A protocol of a pilot randomised trial (Action-RESPOND) to support rural and regional communities with implementing community-based systems thinking obesity prevention initiatives.

BACKGROUND: Over a quarter of children aged 2-17 years living in Australia are overweight or obese, with a higher prevalence reported in regional and remote communities. Systems thinking approaches that seek to support communities to generate and implement locally appropriate solutions targeting intertwined environmental, political, sociocultural, and individual determinants of obesity have the potential to ameliorate this. There have however been reported challenges with implementation of such initiatives, which may be strengthened by incorporating implementation science methods. METHODS: This pilot randomised controlled trial protocol outlines the development and proposed evaluation of a multicomponent implementation strategy (Action-RESPOND). to increase the implementation of community-based systems thinking child obesity prevention initiatives The target of this intervention is ten rural and regional communities (or local government areas as the unit of allocation) within Northeast Victoria who were participants in a whole-of-systems intervention (RESPOND). Action-RESPOND builds on this intervention by assessing the impact of offering additional implementation strategies to five communities relative to usual care. The development of the multicomponent implementation strategy was informed by the Promoting Action on Research Implementation in Health Services (PARIHS) framework and consists of seven implementation strategies primarily delivered via 'facilitation' methods. Implementation strategies aimed to ensure initiatives implemented are i) evidence-based, ii) address community's specific needs and iii) are suitable for local context. Strategies also aimed to increase the community's capacity to implement, through iv) improving the health promotion team's implementation knowledge and skills, fostering v) leadership, vi) physical resources and vii) community culture to drive implementation. The feasibility, acceptability, potential impact, and cost of the strategy will be assessed at baseline and follow up using surveys administered to key representatives within the community and internal records maintained by the research team. DISCUSSION: By leveraging an existing community-based whole-of-systems intervention, Action-RESPOND offers a unique opportunity to collect pilot feasibility and early empirical data on how to apply implementation and systems science approaches to support obesity prevention in rural and regional communities in Victoria.

The COVID-19 ambulance response assessment (CARA) study: a national survey of ambulance service healthcare professionals' preparedness and response to the COVID-19 pandemic.

Background: The COVID-19 pandemic placed significant demand on the NHS, including ambulance services, but it is unclear how this affected ambulance service staff and paramedics in other clinical settings (e.g. urgent and primary care, armed services, prisons). This study aimed to measure the self-perceived preparedness and impact of the first wave of the pandemic on paramedics' psychological stress and perceived ability to deliver care. Methods: Ambulance clinicians and paramedics working in other healthcare settings were invited to participate in a three-phase sequential online survey during the acceleration (April 2020), peak (May 2020) and deceleration (September/October 2020) phases of the first wave of COVID-19 in the United Kingdom. Recruitment used social media, Trust internal bulletins and the College of Paramedics' communication channels, employing a convenience sampling strategy. Data were collected using purposively developed open- and closed-ended questions and the validated general health questionnaire-12 (GHQ-12). Data were analysed using multi-level linear and logistic regression models. Results: Phase 1 recruited 3717 participants, reducing to 2709 (73%) by phase 2 and 2159 (58%) by phase 3. Participants were mostly male (58%, n = 2148) and registered paramedics (n = 1992, 54%). Mean (standard deviation) GHQ-12 scores were 16.5 (5.2) during phase 1, reducing to 15.2 (6.7) by phase 3. A total of 84% of participants (n = 3112) had a GHQ-12 score ≥ 12 during the first phase, indicating psychological distress. Participants that had higher GHQ-12 scores were feeling unprepared for the pandemic, and reported a lack of confidence in using personal protective equipment and managing cardiac arrests in confirmed or suspected COVID-19 patients. Conclusions: Most participants reported psychological distress, the reasons for which are multi-factorial. Ambulance managers need to be aware of the risks to staff mental health and take action to mitigate these, to support staff in the delivery of unscheduled, emergency and urgent care under these additional pressures.

