Profiling of whole transcriptomes has become a cornerstone of molecular biology and an invaluable tool for the characterization of clinical phenotypes and the identification of disease subtypes. Analyses of these data are becoming ever more sophisticated as we move beyond simple comparisons to consider networks of higher-order interactions and associations. Gene regulatory networks (GRNs) model the regulatory relationships of transcription factors and genes and have allowed the identification of differentially regulated processes in disease systems. In this perspective, we discuss gene targeting scores, which measure changes in inferred regulatory network interactions, and their use in identifying disease-relevant processes. In addition, we present an example analysis for pancreatic ductal adenocarcinoma (PDAC), demonstrating the power of gene targeting scores to identify differential processes between complex phenotypes, processes that would have been missed by only performing differential expression analysis. This example demonstrates that gene targeting scores are an invaluable addition to gene expression analysis in the characterization of diseases and other complex phenotypes. A core tenet of molecular biology is that phenotypic differences are reflected through patterns of differential expression of key genes involved in relevant biological processes. Since its inception, whole-genome transcript profiling has been an invaluable tool for exploring these associations and has been used in a range of applications, including identification of clinically relevant molecular subtypes in cancer exhibiting different morbidities and implications for treatment together with characteristic genes associated with these phenotypes . Studiesrelationships within a system rather than simply the state of individual components. This is an important distinction, as can be illustrated with a small toy example first described in differentially co-expressed between groups. For example, in healthy individuals, gene G1 is co-expressed with gene G2 , several studies have used expression profiling to identify molecular subtypes subtypes . HoweverIn 2013, PANDA has been used to investigate gene regulatory relationships in several disease contexts, including chronic obstructive pulmonary disease (COPD) , asthma The use of GRNs in the analysis of disease relies on analysis of the “gene targeting score,” a numerical score representing the extent to which a gene is targeted by TFs in a given biological context. The gene targeting score is calculated by summing the weights of all inbound regulatory edges for a gene . BecauseA study of COPD by PDAC is a lethal disease involving heterogeneous tumors composed of diverse cell types including tumor epithelial cells and components of the tumor microenvironment such as immune cells and fibroblasts. Molecular subtypes of PDAC have been identified through gene expression analysis , and theTo identify factors driving these subtypes, we compared differential gene expression and differential GRN gene targeting scores between basal-like and classical subtypes of 150 PDAC tumors using TCGA  transcriThe three genes found to be most significantly differentially targeted in GRNs, but not differentially expressed, between basal-like and classical subtypes are folate receptor beta (FOLR2), hedgehog interacting protein (HHIP), and the CD209 antigen C-type lectin domain family 4 member L (CD209). FOLR2 encodes the folate receptor 2 protein and is known to be overexpressed in tumor-associated macrophages . HHIP coRanking genes according to three different metrics, differential targeting, differential co-expression, and differential expression, we performed ranked gene set enrichment analysis  to identThe identification of keratinization as enriched in differentially expressed genes is consistent with previous studies that identified genes encoding keratins and laminins as biomarkers for basal-like tumors . The facThis analysis of PDAC subtypes, although abbreviated, demonstrates the power of using GRN inference and gene targeting score analysis to identify regulatory processes that characterize distinct phenotypes—including processes that are distinct from those that are associated with patterns of gene expression. The biologically relevant differences we see in targeting but not expression or co-expression suggest that regulatory control, even if not activated, is important in defining health and disease.There is growing experimental evidence of the importance of complex regulatory processes in distinguishing phenotypes in health and disease. For example, the Wilms tumor-1 (WT1) TF is a master regulator that targets several essential genes in kidney podocyte cells. Taken together, the results reported by Ettou and Carnesecchi illustrate the complexity of regulatory processes and the importance that regulatory targeting plays in defining phenotype, even in instances in which a key regulator does not itself substantially change in its expression levels. Their results also point to the importance of modeling both “direct” and “indirect” regulation of genes by TFs and the complexes they form. Among the methods for GRN inference, PANDA  is singular in considering interactions between TF proteins in its model. PANDA’s integrative approach using TF–TF interactions, predicted TF–gene regulatory relationships, and gene co-expression data, refines the inputs to optimize agreement between them; the resulting networks provide unique insight into regulatory processes that are linked to phenotypes.The work summarized in this perspective demonstrates the value of the gene targeting score as a metric for assessing the drivers of phenotypic differences. Gene targeting scores not only capture structural characteristics of regulatory networks but also allow for the identification of processes that may be activated in response to appropriate stimuli and in this way help to define phenotypes and disease subtypes. For example, Our application of PANDA and LIONESS in comparing PDAC subtypes demonstrates the value of the GRN-based approach and of using network-based metrics such as gene targeting to characterize properties of biological systems. We constructed sample-specific GRNs for 150 PDAC tumors and used gene targeting to compare the topologies of networks derived from basal-like and classical tumor subtypes. We found that differential targeting analysis identified compelling differences between the two subtypes in the regulation of processes related to cell cycle, immune, and epigenetic functions, none of which were seen in a standard differential expression analysis. Given that PDAC tumors are known to exhibit immune infiltration, and that the subtypes differ in both their epigenetic landscapes and patient survival, our identification of relevant processes illustrates how GRN-based methods can provide important and relevant biological insights into disease-associated processes beyond what is seen using other analytical methods.PANDA and LIONESS software for GRN analyses and identification of differential targeting are freely available as open-source tools with extensive documentation (netzoo.github.io) and can easily be implemented in most analytical workflows. We hope that this review motivates the broader use and appreciation of gene targeting analysis.https://jhubiostatistics.shinyapps.io/recount/). We provide an interactive Jupyter notebook hosted in netbooks (netbooks.networkmedicine.org) to reproduce the differential targeting analysis and the PDAC gene regulatory networks are available in GRAND database (https://grand.networkmedicine.org/cancers).Publicly available data analyzed in this study were obtained from recount2 (DW drafted the manuscript and performed the analysis. All authors discussed, planned, reviewed and edited the manuscript.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.


