|Year : 2016 | Volume
| Issue : 4 | Page : 118-125
Challenges and new strategies for Gulf War illness research
Henry H. Q. Heng
Center for Molecular Medicine and Genomics; Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA
|Date of Submission||02-Nov-2016|
|Date of Acceptance||22-Nov-2016|
|Date of Web Publication||18-Jan-2017|
Henry H. Q. Heng
Department of Pathology, Wayne State University School of Medicine, 3226 Scott Hall, 540 E. Canfield, Detroit, MI 48201
Source of Support: None, Conflict of Interest: None
Gulf War illness (GWI) research has generated an abundance of interesting but diverse data. While increased molecular mechanisms have been identified, the high levels of heterogeneity for initial trigger factors, cellular defects, and symptoms continuously challenge the efforts of clinical implications of the research, including the search for biomarkers and the common mechanism of GWI. In this analysis, I consider GWI as an adaptive illness condition where system stresses and genome instability-mediated cellular evolution play an important role. By further defining GWI as an environmental illness caused by extremely high levels of specific Gulf War (GW) stresses, the challenges for GWI research are briefly reviewed, with comparisons to other common and complex diseases such as cancer. Based on the new discovery that many GWI patients display elevated genome instability coupled with increased cellular stress, a general model of GWI is proposed to unify GW-specific stress, cellular damage, and genome-heterogeneity-mediated cellular adaptation and evolution, as well as diverse-related symptoms. Finally, some new strategies are suggested based on the general model of GWI.
Keywords: Common and complex disease/illness, complex adaptive systems, environmental illness, general model for Gulf War illness, genome instability, Gulf War illness, instability-mediated cellular evolution, stress
|How to cite this article:|
Heng HH. Challenges and new strategies for Gulf War illness research. Environ Dis 2016;1:118-25
| Introduction|| |
This year marks the 25 th anniversary of the Persian Gulf War (GW). Even though the length of the war was exceedingly short, the resulting GW illness (GWI) had had a lasting impact on 25%-30% of veterans; ,, patients display a clinical condition which is hard to explain basing on the current medical concepts. The definition of the illness is less clear due to the heterogeneity of GWI's etiology and symptoms (there is still no generally accepted case definition); even routine clinical laboratory tests are ineffective and the search for biomarkers has been largely unsuccessful.
Since the original reports of the mysterious clinical phenomenal, GWI research has gone through many controversies. From the initial high skepticism to current active research supported by various government agencies, the overall attitude has changed. However, some of the long-standing arguments remain. For example, different names are used by different organizations (such as "chronic multi-symptom illness" vs. "Gulf War illness"), and there are different research priorities for GWI studies.  In recent years, many biological tools were applied to search for the causes and mechanisms of GWI, and increased attention has been paid to the issue of GW-specific chemical/biological/other types of exposure (such as low-level chemical warfare agents, pesticides, preventive medications, oil well fires, and depleted uranium [DU]). , While many diverse molecular mechanisms have been linked to GWI, which supports the idea that GWI has a physiological basis rather than the previous assumption that it is mainly a psychiatric illness, or a condition similar to posttraumatic stress disorder (PTSD), most individual research projects have failed to establish the general concept of GWI.
Following observations/synthesis further explain why it has been so difficult to deal with GWI: (1) there are large numbers of heterogeneous factors that can be strong enough (either separately or working together) to impact a small number of individuals but are invisible for a large patient population. This explains why a significant linkage can often be found when a smaller, more defined sample size is used, and unfortunately, such significance is diminished when a large sample with increased heterogeneity is used; (2) even when exposed to strong causative factors (such as pesticide and pyridostigmine bromide [PB]), according to White et al.,  only a portion of veterans develop GWI; (3) there is a diverse spectrum of symptoms for GWI patients. Widespread pain, fatigue, skin rashes, memory, and gastrointestinal as well as respiratory problems are commonly reported, but not all patients display identical symptoms; (4) there is a certain degree of overlapping in the symptoms of GWI with other diseases/illness, including chronic fatigue syndrome, inflammatory bowel disease, PTSD, and multiple chemical sensitivity syndrome; (5) individual symptoms observed in GWI can be detected commonly in the general population (even though the frequencies are often different), especially for mild forms of GWI; (6) a quarter of a century has passed - it is hard to perform experiments to pinpoint the initial factors which require precise information. Furthermore, the detection of some initial exposure factors has become less obvious, yet the illness continues for many patients, and there are increased numbers of GWI patients who need care with the general aging of the population.