Regional impacts of warming on biodiversity and biomass in high latitude stream ecosystems across the Northern Hemisphere.

Warming can have profound impacts on ecological communities. However, explorations of how differences in biogeography and productivity might reshape the effect of warming have been limited to theoretical or proxy-based approaches: for instance, studies of latitudinal temperature gradients are often conflated with other drivers (e.g., species richness). Here, we overcome these limitations by using local geothermal temperature gradients across multiple high-latitude stream ecosystems. Each suite of streams (6-11 warmed by 1-15°C above ambient) is set within one of five regions (37 streams total); because the heating comes from the bedrock and is not confounded by changes in chemistry, we can isolate the effect of temperature. We found a negative overall relationship between diatom and invertebrate species richness and temperature, but the strength of the relationship varied regionally, declining more strongly in regions with low terrestrial productivity. Total invertebrate biomass increased with temperature in all regions. The latter pattern combined with the former suggests that the increased biomass of tolerant species might compensate for the loss of sensitive species. Our results show that the impact of warming can be dependent on regional conditions, demonstrating that local variation should be included in future climate projections rather than simply assuming universal relationships.

Route of drug administration in out-of-hospital cardiac arrest: A protocol for a randomised controlled trial (PARAMEDIC-3).

Aims: The PARAMEDIC-3 trial evaluates the clinical and cost-effectiveness of an intraosseous first strategy, compared with an intravenous first strategy, for drug administration in adults who have sustained an out-of-hospital cardiac arrest. Methods: PARAMEDIC-3 is a pragmatic, allocation concealed, open-label, multi-centre, superiority randomised controlled trial. It will recruit 15,000 patients across English and Welsh ambulance services. Adults who have sustained an out-of-hospital cardiac arrest are individually randomised to an intraosseous access first strategy or intravenous access first strategy in a 1:1 ratio through an opaque, sealed envelope system. The randomised allocation determines the route used for the first two attempts at vascular access. Participants are initially enrolled under a deferred consent model.The primary clinical-effectiveness outcome is survival at 30-days. Secondary outcomes include return of spontaneous circulation, neurological functional outcome, and health-related quality of life. Participants are followed-up to six-months following cardiac arrest. The primary health economic outcome is incremental cost per quality-adjusted life year gained. Conclusion: The PARAMEDIC-3 trial will provide key information on the clinical and cost-effectiveness of drug route in out-of-hospital cardiac arrest.Trial registration: ISRCTN14223494, registered 16/08/2021, prospectively registered.

Microplastic pollution on historic facades: Hidden 'sink' or urban threat?

Despite the increasing concerns surrounding the health and environmental risks of microplastics (MPs), the research focus has primarily been on their prevalence in air and the oceans, consequently neglecting their presence on urban facades, which are integral to our everyday environments. Therefore, there is a crucial knowledge gap in comprehending urban MP pollution. Our pioneering interdisciplinary study not only quantifies but also identifies MPs on historic facades, revealing their pervasive presence in a medium-sized urban area in the UK. In this case study, we estimated a mean density of 975,000 fibres/m^2 (0.10 fibres/mm^2) for fibre lengths between 30 and 1000 µm with a ratio of 1:5 for natural to artificial fibres. Our research identifies three groups of fibre length frequencies across varied exposure scenarios on the investigated urban facade. Sheltered areas (4m height) show a high prevalence of 60-120 µm and 180-240 µm fibres. In contrast, less sheltered areas at 3m exhibit lower fibre frequencies but similar lengths. Notably, the lowest area (2-1.5m) features longer fibres (300-1000 µm), while adjacent area S, near a faulty gutter, shows no fibres, highlighting the impact of exposure, altitude, and environmental variables on fibre distribution on urban facades. Our findings pave one of many necessary paths forward to determine the long-term fate of these fibres and provoke a pertinent question: do historic facades serve as an urban 'sink' that mitigates potentially adverse health impacts or amplifies the effects of mobile microplastics? Addressing MP pollution in urban areas is crucial for public health and sustainable cities. More research is required to understand the multi-scale factors behind MP pollution in large cities and to find mitigation strategies, paving the way for effective interventions and policies against this growing threat.