This paper reviews developments in climate science and hydrological modelling studies in Zimbabwe over the past 29 years in an effort to expose knowledge gaps within this research domain. We initially give a global and regional overview and then follow a systematic thematic approach in reviewing specifically online published, peer-reviewed journal articles on climate change/variability and hydrological modelling in Zimbabwe. The state and progress towards advanced integrated climate and hydrological modelling research are assessed, tracking benchmarks in the research methodologies (tools and techniques) used therein including geographic information systems and remote sensing. We present descriptive summaries of key findings, highlighting the main study themes (categories) and general conclusions arising from these studies while examining their implications for future climate and hydrological modelling research in Zimbabwe. Challenges associated with climate and hydrological modelling research in Zimbabwe are also briefly discussed and the main knowledge gaps in terms of research scope and methodologies employed in the reviewed studies also exposed. We conclude by presenting plausible potential areas of focus in updating and advancing scientific knowledge to better understand the climate-land use-hydrology nexus in Zimbabwe. While this paper is primarily relevant for researchers, the general findings are also important for policy-makers since it exposes potential areas for policy intervention or agenda setting in as far as climate and hydrology science research is concerned so as to effectively address pertinent questions in this domain in Zimbabwe. A review of global climate changes since 1700 has revealed that over the centuries, twenty climatic events covering continental-scale temperature fluctuations, hydroclimatic anomalies, stratospheric perturbations and general atmospheric composition changes have occurred, impacting millions of people in many ways . As suchIn developing countries in Africa for example, where the impacts of climate system changes are predicted to be manifest in more uncertain terms –37, expaDespite all the advances made in the aforementioned studies, knowledge gaps are well acknowledged particularly considering the inherent uncertainties in the new developments in climate science/modelling and climate impact assessment techniques . Tools aFurthermore, considering the acknowledgement of spatio-temporal land use and land cover change (LULCC) as an important factor (with both direct and indirect implications) on hydrological systems –64, atteWe adopted a systematic search for relevant peer-reviewed literature from a range of databases searched using Google Scholar (GS) search engine leveraging its strength of cataloguing 100 million records of academic literature and most importantly being able to competently find potentially valuable grey literature  . We alsoClimate change refers to a statistically significant variation in either the mean state of the climate or in its variability, persisting for an extended period  due to natural internal processes or external forcings, or persistent anthropogenic changes in the composition of the atmosphere or in land use . Most scFindings by the Inter-governmental Panel on Climate Change (IPCC) experts –88 and ovis-à-vis the spatio-temporal dynamics of climatic events such as the El Niño-Southern Oscillation (ENSO). Among other conclusions drawn, all these have revealed a need for pragmatic policy development buttressed by sound scientific evidence to guide mitigation and adaptation strategies especially in developing countries such as Zimbabwe [Climate vulnerability describes the degree to which a system is susceptible to, and unable to cope with, adverse effects of climate change and variability and extremes . It is aZimbabwe .Climate in Zimbabwe is highly variable  and thusFigure One prominent study shown in Table On rainfall variability, studies have revealed that inter-annual rainfall variability in the country are largely influenced by external forcing of a near-global or hemispheric origin such the ENSO, the Inter-tropical Convergence Zone (ITCZ) to the North and the westerly cloud-bands to the south rather than regional or local-scale factors –119. On Within the general climate studies reviewed in this paper, the predominant area of focus has been understanding the rainfall dynamics , 125 witin situ climatic data such as rainfall and temperature measurements. Furthermore, where such data is available, often it is incomplete due to poor distribution and investment in necessary infrastructure/facilities to observe important climatic phenomena. Other data access challenges relate to (1) inaccessibility due to bureaucratic red-tapes and prohibitive costs for long-term climatic datasets charged by government agencies such as the Meteorological Department, (2) inconsistent and poor spatial coverage which often renders it of limited use in climate research in the country. This is also confirmed by Gumindoga et al. [. [While advances in climate research have seen the move towards the use of GIS and RS/Earth observation (EO) technology to (1) augment climate data series, and (2) assist in better and advanced analyses of climate dynamics in space and time globally –138 and a et al.  who notea et al. , Dlaminia et al. , Kamusoka et al.  and Mpalt al. [.  have expClimate modelling science is a highly active field of research with rapid advancements in knowledge marked and driven by rapid developments in the tools and techniques (models) used in this domain. Two main types of models, i.e. Global Climate Models (GCMs) and Regional Climate Models (RCMs), are used in climate modelling studies. GCMs are numerical tools/models representing physical processes in the atmosphere, ocean, cryosphere and land surface used for simulating the response of the global climate system to increasing greenhouse gas concentrations . ExampleTo resolve the shortcomings of GCMs, downscaling techniques –166 haveNumerous climate modelling studies have been done both at global and regional scale in an effort to better understand the past, present and future climate dynamics in space and time. While significant progress has been realised in global climate modelling science, e.g. , 171–174On the contrary, downscaled RCMs have demonstrated more competence in simulating local climatic conditions compared to GCMs , 177–180Despite the advances in climate modelling science globally and regionally as earlier alluded to, the scope of climate modelling research in Zimbabwe has been rather limited. Of the 107 prominent climate studies done in Zimbabwe (covered in this review), only 8% of these directly and indirectly involved climate modelling at some level as earlier shown in Fig. From all these reviewed modelling studies, most used GCM simulations directly, which could have had negative implications on the accuracy of their findings due to the known inherent limitations of GCMs application at a local level. A few exceptions such as Pedersen et al.  and Moyovis-à-vis all the earlier mentioned factors. Of note has been the widespread use of climate model simulations (from both GCMs and RCMs) in climate impact models to explore how natural and human systems may be affected by climate change [A number of climate scholars have explored the impacts of climate change and/or variability on various natural and human systems , 207–210e change , 155. The change .While these impacts are well acknowledged to be more devastating in vulnerable communities in developing countries due to their weak institutional arrangements and policies for resilience and adaptation , climateIn this review, 52 of the 107 39%) climate studies done in Zimbabwe over the past 29 years were found to be climate impact studies as earlier alluded to. Table 9% climatSome of the emerging general conclusions from the reviewed impact studies are presented hereon. Climate-agricultural