Anatomical Proximity Between Sciatic Nerve and Ischial Spine and its Relationship to the Development of Deep Gluteal Pain Syndrome.

OBJECTIVE: Deep gluteal syndrome (DGS) is a medical diagnosis in which the pathoanatomy of the subgluteal space contributes to pain. The growing recognition that gluteal neuropathies can be associated with the presence of a bone-neural conflict with irritation or compression may allow us to shed some light on this pathology. This study aims to determine whether the location of the sciatic nerve in relation to the ischial spine contributes to the development of DGS. METHODS: The sciatic nerve - ischial spine relationship was analyzed based on magnetic resonance imaging (MRI) in 15 surgical patients who underwent piriformis release, and in 30 control patients who underwent MRI of the pelvis for reasons unrelated to sciatica. The sciatic nerve exit from the greater sciatic foramen was classified as either zone A (medial to the ischial spine); zone B (on the ischial spine); or zone C (lateral to the ischial spine). RESULTS: The sciatic nerve was significantly closer to the ischial spine in surgical patients than in MRI controls (P=0.014). When analyzing patients of similar age, sciatic nerves in surgical patients were significantly closer (P=0.0061) to the ischial spine, and located in zone B significantly more (P=0.0216) as compared to MRI controls. Patients who underwent surgery for piriformis release showed a significant decrease in pain postoperatively (P<0.0001). CONCLUSIONS: The results from this study suggest that the relationship between the ischial spine and sciatic nerve may play a role in the development of DGS. This may also help establish which patients would benefit more from surgical intervention.

Patients With Generalized Joint Hypermobility Have Thinner Superior Hip Capsules and Greater Hip Internal Rotation on Physical Examination.

Purpose: To compare preoperative hip range of motion (ROM), hip capsular thickness on magnetic resonance imaging (MRI), and bony morphology on radiographs and computed tomography (CT) between patients with and without joint hypermobility as measured by the Beighton Test score (BTS), with subanalysis based on sex and age. Methods: Consecutive patients who underwent hip arthroscopy for a diagnosis of femoroacetabular impingement syndrome with or without dysplasia were retrospectively reviewed. Patient BTS, hip ROM, demographics, surgical data, morphologic measures on radiographs and CT, and MRI findings including hip capsule thickness at various locations were compiled. Multiple statistical tests were performed, including multivariable linear or logistic regression models, while controlling for BTS, age, and sex. Results: In total, 99 patients were included with a mean age of 29 ± 9.9 years; 62 (62.6%), were female. Forty patients (40.4%) had a BTS ≥4. Female patients (P < .001) and younger patients (26.7 vs 30.9 years, P = .030) were more likely to have a BTS ≥4. Male patients had significantly thicker superior capsules (3.4 mm vs. 2.8 mm, P = .034). BTS was not associated with capsular thickness when controlling for sex. On CT, femoral version (18.9° vs 11.4°, P < .001), and McKibben index (37.8° vs. 28.2°, P < .001) were significantly greater in those with a BTS ≥4. Patients with a BTS ≥4 had more hip internal rotation at 90° of flexion (15.0° vs 10.0°, P < .001), when prone (30.0° vs 20.0°, P = .004), and in extension (10.0° vs. 5.0°, P < .001). Conclusions: All female patients, regardless of Beighton score, and all patients with a BTS ≥4 indicated for primary hip arthroscopy for femoroacetabular impingement syndrome with or without dysplasia were more likely to have thinner superior hip capsules on MRI and greater hip internal rotation on exam. Bony morphologic differences exist between sexes and between patients with and without hypermobility, likely contributing to differences in ROM. Level of Evidence: III, retrospective cohort study.

A spatially explicit model for estimating risks of pesticide exposure to bird populations.

Pesticides are used widely in agriculture and have the potential to affect non-target organisms, including birds. We developed an integrated modeling system to allow for spatially-explicit evaluation of potential impacts to bird populations following exposures to pesticides. Our novel methodology builds upon three existing models: the Terrestrial Investigation Model (TIM), the Markov Chain Nest Productivity Model (MCnest), and HexSim to simulate population dynamics. We parameterized the integrated modeling system using information required under the Federal Insecticide, Fungicide, and Rodenticide Act, together with species habitat and life history data available from the scientific literature as well as landcover data representing agricultural areas and species habitat. Our case study of the federally threatened California Gnatcatcher (Polioptila californica) illustrates how the integrated modeling system can estimate the population-scale consequences of pesticide applications. We simulated impacts from two insecticides applied to wheat: one causing mortality (survival stressor), and the other causing reproductive failure (reproductive stressor). We observed declines in simulated gnatcatcher abundance and changes in the species' distribution following applications of each pesticide; however, the impacts of the two pesticides were different. Our methodology attempts to strike a balance between biological realism and model complexity and should be applicable to a wide array of species, systems, and stressors.