Reviewing ecological implications of mycorrhizal fungal interactions in the Brassicaceae.

Mycorrhizal associations are plant-fungal mutualisms that are fairly ubiquitous and likely evolved multiple times in phylogenic history; however, some plant families have consistently been identified as non-mycorrhizal, including the Brassicaceae. In this paper, we reviewed the literature and DNA databases for potential mechanisms that preclude mycorrhizal symbioses in the Brassicaceae and for exceptions to the general observation of non-mycorrhizal status within this plant family. In instances of association between members of the Brassicaceae and arbuscular mycorrhizal fungi we posed hypotheses for why these interactions occur in the species and sites observed. Instances of inconsistent association with mycorrhizal fungi were attributed to inter- and intraspecific variations in plant biology, disagreements in vernacular, methodology contradicting historical mycorrhizal surveys, and association being a facultative, variable trait that is determined by species-site interactions. We propose further research on a) the extent of mycorrhizal association in the Brassicaceae, b) the molecular mechanisms dictating association, and c) whether Brassicaceae-mycorrhizal fungal interactions result in nutrient transfer, and their particular roles in the family's distribution across heterogeneous and harsh environments.

The combined effects of treated sewage discharge and land use on rivers.

Freshwater ecosystems are increasingly threatened by multiple anthropogenic stressors. Release of treated sewage effluent and pollution from agricultural or urban sources can independently reduce water quality with implications for ecological communities. However, our knowledge of the combined effects of these stressors is limited. We performed a field study to quantify the combined effect of treated sewage discharge and land use on nutrient concentrations, sewage fungus presence and communities of macroinvertebrates and benthic algae. Over three seasons in four rivers we found that a model which included an interaction between sewage pollution and time of the year (i.e. months) was the best predictor of nutrient concentrations and the abundance of algae and sewage fungus. Both macroinvertebrate and algae communities shifted downstream of sewage input. Specifically, more tolerant groups, such as cyanobacteria and oligochaetes, were more abundant. The EPT (Ephemeroptera, Plecoptera and Tricoptera) water quality score was best explained by an interaction between month and agriculture in the surrounding landscape. Overall, our results show that sewage discharge has a significant impact on water quality and benthic riverine communities, regardless of the surrounding land uses. Agricultural inputs, however, could be more important than treated sewage discharge in reducing the abundance of sensitive invertebrate taxa. We need both improvements to wastewater treatment processes and reductions in agricultural pollution to reduce threats to vulnerable freshwater communities.

Winter is coming: Interactions of multiple stressors in winter and implications for the natural world.

Winter is a key driver of ecological processes in freshwater, marine and terrestrial ecosystems, particularly in higher latitudes. Species have evolved various adaptive strategies to cope with food limitations and the cold and dark wintertime. However, human-induced climate change and other anthropogenic stressors are impacting organisms in winter in unpredictable ways. In this paper, we show that global change experiments investigating multiple stressors have predominantly been conducted during summer months. However, effects of anthropogenic stressors sometimes differ between winter and other seasons, necessitating comprehensive investigations. Here, we outline a framework for understanding the different effects of anthropogenic stressors in winter compared to other seasons and discuss the primary mechanisms that will alter ecological responses of organisms (microbes, animals and plants). For instance, while the magnitude of some anthropogenic stressors can be greater in winter than in other seasons (e.g. some pollutants), others may alleviate natural winter stress (e.g. warmer temperatures). These changes can have immediate, delayed or carry-over effects on organisms during winter or later seasons. Interactions between stressors may also vary with season. We call for a renewed research direction focusing on multiple stressor effects on winter ecology and evolution to fully understand, and predict, how ecosystems will fare under changing winters. We also argue the importance of incorporating the interactions of anthropogenic stressors with winter into ecological risk assessments, management and conservation efforts.