impact studies generally revealed that smallholder agricultural production is significantly constrained by high temperature and low rainfall in Zimbabwe  and thatAs earlier presented, there are other emerging themes related to ecosystem impacts . MatarirSome researchers in Zimbabwe such as Cobo et al.  and DaviRelative to these developments in methodologies in climate impact studies, there has been an increase in the integration of indigenous knowledge systems in climate research in Zimbabwe over the past decade. These studies have chattered a new frontier in climate research aimed at understanding aspects such as seasonal climate forecasts –259 and Hydrological models are representative simplifications of complicated hydrological processes using mathematical means to demonstrate the principal elements of the processes, their combination and function as a comprehensive hydrologic system . These hvis-à-vis human activities in Korea [As alluded to earlier on, over the years, GIS and RS techniques have become indispensable in most state-of-the-art hydrological models premising on the extensive spatio-temporal data capture and analysis capabilities of these technologies. Three main applications of RS in hydrological modelling presented in numerous studies can be summarised as, (1) model parameter estimation with the aid of multi/hyper-spectral satellite data; (2) computation of historic monthly runoff using satellite data as input; and (3) real-time flood forecasting using radar rainfall measurements as input , 281. Inin Korea , monitorin Korea , 290 andin Korea , 291–293in Korea . In Afriin Korea , 295–299in Korea , and Troin Korea , 301. AlTo this end, in the face of considerable uncertainty in determining water availability/security relative to climate and land use-land cover changes which impact of hydrologic conditions, it is critical for water resources managers and decision makers to have a better and simplified understanding of past, present and ideally future hydrological processes dynamics/scenarios through sound water resources studies (which leverage GIS and Remote sensing technology) .abcd model [Of the 107 studies reviewed in this study, 7% directly and indirectly involved hydrological modelling, indicating very limited hydrological modelling research in Zimbabwe over the period under review. Hydrological modelling studies in Zimbabwe date back to 1986 when Knudsen et al.  tested tcd model  and the cd model  to estimcd model  and the cd model . The flocd model  has beenA review of the scope of coverage of these studies revealed that all seven water catchments in Zimbabwe . Furthermore, considering that the global and regional climate forecasts indicate worsening of conditions, it is thus very important that climate science in Zimbabwe is updated to generate new and contextual knowledge leveraging on cutting edge recently developed tools and techniques rather than rely on outdated conclusions from past studies to inform climate policy formulation and strategy development for the country.Furthermore, in this review, it emerged that climate modelling research is still a largely grey area in Zimbabwe. Most past studies have used GCMs and only a few have used RCMs with limited to no bias corrections and due consideration of the region-specific nature of most of these models. The implication of this are potential biases and errors and thus limited local applicability of some of their findings considering also recent developments and cautions in application of these tools at a local scale. This, thus, necessitates further expansion of knowledge on the same by leveraging on the potential presented by new and advanced Southern Africa regions-specific GCMs and RCMs such as the CCAM which have the ability to generate accurate climate perturbations at regional and local scale through advanced downscaling and bias correction techniques. New studies could expand knowledge by modelling impact scenarios within agriculture, biodiversity and hydrology such as surface run-off which influences overall water availability and thus security in Zimbabwe. Advancing knowledge in this regard will be vital especially for identifying, for example, the hydrologic consequences of changes in important climatic variables such as temperature, precipitation, and other landscape variables such as land use-land cover. This could contribute to holistic policy development and effective planning of current and future water management and security interventions. Furthermore, highly prohibitive costs of in situ current and historic climate and hydrological data imposed by governmental agencies such as the Zimbabwe National Water Authority (ZINWA) and the Meteorological Services Department are noted to be one of the potential serious bottlenecks impeding climate science research in the country. It is therefore important for the Government of Zimbabwe to address this by coming up with more pragmatic data-access policies that will make climate datasets more easily available and accessible to the Zimbabwean scientific community so as to encourage more research. This will allow for unhindered fast progress or advancement of climate science research in Zimbabwe, exploiting also the available national supercomputing capabilities at the ZCHPC.vis-à-vis the already acknowledged highly vulnerable climate of Zimbabwe and the predicted worsening future climatic conditions in the country, it thus becomes very critical that deliberate efforts cascading from policy level, prioritise climate-hydrology modelling research in Zimbabwe. This is because all these aspects speak to present and future sustainable development in terms of water security and livelihoods.Hydrological modelling is a relatively grey area of research in Zimbabwe with very few studies reviewed herein covering this research domain. Of the seven water catchments in Zimbabwe, the Manyame and the Mazowe catchments have received most attention as frontiers of hydrological modelling research in Zimbabwe whilst the Gwayi, the Runde, the Save and the Sanyati catchments have had least coverage. While some hydrological modelling research has been done on the Mzingwane catchment, the scientific knowledge is outdated, i.e. has been outpaced by advances in techniques and tools developed and used in this domain over the past two decades globally. With such knowledge gaps, Regarding the types of models, there is generally a need to test or apply new/advanced coupled hydrological models to better understand interlinkages between climate-hydrology and land use in Zimbabwe to update existing knowledge to be abreast with global and regional developments within this domain. In order to achieve this, approaches encompassing coupling of distributed hydrological models and properly downscaled GCM/RCM simulations as advocated for by various researchers should be considered. Such approaches could enhance understanding of local feedback mechanisms and interrelations between key natural-human systems influencing community livelihoods which is a specialised area of research within this domain. Furthermore, we note a relatively new and important frontier of climate-hydrology research, i.e. integration of indigenous knowledge systems (IKS) in the context of climate adaptation and mitigation in Zimbabwe which has to be encouraged and streamlined within this domain.Overall, we conclude that climate science and hydrological modelling research in Zimbabwe is lagging behind vis-à-vis global and regional developments within these domains and thus the need to adopt a more systematic and holistic approach exploiting among other tools and techniques, coupled systems-based approaches  for better understanding of past, present and future climatic conditions and their hydrological impacts. This should be done without negating the need of developing new and/or fine-tuning the existing climate related and other relevant policy, legislative and institutional frameworks in Zimbabwe.