Knowing all of these issues, how should we move the field forward? One popular approach is to continually push the identification of initial trigger factors as well as current molecular targets (such as specific types of chemical exposure, initially damaged genetic or cellular components, and response systems), and further design the diagnostic and treatment tools based on these specific molecular mechanisms, which should lead to the discovery of new biomarkers. This is also the rationale of performing large-scale-omics studies among patients. Such ideas fit the current trend of using -omics technologies to analyze diseases, including cancer. Unfortunately, the real success rate using a large-scale -omics approach in cancer has been limited despite high hopes. For example, in the face of heterogeneity, the results of most whole-genome scans used to identify key genes for common and complex diseases have not fulfilled expectations. ,, There is increased confusion in cancer research when more cancer genomes are sequenced. Yes, a large number of gene mutations for a given cancer type can be found, but how can one use these gene mutations when most of them are not commonly shared by a majority of patients (most of these so-called "driver gene mutations" occur in <1%-2% of the patient population)? How does one target them when they are constantly changing like moving targets, especially during treatment? Now, increased concerns have been raised in the fields of genomics and cancer research to search for new paradigms rather than simply data accumulation. ,,, Fortunately, as a researcher who is involved both cancer evolution and GWI projects, I see the clear similarity between these two fields. GWI and cancer are both common and complex clinical conditions where heterogeneity is the fundamental feature. Since cancer research represents a frontier in molecular medicine with ample bouts of success and failure, it would be beneficial to learn from it, to avoid repeating similar strategic mistakes. One of the most essential realizations for current cancer research is to consider cancer progression as an evolutionary process. By treating cancer as an adaptive system, many decades' long paradoxes are solved, which start to challenge the method of focusing on individual gene mutation.  It is thus timely to apply the evolutionary concept to GWI research as we recently have also illustrated that elevated genome instability represents a key feature of GWI. 
In this analysis, I will try to make the case that GWI is a common and complex illness condition based on the diverse contributing factors, variable symptoms, and ongoing cellular genome instability. ,,,, By injecting the concept of somatic cell evolution into GWI studies, the relationship of GW-related genetic and environmental factors will be discussed. The efforts of connecting the dots based on the genome theory have led to a new model for GWI where the initial GW-specific triggers generated cellular damages, leading in turn to somatic cellular evolution coupled with genome instability. This model not only states that GWI has its solid physiological basis but also explains why GWI displays high diversity like other common and complex diseases/illnesses. Such synthesis will promote the general acceptance of GWI in the medical community and offer new strategies for GWI research.
| Gulf war illness is a real illness condition with diverse physiological and pathological features|| |
After years of research, it is now clear that GWI is real with an identifiable physiological and/or pathological basis. Rapidly accumulated literature can be found in the following papers. ,,, To make this point, I shall briefly list some recent examples to illustrate how GWI patients display various physiological or molecular as well as behavioral defects.
Specific molecular defects
Mitochondrial dysfunction has been observed in GWI patients.  As some GW-related exposures can be toxic to mitochondria, and mitochondria are closely linked to many GWI symptoms including fatigue, muscle, and brain function, such a correlation is of importance. Blood biomarkers (serum proteins associated with inflammation) were also identified in GWI patients.  In addition, a variety of abnormalities in blood hormone have been reported in GWI patients. 
Based on gene expression signatures, it was found that GWI may be linked with dysregulation in genetic pathways involved in immune signaling, particularly tumor necrosis factor-alpha signaling, and sex steroid signaling. Not surprisingly, the expression pattern of GWI most closely resembles brain disorders with musculoskeletal problems and dysregulation of immunity.
Chromosomal translocations have been linked to DU exposure.  Recently, three-color fluorescence in situ hybridization (FISH) detection has, however, failed to support this conclusion.  Note that this cytogenetic study has only scored translocations. If other types of chromosomal aberrations (such as defective mitotic figures) are scored, it is likely that there will be a difference. ,,,, In addition, FISH data could be reinterpreted for a few outliers who display high level of multiple chromosomal aberrations. Nevertheless, it is necessary to examine GWI patients with severity of illness condition with history of DU exposure. It is interesting to know how long the radiation-induced-specific chromosomal aberrations can be detected in GWI patients.