The social sciences are increasingly ill-equipped to design system-level reforms.

Our social policy landscape is characterized by incrementalism, while public calls for more radical reform get louder. But the social sciences cannot be relied upon to generate a steady stream of radical, system-level policies. Long-standing trends in social science - in particular, increasing specialization, an increasing emphasis on causal inference, and the growing replication crisis - are barriers to system-level policy development.

What does the future look like for kelp when facing multiple stressors?

As primary producers and ecosystem engineers, kelp (generally Order Laminariales) are ecologically important, and their decline could have far-reaching consequences. Kelp are valuable in forming habitats for fish and invertebrates and are crucial for adaptation to climate change by creating coastal defenses and in providing key functions, such as carbon sequestration and food provision. Kelp are threatened by multiple stressors, such as climate change, over-harvesting of predators, and pollution. In this opinion paper, we discuss how these stressors may interact to affect kelp, and how this varies under different contexts. We argue that more research that bridges kelp conservation and multiple stressor theory is needed and outline key questions that should be addressed as a priority. For instance, it is important to understand how previous exposure (either to earlier generations or life stages) determines responses to emerging stressors, and how responses in kelp scale up to alter food webs and ecosystem functioning. By increasing the temporal and biological complexity of kelp research in this way, we will improve our understanding allowing better predictions. This research is essential for the effective conservation and potential restoration of kelp in our rapidly changing world.

Perceived impacts of COVID-19 and bushfires on the implementation of an obesity prevention trial in Northeast Victoria, Australia.

BACKGROUND: Calls for the adoption of a systems approach to chronic disease prevention date back at least ten years because of the potential to empower communities to identify and address the complex causes of overnutrition, undernutrition and climate change. Australia, like many countries, has high levels of obesity and extreme climate events. The Reflexive Evidence and Systems interventions to Prevent Obesity and Non-communicable Disease (RESPOND) trial aims to prevent unhealthy weight gain in children in 10 intervention and two pilot communities in north-east Victoria, Australia using community-based participatory approaches informed by systems science. Intervention activities co-designed in 2019 were disrupted by COVID-19 and bushfires. This paper explores the impacts of these 'shocks' on the local prevention workforce to implement actions within communities. METHODS: A case study design involving one-hour online focus groups and an on-line survey (November 2021-February 2022). Purposive sampling was used to achieve diverse representation from RESPOND stakeholders including local council, health services, primary care partnerships and department of health. The focus group interview schedule and survey questions were based on Durlak and DuPre's implementation factors. RESULTS: Twenty-nine participants from seven different communities participated in at least one of nine focus groups to discuss the impacts of COVID-19 and bushfires on localised implementation. Twenty-eight participants (97% of focus group sample) also completed the on-line survey. Implementation of RESPOND stalled or stopped in most communities due to bushfires and/or COVID-19. These shocks resulted in organisational priorities changing, loss of momentum for implementation, redeployment of human resources, culminating in fatigue and exhaustion. Participants reported adaptation of RESPOND, but implementation was slowed due to limited resources. CONCLUSION: Further research is needed to advance risk management strategies and protect resources within health promotion. System shocks such as bushfires and COVID-19 are inevitable, and despite multiple adaptation opportunities, this intervention approach was not 'shock proof'.

Lived experience of participants who engaged in the co-creation of initiatives to improve children's health in a rural Australian community.