This review summarizes currently available literature for or against a role of AMPK in MET-mediated protection against DOX cardiotoxicity. It also highlights the emerging evidence suggesting distinct roles of the AMPK subunit isoforms in mediating the functions of unique AMPK holoenzymes composed of different combinations of isoforms. Moreover, the review provides a perspective regarding future studies that may help fully elucidate the relationship between MET, AMPK and DOX cardiotoxicity.Doxorubicin (DOX) is an extremely effective and wide-spectrum anticancer drug, but its long-term use can lead to heart failure, which presents a serious problem to millions of cancer survivors who have been treated with DOX. Thus, identifying agents that can reduce DOX cardiotoxicity and concurrently enhance its antitumor efficacy would be of great clinical value. In this respect, the classical antidiabetic drug metformin (MET) has stood out, appearing to have both antitumor and cardioprotective properties. MET is proposed to achieve these beneficial effects through the activation of AMP-activated protein kinase (AMPK), an essential regulator of mitochondrial homeostasis and energy metabolism. AMPK itself has been shown to protect the heart and modulate tumor growth under certain conditions. However, the role and mechanism of the hypothesized MET-AMPK axis in DOX cardiotoxicity and antitumor efficacy remain to be firmly established by  This mini-review will extract evidence from currently available literature for or against a role of AMPK in MET-mediated protection against DOX cardiotoxicity. For the effects of MET and AMPK in antitumor therapies, the readers are referred to other review articles published elsewhere (The anthracycline doxorubicin (DOX) has been widely used for over 5 decades and is a highly effective chemotherapeutic agent for the treatment of a broad spectrum of cancers including various solid tumors and leukemia. Unfortunately, DOX chemotherapy can cause severe cardiotoxic effects –3. Acutelsewhere –24.per se  including superoxide anions . Apparently, further clinical trials are needed to confirm the cardioprotective effects of MET in cancer patients treated with DOX. MET has been suggested to antagonize DOX cardiotoxicity through several mechanisms (left panel in Metformin (MET) is an oral biguanide agent that was first utilized to treat diabetes in France in 1957  and apprper se should improve the application of DOX in antitumor therapy.Several epidemiological studies, meta-analyses and animal studies have revealed that MET has anti-neoplastic and chemopreventive activities , 81 despin vivo.AMP-activated protein kinase (AMPK) is a heterotrimeric protein kinase composed of a catalytic α subunit and two regulatory subunits (β and γ). Each subunit has multiple isoforms encoded by distinct genes , and they combine to form 12 different AMPK holoenzymes . All isoin vivo in immunodeficient mice  to QL and a research grant from the American Osteopathic Association  to TN.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Diabetic macular oedema (DMO) is an important cause of moderate vision loss in people with diabetes. Advances in imaging technology have shown that a significant proportion of patients with DMO respond sub-optimally to existing treatment options. Identifying associations and predictors of response before treatment is initiated may help in explaining visual prognosis to patients and aid the development of personalized treatment strategies. Imaging features, such as central subfoveal thickness, photoreceptor integrity, disorganization of retinal inner layers, choroidal changes, and macular perfusion, have been reported to be prognostic factors of visual acuity (VA) in DMO. In this review we evaluated each risk factor to understand their relative importance in visual prognostication of DMO eyes post-treatment. Although individually, some of these factors may not be significant predictors, in combination they may form phenotypes that can inform visual prognosis. Stratification based on these phenotypes needs to be developed to progress to personalized medicine for DMO. Diabetic macular oedema (DMO) is the most frequent cause of moderate vision loss in people with diabetes. In 2019, there were approximately 28 million people with DMO globally . ExpectaPresenting VA is a definite prognostic marker. However, there are some caveats. Firstly, ceiling effect in eyes with good VA means that change in VA is not a good indicator of visual outcome in this group and the outcome in these eyes needs to focus on prevention of visual loss. Secondly, eyes with new-onset CI-DMO do not always present with visual impairment. However, if left untreated, visual deterioration may occur in some of these eyes. In DRCR Protocol V trial, 18.6% of eyes with good vision at presentation had a reduction of VA by 10 ETDRS letters or more after an observation period of 2 years and needed injections . The exaOn the contrary, in DMO eyes with visual impairment of 6/12 or worse (Snellen), baseline VA is a predictor of response to anti-VEGF treatment. The RESTORE study showed that patients with poorer starting VA had greater gains in VA with ranibizumab than those with better presenting VA . The posA decrease in CST on OCT is the most reliable objective measure of anatomical treatment response of DMO. It is also the most common secondary anatomical outcome measure used to substantiate primary visual outcomes in clinical trials on interventions for DMO. However, reduction of CST does not mirror final VA outcome and is not a definite predictor of VA ,14,15,16There are several OCT morphological phenotypes of DMO. These include diffuse retinal thickening (DRT), cystoid macular oedema (CMO) and neurosensory detachment (NSD) . These mHowever, association of cysts with other OCT features determine visual outcome. Cysts that are associated with photoreceptor damage negatively affect visual outcomes ,23,24. ISubretinal fluid (SRF) accumulation has been reported to be present in 15–30% of eyes with DMO . The prePhotoreceptors may be affected by the overlying capillary non-perfusion or continual fluid accumulation can secondarily affect the outer layers ,40. EnhaMicroperimetry data have revealed that loss of EZ may lead to 3.28 dB reduction in retinal sensitivity . Some auDot-like hyperreflective lesions within retinal layers have been described in OCT of DMO eyes, known as hyperreflective foci or dots (HRF/ HRD). These HRF have been proposed as lipoprotein exudates which pass into the interstitium after a breach in the inner blood-retinal barrier, and may possibly be precursors of hard exudates ,54. HypeA reduction of HRF has been seen with anti-VEGF injections ,60. The In summary, HRFs seem to be a bridge between the subclinical breakdown of the inner blood–retina barrier and the clinical swelling of retinal layers, and may indicate microvascular damage. However, more research is required to understand its relevance as a visual prognostic indicator . MoreoveDisorganization of inner retinal layers (DRIL) is believed to be a secondary morphological change of the retina when the synaptic connections in the bipolar, horizontal and amacrine cells are affected, leading to loss of transmission between the inner retina and outer retina . In DMO,DRIL has been proposed as a robust and surrogate biomarker of visual function in existing or resolved DMO ,74. DRILDRIL at the parafoveal area may be associated with a worse baseline VA in DMO eyes. Presence of DRIL at initiation of treatment, new-onset DRIL or increase in DRIL have all been reported as poor prognostic indicator of visual outcome in DMO eyes ,82,83. RIt is important that DRIL reversal be re-examined. However, these findings show that there may be a minimum area of DRIL required before visual function is affected. Reversal of DRIL is suggestive of decompression of the retina or realignment of neuronal and glial cells after transient disorganization in DMO. The definition or grading of DRIL in eyes with DMO may be challenging. Previous studies have assessed DRIL using SDOCT imaging via a Heidelberg Spectralis system , using a standard imaging protocol of 49 B-scans spanning a 20 × 20 frame in high-resolution mode . InvestiThere are contradicting reports on the changes in choroidal thickness and DMO. Firstly, investigators have shown increased choroidal thickness in DMO in keeping with the fact that choroidal vasculature is dependent on VEGF . A higheOptical coherence tomography angiography (OCTA) is a noninvasive technique by which signals detected from blood flow in retinal and choroidal vasculature can be used to yield blood flow maps and quantify retinal perfusion in all vascular layers of the retina and the choroid . CurrentMacular oedema may affect the reproducibility and effectiveness of OCTA in the measurement of FAZ area, perimeter and circularity, flow in CC and vascular density (VD) indices, especially in DCP ,107. NonRISE/RIDE study data suggest that anti-VEGF is efficacious in DMO irrespective of macular perfusion status at baseline . There iThe role of macular perfusion in final visual prognosis is certain but the best parameter to measure macular perfusion on OCT-A remains to be understood.The association of baseline diabetic retinopathy severity score (DRSS) score with visual outcome of patients with CI-DME is also of interest. Patients who show a limited early response to treatment may have better baseline VA, thinner CMT and lesser severity of diabetic retinopathy . The oveThere is significant evidence that systemic risk factors such as hyperglycaemia, hypertension and hyperlipidemia need to be optimally controlled before and after the onset of DMO and this needs to be emphasized to each patient. However, people with optimally controlled systemic risk factors do develop visual impairment due to DMO and some with poorly controlled risk factors do not develop DMO throughout their whole diabetes history. There is insufficient evidence that suboptimal control of any of these systemic risk factors influences visual prognosis due to DMO. These observations suggest that local ocular features are relatively more important in determining the visual status of eyes with DMO.This review on factors determining visual impairment in DMO or visual prognostic factors in eyes post-treatment suggest the need for a systematic evaluation of both subjective and objective definite predictive factors in a well characterized cohort of sufficient sample size. The relative importance of these factors is unclear. Baseline VA is an important predictor of final visual gain, and patients need to be treated early, to prevent irreversible VA loss. However, even if patients present with visual loss at a later stage, initiating prompt treatment may still help preservation of remaining vision. OCT has significant importance in deciding initiation and continuation of treatment in DMO eyes. Although a change in central subfoveal thickness is a secondary outcome in clinical trials and is used for monitoring anatomical treatment response, it is not a visual prognostic indicator. Ultrastructural features, such as photoreceptor integrity and the presence of DRIL, may serve as better prognostic indicators. Although poor macular perfusion is likely to have a negative impact, further studies on it are required to ascertain the best parameter to measure macular perfusion. Systemic factors do not seem to have a significant role as a visual prognostic indicator. Although individual factors may not be of significance, the combination of these may form response phenotypes that are of prognostic significance. Prognostic models on visual impairment should be developed before personalised medicine can be provided for patients with DMO.


