GAP), as implemented in the DESiGN trial, is cost‐effective in terms of antenatal detection of small‐for‐gestational‐age (SGA) neonate, when compared with standard care.To determine whether the Growth Assessment Protocol  trial, a cluster randomized controlled trial. Singleton, non‐anomalous pregnancies which delivered after 24 + 0 gestational weeks between November 2015 and February 2019 were analyzed. Probabilistic decision modeling using clinical trial data was undertaken. The main outcomes of the study were the expected incremental cost, the additional number of SGA neonates identified antenatally and the incremental cost‐effectiveness ratio (ICER)  of implementing GAP. Secondary analysis focused on the ICER per infant quality‐adjusted life year (QALY) gained.This was an incremental cost‐effectiveness analysis undertaken from the perspective of a GAP over standard care was £34 559 per 1000 births, with a 68% probability that implementation of GAP would be associated with increased costs to sustain program delivery. GAP identified an additional 1.77 SGA neonates per 1000 births . The ICER for GAP was £19 525 per additional SGA neonate identified, with a 44% probability that GAP would both increase cost and identify more SGA neonates compared with standard care. The probability of GAP being the dominant clinical strategy was low (11%). The expected incremental cost per infant QALY gained ranged from £68 242 to £545 940, depending on assumptions regarding the QALY value of detection of SGA.The expected incremental cost  of GAP is weak based on the analysis reported in our study. However, this conclusion should be viewed taking into account that cost‐effectiveness analyses are always limited by the assumptions made. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.The economic case for replacing standard care with  What are the novel findings of this work?The Growth Assessment Protocol (GAP), as implemented in the DESiGN  trial, is expected to cost an additional £34 559 per 1000 births. In terms of cost‐effectiveness, it is most likely that GAP is both more clinically effective and more costly than standard care (44% probability), while the chances of it being both more clinically effective and less costly are low.What are the clinical implications of this work?When implemented as it was in sites recruited to the DESiGN trial, the economic case for replacing standard care with GAP to improve antenatal detection of small‐for‐gestational age and stillbirth is weak.th centile)Reducing the prevalence of stillbirth is a global priorityvs 27.7%; adjusted difference, 2.4% ; P = 0.58)The DESiGN  trial was the first pragmatic cluster randomized controlled trial that compared the effect of GAP against standard care in the UKEconomic evaluation in healthcare research is recommended to assist decision‐making regarding the adoption and extent of implementation of an interventionThis report was written in accordance with the Consolidated Health Economic Evaluation Reporting Standards (CHEERS)A probabilistic cost‐effectiveness analysis was undertaken using decision‐analytic methods applied to clinical data from the DESiGN trial. Costs were estimated from the perspective of a National Health Service (NHS) provider. Costs and clinical outcomes in hospitals randomized to implement GAP were compared with those in hospitals randomized to continue standard care. Ethical approval for the DESiGN trial was obtained through the Health Research Authority Integrated Research Applications System from the London Bloomsbury Research Ethics Committee Ref. /LO/1632 n = 7) or to standard care (n = 6) between November 2015 and July 2017. Two cluster sites allocated to GAP withdrew before commencing implementation due to concerns over its expected financial impact. Neither site was therefore used to evaluate the effect of the intervention, although their data were used for other purposes, as explained later. The five remaining cluster sites implemented GAPThirteen cluster sites  were allocated randomly to the GAP intervention  and during the prerandomization phase (1 year prior to cluster randomization) for baseline adjustments.The GAP intervention was designed by a team at The Perinatal Institute, Birmingham, UK. It involves additional staff training, stratification of pregnant women according to risk of SGA, SGA screening protocols that differ according to risk strata, use of fetal or birth‐weight centiles customized to the woman's  and the baby's  characteristics to define SGA, and audit of missed cases of SGAFetal surveillance according to GAP commenced at 24 weeks' gestation. Costs incurred before this gestational age were not expected to vary according to study arm and were not included. After 24 weeks, we included all major antenatal, intrapartum, neonatal and postnatal costs until the mother or infant was discharged from the care episode that included birth. Costs were not discounted, because all were expected to occur within a single year.All data required for analysis of clinical outcomes and costs were obtained from routine electronic patient records (EPRs). Our data collection and management methods, including a detailed description of data quality checks, have been published previouslyth centile at the last fetal growth scan, using Hadlock centiles in the standard care arm and Gestation‐Related Optimal Weight (GROW) centiles in the intervention arm)th centile by both UK90 population reference charts and GROW charts)The primary outcome of the DESiGN trial was antenatal detection of SGA , as one site in each trial arm did not contribute data on antenatal hospital admissions. Unlike antenatal care costs, subsequent costs were expected to vary according to screening outcome but not treatment arm. They were, therefore, included without stratification according to treatment arm, and all 13 sites contributed data to calculate intrapartum costs. Due to the limited availability of data, only nine sites were used to calculate postnatal costs  and 11 sites were used to calculate neonatal costs .For estimating resource use during the antenatal period, data from ultrasound scans and antenatal inpatient admissions were generally available. Data from antenatal appointments and unscheduled outpatient attendances were missing either completely or partially  for five of the six standard‐care sites. To maximize the number of clusters available for antenatal cost analysis, these resource items were excluded from the base‐case analysis. This pragmatic decision was guided by the hypothesis that the main cost impact of GAP would most likely arise from an increased number of scans. The effect of excluding these data was explored further by sensitivity analysis. The primary economic analysis was subsequently carried out using nine cluster sites for antenatal costs  who attended the site‐wide training launches was obtained from the intervention provider. The time taken to complete each training type was estimated as the median time reported by participants in semi‐structured interviews conducted during the trial process evaluationUnit costs for each maternity or neonatal care activity were estimated following a systematic review of maternity costs published as part of economic evaluations conducted in the UKThe cost‐effectiveness model linked the costs of care to the four mutually exclusive screening outcomes Figure . The twoTo reflect uncertainty in the input parameters, expected principally from trial sampling error, the cost‐effectiveness analysis was conducted probabilistically. Uncertainty around intervention cost‐effectiveness was therefore presented as the probability of observing alternative cost‐effectiveness outcomes and by plotting a 95% confidence ellipse for the cost‐effectiveness planeFor the main trial, a cluster‐summary approach was used to extract statistical information required for probabilistic economic modelingFor input parameters that are potentially subject to a treatment effect of GAP , the two sites allocated to GAP that did not attempt implementation , probability distributions were again generated using Monte‐Carlo simulation from a prespecified probability distribution. Probability distributions were parameterized using the relevant cluster summary data. In all cases, the selection of an appropriate distribution was guided by the need to generate a plausible range of parameter values .th percentile according to population charts for standard care and according to the customized standard (GROW charts) for GAPTo assess whether exclusion of unscheduled and scheduled outpatient attendances or appointments from antenatal costs may have introduced bias into comparisons between GAP and standard care, our probabilistic analysis of the total cost of hospital care was repeated for two alternative scenarios: the base‐case plus an uplift for unscheduled attendance costs and the base‐case plus an uplift for scheduled clinic appointment costs . The sensitivity of our main conclusions to the use of an alternative definition of SGA status at birth was also tested. The secondary definition of SGA was birth weight < 10To aid interpretation of our findings, a secondary analysis was performed to recalibrate the antenatal detection of SGA births into neonate quality‐adjusted life year (QALY) gains arising from prevention of stillbirth. QALYs are the accepted outcome metric for establishing whether new healthcare technologies are a cost‐effective use of NHS resourcesClinical trial data were used to determine the baseline incidence of stillbirth among SGA births in which SGA was not detected antenatally. Previous studies have suggested that 50% of stillbirths occurring among cases with undetected SGA could be avoided if SGA were detectedAs an extension of our secondary analysis, a conditional incremental net benefit (INB) analysis was also performedThe economic modeling drew on data from 209 314 pregnancies, of which 19 312 pregnancies (nine sites) were analyzed for antenatal costs during the comparison phase, 85 575 pregnancies (13 sites) were analyzed for intrapartum costs, 60 071 pregnancies (nine sites) were analyzed for postnatal costs and 73 006 pregnancies (11 sites) were analyzed for neonatal costs. For clinical outcomes during the comparison phase, 13 810 pregnancies in the standard‐care arm and 8882 pregnancies in the intervention arm were analyzed. For adjustments of clinical outcomes using baseline data, 29 404 pregnancies were included in the standard‐care arm and 21 596 pregnancies were included in the intervention arm. The consort diagram, characteristics of women included during the prerandomization and comparison phases and results of the analysis for primary and secondary clinical outcomes have been published previouslyModel parameter values estimated from the trial data based on the primary and secondary definitions of small baby identified at birth are described in Table The expected clinical benefit of GAP in terms of antenatal detection of SGA, as observed in the DESiGN trial, was marginal. An additional 1.77 SGA cases were detected per 1000 births . The ICER for GAP using the primary SGA definition was £19 525 per additional SGA neonate identified, with a 44% probability that GAP would increase the total cost of care and be clinically beneficial compared with standard care. There was only an 11% probability that GAP