception of antibiotic policy (in the context of the country stance on antibiotic use) and campaigns; antibiotic availability; key influencers (celebrities and public figures) discussing AMR; and the biggest changes in AMR conversations before and after the advent of the COVID-19 pandemic.Following qualitative analysis, the first workshop was held to define the consumer profiles (Step 6). Workshop participants included analysis teams from all countries, Reckitt and Lumanity (the agency commissioned to carry out the study). Key beliefs and perceptions were summarized and organized along two axes: ‘in favor of antibiotics’ versus ‘opposed to antibiotics’ and ‘health literate’ versus ‘misinformed’. Where multiple individual beliefs were clustered together, these were grouped into different consumer profiles. An interim report was generated outlining the preliminary findings and identifying the additional key questions to explore (Step 7).Step 8 consisted of a subsequent qualitative analysis to further refine and add detail to the consumer profiles, including discussions centering on consumer perceptions of interactions with HCPs in the path of receiving antibiotics; biggest changes in the sore throat conversations before and after the advent of the COVID-19 pandemic; sore throat channel breakdown analysis to determine which social media channels were used by different stakeholder groups and which were the most prominent types of conversation on these channels; WAAW; and Strepsils. During the second workshop (Step 9), analysis teams from each country, Reckitt and Lumanity assessed the prevalence of consumer profiles and shifts due to COVID-19. Key findings from the qualitative analyses and the workshops were distilled into a final report (Step 10) detailing the main areas of implications and the key messages from the study.Key themes from the social media research were presented to a global group of pharmacists attending a Global Respiratory Infection Partnership workshop, which was held at an international pharmacy conference  World Congress of Pharmacy and Pharmaceutical Sciences 2022). The workshop assessed whether consumer profiles and perceptions were recognized by pharmacists in their country. In addition, the workshop aimed to define the questions consumers in each profile should be asked and potential responses that could be provided to address misconceptions (Step 11). The analysis formed the basis for our recommended strategies and resources that could be implemented to address consumer misconceptions and help tackle AMR (Step 12).Our social media listening study illustrated a number of misconceptions on sore throat, antibiotic use and AMR, and further showed that COVID-19 has impacted conversations and the patient response to early sore throat symptoms. The knowledge obtained from the study provides an opportunity to address the diverse consumer misconceptions through HCP interventions, both in person and in the social media space, and via other stakeholders, to effectively mitigate the challenge of AMR. One of the objectives of the WHO global action plan on AMR is to increase the awareness and understanding of AMR using strategies that focus on communication. Therefore, future efforts should focus on developing materials and messages that tackle identified misconceptions in a succinct and impactful way. In addition, finding the right people and channels to spread correct messaging to address misconceptions is of great importance.


Addressing climate change and biodiversity loss will be the defining ecological, political, and humanitarian challenge of our time. Alarmingly, policymakers face a narrowing window of opportunity to prevent the worst impacts, necessitating complex decisions about which land to set aside for biodiversity preservation. Yet, our ability to make these decisions is hindered by our limited capacity to predict how species will respond to synergistic drivers of extinction risk. We argue that a rapid integration of biogeography and behavioral ecology can meet these challenges because of the distinct, yet complementary levels of biological organization they address, scaling from individuals to populations, and from species and communities to continental biotas. This union of disciplines will advance efforts to predict biodiversity’s responses to climate change and habitat loss through a deeper understanding of how biotic interactions and other behaviors modulate extinction risk, and how responses of individuals and populations impact the communities in which they are embedded. Fostering a rapid mobilization of expertise across behavioral ecology and biogeography is a critical step toward slowing biodiversity loss. The dual crises of anthropogenic climate change and biodiversity loss are quickly eroding the biosphere’s ability to maintain conditions necessary for human flourishing and societal stability –4. While53Decisions regarding land use are emerging as a key focus for trade-offs between provisioning human populations, climate change mitigation, and biodiversity conservation, and thus represent an important focus for transdisciplinary collaboration –11. Glob1)What factors determine whether species will be able to move geographically, adapt in situ, or face increased extinction risk in response to changing environmental conditions? Across species, what factors modulate different outcomes?2)What are the impacts of individual species  on ecosystem function? Which species, if lost, would trigger a collapse of critical ecosystem services?3)How do we rapidly scale up from traditional experimental approaches and existing data to address these questions, so that results may be translated broadly across taxa and geographic regions?Given the sweeping impact of these crises, the complexity of interventions, and the narrowing window for the most effective response, developing habitat-based solutions for biodiversity conservation in a rapidly changing biosphere is essential. However, identifying solutions that prevent large-scale extinction requires addressing critical questions about biodiversity dynamics that—despite widespread interest—have proven challenging to answer thus far:Thus, a core scientific challenge is navigating differences in geographical scales and levels of biological organization—from understanding the role of variation in responses to change within and among populations, to