Pop-guide: Population modeling guidance, use, interpretation, and development for ecological risk assessment.

The assimilation of population models into ecological risk assessment (ERA) has been hindered by their range of complexity, uncertainty, resource investment, and data availability. Likewise, ensuring that the models address risk assessment objectives has been challenging. Recent research efforts have begun to tackle these challenges by creating an integrated modeling framework and decision guide to aid the development of population models with respect to ERA objectives and data availability. In the framework, the trade-offs associated with the generality, realism, and precision of an assessment are used to guide the development of a population model commensurate with the protection goal. The decision guide provides risk assessors with a stepwise process to assist them in developing a conceptual model that is appropriate for the assessment objective and available data. We have merged the decision guide and modeling framework into a comprehensive approach, Population modeling Guidance, Use, Interpretation, and Development for Ecological risk assessment (Pop-GUIDE), for the development of population models for ERA that is applicable across regulatory statutes and assessment objectives. In Phase 1 of Pop-GUIDE, assessors are guided through the trade-offs of ERA generality, realism, and precision, which are translated into model objectives. In Phase 2, available data are assimilated and characterized as general, realistic, and/or precise. Phase 3 provides a series of dichotomous questions to guide development of a conceptual model that matches the complexity and uncertainty appropriate for the assessment that is in concordance with the available data. This phase guides model developers and users to ensure consistency and transparency of the modeling process. We introduce Pop-GUIDE as the most comprehensive guidance for population model development provided to date and demonstrate its use through case studies using fish as an example taxon and the US Federal Insecticide Fungicide and Rodenticide Act and Endangered Species Act as example regulatory statutes. Integr Environ Assess Manag 2021;17:767-784. © 2020 SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Predicting impacts of chemicals from organisms to ecosystem service delivery: A case study of insecticide impacts on a freshwater lake.

Assessing and managing risks of anthropogenic activities to ecological systems is necessary to ensure sustained delivery of ecosystem services for future generations. Ecological models provide a means of quantitatively linking measured risk assessment endpoints with protection goals, by integrating potential chemical effects with species life history, ecological interactions, environmental drivers and other potential stressors. Here we demonstrate how an ecosystem modeling approach can be used to quantify insecticide-induced impacts on ecosystem services provided by a lake from toxicity data for organism-level endpoints. We used a publicly available aquatic ecosystem model AQUATOX that integrates environmental fate of chemicals and their impacts on food webs in aquatic environments. By simulating a range of exposure patterns, we illustrated how exposure to a hypothetical insecticide could affect aquatic species populations (e.g., recreational fish abundance) and environmental properties (e.g., water clarity) that would in turn affect delivery of ecosystem services. Different results were observed for different species of fish, thus the decision to manage the use of the insecticide for ecosystem services derived by anglers depends upon the favored species of fish. In our hypothetical shallow reservoir, water clarity was mostly driven by changes in food web dynamics, specifically the presence of zooplankton. In contrast to the complex response by fishing value, water clarity increased with reduced insecticide use, which produced a monotonic increase in value by waders and swimmers. Our study clearly showed the importance of considering nonlinear ecosystem feedbacks where the presence of insecticide changed the modeled food-web dynamics in unexpected ways. Our study highlights one of the main advantages of using ecological models for risk assessment, namely the ability to generalize to meaningful levels of organization and to facilitate quantitative comparisons among alternative scenarios and associated trade-offs among them while explicitly accounting for different groups of beneficiaries.

Os Conundrum: Identifying Symptomatic Sesamoids and Accessory Ossicles of the Foot.