would be superior to standard practice in terms of cost‐effectiveness, a 24% probability that standard care would be dominant and a 21% probability that GAP would reduce the total cost but would detect fewer SGA cases antenatally  led to a reduction in the total incremental cost of GAP, to £30 861 per 1000 births, and a small increase in the expected number of additional SGA babies identified antenatally, to 2.52 per 1000 births. The ICER for GAP using the secondary SGA definition was £12 246 per additional case identified. Probability values were close to those observed in the primary analysis, with a 45% probability that GAP would increase the total cost of care but would be clinically beneficial, a 10% probability that GAP would be dominant, a 20% probability that standard care would be dominant and a 25% probability that GAP would reduce the total cost but would detect fewer SGA cases antenatally.An uplift applied separately for antenatal appointments and unscheduled attendance costs had little impact on the total incremental cost of GAP Appendix .th percentile within the distribution for this parameter  increase costs to NHS providers while offering only marginal clinical benefit. After full consideration of the margins of uncertainty around economic and clinical parameters of relevance, the expected incremental cost of GAP was estimated to be £34 559 per 1000 births, although some uncertainty remains regarding the magnitude of this effect . Overall, 31% of the expected incremental cost of GAP was attributable to implementation of the program. Compared with other estimated resource effects, these costs are least affected by sampling uncertainty inherent to a clinical trial. There was no convincing evidence that GAP was the dominant clinical strategy in terms of cost‐effectiveness . Taking into account sampling error in the trial data, GAP allowed only marginal expected clinical gains, at an additional cost, at the NHS sites that participated in the trial. A secondary analysis revealed no convincing evidence that GAP provided a cost‐effective alternative to standard care within participating clusters when applying to our findings a cost‐effectiveness threshold routinely adopted by the NHS.The main strength of our study is that the evaluation was based on resource‐use data recorded routinely during clinical practice. It is therefore likely to offer a reliable assessment of the impact of GAP implementation on hospital resources within the study sites randomized to the program. GAP was compared with current standard practice, rather than with absence of care. Therefore, the findings reflect the expected increase in cost associated with implementing GAP compared with current practice One limitation of our study is the adopted time horizon. Estimates of cost were restricted to those incurred by the NHS provider until the end of the care episode that included birth. We did not account for infant and adult healthcare costs due to morbidity associated with preterm or early term birth that may follow SGA detection or intermediate and long‐term health or social costs associated with prevention of stillbirth, including any costs of litigation (estimates have been published previously)We were also limited by the availability and quality of data collected from some clusters. One site implementing GAP was excluded from some analyses because it could not provide data on true‐negative and false‐positive SGA diagnoses. Hospital administrative data were missing entirely or could not be used for two sites allocated to standard care and were missing partially  for some resource items at three of the remaining standard‐care clusters. Exclusion of scheduled and unscheduled antenatal hospital appointments or day attendances because of these missing data had only a small effect on ICER, as shown by the sensitivity analysis. In all clusters, we were unable to distinguish between women who had absence of an activity recorded because it had occurred elsewhere, those who had not undergone the activity anywhere and those who underwent the activity, but without it being recorded. We introduced assumptions to which plausible limits were applied to deal with this issue.Another limitation is the choice of primary SGA definition based on both population and customized weight charts. Using this definition, false‐positive screening outcomes were defined in approximately 5% of babiesFinally, the findings and implications of this economic evaluation are applicable only to healthcare systems that have similar resource availability and national protocols to those of the clusters included within the DESiGNtrial.The cost‐effectiveness of GAP has not been studied previously. The GAP provider conducted a cost‐benefit analysis in which the effect of increasing the frequency of fetal growth scans for women at high risk of SGA was studiedOur economic evaluation is not supportive of GAP providing a cost‐effective improvement to care processes aimed at prevention of stillbirth. The expectation based on evidence from this evaluation is that it will increase the costs of hospital care and require an ongoing resource commitment in terms of staff training and software licensing. These additional costs need to be balanced against the small expected incremental clinical benefit that GAP may offer compared with standard care. We estimated that, even with highly optimistic  assumptions regarding preventable numbers of stillborn infants arising from early detection, the QALY value of stillbirth prevention linked to these small clinical gains would be of insufficient magnitude to justify the costs when judged against cost‐effectiveness thresholds used in NHS decision‐making. It is likely that this conclusion would have been strengthened if our analysis had included long‐term NHS costs and impact on QALYs arising from stillbirth prevention and iatrogenic preterm birth. Other long‐term cost‐ and QALY‐related benefits that it has been claimed are linked to the early detection of SGA birth  would need to be substantial to offset our core findings. This seems unlikely, given the low additional rates of antenatal detection observed using GAP in this study.The economic case for replacing standard care with GAP is weak based on the analysis and evidence reported herein. This conclusion should be viewed taking into account that cost‐effectiveness analyses are always limited by the assumptions made, and our study is no different.Appendix S1 Additional description of study methodologyClick here for additional data file.Appendix S2 Activities within maternity and neonatal care pathways that were hypothesized to vary with implementation of the Growth Assessment Protocol (GAP)Click here for additional data file.Appendix S3 Cost inputs for economic modelClick here for additional data file.Appendix S4 Results of sensitivity analysisClick here for additional data file.


Humans are inherently social beings. Being suggestible to each other's expectations enables pro‐social skills that are crucial for social learning and adaptation. Despite their high relevance for psychiatry, the neurobiological mechanisms underlying social adaptation are still not well understood. This review, therefore, provides a conceptual framework covering various distinct mechanisms underlying social adaptation and explores the neuropharmacology — in particular the role of the serotonin (5‐HT) system — in modulating these mechanisms. This article reviews empirical results on social influence processing and reconciles them with recent findings from psychedelic research on social processing to elucidate neurobiological and neuropharmacological underpinnings of social adaptation. Various computational, neurobiological, and neurochemical processes are involved in distinct mechanisms underlying social adaptation such as the multisensory process of social information integration that is crucial for the forming of self‐representation and representations of social norms. This is again associated with self‐ and other‐perception during social interactions as well as value‐based decision‐making that guides our behavior in daily interactions. We highlight the critical role of 5‐HT in these processes and suggest that 5‐HT can facilitate social learning and may represent an important target for treating psychiatric disorders characterized by impairments in social functioning. This framework also has important implications for psychedelic‐assisted therapy as well as for the development of novel treatment approaches and future research directions. Our social environment has a constant influence on our behaviour. Nevertheless, our understanding of the neurobiopharmacological underpinnings of social influence processing is still limited. This review provides a conceptual framework covering distinct mechanisms underlying social adaptation. It specifically elucidates the fundamental role of serotonin suggested to facilitate social learning by modulating social information integration. Recent pharmacological challenge studies with psychedelics suggest that in particular the serotonin 2A receptor plays a crucial role in the forming of self‐representations and social norms. Therefore, this framework has important implications for psychedelic‐assisted therapy as well as the development of novel treatment approaches in psychiatry. DAdopaminedmPFCdorsomedial prefrontal cortexdACCdorsal anterior cingulate cortexLSDlysergic acid diethylamidemPFCmedial prefrontal cortexNAccnucleus accumbensPEprediction errorPsipsilocybin5‐HT5‐hydroxytryptamine, SerotoninRNraphe nucleiRPEreward prediction errorSSRIselective serotonin reuptake inhibitorvmPFCventromedial prefrontal cortexVSventral striatumVTAventral tegmental area1Humans are inherently social beings. Most of an individual's decisions and actions are made in response to other individuals  bottom‐up sensory input and 2) cognitive top‐down influences such as social knowledge, expectations, emotional states, past experiences, and contextual factors  and in the long term may impact social interactions  based on many decision variables  and influenced by emotion, cognition and motivation  as key regions for value‐based decision‐making and behavior change  associated with social reward experience  or l‐tryptophan has been shown to induce positive and negative alterations in social perception  of the PFC   and changed meaning of percepts    and integrating findings from different fields to better understand neurobiological mechanisms involved in distinct components of social influence will provide further insights and create a more comprehensive understanding. So far research on social influence mainly focused on mechanisms within single brains at the individual level. However, to better understand the social influence and its underlying neurobiological mechanisms, analysis of natural real‐life interactions between many brains should also be considered as our brain is embedded in a complex system of social structures. A better understanding of the neurobiology of social influence processing is not only of high relevance for psychiatric treatment but has implications for almost all parts of our daily lives.KHP is currently an employee of Hoffmann‐La Roche. The authors declare no further potential conflict of interest.PD and KHP have written the manuscript. FXV has revised the manuscript.