the implication of these responses at the species and community level—to predict the chances of persistence of all levels of biodiversity  in the available habitats of the future. Different aspects of this challenge tend to be the foci of separate biological disciplines, each with the capacity to contribute unique insights into the questions above.We argue that an urgent integration of biogeography  with beBiogeography and behavioral ecology are both highly integrative, allowing the translation of the findings of other research disciplines into an explicitly ecological and evolutionary context. This translation enables the prediction of potential consequences of environmental change. Numerous disciplines  generate data that are relevant to such predictions , but a behavioral ecology perspective translates those findings into a real-world context . SimilarAll of this points to a critical feature of transdisciplinary biogeography of behavior research that is absent from the other sets of collaborations outlined above: capacity for translation of biological patterns and eco-evolutionary processes across taxonomic and geographic scales . In bothAs environmental conditions change, the extent to which species will be able to track favorable conditions or adapt to disturbances within their current range is critical to their persistence and the ecological services they provide. Ranges are the geographic realization of each species’ ecological niche, restricted to regions the species can access via dispersal , 29, andBiogeographers have long sought to predict the impacts of climate change on biodiversity, including using forecast methods to predict the locations of species’ ranges under future climate conditions , 42 and How species behaviorally interact with their biotic and abiotic environment is a critical component of whether habitats designated for biodiversity conservation will succeed in allowing either persistence or successful movement to new habitats –53. Thes51how and why organisms do what they do to survive and reproduce , which typically defend habitat patches within reefs from both con- and hetero-specifics  show evidence of significant range contraction based upon both historical resurvey data  and their bark scorpion prey (Centruroides spp.), iconic denizens of the North American deserts, exhibit a geographic mosaic of sympatric and allopatric populations across arid landscapes Onychomysndscapes , 27. Scondscapes . With clWe propose a two-pronged approach to explore the impacts of climate change in this system: First, range maps or species occurrences enable the building of baseline predictions of range dynamics under climate change, which can be validated against the distributions of biotic interactions (including predator–prey and among sister species) and variation in the strength of reciprocal selection (if known) in different environments across the geographic mosaic. An important output of these models would be to estimate the sensitivity of range predictions for individual species on the extent to which biotic interactions are incorporated. Second, these model-based approaches might identify key field locations to monitor for early indications of changes in geographic overlap or interaction strength among species to further refine predictions of range shifts and changes in community composition . Both stHabitat Loss, below). In general, phenotypic plasticity—and heritable variation in plasticity among individuals in different environments   are often treated as relatively set . This may not reflect how variation in behavior, including standing variation or as a result of plasticity, may shape the ability of species to adapt, acclimatize, or relocate in response to change , 55. Theronments —will lik elegans  and Acron coral)  have ideBehavioral plasticity, or the ability of organisms to flexibly adjust their behavior in response to the environment, has been proposed as a major mechanism for predicting species survival in the face of climate change , 98 and Stylea plicada improved offspring survival under conditions that matched those of their fathers, implicating sperm-mediated effects in offspring habitat selection and survival , which are widely distributed in the northern hemisphere and are rarely targeted by conservation strategies due to their historical abundance, despite their ecological importance in food webs  in the face of climate change requires modelling how behavioral nuances are likely to impact persistence of populations in spatially complex constellations of remaining habitat , 40. ThuGeographically realistic mechanistic models and emerging computational tools like machine learning and artificial intelligence have already shown significant promise in predicting how the impacts of climate change, habitat loss and species exploitation are likely to impact communities. For example, spatially explicit, mechanistic simulations of predator–prey dynamics in size-structured marine food webs showed that trophic interactions limited species’ abilities to shift their ranges under climate change . MachineWe envision several opportunities where computational innovations that integrate biogeographic and behavioral data can strengthen our ability to predict future biodiversity responses to global change at geographic scales relevant to conservation. Predictions based on well-studied interactions can be extended to under-sampled geographic regions using machine learning based on phylogenetic relationships, behavioral and functional traits, environmental conditions, and documented patterns of coexistence within specific environments. For well-studied behavioral systems, machine learning might aid in identifying critical individual behaviors or biotic interactions that impact species persistence. Machine learning and mechanistic models, together, can also be used to predict the types of environmental change most likely to impact a local network or community given its constituent species. Similar search methods applied to genomic resources could detect levels of neurogenetic variation and plasticity suggestive of behavioral adaptation, which could feed into the types of experimental approaches described for the grasshopper mouse and stickleback systems. Novel approaches to combine disparate data types will significantly expand our ability to identify species most exposed to extinction risk