OBJECTIVE. Sesamoids and accessory ossicles are frequently encountered normal osseous structures in the foot that may be an uncommon cause of pain. Familiarity with their imaging findings allows the radiologist to provide reassurance in normal cases and increase confidence when making the relatively uncommon diagnosis of a pathologic sesamoid or symptomatic ossicle. CONCLUSION. Image-guided injections targeted to the symptomatic ossicle can confirm the suspected diagnosis and predict therapeutic outcomes before surgical intervention.

Predicting impacts of chemicals from organisms to ecosystem service delivery: A case study of endocrine disruptor effects on trout.

We demonstrate how mechanistic modeling can be used to predict whether and how biological responses to chemicals at (sub)organismal levels in model species (i.e., what we typically measure) translate into impacts on ecosystem service delivery (i.e., what we care about). We consider a hypothetical case study of two species of trout, brown trout (Salmo trutta; BT) and greenback cutthroat trout (Oncorhynchus clarkii stomias; GCT). These hypothetical populations live in a high-altitude river system and are exposed to human-derived estrogen (17α­ethinyl estradiol, EE2), which is the bioactive estrogen in many contraceptives. We use the individual-based model inSTREAM to explore how seasonally varying concentrations of EE2 could influence male spawning and sperm quality. Resulting impacts on trout recruitment and the consequences of such for anglers and for the continued viability of populations of GCT (the state fish of Colorado) are explored. inSTREAM incorporates seasonally varying river flow and temperature, fishing pressure, the influence of EE2 on species-specific demography, and inter-specific competition. The model facilitates quantitative exploration of the relative importance of endocrine disruption and inter-species competition on trout population dynamics. Simulations predicted constant EE2 loading to have more impacts on GCT than BT. However, increasing removal of BT by anglers can enhance the persistence of GCT and offset some of the negative effects of EE2. We demonstrate how models that quantitatively link impacts of chemicals and other stressors on individual survival, growth, and reproduction to consequences for populations and ecosystem service delivery, can be coupled with ecosystem service valuation. The approach facilitates interpretation of toxicity data in an ecological context and gives beneficiaries of ecosystem services a more explicit role in management decisions. Although challenges remain, this type of approach may be particularly helpful for site-specific risk assessments and those in which tradeoffs and synergies among ecosystem services need to be considered.

Fully Automated Diagnosis of Anterior Cruciate Ligament Tears on Knee MR Images by Using Deep Learning.

PURPOSE: To investigate the feasibility of using a deep learning-based approach to detect an anterior cruciate ligament (ACL) tear within the knee joint at MRI by using arthroscopy as the reference standard. MATERIALS AND METHODS: A fully automated deep learning-based diagnosis system was developed by using two deep convolutional neural networks (CNNs) to isolate the ACL on MR images followed by a classification CNN to detect structural abnormalities within the isolated ligament. With institutional review board approval, sagittal proton density-weighted and fat-suppressed T2-weighted fast spin-echo MR images of the knee in 175 subjects with a full-thickness ACL tear (98 male subjects and 77 female subjects; average age, 27.5 years) and 175 subjects with an intact ACL (100 male subjects and 75 female subjects; average age, 39.4 years) were retrospectively analyzed by using the deep learning approach. Sensitivity and specificity of the ACL tear detection system and five clinical radiologists for detecting an ACL tear were determined by using arthroscopic results as the reference standard. Receiver operating characteristic (ROC) analysis and two-sided exact binomial tests were used to further assess diagnostic performance. RESULTS: The sensitivity and specificity of the ACL tear detection system at the optimal threshold were 0.96 and 0.96, respectively. In comparison, the sensitivity of the clinical radiologists ranged between 0.96 and 0.98, while the specificity ranged between 0.90 and 0.98. There was no statistically significant difference in diagnostic performance between the ACL tear detection system and clinical radiologists at P < .05. The area under the ROC curve for the ACL tear detection system was 0.98, indicating high overall diagnostic accuracy. CONCLUSION: There was no significant difference between the diagnostic performance of the ACL tear detection system and clinical radiologists for determining the presence or absence of an ACL tear at MRI.© RSNA, 2019Supplemental material is available for this article.

Sensitivity analyses for simulating pesticide impacts on honey bee colonies.