Phone-based interviews present a range of ethical challenges, including how to ensure informed consent and privacy and maintain confidentiality. Our paper presents conceptual and practical ethical considerations taken into account across three telephone studies on the impact of COVID-19 conducted following India’s nationwide lockdown imposed in March 2020. Two studies captured COVID-19 response impact on primary-level Reproductive Maternal Neonatal and Child Health (RMNCH) services and on provider wellness, respectively. The third study focused on how the gendered experience of COVID-19 and the state’s response to control transmission impacted women’s lives, focusing on health services, livelihood, entitlements and social change, by interviewing individual women. The ethical challenges as well as the advantages of digital data collection are presented with recommendations for low-resource settings. Ethical considerations included the above challenges as well as avoiding posing unreasonable time burden on the respondents, framing questions with a gendered lens, considering emotional states given contagion concerns and economic uncertainties, and redressing pandemic-induced distress. Using scripted Hindi was challenging in consent-taking, as was protecting household respondents’ privacy and confidentiality during lockdown. Unanticipated positive ethical implications of using a telephone approach included providing respondents privacy and catharsis, respondents choosing convenient interview times and affording health providers more privacy than institutional inperson interviews. Internalising empathy, respect and appreciative enquiry are key to establishing rapport in the absence of prior relationships. Institutional Review Board (IRB) time limits on call duration need to be flexible to allow for ‘active listening’ and empathetic enquiry in surveys on the impact of COVID-19. Phone-based studies under COVID-19 face numerous ethical challenges around ensuring consent and confidentiality, protecting respondents’ privacy and accessing vulnerable populations.Collecting data telephonically can have unanticipated and positive advantages over in- person data collectionIRB panels need to rapidly develop flexible guidelines that enable remote data collection in a timely manner and that take pandemic conditions and stresses into account.Public health emergencies necessitate rapid research to inform policymakers and align response efforts with evolving population needs.3Phone-based data collection presents a unique set of ethical challenges around consent, confidentiality, representativeness, data quality and respondents’ privacy, posing conceptual and practical considerations.4The absence of visual cues in telephone interviews can affect data quality owing to loss of rich non-verbal data.7The gender gap in phone ownership as well as the social constraints in their use or accessMuch of the existing literature on the ethics of digital research methods focuses on the global West. Studies that explore improving the efficacy of phone-based data collection in LMICs also emanate from the global West and focus on quantitative methods-oriented technological tools.In March 2020 India imposed a nationwide lockdown, which required our data collection to pivot to phone-based studies of the impact of COVID-19. These included two facility provider studies: an ongoing facility ethnography study that shifted from inperson fieldwork at two primary care facilities to phone interviews with providers,The facility ethnography study was part of a learning exercise to understand contextual factors shaping provider practices at primary-level facilities. The study was conducted as part of the Oxford Policy Management’s ongoing work providing learning and evaluation support to the Bill and Melinda Gates Foundation’s health system strengthening programmes in Bihar. The study initially involved embedding two three-person teams at two facilities, in four sequential rounds of data collection (2019–2020). This study shifted to phone interviews to understand the primary health system response, the impact of COVID-19 on services and the workforce challenges. In chronicling the evolving situation, the team sought to understand the health system’s adaptive capacity and resilience to inform COVID-19 response and recovery.The COVID-19 provider study, a state-wide phone survey of a sample of primary-level health providers at 95 public facilities across 95 blocks , aimed to understand COVID-19 response preparedness and changes in service delivery, document the impact on essential and Reproductive, Maternal, Neonatal and Child Health (RMNCH) services, and understand provider safety, wellness, challenges and personal resilience, all from the perspectives of providers (doctors and nurses). The study also aimed to document local strategies developed to mitigate the impact of COVID-19 that can benefit others.The community women study aimed to understand women’s perspectives of the pandemic’s impact at the individual, household and community levels. It explored the gendered experience of COVID-19 by understanding how the pandemic and state response to control transmission impacted women’s lives, focusing on health services, livelihood, entitlements and social change. The purpose was to inform organisations working with the government on the concerns and priorities of women and girls, as the government moves towards the pandemic’s recovery phase. Short qualitative interviews were conducted telephonically with 48 women across two districts and six blocks in rural Bihar using an open-ended interview guide. The respondents included SHG leaders, group members and JEEViKA community mobilisers.The next section outlines the ethical challenges faced from planning to data analysis and how these were addressed. These included assessing the research burden, acquiring consent to contact respondents by phone, ensuring informed consent to participate, safeguarding privacy, anonymity and confidentiality, minimising time obligations, redressing expressions of pandemic-induced stress or distress, and mitigating data security risks.An important ethical consideration was assessing the absolute need for the research given COVID-19’s burden on respondents. Bihar’s population experienced lockdown-induced economic hardships, in addition to contagion fears and mass worker migration, with a dynamic, evolving situation changing daily. Health service providers bore the double burden of home stress and heavy facility workload. Research relevance must be questioned under these conditions, avoiding research duplication and targeting similar respondents by consulting research-aggregating platforms like CORE Net  and by collaborating with researchers in geographical settings. This was taken into account by all three studies, with the ultimate decision that each filled relevant and timely knowledge needs.As in all data collection, trust and rapport are essential for quality information exchange. The facility ethnography study’s prior relationship with the respondents placed those interviews within pre-existing rapport, facilitating information-sharing. The two other studies approached the respondents via familiar institutional partners. The COVID-19 provider study attempted to allay respondents’ concerns by having district-level administrators inform them of the impending study and its objectives, with unclear effectiveness. The community women study partially bridged unfamiliarity by approaching women through a partner organisation already working with these women, which contacted respondents and explained the study, who then expected the calls.Phone-based research may miss the most vulnerable who lack phone access. In Bihar, the most vulnerable, often rural women, may not have phones or may be unable to independently use a male relative’s phone. The community women study only reached women with their own phones, who were part of the JEEViKA network. Some respondents described other vulnerable women who did not have phones. This obviously has implications for sampling representativeness and relevance of findings if the objective is to reach the society’s most disadvantaged.Accessing telephone numbers and acquiring consent to be contacted are areas that require navigating with care due to invasion of privacy and potential for coercion. In the facility ethnography study, providers initially shared their contacts and consented to be contacted at the initiation of inperson fieldwork. In the facility-based COVID-19 provider study, accessing phone numbers was more complex. Respondents’ contacts were accessed from the publicly available State Health Society directory and steps were put in place to acquire consent to call them on these numbers by sending an opt-out SMS (short message service) prior to phoning. In the community women study, contacts were accessed through the partner organisation, with women’s verbal consent to be called for a later interview recorded.For the facility ethnography study, as engagement with respondents was already ongoing, verbal recorded consent was not required. The COVID-19 provider and community women studies both recorded verbal consent to conduct the interviews; the former sent a copy of the consent back to the respondents via SMS to ensure transparency, while the latter also recorded the respondents’ consent to the partner organisation to ensure no coercion was applied.In designing, it is crucial to consider the length of informed consent statements and word choice.Ebola and COVID-19 have both revealed pandemics’ gendered effects on womenResearchers across all three studies tried to limit the time burden by conducting interviews at the respondents’ convenience, engaging over two to three calls if the respondents preferred. The COVID-19 provider study removed previously answered background questions from subsequent rounds, replacing these in the interview tool with new questions to stay within time limitations. Avoiding lengthy limitations made comprehensive probing and triangulating issues difficult in all three studies. The COVID-19 provider study limited probing to answering question options, except for open-ended questions. The community women study adapted the interview approach, focusing on issues respondents spoke about at length instead of answering all questions in the tool. All three studies had varied response durations across all rounds, with the same respondents giving varying time in different rounds. Some respondents spoke for 15–20 min, while others—even burdened facility providers—were eager to spend over an hour in several instances.Interviewing in local dialects builds trust and creates rapport,The facility ethnography study’s prior relationship with the respondents placed those interviews on a foundation of pre-existing rapport. The COVID-19 provider study explained consent language in detail, ensuring the respondents fully understood, and scheduled interviews at the respondents’ preferred time. The community women study partially bridged unfamiliarity by approaching women through a partner organisation, which contacted respondents, explained the study and obtained their consent to be called. This notwithstanding, researchers put significant effort in rapport-building, making two call rounds: first obtaining consent to be interviewed and scheduling, followed by the interview call. All studies trained interviewers to be patient and empathetic, to use a conversational tone and to ask after respondents’ well-being. However, to build trust and rapport, consent-seeking often took up to 15–20 min in the latter two studies.Researchers in all three studies were coached in active listening and maintaining affirmative enquiry, even if respondents gave socially appropriate responses, and to not question or doubt respondents’ credibility in any way. Phone interviews are inherently limited by the absence of visible cues, and spoken language nuances are even more critical.Awareness of respondents’ contexts is key to ensure privacy and confidentiality. Across our three studies there were two vulnerable groups: facility providers airing facility challenges and community women facing three kinds of vulnerabilities—their responses could reflect negatively on the programme they were part of and on the government’s COVID-19 response or affect their home surroundings. All study teams asked respondents when a good time would be to contact them and called back at another timewhen privacy was easier to ensure.Sharing sensitive information over the phone can put respondents at riskThe respondents of the facility ethnography study were open in sharing the problems they faced; this information was carefully anonymised, ensuring that the responses represented the respondents’ real-time concerns without affecting confidentiality. The community women study did not always follow the trend or thematic analysis and ensured that all concerns, even those raised by one woman, were reflected in the findings.Under the pandemic, researchers must