OBJECTIVE: To describe participants' lived experience of co-creating and implementing initiatives to improve children's health. DESIGN: This manuscript reports an embedded case study design, which aims to describe participants' lived experiences of co-creating community-based initiatives. Information was gathered from an online survey and two focus groups. The two transcribed discussions from the focus groups were analysed using a 6-step phenomenological process. SETTING: Mansfield, Australia, population 4787, is one of ten local government areas (LGA) participating in the Reflexive Evidence and Systems Interventions to Prevent Obesity and Non-communicable Disease (RESPOND) project. PARTICIPANTS: Participants were purposively selected from established community groups previously engaged by RESPOND using a co-creation approach. The recruitment for the focus groups was a convenient sampling from participants that provided their email addresses in the online survey. RESULTS: Eleven participants completed the online survey. A total of ten participants attended the two focus groups of 1-h duration: five participants in each. Participants reported feeling empowered to create unique, locally relevant and readily adaptable community-wide change. They were supported by a strong partnership that mobilised funding for a part-time health promotion employee. Strengthened social connections were an unexpected though highly valued outcome. CONCLUSION: Co-creation processes may assist stakeholders in delivering prevention strategies in ways that are empowering for them, responsive to the changing needs of the community, strengthen organisational partnerships and enhance community participation, social inclusion and engagement.

Chemical Mixtures and Multiple Stressors: Same but Different?

Ecosystems are strongly influenced by multiple anthropogenic stressors, including a wide range of chemicals and their mixtures. Studies on the effects of multiple stressors have largely focussed on nonchemical stressors, whereas studies on chemical mixtures have largely ignored other stressors. However, both research areas face similar challenges and require similar tools and methods to predict the joint effects of chemicals or nonchemical stressors, and frameworks to integrate multiple chemical and nonchemical stressors are missing. We provide an overview of the research paradigms, tools, and methods commonly used in multiple stressor and chemical mixture research and discuss potential domains of cross-fertilization and joint challenges. First, we compare the general paradigms of ecotoxicology and (applied) ecology to explain the historical divide. Subsequently, we compare methods and approaches for the identification of interactions, stressor characterization, and designing experiments. We suggest that both multiple stressor and chemical mixture research are too focused on interactions and would benefit from integration regarding null model selection. Stressor characterization is typically more costly for chemical mixtures. While for chemical mixtures comprehensive classification systems at suborganismal level have been developed, recent classification systems for multiple stressors account for environmental context. Both research areas suffer from rather simplified experimental designs that focus on only a limited number of stressors, chemicals, and treatments. We discuss concepts that can guide more realistic designs capturing spatiotemporal stressor dynamics. We suggest that process-based and data-driven models are particularly promising to tackle the challenge of prediction of effects of chemical mixtures and nonchemical stressors on (meta-)communities and (meta-)food webs. We propose a framework to integrate the assessment of effects for multiple stressors and chemical mixtures. Environ Toxicol Chem 2023;42:1915-1936. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Extensive regional variation in the phenology of insects and their response to temperature across North America.

Climate change models often assume similar responses to temperatures across the range of a species, but local adaptation or phenotypic plasticity can lead plants and animals to respond differently to temperature in different parts of their range. To date, there have been few tests of this assumption at the scale of continents, so it is unclear if this is a large-scale problem. Here, we examined the assumption that insect taxa show similar responses to temperature at 96 sites in grassy habitats across North America. We sampled insects with Malaise traps during 2019-2021 (N = 1041 samples) and examined the biomass of insects in relation to temperature and time of season. Our samples mostly contained Diptera (33%), Lepidoptera (19%), Hymenoptera (18%), and Coleoptera (10%). We found strong regional differences in the phenology of insects and their response to temperature, even within the same taxonomic group, habitat type, and time of season. For example, the biomass of nematoceran flies increased across the season in the central part of the continent, but it only showed a small increase in the Northeast and a seasonal decline in the Southeast and West. At a smaller scale, insect biomass at different traps operating on the same days was correlated up to ~75 km apart. Large-scale geographic and phenological variation in insect biomass and abundance has not been studied well, and it is a major source of controversy in previous analyses of insect declines that have aggregated studies from different locations and time periods. Our study illustrates that large-scale predictions about changes in insect populations, and their causes, will need to incorporate regional and taxonomic differences in the response to temperature.

Differences of morphological attributes between 62 proximal and distal subchondral cystic lesions of the proximal phalanx as determined by radiography and computed tomography.