Socio‐economic (SE) status is closely linked to health status and the mechanisms of this association are complex. One important adverse effect of SE disadvantage is vulnerability to cancer and cancer is a major cause of morbidity and mortality in Australia.We aimed to estimate the effect of SE status on mortality rates from ovarian, cervical, and endometrial cancer.National mortality data were obtained from the Australian Bureau of Statistics (ABS) for the calendar years from 2001 to 2018, inclusive. Individual deaths were grouped by the ABS Index of Relative Socio‐economic Advantage and Disadvantage. Population data were obtained to provided denominators allowing calculation of mortality rates (deaths per 100 000 women aged 30–79 years). Statistical analyses performed included tabulating point‐estimates of mortality rates and their changes over time and modelling the trends of rates using maximum likelihood method.Age‐standardised mortality rates for ovarian and cervical cancer fell over the study period but increased for endometrial cancer. There was clear evidence of a SE gradient in the mortality rate for all three cancers. This SE gradient increased over the study period for ovarian and cervical cancer but remained unchanged for endometrial cancer.Women at greater SE disadvantage have higher rates of death from the commonest gynaecological cancers and this gradient has not reduced over the last two decades. After the COVID‐19 pandemic efforts must be redoubled to ensure that Australians already at risk of ill health do not face even greater risks because of their circumstances. It has long been recognised that an individual's socio‐economic (SE) status – their family circumstances, housing, working conditions, income, and education – is closely linked to their health status.Cancer is a major cause of morbidity and mortality in Australia: malignant conditions account for approximately three of every ten deaths.An individual's risk of an adverse outcome of cancer is generally associated with multiple factors: their risk of developing a malignant disease; the stage at diagnosis; co‐morbidities in affected individuals; and, access to good‐quality medical care in managing disease.International Classification of Diseases – Version 10 (ICD‐10) for coding of cause of death.National mortality data for endometrial, ovarian, and cervical cancer were obtained from the Australian Bureau of Statistics (ABS) for the calendar years from 2001 to 2018 inclusive. The ABS carries national responsibility for compiling the national data on deaths in Australia. Mortality data are obtained from all Australian state and territory Registrars of Births, Deaths and Marriages, and the notifications are supplemented by information from the National Coroners Information System (NCIS). Information about an individual's cause of death as used by the ABS is supplied by the medical practitioner who certifies the death or, in certain circumstances, by a coroner. The ABS uses the For our measure of SE status we used the ABS classification of Socio‐Economic Indexes for Areas (SEIFA) which ranks areas in Australia according to relative SE advantage and disadvantage and is based on information from the five‐yearly Australian National Census.Population data were obtained from the ABS to allow the calculation of the total number of women aged 30–79 years , later used as the denominator in calculating mortality rates. We used point‐estimates for June of each year of the study according to Statistical Areas Level 2 (SA2) which are medium‐sized ‘general purpose’ to represent a community that interacts together socially and economically.The overall mean age‐standardised rate of mortality  for ovarian cancer over the study period (9.71) was considerably higher than that of cervical (2.72) and endometrial (2.56) cancer over the study period , women at moderate SE disadvantage  and women in the highest SE groups . There was a clear and significant SE gradient for all three malignancies: ovarian Fig. ; cervicaP = 0.198 and P = 0.386 for differentiating linear and quadratic components among quintiles respectively).Mortality from ovarian cancer decreased across all SE groups over the study period Fig. . We idenP = 0.006) due to the lowest SE groups experiencing the largest decrease in mortality rates – from 0.6 to 0.4/100 000 – with large year‐to‐year fluctuations prior to 2009. After 2009 the mortality rate for the most disadvantaged women remained stable. The other SE groups showed gradual decrease status over the study period.Over the study period, cervical cancer mortality showed a net decrease across all socio‐economic groups Fig. . The ratIn this study we have demonstrated a significant gradient in mortality rates for the three commonest gynaecological cancers and, importantly, that this disparity in mortality between women at greatest and least SE disadvantage was increasing prior to the COVID‐19 pandemic. A limitation of this study is that it was not possible to adjust for co‐morbidities and staging at diagnosis. However, the focus of the study was not on modelling individual effects but to provide a population‐level estimate of the ecological effect of SE status on cancer mortality rates and to determine whether these effects were increasing or narrowing over time.Inequality and entrenched disadvantage have a negative effect on social cohesion and population wellbeing. The Australian Productivity Commission (APC) has studied inequality, poverty and disadvantage in Australia using a number of metrics including the Gini coefficient.The highest mortality rate was for ovarian cancer, the fifth most common cancer in Australian women.In many respects cervical cancer is a prototype disease for which SE inequality is a major risk factor. Cervical cancer is a less common disease for Australian women now, ranking as the 14th most commonly diagnosed cancer by gender with fewer than 1000 new diagnoses of invasive disease each year.Commencement of the HPV vaccination in Australia in 2007 has led to vaccine coverage rates in women of up to 85%.The risk factors for endometrial cancer have been difficult to disentangle and a recent comprehensive review of the literature concluded that increased body mass index (BMI), nulliparity, and diabetes were most strongly associated with increased risk.This population‐based study has shown that mortality rates for the three most common gynaecological cancers follow a gradient with women at greater SE disadvantage having higher rates of death. Importantly, the gradient has not reduced over the last two decades and, indeed, seems to have increased. An individual's risk of cancer is strongly influenced by their SE status, but so too are many other aspects of health. Even before the COVID‐19 pandemic there is evidence that social and health inequality are increasing in Australia. In the aftermath of the pandemic it is important that efforts are redoubled to ensure that Australians already at risk of ill health do not face even greater risks because of their circumstances.


Authentic research experiences (AREs) are a powerful strategy for inspiring and retaining students in science, technology, engineering, and math (STEM) fields. However, recent demand for virtual learning has emphasized the need for remote AREs that also foster a sense of community and interpersonal connections among participants. Here, we describe an ARE activity that leverages digitized diet data from natural history collections to provide students with collaborative research experience across any learning environment. Using magnified photographs of frog stomach contents collected in the Peruvian Amazon, we designed an open‐source “bowl game” competition that challenges students to identify, measure, and compare diet items across vouchered frog specimens (“Batrachian Barf Bowl”). To demonstrate learning outcomes, we ran this activity with 39 herpetology class students from the University of Notre Dame and the University of Michigan. We used pre‐ and post‐activity assessments to evaluate effectiveness, scientific accuracy of results, and impact on student well‐being. With minimal preparation and training in invertebrate identification, students were successful in identifying hundreds of frog diet items to taxonomic order, although accuracy varied among clades . While we found no difference in science identity, community, or self‐efficacy between the two institutions at either time point (pre‐ and post‐activity), we found that well‐being was significantly higher for both sets of students after the activity. Overall, this approach offers a model for combining active learning with museum collections to provide experiential research opportunities that highlight the power of scientific collaboration. We describe an authentic research activity (ARE) activity that leverages digitized diet data from natural history collections to provide students with collaborative research experience across any learning environment. Using magnified photographs of frog stomach contents collected in the Peruvian Amazon, we designed an open‐source “bowl game” competition that challenges students to identify, measure, and compare diet items across vouchered frog specimens (“Batrachian Barf Bowl”). This activity offers a model for combining game‐based learning with museum collections to provide experiential research opportunities highlighting the power of scientific collaboration. Students gain valuable, practical experience in their chosen career fields prior to entering the job market post‐graduation . Because frogs do not chew their invertebrate food, these photographs contain many well‐preserved prey items that can be identified to taxonomic order . To capitalize on the appeal of alliteration, we called the frog diet samples “barf” since the stomach flushing process is akin to inducing frogs to vomit. To further foster a sense of fun, we commissioned a logo for the Batrachian Barf Bowl that can also be used for future iterations of the activity  as identification resources for “unknown species.”Collaboration for successful scientific inquiry: To provide an experience in scientific collaboration and networking to solve challenges too big for any one person to solve alone.Foster a sense of connection among students: To improve student well‐being through inter‐institutional course collaborations.We designed this laboratory activity around six main goals with specific learning objectives:Within the Ecological Society of America's (ESA's) Four‐Dimensional Ecology Education (4DEE) Framework, this activity covers the dimensions of Core Ecological Concepts and Ecology Practices  as it exposes students to using dichotomous keys to assess realized diet niches across species  were offered concurrently at the University of Notre Dame  and the University of Michigan  in the second semester of the 2020–2021 academic year. There were 12 students in the University of Notre Dame Herpetology class, including eleven seniors and one junior. Nine students had declared majors in a field of biology , two were majoring in non‐biology STEM areas, and one was not majoring in a STEM area. There were 27 students in the University of Michigan class, including 23 seniors and four Master's students. All undergraduate students had declared majors in fields of biology (7 distinct majors), and all graduate students were pursuing degrees in the Environment and Sustainability program  were removed from the dataset so that a total of 7 Notre Dame students and 12 Michigan students were included in the analyzed dataset . Likert scale responses were converted to numbers , and student constructs  were calculated by averaging the responses from the respective instruments. For example, a student's responses to the five science identity questions were averaged to calculate their overall science identity score.U test in SPSS 27.0 (IBM 2021) to compare the construct scores between institutions to identify variation . We also evaluated the student scores collectively for change between pre‐ and post‐activity measurements using paired t‐tests in SPSS.We used the Mann–Whitney 33.1All 12 of the Notre Dame students participated in the activity synchronously with 15 of the Michigan students. These 27 students were divided into eight groups that had three or four students. The other 10 Michigan students completed the activity asynchronously individually or in self‐selected pairs. The synchronous teams were instructed to select a team name and several of the asynchronous students also chose a moniker. This aspect of the activity allowed the students to flex their creativity and humor, with team names including