consider contagion fears and economic precarity, and questions should consider respondents’ emotional state. In the facility ethnography study, the interviewers were mindful of structural inequities highlighted by the pandemic and faced by some respondents, taking care that conversations were not confirmatory of their subordinate position. Instead of questions around personal protective equipment (PPE) availability for example, proxy questions asked about changes in equipment supplies and coping with stress. The COVID-19 provider study asked direct questions about the leading causes of stress and how these could best be addressed in the respondents’ views. Some respondents expressed themselves at length; the approach provided them with a much-needed platform to voice worries and concerns. COVID-19 mental health support platforms were shared with respondents in that study and were also available to the respondents of the community women study who expressed the need.A common misunderstanding encountered by the community women study researchers was the respondents assuming calls were to provide COVID-19 information or assistance. Clearly explaining study purpose, risks and benefits is critical to avoid raising false expectations, and this was done repeatedly. However, some researchers continued to be asked for information and support by community women respondents of comparatively lesser means. Researchers referred these women to the JEEViKA network while being mindful of their concerns, continuing to be empathetic and conducting the interview in a conversational and not in an extractive manner. While the respondents accepted that the researchers could not provide real-time solutions to accessing entitlements or fears about husbands returning to the city for work, some researchers felt an ethical dilemma in not supporting the women in any way.The facility ethnography team’s prior embedding yielded rich contextual background information against which to weigh quality of responses, in addition to triangulating information from other study provider interviews and with findings by consortium partners. Other strategies to ensure data quality included review of secondary research and local media reports. Access to phone recordings enables quality checks and better monitoring of interview quality over inperson interviews. One of the takeaways from shifting to phone platforms is reconsidering the framing of data robustness when research is conducted during a time of crisis. The community women study data were also contextualised against gender-focused research by development partners.Safeguards to maintain data security were applied across all studies and included mitigating misuse of contact details as well as securing data while following a ‘privacy by design’ principle across the data responsibility chain.The telephone interviews allowed critical research when inperson methods were impossible, while still maintaining data quality. For health providers for whom institutional settings were a barrier to information-sharing, the privacy afforded by phone interviews offered a platform and a voice to share facility-based challenges they faced both preceding and during the COVID-19 response, which many were keen to express. In the facility-based, inperson phases of the facility ethnography study, ensuring complete privacy was not possible. When the study shifted to phone interviews, the respondents were much more forthcoming about the service delivery challenges they faced, challenges that preceded the pandemic as well as those that resulted from it. Previously hesitant to speak critically in the workplace, these respondents were much more open in the telephone interviews about the challenges posed by the routine, top-down monthly service delivery targets they were expected to reach, for example. They were also open about the scarcity of PPE distribution in the early weeks of COVID-19. Conducting interviews at the respondents’ convenience was another advantage of phone-based data collection. The respondents of the facility ethnography study were often interviewed in the evening, if they specified a preference for this time frame. Another advantage shared by all three studies was splitting the interview over several calls at the respondent’s convenience. This would not have been possible in inperson interviews given the challenging logistics involved in revisiting the remote study sites.The phone platform offered similar anonymity to women to share their pandemic experiences. The social isolation and the latent loss of agency due to movement limitations meant women were unable to meet and share their concerns with other women. Qualitative phone interviews under these conditions may offer a covert benefit by creating a space for women to voice their concerns and be heard.Contacting respondents at their convenient time, which is difficult with inperson data collection, is another advantage of phone interviews. Easier monitoring of interview quality is another advantage.The gender gap in phone ownership as well as the social constraints in their use or accessAccess to subjects and recruitment in rural areas will always depend on the target population’s characteristics: on the respondent category, on the geography of the locale, on respondents’ literacy and on their degree of autonomy and gender. Where all respondents are familiar with the basic technology, have autonomy and are empowered, recruitment for remote data collection faces a level field and is an effective approach. However, where telephone usage is controlled by societal gender norms, digital inequalities across gender will impede access to subjects, who may be those who are most vulnerable. It will remain challenging to reach constituencies who are not comfortable with using telephones, where only local dialects are spoken or where there is low literacy. In such communities, rapport-building is especially challenging and digital approaches inevitably risk being exclusionary to some degree. Researchers must be aware of the lacunae in who they can reach in such environments and why, and build strategies to ameliorate or minimise these challenges to access wherever possible.The effectiveness of remote data collection is also dependent on the subject of the study; research about sensitive topics by telephone, such as domestic violence or sexual and reproductive health concerns in adolescents, will remain challenging. Conducting focus group discussions remotely will also remain problematic as the platform does not lend itself to interactive group dynamics and effective information exchange in the same way as face-to face group discussions do.Under the COVID-19 pandemic, it is important to consider the affective atmosphere before undertaking research and adapting to disruptions in normal routines and the existing uncertainty when shifting to remote fieldwork.Considering vulnerabilities as well as inequalities exacerbated by the pandemic and probing the societal value of research studies conducted with empathy can yield methodologically and ethically sound research based on reflexivity and restraint.27The very short time limits on call duration (sometimes as little as 15 min) imposed by IRB panels and the standardised wordings of consent forms should be more flexible to allow for full explanations of consent, rapport-building and active listening. Unduly burdening respondents with a lengthy interview during a pandemic is a valid IRB concern. However, explaining consent forms adequately, building rapport, establishing trust and conducting an interview can take up to or even more than 45 min. This was the case in the two studies described here that were telephone-based from the inception, where calls routinely ran over the time limits that the IRB panel would have preferred. Explaining complex consent language was very time-consuming in both studies. Interviewers were also flexible regarding call duration, for example with community women respondents who were stressed and who sought reassurance. Similarly, the facility provider study allowed respondents the time they needed if they wished to stay on the line and share their work concerns. Empathetic enquiry in surveys on the impact of COVID-19 requires calls of longer duration than normally allowed given the extreme stress the pandemic is invoking. In the words of a facility ethnography study team member, “To be ethical, we actually need more time, not less.”IRB bodies need to rapidly develop ethical guidelines enabling remote data collection with amenable processes that may differ from procedures applied in normal situations. IRB bodies also need to adapt to the time-sensitiveness of COVID-19 research enquiries, where situations are rapidly evolving on the ground and where procedural time lags in awarding clearance to go forward result in loss of valuable data capture at critical times during the pandemic.Going forward, for digital data collection to be maximally effective, it should ideally include a mix of inperson fieldwork, even for a brief period, to establish some degree of rapport before moving to remote interviews. Finally, phone interviewers will always need an ethically based understanding of respondents’ vulnerabilities when conducting research in times of crisis.


Intravitreal therapy is widely recognized as a major milestone in ophthalmology being one of the most commonly performed ocular procedures . The sprSince diabetic retinopathy (DR) still remains the leading cause of blindness among working-age adults , ophthalThe global COVID-19 pandemic led many governments from different nations to adopt protective and strict measures to reduce its spread. In these unprecedented circumstances, many healthcare systems are overwhelmed and under stress.In this scenario, there is an urgent need to support ophthalmologists who are treating patients with intravitreal injections in decision-making protocols. In order to provide continuity of care, and to reduce the risk of contamination, series of protection measures have been proposed . NeverthDiabetic patients are considered at high risk for COVID-19 complications and should not be exposed to avoidable risks, including the injections procedure itself. However, continuation of care, where possible, is important to avoid irreversible vision loss.For non-monocular patients with diabetic macular edema (DME), postponement (>4–6 months) of appointments has been proposed . As receAnti-vascular endothelial growth factor (VEGF) injections represent generally a first-line therapy for several retinal disorders including DME , but monAll these mechanisms of action work in aggregate, resulting in decreased macular edema and VEGF production, fibrin deposition, capillary leakage and migration of inflammatory cells . There iCataract progression and intraocular pressure rise are the most common side effects, but often rather easily manageable . AdditioOn this background, a good selection of patients with DME who can benefit from observation or a single intravitreal DEX injection rather than monthly anti-VEGF injections, could be of great importance in reducing the burden of injections of clinics and hospitals. Treating eligible subjects with DME showing the previously mentioned OCT biomarkers, could indeed reduce the burden of care delivery for patients and health system. Considering that the IOP increase after the injection is typically noticed within the first 2 weeks, IOP lowering eye drops together with a post-injection visit should be taken into account for patients with high risk for glaucoma.Almost one year is gone since the WHO declared the global pandemic and new more contagious virus variants are now emerging. Physicians may be dealing with this emergency status for the next 1 or 2 years.In our opinion, by tailoring the treatment to patients in most need, equity can be considered the ethical value that support the decisionmaking by the treating provider.Although an evidence-based clinical practice guideline for intravitreal injections is not yet available, we believe that these considerations about management of diabetic patients with DME, could be useful for ophthalmologists from most affected countries who will be under public health COVID-19 measures and restrictions for the next months. Saving costs, resources and time is an important goal for all health workers who are facing this common enemy in first line.