OBJECTIVE: To determine morphological characteristics of subchondral cystic lesions (SCLs) in the proximal phalanx (PP) of adult horses. SAMPLE: Radiographs and/or CT scans of PP from 46 horses. PROCEDURES: There were horses with a SCL in PP, which was diagnosed by radiography and/or computed tomography, included. Additional data (signalment, history, orthopedic examination) were collected retrospectively for each case. RESULTS: Forty-six horses met the required inclusion criteria, with a total of 62 SCLs. Forty-three SCLs (70.5%) were located in the proximal PP (group A). Forty-four percent of these were associated with short, incomplete fractures, while 30 of the proximal PP SCLs (69.7%) were found mid sagittal. Proximal SCLs mostly showed a blurred, irregular shape (62.8%) and long, as well as wide, but shallow shapes in CT. Eighteen SCLs (29.5%) were found in the distal PP, near the proximal interphalangeal joint (group B). In contrast to the described proximal SCLs, the distal SCLs were of circular or oval shape, well delineated (77.8%), and distinctly larger. Horses of group A were significantly older (mean age, 11.47 years) than horses of group B (mean age, 6.72 years). CLINICAL RELEVANCE: The distribution and morphological attributes of proximal PP SCLs as well as their association to subchondral bone lesions and short, incomplete proximal fractures indicate more recently developed lesions due to chronic stress factors, such as repetitive trauma to the cartilage and subchondral bone. In contrast, morphology and distribution of distal SCLs showed high accordance with developmental bone cysts originating from a failure of endochondral ossification.

Local stressors mask the effects of warming in freshwater ecosystems.

Climate warming is a ubiquitous stressor in freshwater ecosystems, yet its interactive effects with other stressors are poorly understood. We address this knowledge gap by testing the ability of three contrasting null models to predict the joint impacts of warming and a range of other aquatic stressors using a new database of 296 experimental combinations. Despite concerns that stressors will interact to cause synergisms, we found that net impacts were usually best explained by the effect of the stronger stressor alone (the dominance null model), especially if this stressor was a local disturbance associated with human land use. Prediction accuracy depended on stressor identity and how asymmetric stressors were in the magnitude of their effects. These findings suggest we can effectively predict the impacts of multiple stressors by focusing on the stronger stressor, as habitat alteration, nutrients and contamination often override the biological consequences of higher temperatures in freshwater ecosystems.

Are experiment sample sizes adequate to detect biologically important interactions between multiple stressors?

As most ecosystems are being challenged by multiple, co-occurring stressors, an important challenge is to understand and predict how stressors interact to affect biological responses. A popular approach is to design factorial experiments that measure biological responses to pairs of stressors and compare the observed response to a null model expectation. Unfortunately, we believe experiment sample sizes are inadequate to detect most non-null stressor interaction responses, greatly hindering progress. Using both real and simulated data, we show sample sizes typical of many experiments (<6) can (i) only detect very large deviations from the additive null model, implying many important non-null stressor-pair interactions are being missed, and (ii) potentially lead to mostly statistical outliers being reported. Computer code that simulates data under either additive or multiplicative null models is provided to estimate statistical power for user-defined responses and sample sizes, and we recommend this is used to aid experimental design and interpretation of results. We suspect that most experiments may require 20 or more replicates per treatment to have adequate power to detect nonadditive. However, estimates of power need to be made while considering the smallest interaction of interest, i.e., the lower limit for a biologically important interaction, which is likely to be system-specific, meaning a general guide is unavailable. We discuss ways in which the smallest interaction of interest can be chosen, and how sample sizes can be increased. Our main analyses relate to the additive null model, but we show similar problems occur for the multiplicative null model, and we encourage similar investigations into the statistical power of other null models and inference methods. Without knowledge of the detection abilities of the statistical tools at hand or the definition of the smallest meaningful interaction, we will undoubtedly continue to miss important ecosystem stressor interactions.

Simulated Kick Injury to the Mandible in Horses: Study of Fracture Configurations and Physical Parameters of the Impact.