Herpetologeniuses, TOADally Ribbitting, Barfonidae, Barf Brigade, Barftrachians, Bug Crew, and Frognatic.3.2N = 9–21). Asynchronous groups who were instructed to analyze a specific number of frog individuals and were not time‐limited made a mean of 17 identifications (range: N = 12–37). Of the identifications, the mean number that was correct was the same for both the synchronous and asynchronous groups (70%), although the standard deviation was higher for the synchronous group (±23%) compared to the asynchronous group (±10%).Together, students assigned an identification to 180 prey items. There was notable variation in the number of identifications that each synchronous group completed during the class period, with a mean of 11 identified prey items per group (range: N = 50) showed the opposite pattern, being less common in the synchronous groups (mean: 11% of prey items not documented) than the asynchronous ones (mean: 22% of prey items not documented). For some groups, false negatives might not be cases of unobserved prey, but rather unidentifiable prey. While we encouraged students to attempt an identification for all items, we were not explicit in stating that they should write “unknown” rather than omitting prey items for which they could not hazard a guess.Misidentified prey items were more common in the synchronous groups (mean: 32% of prey misidentified) than in asynchronous (mean: 21% of prey misidentified). False negatives . One was misidentified as a Hymenopteran. We were surprised that caterpillars (larvae of Lepidoptera) were misidentified three times: once as a Diptera and twice as Tubellaria. After seeing this pattern in the results, we reviewed the identification keys that we had provided to students and realized that none of them included a caterpillar. Instead, the incorrect identifications that they selected were the most probable if a student strictly followed the key and did not have strong prior knowledge about larval lepidopterans. More generally, misidentifications tended to skew towards prey items from common orders being assigned to various uncommon orders that were provided on generalized keys, but not present in the dataset , beetles , and ants .Snails with shells were easily identifiable, although the level of specificity varied among groups. A slug (Mollusca: Gastropoda: Heterobranchia) was not recorded and therefore was a false negative. Other taxa that were frequently identified correctly are spiders . However, we found well‐being was higher for Notre Dame students than for Michigan students at both time points . When asked if they enjoyed meeting herpetology students from another university, 88% of students indicated that they did, with 65% of students explaining why and 18% including limitations or constructive feedback , with one writing,Not particularly. It was pretty awkward to meet people on Zoom, so we didn't have the ability to form a good relationship before working together.The two students who did not enjoy meeting other herpetology students had similar feedback I really liked contributing to real research. I have not had a chance to do any of my own research as a full‐time student with an off‐campus job, so this was an opportunity that I was very excited for. .Another student enjoyed “doing a fun new activity with other students in a competitive environment”  would make the experience go more smoothly.When asked what they liked least about Barf Bowl, 47% of students felt the activity was too short. One student provided constructive feedback, writing,It felt less like a competition and more like we were just helping with research.Approximately 35% of students indicated that they disliked that the activity was remote, and 35% of students were unclear about the intent of the activity Table . For exaTwo students indicated that they did not enjoy the challenge of identifying organisms with which they were not familiar.4In this paper, we present a unique inter‐institutional undergraduate educational activity that engages students with real data and provides the opportunity to work collaboratively with peers. The majority of students enjoyed meeting herpetology students from another institution, indicating the activity was successful in forming connections across institutions. The similar measurements of science identity, the scientific community, and self‐efficacy at both institutions suggest the two classes had similar student audiences who would pair well together. Additionally, we found that, collectively, the well‐being of student participants increased after the Barf Bowl, an affective goal for our collaborative activity. However, since we did not survey a control group, such as a herpetology class that did not participate in Barf Bowl, we cannot conclusively attribute this increase to participation in the activity. We also observed significantly higher well‐being in the class that was conducted in‐person, which may be a side effect of campuses that held classes in‐person. Because of our small sample size , we recommend interviews as a follow‐up to better understand the impact that in‐person classes might have on the well‐being of students in natural history and biodiversity courses.While we present this activity within an inter‐institutional framework, it can also easily be implemented with just one class, either in person or virtually, to achieve the first five of our learning goals. In providing the prey photographs and instructional materials, we intend to offer a flexible activity concept and we encourage instructors to modify the implementation of the activity to best suit the needs of their class and situation.4.1Providing undergraduate students with the opportunity to conduct genuine research is a powerful tool for the retention of students in STEM fields ; data curation ; formal analysis ; funding acquisition ; investigation ; methodology ; project administration ; resources (lead); supervision ; writing – original draft ; writing – review and editing . Hayley Layne Crowell: Conceptualization ; data curation ; investigation ; methodology ; project administration ; supervision (supporting); writing – original draft ; writing – review and editing . Lisa L Walsh: Data curation ; formal analysis ; investigation ; methodology ; visualization (supporting); writing – original draft (supporting). Alison Davis Rabosky: Conceptualization ; formal analysis ; funding acquisition ; investigation ; methodology ; project administration ; supervision (lead); visualization (lead); writing – review and editing .The authors of this manuscript declare no competing interests.This article has earned an Open Data badge for making publicly available the digitally‐shareable data necessary to reproduce the reported results. The data is available at [[insert provided URL from Open Research Disclosure Form]].Appendix S1 Participant demographicsClick here for additional data file.Appendix S2 Activity handoutClick here for additional data file.Appendix S3 Template diet data spreadsheetClick here for additional data file.Appendix S4 Student activity resultsClick here for additional data file.Appendix S5 Pre‐ and post‐activity student surveysClick here for additional data file.Appendix S6 Student survey resultsClick here for additional data file.Appendix S7 Frog taxonomic identificationClick here for additional data file.


The visual cortex has been extensively studied to investigate its role in object recognition but to a lesser degree to determine how action planning influences the representation of objects' features. We used functional MRI and pattern classification methods to determine if during action planning, object features (orientation and location) could be decoded in an action‐dependent way. Sixteen human participants used their right dominant hand to perform movements (Align or Open reach) towards one of two 3D‐real oriented objects that were simultaneously presented and placed on either side of a fixation cross. While both movements required aiming towards target location, Align but not Open reach movements required participants to precisely adjust hand orientation. Therefore, we hypothesized that if the representation of object features is modulated by the upcoming action, pre‐movement activity pattern would allow more accurate dissociation between object features in Align than Open reach tasks. We found such dissociation in the anterior and posterior parietal cortex, as well as in the dorsal premotor cortex, suggesting that visuomotor processing is modulated by the upcoming task. The early visual cortex showed significant decoding accuracy for the dissociation between object features in the Align but not Open reach task. However, there was no significant difference between the decoding accuracy in the two tasks. These results demonstrate that movement‐specific preparatory signals modulate object representation in the frontal and parietal cortex, and to a lesser extent in the early visual cortex, likely through feedback functional connections. The visual cortex has been extensively studied to examine its role in object recognition but to a lesser extent to determine how action planning influences the representation of objects' features. We provide evidence that the same object properties can be differentially decoded in the fronto‐parietal and early visual cortex depending on the upcoming interactions with the object. These results suggest that movement‐specific preparatory signals modulate object representation in the visual cortex, likely through feedback functional connections. Picking up a pen, for example, would be more successful when one is focused on its orientation rather than its colour. Considerable research has investigated the role of fronto‐parietal reaching and grasping networks in successfully executing actions  is reactivated at the time of delayed actions despite the absence of visual information  would be modulated in a task‐specific fashion.2Our main question was aimed to investigate whether action planning modulated the activity pattern elicited by the visual presentation of two simultaneously presented objects. If the representation of an object is shaped by the intended action, we would see enhanced dissociation between the two oriented objects when participants were planning an action that had to be adjusted to the orientation of the object (Align) as compared with a movement for which object orientation was irrelevant (Open reach) Figure . Therefo2.1The experimental and retinotopic mapping sessions took place on two different days. The experimental session lasted approximately 2 h, including screening and set‐up time, while the retinotopic mapping session took approximately 30 min to be completed.2.2Twenty‐six right‐handed volunteers  participated in this study. The age range of participants was 20–45, with an average age of 30.4 years. Sixteen participants volunteered for the experimental runs and 14 participants took part in the independent localizer runs for retinotopic mapping. Four of these participants took part in both sessions. All participants had normal or corrected‐to‐normal vision, and none of the participants had any known neurological deficit. All participants provided informed consent, and approval was obtained from the ethics committee for experiments involving human participants at the University of Trento.2.3The experimental set‐up is illustrated in Figure To limit motion artefacts, the right upper arm was supported with foam and gently restrained. Reaches were thus performed by movements of the right forearm and hand. A button box was placed around the participants' abdomen and served as the starting point for each trial. Hand actions were monitored with a Sony HDR‐UX1E digital video camera. The lights were on throughout the experiment, and the hand was visible to participants. Participants wore headphones to hear auditory instructions and cues.2.4We used functional magnetic resonance imaging (fMRI) to measure the blood‐oxygenation‐level dependent (BOLD) signal  during which participants rested. This phase was included in the baseline, together with the ITI. Align movements consisted of reaching to the CCW‐left or CW‐right object and adjusting the hand precisely over it, as in a manual orientation matching task. The Open reach movements consisted of moving the hand above the instructed object with an open palm. Therefore, while both movements were directed to one of the two object locations, only Align movements also required adjusting the hand according to the orientation of the object. In both movement types, participants touched the object during the execution of the movement. Each participant was trained