and forecast the impact of their loss on their communities and ecosystems. However, these opportunities will require deliberate efforts to connect people with different types of expertise, and appropriate recognition for diverse contributions, including data provisioning, model calibration, translation of results into conservation recommendations, and communication to diverse stakeholders.Above, we highlighted three areas where convergent “biogeography of behavior” research can lead to significant gains in predicting biodiversity dynamics in a rapidly changing world. However, that research will only take us part of the way toward a solution, and it is critical that researchers also contribute to translating this knowledge into meaningful conservation actions. Fostering action requires making data and findings accessible and interpretable across disciplines and strengthening interactions between conservation practitioners and academics. It may also require consideration of how we prioritize and assign credit for collaboration and encouragement of conservation-oriented outcomes of basic research.One key step forward will be recognizing where opportunities exist to immediately contribute, particularly for researchers who generate data relevant to the biodiversity dynamics described above, but who have not traditionally seen themselves as global change researchers. For biogeographers, this may mean improved communication around areas of uncertainty in geographic models and their potential impact on different conservation applications , 137, paFacilitating the translation of convergent research into conservation actions that benefit biodiversity and society also requires participation across a broad group of scientists. Fundamentally, investigators need to interact across disciplines to address questions across geographic and taxonomic scales, and with conservation practitioners to identify and fill key knowledge gaps that limit our ability to predict species’ responses to change , expanding the scope of basic research across calls to translate results into tangible, applied conservation outcomes could greatly catalyze meaningful activities. Action could be further incentivized in the USA by considering development of biodiversity conservation plans, actions, or knowledge-sharing as potential Broader Impacts  of research-oriented proposals. This would motivate “closing the loop” to bring conservation-relevant research into conservation planning, without requiring new funding programs. In addition, universities need to find approaches to stimulate convergent research, as well as recognize and reward its translation to applied conservation outcomes as research activity. Providing seed funding for collaboration workshops or the initiation of convergence centers around global challenges like climate change and biodiversity loss is a positive move; however, care should be taken to ensure that such opportunities are not restricted to large, well-established research teams, as this limits the potential for a broader, more impactful outcome. Desired outcomes from these collaborations should include translational applications for biodiversity conservation that can be implemented by state, national, international, or non-governmental conservation organizations—innovations that are in the public interest but are unlikely to contribute significantly to revenue.Given widespread biodiversity loss, the increasingly realized impacts of climate change, and a limited window for making informed decisions, we need an all-hands-on-deck approach that builds on our combined expertise to determine where and how to preserve the diversity that still exists, given ongoing changes in habitat. By deliberately integrating across biogeography and behavioral ecology to address key information gaps on biodiversity responses to environmental change, we can contribute the scientific guidance needed to inform complex decisions on where setting aside habitats to conserve biodiversity might be most effective. These actions have the added benefit of mitigating the impacts of climate change on human populations, fostering stronger linkages among scientists working on these problems, and leveraging emerging analytical methods that will integrate existing data into new predictive frameworks.


In recent research, psychological disorders have been increasingly defined as complex dynamic systems in which symptoms are interconnected and influence each other, thereby forming symptom networks. This paradigm shift calls for the analysis and interpretation of relationships between symptoms that are complex, potentially non-linear, and dynamic. Dynamic Time Warping (DTW) is used to measure similarity in temporal sequences, and has recently been found effective in modelling psychopathology symptom networks.We aim to demonstrate that DTW could also be used to model the network structure in Ecological Momentary Assessment (EMA) data.355 participants of the Netherlands Study of Depression and Anxiety (NESDA), of which 100 with and 255 without current disorder, completed EMA assessments of 20 symptoms  five times a day for two weeks. DTW analysis was performed on the group level, comparing participants suffering from mood disorders to healthy controls. DTW distances were visualized as an undirected symptom network, in which we adjusted for the average symptom severity per item per person.DTW analysis of close to half a million symptom scores yielded six symptom dimensions based on their aggregated similarity of changes over time within the participants. Surprisingly, negative affect symptom networks were found to be less strongly connected in those currently suffering from mood disorders than in controls, whereas the network density of (reverse-coded) positive affect symptoms was more closely connected in this group. This is contrary to the results of previous studies, where negative affect-related symptom networks of those with mood disorders were found to be more strongly interconnected.DTW is a promising new technique for analyzing EMA data and modeling dynamic symptom networks at both the individual and group levels. Using EMA data, symptom networks and dimensions can be modeled with great structural and temporal detail. Incorporating the temporal symptom dynamics may highlight the importance of the independent trajectories of negative mood symptoms.None Declared