We employ Monte Carlo simulation and sensitivity analysis techniques to describe the population dynamics of pesticide exposure to a honey bee colony using the VarroaPop+Pesticide model. Simulations are performed of hive population trajectories with and without pesticide exposure to determine the effects of weather, queen strength, foraging activity, colony resources, and Varroa populations on colony growth and survival. The daily resolution of the model allows us to conditionally identify sensitivity metrics. Simulations indicate queen strength and forager lifespan are consistent, critical inputs for colony dynamics in both the control and exposed conditions. Adult contact toxicity, application rate and nectar load become critical parameters for colony dynamics within exposed simulations. Daily sensitivity analysis also reveals that the relative importance of these parameters fluctuates throughout the simulation period according to the status of other inputs.

Deep Learning Approach for Evaluating Knee MR Images: Achieving High Diagnostic Performance for Cartilage Lesion Detection.

Purpose To determine the feasibility of using a deep learning approach to detect cartilage lesions (including cartilage softening, fibrillation, fissuring, focal defects, diffuse thinning due to cartilage degeneration, and acute cartilage injury) within the knee joint on MR images. Materials and Methods A fully automated deep learning-based cartilage lesion detection system was developed by using segmentation and classification convolutional neural networks (CNNs). Fat-suppressed T2-weighted fast spin-echo MRI data sets of the knee of 175 patients with knee pain were retrospectively analyzed by using the deep learning method. The reference standard for training the CNN classification was the interpretation provided by a fellowship-trained musculoskeletal radiologist of the presence or absence of a cartilage lesion within 17 395 small image patches placed on the articular surfaces of the femur and tibia. Receiver operating curve (ROC) analysis and the κ statistic were used to assess diagnostic performance and intraobserver agreement for detecting cartilage lesions for two individual evaluations performed by the cartilage lesion detection system. Results The sensitivity and specificity of the cartilage lesion detection system at the optimal threshold according to the Youden index were 84.1% and 85.2%, respectively, for evaluation 1 and 80.5% and 87.9%, respectively, for evaluation 2. Areas under the ROC curve were 0.917 and 0.914 for evaluations 1 and 2, respectively, indicating high overall diagnostic accuracy for detecting cartilage lesions. There was good intraobserver agreement between the two individual evaluations, with a κ of 0.76. Conclusion This study demonstrated the feasibility of using a fully automated deep learning-based cartilage lesion detection system to evaluate the articular cartilage of the knee joint with high diagnostic performance and good intraobserver agreement for detecting cartilage degeneration and acute cartilage injury. © RSNA, 2018 Online supplemental material is available for this article .

Fully automated segmentation and quantification of visceral and subcutaneous fat at abdominal CT: application to a longitudinal adult screening cohort.

OBJECTIVE: To investigate a fully automated CT-based adiposity tool, applying it to a longitudinal adult screening cohort. METHODS: A validated automated adipose tissue segmentation algorithm was applied to non-contrast abdominal CT scans in 8852 consecutive asymptomatic adults (mean age, 57.1 years; 3926 M/4926 F) undergoing colonography screening. The tool was also applied to follow-up CT scans in a subset of 1584 individuals undergoing longitudinal surveillance (mean interval, 5.6 years). Visceral and subcutaneous adipose tissue (VAT and SAT) volumes were segmented at levels T12-L5. Primary adipose results are reported herein for the L1 level as mean cross-sectional area. CT-based adipose measurements at initial CT and change over time were analyzed. RESULTS: Mean VAT values were significantly higher in males (205.8 ± 107.5 vs 108.1 ± 82.4 cm2; p < 0.001), whereas mean SAT values were significantly higher in females (171.3 ± 111.3 vs 124.3 ± 79.7 cm2; p < 0.001). The VAT/SAT ratio at L1 was three times higher in males (1.8 ± 0.7 vs 0.6 ± 0.4; p < 0.001). At longitudinal follow-up CT, mean VAT/SAT ratio change was positive in males, but negative in females. Among the 502 individuals where the VAT/SAT ratio increased at follow-up CT, 333 (66.3%) were males. Half of patients (49.6%; 786/1585) showed an interval increase in both VAT and SAT at follow-up CT. CONCLUSION: This robust, fully automated CT adiposity tool allows for both individualized and population-based assessment of visceral and subcutaneous abdominal fat. Such data could be automatically derived at abdominal CT regardless of the study indication, potentially allowing for opportunistic cardiovascular risk stratification. Advances in knowledge: The CT-based adiposity tool described herein allows for fully automated measurement of visceral and subcutaneous abdominal fat, which can be used for assessing cardiovascular risk, metabolic syndrome, and for change over time.