and tested in a short practice session (10–15 min) prior to the fMRI experiment. The hand was monitored with a camera to confirm that participants were performing the correct tasks during the fMRI experiment.Each run included seven trials per experimental condition, for a total of 28 trials per run. Each trial type was presented in counterbalanced order for a run time of ~12.5 min. Participants completed five functional runs for a total of 140 trials per subject .2.5This study was conducted at the University of Trento's Center for Mind/Brain Sciences (CIMeC) in Mattarello, Italy, using a 4 T Bruker MedSpec whole body MRI system , equipped with Siemens Magnetom Sonata gradients  and an eight‐channel head coil. Functional data were acquired using T2*‐weighted segmented gradient echo‐planar imaging sequence . Each volume was composed of 35 slices for experimental runs, 33 slices for eccentricity mapping which were collected in interleaved order. During each experimental session, a T1‐weighted anatomical reference volume was acquired using a MPRAGE sequence .2.6Data were analysed using Brain Voyager QX software version 2.8.4 . The first three volumes of each functional scan were discarded to avoid T1 saturation effects. For each run, slice scan time correction (cubic spline), temporal filtering (removing frequencies <2 cycles/run) and 3D motion correction (trilinear/sinc) were performed. To complete 3D motion correction, each volume of a run was aligned to the volume of the functional scan that was closest in time to the anatomical scan. Seven runs showing abrupt head movements greater than 1 mm were discarded from the analyses. The data were transformed into Talairach space .We analysed the data from the experimental runs using a group random‐effects (RFX) GLM that included one predictor for each of the four conditions  and three trial phases  resulting in a total of 12 predictors of interest. In addition, we included six motion correction parameters as predictors of no interest. Each predictor was derived from a rectangular‐wave function  convolved with a standard haemodynamic response function . The GLM was performed on %‐transformed beta weights  can be distinguished from the activity pattern elicited by action planning, before participants performed the action , with an LDA classifier (http://cosmomvpa.org/matlab/cosmo_classify_lda.html#cosmo-classify-lda). For each participant, we estimated a GLM on unsmoothed data modelling every trial per condition. The four experimental conditions  by three phases of the trial  by seven repetitions per run by five runs gave rise to a total of 420 regressors of interest per subject. In addition, we modelled movement parameters (three rotations and three translations) as predictors of no interest. We adopted a ‘leave‐one‐run‐out’ cross‐validation approach to estimate the accuracy of the LDA classifier.We used a combination of in‐house software (using MATLAB) and the CoSMo MVPA Toolbox for MATLAB  for each voxel in the ROI. Each phase included the volumes defined in the predictors for the GLM estimated on unsmoothed data. In particular, the Plan phase consisted of three volumes following the Instruction phase, while the Execution phase consisted of one volume following the Plan phase.To provide inputs for the LDA classifier, the 2.11We examined whether object information is encoded in similar ways in the two Action conditions (Align and Open reach) by testing whether the LDA classifier trained to discriminate between two objects (CCW‐Left vs. CW‐Right) in one of the two Action types could then be used to accurately predict trial identity when tested on the other Action type. The trials of the train and test runs were taken from different Action conditions such that the training was performed considering the pairwise comparison between the two objects (CCW‐Left vs. CW‐Right) in the Open reach condition and tested in the Align condition, and vice versa.2.12t test versus 50% chance decoding. To further explore whether the decoding accuracy was higher for the dissociation between the two objects in Align than Open reach movements, we performed two‐tailed paired sample t tests between the decoding accuracies in the two movement types. To control for multiple comparisons and reduce type I errors, a false discovery rate (FDR) correction of q ≤ .05 was applied, based on the number of ROIs and the number of t tests performed within each time phase  from their left EVC ROI and calculated that two‐tailed t tests with 16 participants would provide a power of .87.We used G*Power to perform a post hoc power analysis based on a recent study that has shown significant decoding accuracy for the dissociation between different action plans in the EVC . Activation maps for group voxelwise results were overlaid on the average inflated brains of all participants by cortex‐based alignment Figure .To correct for multiple comparisons, we performed cluster threshold correction for each activation map generated with a voxelwise contrast by using Brain Voyager's cluster‐level statistical threshold estimator plug‐in . In particular, the atlas provides the probabilistic maps generated from a large population of individual subjects (N = 53) tested with standard retinotopic mapping procedures and allows defining the likelihood of a given coordinate being associated with a given functional region for results obtained from any independent dataset once transformed into the same standard space. Therefore, we converted the probabilistic maps from MNI to Talairach space and used them to define V2d. In the second step, within each group ROI, we defined individual ROIs, separately for each participant, as spheres with radius of 6 mm centred around each individual peak voxel resulting from the single‐subject GLM contrasts (action execution > baseline). This approach ensured that all regions were objectively selected and that all ROIs had the same number of anatomical voxels (925 mm3). The averaged Talairach coordinates of individual ROIs are shown in Table For each participant, we localized individual ROIs in two main steps. In the first step, we outlined the areas based on the group activation map obtained with the RFX‐GLM contrast: (action execution > baseline), by circumscribing group ROIs (9 mm radius) around their expected anatomical landmarks Figure . Dorsal 33.1The Talairach coordinates of each ROI are specified in Table Before performing MVPA, we examined whether we could detect differences in processing objects features during the planning phase using the univariate contrast of: (Plan Align CCW‐left > Plan Align CW‐right) and (Plan Open reach CCW‐left > Plan Open reach CW‐right). These contrasts did not reveal any active voxel. This is expected given that participants were lying still and viewed both objects in the lower periphery simultaneously. Therefore, at this point of the task, there was no difference in sensory or motor signals in the two conditions that could have elicited higher activation in one case than the other. Figure 3.2Statistical values for each comparison are specified in Table As shown in Figure In the execution phase, we found significant decoding of object orientation for Align but not Open reach movements in bilateral SPOC, pIPS, aIPS, dPM and LOC. However, only bilateral pIPS and aIPS showed higher dissociation of object orientation in Align than Open reach movements. In addition, bilateral calcarine area, foveal cortex and left MT showed significant dissociation of object features in Align and Open reach conditions, as well as higher dissociation for Align than Open reach movements in bilateral calcarine area, suggesting that vision of the moving hand enhanced dissociations in the EVC during movement execution.3.3As shown in Figure 4We examined whether and how early in the visual cortex the representation of object location and orientation is modulated by action planning. We found that during action planning and execution, the activity pattern in SPOC, pIPS, aIPS and dPM cortex allowed dissociating between the two concurrently presented objects in Align movements, which required orienting the hand according to object features, but not Open reach movements, which did not require adjusting hand orientation. Further, the dissociation was higher when planning an Align than an Open reach tasks. This suggests that upcoming actions enhance the representation of object properties that are relevant for the particular movement. Further, in the EVC we could reliably decode object features during the planning phase, but there was no difference between Align and Open reach movements. Taken together, these results provide a whole‐brain, framework for understanding how action‐relevant object features are cortically represented during action planning.Our results show that the representation of objects features, such as orientation and location, is shaped by the upcoming action seconds before participants initiate a movement. This is likely due to the fact that different objects require different motor plans. Previous studies have shown the involvement of the fronto‐parietal cortex in adjusting hand orientation during action execution. For instance, the superior end of the parietal occipital cortex in humans (SPOC) and macaques (V6A) has been shown to play a key role in processing wrist movements for hand orientation , we suggest that these areas predominantly receive location‐relevant feedback. However, we cannot disambiguate whether object location or orientation drives the modulation, as the object on the left was oriented at about −45° while the one on the right was oriented approximately at 45°. In addition, both objects were present at the same time. As a consequence, our classification results may reflect tuning to object location, orientation, or both. However, in areas that show higher dissociation between the two objects for Align than Open Reach, such as SPOC, pIPS, aIPS and dPM, it is likely that object orientation allows for decoding, as it is relevant for Align movements but not coarse Open reach movements.The cross‐decoding analysis allowed determining whether object information is encoded in similar ways in the two Action types or whether feature encoding is different across the two movements. Our results indicate that object features cannot be generalized across the two Action types in sensorimotor of dorsal and ventral visual stream. This is in line with the idea that the representation of object features is shaped by the upcoming action, even if the retinal inputs are exactly the same for different action plans. On the other hand, the results in left V2d and foveal cortex showed that object representation can be generalized across action plans but only when the classifier is trained on the Align and tested on the Open reach condition. This can be explained by the fact that object features encoding is enhanced in the Align condition, which requires detailed processing of object location and orientation, while the Reach condition only requires a coarse representation of the targets.We filter feature information from redundant stimuli in the world around us to successfully plan actions. Behavioural and neural evidence has shown that attention is directed to the location of a planned movement (Bekkering & Neggers, 5To conclude, our results indicate that the representation of a workspace with two oriented targets varies as a function of the planned action. This is evident in dorsal stream areas, known to be specialized in action preparation, and to a lesser extent in the EVC. Our findings suggest a role of these areas in predictive coding of actions based on internal models that take into account visual and somatosensory anticipations of upcoming movements, as well as object features that are relevant for subsequent actions. This mechanism might be mediated by bidirectional functional connections between dorsal stream areas, known to be involved in action planning, and the EVC. Feedback connections from the dorsal stream areas might tune the signal in the EVC to enhance the representation of action‐relevant object features.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.SM conceived and designed the study. JVI and SM collected the fMRI data. JVI performed pre‐processing, univariate analysis and psychophysiological interaction analysis. SM performed multivariate analysis. JVI wrote the first draft of the manuscript. SM wrote sections of the manuscript and revised it. All authors read, revised and approved the submitted version of the manuscript.https://publons.com/publon/10.1111/ejn.15776.The peer review history for this article is available at