Significantly, many GWI patients display elevated genome instability, measured by the increased frequencies of nonclonal chromosome aberrations (NCCAs). , To systematically measure the NCCAs, spectral karyotyping was used to monitor all chromosomal changes, plus many novel types of aberrations, most of which were ignored for cytogenetic analyses.  With such a platform, genome instability has been linked to GWI.
Different neuroimaging methods have been applied to GWI including structural and functional magnetic resonance imaging and electroencephalography. In addition to consistent reports that white and gray matter volumes in cortical areas are reduced in GWI patients, ,, the brain functional anomalies were also observed, and fatigue and pain were linked to the diminishing of white matter integrity. Recently, word-finding impairment has been studied in subgroup of GWI patients. These patients also showed reduced activity in the thalamus, putamen, and amygdala, and increased activity in the right hippocampus when compared to controls. 
It should be pointed out that there are inconsistencies among reports. As I mentioned earlier, when the sample size was increased, the significance of a given linkage (between GWI and a specific mechanism) examined often could actually be reduced, which, on the surface, challenges the linkage established in other studies with smaller sample size. However, in reality, such phenomena are rather common for many common and complex diseases, reflecting the nature of the heterogeneity of said illness. Furthermore, according to the traditional definition of a given disease (such as an infectious disease), causative factor, pathological process, and symptoms should be the same or similar. This definition is far from the case when it comes to GWI. No wonder the medical community was initially hesitant to consider GWI. Something interesting to note, however, is that the medical community is much more flexible when discussing other complex diseases/illness conditions which are less straightforward to define than infectious diseases with the same infectious agent and/or typical genetic diseases with common genetic defects. For example, for most sporadic solid cancers, or many metabolic and mental diseases, trigger factors are highly diverse and hard to understand. Equally disappointingly, they also face similar challenges as GWI. However, a few would argue against accepting these cases as diseases. As I will discuss more in the following section, highly diverse contributing factors are common in most common and complex diseases, which should not be used to against the acceptance of GWI's legitimacy.
| Gulf war illness is an environmental illness|| |
If most typical Mendelian diseases are genetic diseases, the rest of common and complex diseases should be classified as environmental diseases.  Here, we define environmental diseases as mainly contributed to by environmental factors rather than highly penetrated genotypes. Many environmental diseases could have some genetic components as well, but genetics does not play the dominating rules at the patient population level. Infectious diseases are typical environmental diseases even though increased genetic factors have been identified. , Most metabolic diseases are environmental diseases except for some familial types where genetic components play more significant roles for disease formation. So far, most GWI cases are contributed by environmental impacts of the GW. Limited studies have also identified some genetic vulnerabilities and factors to some types of GW exposure. For example, based on the gene exposure interaction study of 304 GW veterans, it was found that veterans with less active genetic variants of the butyrylcholinesterase enzyme were at increased greater risk for GWI if they used PB compared to veterans with these genotypes who did not use PB.  Another example is the finding that many GWI patients display increased genome instability.  Since it is well known that there is a variable baseline of genome instability among individuals, such internal instability could further contribute to induced genome instability. However, genetic impact should be secondary when compared to war environmental factors in the context of the patient population, as most GWI patients do not have obvious genetic causative factors. Such predictions are supported by the current cancer research. For most cancer cases, the environmental factor plays a major role (especially for sporadic cancers). For a small percentage of patients, genetic factors play dominating contributing roles (in cases of familial cancer genes), while for the rest of minority cases, genetic factors play secondary roles (in cases of cancer susceptibility genes). If some genetic factors will play a main role in GWI following GW-specific exposure, we predict that these cases will account only for a minority population, similar to the distribution of cancer.