OBJECTIVE: The goal of this study was to generate mandibular fractures in three regions of the diastema using a metal impactor to simulate a kick from a horse and to determine the mean deceleration in the initial phase of the impact event, the maximum contact force, the impact energy necessary to create a fracture and the duration of the impact. STUDY DESIGN: Thirty heads of horses aged between 5 and 20 years and euthanatized for various reasons were used. The heads were attached to a steel bar at the occiput at an axial angle of 45 degrees so that the body of the mandible was positioned horizontally and directly under the trajectory of the impactor. A 2 kg solid impactor was dropped with velocities of 6 to 14 m/s to simulate a kick from a horse. The impact was recorded using a high-speed video camera with a frame rate of 30,000 frames per second. Radiographs of the heads were obtained before and after the simulated kick. RESULTS: Mandibular fractures with configurations similar to those seen in clinical practice were generated at all three locations. The mean deceleration increased with impact velocity and with more cranially located impact positions. Absorbed energy increased with increasing impact velocity when no fracture was generated. CONCLUSION: The susceptibility to experimental fracture of the diastema increased from rostral to caudal locations, which is most probably caused by decreasing mandibular bone strength and an increase in the curvature at the lateroventral aspect of the mandible in that region. Physical parameters depended on fracture occurrence and type.

Interactive effects of multiple stressors vary with consumer interactions, stressor dynamics and magnitude.

Predicting the impacts of multiple stressors is important for informing ecosystem management but is impeded by a lack of a general framework for predicting whether stressors interact synergistically, additively or antagonistically. Here, we use process-based models to study how interactions generalise across three levels of biological organisation (physiological, population and consumer-resource) for a two-stressor experiment on a seagrass model system. We found that the same underlying processes could result in synergistic, additive or antagonistic interactions, with interaction type depending on initial conditions, experiment duration, stressor dynamics and consumer presence. Our results help explain why meta-analyses of multiple stressor experimental results have struggled to identify predictors of consistently non-additive interactions in the natural environment. Experiments run over extended temporal scales, with treatments across gradients of stressor magnitude, are needed to identify the processes that underpin how stressors interact and provide useful predictions to management.

Universal Germline Panel Testing for Individuals With Pheochromocytoma and Paraganglioma Produces High Diagnostic Yield.

BACKGROUND: Practice guidelines to identify individuals with hereditary pheochromocytomas and paragangliomas (PPGLs) advocate for sequential gene testing strategy guided by specific clinical features and predate the routine use of multigene panel testing (MGPT). OBJECTIVE: To describe results of MGPT for hereditary PPGL in a clinically and ancestrally diverse cohort. SETTING: Commercial laboratory based in the United States. METHODS: Clinical data and test results were retrospectively reviewed in 1727 individuals who had targeted MGPT from August 2013 through December 2019 because of a suspicion of hereditary PPGL. RESULTS: Overall, 27.5% of individuals had a pathogenic or likely pathogenic variant (PV), 9.0% had a variant of uncertain significance, and 63.1% had a negative result. Most PVs were identified in SDHB (40.4%), followed by SDHD (21.1%), SDHA (10.1%), VHL (7.8%), SDHC (6.7%), RET (3.7%), and MAX (3.6%). PVs in FH, MEN1, NF1, SDHAF2, and TMEM127 collectively accounted for 6.5% of PVs. Clinical predictors of a PV included extra-adrenal location, early age of onset, multiple tumors, and positive family history of PPGL. Individuals with extra-adrenal PGL and a positive family history were the most likely to have a PV (85.9%). Restricting genetic testing to SDHB/C/D misses one-third (32.8%) of individuals with PVs. CONCLUSION: Our data demonstrate a high diagnostic yield in individuals with and without established risk factors, a low inconclusive result rate, and a substantial contribution to diagnostic yield from rare genes. These findings support universal testing of all individuals with PPGL and the use of concurrent MGPT as the ideal platform.