Recently, distinct bacteria were found within the microbiota of crop plants that confer disease resistance to their hosts. Although it is well known that the interplay between microbes and plants can result in improved plant health, the phenomenon of holistically disease‐preventing bacteria is new. Here, we put the recent discoveries of disease‐preventing bacteria in context with decade‐long plant microbiome research that has preceded them. In addition, we provide explanations as to why disease resistance in certain plants, mediated by specific bacteria, has only recently been discovered. We argue that such findings were primarily limited by technological constraints and that analogous findings are very likely to be made with other plant species. The general concept may even be extendable to additional groups of organisms. We, therefore, suggest the introduction of the specific term  It will likely take decades before we know with sufficient certainty the frequency with which they occur in nature and if they constitute specifically co‐evolved, complementary mechanisms of disease protection in distinct host organisms. In the near future, their discovery can be facilitated if microbiome researchers implement the general hypothesis that a disease‐preventing microorganism might be involved whenever disease‐resistant phenotypes within an otherwise disease‐susceptible population are not attributable to (i) acquired immunity, (ii) innate immunity and (iii) other variations in host genetics; including epigenetics. Currently, there are several challenges that impede the discovery of disease‐preventive microorganisms. We argue that they are particularly of technical nature, especially with regard to the limitations that still exist in the generation and processing of microbiome data. Discovery of disease‐preventing microorganisms will require targeted correlation analyses in most cases. However, microbiome‐wide correlation analyses still mostly rely on short sequence fragments of distinct marker genes, which limit the resolution of potential discoveries  in order to facilitate an unambiguous definition of disease‐preventing microorganisms in the plant microbiota and potentially beyond. It derives from the ancient Greek goddess Soteria (Ancient Greek: ∑ωτηρία), which was believed to provide safety and deliverance from harm  in absence of the soterobiont. Whenever there may be doubts on a soterobiont's efficacy in conferring disease resistance, immunodeficient host models should be employed to confirm the implications of a potential candidate organism. All the above‐mentioned traits provide a rough framework for the characterization of soterbionts; it will certainly require further refinement after the discovery of more disease‐preventing microorganisms in the future.We argue that a specific designation for disease‐preventing microorganisms could draw further attention in this direction and result in more targeted approaches for their identification in the future. We, therefore, suggest the introduction of the specific term ies Fig. . It can soterobionts were only recently described, they might be widespread constituents of the microbiota and could explain certain disease resistance in individuals or populations that was previously unknown. It is imperative that their occurrence in the microbiota of higher organisms be further explored in order to harness their potential for disease prevention and development of therapeutic agents. Future discoveries will not only rely on technological developments, but primarily on hypothesis‐driven microbiome analyses of healthy and diseased individuals where soterobionts may be involved.The discovery of disease‐preventing microorganisms could provide the basis for new approaches to address prevalent diseases in plants, animals and humans. Although


Enicognathus ferrugineous) shows close ecological and evolutionary relationships with the Andean Araucaria (Araucaria araucana), so any alteration in these interactions may have negative consequences for both partners and for ecosystem functioning and structure. We conducted extensive roadside surveys to estimate the abundance of parakeets in the northern Patagonian Andes over 4 years and recorded the food plants consumed by foraging flocks. The use of native habitats and humanized areas like villages and farms was influenced by the Araucaria seed crop. In masting years, the large seed crop allowed a massive use of this resource during the non‐breeding season, and even during the breeding season. The exploitation of exotic plants was minor in the masting year, but became predominant in non‐masting years, especially during the non‐breeding season. This feeding switch towards exotic plants primarily arose because the low Araucaria seed crop in non‐masting years is entirely consumed just after production by domestic and wild exotic mammals living in Araucaria forests year‐round, thus forcing the displacement of parakeets towards anthropic habitats to exploit exotic plants. Given the degradation of the remaining Andean Araucaria forests due to the impact of exotic mammals on the ecological interaction between Araucaria and Austral parakeets, ambitious programs to exclude or reduce the density of these alien mammals, including livestock, are warranted.In fragile ecosystems, the introduction of exotic species could alter some ecological processes. The Austral parakeet ( The results of this study show that the inter‐annual dependence of Austral parakeets on native habitats is influenced by the masting seed production strategy of Araucaria, a key species in the northern Patagonian Andes. Currently, this dependence seems to be largely modulated by disturbing factors promoting a feeding shift to exotic plants in anthropic habitats, especially during non‐masting years. Among tAmong generalist plant consumers, psittacines (Psittaciformes) have been recently highlighted as exerting an important role in ecosystem structure and functioning  is a keystone species with which the Austral parakeet (Enicognathus ferrugineous) has had a close ecological and evolutionary relationship . These exotic species may consume large quantities of seeds and deplete the crop in years of low production, which imply a threat to the Austral parakeet population largely dependent on this crucial resource during the non‐breeding season , including a masting year. We aimed to explore whether food depletion (Araucaria seeds) due to exotic mammals can induce a feeding shift in the Austral parakeet towards exotic plant species in urban and cultivated areas during the critical non‐breeding season and whether this depends on the production of Araucaria seeds in masting versus non‐masting years. We hypothesized that the natural low diversity of alternative trophic resources during the non‐breeding season, further reduced by native habitat destruction and fragmentation, could force Austral parakeets to search for novel food resources represented by exotic plant species in urban and cultivated areas when Araucaria seeds are not available in non‐masting years due to the consumption by exotic mammals. Therefore, we predict that the dependence on food from urban and other anthropic habitats should be especially high in years of low production of Araucaria seeds (non‐masting years). We discuss whether these novel food resources from exotic species can represent a suitable opportunity, although with potential threats associated with anthropogenic environments, for Austral parakeet populations, and the ecological consequences for seed dispersal.22.1https://ecoregions2017.appspot.com/ (accessed 12 July 2021). Several National Parks are present in the area: Nahuel Huapi and Lanín in Argentina, Huerquehue, Villarica, Conguillo and Nahuelbuta in Chile  which correspond to two Ecoregions  according to e Figure . The are2.2The Araucaria is an endangered conifer tree endemic to the southern Andes . The remaining inter‐mast study years (hereafter non‐masting years) showed low production with 1 and 2.9 cones/tree in 2014 and 2015, respectively  or medium production  with density estimates accounting for differences in detectability , and allows the calculation of relative abundances  for species that yield insufficient encounters for modeling detectability . This field‐based habitat classification represents a general approximation of the actual fine‐grained composition of the landscape due to its heterogeneous nature, often including a variable mixture of habitat patches changing over years as a consequence of the continuous degradation and transformation of natural habitats by human activities. To deal with this challenge of habitat classification, we relied on the dominant habitat in each patch and divided the surveys into as many patches as necessary depending on the often frequent changes in habitat composition, which was assessed in situ based on visual observation on both sides of the road traveled. We used these five habitat categories for graphical representation of raw data. For statistical modeling (see below), we created the variable habitat type with two levels: anthropic (pooling the two anthropogenic habitats) and native (pooling the three native environments). Abundance by habitat was estimated as the total number of parakeets recorded divided by the kilometers surveyed, considering each habitat patch as the sampling unit  , plant species, item exploited in the case of Araucaria, and habitat. Stops were extended long enough  to record this information by coordinating the activities of the two or three observers, following the methods described previously  sampled in the masting year (2013) was recorded by using the same methodology , the seed abundance below the same marked trees   to analyze the abundance of parakeets according to season (categorized in breeding and non‐breeding seasons), habitat, Araucaria seed production (categorized in masting and non‐masting years), and their interactions. Given the scarcity of parakeet observations in some combinations of habitat × season × Araucaria crop production categories, we simplified the statistical analysis by pooling habitats into native or anthropic (see above). We used as a response variable the number of parakeets recorded in each habitat patch across surveys, by using the 2225 habitat patches surveyed as the sample unit. Therefore, we included patch length (in km) as a covariate to control for survey effort in each patch. The ecoregion  in which each transect was included was fitted in models as a fixed factor, given the expected differences in the relative abundance of parakeets between them (see above). The analysis was run using the package glmmTMB in R to correct for zero‐inflation  was analyzed according to season and Araucaria seed production by the mean of Fisher's exact test. Factors affecting the exploitation of native versus exotic plants were analyzed by GLM using the binomial error distribution  and the logistic link function, by considering the flock (n = 354) as the analysis unit. Season, ecoregion, and the abundance of Araucaria seed production (masting or non‐masting years) were considered as predictor variables (fixed factors).The frequency of use of each habitat  by flocks of foraging parakeets (p < .05) according to the χ2 likelihood ratio.To explore the specific importance of Araucaria as a key resource for Austral parakeets depending on season and masting seed production, we conducted a log linear analysis to examine the relationship between more than two categorical variables. We grouped food species into three categories , while two categories were used for season (breeding and non‐breeding) and Araucaria seed production (masting and non‐masting years). The analysis was conducted in a hierarchical fashion, starting with the three‐order interaction, and then proceeding backward until all two‐order interactions maintained in the model reached statistical significance  where the season, ecoregion, Araucaria seed production (masting or non‐masting years), and type of food (native or exotic) were considered as explanatory factors.Statistical analyses and checking of model assumptions were performed using SPSS software v. 26 (IBM SPSS Statistics) for Fisher's exact test and log‐linear analysis, and the R statistical platform  and not evenly distributed across habitats, seasons and years. The averaged conditional count model obtained Table  than in 3.2Nothofagus forests during the breeding season, especially in the masting year, while the frequency of use of urban areas increased in the non‐masting years  than in the non‐masting years  during the breeding season . In the non‐breeding season, the same pattern