For different types of environmental diseases/illness, the numbers involving environmental factors vary. For infectious diseases, for example, the common key factor is the infectious agent, which is relatively easier to be identified by comparing patient populations. In contrast, for GWI, due to the fact that a large number of key factors can respectively (or when combined) impact different individuals (from exposure to chemicals, bioagents, radiation, to burning of oil wells), it is harder to identify a common biomarker for a heterogeneous patient population. Even for a given infectious disease, there are additional factors involved regarding the environmental context for this infectious agent (from the season/weather to the geographic location, from the social structure to the individual's immune system status). Because the infectious agent represents a commonly shared causative factor among others, when increasing the population size, it can easily stand out (whereas other factors can be washed out by the average method),  and the medical community tends to easily accept the definition of this disease.
Other interesting aspects of environmental diseases include exposure time and dosage. The exposure dosage could be high or low and the time could be long or short, which further promotes the response diversity when it comes to different individuals. This might be the reason why it is easier to demonstrate the correlation of a certain chemical to a phenotype using animal models than it is to demonstrate it in a patient population. In most animal models, heterogeneity is significantly reduced compared to any natural population (with selected pure mouse stains, specific feeding/housing environments and no real evolutionary competition), so the more linear models can demonstrate the correlation between specific exposures to phenotypes.  However, the effective approaches that drastically reduce heterogeneity often change the nature of the very illness or condition under investigation, which makes translational research difficult.
Accepting GWI as an environmental illness helps understand the diverse factors associated with GWI, as well as some unique features. For example, GW factors, whatever they are, can affect such a large number of returning soldiers within a relatively brief exposure time that they indeed represent powerful environmental causative factors for GWI. The brief length of the GW and the limited penetration of exposure, thus, should not be used to dismiss GWI. It is also worthwhile to point out that GW personnel were often exposed to high levels of pesticides and insect repellants. In fact, PB was widely used in the 1991 GW to protect possible nerve gas attacks.  Clearly, the "toxic wounds" represent a unique feature of the GW.  Based on the relationship between stress levels, genome instability, and disease phenotypes, , it is logical to propose that the extremely high GW-specific stress (unique chemical/biological exposure, DU…), with the combination of general war stresses shared by any war conditions, mainly contribute to GWI.
| Connecting the Dots for Gulf War Illness: The Search For A General Model|| |
For many environmental diseases, the causative environmental agents constantly presented are coupled with disease progressions. GWI is rather unique as the initial triggers occurred 25 years ago. There are at least four circumstances (or their combined nature) that can explain current GWI patients: First, the initial triggers are still presented in most GWI patients which continuously contribute to the illness phenotype; second, the initial trigger had caused cellular damages, and something else caused by such damages is currently going on (such as somatic cell evolution including heterogeneity mediated cellular adaptation), and the initial factor no longer contributes to the illness; third, the initial factor is still present, but with a significantly reduced impact, plus other factors caused by the initial damage remains; fourth, in addition to the initial GWI, other disease or illness conditions can further complicate the symptoms. Studies are needed to confirm these situations and possibly group patients into subgroups. If the initial factors are not detectable, new strategies are required. Clearly, there must be somatic cell evolution involved, which fits the concept of most common and complex diseases/illnesses well. ,,,
Somatic cell evolution has recently received much attention in the field of disease studies including cancer, ,,, not only because cancer represents an evolutionary process at the somatic cell level but also because, for the majority of cancers, the pattern of somatic cell evolution is punctuated, including genotype evolution. In other words, the initial causative factors, such as specific genetic defect, infection, or other environmental condition, can trigger the initiation of cancer evolution, but during the process, the initial factor can often be lost (or replaced), as the genetic landscape often is very different between initial/earlier stages and the later stages. Despite the change of the driver mutations, cancer evolution marches on. Based on the pattern of the two phases of cancer evolution (punctuated phase and stepwise phases), and the fact that large number of factors can trigger the cancer evolution in a stochastic fashion, the evolution mechanism of cancer has been proposed to explain the large number of specific molecular mechanisms of the cancer (like the large number of gene mutations). Such analysis has unified individual molecular mechanisms to cancer evolution, which also explain why individual pathways are less important for cancer evolution when compared to overall genome instability.  Importantly, most of the trigger factors are unified by their contributions to elevate genome instability or evolutionary potential. Finally, the stress, genome alteration, and cancer evolutionary model was proposed by us, which offers new insight for cancer evolution.  The take-home message is that it is not effective for clinical prediction if only by focusing on the initial factors for cancer evolution. In contrast, monitoring the overall genome instability is more important for these highly dynamic complex adaptive systems.