A framework for linking population model development with ecological risk assessment objectives.

The value of models that link organism-level impacts to the responses of a population in ecological risk assessments (ERAs) has been demonstrated extensively over the past few decades. There is little debate about the utility of these models to translate multiple organism-level endpoints into a holistic interpretation of effect to the population; however, there continues to be a struggle for actual application of these models as a common practice in ERA. Although general frameworks for developing models for ERA have been proposed, there is limited guidance on when models should be used, in what form, and how to interpret model output to inform the risk manager's decision. We propose a framework for developing and applying population models in regulatory decision making that focuses on trade-offs of generality, realism, and precision for both ERAs and models. We approach the framework development from the perspective of regulators aimed at defining the needs of specific models commensurate with the assessment objective. We explore why models are not widely used by comparing their requirements and limitations with the needs of regulators. Using a series of case studies under specific regulatory frameworks, we classify ERA objectives by trade-offs of generality, realism, and precision and demonstrate how the output of population models developed with these same trade-offs informs the ERA objective. We examine attributes for both assessments and models that aid in the discussion of these trade-offs. The proposed framework will assist risk assessors and managers to identify models of appropriate complexity and to understand the utility and limitations of a model's output and associated uncertainty in the context of their assessment goals. Integr Environ Assess Manag 2018;14:369-380. Published 2017. This article is a US Government work and is in the public domain in the USA.

A framework for predicting impacts on ecosystem services from (sub)organismal responses to chemicals.

Protection of ecosystem services is increasingly emphasized as a risk-assessment goal, but there are wide gaps between current ecological risk-assessment endpoints and potential effects on services provided by ecosystems. The authors present a framework that links common ecotoxicological endpoints to chemical impacts on populations and communities and the ecosystem services that they provide. This framework builds on considerable advances in mechanistic effects models designed to span multiple levels of biological organization and account for various types of biological interactions and feedbacks. For illustration, the authors introduce 2 case studies that employ well-developed and validated mechanistic effects models: the inSTREAM individual-based model for fish populations and the AQUATOX ecosystem model. They also show how dynamic energy budget theory can provide a common currency for interpreting organism-level toxicity. They suggest that a framework based on mechanistic models that predict impacts on ecosystem services resulting from chemical exposure, combined with economic valuation, can provide a useful approach for informing environmental management. The authors highlight the potential benefits of using this framework as well as the challenges that will need to be addressed in future work. Environ Toxicol Chem 2017;36:845-859. © 2017 SETAC.

Agent-based model for Johne's disease dynamics in a dairy herd.

Johne's disease is an infectious gastrointestinal disease in ruminants caused by Mycobacterium avium subsp. paratuberculosis that causes diarrhea, emaciation, decreased milk production and eventually death. The disease is transmitted in utero and via milk and colostrums to calves, and fecal-orally to all age classes. Financial losses due to the disease are estimated to be over $200 million in the US dairy industry. The goal of this study was to evaluate the cost effectiveness of control measures based on diagnosis with a sensitive ELISA, EVELISA. An agent-based, discrete time model was developed to simulate Johne's disease dynamics in a US dairy herd. Spatial aspects of disease transmission were taken into account by using six spatial compartments. The effects on disease prevalence were studied with and without transmission routes included in the model. Further, using the model, cost effectiveness of ELISA-based Johne's disease control was evaluated. Using the parameters we collected and assumed, our model showed the initial prevalence of Johne's disease (33.1 ± 0.2%) in the farm increased to 87.7 ± 1.7% in a 10 year-simulation. When ELISA-based control measures were included in the simulation, the increase in prevalence was significantly slowed down, especially when EVELISA was used. However, the level of the prevalence was still higher than the initial level after 10 year simulation even with the ELISA-based diagnostic intervention. The prevalence was further reduced when quarterly ELISA testing was included. The cost analysis showed that the quarterly ELISA and EVELISA testing could bring $44.8 and $51.5/animal/year more revenues, respectively, to a dairy farm.

Overcoming Allee effects through evolutionary, genetic, and demographic rescue.