Compulsive exercise is linked with poorer treatment outcomes in people with eating disorder (EDs). High-performance athletes represent a growing and complex subcomponent of the broader ED population, and emergent evidence indicates that different conceptualisations of compulsive exercise are needed in this population. Existing randomised controlled trials in ED populations have demonstrated small treatment effects on compulsive exercise compared with control groups; however, athletes were sparsely sampled across these studies. Thus, the extent to which current treatments for compulsive exercise in EDs are also effective in high-performance athletes is unknown. For this opinion paper, we sought representation from high-performance sports leadership, someone with lived experience of both an ED and high-performance athletics, and ED clinical experts. We discuss the utility of recommending exercise abstinence in ED treatment with athletes, as well as a number of other treatment strategies with some evidence in other contexts for further consideration and research in this population. These include using mindfulness-based interventions as an adjunct to cognitive-behavioural therapies, using wearable technologies and self-reported fatigue to inform training decisions, and incorporating greater exercise variation into training programs. We also offer practical considerations for clinicians seeking to apply foundational elements of cognitive-behavioural interventions  into an ED treatment program for a high-performance athlete. Future research is needed to examine characteristics of pathological compulsive exercise in athletes and whether available treatments are both feasible and effective in the treatment of compulsive exercise in athletes with an ED. There is limited research on how to manage and treat compulsive exercise in high-performance athletes with an eating disorder.While sport and exercise abstinence is often needed in people with a severe eating disorder with significant medical risk, there are several drawbacks that should be considered when recommending sport and exercise abstinence in a high-performance athlete with an eating disorder of mild or moderate severity.Several strategies offer promise in treating compulsive exercise in high-performance athletes and warrant further research, including incorporating elements from mindfulness-based interventions, using wearable technologies to inform training decisions, and including greater exercise variation into a training program.excessive from non-excessive exercise [Unhealthy exercise has long been considered a core feature of anorexia nervosa (AN) and bulimia nervosa. Earlier researchers used the term excessive exercise to describe this pattern of exercise behaviour often observed in people with eating disorders (EDs), purporting specific quantitative limits to demarcate exercise . The curexercise , 3, and exercise .d = − 0.23) were found across a range of ED diagnoses when compared with control groups [At present, compulsive exercise is the most commonly used term amongst ED professionals to describe unhealthy exercise . Dittmerl groups .Table 1DRates of EDs and compulsive exercise differ as a function of gender and sport domain. In the general population, women are almost four times as likely as men to develop an ED over their lifetime  and are This methodological decision to exclude athletes is understandable as there are several unique challenges associated with sampling athletes with an ED that are not present with non-athletic populations. These include: (a) increased participant heterogeneity if not all included participants are athletes; (b) treatment adherence could be poor if treatment sessions are scheduled during the competition season, particularly if travel is involved; (c) treatment will need to be adapted to account for the athlete’s increased energy expenditure; and (d) treatment will likely require cooperation with external parties  who may have conflicting goals to the clinician. Due to these practical considerations, little is known about how to adapt current treatment programs for high-performance athletes with an ED and/or compulsive exercise. This article discusses a number of treatment considerations related to both the assessment and treatment of compulsive exercise in athletes with an ED.One important milestone for ED treatment is the successful reduction of compulsive exercise, if present. However, some of the criteria used to define compulsive exercise in EDs  are hallIt is insufficient to assess pathological compulsive exercise in athletes based solely on the quantity of sport-specific exercise behaviours, as almost all high-performance athletes would appear to meet existing compulsive exercise criteria from this perspective. With representation from high-performance sports leadership , lived experience of both an ED and high-performance sport, and ED clinical experts, we have identified two potential behavioural indicators of clinically significant compulsive exercise specific to high-performance athletes. These include: (a) whether the athlete has flexibility to reduce their exercise in certain instances, including between major competitions or seasons, during injury and/or illness, or during a prescribed reduction in training load , without experiencing substantial distress and guilt; and (b) whether the athlete performs additional exercise outside of scheduled training sessions, either to manipulate weight and/or body composition, or for affect regulation purposes. Evidence suggests that understanding an athlete’s degree of compulsion to exercise can inform appraisal of their ED severity . OverallGiven the maintaining role of compulsive exercise in ED symptomology, clinicians face a dilemma as to whether an ED can be successfully treated in an athlete who continues to ‘compulsively exercise’ to meet the demands of their sport. Our clinical experience highlights the difficulties associated with treating an ED without being able to make relevant changes to exercise behaviour, either through partial or complete abstinence, or recommending alternative forms of exercise. However, there is a dearth of research exploring the treatment factors that affect ED prognosis in high-performance athletes.One treatment approach often used in ED treatment regardless of athletic status has been to disregard the client’s sporting and exercise goals, and encourage complete abstinence from sport and exercise until significant reductions in ED symptomology have been achieved , 29. OncHowever, the decision of whether to incorporate sport and exercise abstinence in people with an ED of mild or moderate severity is more nuanced. Several reviews indicate that inclusion of structured exercise performed under supervision does not interfere with treatment goals of weight restoration in underweight patients with an ED –34. As sConsidering this evidence base, there are a number of important considerations when recommending complete exercise abstinence in athletes with an ED of mild or moderate severity. Firstly, many athletes derive a large portion of their income, self-esteem, and sense of identity from their sporting performances, and could suffer notable financial  and/or psychiatric distress if complete abstinence from sport was prescribed without sufficient evidence to support its efficacy , 37. ED Psychoeducation is an essential component of ED treatment and general discussion topics have been described in detail in seminal ED treatment manuals , 44. ForThe link between compulsive exercise, low energy availability (LEA), and relative energy deficiency in sport (RED-S) offers a useful education topic for athletes and performance support staff. Energy availability is the amount of energy remaining to support the body’s health and functioning once energy expenditure from exercise is subtracted from dietary energy intake . LEA reswithin a given sport associates with optimal performance. As such, staff involved in the planning of an athlete’s diet are encouraged to base food choices around what maximises performance for the athlete as an individual, rather than in an attempt to meet a pre-conceived  assumption about the anthropometric proportions of a successful athlete.The main principle of body diversity is that different athletes perform best at different shapes and sizes. While there are undeniable differences in body shape between athletes from disparate sports , there is variation in the exact weight and shape that each athlete Two systematic reviews indicate that mindfulness-based interventions can be effective in non-athletic populations at reducing ED behaviours, overvaluation of weight and shape, and improving emotion regulation , 47. As Wearable technologies have received considerable public and scientific attention in the past half-decade as non-invasive tools to gather biometric data in athletes and the general population. A growing body of literature supports the efficacy of these wearable technologies in assessing physiological variables such as heart rate variability (HRV) and sleep architecture –52. ManyOne focus of ED treatment for athletes could be to work with them and/or their support team to learn to match the intensity of training sessions to their recovery, assessed using wearable technologies (objectively), and self-reported fatigue and muscle soreness (subjectively). For example, where medically and psychiatrically appropriate, if an athlete feels energetic, reports minimal muscle soreness, and wearable technologies indicate sufficient recovery , a higher-intensity and/or longer duration training session could be scheduled . In contExposure and response prevention (ERP) is one of the core treatment strategies for compulsive behaviours, such as obsessive–compulsive disorder . It has Central to a cognitive behavioural therapy (CBT) intervention for EDs is a discussion of beliefs around the role of exercise in weight management and as a means for reward or punishment , 44. In The testing of distorted beliefs and assumptions about food and exercise with behavioural experiments is one of the foundational elements of CBT-E , 44. HowTreatment interventions that produced significant reductions in compulsive exercise in non-athletes with EDs included appropriate variation within their exercise programs , 21, 42.Regulating emotions without the use of food or exercise is a challenge for many people with EDs , 62. CliHigh-performance athletes represent a growing and complex subcomponent of the broader ED population and it is unclear the extent to which current conceptualisations of, and treatments for, compulsive exercise translate to sporting populations. Clinicians working with high-performance athletes with EDs face a number of unique challenges and some have adopted the perspective that abstinence from sport is a requirement for successful ED treatment. In this article, we discuss the limitations of this treatment approach for people with an ED of mild or moderate severity, and the utility of a range of other clinical tools to address problematic exercise behaviour in athletes. Further qualitative and quantitative research with athletes, coaches, and clinicians is needed to understand whether existing treatment strategies from CBT-E and those proposed in this article are both feasible and effective for reducing compulsive exercise in high-performance athletes with an ED.