of habitat use was found  or non‐masting years  was more acute .Austral parakeets fed in all habitat types considered. A high proportion of flocks exploited native, pure and mixed Araucaria and s Figure . Poolingd Figure  but the Nothofagus spp., and Acaena splendens , fungi (Cyttaria spp.), lichens (Usnea spp.) and invertebrates , including angiosperms and gymnosperms  were feeding on native species while the other half of flocks  were fed on exotic species (Table n = 354) was lower in masting  than in non‐masting years , while controlling for a higher consumption, although not statistically significant, of exotic plants in the Patagonian steppe ecoregion and during the non‐breeding season . Significant interactions between food type and Araucaria seed production , and between food type and season  were found. The fit of the model was adequate . These results show that in the breeding season Austral parakeets mostly foraged on native species, especially on Araucaria during the masting year , season and Araucaria seed production showed no significant three‐way interactions . According to the averaged GLM model, flock size was influenced by food type (native or exotic), Araucaria seed production (masting or non‐masting) and their interaction, and season, while controlling for the smaller flock sizes in the Patagonian steppe ecoregion  and non‐masting years . In contrast, they fed on both seeds and other food resources  during the breeding season of the masting year , but exclusively on other food resources in non‐masting years  due to the lack of available seeds on the ground, as assessed by searching below a large sample of marked and randomly selected trees. Overall, the consumption of seeds and other food differed between masting and non‐masting years .When exploiting food resources provided by Araucaria, Austral parakeets fed exclusively on seeds during the non‐breeding season, both in masting  gathers each year in a very local area to feed on and disperse the seeds of the other Araucaria species in America, the Parana pine (A. angustifolia), also exploited and dispersed by other parrot species  is mostly dispersed by the Sulfur‐crested cockatoo , although this food‐ and habitat‐generalist species only depends on Araucaria seeds locally and during a reduced time period  and palms (Arecaceae) with large fruits  of novel food resources for them (Araucaria seeds) and providers of novel resources for native species . The feeding switch towards exotic plants arose because the low Araucaria seed crop in non‐masting years is entirely consumed just after production by domestic and wild exotic mammals living in Araucaria forests year‐round, thus forcing the displacement of parakeets towards anthropic habitats to exploit exotic plants. Effective methods to reverse the degradation of the remaining Andean Araucaria forests are warranted, including ambitious programs to eradicate invasive alien mammals and to exclude or reduce the density of livestock in this singular and highly threatened ecosystem. The population trend of the Austral parakeet is not known in detail, and there is no accurate information on its long‐distance movements. These questions should be addressed in specific studies monitoring abundance, for which this study can serve as a reference given the large spatial and temporal sampling effort covering years with and without Araucaria masting. Despite the risks inherent in their exploitation, anthropogenic resources could represent a valuable food source in particular seasons or circumstances that could help sustain this and other species. Proper management based on specific research on the actual value of novel resources could help to achieve a positive outcome in terms of conservation.Guillermo Blanco: Conceptualization ; formal analysis ; investigation ; methodology ; supervision ; validation ; visualization ; writing – original draft . Pedro Romero‐Vidal: Conceptualization ; formal analysis ; investigation ; methodology ; validation ; visualization ; writing – review and editing . José L. Tella: Funding acquisition ; investigation ; methodology ; project administration ; supervision ; validation ; visualization ; writing – review and editing . Fernando Hiraldo: Conceptualization ; data curation ; investigation ; methodology ; supervision ; validation ; visualization ; writing – review and editing .All authors declare no competing interests.Supporting InformationClick here for additional data file.


Adenanthos cygnorum (Proteaceae), and studied their function and interaction. We observed that the same ants frequently visit both structures, seeds are attractive to vertebrate granivores but are released into a leafy cup from where they are harvested by ants and taken to their nests, from which seeds, lacking elaiosomes, germinate after fire. We showed that juvenile plants do not produce EFNs and are not visited by ants. We conclude that EFNs are not just an indirect adaptation to minimize herbivory via aggressive ant visitors (the role of a minority) but specifically enhance reproductive success in two ways: First, by inducing ants to visit the plant as a reliable food source throughout the year. Second, by promoting discovery of the seasonally available, elaiosome‐bearing seeds for transport to their nests (the majority of visitors), so avoiding the risk of granivory should seeds instead fall to the ground. Parasitoid wasps play a supporting role in controlling the main insect herbivore whose larvae devour the reproductive apices. Thus, the EFN‐elaiosome relationship has three components that enhance species fitness: foliage protection, seed transport, and granivore escape. A similar system has been described only once before (in an unrelated biome) and, consistent with the objectives of ecology as an integrative science, deserves wider study.Thousands of plants produce both extrafloral nectaries (EFNs) on their leaves and nutrient‐rich appendages on their diaspores (elaiosomes). Although their individual ecology is well‐known, any possible functional link between these structures has almost always been ignored. Here, we recognized their co‐presence in the shrub,  Thousands of flowering plants produce both extrafloral nectaries on their leaves and seeds with nutrient‐rich appendages. Their possible interaction was examined in an Australian shrub here and shown that their co‐presence serves to attract ants to the plant throughout the year that then take the seeds from the plant to their nests during the flowering season rather than allowing the seeds to fall to the ground where they are likely to be consumed by birds and rodents. Top of the list is the major family Fabaceae where they are co‐present in perhaps 50% of species, approaching universality in the huge genus Turneria ulmifolia, that we could find , grows as a thicket from soil‐stored seeds after soil disturbance or, historically more generally, fire  and continued on an ad hoc basis for the next 40 years. The woolly bush, e Figure . This spe Figure . It is tBanksia trees are not in flower, although seed set is only 1–3% ; six native rodent granivores  have been recorded historically in the area  was a regular consumer of seeds under crowns of the study plants and, rarely, ringneck parrots  were observed consuming seeds on the plant. An endemic ground parrot , four quail species  and two pigeons  have been recorded from the area historically and they remain active in more remote sclerophyll shrublands/woodlands elsewhere where A. cygnorum also occurs . Both study sites covered 0.1 ha with t Figure . Weekly t Figure . Ants weRhytidoponera violacea, but uncertain as they had been abandoned) to a depth of 8 cm at the start of the wet season after a summer fire. We later unearthed 20 seedlings from the same burnt patch and estimated their depth of burial from the foot of the hypocotyl to the surface where the hypocotyl turned green  if they routinely fed at the EFNs during the study period, (b) if they were observed to transport seeds from the plants and/or removed seeds placed by us in their pathway, and (c) if they attempted to remove 10 Xylorictid moth larvae (collected from their protective shelters of webbed frass) placed on the plant. Transport of seeds to their nests was followed on three occasions. We excavated six nests  leaf cups on the plant, or (b) beneath crowns of the plants, made a difference to the rate of seed removal by other means. Twelve isolated plants of similar size were located in the study area and 3 × 5 lots of caruncle‐bearing seeds placed under each of six plants and in the leaf cups of six plants in a haphazard fashion. Half of these in turn either had a ring of the sticky resin, tanglefoot®, placed on the ground around the edge of the crown, intended to prevent access to ants either on the ground or on the plant, or were left intact, to give four treatments in a 2 × 2 interaction design.4Campoletis sp. (Ichneumonidae), fed at the EFNs. They laid their eggs on the pupae of a specialist phytophagous moth, Xylorycta sp. (Xyloryctidae), that webs together the terminal leaves of adult branchlets and feeds on the reproductive apices . Seven of 10 pupae that we removed from their shelters hatched into Campoletis wasps instead of moths. (2) Visits by ants to juvenile plants, which lack EFNs, were negligible compared with the scores on adults at any time (plants were not inspected at night), even when adjusted for plant size  of nine ant species that visited the EFNs, when presented with 10 larvae, immediately grasping and carrying them down the plant  were only abundant on the juveniles species and a few wasps systematically visiting the EFNs, with flies, lacewings and bugs making fleeting visits, throughout the year but especially during warm weather Figure . Since aIridomyrmex conifer) while the other (Rhytidoponera sp. 3) did not. Seeds were carried to nests up to 8 m away, although most nests were clustered around individual shrubs  removed within 2 days when access was unfettered, and only a few (≤10%) removed within 2 days when ringed by resin Figure . It is cA. cygnorum once the central role of EFNs in seed dispersal, storage and germination via ants is recognized.It is now clear that the co‐presence of EFNs and elaiosome‐bearing seeds forms a syndrome directed at maximizing species fitness by (1) inducing regular visits to the plant by both parasitoid wasps and aggressive and/or seed‐transporting ants, (2) attracting seed‐harvesting ants, and 3) enabling seed transport from the site of production rather than allowing them to fall to the ground where there is a greatly increased likelihood of seed removal by vertebrate granivores Figure . Ants on enablingTurneria ulmifolia (see next paragraph). A. cygnorum does not appear to support the dispersal‐distance hypothesis  retention of seeds in the persistent fruits and (b) EFNs attracting a suite of ants with distinct roles: either protection or transport  the threat from “large” ground‐dwelling granivores is substantial and sustained (nutrient‐rich seeds in this nutrient‐impoverished environment are at a premium). In regard to the last point, Cuautle et al.  in the vicinity of the woolly bush. Although EFNs are not involved, the leaves produced by mature plants mimic or conceal the fruits (crypsis) to achieve similar ends although the seeds are later released in response to fire upon which they become vulnerable to granivores  and elaiosome‐bearing diaspores. If ecology is to fulfill its stated role as an integrative science, then here lie many opportunities to demonstrate and consolidate that role, rather than treating the different organs of plants as acting independently of each other, as has usually been done. Quite apart from examining to what extent this phenomenon is widespread among species with different growth forms and habitat‐types throughout the world, our work must be regarded as exploratory and many aspects we raise require further investigation within this species over time, space and circumstance. For example, we paid no attention to nectar properties but note that herbivore damage my lead to increased exudation and visits by ants among some plants Heil, .Byron B. Lamont: Conceptualization (lead); formal analysis ; investigation (supporting); methodology ; project administration (lead); supervision (lead); visualization (lead); writing – original draft (lead). James Grey: Conceptualization (supporting); data curation (lead); formal analysis ; investigation (lead); methodology (supporting); resources (lead).This study was part of the postgraduate diploma of JG but was otherwise unfunded.Figure S1Click here for additional data file.