Despite the amplified threats of extinction facing small founder populations, successful colonization sometimes occurs, bringing devastating ecological and economic consequences. One explanation may be rapid evolution, which can increase mean fitness in populations declining towards extinction, permitting persistence and subsequent expansion. Such evolutionary rescue may be particularly important, given Allee effects. When a population is introduced at low density, individuals often experience a reduction in one or more components of fitness due to novel selection pressures that arise from diminished intraspecific interactions and positive density dependence (i.e. component Allee effects). A population can avoid extinction if it can adapt and recover on its own (i.e. evolutionary rescue), or if additional immigration sustains the population (i.e. demographic rescue) or boosts its genetic variation that facilitates adaptation (i.e. genetic rescue). These various forms of rescue have often been invoked as possible mechanisms for specific invasions, but their relative importance to invasion is not generally understood. Within a spatially explicit modelling framework, we consider the relative impact of each type of rescue on the probability of successful colonization, when there is evolution of a multi-locus quantitative trait that influences the strength of component Allee effects. We demonstrate that when Allee effects are important, the effect of demographic rescue via recurrent immigration overall provides the greatest opportunity for success. While highlighting the role of evolution in the invasion process, we underscore the importance of the ecological context influencing the persistence of small founder populations.

Do invasive species perform better in their new ranges?

A fundamental assumption in invasion biology is that most invasive species exhibit enhanced performance in their introduced range relative to their home ranges. This idea has given rise to numerous hypotheses explaining "invasion success" by virtue of altered ecological and evolutionary pressures. There are surprisingly few data, however, testing the underlying assumption that the performance of introduced populations, including organism size, reproductive output, and abundance, is enhanced in their introduced compared to their native range. Here, we combined data from published studies to test this hypothesis for 26 plant and 27 animal species that are considered to be invasive. On average, individuals of these 53 species were indeed larger, more fecund, and more abundant in their introduced ranges. The overall mean, however, belied significant variability among species, as roughly half of the investigated species (N=27) performed similarly when compared to conspecific populations in their native range. Thus, although some invasive species are performing better in their new ranges, the pattern is not universal, and just as many are performing largely the same across ranges.

Using network properties to predict disease dynamics on human contact networks.

Recent studies have increasingly turned to graph theory to model more realistic contact structures that characterize disease spread. Because of the computational demands of these methods, many researchers have sought to use measures of network structure to modify analytically tractable differential equation models. Several of these studies have focused on the degree distribution of the contact network as the basis for their modifications. We show that although degree distribution is sufficient to predict disease behaviour on very sparse or very dense human contact networks, for intermediate density networks we must include information on clustering and path length to accurately predict disease behaviour. Using these three metrics, we were able to explain more than 98 per cent of the variation in endemic disease levels in our stochastic simulations.

Allee effects, adaptive evolution, and invasion success.

The mechanisms that facilitate success of an invasive species include both ecological and evolutionary processes. Investigating the evolutionary dynamics of founder populations can enhance our understanding of patterns of invasiveness and provide insight into management strategies for controlling further establishment of introduced populations. Our aim is to analyze the evolutionary consequences of ecological processes (i.e., propagule pressure and threshold density effects) that impact successful colonization. We address our questions using a spatially-explicit modeling approach that incorporates dispersal, density dependent population growth, and selection. Our results show that adaptive evolution may occur in small or sparse populations, providing a means of mitigating or avoiding inverse density dependent effects (i.e., Allee effects). The rate at which this adaptation occurs is proportional to the amount of genetic variance and is a crucial component in assessing whether natural selection can rescue a population from extinction. We provide theoretical evidence for the importance of recognizing evolution in predicting and explaining successful biological invasions.

In vivo reprogramming of adult pancreatic exocrine cells to beta-cells.

One goal of regenerative medicine is to instructively convert adult cells into other cell types for tissue repair and regeneration. Although isolated examples of adult cell reprogramming are known, there is no general understanding of how to turn one cell type into another in a controlled manner. Here, using a strategy of re-expressing key developmental regulators in vivo, we identify a specific combination of three transcription factors (Ngn3 (also known as Neurog3) Pdx1 and Mafa) that reprograms differentiated pancreatic exocrine cells in adult mice into cells that closely resemble beta-cells. The induced beta-cells are indistinguishable from endogenous islet beta-cells in size, shape and ultrastructure. They express genes essential for beta-cell function and can ameliorate hyperglycaemia by remodelling local vasculature and secreting insulin. This study provides an example of cellular reprogramming using defined factors in an adult organ and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.