The patterns of diet specialization in food webs determine community structure, stability, and function. While specialists are often thought to evolve due to greater efficiency, generalists should have an advantage in systems with high levels of variability. Here we test the generalist-disturbance hypothesis using a dynamic, evolutionary food web model. Species occur along a body size axis with three traits  that evolve independently and determine interaction strengths. Communities are assembled via ecological and evolutionary processes, where species biomass and persistence are driven by a bioenergetics model. New species are introduced either as mutants similar to parent species in the community or as invaders, with dissimilar traits. We introduced variation into communities by increasing the dissimilarity of invading species across simulations. We found that strange invaders increased the variability of communities which increased both the degree of generalism and the relative persistence of generalist species, indicating that invasion disturbance promotes the evolution of generalist species in food webs. Ecological specialization is likely a major factor in the generation and maintenance of diversity, and the subsequent stability of ecological communities2. This is particularly important in food webs, where species’ specialization in the form of diet breadth  determines food web structure and, therefore, influences their stability. For example, higher levels of generalism (diet breadth) across consumers increases the connectance of food webs, which can reduce their local stability (around equilibria3) but increase their robustness to species extinctions4 and resistance to species invasions5. Moreover, generalism can increase species persistence when consumers are adaptive foragers7.Ecologists and evolutionary biologists have long sought to understand the patterns of specialization in species across communities and the evolutionary mechanisms responsible for driving specialization9. For example, many insect herbivores specialize on one or a few plant families10, and show specialized chemical adaptations that optimize the capture, uptake, and processing of biomass acquired from the plants they consume8. Generalists, on the other hand, are assumed to incur trade-offs, where organisms consuming many different resources are likely to be less efficient in consuming each of them than specialized organisms with specific adaptations for their exploitation11—the classic “jack-of-all-trades, master-of-none” hypothesis12.Numerous hypotheses have been proposed to explain the evolution of feeding specialization with many suggesting that specialists gain an adaptive advantage through greater efficiency when specialized behaviors and chemical pathways streamline the acquisition of resources11. This generalist-disturbance hypothesis suggests that communities with higher levels of environmental and community variability across time should be comprised of greater proportions of generalist species that can withstand variability by relying on other available resources when specialist species cannot. However, despite the rather intuitive nature of this hypothesis, it has proved difficult to demonstrate because of the evolutionary timescales over which these processes occur11. Some indirect evidence comes from palaeoecological records which show that specialist species, in a broad sense, are more prone to extinction under episodes of environmental change14. Modern records also indicate that specialists are disproportionately in decline in the face of global environmental change15. Small scale experimental evolution studies have demonstrated that the niche width (abiotic or biotic) of microbial organisms can be broadened within individual populations under conditions of increased variability11. Some theoretical studies have tested the evolutionary impact of temporal variability on simplified consumer-resource systems16 and in host–pathogen antagonistic systems17, showing that generalism within individual populations can be promoted under increased variability in abiotic resources. Despite this work, few studies have attempted to mechanistically test the impact of variability on the evolution of specialists and generalists at the scale of complex ecological communities, such as food-webs.Despite the trade-offs in efficiency assumed for generalists, it is widely hypothesized that species consuming a wider range of resources will be favored over specialists when environments are more variable, making specific resources difficult to acquire20, having effects on both ecological21 and evolutionary19 timescales. Invading species have the potential to disrupt community composition and network structure, particularly in food webs21, by exploiting enemy free niche space, serving as novel resources, and by increasing predatory and competitive pressure21. These effects can drive changes in the population densities of resident species, which can cascade through communities, potentially resulting in extinction21. Specifically, we tested whether invader strangeness  increases resource and community variability through time by disrupting consumer-resource dynamics and disturbing food web structure through cascading extinctions (as shown with other food web models22), and whether this disturbance promotes generalism  increased across the simulations  = 0.12, with 61.7% deviance explained) and community biomass  significantly increased with the increase in invader strangeness (z). Moreover, mean species turnover significantly increased  with increasing invader strangeness (z), indicating strange invaders are driving more rapid extinction rates in the simulated communities.Adding increasingly strange invaders into simulated evolutionary food webs increased the variability of communities. All environmental and community variation metrics increased as invader strangeness  and median , feeding range (s) , the realized feeding range (Table R2 = 0.60). This indicates that more species were functioning as generalist consumers with greater disturbance as the proportion of connections per consumer per community increased.In addition to our metrics of fundamental feeding range (ge Table  or the mz) increases. Lifespan slopes, which represent the relationship between species lifespan and feeding range across communities for each simulation, increased, indicating that generalist species persist longer in comparison to specialist species as invader strangeness increases . However, this effect plateaus at higher values of z, indicating that the benefit to generalists of increased variation has diminishing returns when variation in the environment and the community becomes too high.Both metrics of generalist persistence suggest that generalist species become more dominant in communities as invader strangeness (z) and species type  in our model was significant, suggesting that the increase in invader strangeness affects generalists differently than specialists . Although the mean lifespan of generalists did not increase substantially across the invader strangeness parameter sweep, specialist lifespan significantly decreased, indicating that generalists persist in communities for an increasing proportion of time relative to specialists. Thus, the relative persistence of generalists compared to specialists increased with the increase in invader strangeness. Again, the observed non-linearity at low values of z was seen in the relative persistence data, where at very low values of z, specialist lifespan decreased  caused by invasion on populations interacting via consumer-resource and competitive interactions at a community scale, and the evolution of foraging traits  of resident species under those conditions through mutation and extinction.Understanding the observed patterns of specialization across ecological communities has long been a goal of community ecology and evolutionary biology11. Collectively, these results support the hypothesis that generalist consumer species can be selected for and maintained in complex communities with high levels of variability and disturbance.Our results support the hypothesis that invasion increases disturbance and promotes the evolution of generalist consumers in food webs. We demonstrate that increasing the strangeness of invading species in evolving food web communities increases the overall variability of resource and community biomass Fig. a,b and tz parameter  within communities become dominated mainly by highly efficient specialist species with a high degree of overlap in their feeding kernels  slightly increases from 0.1, the probability that invaders come into communities with more novel traits increases and the overlap in species feeding kernels within trophic levels is reduced, with species occupying a larger range of feeding niches  values for mutant species only, which were not directly manipulated. Moreover, using species lifespan as a gauge of persistence avoids this problem by focusing on the survival of specialists and generalists regardless of their origin. That is, the survival of species in the community is determined principally by community composition and variability, and should not be biased by the traits of invading species even if more generalist species were being introduced at higher z values. Thus, assessing persistence of specialists and generalists based on survivorship is the most direct metric for testing our hypothesis, regardless of the source of disturbance in communities.One potential limitation of our approach is the direct manipulation of the traits of invading species. Because specialist species are more efficient consumers in our model, many of the species that persist in communities tend to have small feeding ranges. As we make invaders increasingly different from what is already present in the community, introduced species may be more likely to have larger feeding range values. We managed this potential bias by assessing fundamental feeding range 21 will house a higher proportion of generalist species.Our results support the long-held hypothesis of increased selection for generalists under increased environmental variation21. Assuming that invader strangeness represents the functional diversity of the surrounding community, our modeling approach may also help to understand the patterns of specialization and diversity maintenance at broader spatial scales, such as metacommunities24. Simulation experiments with eco-evolutionary models can guide and supplement empirical evidence in understanding these questions which may be difficult to test given the long-term time scale of these processes. Our results show that invasions shape the structure of consumer-resource communities in both ecological and evolutionary time by driving species turnover and extinction rates, and ultimately, influencing the degree of feeding generalism amongst species. While the aim of this project was mainly to illuminate the impact of invasion on long-term evolutionary processes, our results also further demonstrate the importance of the active management of invasive species20, which may fundamentally alter the structure and stability of ecological communities.Additionally, this work further demonstrates the molding power of invasion on communities. We provide supporting evidence of invasion as a major driver of local biodiversity change by increasing variability in communities and potentially leading to increased rates of extinction26 to show that biodiversity can be maintained in multitrophic networks despite ongoing species turnover when feeding traits are allowed to evolve independent of body mass. The model includes consumptive and competitive interactions, where interaction strengths are determined by the traits of consumer species and their resources. All species possess three traits, a body mass or size  and Allhoff & Drossel (2016), which build on previous models5 and AllDynamics are governed by a bioenergetics consumer-resource model, where parameters are scaled to the body mass of species, following previous developments in Yodzis & Innes 1992) and Brose et al. (2006). The rate of change of consumer biomass  are more likely to generate new mutant species. The parents of invader species are chosen randomly, with equal probability given to all extant species in the community. Both mutants and invaders are introduced into the system at the extinction threshold biomass  for each simulation. To test if invasion would increase disturbance and variability in communities and drive the evolution of more generalized species, we conducted simulations where invaders were introduced with an increased probability of having trait values that were divergent from parent species. We controlled this by manipulating the invader strangeness parameter , which is built into our model given the formulation of the attack rate parameter  of the basal resource biomass across time for each simulation and pooled these data for all simulation replicates across the invader strangeness parameter sweep. To assess variation at the community level, we used a similar approach to calculate variability in community biomass. For this metric, we summed the population biomasses of all species in the community for each given time interval output (excluding species introduced at that time step) and calculated the SD of these values across time for each individual simulation.Finally, to further assess community variability and to determine if increasing invader strangeness drives increased extinction in communities, we calculated species turnover for each time output. Species turnover was measured as the percentage change in the composition of species in communities between each time output . We then calculated mean species turnover over time for each simulation replicate and pooled all data together. To account for the non-linearity observed in our variation data see “” we condTo determine if the degree of generalism and the proportion of generalist species in food webs increased as invader strangeness increased, we calculated the mean and median feeding range (mentclass2pt{minims) Table ”.Additionally, we calculated a measure of the realized feeding range of consumers , to determine the trend or “lifespan slope” for each simulation under different levels of invader strangeness .For the second approach, we aimed to determine the relative persistence of species by binning “generalist” and “specialist” species based on feeding range traits and comparing species lifespans between these groups. For this analysis we split species into bins, where specialist species included all species with feeding range Supplementary Information.