To investigate whether the effect of cystic fibrosis‐related diabetes (CFRD) on the composite outcome of mortality or transplant could act through lung function, pulmonary exacerbations and/or nutritional status.n = 2750). Rate of death or transplant was compared between patients who did and did not develop CFRD (with insulin use) during follow‐up using Poisson regression, separately by sex. Causal mediation methods were used to investigate whether lung function, pulmonary exacerbations and nutritional status lie on the causal pathway between insulin‐treated CFRD and mortality/transplant.A retrospective cohort of adult cystic fibrosis (CF) patients who had not been diagnosed with CFRD were identified from the UK Cystic Fibrosis Registry (At all ages, the mortality/transplant rate was higher in both men and women diagnosed with CFRD. Pulmonary exacerbations were the strongest mediator of the effect of CFRD on mortality/transplant, with an estimated 15%  of the effect at 2 years post‐CFRD diagnosis attributed to exacerbations, growing to 24%  at 4 years post‐diagnosis. Neither lung function nor nutritional status were found to be significant mediators of this effect. Estimates were similar but with wider confidence intervals in a cohort that additionally included people with CFRD but not using insulin.There is evidence that pulmonary exacerbations mediate the effect of CFRD on mortality but, as they are estimated to mediate less than one‐quarter of the total effect, the mechanism through which CFRD influences survival may involve other factors. What is already known?Among people with cystic fibrosis, those with cystic fibrosis‐related diabetes (CFRD) experience increased mortality.The mechanisms underlying this effect are not well understood.What this study has found?This study found evidence that pulmonary exacerbations mediate a portion of the effect of CFRD on mortality or transplant.Lung function and nutritional status were not found to be significant mediators of this effect.What are the implications of the study?There is evidence that CFRD leads to increased pulmonary exacerbations which, in turn, adversely affect survival. This highlights the importance of reducing the risk of pulmonary exacerbations.1Cystic fibrosis (CF) is a life‐shortening disease affecting more than 10,500 people in the UK.There is consistent evidence that CFRD negatively impacts survivalIn this retrospective cohort‐based exploratory analysis using UK CF Registry data, we aimed to investigate the extent to which the effect of CFRD on mortality or transplant is mediated through lung function, pulmonary exacerbations or nutritional status. This is the first application of causal mediation methods to study multiple candidate mechanisms in CFRD. We apply a recently proposed method designed for a setting with a survival outcome, repeatedly measured mediators and adjustment for confounding by other time‐updated covariates.22.11%),2). 4% of FEV1% and 2% of BMI measurements were missing; values were filled in using the last observation carried forward. Less than 3% of IV days data was missing; values were filled in with zero. Calendar year of the visit and sex  are also used in the analysis. A person with CFRD was considered to be insulin‐treated if chronic insulin therapy was initiated prior to the annual review following diagnosis of CFRD. The outcome was time to the composite of death or lung transplantation. We chose this outcome because lung transplantation is offered when patients have advanced lung disease and because disease trajectories are different post‐transplant.Anonymised data for people with CF were extracted from annual review records in the UK Cystic Fibrosis Registry for visits between 1/1/2010 and 31/12/2020. The registry, administered by the Cystic Fibrosis Trust, is a Research Ethics Committee approved research database (REC ref:07/Q0104/2) holding systematically collected data on ≥99% of people with CF in the UK.To define the analysis set, we also used data on pancreatic insufficiency (defined by pancreatic enzyme supplementation) and CF genotype class, which was defined as high risk or low risk based on previously described genotype criteria.2.21% and BMI  that acts on the outcome (death/transplant) via the mediator, which is referred to as the indirect effect. The remainder of the total exposure effect acts either directly on the outcome or via other pathways not involving the mediator (direct effect).1% and BMI. Figure Three potential mediators were investigated separately: lung function, pulmonary exacerbations and nutritional status. In each mediation analysis, one of these variables was selected as the candidate mediator and the other two were included as possible time‐varying mediator‐outcome confounders. We controlled for four baseline confounders of the exposure–outcome relationship: sex, calendar year (to control for differing treatments/management over the study period), FEVt = 0), comprising CFRD status at the visit, baseline covariates measured prior to that (time t = −1), and mediators and outcomes measured subsequent to that . CFRD status taken at t=0 is assumed fixed. This is repeated at each visit up to and including the visit at which CFRD status is ‘Yes’ or up to the last visit for people with CFRD status ‘No’, creating a sequence of datasets for each individual. Time t = 0 refers to the first visit in each sequence. For example, if visits are recorded for an individual annually at ages 20–23 and they were first diagnosed with CFRD at age 23, this individual would have four sequences used in the analysis, three starting with CFRD status ‘No’  and one starting with CFRD status ‘Yes’ . The sequences of individual datasets are combined across all individuals for the analysis.For this analysis, CFRD status (Yes—exposed or No—unexposed) is noted at each annual review. At each visit, ‘baseline covariates’ refer to those measured in the previous year, that is, prior to ascertainment of CFRD status. Measures of the mediator and covariates are also available approximately annually between the recording of CFRD status and the time of the outcome or censoring. For each individual, we create an individual dataset starting at each visit  were deaths and 123 (32%) were transplants. The crude mortality/transplant rate during the 21,253 person‐years of follow‐up was 1.8 per 100 person‐years. Figure 3.3Figure To illustrate the effect of mediation, for each of the three mediators, we plot the estimated probability of death/transplant over time in Figure 3.3.1In the sensitivity analysis that included individuals diagnosed with CFRD regardless of their insulin treatment status, we also found the strongest evidence for mediation through pulmonary exacerbations. Estimated percent mediated through pulmonary exacerbations was 20% , 28%  and 32%  at 2, 3 and 4 years after evaluation of CFRD, respectively Figure .4In this study, we found greater mortality/transplant rate in adults with CFRD compared to those without for both men and women. The mediation analysis suggested that pulmonary exacerbations mediate a portion of the effect of CFRD on mortality or transplant, but there was little evidence that lung function and nutritional status were significant mediators. Pulmonary exacerbations were estimated to mediate 24% of the effect at 4 years post‐CFRD diagnosis in the insulin‐treated cohort. A sensitivity mediation analysis using a cohort formed regardless of insulin treatment status found similar results.These findings have important implications for clinical teams. Importantly, they reinforce the need to reduce the risk of pulmonary exacerbations at every opportunity, with particular focus on treatments known to be effective, including inhaled antibiotics for bacterial suppression, mucoactive therapies such as dornase alfa and more recently CFTR modulators, which have a marked effect on exacerbation risk. Although pulmonary exacerbations are well known to be associated with worse long‐term outcomes such as survival,This study is the first to quantitatively investigate pulmonary exacerbations, lung function and nutritional status as potential mediators of the effect of CFRD on mortality or transplant. The mediation method usedUsing the UK CF Registry dataset, our study population was relatively large and, as it is a national, unselected dataset, it is representative of people with CF throughout the UK. Because the frequency of measurements is pre‐defined via the annual review process, there was no selection bias due to timing of the clinical visits. However, mediator measurements for lung function and nutritional status were only captured approximately annually. If physiological changes in the mediators caused by CFRD, which, in turn, affect survival, are evolving more quickly or if important variability is missed in annual measurements, this could attenuate the estimated mediation effect.CFRD can be difficult to diagnose both because temporary hyperglycaemia is common during acute illness and because many people with CF have fluctuating glucose levels throughout the day.The physiological pathways through which CFRD affects mortality may take many years to be realised but our analysis was limited to 4 years post‐diagnosis of CFRD and so did not capture longer‐term mediation. Due to limited data in later years, the mediation estimates have wide confidence intervals. Also, we treated diagnosis of CFRD as a fixed exposure for each person at each age but many people who did not have CFRD initially went on to develop CFRD later. The ability to account for a time‐varying exposure would be a helpful methodological advance.In conclusion, this mediation analysis found evidence that pulmonary exacerbations mediate a portion of the effect of CFRD on death or transplant. As less than one‐quarter of the total effect was mediated through exacerbations, this leaves an open question about what other mechanisms exist to explain the effect of CFRD on mortality. A related question is whether the search for these mechanisms should begin at some time prior to diagnosis of CFRD when physiological changes may have already begun.NJS reports receiving honoraria for speaking engagements from Vertex, Gilead, Chiesi and Teva. He also reports honoraria for advisory boards from Vertex, Chiesi, Gilead and Menarini.Data S1Click here for additional data file.