Recently, genome variation-mediated evolutionary model of cancer has been expanded toward other common and complex diseases. ,,, The rationale of such an effort is straightforward: Researchers who study many common and complex diseases share the same frustration as cancer researchers do. In general, for these diseases, contributing factors and their molecular pathways are highly heterogeneous; thus, it is challenging to perform precise diagnoses or disease predictions based on diverse molecular markers, and targeting molecular component alone is less effective when controlling symptoms. ,,,, Furthermore, increased genome alterations are commonly detected in many diseases and illness conditions, ,,,, and many different molecular defects can lead to elevated genome instability through stress response, so it is now realized that cellular adaptation requires multiple genomic changes including genome alteration, which also promote diseases as a trade-off. ,
Interestingly, the similarities between GWI and cancer research have pushed us to apply the genome theory to other common and complex diseases. ,, Similar to cancer, the diverse trigger factors of GWI can be linked to elevated genome instability, coupled with the elevated cellular stress. Furthermore, diverse molecular defects can all be linked to general stress, which can be linked to the genome system,  and the stress-cellular adaptation interaction represents a driving force for somatic cell evolution. Together, we propose a general model of GWI as illustrated in the following [Figure 1].
According to this model, the formation of GWI can be illustrated by three phases: The initial phase where GW-specific factors trigger the potential of illness development, the cellular evolution phase which immediately follows, where various multiple leveled genetic alterations promote somatic cell evolution, and the illness phase where patients display different symptoms.
Note that some clarifications are needed for the terms used in this model: GW-specific stresses refer to high-level stresses such as single specific type of chemical exposure, which differs from other general war-related stresses. However, it is likely that different types of stresses can work together to produce a perfect storm.
Our recent studies suggest a model addressing stress and its consequent genetic alteration responses. When stress levels are low (within a normal physiological range, for example), system homeostasis can be restored with the cost of energy. However, if stress is higher than within a normal range, the system has to change to adapt which will likely pay the price to recovery, leading to gene mutations and/or epigenetic alterations. The genome-level changes can happen when the stress is very high, which requires cells to completely change their genomes. 
GWI also has its own unique challenge: While many types of common and complex diseases or illnesses can be linked to an unstable genome, many of them have defined target tissues/organs. In contrast, there are multiple tissue/organs involved in GWI patients. Further research is needed to fill the gaps between genome instability and various symptoms. One possibility is that genome alteration-mediated somatic cell evolution represents a stressful condition for an individual's system.
As illustrated in [Figure 1], since the symptoms themselves can further impact somatic cell evolution, it is possible that different additional illness conditions can be compounded to GWI patients, which can be an explanation for the issue of multimorbidity.  The multiple stages of the feedback relationship also make clinical predictions difficult.
| New strategies for gulf war illness|| |
With new understandings of GWI as an adaptive condition where stochastic somatic cell evolution is the key player, there should be no more surprises when diverse molecular mechanisms are continuously discovered. As predicted by our GWI model, many more individual molecular defects will be linked to GWI in the near future even though each of these mechanisms will only account for a portion of the patient population. A similar situation has already happened to the field of cancer research where thousands of gene mutations and pathways have been linked to cancer (compared to the few gene mutations that were discovered during the first two decades cancer's molecular study), and each of the gene mutations has limited diagnosis value (except a few mutation with high frequencies within the patient population). Currently, the status of genome instability seems to have better prediction power than individual gene mutations. Based on important information on cancer and other common and complex diseases, and the recent finding that GWI is linked to genome instability and increased cellular stress, this new general model of GWI now introduced to unify GWI research. Thus, the following tasks are urgently needed:
- We need to continue to educate the medical community that the GWI is a real common and complex clinical condition. The heterogeneity of both symptoms and etiology is one unique characteristic of GWI, and many seemingly contradicting findings in fact reflect this key feature
- Researchers need to focus more on the symptoms and the impact of evolutionary somatic cellular process, rather than the initial factors, if the current illness progression has little to do with initial factors. If, however, the initial triggers are still making dominating impacts on the illness conditions, the future strategy will be adjusted accordingly
- Genome-level studies need further validation and expansion with large quantities of patients. More importantly, genome instability should be used as a platform to unify large numbers of individual molecular mechanisms. In addition, types of chromosomal abnormalities need to be characterized and classified, to study correlations within subgroups of patients. As illustrated by other common and complex diseases/illnesses in contrast to these single-gene genetic diseases, just focusing on the gene has very limited clinical applications. Observed genome-level alterations in patients should be more clinically useful than gene-level defects as any single genome-level change can impact hundreds if not thousands of genes 
- Accordingly, classifying GWI patients into subgroups is of importance. These subgroups should include patients with or without the strong influence of initial factors, with or without overall unstable genomes, with or without the dominance of specific molecular pathways, and with or without good response to a given treatment. Classifying GWI patients into subgroups based on unique biomarkers is a good approach, given the observation that different types of genome aberrations can be dominant in different GWI patients
- Different research groups should share samples for comparative analyses. Such comparisons can rank different biomarkers in terms of their coverage in patient population, and investigate the potential of combinational uses of different biomarkers
- Direct measurements of stress levels and stress responses for patients are of importance. Our recent study has illustrated that it is possible that different types of endoplasmic reticulum stress can be linked to different GWI patients with genome instability profiles. While such links can explain how elevated genome instability generates cellular stress, it also makes the situation more complicated, as the cellular stress could also further destabilize the genome. Nevertheless, the frequencies of genome instability can be used to measure the high levels of cellular stress. Moreover, genome alteration could also serve as a strategy to increase cellular adaptation,  so a low level of genome alteration might have some benefits
- Individual or combinational biomarkers are also needed to correlate illness severities. In this case, a longitudinal study is needed to monitor illness progression. In addition, the genome instability status should be monitored during treatment, and we should avoid the further destabilizing the genome, as it could trigger other types of diseases such as cancer. Under a similar consideration, drastic treatments need to be avoided, as the increased overall stability or health homeostasis should improve GWI
- As for the applying biomarkers for GWI diagnosis: At this stage, many biomarkers should be considered valuable when at high abnormal ranges. For example, symptoms plus high levels of genome instability should positively diagnose the illness conditions
- More attention should be paid to the issue of multimorbidity, especially knowing that genome instability is involved in GWI, and that the patient population is aging. Correlation studies to link GWI with other diseases should be performed as well
- Finally, according to our GWI model, avoiding further introductions of high-stress levels for GWI patients is of importance, as the treatment options could further generate cellular stresses which likely will lead to unstable genome associated illnesses. In contrast, treatments should reduce cellular stresses, increase overall homeostasis, and improve the individual's health.
This article is part of a series of studies entitled "The mechanisms of somatic cell and organismal evolution." I would like to thank Julie Heng for editing and Eric Heng for the diagram.
Financial support and sponsorship
This work was partially supported by the grant from the DOD (GW093028).
Conflicts of interest
There are no conflicts of interest.
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| ||Brain Sciences. 2021; 11(7): 845 |
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||Grappling with Gulf War Illness: Perspectives of Gulf War Providers
| ||Girija Kaimal,Rebekka Dieterich-Hartwell |
| ||International Journal of Environmental Research and Public Health. 2020; 17(22): 8574 |
|[Pubmed] | [DOI]|
||A role for neuroimmune signaling in a rat model of Gulf War Illness-related pain
| ||Michael J. Lacagnina,Jiahe Li,Sabina Lorca,Kenner C. Rice,Kimberly Sullivan,James P. OśCallaghan,Peter M. Grace |
| ||Brain, Behavior, and Immunity. 2020; |
|[Pubmed] | [DOI]|
||Understanding aneuploidy in cancer through the lens of system inheritance, fuzzy inheritance and emergence of new genome systems
| ||Christine J. Ye,Sarah Regan,Guo Liu,Sarah Alemara,Henry H. Heng |
| ||Molecular Cytogenetics. 2018; 11(1) |
|[Pubmed] | [DOI]|
||Corticosterone primes the neuroinflammatory response to Gulf War Illness-relevant organophosphates independently of acetylcholinesterase inhibition
| ||Alicia R. Locker,Lindsay T. Michalovicz,Kimberly A. Kelly,Julie V. Miller,Diane B. Miller,James P. OśCallaghan |
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|[Pubmed] | [DOI]|